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Early |
Pascua et al., Epidemiology International Journal, doi:10.23880/eij-16000234 |
Repurposing Drugs for Covid-19 by a Developing Country |
Details
Review of a multiphasic multidrug early treatment protocol for COVID-19 in Honduras, showing one death from 415 patients, which was for a patient not receiving early treatment (presenting on the 5th day in need of hospitalization and supp.. |
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Early treatment study
Early treatment study
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Repurposing Drugs for Covid-19 by a Developing Country |
Pascua et al., Epidemiology International Journal, doi:10.23880/eij-16000234 |
Review of a multiphasic multidrug early treatment protocol for COVID-19 in Honduras, showing one death from 415 patients, which was for a patient not receiving early treatment (presenting on the 5th day in need of hospitalization and supplemental oxygen). Treatment included ivermectin, aspirin, colchicine, fluvoxamine, and famotidine.
Pascua et al., 5/20/2022, Honduras, Central America, peer-reviewed, 31 authors, study period November 2020 - October 2021.
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Late |
Silva et al., Frontiers in Cellular and Infection Microbiology, doi:10.3389/fcimb.2022.899702 |
death, ↓32.3%, p=0.57 |
Clinical-Epidemiology Aspect of Inpatients With Moderate or Severe COVID-19 in a Brazilian Macroregion: Disease and Countermeasures |
Details
Retrospective 395 hospitalized patients in Brazil, showing mortality HR 0.59 for antiparasitic use, however there were only 8 patients treated and authors do not distinguish between albendazole and ivermectin. |
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Late treatment study
Late treatment study
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Clinical-Epidemiology Aspect of Inpatients With Moderate or Severe COVID-19 in a Brazilian Macroregion: Disease and Countermeasures |
Silva et al., Frontiers in Cellular and Infection Microbiology, doi:10.3389/fcimb.2022.899702 |
Retrospective 395 hospitalized patients in Brazil, showing mortality HR 0.59 for antiparasitic use, however there were only 8 patients treated and authors do not distinguish between albendazole and ivermectin.
risk of death, 32.3% lower, RR 0.68, p = 0.57, treatment 8, control 387, adjusted, OR converted to RR, ivermectin or albendazole, multivariable, control prevalance approximated with overall prevalence.
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Silva et al., 5/20/2022, retrospective, Brazil, South America, peer-reviewed, mean age 58.4, 28 authors, study period 25 March, 2020 - 21 October, 2020.
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In Silico |
Alvarado et al., Computational Biology and Chemistry, doi:10.1016/j.compbiolchem.2022.107692 |
In Silico |
Interaction of the New Inhibitor Paxlovid (PF-07321332) and Ivermectin With the Monomer of the Main Protease SARS-CoV-2: A Volumetric Study Based on Molecular Dynamics, Elastic Networks, Classical Thermodynamics and SPT |
Details
In Silico study comparing ivermectin and paxlovid Mpro interaction, showing similar interaction for paxlovid and the ivermectin B1a homologue, a different mechanism for ivermectin B1b, and interaction at different sites for paxlovid. |
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In Silico
In Silico
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Interaction of the New Inhibitor Paxlovid (PF-07321332) and Ivermectin With the Monomer of the Main Protease SARS-CoV-2: A Volumetric Study Based on Molecular Dynamics, Elastic Networks, Classical Thermodynamics and SPT |
Alvarado et al., Computational Biology and Chemistry, doi:10.1016/j.compbiolchem.2022.107692 |
In Silico study comparing ivermectin and paxlovid Mpro interaction, showing similar interaction for paxlovid and the ivermectin B1a homologue, a different mechanism for ivermectin B1b, and interaction at different sites for paxlovid.
Alvarado et al., 5/14/2022, peer-reviewed, 12 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Late |
Babalola et al., Research Square, doi:10.21203/rs.3.rs-1576399/v1 (Preprint) |
Ivermectin is associated with increase in SPO2 in hypoxemic SARS-CoV-2 patients: pharmacodynamic profile and correlates |
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Extended analysis of , showing significantly faster and greater improvement in SpO2 with ivermectin treatment. |
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Late treatment study
Late treatment study
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Ivermectin is associated with increase in SPO2 in hypoxemic SARS-CoV-2 patients: pharmacodynamic profile and correlates |
Babalola et al., Research Square, doi:10.21203/rs.3.rs-1576399/v1 (Preprint) |
Extended analysis of [Thairu], showing significantly faster and greater improvement in SpO2 with ivermectin treatment.
Babalola et al., 4/27/2022, preprint, 6 authors.
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Early, Late, PrEP, PEP |
Covid Analysis (Preprint) (meta analysis) |
meta-analysis v189 |
Ivermectin for COVID-19: real-time meta analysis of 82 studies |
Details
• Statistically significant improvements are seen for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance. All remain significant after exclusions. 53 studies from 48 independent teams in 22 differ.. |
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Early, Late, PrEP, PEP
Early, Late, PrEP, PEP
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Ivermectin for COVID-19: real-time meta analysis of 82 studies |
Covid Analysis (Preprint) (meta analysis) |
• Statistically significant improvements are seen for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance. All remain significant after exclusions. 53 studies from 48 independent teams in 22 different countries show statistically significant improvements in isolation (39 primary outcome, 36 most serious outcome).• Meta analysis using the most serious outcome shows 63% [53‑72%] and 83% [74‑89%] improvement for early treatment and prophylaxis, with similar results after exclusion based sensitivity analysis, for primary outcomes, for peer-reviewed studies, and for RCTs.• Results are very robust — in worst case exclusion sensitivity analysis 54 of 82 studies must be excluded to avoid finding statistically significant efficacy.• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 24% of ivermectin studies show zero events in the treatment arm.Multiple treatments are typically used in combination, which may be significantly more effective.• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.• Over 20 countries have adopted ivermectin for COVID-19. The evidence base is much larger and has much lower conflict of interest than typically used to approve drugs.• All data to reproduce this paper and sources are in the appendix. See [Bryant, Hariyanto, Kory, Lawrie, Nardelli] for other meta analyses with similar results confirming efficacy. Evidence base used for other COVID-19 approvals | Medication | Studies | Patients | Improvement | Molnupiravir (UK) | 1 | 775 | 50% | Budesonide (UK) | 1 | 1,779 | 17% | Remdesivir (USA EUA) | 1 | 1,063 | 31% | Casirivimab/i.. (USA EUA) | 1 | 799 | 66% | Ivermectin evidence | 82 | 129,808 | 64% [56‑71%] |
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Review |
Marinos, A. (Review) (Preprint) |
review |
The Problem With The TOGETHER Trial |
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Analysis of serious problems with the Together Trial. Also see . |
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Review
Review
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The Problem With The TOGETHER Trial |
Marinos, A. (Review) (Preprint) |
Analysis of serious problems with the Together Trial. Also see [Marinos].
Marinos et al., 4/13/2022, preprint, 1 author.
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Animal |
Zheng et al., International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121719 |
animal study |
Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties |
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In Vitro and mouse study proposing a method for improving ivermectin pharmacokinetics and bioavailability using delivery via red blood cells. |
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Animal study
Animal study
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Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties |
Zheng et al., International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121719 |
In Vitro and mouse study proposing a method for improving ivermectin pharmacokinetics and bioavailability using delivery via red blood cells.
Zheng et al., 5/31/2022, China, Asia, peer-reviewed, 13 authors.
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Late |
Ravikirti et al., Research Square, doi:10.21203/rs.3.rs-1522422/v1 (Preprint) |
death, ↓2.8%, p=0.82 |
Association between Ivermectin treatment and mortality in Covid-19: A hospital-based case-control study |
Details
Retrospective 965 late stage (44% severe, 27% ICU) hospitalized patients in India, showing no significant difference with ivermectin treatment. Overall mortality was very high, suggesting very late treatment. The low non-weight-adjusted d.. |
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Late treatment study
Late treatment study
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Association between Ivermectin treatment and mortality in Covid-19: A hospital-based case-control study |
Ravikirti et al., Research Square, doi:10.21203/rs.3.rs-1522422/v1 (Preprint) |
Retrospective 965 late stage (44% severe, 27% ICU) hospitalized patients in India, showing no significant difference with ivermectin treatment. Overall mortality was very high, suggesting very late treatment. The low non-weight-adjusted dose may not be very effective with such late stage patients. 210 patients were excluded due to early discharge, which may have been patients with earlier onset that are more likely to benefit with ivermectin. Age grouping is very unusual with no breakdown of ages for the 71% of patients >45. Numbers may be unreliable, e.g., cardiovascular disease counts and/or percentages for IVM appear incorrect. Details of adjustments are not provided.
risk of death, 2.8% lower, RR 0.97, p = 0.82, treatment 53 of 171 (31.0%), control 254 of 794 (32.0%), NNT 100, OR converted to RR.
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Excluded in after exclusion results of meta analysis:
exclusion of patients in less severe condition, data/analysis concerns.
Ravikirti et al., 4/6/2022, retrospective, India, South Asia, preprint, 7 authors, study period 1 April, 2021 - 15 May, 2021, dosage varies.
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In Vitro |
Delandre et al., Pharmaceuticals, doi:10.3390/ph15040445 (In Vitro) |
In Vitro |
Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants |
Details
In Vitro study with 30 COVID-19 strains from 14 variants, showing stronger efficacy with ivermectin compared to CQ and remdesivir, and relatively homogeneous efficacy with ivermectin regardless of strain/variant, in contrast to results fo.. |
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In Vitro
In Vitro
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Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants |
Delandre et al., Pharmaceuticals, doi:10.3390/ph15040445 (In Vitro) |
In Vitro study with 30 COVID-19 strains from 14 variants, showing stronger efficacy with ivermectin compared to CQ and remdesivir, and relatively homogeneous efficacy with ivermectin regardless of strain/variant, in contrast to results for CQ and remdesivir.
Delandre et al., 4/2/2022, peer-reviewed, 12 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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News |
Reis et al., New England Journal of Medicine, doi:10.1056/NEJMoa2115869 (News) |
news |
Effect of Early Treatment with Ivermectin among Patients with Covid-19 |
Details
The Together RCT can be found at . Studies are listed under the date they first became available (August 6, 2021 for this study). |
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News
News
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Effect of Early Treatment with Ivermectin among Patients with Covid-19 |
Reis et al., New England Journal of Medicine, doi:10.1056/NEJMoa2115869 (News) |
The Together RCT can be found at [c19ivermectin.com]. Studies are listed under the date they first became available (August 6, 2021 for this study).
Reis et al., 3/30/2022, preprint, 27 authors.
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In Silico |
Aminpour et al., Computation, doi:10.3390/computation10040051 |
In Silico |
In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds |
Details
In Silico analysis identifying strong or moderate affinity bindings for ivermectin to multiple sites on the spike protein, CD147 and α7nAChr, which may provide effective competitive binding for all variants of SARS-CoV-2. Ivermectin had t.. |
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In Silico
In Silico
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In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds |
Aminpour et al., Computation, doi:10.3390/computation10040051 |
In Silico analysis identifying strong or moderate affinity bindings for ivermectin to multiple sites on the spike protein, CD147 and α7nAChr, which may provide effective competitive binding for all variants of SARS-CoV-2.Ivermectin had the highest affinity to the α7nAChr receptor. Analysis showed a potential direct binding of SARS-CoV-2 spike protein to α7nAChr, suggesting mediation of SARS-CoV-2 cellular entry, and potentially shedding light on aspects of COVID-19 including the loss of smell and taste, cytokine storm, and impairment of endothelium-dependent acetylcholine-induced vasodilation.
Aminpour et al., 3/25/2022, peer-reviewed, 12 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Meta |
Bitterman et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2022.3079 |
Comparison of Trials Using Ivermectin for COVID-19 Between Regions With High and Low Prevalence of Strongyloidiasis |
Details
Analysis of a small subset of 12 ivermectin trials showing a relationship with efficacy and strongyloides prevalence. This analysis is confounded by treatment delay, dose, conflicts of interest, and other factors, and the effect disappear.. |
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Meta
Meta
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Comparison of Trials Using Ivermectin for COVID-19 Between Regions With High and Low Prevalence of Strongyloidiasis |
Bitterman et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2022.3079 |
Analysis of a small subset of 12 ivermectin trials showing a relationship with efficacy and strongyloides prevalence. This analysis is confounded by treatment delay, dose, conflicts of interest, and other factors, and the effect disappears when analyzing all studies, all RCTs, or all mortality results, as detailed in [ivmmeta.com].Although the first author has responded to the confounders on Twitter, we do not see mention of them in the paper. Author is also aware that the larger sets of all trials, all RCTs, or all mortality results do not show the effect, however we also do not see this mentioned in the paper. These omissions suggest investigator bias. Author claims they could not discuss these issues due to publication delays, however the paper was accepted Jan 31, 2022, and author was aware of the issues months before, for example discussing treatment delay and dose in Nov 2021. These confounders are also basic and not really possible to miss.The meta analysis for [Hashim] includes critical patients, however these patients were always allocated to the treatment arm for ethical reasons, therefore including them is not logical and introduces substantial bias. According to the author response, this appears to have been known, suggesting investigator bias. Authors include [Shahbaznejad] where the only death was a critical patient that died within 24 hours of admission.Although authors note following PRISMA guidelines, we do not see registration of the protocol or discussion thereof. We note that the current protocol is the result of multiple changes to the original methodology as posted on Twitter: from 3 groups to 2 groups, altering the included studies, and switching from using one source for prevalence estimates to selecting estimate sources on a per study basis, which allows potential bias in the selection. Notably, this resulted in moving the Together Trial (Brazil) into the low prevalence category.Author's results rely on trials with a very small number of mortality events — the high stronglyoides prevalance group has trials with 1, 3, 4, and 13 events. Authors do mention limitations due to the small number of events and the reliability of strongyloides estimates.Authors changed from taking all prevalence estimates from the same source, to using a separate source for the two Brazilian studies. This moved those trials to the low prevalence group, which was required to show the effect. However, according to [], authors have mixed adjusted and unadjusted prevalence estimates, and after adjustment the new source would also place these studies in the high prevalence group.Authors indicate no conflicts of interest, however the first author has been an investigator on a Pfizer trial, which may be NCT04092452, showing completion in January 2022 [clinicaltrials.gov, openpaymentsdata.cms.gov].For other issues see [medicospelavidacovid19.com.br, ].
Bitterman et al., 3/21/2022, peer-reviewed, 4 authors, trial NCT04092452.
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Animal |
Albariqi et al., International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121688 |
animal study |
Pharmacokinetics and Safety of Inhaled Ivermectin in Mice as a Potential COVID-19 Treatment |
Details
Mouse study of an inhaled ivermectin formulation, showing high concentrations in the lung and bronchoalveolar lavage fluid, exceeding the required concentration for efficacy based on in vitro studies. |
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Animal study
Animal study
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Pharmacokinetics and Safety of Inhaled Ivermectin in Mice as a Potential COVID-19 Treatment |
Albariqi et al., International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121688 |
Mouse study of an inhaled ivermectin formulation, showing high concentrations in the lung and bronchoalveolar lavage fluid, exceeding the required concentration for efficacy based on in vitro studies.
Albariqi et al., 3/18/2022, peer-reviewed, 9 authors.
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Dosing |
Albariqi et al., Journal of Aerosol Medicine and Pulmonary Drug Delivery, doi:10.1089/jamp.2021.0059 (Dosing) |
dosing study |
Preparation and Characterization of Inhalable Ivermectin Powders as a Potential COVID-19 Therapy |
Details
Creation and analysis of an inhalable dry powder formulation of ivermectin for COVID-19. |
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Dosing
Dosing
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Preparation and Characterization of Inhalable Ivermectin Powders as a Potential COVID-19 Therapy |
Albariqi et al., Journal of Aerosol Medicine and Pulmonary Drug Delivery, doi:10.1089/jamp.2021.0059 (Dosing) |
Creation and analysis of an inhalable dry powder formulation of ivermectin for COVID-19.
Albariqi et al., 3/11/2022, peer-reviewed, 8 authors.
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News |
Harper, P. (News) |
news |
Professor tied to altered Andrew Hill paper also prepared 'Ivermectin Evidence' for World Health Organisation |
Details
Forensic analysis of the Hill meta analysis discovering an unlisted author potentially connected to changes and also related to the WHO ivermectin analysis. Author notes that "the person who allegedly edited the Andrew Hill paper .. |
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News
News
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Professor tied to altered Andrew Hill paper also prepared 'Ivermectin Evidence' for World Health Organisation |
Harper, P. (News) |
Forensic analysis of the Hill meta analysis discovering an unlisted author potentially connected to changes and also related to the WHO ivermectin analysis.Author notes that "the person who allegedly edited the Andrew Hill paper on Ivermectin, is the person in receipt of consultancy fees from pharma with competing products, is the person who prepared the evidence base for the World Health Organisation to make their recommendation on Ιvermectin."Author also notes: "I absolutely do not support anyone, in any way, who wishes to contact any of the people named in my articles. As I have stated before, what I [am] showing here are people caught inside a system with a great many competing interests. It’s not easy to be well adjusted to a medical research industry that is entirely broken."See also: [philharper.substack.com, philharper.substack.com (B)].
Harper et al., 3/7/2022, preprint, 1 author.
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News |
Lawrie, T. (News) |
news |
A Letter to Dr. Andrew Hill |
Details
Documentary about the external forces changing the conclusions of the Hill et al. meta analysis, and the subsequent negative impact around the world. |
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News
News
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A Letter to Dr. Andrew Hill |
Lawrie, T. (News) |
Documentary about the external forces changing the conclusions of the Hill et al. meta analysis, and the subsequent negative impact around the world.
Lawrie et al., 3/4/2022, preprint, 1 author.
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Late |
Soto et al., PLOS ONE, doi:10.1371/journal.pone.0264789 |
death, ↑41.0%, p=0.001 |
Mortality and associated risk factors in patients hospitalized due to COVID-19 in a Peruvian reference hospital |
Details
Retrospective 1,418 very late stage (46% mortality) patients in Peru, showing higher mortality with ivermectin. There is strong confounding by indication, for example 48% of patients with baseline SpO2 <70% were treated compared with 22% .. |
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Late treatment study
Late treatment study
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Mortality and associated risk factors in patients hospitalized due to COVID-19 in a Peruvian reference hospital |
Soto et al., PLOS ONE, doi:10.1371/journal.pone.0264789 |
Retrospective 1,418 very late stage (46% mortality) patients in Peru, showing higher mortality with ivermectin. There is strong confounding by indication, for example 48% of patients with baseline SpO2 <70% were treated compared with 22% for SpO2 >95%. The more extreme Cox result compared to the event counts also supports this. There may also be significant confounding by time with SOC changing substantially over the first few months of the pandemic. Patients may overlap with those in [Soto-Becerra]. The results in the table and text do not match.
risk of death, 41.0% higher, HR 1.41, p = 0.001, treatment 280 of 484 (57.9%), control 374 of 934 (40.0%), adjusted, multivariable.
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Excluded in after exclusion results of meta analysis:
substantial unadjusted confounding by indication likely, substantial confounding by time possible due to significant changes in SOC and treatment propensity near the start of the pandemic.
Soto et al., 3/2/2022, retrospective, Peru, South America, peer-reviewed, median age 58.0, 10 authors, study period April 2020 - August 2020, dosage not specified.
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Late |
Efimenko et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.12.096 |
death, ↓69.2%, p<0.0001 |
Treatment with Ivermectin Is Associated with Decreased Mortality in COVID-19 Patients: Analysis of a National Federated Database |
Details
PSM retrospective 41,608 patients in the USA, 1,072 treated with ivermectin and 40,536 treated with remdesivir, showing lower mortality with ivermectin treatment. This study was presented at a conference (IMED 2021). Submissions were peer.. |
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Late treatment study
Late treatment study
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Treatment with Ivermectin Is Associated with Decreased Mortality in COVID-19 Patients: Analysis of a National Federated Database |
Efimenko et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.12.096 |
PSM retrospective 41,608 patients in the USA, 1,072 treated with ivermectin and 40,536 treated with remdesivir, showing lower mortality with ivermectin treatment.This study was presented at a conference (IMED 2021). Submissions were peer-reviewed. The treatment/control group sizes align with the estimated percentage of hospitals that used ivermectin vs. remdesivir. Hospitals in the USA receive financial incentives to use remdesivir.Note that the authors are in a unfortunate position where they have to choose between their careers and supporting the efficacy of ivermectin. In the USA, physicians may be fired, lose their license, and become unemployable in similar positions if they accurately describe ivermectin research.Authors do not plan to submit to a journal, providing further evidence of a negative publication bias for ivermectin research.
risk of death, 69.2% lower, OR 0.31, p < 0.001, treatment 1,072, control 40,536, propensity score matching, RR approximated with OR.
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Efimenko et al., 2/28/2022, retrospective, propensity score matching, USA, North America, peer-reviewed, 6 authors, study period 1 January, 2020 - 11 July, 2021, dosage not specified, this trial compares with another treatment - results may be better when compared to placebo.
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Late |
Thairu et al., Research Square, doi:10.21203/rs.3.rs-1373673/v1 (Preprint) |
death, ↓87.9%, p=0.12 |
A comparison of Ivermectin and Non Ivermectin based regimen for covid 19 in Abuja: effects on virus clearance, Days-to-Discharge and Mortality |
Details
PSM retrospective 87 patients in Nigeria, 61 treated with ivermectin, showing lower mortality, faster recovery, and faster viral clearance with ivermectin treatment. All patients received zinc and vitamin C. A synergistic effect was seen .. |
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Late treatment study
Late treatment study
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A comparison of Ivermectin and Non Ivermectin based regimen for covid 19 in Abuja: effects on virus clearance, Days-to-Discharge and Mortality |
Thairu et al., Research Square, doi:10.21203/rs.3.rs-1373673/v1 (Preprint) |
PSM retrospective 87 patients in Nigeria, 61 treated with ivermectin, showing lower mortality, faster recovery, and faster viral clearance with ivermectin treatment. All patients received zinc and vitamin C. A synergistic effect was seen for viral clearance when ivermectin and remdesivir were combined, as predicted by In Vitro research [Jeffreys]. Subject to confounding by time, with ivermectin patients from April-June 2021, and non-ivermectin patients from September-November 2021.
risk of death, 87.9% lower, RR 0.12, p = 0.12, treatment 0 of 21 (0.0%), control 4 of 26 (15.4%), NNT 6.5, relative risk is not 0 because of continuity correction due to zero events, propensity score matching.
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risk of death, 93.0% lower, RR 0.07, p = 0.007, treatment 0 of 61 (0.0%), control 4 of 26 (15.4%), NNT 6.5, relative risk is not 0 because of continuity correction due to zero events, all patients.
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time to discharge, 54.6% lower, relative time 0.45, p < 0.001, treatment 61, control 26, propensity score matching.
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risk of no viral clearance, 94.8% lower, RR 0.05, p = 0.001, treatment 0 of 21 (0.0%), control 10 of 26 (38.5%), NNT 2.6, relative risk is not 0 because of continuity correction due to zero events, propensity score matching, day 21.
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risk of no viral clearance, 95.2% lower, RR 0.05, p < 0.001, treatment 1 of 21 (4.8%), control 26 of 26 (100.0%), NNT 1.1, propensity score matching, day 14.
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risk of no viral clearance, 28.6% lower, RR 0.71, p = 0.005, treatment 15 of 21 (71.4%), control 26 of 26 (100.0%), NNT 3.5, propensity score matching, day 5.
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Excluded in after exclusion results of meta analysis:
significant confounding by time possible due to separation of groups in different time periods.
Thairu et al., 2/25/2022, retrospective, Nigeria, Africa, preprint, 5 authors, study period April 2021 - November 2021, dosage 200μg/kg days 1-5.
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Submit Corrections or Comments
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News |
Lim et al., JAMA, doi:10.1001/jamainternmed.2022.0189 (data 11/3/21) (News) |
news |
Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial |
Details
The I-TECH RCT can be found at . Studies are listed under the date they first became available (November 3, 2021 for this study). |
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News
News
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Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial |
Lim et al., JAMA, doi:10.1001/jamainternmed.2022.0189 (data 11/3/21) (News) |
The I-TECH RCT can be found at [c19ivermectin.com]. Studies are listed under the date they first became available (November 3, 2021 for this study).
Lim et al., 2/18/2022, preprint, 26 authors.
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Submit Corrections or Comments
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Early |
Manomaipiboon et al., Research Square, doi:10.21203/rs.3.rs-1290999/v1 (Preprint) |
no recov., ↓43.5%, p=0.26 |
Efficacy and safety of ivermectin in the treatment of mild-to-moderate COVID-19 infection: A randomized, double blind, placebo, controlled trial |
Details
Small RCT with 72 low-risk patients in Thailand, showing improved recovery with ivermectin, without statistical significance. All patients recovered and there was no escalation of care in either group. There were no adverse events. |
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Early treatment study
Early treatment study
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Efficacy and safety of ivermectin in the treatment of mild-to-moderate COVID-19 infection: A randomized, double blind, placebo, controlled trial |
Manomaipiboon et al., Research Square, doi:10.21203/rs.3.rs-1290999/v1 (Preprint) |
Small RCT with 72 low-risk patients in Thailand, showing improved recovery with ivermectin, without statistical significance. All patients recovered and there was no escalation of care in either group. There were no adverse events.
risk of no recovery, 43.5% lower, RR 0.57, p = 0.26, treatment 3 of 36 (8.3%), control 6 of 36 (16.7%), NNT 12, adjusted, OR converted to RR, resolution of symptoms, day 28.
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recovery time, 15.3% lower, RR 0.85, p = 0.57, treatment 36, control 36, time to resolution of symptoms.
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risk of no viral clearance, 5.0% lower, RR 0.95, p = 1.00, treatment 19 of 36 (52.8%), control 20 of 36 (55.6%), NNT 36, day 14, primary outcome.
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risk of no viral clearance, 3.3% lower, RR 0.97, p = 1.00, treatment 29 of 36 (80.6%), control 30 of 36 (83.3%), NNT 36, day 7.
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Manomaipiboon et al., 2/2/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Thailand, South Asia, preprint, 8 authors, dosage 12mg days 1-5.
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In Vitro |
Kowa News Release (News) (In Vitro) |
news |
Antiviral effect of ivermectin confirmed for omicron |
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Kowa reports that ivermectin is effective for omicron in In Vitro research. |
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In Vitro
In Vitro
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Antiviral effect of ivermectin confirmed for omicron |
Kowa News Release (News) (In Vitro) |
Kowa reports that ivermectin is effective for omicron in In Vitro research.
Kowa et al., 1/31/2022, preprint, 1 author.
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Early |
de Jesús Ascencio-Montiel et al., Archives of Medical Research, doi:10.1016/j.arcmed.2022.01.002 |
death/hosp., ↓59.0%, p<0.0001 |
A Multimodal Strategy to Reduce the Risk of Hospitalization/death in Ambulatory Patients with COVID-19 |
Details
Retrospective 28,048 COVID+ patients in Mexico, 7,898 receiving a treatment kit including low dose ivermectin, AZ, aspirin, and acetaminophen, shower lower mortality/hospitalization for those receiving the kit. Delivery of the treatment k.. |
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Early treatment study
Early treatment study
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A Multimodal Strategy to Reduce the Risk of Hospitalization/death in Ambulatory Patients with COVID-19 |
de Jesús Ascencio-Montiel et al., Archives of Medical Research, doi:10.1016/j.arcmed.2022.01.002 |
Retrospective 28,048 COVID+ patients in Mexico, 7,898 receiving a treatment kit including low dose ivermectin, AZ, aspirin, and acetaminophen, shower lower mortality/hospitalization for those receiving the kit. Delivery of the treatment kit was based on availability in the medical units. Adherence is unknown and may be low. Adjusted results are only provided for combined mortality/hospitalization.
risk of death/hospitalization, 59.0% lower, RR 0.41, p < 0.001, treatment 7,898, control 20,150, adjusted, multivariable, primary outcome.
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risk of death/hospitalization, 71.0% lower, RR 0.29, p < 0.001, treatment 5,557, control 12,526, adjusted, with phone call followup, multivariable.
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risk of death, 15.0% lower, RR 0.85, p = 0.16, treatment 101 of 7,898 (1.3%), control 303 of 20,150 (1.5%), NNT 445, unadjusted, excluded in exclusion analyses:
unadjusted results with alternate outcome adjusted results showing significant changes with adjustments.
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risk of mechanical ventilation, 9.1% lower, RR 0.91, p = 0.51, treatment 77 of 7,898 (1.0%), control 216 of 20,150 (1.1%), NNT 1031, unadjusted, excluded in exclusion analyses:
unadjusted results with alternate outcome adjusted results showing significant changes with adjustments.
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risk of hospitalization, 47.6% lower, RR 0.52, p < 0.001, treatment 485 of 7,898 (6.1%), control 2,360 of 20,150 (11.7%), NNT 18, unadjusted, excluded in exclusion analyses:
unadjusted results with alternate outcome adjusted results showing significant changes with adjustments.
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risk of progression, 41.8% lower, RR 0.58, p < 0.001, treatment 435 of 7,898 (5.5%), control 1,906 of 20,150 (9.5%), NNT 25, unadjusted, ER, excluded in exclusion analyses:
unadjusted results with alternate outcome adjusted results showing significant changes with adjustments.
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de Jesús Ascencio-Montiel et al., 1/24/2022, retrospective, Mexico, North America, peer-reviewed, 10 authors, dosage 6mg days 1-2, this trial uses multiple treatments in the treatment arm (combined with AZ, acetaminophen, aspirin) - results of individual treatments may vary.
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In Vitro |
Liu et al., bioRxiv, doi:10.1101/2022.01.20.477147 (Preprint) (In Vitro) |
In Vitro |
SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level |
Details
In Vitro study showing that ivermectin and meclizine may be protective for heart muscle damage due to SARS-CoV-2. |
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In Vitro
In Vitro
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SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level |
Liu et al., bioRxiv, doi:10.1101/2022.01.20.477147 (Preprint) (In Vitro) |
In Vitro study showing that ivermectin and meclizine may be protective for heart muscle damage due to SARS-CoV-2.
Liu et al., 1/23/2022, preprint, 15 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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In Silico |
Parvez et al., arXiv:2201.08176 [q-bio.OT] (Preprint) |
In Silico |
Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host-pathogen interaction, pathogenicity and possible therapeutics |
Details
In Silico analysis of the omicron variant and 10 treatments reported effective for previous variants, predicting that all will be effective for omicron, with ivermectin showing the best results. |
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In Silico
In Silico
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Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host-pathogen interaction, pathogenicity and possible therapeutics |
Parvez et al., arXiv:2201.08176 [q-bio.OT] (Preprint) |
In Silico analysis of the omicron variant and 10 treatments reported effective for previous variants, predicting that all will be effective for omicron, with ivermectin showing the best results.
Parvez et al., 1/20/2022, preprint, 7 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Late |
Zubair et al., Monaldi Archives for Chest Disease, doi:10.4081/monaldi.2022.2062 |
death, ↑9.0%, p=1.00 |
The effect of ivermectin on non-severe and severe COVID-19 disease and gender-based difference of its effectiveness |
Details
Retrospective 188 hospitalized patients in Pakistan, 90 treated with ivermectin, showing no significant differences with treatment. The ivermectin group had more severe disease (66% vs 58%, with 6x higher risk for severe disease patients).. |
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Late treatment study
Late treatment study
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The effect of ivermectin on non-severe and severe COVID-19 disease and gender-based difference of its effectiveness |
Zubair et al., Monaldi Archives for Chest Disease, doi:10.4081/monaldi.2022.2062 |
Retrospective 188 hospitalized patients in Pakistan, 90 treated with ivermectin, showing no significant differences with treatment. The ivermectin group had more severe disease (66% vs 58%, with 6x higher risk for severe disease patients), and more male patients (70% vs. 65%). Higher use of remdesivir and steroids in the ivermectin group also suggests that ivermectin was more likely to be given to patients in more severe condition. There were no side effects seen with ivermectin. Authors note that significantly improved ferritin levels were seen with treatment. Authors state that ivermectin patients received 2 12mg doses, 24 hours apart, but later state that the dosage was not standardized.
risk of death, 9.0% higher, RR 1.09, p = 1.00, treatment 5 of 90 (5.6%), control 5 of 98 (5.1%), unadjusted.
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hospitalization time, 8.0% higher, relative time 1.08, p = 0.40, treatment 90, control 98, unadjusted, Table 3, mean number of days.
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Excluded in after exclusion results of meta analysis:
substantial unadjusted confounding by indication likely, unadjusted results with no group details.
Zubair et al., 1/18/2022, retrospective, Pakistan, South Asia, peer-reviewed, 8 authors, study period October 2020 - February 2021, dosage 12mg single dose.
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Early |
Tyson et al., Preprint (Preprint) |
death, ↓99.8%, p<0.0001 |
Low Rates of Hospitalization and Death in 4,376 COVID-19 Patients Given Early Ambulatory Medical and Supportive Care. A Case Series and Observational Study. |
Details
Retrospective 4,376 patients with mild/moderate COVID-19 in the USA treated with multiple medications including HCQ/ivermectin, favipiravir, vitamin C, D, quercetin, zinc, mAbs, budesonide, dexamethasone, prednisone, and colchicine (exact.. |
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Details
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Early treatment study
Early treatment study
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Low Rates of Hospitalization and Death in 4,376 COVID-19 Patients Given Early Ambulatory Medical and Supportive Care. A Case Series and Observational Study. |
Tyson et al., Preprint (Preprint) |
Retrospective 4,376 patients with mild/moderate COVID-19 in the USA treated with multiple medications including HCQ/ivermectin, favipiravir, vitamin C, D, quercetin, zinc, mAbs, budesonide, dexamethasone, prednisone, and colchicine (exact treatments specific to each patient), showing significantly lower hospitalization and mortality compared to the surrounding community.
risk of death, 99.8% lower, RR 0.002, p < 0.001, treatment 0 of 3,962 (0.0%), control 471 of 20,921 (2.3%), NNT 44, relative risk is not 0 because of continuity correction due to zero events, All AVUC mild patients vs. Imperial County (corrected).
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risk of hospitalization, 99.8% lower, RR 0.002, p < 0.001, treatment 2 of 3,962 (0.1%), control 4,343 of 20,921 (20.8%), NNT 4.8, All AVUC mild patients vs. Imperial County (corrected).
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risk of death, 97.0% lower, RR 0.03, p < 0.001, treatment 3 of 4,375 (0.1%), control 471 of 20,921 (2.3%), NNT 46, All AVUC patients vs. Imperial County (corrected).
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risk of hospitalization, 99.0% lower, RR 0.010, p < 0.001, treatment 9 of 4,375 (0.2%), control 4,343 of 20,921 (20.8%), NNT 4.9, All AVUC patients vs. Imperial County (corrected).
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Tyson et al., 1/13/2022, retrospective, USA, North America, preprint, 13 authors.
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Early |
Abbas et al., Indian Journal of Pharmaceutical Sciences, doi:10.36468/pharmaceutical-sciences.spl.416 |
death, ↑4.0%, p=1.00 |
The Effect of Ivermectin on Reducing Viral Symptoms in Patients with Mild COVID-19 |
Details
RCT 99 ivermectin and 103 control low risk patients in China, up to 7 days from symptom onset, showing statistically significant improvement in recovery with treatment, and non-statistically significant improvements in recovery time and.. |
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Early treatment study
Early treatment study
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The Effect of Ivermectin on Reducing Viral Symptoms in Patients with Mild COVID-19 |
Abbas et al., Indian Journal of Pharmaceutical Sciences, doi:10.36468/pharmaceutical-sciences.spl.416 |
RCT 99 ivermectin and 103 control low risk patients in China, up to 7 days from symptom onset, showing statistically significant improvement in recovery with treatment, and non-statistically significant improvements in recovery time and deterioration.Authors selectively omitted the p-value for recovery which shows statistical significance. Very little information on the patients is provided (only age, gender, and insurance status). The table, text, and abstract show three different versions of recovery numbers. The table and abstract show two different versions of recovery time. The abstract contains a hazard ratio that is not in the text, and no statistical methods are reported. Given the selective omission of the statistically significant recovery p-value, three different sets of numbers for that outcome, and other inconsistencies, the data in this study does not appear to be very reliable. Administration was specified on an empty stomach, reducing lung tissue concentration by ~2.5x according to Guzzo et al. Patients >50 were excluded.
risk of death, 4.0% higher, RR 1.04, p = 1.00, treatment 1 of 99 (1.0%), control 1 of 103 (1.0%).
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deterioration of 2 or more points, 40.5% lower, RR 0.59, p = 0.54, treatment 4 of 99 (4.0%), control 7 of 103 (6.8%), NNT 36.
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escalation of care, 14.9% lower, RR 0.85, p = 0.82, treatment 9 of 99 (9.1%), control 11 of 103 (10.7%), NNT 63.
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fever during study, 17.9% lower, RR 0.82, p = 0.58, treatment 15 of 99 (15.2%), control 19 of 103 (18.4%), NNT 30.
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risk of no recovery, 35.6% lower, RR 0.64, p = 0.04, treatment 26 of 99 (26.3%), control 42 of 103 (40.8%), NNT 6.9, primary outcome.
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recovery time, 30.8% lower, relative time 0.69, p = 0.08, treatment 99, control 103, primary outcome.
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Excluded in after exclusion results of meta analysis:
very minimal patient information, three different results for the recovery outcome, selective omission of the statistically significant recovery p-value, and other inconsistencies.
Abbas et al., 12/31/2021, Double Blind Randomized Controlled Trial, placebo-controlled, China, Asia, peer-reviewed, 3 authors, dosage 300μg/kg days 1-5.
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PrEPPEP |
Kerr et al., Research Gate, doi:10.13140/RG.2.2.26793.52327 (Preprint) |
death, ↓45.0%, p=0.046 |
COVID-19 In-Hospital Mortality Rate is Reduced by Prophylactic Use of Ivermectin: Findings From a City-Wide, Prospective Observational Study Using Propensity Score Matching (PSM) |
Details
PSM retrospective 378 hospitalized patients in Brazil, showing lower mortality for patients that were on ivermectin prophylaxis before admission (not taking into account the lower risk of being hospitalized shown in the related larger stu.. |
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Prophylaxis study
Prophylaxis study
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COVID-19 In-Hospital Mortality Rate is Reduced by Prophylactic Use of Ivermectin: Findings From a City-Wide, Prospective Observational Study Using Propensity Score Matching (PSM) |
Kerr et al., Research Gate, doi:10.13140/RG.2.2.26793.52327 (Preprint) |
PSM retrospective 378 hospitalized patients in Brazil, showing lower mortality for patients that were on ivermectin prophylaxis before admission (not taking into account the lower risk of being hospitalized shown in the related larger study). 47124221.2.0000.5485.
risk of death, 45.0% lower, RR 0.55, p = 0.046, treatment 12 of 52 (23.1%), control 22 of 52 (42.3%), NNT 5.2, adjusted, propensity score matching, multivariable.
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Excluded in meta analysis:
patients in this study are a subset of those in a larger study, not taking into account the lower risk of hospitalization shown in the related larger study.
Kerr et al., 12/31/2021, retrospective, propensity score matching, Brazil, South America, preprint, 9 authors, study period July 2020 - December 2020, dosage 200μg/kg days 1, 2, 16, 17, 0.2mg/kg/day for 2 days every 15 days.
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Late |
Shimizu et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.12.024 |
death, ↓99.9%, p<0.001 |
Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis |
Details
Retrospective 88 ventilated COVID-19 patients in Japan, 39 treated with ivermectin within 3 days of admission, showing significantly reduced incidence of GI complications and mortality, and increased ventilator-free days with treatment. |
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Late treatment study
Late treatment study
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Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis |
Shimizu et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.12.024 |
Retrospective 88 ventilated COVID-19 patients in Japan, 39 treated with ivermectin within 3 days of admission, showing significantly reduced incidence of GI complications and mortality, and increased ventilator-free days with treatment.
risk of death, 99.9% lower, HR 0.001, p < 0.001, treatment 0 of 39 (0.0%), control 8 of 49 (16.3%), NNT 6.1, adjusted, Cox proportional hazard regression.
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ventilator free days, 47.9% lower, OR 0.52, p = 0.03, treatment 39, control 49, adjusted, proportional odds logistic regression, primary outcome, RR approximated with OR.
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ventilation time, 38.5% lower, relative time 0.62, p < 0.001, treatment 39, control 49.
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ICU free days, 42.8% lower, OR 0.57, p = 0.06, treatment 39, control 49, adjusted, proportional odds logistic regression, RR approximated with OR.
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ICU time, 37.5% lower, relative time 0.62, p < 0.001, treatment 39, control 49.
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GI complications while ventilated, 77.9% lower, RR 0.22, p = 0.03, treatment 39, control 49, adjusted, Cox proportional hazard regression.
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Shimizu et al., 12/31/2021, retrospective, Japan, Asia, peer-reviewed, 11 authors, study period December 2020 - May 2021, dosage 200μg/kg days 1, 14.
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Submit Corrections or Comments
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Review |
Semiz, S., Biomolecular Concepts, doi:10.1515/bmc-2021-0017 (Review) |
review |
SIT1 transporter as a potential novel target in treatment of COVID-19 |
Details
Review of the potential connections between SLC6A20/SIT1, ACE2, Type 2 Diabetes, and COVID-19 severity. This provides another potential mechanism of action for ivermectin as a partial agonist of glycine-gated chloride channels, interferin.. |
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Review
Review
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SIT1 transporter as a potential novel target in treatment of COVID-19 |
Semiz, S., Biomolecular Concepts, doi:10.1515/bmc-2021-0017 (Review) |
Review of the potential connections between SLC6A20/SIT1, ACE2, Type 2 Diabetes, and COVID-19 severity. This provides another potential mechanism of action for ivermectin as a partial agonist of glycine-gated chloride channels, interfering with cytokine storm by inducing activation of glycine receptors. Author recommends investigating targeting of the SIT1 transporter and glycine levels in the treatment of COVID-19, particularly for severe cases associated with hyperglycemia, inflammation, and T2D.
Semiz et al., 12/30/2021, peer-reviewed, 1 author.
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Submit Corrections or Comments
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Late |
Mustafa et al., Exploratory Research in Clinical and Social Pharmacy, doi:10.1016/j.rcsop.2021.100101 |
death, ↓63.7%, p=0.09 |
Pattern of medication utilization in hospitalized patients with COVID-19 in three District Headquarters Hospitals in the Punjab province of Pakistan |
Details
Retrospective 444 hospitalized patients in Pakistan, showing lower mortality with ivermectin treatment in unadjusted results, not reaching statistical significance. Ivermectin was mostly used with patients in severe condition. Dose ranged.. |
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Late treatment study
Late treatment study
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Pattern of medication utilization in hospitalized patients with COVID-19 in three District Headquarters Hospitals in the Punjab province of Pakistan |
Mustafa et al., Exploratory Research in Clinical and Social Pharmacy, doi:10.1016/j.rcsop.2021.100101 |
Retrospective 444 hospitalized patients in Pakistan, showing lower mortality with ivermectin treatment in unadjusted results, not reaching statistical significance. Ivermectin was mostly used with patients in severe condition. Dose ranged from 12mg to 36mg for up to seven days.
risk of death, 63.7% lower, RR 0.36, p = 0.09, treatment 3 of 73 (4.1%), control 42 of 371 (11.3%), NNT 14.
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Excluded in after exclusion results of meta analysis:
unadjusted results with no group details.
Mustafa et al., 12/29/2021, retrospective, Pakistan, South Asia, peer-reviewed, 7 authors, dosage varies.
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Submit Corrections or Comments
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Late |
Baguma et al., Research Square, doi:10.21203/rs.3.rs-1193578/v1 (Preprint) |
death, ↓96.8%, p=0.31 |
Characteristics of the COVID-19 patients treated at Gulu Regional Referral Hospital, Northern Uganda: A cross-sectional study |
Details
Retrospective COVID+ hospitalized patients in Uganda, showing no statistically significant difference in mortality with ivermectin, however there were only 7 patients receiving ivermectin. |
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Late treatment study
Late treatment study
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Characteristics of the COVID-19 patients treated at Gulu Regional Referral Hospital, Northern Uganda: A cross-sectional study |
Baguma et al., Research Square, doi:10.21203/rs.3.rs-1193578/v1 (Preprint) |
Retrospective COVID+ hospitalized patients in Uganda, showing no statistically significant difference in mortality with ivermectin, however there were only 7 patients receiving ivermectin.
risk of death, 96.8% lower, RR 0.03, p = 0.31, treatment 7, control 474, adjusted, OR converted to RR, multivariable, control prevalance approximated with overall prevalence.
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Baguma et al., 12/28/2021, retrospective, Uganda, Africa, preprint, 16 authors, study period March 2020 - October 2021, dosage not specified.
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Submit Corrections or Comments
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Review |
Zaidi et al., The Journal of Antibiotics, doi:10.1038/s41429-021-00491-6 (Review) |
review |
The mechanisms of action of ivermectin against SARS-CoV-2—an extensive review |
Details
Extensive review of 20 mechanisms of action of ivermectin for SARS-CoV-2. |
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Review
Review
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The mechanisms of action of ivermectin against SARS-CoV-2—an extensive review |
Zaidi et al., The Journal of Antibiotics, doi:10.1038/s41429-021-00491-6 (Review) |
Extensive review of 20 mechanisms of action of ivermectin for SARS-CoV-2.
Zaidi et al., 12/21/2021, peer-reviewed, 2 authors.
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Submit Corrections or Comments
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Late |
Jamir et al., Cureus, doi:10.7759/cureus.20394 |
death, ↑53.0%, p=0.13 |
Determinants of Outcome Among Critically Ill Police Personnel With COVID-19: A Retrospective Observational Study From Andhra Pradesh, India |
Details
Retrospective 266 COVID-19 ICU patients in India, showing significantly lower mortality with PVP-I oral gargling and topical nasal use, and non-statistically significant higher mortality with ivermectin and lower mortality with remdesivir. |
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Late treatment study
Late treatment study
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Determinants of Outcome Among Critically Ill Police Personnel With COVID-19: A Retrospective Observational Study From Andhra Pradesh, India |
Jamir et al., Cureus, doi:10.7759/cureus.20394 |
Retrospective 266 COVID-19 ICU patients in India, showing significantly lower mortality with PVP-I oral gargling and topical nasal use, and non-statistically significant higher mortality with ivermectin and lower mortality with remdesivir.
risk of death, 53.0% higher, RR 1.53, p = 0.13, treatment 32 of 76 (42.1%), control 69 of 190 (36.3%), adjusted, multivariable Cox regression.
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Jamir et al., 12/13/2021, retrospective, India, South Asia, peer-reviewed, 6 authors, study period June 2020 - October 2010, dosage not specified.
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Submit Corrections or Comments
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PrEPPEP |
Kerr et al., Cureus, doi:10.7759/cureus.21272 (preprint 12/11/2021) |
death, ↓70.0%, p<0.0001 |
Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching |
Details
PSM retrospective 220,517 patients in Brazil,133,051 taking ivermectin as part of a citywide prophylaxis program, showing significantly lower hospitalization and mortality with treatment. CAAE:47124221.2.0000.5485. Additional results are .. |
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Prophylaxis study
Prophylaxis study
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Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching |
Kerr et al., Cureus, doi:10.7759/cureus.21272 (preprint 12/11/2021) |
PSM retrospective 220,517 patients in Brazil,133,051 taking ivermectin as part of a citywide prophylaxis program, showing significantly lower hospitalization and mortality with treatment. CAAE:47124221.2.0000.5485.Additional results are presented here: [odysee.com], including improved efficacy with analysis based on irregular/regular use, and a strong dose-response relationship.Confirmation from independent analysis of the raw data: [].
risk of death, 70.0% lower, RR 0.30, p < 0.001, treatment 25 of 3,034 (0.8%), control 79 of 3,034 (2.6%), NNT 56, adjusted, multivariate linear regression, propensity score matching.
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risk of hospitalization, 67.0% lower, RR 0.33, p < 0.001, treatment 44 of 3,034 (1.5%), control 99 of 3,034 (3.3%), adjusted, multivariate linear regression, propensity score matching.
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risk of case, 44.5% lower, RR 0.56, p < 0.001, treatment 4,197 of 113,845 (3.7%), control 3,034 of 45,716 (6.6%), NNT 34.
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Kerr et al., 12/11/2021, retrospective, propensity score matching, Brazil, South America, peer-reviewed, 9 authors, study period July 2020 - December 2020, dosage 200μg/kg days 1, 2, 16, 17, 0.2mg/kg/day for 2 days every 15 days.
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Submit Corrections or Comments
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Safety |
Wentzel et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab466.728 |
safety analysis |
Systematic Review and Meta-Analysis of Ivermectin Safety Profile in COVID-19 Trials |
Details
Systematic review and meta-analysis of safety in ivermectin COVID-19 trials, showing no significant difference in adverse events between treatment and control arms. Authors conclude that ivermectin is safe and well-tolerated. |
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Details
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Safety
Safety
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Systematic Review and Meta-Analysis of Ivermectin Safety Profile in COVID-19 Trials |
Wentzel et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab466.728 |
Systematic review and meta-analysis of safety in ivermectin COVID-19 trials, showing no significant difference in adverse events between treatment and control arms. Authors conclude that ivermectin is safe and well-tolerated.
Wentzel et al., 12/4/2021, peer-reviewed, 7 authors.
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Submit Corrections or Comments
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Review |
Behl et al., Science of The Total Environment, doi:10.1016/j.scitotenv.2021.152072 (Review) |
review |
CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target |
Details
Review of the cluster of differentiation 147 (CD147) transmembrane protein as an entry route for SARS-CoV-2, correlation with observed characteristics of COVID-19, and relevant potential therapeutics including azithromycin, melatonin, sta.. |
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Details
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Review
Review
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CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target |
Behl et al., Science of The Total Environment, doi:10.1016/j.scitotenv.2021.152072 (Review) |
Review of the cluster of differentiation 147 (CD147) transmembrane protein as an entry route for SARS-CoV-2, correlation with observed characteristics of COVID-19, and relevant potential therapeutics including azithromycin, melatonin, statins, beta adrenergic blockers, ivermectin, and meplazumab.
Behl et al., 12/1/2021, peer-reviewed, 9 authors.
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Submit Corrections or Comments
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In Vitro |
Jitobaom et al., Research Square, doi:10.21203/rs.3.rs-1069947/v1 (Preprint) (In Vitro) |
In Vitro |
Synergistic Anti-SARS-CoV-2 Activity of Repurposed Anti-Parasitic Drug Combinations |
Details
In Vitro study showing a strong synergistic effect of combinations of ivermectin, niclosamide, and chloroquine, with >10x reduction in IC50 compared to individual drugs. |
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Details
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In Vitro
In Vitro
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Synergistic Anti-SARS-CoV-2 Activity of Repurposed Anti-Parasitic Drug Combinations |
Jitobaom et al., Research Square, doi:10.21203/rs.3.rs-1069947/v1 (Preprint) (In Vitro) |
In Vitro study showing a strong synergistic effect of combinations of ivermectin, niclosamide, and chloroquine, with >10x reduction in IC50 compared to individual drugs.
Jitobaom et al., 11/30/2021, preprint, 8 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Late |
Ferreira et al., Revista da Associação Médica Brasileira, doi:10.1590/1806-9282.20210661 |
death, ↑5.0%, p=1.00 |
Outcomes associated with Hydroxychloroquine and Ivermectin in hospitalized patients with COVID-19: a single-center experience |
Details
Retrospective 230 hospitalized patients in Brazil showing no significant difference with ivermectin treatment. Authors note that the treatments were more likely to be offered to sicker patients. Authors indicate that they do not know when.. |
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Late treatment study
Late treatment study
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Outcomes associated with Hydroxychloroquine and Ivermectin in hospitalized patients with COVID-19: a single-center experience |
Ferreira et al., Revista da Associação Médica Brasileira, doi:10.1590/1806-9282.20210661 |
Retrospective 230 hospitalized patients in Brazil showing no significant difference with ivermectin treatment. Authors note that the treatments were more likely to be offered to sicker patients. Authors indicate that they do not know when medication was started, which in some cases could have been after ICU admission or intubation. Baseline total chest CT opacities was 20% for ivermectin vs. 15% for control. Dosage is unknown.
risk of death, 5.0% higher, RR 1.05, p = 1.00, treatment 3 of 21 (14.3%), control 11 of 81 (13.6%).
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risk of death/intubation, 54.3% higher, RR 1.54, p = 0.37, treatment 6 of 21 (28.6%), control 15 of 81 (18.5%).
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risk of death/intubation/ICU, 62.4% higher, RR 1.62, p = 0.27, treatment 8 of 21 (38.1%), control 19 of 81 (23.5%).
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Excluded in after exclusion results of meta analysis:
unadjusted results with no group details, substantial unadjusted confounding by indication likely.
Ferreira et al., 11/26/2021, retrospective, Brazil, South America, peer-reviewed, 5 authors, study period 12 March, 2020 - 8 July, 2020, average treatment delay 7.0 days, dosage not specified.
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Late |
Ozer et al., Journal of Medical Virology, doi:10.1002/jmv.27469 |
death, ↓75.0%, p=0.09 |
Effectiveness and Safety of Ivermectin in COVID‐19 Patients: A Prospective Study at A Safety‐Net Hospital |
Details
Small prospective PSM study in the USA, showing 75% lower mortality with ivermectin treatment, without reaching statistical significance, significantly shorter ventilation and ICU time, and longer hospitalization time. Authors leave the s.. |
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Late treatment study
Late treatment study
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Effectiveness and Safety of Ivermectin in COVID‐19 Patients: A Prospective Study at A Safety‐Net Hospital |
Ozer et al., Journal of Medical Virology, doi:10.1002/jmv.27469 |
Small prospective PSM study in the USA, showing 75% lower mortality with ivermectin treatment, without reaching statistical significance, significantly shorter ventilation and ICU time, and longer hospitalization time.Authors leave the statistically significant improvements in ventilation and ICU time out of the abtract and conclusions, and incorrectly state that there were no differences in other outcomes (there were no statistically significant differences) [nature.com]. Authors are ambiguous on the primary outcome, referring to the primary mortality outcome in one case, and "clinical outcomes, measured by the rate of intubation, length of hospital stay, and mechanical ventilation duration" in another case.The longer hospitalization time may be partially due to the greater mortality in the control group.
risk of death, 75.0% lower, RR 0.25, p = 0.09, treatment 2 of 60 (3.3%), control 8 of 60 (13.3%), NNT 10.0, PSM.
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risk of mechanical ventilation, 12.6% lower, RR 0.87, p = 0.20, treatment 3 of 60 (5.0%), control 2 of 60 (3.3%), OR converted to RR, PSM, multivariable.
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ventilation time, 83.3% lower, relative time 0.17, p = 0.002, treatment 60, control 60.
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risk of ICU admission, 48.7% lower, RR 0.51, p = 0.42, treatment 6 of 60 (10.0%), control 3 of 60 (5.0%), OR converted to RR, PSM, multivariable.
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ICU time, 70.6% lower, relative time 0.29, p < 0.001, treatment 60, control 60.
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hospitalization time, 9.0% higher, relative time 1.09, p = 0.09, treatment 60, control 60, PSM, multivariable.
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Ozer et al., 11/23/2021, prospective, USA, North America, peer-reviewed, 12 authors, dosage 200μg/kg days 1, 3.
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PrEPPEP |
Samajdar et al., Journal of the Association of Physicians India, 69:11 |
cases, ↓79.8%, p<0.0001 |
Ivermectin and Hydroxychloroquine for Chemo-Prophylaxis of COVID-19: A Questionnaire Survey of Perception and Prescribing Practice of Physicians vis-a-vis Outcomes |
Details
Physician survey in India with 164 ivermectin prophylaxis, 129 HCQ prophylaxis, and 81 control patients, showing significantly lower COVID-19 cases with treatment. Details of the treatment and control groups and the definition of cases ar.. |
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Prophylaxis study
Prophylaxis study
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Ivermectin and Hydroxychloroquine for Chemo-Prophylaxis of COVID-19: A Questionnaire Survey of Perception and Prescribing Practice of Physicians vis-a-vis Outcomes |
Samajdar et al., Journal of the Association of Physicians India, 69:11 |
Physician survey in India with 164 ivermectin prophylaxis, 129 HCQ prophylaxis, and 81 control patients, showing significantly lower COVID-19 cases with treatment. Details of the treatment and control groups and the definition of cases are not provided, and the results are subject to survey bias. Authors also report on community prophylaxis but present only combined ivermectin/HCQ results.
risk of case, 79.8% lower, RR 0.20, p < 0.001, treatment 12 of 164 (7.3%), control 29 of 81 (35.8%), NNT 3.5, OR converted to RR, physician survey.
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risk of case, 48.6% lower, RR 0.51, p = 0.03, treatment 11 of 109 (10.1%), control 39 of 200 (19.5%), NNT 11, OR converted to RR, combined ivermectin or HCQ in community.
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Excluded in after exclusion results of meta analysis:
minimal details provided, unadjusted results with no group details, results may be significantly affected by survey bias.
Samajdar et al., 11/17/2021, retrospective, India, South Asia, peer-reviewed, 9 authors, study period 1 September, 2020 - 31 December, 2020, dosage not specified.
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Late |
Stone et al., Research Square, doi:10.21203/rs.3.rs-1048271/v1 (Preprint) |
Rapid increase of SpO2 on room air for 34 severe COVID-19 patients after ivermectin-based combination treatment: 55-62% normalization within 12-24 hours |
Details
Retrospective severe COVID-19 patients in Zimbabwe treated with ivermectin, doxycycline, and zinc. For 34 with SpO2 tracking, there was rapid improvement in SpO2, with 55% recovery towards SpO2=97 within 12 hours. For all 92 severe cases,.. |
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Late treatment study
Late treatment study
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Rapid increase of SpO2 on room air for 34 severe COVID-19 patients after ivermectin-based combination treatment: 55-62% normalization within 12-24 hours |
Stone et al., Research Square, doi:10.21203/rs.3.rs-1048271/v1 (Preprint) |
Retrospective severe COVID-19 patients in Zimbabwe treated with ivermectin, doxycycline, and zinc. For 34 with SpO2 tracking, there was rapid improvement in SpO2, with 55% recovery towards SpO2=97 within 12 hours. For all 92 severe cases, there was 2 deaths and 2 additional progressions prior to recovery, significantly less than a predicted 7 deaths and 17 deteriorations based on demographics and risk factors.
Stone et al., 11/9/2021, preprint, 7 authors.
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Late |
Lim et al., JAMA, doi:10.1001/jamainternmed.2022.0189 (data 11/3/21) |
death, ↓69.0%, p=0.09 |
Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial |
Details
RCT 490 late stage (>65% lung change chest radiography at baseline) hospitalized patients in Malaysia, showing no significant differences. Mortality was 1.2% for ivermectin vs. 4% for control. If the same event rates continue, the trial w.. |
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Late treatment study
Late treatment study
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Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial |
Lim et al., JAMA, doi:10.1001/jamainternmed.2022.0189 (data 11/3/21) |
RCT 490 late stage (>65% lung change chest radiography at baseline) hospitalized patients in Malaysia, showing no significant differences.Mortality was 1.2% for ivermectin vs. 4% for control. If the same event rates continue, the trial would need to add ~13% more patients to reach statistical significance.i.e., by continuing the trial for ~2 weeks, there is a reasonable chance of the result being a statistically significant ~69% reduction in mortality, which would equate to ~4 million lives saved if adopted at the start of the pandemic.The mortality reduction is consistent with the results from all trials to date. While not reaching the significance threshold with the specified test, Bayesian analysis shows a 97% probability that ivermectin reduces mortality [normanfenton.com].Authors describe the mortality results as "similar" and they are not mentioned in the visual abstract or the conclusion, suggesting substantial investigator bias with a preference for a null result.The primary outcome is based on SpO2 <95%, however baseline SpO2 is not provided. This outcome is of limited use in evaluating treatment because it occurred before the end of treatment for > ~80% of patients. The trial was open label and the primary outcome is subject to investigator bias - clinicians could easily bias the results by altering how they monitor SpO2, how precisely they enforced the threshold, or other aspects of SOC such as propensity to use prone positioning. Authors indicate the 95% value is from clinical stage 4, however the Malaysian government defines 94% as the threshold for stage 4 [covid-19.moh.gov.my], as per the NIH definition [covid19treatmentguidelines.nih.gov]. Using death/IMV/NIV/high flow for severe (as per WHO) also shows more favorable results [].The mortality rate among all patients is too low to detect a 69% benefit with statistical significance, however the primary outcome gives us a subset of patients with severe cases that had progressed to SpO2 <95% shortly after randomization (and mostly before treatment ended). This result is statistically significant. For more discussion see: [twitter.com (B), ].The trial started May 31, 2021 and outcomes were changed in the trial record on June 16, 2021 [clinicaltrials.gov]. Previously the only clinical outcomes listed (under secondary outcomes) were mortality and clinical response, both at 28 days. Clinical response at 28 days would be more informative than complete recovery at day 5 as reported.Contact information was deleted in the trial record on November 3, 2021 [clinicaltrials.gov (B)].Data sharing: authors report that the data is available, send requests to: stevenlimcl@gmail.com. NCT04920942.
risk of death, 69.0% lower, RR 0.31, p = 0.09, treatment 3 of 241 (1.2%), control 10 of 249 (4.0%), NNT 36.
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risk of death, 75.2% lower, RR 0.25, p = 0.02, treatment 3 of 52 (5.8%), control 10 of 43 (23.3%), NNT 5.7, among patients progressing to severe cases (mostly before treatment ended).
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risk of mechanical ventilation, 59.0% lower, RR 0.41, p = 0.17, treatment 4 of 241 (1.7%), control 10 of 249 (4.0%), NNT 42.
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risk of ICU admission, 22.0% lower, RR 0.78, p = 0.79, treatment 6 of 241 (2.5%), control 8 of 249 (3.2%), NNT 138.
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risk of progression, 31.1% lower, RR 0.69, p = 0.29, treatment 14 of 241 (5.8%), control 21 of 249 (8.4%), NNT 38, death/IMV/NIV/high flow (WHO severe cases).
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risk of progression, 25.0% higher, RR 1.25, p = 0.25, treatment 52 of 241 (21.6%), control 43 of 249 (17.3%), primary outcome.
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hospitalization time, 5.5% higher, relative time 1.05, p = 0.38, treatment 241, control 249.
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risk of no recovery, 2.5% higher, RR 1.02, p = 0.86, treatment 116 of 241 (48.1%), control 116 of 247 (47.0%), day 5.
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Lim et al., 11/3/2021, Randomized Controlled Trial, Malaysia, Europe, peer-reviewed, 26 authors, study period 31 May, 2021 - 9 October, 2021, average treatment delay 5.1 days, dosage 400μg/kg days 1-5, trial NCT04920942 (I-TECH).
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Late |
Rezk et al., Zagazig University Medical Journal, doi:10.21608/zumj.2021.92746.2329 |
death, ↓80.0%, p=0.50 |
miRNA-223-3p, miRNA- 2909 and Cytokines Expression in COVID-19 Patients Treated with Ivermectin |
Details
Prospective 320 hospitalized moderate COVID-19+ patients in Egypt, 160 treated with ivermectin, showing lower mortality, improved recovery, and decreased cytokine expression with treatment. All patients were treated with HCQ. 7890/26-8-20.. |
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Late treatment study
Late treatment study
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miRNA-223-3p, miRNA- 2909 and Cytokines Expression in COVID-19 Patients Treated with Ivermectin |
Rezk et al., Zagazig University Medical Journal, doi:10.21608/zumj.2021.92746.2329 |
Prospective 320 hospitalized moderate COVID-19+ patients in Egypt, 160 treated with ivermectin, showing lower mortality, improved recovery, and decreased cytokine expression with treatment. All patients were treated with HCQ. 7890/26-8-2020.
risk of death, 80.0% lower, RR 0.20, p = 0.50, treatment 0 of 160 (0.0%), control 2 of 160 (1.2%), NNT 80, relative risk is not 0 because of continuity correction due to zero events.
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risk of progression, 55.6% lower, RR 0.44, p = 0.06, treatment 8 of 160 (5.0%), control 18 of 160 (11.2%), NNT 16, 2 weeks, including deaths.
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risk of no recovery, 33.4% lower, RR 0.67, p = 0.27, treatment 14 of 145 (9.7%), control 20 of 138 (14.5%), NNT 21, 4 weeks, more patients were lost to followup in the control group.
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time to viral-, 27.3% lower, relative time 0.73, p = 0.01, treatment 160, control 160.
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Rezk et al., 10/30/2021, prospective, Egypt, Africa, peer-reviewed, 4 authors, dosage 36mg days 1, 3, 6.
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PrEPPEP |
Verma et al., Indian Journal of Community Health, 33:3 |
Assessing Knowledge, Attitude, and Practices towards Ivermectin Pre-exposure Prophylaxis for COVID-19 among Health Care Workers |
Details
Survey of 306 healthcare workers involved in the medication of COVID-19 patients in India. 71% indicated that ivermectin had a protective effect for COVID-19. |
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Prophylaxis study
Prophylaxis study
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Assessing Knowledge, Attitude, and Practices towards Ivermectin Pre-exposure Prophylaxis for COVID-19 among Health Care Workers |
Verma et al., Indian Journal of Community Health, 33:3 |
Survey of 306 healthcare workers involved in the medication of COVID-19 patients in India. 71% indicated that ivermectin had a protective effect for COVID-19.
Verma et al., 10/28/2021, peer-reviewed, 6 authors.
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Review |
Low et al., Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, doi:10.1016/j.bbadis.2021.166294 (Review) |
review |
Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication |
Details
Review of the antiviral characteristics of ivermectin and mechanisms of action. Authors note that ivermectin has proven effective for HIV-1, Adenovirus, flu, SARS-CoV, and more; due to genomic similarity between SARS-CoV-2 and SARS-CoV, t.. |
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Review
Review
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Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication |
Low et al., Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, doi:10.1016/j.bbadis.2021.166294 (Review) |
Review of the antiviral characteristics of ivermectin and mechanisms of action. Authors note that ivermectin has proven effective for HIV-1, Adenovirus, flu, SARS-CoV, and more; due to genomic similarity between SARS-CoV-2 and SARS-CoV, the role of the IMPα/β1 complex for viral protein (NSP12-RdRp) shuttling between the nucleus and cytoplasm holds great potential; and that ivermectin exhibits great potential in reducing SARS-CoV-2 viral replication via numerous modes of action, such as the disruption of the Importin heterodimer complex (IMPα/β1).
Low et al., 10/20/2021, peer-reviewed, 3 authors.
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Early |
Borody et al., TrialSite News (Preprint) |
death, ↓92.3%, p=0.03 |
Combination Therapy For COVID-19 Based on Ivermectin in an Australian Population |
Details
Retrospective 600 PCR+ outpatients in Australia treated with ivermectin, zinc, and doxycycline, showing significantly lower mortality and hospitalization with treatment. This trial uses a synthetic control group, and the preliminary repor.. |
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Early treatment study
Early treatment study
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Combination Therapy For COVID-19 Based on Ivermectin in an Australian Population |
Borody et al., TrialSite News (Preprint) |
Retrospective 600 PCR+ outpatients in Australia treated with ivermectin, zinc, and doxycycline, showing significantly lower mortality and hospitalization with treatment. This trial uses a synthetic control group, and the preliminary report provides minimal details.
risk of death, 92.3% lower, RR 0.08, p = 0.03, treatment 0 of 600 (0.0%), control 6 of 600 (1.0%), NNT 100, relative risk is not 0 because of continuity correction due to zero events.
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risk of hospitalization, 92.9% lower, RR 0.07, p < 0.001, treatment 5 of 600 (0.8%), control 70 of 600 (11.7%), NNT 9.2, primary outcome.
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Excluded in after exclusion results of meta analysis:
preliminary report with minimal details.
Borody et al., 10/19/2021, retrospective, Australia, Oceania, preprint, 2 authors, study period 1 June, 2021 - 30 September, 2021, dosage 24mg days 1-10, this trial uses multiple treatments in the treatment arm (combined with zinc and doxycycline) - results of individual treatments may vary.
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In Vitro |
Segatori et al., Viruses, doi:10.3390/v13102084 (In Vitro) |
In Vitro |
Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients |
Details
Gene expression analysis of nasopharyngeal swabs of COVID-19 positive and negative patients, and in vitro study supporting the use of ivermectin and atorvastatin for COVID-19, and the efficacy of ivermectin at clinically relevant dosages... |
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In Vitro
In Vitro
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Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients |
Segatori et al., Viruses, doi:10.3390/v13102084 (In Vitro) |
Gene expression analysis of nasopharyngeal swabs of COVID-19 positive and negative patients, and in vitro study supporting the use of ivermectin and atorvastatin for COVID-19, and the efficacy of ivermectin at clinically relevant dosages.Experiments showed that ivermectin and atorvastatin halted NF‐κB activation, impaired importin and Rho GTPases gene expression, and inhibited importin α nuclear accumulation. Authors note that ivermectin and atorvastatin's targetting of importin‐mediated nuclear trafficking may also indicate applicability to other infections including dengue fever, zika, and influenza.Authors show that an ivermectin concentration as low as 0.2μM for 24h produced a similar effect on the inhibition of importin α nuclear to cytoplasmic distribution as that of a 2.5μM for 1h. This suggests that a sustained exposure to lower concentrations could interfere with the host cell machinery that SARS-CoV-2 requires for replication. Experiments also indicate improved results with the combination of ivermectin and atorvastatin.
Segatori et al., 10/15/2021, peer-reviewed, 11 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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In Vitro |
Jitobaom et al., Research Square, doi:10.21203/rs.3.rs-941811/v1 (Preprint) (In Vitro) |
In Vitro |
Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2 |
Details
In Vitro study showing a strong synergistic effect of ivermectin and favipiravir. Combining multiple antiviral drugs with different mechanisms of action helps to minimize drug resistance and toxicity. For ivermectin alone, IC50 for Calu-3.. |
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In Vitro
In Vitro
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Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2 |
Jitobaom et al., Research Square, doi:10.21203/rs.3.rs-941811/v1 (Preprint) (In Vitro) |
In Vitro study showing a strong synergistic effect of ivermectin and favipiravir. Combining multiple antiviral drugs with different mechanisms of action helps to minimize drug resistance and toxicity.For ivermectin alone, IC50 for Calu-3 was 0.2µM, supporting in vivo efficacy at 0.6 mg/kg.
Jitobaom et al., 10/14/2021, preprint, 8 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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News |
Goodkin, M. (News) |
news |
Are Major Ivermectin Studies Designed for Failure? |
Details
Discussion of flaws in ivermectin trials creating a bias towards not finding an effect. |
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News
News
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Are Major Ivermectin Studies Designed for Failure? |
Goodkin, M. (News) |
Discussion of flaws in ivermectin trials creating a bias towards not finding an effect.
Goodkin et al., 10/14/2021, preprint, 1 author.
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Review |
Fordham et al., OSF Preprints, doi:10.31219/osf.io/mp4f2 (Review) (Preprint) |
review |
The uses and abuses of systematic reviews |
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Analysis of defects in the Popp et al. meta analysis. |
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Review
Review
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The uses and abuses of systematic reviews |
Fordham et al., OSF Preprints, doi:10.31219/osf.io/mp4f2 (Review) (Preprint) |
Analysis of defects in the Popp et al. meta analysis.
Fordham et al., 10/7/2021, preprint, 4 authors.
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Submit Corrections or Comments
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In Silico |
Francés-Monerris et al., Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C |
In Silico |
Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection |
Details
In Silico molecular dynamics study showing that ACE2 and ACE2/RBD aggregates form persistent interactions with ivermectin. |
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In Silico
In Silico
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Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection |
Francés-Monerris et al., Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C |
In Silico molecular dynamics study showing that ACE2 and ACE2/RBD aggregates form persistent interactions with ivermectin.
Francés-Monerris et al., 10/5/2021, peer-reviewed, 8 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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N/A |
TrialSite News (News) |
news |
Committed to Medical Evidence, a Prominent Ivermectin Group is Eradicated from the Memories of Cyberspace |
Details
Report on Twitter's censorship of the British Ivermectin Recommendation Development group. |
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N/A
N/A
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Committed to Medical Evidence, a Prominent Ivermectin Group is Eradicated from the Memories of Cyberspace |
TrialSite News (News) |
Report on Twitter's censorship of the British Ivermectin Recommendation Development group.
TrialSite News et al., 10/2/2021, preprint, 1 author.
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Submit Corrections or Comments
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Late |
Babalola et al., Research Square, doi:10.21203/rs.3.rs-950352/v1 (Preprint) |
A Randomized Controlled Trial of Ivermectin Monotherapy Versus Hydroxychloroquine, Ivermectin, and Azithromycin Combination Therapy in Covid-19 Patients in Nigeria |
Details
Small RCT with 61 patients in Nigeria, all patients treated with ivermectin, zinc, and vitamin C, showing no significant improvements in recovery with the addition of HCQ+AZ. PACTR202108891693522. |
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Late treatment study
Late treatment study
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A Randomized Controlled Trial of Ivermectin Monotherapy Versus Hydroxychloroquine, Ivermectin, and Azithromycin Combination Therapy in Covid-19 Patients in Nigeria |
Babalola et al., Research Square, doi:10.21203/rs.3.rs-950352/v1 (Preprint) |
Small RCT with 61 patients in Nigeria, all patients treated with ivermectin, zinc, and vitamin C, showing no significant improvements in recovery with the addition of HCQ+AZ. PACTR202108891693522.
Babalola et al., 10/1/2021, preprint, 6 authors.
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Early |
Mayer et al., Frontiers in Public Health, doi:10.3389/fpubh.2022.813378 (preprint 9/23/2021) |
death, ↓55.1%, p<0.0001 |
Safety and Efficacy of a MEURI Program for the Use of High Dose Ivermectin in COVID-19 Patients |
Details
Retrospective 21,232 patients in Argentina, 3,266 assigned to ivermectin treatment, showing lower mortality with treatment. Greater benefits were seen for patients >40, and a dose dependent response was found. For more discussion see . |
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Early treatment study
Early treatment study
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Safety and Efficacy of a MEURI Program for the Use of High Dose Ivermectin in COVID-19 Patients |
Mayer et al., Frontiers in Public Health, doi:10.3389/fpubh.2022.813378 (preprint 9/23/2021) |
Retrospective 21,232 patients in Argentina, 3,266 assigned to ivermectin treatment, showing lower mortality with treatment. Greater benefits were seen for patients >40, and a dose dependent response was found. For more discussion see [].
risk of death, 55.1% lower, RR 0.45, p < 0.001, treatment 3,266, control 17,966, adjusted, OR converted to RR, Figure 3, multivariable.
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risk of ICU admission, 65.9% lower, RR 0.34, p < 0.001, treatment 3,266, control 17,966, adjusted, OR converted to RR, Figure 3, multivariable.
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risk of death, 27.6% lower, RR 0.72, p = 0.03, treatment 3,266, control 17,966, OR converted to RR, unadjusted.
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risk of ICU admission, 26.0% lower, RR 0.74, p = 0.13, treatment 3,266, control 17,966, OR converted to RR, unadjusted.
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Mayer et al., 9/23/2021, retrospective, Argentina, South America, peer-reviewed, 14 authors, dosage 540μg/kg days 1-5, mean prescribed dose.
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News |
Scheim, D., TrialsSite News (News) |
news |
Merck’s deadly Vioxx playbook, redux: a debunked smear campaign against its competing drug—the FDA-approved, Nobel prize-honored ivermectin |
Details
Discussion of Merck's ivermectin statements and past actions related to Vioxx raising significant concerns. |
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News
News
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Merck’s deadly Vioxx playbook, redux: a debunked smear campaign against its competing drug—the FDA-approved, Nobel prize-honored ivermectin |
Scheim, D., TrialsSite News (News) |
Discussion of Merck's ivermectin statements and past actions related to Vioxx raising significant concerns.
Scheim et al., 9/7/2021, preprint, 1 author.
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Early |
Buonfrate et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2021.106516 (preprint 9/6/2021) |
hosp., ↑210.7%, p=0.47 |
High dose ivermectin for the early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof of concept trial |
Details
Early terminated 89 patient RCT with 29 high dose and 32 very high dose ivermectin patients, showing dose dependent viral load reduction, although not reaching statistical significance due to early termination. Since most patients have lo.. |
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Early treatment study
Early treatment study
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High dose ivermectin for the early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof of concept trial |
Buonfrate et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2021.106516 (preprint 9/6/2021) |
Early terminated 89 patient RCT with 29 high dose and 32 very high dose ivermectin patients, showing dose dependent viral load reduction, although not reaching statistical significance due to early termination. Since most patients have low viral load at day 7, there is little room for improvement with a treatment at day 7. Intermediate results may show significantly greater improvement, but are not provided. Authors note that ivermectin remained safe even at the very high dose used, although tolerability was reduced. Adherence was very low in the very high dose arm (~60%).The paper reports 4 SAEs, all resolved, with 3 patients hospitalized in the very high dose ivermectin arm, 1 in the high dose arm, and 0 in the control arm. However, the supplementary data is contradictory, showing 2 grade 3 events in both ivermectin arms (2 infections and infestations, and 2 COVID-19 pneumonia). While this result is not statistically significant, it may be in part due to randomization failure because three times as many patients were randomized in a hospital setting in the ivermectin arms (12/58) compared to the placebo arm (2/29), as shown in supplemental table 2, suggesting higher baseline severity in the ivermectin arms. The very high dose ivermectin arm also had more male patients (73% vs. 45%), higher median weight (79 vs. 70kg), and higher baseline cough (56% vs 42%), pyrexia (56% vs 33%), and anosmia (33% vs 17%) as per supplemental table 2. COVER. NCT04438850.
risk of hospitalization, 210.7% higher, RR 3.11, p = 0.47, treatment 1 of 28 (3.6%), control 0 of 31 (0.0%), continuity correction due to zero event, arm B.
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risk of hospitalization, 610.0% higher, RR 7.10, p = 0.11, treatment 3 of 30 (10.0%), control 0 of 31 (0.0%), continuity correction due to zero event, arm C, very high dose, poorly tolerated with low compliance.
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relative change in viral load, RR 0.80, p = 0.59, treatment mean 2.5 (±2.2) n=28, control mean 2.0 (±4.4) n=29, day 7, arm B, primary outcome.
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relative change in viral load, RR 0.69, p = 0.07, treatment mean 2.9 (±1.6) n=30, control mean 2.0 (±2.1) n=29, day 7, arm C, primary outcome.
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Excluded in after exclusion results of meta analysis:
significant unadjusted group differences, with 3 times as many patients in the ivermectin arms having the baseline visit in a hospital setting, and arm C having large differences in baseline gender, weight, cough, pyrexia, and anosmia, excessive dose for arm C.
Buonfrate et al., 9/6/2021, Double Blind Randomized Controlled Trial, Italy, Europe, peer-reviewed, 18 authors, average treatment delay 4.0 days, dosage 1200μg/kg days 1-5, arm B 600µg/kg, arm C 1200µg/kg, trial NCT04438850.
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Early |
Okogbenin et al., Nigerian Postgraduate Medical Journal, doi:10.4103/npmj.npmj_532_21 |
Clinical characteristics, treatment modalities and outcome of coronavirus disease 2019 patients treated at thisday dome isolation and treatment centre, federal capital territory Abuja, Nigeria |
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Retrospective 300 COVID-19 patients in Nigeria treated with ivermectin, zinc, vitamin C, and azithromycin, reporting no deaths. Authors conclude that early treatment is critical. |
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Early treatment study
Early treatment study
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Clinical characteristics, treatment modalities and outcome of coronavirus disease 2019 patients treated at thisday dome isolation and treatment centre, federal capital territory Abuja, Nigeria |
Okogbenin et al., Nigerian Postgraduate Medical Journal, doi:10.4103/npmj.npmj_532_21 |
Retrospective 300 COVID-19 patients in Nigeria treated with ivermectin, zinc, vitamin C, and azithromycin, reporting no deaths. Authors conclude that early treatment is critical.
Okogbenin et al., 9/3/2021, peer-reviewed, 13 authors.
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Meta |
Marik et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001443 (meta analysis) |
meta-analysis |
Ivermectin, A Reanalysis of the Data |
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Updated meta analysis showing no significant change if Elgazzar et al. is excluded. |
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Meta
Meta
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Ivermectin, A Reanalysis of the Data |
Marik et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001443 (meta analysis) |
Updated meta analysis showing no significant change if Elgazzar et al. is excluded.
Marik et al., 9/2/2021, peer-reviewed, 2 authors.
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Meta |
Neil et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001450 (meta analysis) |
meta-analysis |
Bayesian Hypothesis Testing and Hierarchical Modeling of Ivermectin Effectiveness |
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Updated Bayesian analysis of a subset of ivermectin trials showing that there is strong evidence to support a causal link between ivermectin and COVID-19 severity and mortality, and that the result is robust in sensitivity analysis, inclu.. |
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Meta
Meta
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Bayesian Hypothesis Testing and Hierarchical Modeling of Ivermectin Effectiveness |
Neil et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001450 (meta analysis) |
Updated Bayesian analysis of a subset of ivermectin trials showing that there is strong evidence to support a causal link between ivermectin and COVID-19 severity and mortality, and that the result is robust in sensitivity analysis, including exclusion of Elgazzar et al.
Neil et al., 9/2/2021, peer-reviewed, 2 authors.
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In Silico |
González-Paz et al., Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677 |
In Silico |
Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach |
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In Silico analysis of the components of ivermectin (avermectin-B1a and avermectin-B1b), suggesting different and complementary inhibitory activity of each component, with an affinity of avermectin-B1b for viral structures, and of avermect.. |
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In Silico
In Silico
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Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach |
González-Paz et al., Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677 |
In Silico analysis of the components of ivermectin (avermectin-B1a and avermectin-B1b), suggesting different and complementary inhibitory activity of each component, with an affinity of avermectin-B1b for viral structures, and of avermectin-B1a for host structures.
González-Paz et al., 8/19/2021, peer-reviewed, 9 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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In Silico |
González-Paz et al., Journal of Molecular Liquids, doi:10.1016/j.molliq.2021.117284 |
In Silico |
Structural Deformability Induced in Proteins of Potential Interest Associated with COVID-19 by binding of Homologues present in Ivermectin: Comparative Study Based in Elastic Networks Models |
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In Silico elastic network model analysis of ivermectin components (avermectin-B1a and avermectin-B1b) providing a biophysical and computational perspective of proposed multi-target activity of ivermectin for COVID-19. |
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In Silico
In Silico
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Structural Deformability Induced in Proteins of Potential Interest Associated with COVID-19 by binding of Homologues present in Ivermectin: Comparative Study Based in Elastic Networks Models |
González-Paz et al., Journal of Molecular Liquids, doi:10.1016/j.molliq.2021.117284 |
In Silico elastic network model analysis of ivermectin components (avermectin-B1a and avermectin-B1b) providing a biophysical and computational perspective of proposed multi-target activity of ivermectin for COVID-19.
González-Paz et al., 8/17/2021, peer-reviewed, 9 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Review |
Kory, P., Substack (Review) (Preprint) |
review |
Summary of the Evidence for Ivermectin in COVID-19 |
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Summary of the evidence base for ivermectin and COVID-19 including in vitro and in silico studies, animal studies, pharmacologic studies, clinical observation and experience, observational controlled trials, randomized controlled trials, .. |
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Review
Review
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Summary of the Evidence for Ivermectin in COVID-19 |
Kory, P., Substack (Review) (Preprint) |
Summary of the evidence base for ivermectin and COVID-19 including in vitro and in silico studies, animal studies, pharmacologic studies, clinical observation and experience, observational controlled trials, randomized controlled trials, and epidemiological data.
Kory et al., 8/16/2021, preprint, 1 author.
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Late |
Elavarasi et al., medRxiv, doi:10.1101/2021.08.10.21261855 (Preprint) |
death, ↓19.6%, p=0.12 |
Clinical features, demography and predictors of outcomes of SARS-CoV-2 infection in a tertiary care hospital in India - a cohort study |
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Retrospective 2017 hospitalized patients in India, showing lower mortality with ivermectin treatment in unadjusted results. No group details are provided and this result is subject to confounding by indication. |
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Late treatment study
Late treatment study
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Clinical features, demography and predictors of outcomes of SARS-CoV-2 infection in a tertiary care hospital in India - a cohort study |
Elavarasi et al., medRxiv, doi:10.1101/2021.08.10.21261855 (Preprint) |
Retrospective 2017 hospitalized patients in India, showing lower mortality with ivermectin treatment in unadjusted results. No group details are provided and this result is subject to confounding by indication.
risk of death, 19.6% lower, RR 0.80, p = 0.12, treatment 48 of 283 (17.0%), control 311 of 1,475 (21.1%), NNT 24, unadjusted.
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Excluded in after exclusion results of meta analysis:
unadjusted results with no group details.
Elavarasi et al., 8/12/2021, retrospective, India, South Asia, preprint, 26 authors, dosage not specified.
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N/A |
Pedroso et al., The Brazilian Journal of Infectious Diseases, doi:10.1016/j.bjid.2021.101603 |
Self-prescribed Ivermectin use is associated with a lower rate of seroconversion in health care workers diagnosed with COVID, in a dose-dependent response |
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Retrospective 45 healthcare workes in Brazil, showing lower creation of antibodies with multiple doses of ivermectin, which may be expected due to the antiviral activity as demonstrated in multiple studies. Authors appear unaware of these.. |
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N/A
N/A
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Self-prescribed Ivermectin use is associated with a lower rate of seroconversion in health care workers diagnosed with COVID, in a dose-dependent response |
Pedroso et al., The Brazilian Journal of Infectious Diseases, doi:10.1016/j.bjid.2021.101603 |
Retrospective 45 healthcare workes in Brazil, showing lower creation of antibodies with multiple doses of ivermectin, which may be expected due to the antiviral activity as demonstrated in multiple studies. Authors appear unaware of these studies, citing only earlier in vitro research, which they misinterpret to suggest that therapeutic concentrations are not reached (for details on why this is incorrect see [c19ivermectin.com]). Authors combine no dose and one dose. Clinical outcomes and timing of treatment are not provided.
Pedroso et al., 8/12/2021, peer-reviewed, 11 authors.
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Early |
La Pampa, Argentina (News) |
death, ↓27.4% |
La Pampa expondrá a la comunidad científica los resultados del Programa de Intervención Monitoreado de Ivermectina |
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News report on the use of ivermectin in La Pampa, Argentina, showing lower mortality with treatment. |
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Early treatment study
Early treatment study
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La Pampa expondrá a la comunidad científica los resultados del Programa de Intervención Monitoreado de Ivermectina |
La Pampa, Argentina (News) |
News report on the use of ivermectin in La Pampa, Argentina, showing lower mortality with treatment.
risk of death, 27.4% lower, RR 0.73, treatment 3,269, control 18,149.
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risk of death/ICU, 38.0% lower, RR 0.62, treatment 3,269, control 18,149.
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risk of death, 33.4% lower, RR 0.67, treatment 3,269, control 18,149, >40yo.
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risk of death, 44.0% lower, RR 0.56, treatment 3,269, control 18,149, >40yo including comorbidities.
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Excluded in after exclusion results of meta analysis:
minimal details provided.
La Pampa et al., 8/10/2021, retrospective, Argentina, South America, preprint, 1 author, dosage 600μg/kg days 1-5.
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Review |
Kow et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001441 (Review) |
review |
Pitfalls in Reporting Sample Size Calculation Across Randomized Controlled Trials Involving Ivermectin for the treatment of COVID-19 |
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Review of sample size calculations in ivermectin RCTs, showing that existing RCTs are very underpowered. |
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Review
Review
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Pitfalls in Reporting Sample Size Calculation Across Randomized Controlled Trials Involving Ivermectin for the treatment of COVID-19 |
Kow et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001441 (Review) |
Review of sample size calculations in ivermectin RCTs, showing that existing RCTs are very underpowered.
Kow et al., 8/6/2021, peer-reviewed, 2 authors.
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Early |
Reis et al., New England Journal of Medicine, doi:10.1056/NEJMoa2115869 (results released 8/6/2021) |
death, ↓12.0%, p=0.68 |
Effect of Early Treatment with Ivermectin among Patients with Covid-19 |
Details
Many major issues including multiple impossible numbers, blinding failure, randomization failure, and many protocol violations , as detailed below. Submit Updates or Corrections Also see: Fraudulent Trial On Ivermectin Published By The Wo.. |
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Early treatment study
Early treatment study
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Effect of Early Treatment with Ivermectin among Patients with Covid-19 |
Reis et al., New England Journal of Medicine, doi:10.1056/NEJMoa2115869 (results released 8/6/2021) |
Many major issues including multiple impossible numbers,
blinding failure, randomization failure, and many protocol violations,
as detailed below. Submit
Updates or Corrections
Private comment:
"There is a clear signal that IVM works in COVID patients..
that would be significant if more patients were added..
you will hear me retract previous statements where I had been previously negative" —
Ed Mills, Together Trial co-principal investigator.
[stevekirsch.substack.com]
Public comment:
“There was no indication that ivermectin is clinically useful” —
Ed Mills, Together Trial co-principal investigator.
"..the question of whether this study was stopped too early
in light of the political ramifications of needing to demonstrate that the
efficacy is really unimpressive.. really could be raised.." — Frank
Harrell, "I totally agree with Frank" — Ed Mills
[vimeo.com]
Severity | Issue | Author response |
CRITICAL | Blinding failure |
- |
CRITICAL | Randomization violation, major confounding |
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CRITICAL | Data pledge violation, unavailable over 258 days from protocol, over 53 days from publication |
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CRITICAL | DSMC not independent |
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CRITICAL | Extreme conflicts of interest |
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CRITICAL | Three conflicting death counts |
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CRITICAL | Patient counts for reported period impossible |
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CRITICAL | Placebo arm counts vs. fluvoxamine arm not possible |
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CRITICAL | Conflicting adverse event counts |
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SERIOUS | Widespread community use of ivermectin |
conflicting responses |
SERIOUS | Team selected dose below what they believe is required |
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SERIOUS | Side-effect prevalence consistent with treatment error |
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SERIOUS | Screening to treatment delay unknown |
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SERIOUS | Unknown onset patients included |
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SERIOUS | Conflicting comorbidity counts |
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SERIOUS | Unexplained >6 month delay |
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SERIOUS | Major imputation error |
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SERIOUS | Incorrect conclusion |
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SERIOUS | Missing age information |
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SERIOUS | Mid-trial protocol changes |
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SERIOUS | COI: designed by Cytel |
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SERIOUS | COI: analysis company works closely with Pfizer |
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SERIOUS | Unexpected differences in missing data |
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MAJOR | Unknown onset results dramatically better |
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MAJOR | Mean delay likely excluding unknown onset |
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MAJOR | 3-dose placebo much more effective |
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MAJOR | Multiple conflicting randomization protocols |
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MAJOR | Dominated by Gamma variant, no discussion |
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MAJOR | Viral load protocol violation, high Ct may hide efficacy |
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MAJOR | Conflicting dosing, previously unheard of weight limit |
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MAJOR | Conflicting target enrollment and reasons for termination |
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MAJOR | Soft primary outcome easy to game, selected after single dose arm |
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MAJOR | Conflicting futility thresholds, reported terminated due to futility, but threshold not reached |
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MAJOR | Subgroup analysis protocol violations |
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MAJOR | Many pre-specified outcomes missing |
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MAJOR | Single-dose recruiting continued after change |
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MAJOR | Funding list incorrect, missing Gates Foundation and Unitaid |
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MAJOR | Statistical analysis plan dated after trial start |
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MAJOR | Imputation protocol violation |
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MAJOR | Expected analyses missing |
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MAJOR | Single dose results missing |
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MAJOR | Details of placebo unspecified |
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MAJOR | Vaccine inclusion changes, likely confounding |
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MAJOR | Bayesian probability of superiority, featured for FLV, hidden in appendix |
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MAJOR | Two different per-protocol counts |
modified w/o explanation |
MINOR | Per-protocol conflict with fluvoxamine arm |
required by journal |
Apr 5: The paper was silently updated, with no
indication or explanation of the changes. Changes include: age range, placebo
description, per-protocol count, and death counts (details below).
May 5: The paper was silently updated again. A
new summary notes that authors attempted to screen for previous
ivermectin use, contradicting both the discussion section, where authors claim
they ensured no use for COVID-19, and the exclusion criteria and
interview forms, which do not specify ivermectin use.
May 22 update: there is still no response to data requests,
and the authors continue to maintain radio silence on the many serious issues
[twitter.com].
Delayed >6 months. The paper was
delayed over 6 months with no explanation. The companion fluvoxamine arm,
completed at the same time, was published Aug 23, 2021. The paper was
submitted to NEJM in Sep 2021 [vimeo.com (B)].
COI forms suggest that additional authors were added after submission and the
corresponding author changed from Prof. Mills to Dr. Rayner
[],
whose conflicts include Pfizer, Merck, the Gates Foundation, and the
Australian Goverment.
No response to data request. The trial
registration states that data was to be available at termination and upon
request [clinicaltrials.gov], however
authors have not responded to a request for the data. Even funders of the
trial have been unable to access the data
[odysee.com].
Requests can be sent to thetogethertrial@gmail.com, let us know the outcome.
Three different death counts. In the
original paper, Table 3 shows 21 and 24 deaths, while Table S6 shows 20 and 25
[]. In
Table 3, death and grade 5 events showed the same 21/24 numbers, but different
effect sizes, with 0.81 being closer to the 20/25 counts and the previously
reported number. This is consistent with one death being moved between arms
after manuscript generation, but not updated in Table S6 or the Table 3 AE RR.
This cannot be explained by the safety population excluding patients with zero
doses because the AE control deaths are higher.
In email, a co-principal investigator suggested that the discrepancy was due
to one being COVID-19 deaths and the other being all-cause deaths
[stevekirsch.substack.com].
That explanation does not fit the data because one arm increases while the
other arm decreases.
Both co-principal investigators report in the paper that "they had full
access to all the trial data and vouch for the accuracy and completeness of
the data and for the fidelity of the trial to the protocol."
A third set of death counts, 20 and 24, with RR 0.84, was
presented by a co-principal investigator on Mar 18, 2022
[vimeo.com (C)].
In total, 4 different death relative risks have been presented: Mar 18, 2022
presentation: 0.84, Mar 30 paper: 0.88 (T3), 0.81 (T3 AE), and 0.80 (TS6,
presented as 20 and 25 only without group sizes).
6 days after publication, the paper was updated, with no information given on
what was changed.
In this version, a "respiratory, thoracic and mediastinal disorders" death was
removed from the control arm and an "infections and infestations" death was
added to the ivermectin arm. The paper still indicates RR 0.81 for death AE.
Trial was not blind.
Ivermectin/placebo blinding was done by assigning a letter to each group that
was only known to the pharmacist. If a patient received a 3-dose treatment,
investigators immediately know that the patient is more likely to be in the
treatment group than the control group, because 3-dose placebo was relatively
rare (~46% from PP). If a patient received non-3-day treatment, investigators
immediately know that the patient is not an ivermectin treatment patient.
Moreover, by observing the frequency of allocations, investigators can easily
determine which letter corresponds to active ivermectin 3-day treatment,
thereby removing all blinding. For example, consider 3-dose-ivermectin and
3-dose-placebo being identified by the letters G and K. If allocations to date
have been G:11 and K:20, there is a very high probability that K is
ivermectin. Note that this blinding failure is only obvious because the
journal required the authors to restrict to the 3-day placebo group. Also note
that it would have been trivial to avoid if desired, for example by using a
unique identifier for all medication bottles. Note that there may be
additional reasons for blinding failure, for example the paper specifies
identically shaped bottles, but does not appear to specify identical
appearance tablets
[].
Patient counts do not match
previously released enrollment graph. Authors claim the ivermectin and
control patients were all from on or after March 23, 2021, however independent
analyses of the enrollment graph (contained in this presentation
[dcricollab.dcri.duke.edu])
require including patients prior to this date to reach the reported numbers
[doyourownresearch.substack.com (C), longhaulwiki.com].
The enrollment graph shows much higher enrollement to ivermectin near the
start of the trial. The only way that the number of placebo patients can be
the same as the number of treatment patients is if placebo patients were taken
from an earlier period [Marinos], which creates a nonconcurrent
control group [nejm.org] and
substantial confounding by time as below.
Conflicting placebo arm counts
across IVM/FLV arms. The IVM placebo arm has 679 patients and the FLV
arm has 756. The 679 should be shared between the arms, with 77 extra patients
for FLV. For FLV, there were 34 placebo patients requiring mechanical
ventilation, for IVM there was only 25, indicating that 9 of the extra 77
placebo patients for FLV had mechanical ventilation, a much higher percentage
during a period that had lower deaths and CFR (and included vaccinated
patients). Placebo all-cause hospitalization shows 95/679 for IVM and 99/756
for FLV, i.e., only 4 of the extra 77 patients were hospitalized, but the
paper reports an additional 9 patients with mechanical ventilation.
For FLV, there were 11 grade 1 AEs, for IVM there were 12, with
77 less patients.
For FLV, there were 50 grade 3 AEs, for IVM there were also 50,
meaning the 77 extra patients had 0% grade 3 AEs vs. an expected 7.4%
For FLV, there were 54 CKD patients according to Figure 3 and
eTable1 (2 according to Table 1). For IVM there was 5.
DSMC not independent. Reviewer 1 of the
protocol notes that the DSMC is not independent
[gatesopenresearch.org]. Prof. Thorlund is Vice
President of the contract research organisation (CRO, Cytel), professor at the
sponsoring university, and an author of the protocol. Dr. Häggström is an
employee of the CRO.
[doyourownresearch.substack.com (C), twitter.com (C)]
reveals many other conflicts. Prof. Thorlund has written >100 papers with
Prof. Mills. Prof. Singh has written 29 papers with Prof. Mills. Prof.
Orbinski has written 9 papers with Prof. Mills. The first version of the web
site showed Prof. Mills and Prof. Thorlund as joint leads. Emails pointed to a
company MTEK Sciences, founded by Prof. Mills and Prof. Thorlund (MTEK is
hypothesized to stand for Mills, Thorlund, Edward, Kristian). MTEK received
grants from the Gates Foundation. MTEK also employed Dr. Häggström. MTEK was
acquired by Cytel in 2019. Dr. Häggström works for the Gates Foundation. Two
members of the DSMC have published a paper with members of a well known
anti-ivermectin research group [Thorlund] and Dr. Hill, whose meta
analysis has reports of external influence
[c19ivermectin.com, c19ivermectin.com (B), ].
The trial protocol reports that "an independent DSMC will be established,
composed of scientists of unrivalled reputation and expertise, without
involvement with this research protocol."
Unequal randomization, significant confounding
by time. The trial reports 1:1:1:1 randomization, however independent
analysis shows much higher enrollment in the ivermectin treatment arm towards
the start of the trial
[c19ivermectin.com (C), longhaulwiki.com].
This introduces very significant confounding by time due to the major change
in the distribution of variants. [Zavascki] show dramatically higher
mortality for Gamma vs non-Gamma variants (28 day mortality from symptom onset
aHR 4.73 [1.15-19.41]). Many more patients were randomized to ivermectin vs.
placebo in the first few weeks, for example the first week shows 82 ivermectin
vs. 28 placebo patients, 2.9x higher. The period of excess ivermectin
enrollment coincides closely with a period of significantly higher deaths and
CFR in Brazil.
Missing time from onset patients
show statistically significant efficacy. For the known time since
onset subgroups, both groups show worse results than the overall results
[], with the
missing 317 patients showing significant efficacy RR 0.51, p = 0.02 (compared
to 1.00 and 1.14 for known patients).
Unknown onset patients were enrolled,
subgroup results opposite of previous trials. After imputation, the
percentage of patients in the late treatment subgroup went from 46% to 56%.
87% of the unknown patients were predicted to be in the late group. This is
reasonable and expected — patients that do not recall when the onset was
are more likely to have had onset further in the past. What is not clear is
how these patients could be enrolled in the trial, how many of these patients
had onset >7 days, how this very late 317 patient subgroup could show much
greater efficacy as above, and why authors did not report this result, analyze
this in greater detail, or recommend further research.
Side effect profile consistent with many
treatment patients not receiving authentic ivermectin and/or control patients
receiving ivermectin. The side effects (e.g., gastrointestinal side
effects were lower in the ivermectin arm) suggest that many ivermectin
patients may not have received authentic ivermectin, or that placebo patients
may have taken ivermectin. For comparison, there was a 3.6 times greater
incidence of diarrhea in the treatment arm in [Lim].
A local Brazilian investigator reports that, at
the time of the trial, there was only one likely placebo manufacturer, and
they reportedly did not receive a request to produce identical placebo tablets
[].
They also report that compounded ivermectin in Brazil is considered
unreliable. The protocol reports that "the study medication used will come
from pharmaceutical plants that hold a commercial authorization for their
production, already approved by ANVISA."
Vaccine inclusion changes. The trial
changed from including vaccinated patients to excluding them on Mar 21, 2021
[clinicaltrials.gov (B), twitter.com (F)],
and on Jul 5 the exclusion was changed to specify >14days. As above, meeting
the reported placebo counts likely requires taking placebo patients from the
earlier period, which has very significant confounding due to variant changes,
and additionally confounding due to vaccination. Both of these favor the
placebo group. The original vaccine inclusion criterion is unusual, but is
shown in both the protocol and the clinicaltrials.gov record
[clinicaltrials.gov (C), togethertrial.com].
This may have been chosen to reduce the potential for efficacy. For more on
vaccination inclusion see
[].

Incorrect conclusion. The
conclusion states that ivermectin "did not result in a lower incidence of
[hospitalization] or of [ER observation >6hr]". This is incorrect,
hospitalization was 17% lower, which is not statistically significant with the
sample size and typical statistical analysis. For the Bayesian analysis the
authors use, the ITT probability of superiority for ivermectin was 79.4%,
which is a positive result, the opposite of the conclusion.
Ivermectin use widespread in the
community. Recent ivermectin use was not in the exclusion criteria.
Ivermectin was available OTC, was recommended by the government for COVID-19,
and had nine times higher sales
[twitter.com (H)]. Authors
claim they ensured patients did not use ivermectin via "extensive screening",
but do not explain why this was not an exclusion criterion, or how this
unwritten exclusion was ensured even though there is extensive missing data
related to written exclusion criteria. Similar unwritten exclusions were not
mentioned for other arms
[], a primary
investigator previously stated such an exclusion should not be an issue
[twitter.com (J)], and it
is not mentioned in the interview sheets [osf.io]. After
publication, a co-principal investigator reportedly wrote that "even if
some patients did access IVM, the fact that it is blinded should still
maintain balance", which is incorrect, placebo patients taking ivermectin
are expected to improve, treatment patients that already have significant
tissue distributions may have positive, neutral, or negative responses to
additional treatment.
Single-dose recruiting continued after
change. The trial had requested moving to 3-dose treatment by Feb
15/19, when only 19 patients had been recruited, however the trial continued
recruiting an additional 59 patients to single dose treatment
[twitter.com (K)].
Per-protocol population different to the
contemporary fluvoxamine arm. Table 2 per-protocol numbers show 92%
per-protocol patients for ivermectin and only 42% for control. This appears to
be a post-hoc change selecting only 3-day placebo patients, while similar
selection does not appear to have been done for the companion fluvoxamine
trial (showing 74% and 82% per-protocol patients for fluvoxamine and control)
[Reis].
Multiple conflicting randomization
protocols.
[twitter.com (L)] reviewed
the randomization protocol, finding three different algorithms, and
conflicting versions in the papers.
Time of onset, required for inclusion, missing for 317
patients. For the companion fluvoxamine arm, 24% of patients had an
unknown time from onset, including 179 of the control patients
[Reis]. In this trial, 0 patients have an unspecified time from onset
in Table 1, due to imputation. However, Figure 2 reveals that the time from
onset is unknown for 317 patients, similar to the fluvoxamine paper. However,
time from onset is required for the inclusion criteria. According to Figure 2,
age and BMI also show missing values.
Conflicting comorbidity counts.
The companion fluvoxamine arm ran from Jan 20 to Aug 5, 2021, while this trial
ran from March 23 to Aug 6, 2021 — most control patients should be
shared, with an additional 10% for fluvoxamine from the earlier start. The Aug
6 presentation, which has a date of 9:38am Aug 6 local trial time
[],
shows 678 placebo patients, indicating that either 0 or 1 placebo patients
were randomized on Aug 6. Zero patients should have been randomized on Aug 6,
because authors cannot add patients after unblinding.
The fluvoxamine control arm shows 16/756 control patients with
asthma. The ivermectin control arm has a subset of these patients (679), but
shows a much higher prevalence of asthma (60 patients). This might be possible
due to imputation if there was a very high percentage of missing data, however
imputation does not appear to be a good explanation. For example, placebo CKD
goes from 2 to 5 (FLV->IVM). First, it is not logical to impute CKD on
patients based on the other variables. Second, the protocol specifies
imputation only with up to 20% missing data, making it unlikely that
imputation would add 150% of CKD patients. Third, the degree of change between
FLV and IVM varies dramatically, with IVM reporting 666%, 275%, 150%, and 43%
more patients for CPD, asthma, CKD, and CCD, without any clear explanation for
similar differences in the percentage of missing data (all were collected on
the same interview form).
Conflicting target enrollment.
There are conflicting target enrollment numbers. The protocol showed 800
patients per arm as of Mar 21, 2021 (after the trial started)
[static1.squarespace.com, twitter.com (M)],
the co-principal investigator reported 800 per arm in an interview published
June 14, 2021
[halifaxexaminer.ca],
and the protocol changed to 681 on June 22
[static1.squarespace.com (B)].
However, the trial record from Jan indicates 2724 (681*4) patients
[clinicaltrials.gov (C)],
suggesting that the 800 goal was later, and was kept for fluvoxamine but reverted for
ivermectin.
The fluvoxamine arm which started two months earlier was terminated at the
same time, and was terminated due to superiority [Reis] after 741/756
patients.
Note that Gamma was declining significantly around the termination point,
which likely favors improved efficacy if the trial continued, given the late
treatment and dosage used.
The co-principal investigator reports three different reasons for stopping the
trial [twitter.com (N)]: a) because
they ran out of money, b) because third parties were not supportive, and c) it was done
by the DSMC and was out of their control.
Reportedly terminated for futility although
futility threshold not reached. The trial was reportedly terminated
due to futility
[twitter.com (O)], however
the futility thresholds were 20%, 40% and 60%, and all published probabilities
are >60% (ITT 79.4%). Additionally, the fluvoxamine arm did not have the
higher 60% threshold, only using 40%. Note the DSMC was not independent as
below.
Screening to treatment delay.
Most Together Trial protocols show an additional day delay in already late
treatment for most patients. The Aug 5, 2021 protocol published with the
metformin paper
[ars.els-cdn.com],
shows treatment administration one day after screening, baseline, and
randomization (Table 2, schedule of study activities). This can also be found
in the protocol dated Mar 11, 2021
[drive.google.com].
The protocol attached to the ivermectin paper, dated Feb 15, 2021, shows a
different schedule, stating that the treatment should be administered
on the same day of randomization.
There is no explanation of when this change was made, how the overlapping
metformin and ivermectin arms could use different schedules, or how this
change was implemented (there are many tasks in the screening and baseline
visits). There is no reporting for how many patients received treatment on the
same day. The form for the first treatment visit asks if there were clinical
events including >6hr ER visits since the baseline visit, which would not be
possible if this visit was immediately after randomization. Time of first
treatment was recorded [osf.io], but no information has
been reported. According to [Forrest], WhatsApp messaging and video
was used for recruitment, raising the question of how medication was delivered
in cases where recruitment was done online.

Mean delay. The reported mean
number of days from symptoms to randomization likely only includes known onset
patients and therefore is likely to significantly underestimate the actual
average, in addition to not including the time between randomization and
treatment.
Viral load not reported. The
protocol has change in viral load as an outcome, however only viral clearance
is reported, and without any details (for example, using a high Ct value would
have limited relevance).
Incorrect dose reporting, many
patients at higher risk due to BMI may have received lower per kg doses, and
show lower efficacy. The paper reports 400μg/kg for 3 days, however
the protocol indicates that this was only up to 90kg, meaning that the dose
received for higher-risk high BMI patients was even further reduced from
dosage which is already far below clinician recommendations for the dominant
variant [twitter.com (P)].
50% of patients had BMI ≥30. Much greater efficacy was seen in the low BMI
subgroup (RR 0.77 vs 0.98).
Plasma concentration below known effective
value. [Krolewiecki] show an antiviral effect only with plasma
concentrations above 160ng/mL. Figure S5 shows that the authors expected the
mean concentration to be well below this level
[]. Dosage
requirements are likely to vary significantly depending on many factors
including the variant encountered, time of administration, mode of
administration, patient genetics, concomitant medications, SOC, and the
distribution of the infection in different tissues. However, the dose used is
far below what is recommended by clinicians for post-infection treatment with
the Gamma variant — about 2.5 - 6.5x lower, depending on the
recommendation and which estimate of fasting/fed administration is used. The
trial used fasting administration, however Merck's product information reports
that "administration of 30mg ivermectin following a highfat meal resulted
in an approximate 2.5-fold increase in bioavailability relative to
administration of 30mg ivermectin in the fasted state."
[merck.com].
Moreover Dr. Craig Rayner, a senior investigator on the trial, previously
published research indicating that a higher dose is required
[sciencedirect.com],
raising the question of why the dose and fasting administration was chosen,
especially for the initial single dose regimen.
Primary outcome easy to game, selected after
ivermectin one dose arm. The subjective "emergency room visit for >6
hours" criterion shows higher risk (RR 1.16), while hospitalization is lower
(RR 0.83 all-cause, RR 0.84 COVID-19). The primary outcome results were set on
March 21, 2021, after the single dose ivermectin arm. Given the known public
biases of some investigators, this may have been specifically chosen to reduce
efficacy. Authors claim that the 6hr threshold did not include waiting time,
however the emergency visit form has no mention of waiting time, only
recording presentation and discharge times
[osf.io].
Including contraindicated chronic kidney disease
patients. "Stage IV chronic kidney disease or on dialysis" was an
inclusion criterion, however ivermectin is contraindicated with kidney disease
[Arise, en.wikipedia.org, Nunes] (not always
recognized, and may be less critical with very low dose use for other
conditions). According to Table 1 there were only 7 CKD patients, however two
conflicting numbers are provided in the fluvoxamine paper [Reis]:
Table 1 reports 2 CKD placebo patients - it's not clear how CKD was imputed
for 3 more patients in the smaller IVM group. Moreover, Figure 3 shows 54
placebo CKD patients for FLV.
Antigen test requirement. The
protocol indicates that patients with a negative test may be included if they
become positive a few days later, potentially resulting in a long unreported
delay between randomization and treatment, depending on how investigators
interpreted the protocol. The requirement for a positive antigen test excludes
the possibility of early treatment in many cases - tests have very high false
negative rates in the early stages of infection, and symptoms may appear
before the test becomes positive.
Inconsistent subgroup analysis.
The presented subgroup analysis is inconsistent with plans and with the
fluvoxamine paper, including not presenting pre-specified subgroups,
presenting subgroups that were not pre-specified, presenting different
subgroups to the contemporary fluvoxamine paper, and modifying subgroup
definitions
[twitter.com (R)].
Missing analysis. Authors do
not provide time from onset analysis for either mortality or hospitalization,
only the combined measure including the ER visits where anomalous results are
seen. Authors do not provide per-protocol or mITT results for mortality or
hospitalization. Per-protocol mortality results were provided for the
companion fluvoxamine trial.
Missing outcomes. Many
outcomes specified in the protocol appear to be missing, including the
co-primary outcome of COVID-19 mortality (only all-cause mortality is
provided, specific AE details not provided), time to clinical failure, days
with respiratory symptoms, mortality due to pulmonary complications,
cardiovascular mortality, COVID-19 symptom scale assessment, WHO clinical
worsening scale assessment, and 14 day mortality.
Imputation error. In the
paper authors use imputation in Table 1 but not in Figure 2. Authors also
released a version of Figure 2 with imputation
[togethertrial.com (B)], where the numbers
for age and BMI now match the imputed numbers in Table 1. However, the time
from onset numbers are very different, with the treatment arm showing 302
patients for 0-3 days, and the imputed version of Figure 2 showing 367
[].
Missing age information.
According to Figure 2, 98 patients are missing age information
[].
Unexpected differences in missing
data. Age is unknown for 98 patients, however according to Figure 2,
BMI is missing for only 11 patients, smoking status is unknown for only 2
patients, lung disease is unknown for only one patient, and cardiovascular
disease is known for all patients.
Mid-trial protocol changes. There
were several mid-trial protocol changes on July 5, 2021
[clinicaltrials.gov (D)].
The number of patients for viral load analysis was reduced, only for the
ivermectin arm. All-cause, cardiovascular, and respiratory death outcomes were
deleted (all-cause was reported). Exclusions were modified to allow enrolling
patients vaccinated within the last 14 days. Inclusion criteria were modified
to allow enrolling healthy young people — the criterion "fever >38C
at baseline" was added, allowing enrollment independent of increased
risk.
Statistical analysis plan dated after trial
start. The statistical analysis plan appears to be dated after the
trial started
[twitter.com (T)].
Per-protocol placebo results very
different. The 3-dose placebo appears to have been much more effective
[Marinos, twitter.com (U)].
This
could be consistent with placebo patients accidently receiving
treatment.
Imputation protocol violation.
The protocol specifies multiple imputation with up to 20% of missing data,
however imputation was done with time from symptom onset, which has >23%
missing data
[twitter.com (V)].
Two different per-protocol counts.
Figure 1 shows 228 per-protocol for the control arm, while Table 2 shows 288.
This was modified in the Apr 5 update without explanation.
Conflicting adverse event counts.
Table 3 and Table S6 adverse event counts do not match for any grade, e.g.,
grade 1/2 in Table S6 shows 82 for IVM, while Table 3 shows 65
[]. The
Apr 5 update changed the grade 5 events without explanation, however the other
grades remain conflicting.
Possibly the largest financial conflict of
interest of any trial to date. Disclosed conflicts of interest
include: Pfizer, Merck, Bill & Melinda Gates Foundation, Australian
Government, Medicines Development for Global Health, Novaquest, Regeneron,
Astrazeneca, Daichi Sankyo, Commonwealth Science and Research Organization,
and Card Research. Many conflicts of interest appear unreported. For example,
Unitaid is a sponsor
[Harper, togethertrial.com (C)].
Analysis done by a company that receives
payment from and works closely with Pfizer. All analyses were done by
Cytel. Cytel is a statistical modelling company that helps pharmaceutical
companies get approval — they work very closely with Pfizer
[cytel.com].
Cytel's software and services are used by the top 30 pharmaceutical companies
[cytel.com (B)].
A co-principal investigator works for Cytel and the Gates
Foundation
[empendium.com]:
"The majority of the time I work for a company called Cytel, where I design
clinical trials, predominantly for the Bill & Melinda Gates
Foundation".
Reportedly, the first author's center is funded by
pharmaceutical companies, and independent investigators tried to participate
in the trial but were denied
[odysee.com (B)].
The Gates Foundation is a founding partner of GAVI, which took
out Google ads telling people not to use ivermectin
[], and a
major funder of Unitaid, which may have modified the results of the Hill meta
analysis in a way that prevented adoption
[c19ivermectin.com, c19ivermectin.com (B), ].
Associated with MMS Holdings. The trial is
associated with MMS Holdings
[dcricollab.dcri.duke.edu],
whose mission includes helping pharmaceutical companies get approval and
designing scientific studies that help them get approval. One of their clients
is Pfizer [mmsholdings.com].
Certara. One of the senior investigators was Dr.
Craig Rayner, President of Integrated Drug Development at Certara - another
company with a similar mission to MMS Holdings. They state on their website
that: "Since 2014, our customers have received over 90% of new drug and
biologic approvals by the FDA." One of their clients is Pfizer [certara.com].
Local variant shows very different
characteristics. The trial took place in an area of Brazil where the
Gamma variant was prominent. Brazilian clinicians report that this variant is
much more virulent, and that significantly higher dosage and/or earlier
treatment is required, as may be expected for variants where the peak viral
load is significantly higher and/or reached earlier
[Faria, Nonaka].
Funding list incorrect. The paper
does not include the Bill and Melinda Gates Foundation or Unitaid as funders,
however the Mar 25, 2021 protocol shows the Gates Foundation
[static1.squarespace.com]
and the web site shows Unitaid
[togethertrial.com (C)].
Single dose arm results missing.
Results for the single dose ivermectin arm have not been reported.
Anomalous results from the same region. A local
Brazilian investigator reports that the study was conducted in almost the same
time and location as the Brazilian component of the molnupiravir trial.
Notably, molnupiravir's EUA relied on the unusually higher efficacy observed
in Brazil.
Designed by Cytel. The trial was
designed by Cytel, a company that helps pharmaceutical companies get approval
and that works very closely with Pfizer
[cytel.com, cytel.com (C)].
Cytel's software and services are used by the top 30 pharmaceutical companies
[cytel.com (B)].
Bayesian probability of
superiority hidden in appendix. The bayesian probability of
superiority figure, featured in the main paper for FLV, MET, HCQ, was hidden
in the appendix for IVM
[twitter.com (Y)].
Placebo unspecified. The
placebo appears to be unspecified in the paper and protocol. The initial trial
announcement indicated the placebo was vitamin C
[cytel.com (C)],
which would be an active treatment according to the results of
43 studies (mortality RR
0.75
[0.61-0.91]).
The metformin arm reports using talc, however fluvoxamine and ivermectin do
not appear to report details of the placebo, which could potentially be
different, for example based on manufacturer limitations for matching active
treatment tablets. Authors do not specify the appearance of the placebo tablets, suggesting
that they may not match the treatment tablets, providing an additional reason for blinding failure.
Previous protocol changes. There are two previous
published protocols, both are called "version 1", we refer to them as 1A
(3/11/21 [drive.google.com] )
and 1B (8/5/21 [gatesopenresearch.org]. 1B
deletes subgroup analysis by treatment delay, and deletes a statement
requiring prior approval for amendments. 1B adds the statement: "we
hypothesize that younger patients will benefit more than older
patients."
Patients 50 years old were assigned to different groups in
Table 1 and Figure 2 (≤50 vs. <50).
Greater efficacy was seen for patients >50 (RR 0.77) vs.
patients ≤50 (RR 1.01).
The following comments are prior to the publication. We note
that authors claim they have not included patients prior to the time period
for the 3 dose ivermectin patients, however this conflicts with previously
reported data as per the analyses above.
The trial randomization chart does not match the protocol,
suggesting major problems and indicating substantial confounding by time. For
example, trial week 43, the first week for 3 dose ivermectin, shows ~3x
patients assigned to ivermectin vs. placebo [reddit.com].
Treatment efficacy can vary significantly over time, for example due to
overall improvement in protocols, changes in the distribution of variants, or
changes in public awareness and treatment delays.
[Zavascki] show dramatically higher mortality for Gamma vs non-Gamma
variants (28 day mortality from symptom onset aHR 4.73 [1.15-19.41]), and the
prevalence of the Gamma variant varied dramatically throughout the trial [ourworldindata.org].
This introduces confounding by time, which is common in COVID-19 retrospective
studies and has often obscured efficacy (many retrospectives have more
patients in the treatment group earlier in time when overall treatment
protocols were significantly worse).
According to this analysis [reddit.com],
the total number of patients for the ivermectin and placebo groups do not
appear to match the totals in the presentation (the numbers for the
fluvoxamine arm match) — reaching the number reported for ivermectin
would require including some of the patients assigned to single dose
ivermectin. Reaching the placebo number requires including placebo patients
from the much earlier ivermectin single dose period, and from the early two
week period when zero ivermectin patients were assigned. If these earlier
participants were accidently included in the control group, this would
dramatically change the results in favor of the control group according to
the changes in Gamma variant prevalence.
An investigator from Brazil notes that the gamma variant became
prevailing in the state of Minas Gerais later than in the rest of the country,
with the time when gamma prevailed for the trial locations being more closely
aligned with the start of the ivermectin arm
[ufmg.br].
Due to the substantial differences in disease course and risk between the
variants, authors need to consider only patients recruited during the same
time period.
Treatment delay is currently unknown, however the protocol
allows very late inclusion and a companion trial reported mostly late
treatment. Overall mortality is high for 18+ outpatients. Results may be
impacted by late treatment, poor SOC, and may be specific to local variants
[Faria, Nonaka, Sabino].
Treatment was administered on an empty stomach, greatly reducing expected
tissue concentration [Guzzo] and making the effective dose about
1/5th of current clinical practice. The trial was conducted in Minas Gerais,
Brazil which had substantial community use of ivermectin [otempo.com.br],
and prior use of ivermectin is not listed in the exclusion criteria.
This trial uses a soft primary outcome, easily subject to bias
and event inflation in both arms (e.g., observe >6 hours independent of
indication). There is also an unusual inclusion criteria: "patients with
expected hospital stays of <= 5 days". This is similar to "patients less
likely to need treatment beyond SOC to recover", and would make it very easy
to reduce the effect seen. This is not in either of the published
protocols.
RCTs have a fundamental bias against finding an effect for
interventions that are widely available — patients that believe they
need treatment are more likely to decline participation and take the
intervention [Yeh], i.e. RCTs are more likely to enroll low-risk
participants that do not need treatment to recover (this does not apply to
the typical pharmaceutical trial of a new drug that is otherwise
unavailable). This trial was run in a community where ivermectin is widely
known and used.
The same trial's results for a previous treatment were
initially reported as RR 1.0 [0.45-2.21] [ajtmh.org], while
the final paper reported something very different — HR 0.76 [0.30-1.88]
[jamanetwork.com].
Trial design, analysis, and presentation, along with previous
public and private statements suggest investigator bias. Design: including
very late treatment, additional day before administration, operation in a
region with high community use, specifying administration on an empty
stomach, limiting treatment to 3 days, using soft inclusion criterion and a
soft primary outcome, easily subject to bias. Analysis: authors perform
analysis excluding events very shortly after randomization for fluvoxamine
but not ivermectin, and report viral load results for fluvoxamine but not
ivermectin. Presentation: falsely describing positive but not statistically
significant effects as "no effect, what so ever" [Amrhein, odysee.com (C)].
Prior statements: [odysee.com (C)].
The local Brazilian investigator also reports that nitazoxanide
was tested in the same location, however very few patients reportedly
experienced urine discoloration, while 100% are expected to experience this
side effect; and that 6-hour observation is a poor choice because it is almost
impossible to stay less than 6 hours in Brazil.
For additional issues see: [covid19criticalcare.com, doyourownresearch.substack.com (F), longhaulwiki.com, Marinos, Marinos (B), stevekirsch.substack.com, trialsitenews.com, , , , twitter.com (Z)].
Protocols, approvals, and statistical analysis plans can be found here
[togethertrial.com (D)].
risk of death, 12.0% lower, RR 0.88, p = 0.68, treatment 21 of 679 (3.1%), control 24 of 679 (3.5%), NNT 226.
|
risk of mechanical ventilation, 23.0% lower, RR 0.77, p = 0.38, treatment 19 of 679 (2.8%), control 25 of 679 (3.7%), NNT 113.
|
risk of hospitalization, 17.0% lower, RR 0.83, p = 0.19, treatment 79 of 679 (11.6%), control 95 of 679 (14.0%), NNT 42.
|
extended ER observation or hospitalization, 10.0% lower, RR 0.90, p = 0.42, treatment 100 of 679 (14.7%), control 111 of 679 (16.3%), NNT 62, primary outcome.
|
risk of no viral clearance, no change, RR 1.00, p = 1.00, treatment 106 of 142 (74.6%), control 123 of 165 (74.5%), day 7.
|
Excluded in after exclusion results of meta analysis:
multiple anomalies as per detailed analysis.
Reis et al., 8/6/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 27 authors, study period 23 March, 2021 - 6 August, 2021, dosage 400μg/kg days 1-3, trial NCT04727424 (TOGETHER).
|
Submit Corrections or Comments
|
|
In Silico |
Rana et al., Research Square, doi:10.21203/rs.3.rs-755838/v1 (Preprint) |
In Silico |
A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection |
Details
In silico study showing strong binding affinity of ivermectin and doxycycline for SARS-CoV-2 main protease 3CLpro, and increased binding affinity for the combination of both. |
|
Details
Source
PDF
In Silico
In Silico
|
A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection |
Rana et al., Research Square, doi:10.21203/rs.3.rs-755838/v1 (Preprint) |
In silico study showing strong binding affinity of ivermectin and doxycycline for SARS-CoV-2 main protease 3CLpro, and increased binding affinity for the combination of both.
Rana et al., 8/5/2021, preprint, 3 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
|
Submit Corrections or Comments
|
|
Review |
Santin et al., New Microbes and New Infections, doi:10.1016/j.nmni.2021.100924 (Review) |
review |
Ivermectin: a multifaceted drug of Nobel prize-honored distinction with indicated efficacy against a new global scourge, COVID-19 |
Details
Review concluding that the evidence supports worldwide use of ivermectin for COVID-19, complementary to immunization. Authors note that it is likely non-epitope specific, possibly retaining efficacy with new viral strains. They note that .. |
|
Details
Source
PDF
Review
Review
|
Ivermectin: a multifaceted drug of Nobel prize-honored distinction with indicated efficacy against a new global scourge, COVID-19 |
Santin et al., New Microbes and New Infections, doi:10.1016/j.nmni.2021.100924 (Review) |
Review concluding that the evidence supports worldwide use of ivermectin for COVID-19, complementary to immunization. Authors note that it is likely non-epitope specific, possibly retaining efficacy with new viral strains. They note that ivermectin has been safely used with 3.7 billion doses since 1987, is well tolerated even at much greater than standard doses, and has been used without serious AEs in high-dose COVID-19 treatment studies.
Santin et al., 8/3/2021, peer-reviewed, 5 authors.
|
Submit Corrections or Comments
|
|
Early, Late |
Sathi et al., Journal of Cardiovascular Disease Research, doi:10.31838/jcdr.2021.12.05.11 |
Clinical Effect of the Combination Therapy of Hydroxychloroquine, Azithromycin and Ivermectin in Patients with COVID-19 |
Details
Prospective study of 85 COVID-19 patients including 8 ICU patients treated with ivermectin, HCQ, and AZ, showing all patients improving except for one patient that died 3 days after admission. Authors recommend early treatment. There was .. |
|
Details
Source
PDF
Early, Late
Early, Late
|
Clinical Effect of the Combination Therapy of Hydroxychloroquine, Azithromycin and Ivermectin in Patients with COVID-19 |
Sathi et al., Journal of Cardiovascular Disease Research, doi:10.31838/jcdr.2021.12.05.11 |
Prospective study of 85 COVID-19 patients including 8 ICU patients treated with ivermectin, HCQ, and AZ, showing all patients improving except for one patient that died 3 days after admission. Authors recommend early treatment. There was no control group.
Sathi et al., 7/31/2021, peer-reviewed, 8 authors.
|
Submit Corrections or Comments
|
|
Meta |
Popp et al., Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD015017.pub2 (Preprint) (meta analysis) |
meta-analysis |
Ivermectin for preventing and treating COVID-19 |
Details
This meta analysis is designed to exclude most studies. Authors select a small subset of studies, with a majority of results based on only 1 or 2 studies. Authors split up studies which dilutes the effects and results in a lack of statist.. |
|
Details
Source
PDF
Meta
Meta
|
Ivermectin for preventing and treating COVID-19 |
Popp et al., Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD015017.pub2 (Preprint) (meta analysis) |
This meta analysis is designed to exclude most studies. Authors
select a small subset of studies, with a majority of results based on only 1
or 2 studies. Authors split up studies which dilutes the effects and results
in a lack of statistical significance for most outcomes. Authors perform 16+
meta analyses with very few studies in each analysis, and do not combine the
evidence from all studies. However, we can consider the probability of the
observed results across all outcomes.
Authors find positive results for 11 of 12 primary efficacy
outcomes with events, or 16 of 18 including secondary outcomes. One of the
primary outcomes and two of the secondary outcomes show statistically
significant improvements in isolation. If we assume independence, the
probability that 11+ of 12 primary efficacy outcomes were positive for an
ineffective treatment is p = 0.003. For 16+ of 18 outcomes we get
p = 0.0007. This simple analysis does not take into account the
magnitude of positive effects, or the dependence due to some studies
contributing multiple outcomes, however observation suggests that a full
analysis of the combined evidence is likely to show efficacy.
The study is entirely retrospective in the current version. The
protocol is dated April 20, 2021, and the most recent study included is from
March 9, 2021. The protocol was modified after publication in order to include
a close to null result ( [Beltran Gonzalez] "patients discharged without
respiratory deterioration or death at 28 days"), so the current protocol is
dated July 28, 2021.
Authors excluded many studies by requiring results at a
specific time, for example mortality, ventilation, etc. required results at
exactly 28 days. Authors excluded all prophylaxis studies by requiring
results at exactly 14 days.
Studies comparing with other medications were excluded, however
these studies confirm efficacy of ivermectin. The only case where they could
overstate the efficacy of ivermectin is if the other medication was harmful.
There is some evidence of this for excessive dosage/very late stage use,
however that does not apply to any of the studies here.
Studies using combined treatment were excluded, even when it is
known that the other components have minimal or no effect. 3 of 4 RCTs with
combined treatment use doxycycline in addition [Butler]. Other
studies were excluded by requiring PCR confirmation.
Authors are inconsistent regarding active comparators. They
state that hydroxychloroquine “does not work”, yet excluded trials comparing
ivermectin to a drug they hold to be inactive. On the other hand, remdesivir
was an acceptable comparator, although it is considered to be effective
standard of care in some locations [Fordham].
Authors fail to recognize that Risk of Bias (RoB) domains such
as blinding are far less important for the objective outcome of
mortality.
Authors include [Beltran Gonzalez] as "moderate"
COVID-19, however patients in this study were in severe condition (baseline
SatO2 83).
[Fordham] summarizes several problems:
•unsupported assertions of adverse
reactions to ivermectin, and the outdated claim that unsafe dosing would be
needed to be effective;
•a demand for PCR or antigen testing,
without analysis of reliability and not universally available even in
developed countries at the start of the pandemic;
•contradictions in the exclusion
criteria, including placebo and approved SoC comparators, but rejecting
hydroxychloroquine, though held to be ineffective (and an approved SoC in
some jurisdictions);
•inclusion of “deemed active”
comparators whilst excluding “potentially active” ones;
•exclusion of combination therapies,
though the norm among practising clinicians;
•the rejection of other than RCTs when
the objective is a “complete evidence profile”;
•arbitrary time-points for outcome
measures, excluding non-compliant trials;
•fragmentation of data by location of
care under varying hospitalisation criteria;
•the resulting focus on a small
fraction of the available clinical evidence, with most comparisons based on
single studies with no meta-analysis possible;
•a resulting inpatient mortality
comparison with fewer patients than a June 2020 confounder-matched
study;
•no conclusion on the headline
mortality outcome, when multiple lines of evidence from elsewhere
(including the WHO) point to significant mortality advantage.
Cochrane was reputable in the past, but is now controlled by
pharmaceutical interests. For example, see the news related to the expulsion
of founder Dr. Gøtzsche and the associated mass resignation of board members
in protest [blogs.bmj.com, bmj.com, en.x-mol.com].
For another example of bias see [ebm.bmj.com].
The BiRD group gave the following early comment: "Yesterday’s
Cochrane review surprisingly doesn’t take a pragmatic approach comparing
ivermectin versus no ivermectin, like in the majority of other existing
reviews. It uses a granular approach similar to WHO’s and the flawed Roman et
al paper, splitting studies up and thereby diluting effects. Consequently,
the uncertain conclusions add nothing to the evidence base. A further
obfuscation of the evidence on ivermectin and an example of research waste.
Funding conflicts of interests of the authors and of the journal concerned
should be examined."
Authors report funding from the German Federal Ministry of
Education and Research, which may be influenced by [gcgh.grandchallenges.org].
Popp et al., 7/28/2021, preprint, 8 authors.
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Early |
Ontai et al., Epidemiology International Journal, doi:10.23880/eij-16000217 |
Early multidrug treatment of SARS-CoV-2 (COVID-19) and decreased case fatality rates in Honduras |
Details
Report on the nationwide implementation of multi-drug COVID-19 inpatient and outpatient treatment protocols in Honduras, showing a case fatality rate decrease from 9.33% to 2.97%. No decrease was seen in Mexico, a similar Latin American c.. |
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Early treatment study
Early treatment study
|
Early multidrug treatment of SARS-CoV-2 (COVID-19) and decreased case fatality rates in Honduras |
Ontai et al., Epidemiology International Journal, doi:10.23880/eij-16000217 |
Report on the nationwide implementation of multi-drug COVID-19 inpatient and outpatient treatment protocols in Honduras, showing a case fatality rate decrease from 9.33% to 2.97%. No decrease was seen in Mexico, a similar Latin American country that did not introduce multi-drug treatment protocols at that time. Decreases in COVID-19 case fatality rates in Honduras were associated with both the initial publication of the protocol and a subsequent outreach program. Both inpatient and outpatient protocols include ivermectin as one component.
Ontai et al., 7/25/2021, peer-reviewed, 7 authors.
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|
|
News |
World Ivermectin Day (News) |
news |
World Ivermectin Day |
Details
Joint event by 22 worldwide organizations. |
|
Details
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News
News
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World Ivermectin Day |
World Ivermectin Day (News) |
Joint event by 22 worldwide organizations.
World Ivermectin Day et al., 7/24/2021, preprint, 1 author.
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|
|
Safety |
Mansour et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.108004 |
safety analysis |
Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study |
Details
Safety analysis of an inhaled lyophilized ivermectin formulation, showing 127-fold increase in drug solubility, and identifying safe dosage levels in rats. |
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Safety
Safety
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Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study |
Mansour et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.108004 |
Safety analysis of an inhaled lyophilized ivermectin formulation, showing 127-fold increase in drug solubility, and identifying safe dosage levels in rats.
Mansour et al., 7/23/2021, peer-reviewed, 7 authors.
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|
|
News |
FLCCC Alliance and British Ivermectin Recommendation Development Group (News) |
news |
Joint Statement of the FLCCC Alliance and British Ivermectin Recommendation Development Group on Retraction of Early Research on Ivermectin |
Details
News release noting that ivermectin remains effective after excluding Elgazzar et al. Given the large magnitude effects and 61 studies, excluding one study with ~3% of patients does not significantly change the evidence base. |
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Details
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PDF
News
News
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Joint Statement of the FLCCC Alliance and British Ivermectin Recommendation Development Group on Retraction of Early Research on Ivermectin |
FLCCC Alliance and British Ivermectin Recommendation Development Group (News) |
News release noting that ivermectin remains effective after excluding Elgazzar et al. Given the large magnitude effects and 61 studies, excluding one study with ~3% of patients does not significantly change the evidence base.
FLCCC et al., 7/16/2021, preprint, 2 authors.
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|
Meta |
Neil et al., ResearchGate, doi:0.13140/RG.2.2.31800.88323 (Preprint) (meta analysis) |
meta-analysis |
Bayesian Meta Analysis of Ivermectin Effectiveness in Treating Covid-19 Disease |
Details
Bayesian analysis of a subset of ivermectin trial data concluding that there is overwhelming evidence to support a causal link between ivermectin, COVID-19 severity, and mortality. |
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Details
Source
PDF
Meta
Meta
|
Bayesian Meta Analysis of Ivermectin Effectiveness in Treating Covid-19 Disease |
Neil et al., ResearchGate, doi:0.13140/RG.2.2.31800.88323 (Preprint) (meta analysis) |
Bayesian analysis of a subset of ivermectin trial data concluding that there is overwhelming evidence to support a causal link between ivermectin, COVID-19 severity, and mortality.
Neil et al., 7/12/2021, preprint, 2 authors.
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|
|
In Silico |
Muthusamy et al., Journal of Virology & Antiviral Research |
In Silico |
Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein |
Details
In Silico study identifying 32 anti-parisitic compounds effectively inhibiting the RBD of the SARS-CoV-2 spike protein, with ivermectin being one of the top compounds. |
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Details
Source
PDF
In Silico
In Silico
|
Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein |
Muthusamy et al., Journal of Virology & Antiviral Research |
In Silico study identifying 32 anti-parisitic compounds effectively inhibiting the RBD of the SARS-CoV-2 spike protein, with ivermectin being one of the top compounds.
Muthusamy et al., 7/8/2021, peer-reviewed, 5 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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|
News |
Together Trial (News) |
news |
Together Trial removes mortality and adverse event outcomes, and sublingual administration mid-trial |
Details
Together Trial removes mortality and adverse event outcomes, and sublingual administration mid-trial. |
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Details
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PDF
News
News
|
Together Trial removes mortality and adverse event outcomes, and sublingual administration mid-trial |
Together Trial (News) |
Together Trial removes mortality and adverse event outcomes, and sublingual administration mid-trial.
Together Trial et al., 7/8/2021, preprint, 1 author.
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|
|
Late |
Hazan et al., medRxiv, doi:10.1101/2021.07.06.21259924 (Preprint) |
death, ↓86.2%, p=0.04 |
Effectiveness of Ivermectin-Based Multidrug Therapy in Severe Hypoxic Ambulatory COVID-19 Patients |
Details
Small study of 24 consecutive patients in serious condition (9 days post symptoms, mean SpO2 87.4) using combined treatment with ivermectin, doxycycline, zinc, vitamin D, and vitamin C, showing no mortality or hospitalization with treatme.. |
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Details
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PDF
Late treatment study
Late treatment study
|
Effectiveness of Ivermectin-Based Multidrug Therapy in Severe Hypoxic Ambulatory COVID-19 Patients |
Hazan et al., medRxiv, doi:10.1101/2021.07.06.21259924 (Preprint) |
Small study of 24 consecutive patients in serious condition (9 days post symptoms, mean SpO2 87.4) using combined treatment with ivermectin, doxycycline, zinc, vitamin D, and vitamin C, showing no mortality or hospitalization with treatment. Two patients declined treatment and both died. This study uses a synthetic control arm.
risk of death, 86.2% lower, RR 0.14, p = 0.04, NNT 6.9, relative risk is not 0 because of continuity correction due to zero events.
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risk of hospitalization, 93.5% lower, RR 0.07, p = 0.001, NNT 3.3, relative risk is not 0 because of continuity correction due to zero events, primary outcome.
|
Excluded in after exclusion results of meta analysis:
study uses a synthetic control arm.
Hazan et al., 7/7/2021, retrospective, USA, North America, preprint, 7 authors, average treatment delay 9.2 days, dosage 12mg days 1, 4, 8, this trial uses multiple treatments in the treatment arm (combined with doxycycline, zinc, vitamin D, vitamin C) - results of individual treatments may vary.
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|
News |
Open Letter, Statement of Concern and Request for Retraction, re: Roman et al. (News) |
news |
Open Letter, Statement of Concern and Request for Retraction |
Details
Open letter signed by 40 physicians detailing errors and flaws in the Roman et al. meta analysis, and requesting retraction. |
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Details
Source
PDF
News
News
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Open Letter, Statement of Concern and Request for Retraction |
Open Letter, Statement of Concern and Request for Retraction, re: Roman et al. (News) |
Open letter signed by 40 physicians detailing errors and flaws in the Roman et al. meta analysis, and requesting retraction.
Open Letter et al., 7/3/2021, preprint, 40 authors.
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|
|
Review |
Adegboro et al., African Journal of Clinical and Experimental Microbiology, doi:10.4314/ajcem.v22i3.2 (Review) |
review |
A review of the anti-viral effects of ivermectin |
Details
Review of the antiviral effects of ivermectin. |
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Details
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PDF
Review
Review
|
A review of the anti-viral effects of ivermectin |
Adegboro et al., African Journal of Clinical and Experimental Microbiology, doi:10.4314/ajcem.v22i3.2 (Review) |
Review of the antiviral effects of ivermectin.
Adegboro et al., 7/2/2021, peer-reviewed, 4 authors.
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|
|
Early |
Vallejos et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06348-5 |
death, ↑33.5%, p=0.70 |
Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial |
Details
RCT with 501 relatively low-risk outpatients in Argentina showing hospitalization OR 0.65 [0.32-1.31]. With only 7% hospitalization, this trial is underpowered. The trial primarily includes low-risk patients that recover quickly without t.. |
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Details
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PDF
Early treatment study
Early treatment study
|
Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial |
Vallejos et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06348-5 |
RCT with 501 relatively low-risk outpatients in Argentina showing
hospitalization OR 0.65 [0.32-1.31].
With only 7% hospitalization, this trial is underpowered. The trial primarily
includes low-risk patients that recover quickly without treatment, leaving
minimal room for improvement with treatment. 74 patients had symptoms for >=
7 days and more than 25% of patients were hospitalized within 1 day
(Figure S2). Among the 7 patients requiring ventilation, authors note that
the earlier requirement in the ivermectin group may be due to those patients
having higher severity at baseline. However, authors know the answer to
this - it is unclear why it is not reported. There were more adverse events
in the placebo group than the ivermectin group, suggesting a possible issue
with dispensing or non-trial medication usage.
The companion prophylaxis trial [IVERCOR PREP], which
reported more positive results, has not yet been formally published,
suggesting a negative publication bias.
Authors pre-specify multivariate analysis but do not present
it, however multivariate analysis could significantly change the results.
Consider for example if just a few extra patients in the ivermectin group
were in severe condition based on baseline SpO2. The lower mean SpO2 in the
ivermectin group, and the shorter time to ventilation, are consistent with
this being the case. Additionally, there are 14% more male patients in the
ivermectin group.
An extremely large percentage of patients (55%) were excluded
based on ivermectin use in the last 7 days. However, ivermectin may retain
efficacy much longer (for example antiparasitic activity may persist for
months [Canga]). A significant number of patients may also
misrepresent their prior and future usage — the population is clearly
aware of ivermectin, and patients with progressing disease may be motivated
to take it, knowing that they may be in the control group. Another report
states that 12,000 patients were excluded for recent use of ivermectin [scidev.net]).
RCTs have a fundamental bias against finding an effect for
interventions that are widely available — patients that believe they
need treatment are more likely to decline participation and take the
intervention [Yeh], i.e., RCTs are more likely to enroll low-risk
participants that do not need treatment to recover (this does not apply to
the typical pharmaceutical trial of a new drug that is otherwise
unavailable). This trial was run in a community where ivermectin was very
widely known and used.
risk of death, 33.5% higher, RR 1.33, p = 0.70, treatment 4 of 250 (1.6%), control 3 of 251 (1.2%), OR converted to RR.
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risk of mechanical ventilation, 33.5% higher, RR 1.33, p = 0.70, treatment 4 of 250 (1.6%), control 3 of 251 (1.2%), OR converted to RR.
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risk of hospitalization, 33.0% lower, RR 0.67, p = 0.23, treatment 14 of 250 (5.6%), control 21 of 251 (8.4%), NNT 36, OR converted to RR, primary outcome.
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risk of no viral clearance, 5.0% higher, RR 1.05, p = 0.55, treatment 137 of 250 (54.8%), control 131 of 251 (52.2%), OR converted to RR, day 3.
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risk of no viral clearance, 26.8% higher, RR 1.27, p = 0.29, treatment 38 of 250 (15.2%), control 30 of 251 (12.0%), OR converted to RR, day 12.
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Vallejos et al., 7/2/2021, Double Blind Randomized Controlled Trial, Argentina, South America, peer-reviewed, 29 authors, average treatment delay 4.0 days, dosage 12mg days 1-2, <80kg 12mg, 80-110kg 18mg, >110kg 24mg.
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Review |
Turkia, M., ResearchGate, doi:10.13140/RG.2.2.16973.36326 (Review) (Preprint) |
review |
A Continuation of a Timeline of Ivermectin-Related Events in the COVID-19 Pandemic [June 30, 2021] |
Details
An extension of the ivermectin timeline covering April - June 2021, including WHO's role and funding, Gavi, COVAX, Trusted News Initiative, International Fact-Checking Network, the role of private philantrophy, Frontiers, comparison to th.. |
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Details
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PDF
Review
Review
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A Continuation of a Timeline of Ivermectin-Related Events in the COVID-19 Pandemic [June 30, 2021] |
Turkia, M., ResearchGate, doi:10.13140/RG.2.2.16973.36326 (Review) (Preprint) |
An extension of the ivermectin timeline covering April - June 2021, including WHO's role and funding, Gavi, COVAX, Trusted News Initiative, International Fact-Checking Network, the role of private philantrophy, Frontiers, comparison to the H1N1 pandemic, new treatment protocols, and causal modeling.
Turkia et al., 6/30/2021, preprint, 1 author.
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N/A |
Roman et al., Clinical Infectious Diseases, doi:10.1093/cid/ciab591 (preprint 5/25/21) (meta analysis) |
meta-analysis |
Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials |
Details
This is a severely flawed meta analysis. An open letter signed by 40 physicians detailing errors and flaws, and requesting retraction, can be found at [ trialsitenews.com ] . See also [ bird-group.org ] . Authors cherry-pick to include on.. |
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Details
Source
PDF
N/A
N/A
|
Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials |
Roman et al., Clinical Infectious Diseases, doi:10.1093/cid/ciab591 (preprint 5/25/21) (meta analysis) |
This is a severely flawed meta analysis. An open letter signed
by 40 physicians detailing errors and flaws, and requesting retraction, can
be found at [trialsitenews.com].
See also [bird-group.org].
Authors cherry-pick to include only 4 studies reporting
non-zero mortality and they initially claimed a mortality RR of 1.11
[0.16-7.65]. However, they reported incorrect values for Niaee et al.,
claiming an RR of 6.51 [2.18-19.45], when the correct RR for Niaee et al. is
0.18 [0.06-0.55]. After correction, their cherry-picked studies show >60%
mortality reduction, however authors did not correct the conclusion.
Similarly, for viral clearance and NCT04392713, they report
20/41 treatment, 18/45 control, whereas the correct day 7 clearance numbers
are 37/41 and 20/45 (sum of clearance @72hrs and @7 days), or 17/41 and
2/45 @72 hrs.
The duration of hospital stay for Niaee et al. is also
incorrectly reported, showing a lower duration for the control group.
All of the errors are in one direction - incorrectly reporting
lower than actual efficacy for ivermectin. Authors claim to include all RCTs
excluding prophylaxis, however they only include 10 of the 24 non-prophylaxis
RCTs (28 including prophylaxis at the time of publication). Authors actually
reference meta analyses that do include the missing RCTs, so they should be
aware of the missing RCTs.
The authors state that they have no conflicts of interest on
medRxiv, however Dr. Pasupuleti’s affiliation is Cello Health, whose website
[cellohealth.com] notes that they provide services such as
“brand and portfolio commercial strategy for biotech and pharma”, and
that their clients are "24 of the top 25 pharmaceutical
companies”.
Only one of these errors has been partially fixed as of 5/29 -
the Niaee RR was corrected, but the associated conclusion was not. Other
errors have not been corrected. Comments on this article appear to be
censored, with zero comments posted as of July 5.
Roman et al., 6/28/2021, peer-reviewed, 6 authors.
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|
Review |
Jagiasi et al., The International Journal of Clinical Practice, doi:10.1111/ijcp.14574 (Review) |
review |
Variation in therapeutic strategies for the management of severe COVID-19 in India- A nationwide cross-sectional survey |
Details
Survey of medication use for severe COVID-19 in India, showing 33% adoption of ivermectin as of January 2021. |
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Details
Source
PDF
Review
Review
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Variation in therapeutic strategies for the management of severe COVID-19 in India- A nationwide cross-sectional survey |
Jagiasi et al., The International Journal of Clinical Practice, doi:10.1111/ijcp.14574 (Review) |
Survey of medication use for severe COVID-19 in India, showing 33% adoption of ivermectin as of January 2021.
Jagiasi et al., 6/25/2021, peer-reviewed, 19 authors.
|
Submit Corrections or Comments
|
|
News |
Misiones Ministry of Public Health (News) |
news |
Results from ivermectin use from the Misiones Ministry of Public Health |
Details
News report on ivermectin use in Misiones, Argentina, showing significantly lower hospitalization and mortality, and a dose-dependent effect with improved results for those taking 0.6mg/kg. |
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Details
Source
PDF
News
News
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Results from ivermectin use from the Misiones Ministry of Public Health |
Misiones Ministry of Public Health (News) |
News report on ivermectin use in Misiones, Argentina, showing significantly lower hospitalization and mortality, and a dose-dependent effect with improved results for those taking 0.6mg/kg.
Misiones Ministry of Public Health et al., 6/22/2021, preprint, 1 author.
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Submit Corrections or Comments
|
|
Review |
Lind et al., Journal of General Internal Medicine, doi:10.1007/s11606-021-06948-6 (Review) |
review |
Increase in Outpatient Ivermectin Dispensing in the US During the COVID-19 Pandemic: A Cross-Sectional Analysis |
Details
CDC analysis of ivermectin prescriptions in the US suggesting that, while national health authority recognition is delayed in that country, many physicians are aware of the efficacy demonstrated in clinical trials. |
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Details
Source
PDF
Review
Review
|
Increase in Outpatient Ivermectin Dispensing in the US During the COVID-19 Pandemic: A Cross-Sectional Analysis |
Lind et al., Journal of General Internal Medicine, doi:10.1007/s11606-021-06948-6 (Review) |
CDC analysis of ivermectin prescriptions in the US suggesting that, while national health authority recognition is delayed in that country, many physicians are aware of the efficacy demonstrated in clinical trials.
Lind et al., 6/18/2021, peer-reviewed, 6 authors.
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|
|
Early |
Krolewiecki et al., EClinicalMedicine, doi:10.1016/j.eclinm.2021.100959 |
ventilation, ↑151.9%, p=1.00 |
Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial |
Details
Proof of concept RCT with 30 ivermectin patients and 15 control patients, showing a concentration dependent antiviral activity, but no significant difference in clinical outcomes. There was no significant difference in viral load reductio.. |
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Details
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PDF
Early treatment study
Early treatment study
|
Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial |
Krolewiecki et al., EClinicalMedicine, doi:10.1016/j.eclinm.2021.100959 |
Proof of concept RCT with 30 ivermectin patients and 15 control patients, showing a concentration dependent antiviral activity, but no significant difference in clinical outcomes. There was no significant difference in viral load reduction between groups overall, but a significant difference was found in patients with higher median plasma ivermectin levels (72% vs. 42%, p=0.004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r=0.47, p=0.02). The change in viral load is provided for the <160ng/mL and >160ng/mL groups, but not the overall treatment group. The corrigendum provides individual viral decay rates for computing the overall treatment group viral decay rate. NCT004381884. Authors published a corrigendum: [sciencedirect.com].
risk of mechanical ventilation, 151.9% higher, RR 2.52, p = 1.00, treatment 1 of 27 (3.7%), control 0 of 14 (0.0%), continuity correction due to zero event.
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risk of progression, 3.7% higher, RR 1.04, p = 1.00, treatment 2 of 27 (7.4%), control 1 of 14 (7.1%).
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viral decay rate, 65.6% lower, RR 0.34, p = 0.09, treatment 20, control 14, relative mean viral decay rate (corrigendum table 2), primary outcome.
|
Krolewiecki et al., 6/18/2021, Randomized Controlled Trial, Argentina, South America, peer-reviewed, 23 authors, average treatment delay 3.5 days, dosage 600μg/kg days 1-5, trial NCT004381884.
|
Submit Corrections or Comments
|
|
Meta |
Bryant et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001402 (preprint 3/11/21) (meta analysis) |
death, ↓62.0%, p=0.005 |
Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines |
Details
Systematic review, meta analysis, and trial sequential analysis of 24 RCTs finding mortality RR 0.38 [0.19-0.73]. An update notes potentially inaccurate data collection and/or reporting in some sources . |
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Details
Source
PDF
Meta
Meta
|
Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines |
Bryant et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001402 (preprint 3/11/21) (meta analysis) |
Systematic review, meta analysis, and trial sequential analysis of 24 RCTs finding mortality RR 0.38 [0.19-0.73].An update notes potentially inaccurate data collection and/or reporting in some sources [journals.lww.com].
risk of death, 62.0% lower, RR 0.38, p = 0.005.
|
Bryant et al., 6/17/2021, peer-reviewed, 7 authors.
|
Submit Corrections or Comments
|
|
Early |
Aref et al., International Journal of Nanomedicine, doi:10.2147/IJN.S313093 |
recov. time, ↓63.2%, p=0.0001 |
Clinical, Biochemical and Molecular Evaluations of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Reducing Upper Respiratory Symptoms of Mild COVID-19 |
Details
RCT 114 patients in Egypt, 57 treated with ivermectin mucoadhesive nanosuspension intranasal spray, showing faster recovery and viral clearance with treatment. NCT04716569. |
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Details
Source
PDF
Early treatment study
Early treatment study
|
Clinical, Biochemical and Molecular Evaluations of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Reducing Upper Respiratory Symptoms of Mild COVID-19 |
Aref et al., International Journal of Nanomedicine, doi:10.2147/IJN.S313093 |
RCT 114 patients in Egypt, 57 treated with ivermectin mucoadhesive nanosuspension intranasal spray, showing faster recovery and viral clearance with treatment. NCT04716569.
relative duration of fever, 63.2% lower, relative time 0.37, p < 0.001, treatment 57, control 57, primary outcome.
|
relative duration of dyspnea, 56.4% lower, relative time 0.44, p < 0.001, treatment 57, control 57.
|
relative duration of anosmia, 68.8% lower, relative time 0.31, p < 0.001, treatment 57, control 57.
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relative duration of cough, 64.3% lower, relative time 0.36, p < 0.001, treatment 57, control 57.
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risk of no viral clearance, 78.6% lower, RR 0.21, p = 0.004, treatment 3 of 57 (5.3%), control 14 of 57 (24.6%), NNT 5.2.
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time to viral-, 35.7% lower, relative time 0.64, p < 0.001, treatment 57, control 57.
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Aref et al., 6/15/2021, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 7 authors, dosage not specified, trial NCT04716569.
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Submit Corrections or Comments
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N/A |
Hariyanto et al., Reviews In Medical Virology, doi:10.1002/rmv.2265 (meta analysis) |
death, ↓69.0%, p=0.001 |
Ivermectin and outcomes from Covid-19 pneumonia: A systematic review and meta-analysis of randomized clinical trial studies |
Details
Systematic review and meta analysis of 19 RCTs showing mortality RR 0.31 [0.15-0.62]. |
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Details
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N/A
N/A
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Ivermectin and outcomes from Covid-19 pneumonia: A systematic review and meta-analysis of randomized clinical trial studies |
Hariyanto et al., Reviews In Medical Virology, doi:10.1002/rmv.2265 (meta analysis) |
Systematic review and meta analysis of 19 RCTs showing mortality RR 0.31 [0.15-0.62].
risk of death, 69.0% lower, RR 0.31, p = 0.001.
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Hariyanto et al., 6/6/2021, peer-reviewed, 5 authors.
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Submit Corrections or Comments
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Review |
Wang et al., medRxiv, doi:10.1101/2021.06.01.21258147 (Review) (Preprint) |
review |
Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19 |
Details
Analysis of the manufacturing cost of several COVID-19 medications, showing a cost of $0.55 per course of ivermectin, including excipients, formulation, tax, and profit. |
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Details
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Review
Review
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Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19 |
Wang et al., medRxiv, doi:10.1101/2021.06.01.21258147 (Review) (Preprint) |
Analysis of the manufacturing cost of several COVID-19 medications, showing a cost of $0.55 per course of ivermectin, including excipients, formulation, tax, and profit.
Wang et al., 6/3/2021, preprint, 4 authors.
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Submit Corrections or Comments
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Late |
Abd-Elsalam et al., Journal of Medical Virology, doi:10.1002/jmv.27122 |
death, ↓25.0%, p=0.70 |
Clinical Study Evaluating the Efficacy of Ivermectin in COVID-19 Treatment: A Randomized Controlled Study |
Details
RCT 164 hospitalized patients in Egypt showing lower mortality and shorter hospitalization, but without statistical significance. There were no serious adverse effects. Authors suggest the low dosage may have resulted in lower efficacy th.. |
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Details
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Late treatment study
Late treatment study
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Clinical Study Evaluating the Efficacy of Ivermectin in COVID-19 Treatment: A Randomized Controlled Study |
Abd-Elsalam et al., Journal of Medical Virology, doi:10.1002/jmv.27122 |
RCT 164 hospitalized patients in Egypt showing lower mortality and shorter hospitalization, but without statistical significance. There were no serious adverse effects. Authors suggest the low dosage may have resulted in lower efficacy than other trials, and recommend increased dosage in future trials. Time from symptom onset is not specified.
risk of death, 25.0% lower, RR 0.75, p = 0.70, treatment 3 of 82 (3.7%), control 4 of 82 (4.9%), NNT 82, OR converted to RR, logistic regression, primary outcome.
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risk of mechanical ventilation, no change, RR 1.00, p = 1.00, treatment 3 of 82 (3.7%), control 3 of 82 (3.7%).
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hospitalization time, 19.6% lower, relative time 0.80, p = 0.09, treatment 82, control 82.
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Abd-Elsalam et al., 6/2/2021, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 16 authors, dosage 12mg days 1-3.
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Submit Corrections or Comments
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PrEPPEP |
Mondal et al., Journal of the Indian Medical Association, 119:5 |
symp. case, ↓87.9%, p=0.006 |
Prevalence of COVID-19 Infection and Identification of Risk Factors among Asymptomatic Healthcare Workers: A Serosurvey Involving Multiple Hospitals in West Bengal |
Details
Retrospective 1,470 healthcare workers in India, showing significantly lower risk of symptomatic COVID-19 with ivermectin prophylaxis. |
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Details
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Prophylaxis study
Prophylaxis study
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Prevalence of COVID-19 Infection and Identification of Risk Factors among Asymptomatic Healthcare Workers: A Serosurvey Involving Multiple Hospitals in West Bengal |
Mondal et al., Journal of the Indian Medical Association, 119:5 |
Retrospective 1,470 healthcare workers in India, showing significantly lower risk of symptomatic COVID-19 with ivermectin prophylaxis.
risk of symptomatic case, 87.9% lower, RR 0.12, p = 0.006, treatment 128, control 1,342, adjusted, OR converted to RR, control prevalence approximated with overall prevalence, multivariable, primary outcome.
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Mondal et al., 5/31/2021, retrospective, India, South Asia, peer-reviewed, 11 authors, dosage not specified.
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Submit Corrections or Comments
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In Vitro |
Mountain Valley MD (Preprint) (In Vitro) |
In Vitro |
Mountain Valley MD Receives Successful Results From BSL-4 COVID-19 Clearance Trial on Three Variants Tested With Ivectosol™ |
Details
In Vitro and mouse study with human ACE2 cells, using solubilized ivermectin with Ivectosol™, showing antiviral effect with B.1.1.7, B.1.351, and P.1 variants of SARS-CoV-2. The ability to inject ivermectin potentially reduces the onset o.. |
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Details
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In Vitro
In Vitro
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Mountain Valley MD Receives Successful Results From BSL-4 COVID-19 Clearance Trial on Three Variants Tested With Ivectosol™ |
Mountain Valley MD (Preprint) (In Vitro) |
In Vitro and mouse study with human ACE2 cells, using solubilized ivermectin with Ivectosol™, showing antiviral effect with B.1.1.7, B.1.351, and P.1 variants of SARS-CoV-2.The ability to inject ivermectin potentially reduces the onset of action from ~6 hours to ~15 minutes, with much lower variability.
Mountain Valley MD et al., 5/18/2021, preprint, 1 author.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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News |
FLCCC Public Statement (News) |
news |
FLCCC Alliance Statement on the Irregular Actions of Public Health Agencies and the Widespread Disinformation Campaign Against Ivermectin |
Details
Analysis of the ivermectin recommendations from WHO and others, and a call to action for all citizens, scientists, and media to counter false information. Whistleblowers can submit anonymous reports and images at the bottom of this page. |
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Details
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News
News
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FLCCC Alliance Statement on the Irregular Actions of Public Health Agencies and the Widespread Disinformation Campaign Against Ivermectin |
FLCCC Public Statement (News) |
Analysis of the ivermectin recommendations from WHO and others, and a call to action for all citizens, scientists, and media to counter false information. Whistleblowers can submit anonymous reports and images at the bottom of this page.
FLCCC et al., 5/12/2021, preprint, 9 authors.
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Submit Corrections or Comments
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Early |
Faisal et al., The Professional Medical Journal, doi:10.29309/TPMJ/2021.28.05.5867 |
no recov., ↓68.4%, p=0.005 |
Potential use of azithromycin alone and in combination with ivermectin in fighting against the symptoms of COVID-19 |
Details
RCT 100 outpatients in Pakistan, 50 treated with ivermectin, showing faster recovery with ivermectin. All patients received AZ, zinc, vitamin C, vitamin D, and paracetemol. Details of randomization were not provided. No mortality or hospi.. |
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Details
Source
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Early treatment study
Early treatment study
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Potential use of azithromycin alone and in combination with ivermectin in fighting against the symptoms of COVID-19 |
Faisal et al., The Professional Medical Journal, doi:10.29309/TPMJ/2021.28.05.5867 |
RCT 100 outpatients in Pakistan, 50 treated with ivermectin, showing faster recovery with ivermectin. All patients received AZ, zinc, vitamin C, vitamin D, and paracetemol. Details of randomization were not provided. No mortality or hospitalization was reported.
risk of no recovery, 68.4% lower, RR 0.32, p = 0.005, treatment 6 of 50 (12.0%), control 19 of 50 (38.0%), NNT 3.8, 6-8 days, mid-recovery, primary outcome.
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risk of no recovery, 27.3% lower, RR 0.73, p = 0.11, treatment 24 of 50 (48.0%), control 33 of 50 (66.0%), NNT 5.6, 3-5 days.
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risk of no recovery, 75.0% lower, RR 0.25, p = 0.09, treatment 2 of 50 (4.0%), control 8 of 50 (16.0%), NNT 8.3, 9-10 days.
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Faisal et al., 5/10/2021, Randomized Controlled Trial, Pakistan, South Asia, peer-reviewed, 3 authors, dosage 12mg days 1-5.
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Submit Corrections or Comments
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In Vitro |
Zatloukal et al. (News) (In Vitro) |
news |
News report on In Vitro results from the research institute of Prof. Zatloukal |
Details
News report on In Vitro results from the research institute of Prof. Zatloukal, showing that "ivermectin was able to reduce virus replication by a factor of 1,000 even at low concentrations". |
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Details
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In Vitro
In Vitro
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News report on In Vitro results from the research institute of Prof. Zatloukal |
Zatloukal et al. (News) (In Vitro) |
News report on In Vitro results from the research institute of Prof. Zatloukal, showing that "ivermectin was able to reduce virus replication by a factor of 1,000 even at low concentrations".
Zatloukal et al., 5/5/2021, preprint, 1 author.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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In Silico |
Qureshi et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1906750 |
In Silico |
Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications |
Details
In Silico study showing inhibition of importin-α1 by ivermectin, which disrupts SARS-CoV-2 replication. |
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Details
Source
PDF
In Silico
In Silico
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Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications |
Qureshi et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1906750 |
In Silico study showing inhibition of importin-α1 by ivermectin, which disrupts SARS-CoV-2 replication.
Qureshi et al., 5/5/2021, peer-reviewed, 6 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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Meta |
Karale et al., medRxiv, doi:10.1101/2021.04.30.21256415 (Preprint) (meta analysis) |
meta-analysis |
A Meta-analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation and Adverse Effects with Ivermectin Use in COVID-19 Patients |
Details
Systematic review and meta analysis with 30 studies included in quantitative analysis, showing mortality OR 0.39 [0.22-0.70]. Subgroup analysis of trials with severity data showed mortality OR 0.10 [0.03-0.33] for mild/moderate cases. |
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Details
Source
PDF
Meta
Meta
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A Meta-analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation and Adverse Effects with Ivermectin Use in COVID-19 Patients |
Karale et al., medRxiv, doi:10.1101/2021.04.30.21256415 (Preprint) (meta analysis) |
Systematic review and meta analysis with 30 studies included in quantitative analysis, showing mortality OR 0.39 [0.22-0.70]. Subgroup analysis of trials with severity data showed mortality OR 0.10 [0.03-0.33] for mild/moderate cases.
Karale et al., 5/4/2021, preprint, 12 authors.
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Submit Corrections or Comments
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Early |
Merino et al., Preprint (Preprint) |
hosp., ↓74.4%, p<0.001 |
Ivermectin and the odds of hospitalization due to COVID-19: evidence from a quasi-experimental analysis based on a public intervention in Mexico City |
Details
Analysis of Mexico City's use of an ivermectin-based medical kit, showing significantly lower hospitalization with use. Authors use logistic-regression models with matched observations, including adjustments for age, sex, COVID severity, .. |
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Details
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Early treatment study
Early treatment study
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Ivermectin and the odds of hospitalization due to COVID-19: evidence from a quasi-experimental analysis based on a public intervention in Mexico City |
Merino et al., Preprint (Preprint) |
Analysis of Mexico City's use of an ivermectin-based medical kit, showing significantly lower hospitalization with use. Authors use logistic-regression models with matched observations, including adjustments for age, sex, COVID severity, and comorbidities.This preprint was censored by the original preprint host. Censors claim that the government treatment program, which used approved medications and saved over 500 people from hospitalization, was unethical. In part they also indicate that studies of "the effects of a medication on a disease outcome" are outside the scope of their site, however retroactively censoring a paper for this reason is not appropriate.The author's response (not provided by the censors) can be found here: [].Author's provide the data and code for the study, and the results have been independently verified.
risk of hospitalization, 74.4% lower, RR 0.26, p < 0.001, model 7, same time period, patients receiving kit.
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risk of hospitalization, 68.4% lower, RR 0.32, p < 0.001, model 1, different time periods, administrative rule.
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Merino et al., 5/3/2021, retrospective quasi-randomized (patients receiving kit), population-based cohort, Mexico, North America, preprint, 7 authors, dosage 6mg bid days 1-2.
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Submit Corrections or Comments
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Review |
Kory et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001377 (Review) |
review |
Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 |
Details
Review of ivermectin trials and epidemiological data, concluding that ivermectin is effective for prophylaxis and treatment, and should be globally and systematically deployed in the prevention and treatment of COVID-19. An update notes p.. |
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Details
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Review
Review
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Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 |
Kory et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001377 (Review) |
Review of ivermectin trials and epidemiological data, concluding that ivermectin is effective for prophylaxis and treatment, and should be globally and systematically deployed in the prevention and treatment of COVID-19.An update notes potentially inaccurate data collection and/or reporting in some sources [journals.lww.com].
Kory et al., 4/30/2021, peer-reviewed, 5 authors.
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Submit Corrections or Comments
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Late |
Ahsan et al., Cureus, doi:10.7759/cureus.14761 |
death, ↓50.0%, p=0.03 |
Clinical Variants, Characteristics, and Outcomes Among COVID-19 Patients: A Case Series Analysis at a Tertiary Care Hospital in Karachi, Pakistan |
Details
Retrospective 165 hospitalized patients in Pakistan showing unadjusted lower mortality with combined ivermectin and doxycycline treatment. Details of the ivermectin group compared to other patients are not provided, however ivermectin was.. |
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Details
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Late treatment study
Late treatment study
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Clinical Variants, Characteristics, and Outcomes Among COVID-19 Patients: A Case Series Analysis at a Tertiary Care Hospital in Karachi, Pakistan |
Ahsan et al., Cureus, doi:10.7759/cureus.14761 |
Retrospective 165 hospitalized patients in Pakistan showing unadjusted lower mortality with combined ivermectin and doxycycline treatment. Details of the ivermectin group compared to other patients are not provided, however ivermectin was given to a similar percentage of patients in the mild, moderate, and severe/critical groups (34.5%, 29.1%, and 36.4%), suggesting that ivermectin treatment was not based on severity.
risk of death, 50.0% lower, RR 0.50, p = 0.03, treatment 17 of 110 (15.5%), control 17 of 55 (30.9%), NNT 6.5.
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Excluded in after exclusion results of meta analysis:
unadjusted results with no group details.
Ahsan et al., 4/29/2021, retrospective, Pakistan, South Asia, peer-reviewed, 10 authors, dosage 150μg/kg days 1-2, 150-200µg/kg, this trial uses multiple treatments in the treatment arm (combined with doxycycline) - results of individual treatments may vary.
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Submit Corrections or Comments
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Review |
DiNicolantonio et al., Open Heart, doi:10.1136/openhrt-2021-001655 (Review) |
review |
Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors |
Details
Review suggesting that the effectiveness of ivermectin in the cytokine storm phase of COVID-19 may be, at least in part, an anti-inflammatory effect mediated by increased activation of glycine receptors on leukocytes and possibly vascular.. |
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Details
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Review
Review
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Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors |
DiNicolantonio et al., Open Heart, doi:10.1136/openhrt-2021-001655 (Review) |
Review suggesting that the effectiveness of ivermectin in the cytokine storm phase of COVID-19 may be, at least in part, an anti-inflammatory effect mediated by increased activation of glycine receptors on leukocytes and possibly vascular endothelium.
DiNicolantonio et al., 4/19/2021, peer-reviewed, 3 authors.
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Submit Corrections or Comments
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Early |
Loue et al., J. Infectious Diseases and Epidemiology, doi:10.23937/2474-3658/1510202 |
death, ↓70.0%, p=0.34 |
Ivermectin and COVID-19 in Care Home: Case Report |
Details
Small quasi-randomized (patient choice) study with 25 PCR+ patients in a nursing home offered ivermectin, of which 10 chose to be treated. The mean age was 83.5 in the treatment group and 81.8 in the control group. There was lower mortali.. |
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Details
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Early treatment study
Early treatment study
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Ivermectin and COVID-19 in Care Home: Case Report |
Loue et al., J. Infectious Diseases and Epidemiology, doi:10.23937/2474-3658/1510202 |
Small quasi-randomized (patient choice) study with 25 PCR+ patients in a nursing home offered ivermectin, of which 10 chose to be treated. The mean age was 83.5 in the treatment group and 81.8 in the control group. There was lower mortality and fewer serious cases with treatment.
risk of death, 70.0% lower, RR 0.30, p = 0.34, treatment 1 of 10 (10.0%), control 5 of 15 (33.3%), NNT 4.3.
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risk of severe case, 55.0% lower, RR 0.45, p = 0.11, treatment 3 of 10 (30.0%), control 10 of 15 (66.7%), NNT 2.7.
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Loue et al., 4/17/2021, retrospective quasi-randomized (patient choice), France, Europe, peer-reviewed, 2 authors, dosage 200μg/kg single dose.
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Submit Corrections or Comments
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PrEPPEP |
Morgenstern et al., Cureus, doi:10.7759/cureus.17455 (preprint 4/16/2021) |
hosp., ↓80.0%, p=0.50 |
Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study |
Details
Propensity matched retrospective prophylaxis study of healthcare workers in the Dominican Republic showing significantly lower cases with treatment, and no hospitalization with treatment (versus 2 in the PSM matched control group). The ca.. |
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Details
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Prophylaxis study
Prophylaxis study
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Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study |
Morgenstern et al., Cureus, doi:10.7759/cureus.17455 (preprint 4/16/2021) |
Propensity matched retrospective prophylaxis study of healthcare workers in the Dominican Republic showing significantly lower cases with treatment, and no hospitalization with treatment (versus 2 in the PSM matched control group). The cases with treatment were mostly in the first week, with only one case in the second and third weeks, and none in the fourth week. There were no severe side effects. In post-hoc analysis, as the treatment group discontinued treatment over time, their protection also decreased. NCT04832945.
risk of hospitalization, 80.0% lower, RR 0.20, p = 0.50, treatment 0 of 271 (0.0%), control 2 of 271 (0.7%), NNT 136, relative risk is not 0 because of continuity correction due to zero events, PSM.
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risk of case, 74.0% lower, RR 0.26, p = 0.008, treatment 5 of 271 (1.8%), control 18 of 271 (6.6%), NNT 21, adjusted, PSM, multivariate Cox regression, primary outcome.
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Morgenstern et al., 4/16/2021, retrospective, propensity score matching, Dominican Republic, Caribbean, peer-reviewed, 16 authors, dosage 200μg/kg weekly, trial NCT04832945.
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Submit Corrections or Comments
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In Silico |
Schöning et al., Research Square, doi:10.21203/rs.3.rs-379291/v1 (Preprint) |
In Silico |
Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains |
Details
In Silico study of ivermectin treatment predicting greater efficacy for variants with higher R0. |
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Details
Source
PDF
In Silico
In Silico
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Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains |
Schöning et al., Research Square, doi:10.21203/rs.3.rs-379291/v1 (Preprint) |
In Silico study of ivermectin treatment predicting greater efficacy for variants with higher R0.
Schöning et al., 4/15/2021, preprint, 4 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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PrEPPEP |
Seet et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035 |
symp. case, ↓49.8%, p=0.0009 |
Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial |
Details
Prophylaxis RCT in Singapore with 3,037 low risk patients, showing lower serious cases, lower symptomatic cases, and lower confirmed cases of COVID-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin .. |
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Details
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Prophylaxis study
Prophylaxis study
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Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial |
Seet et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035 |
Prophylaxis RCT in Singapore with 3,037 low risk patients, showing lower serious cases, lower symptomatic cases, and lower confirmed cases of COVID-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin C.The ivermectin dosage was low for 42 days prophylaxis - only a single dose of 200µg/kg, with a maximum of 12mg.Meta-analysis of vitamin C in 6 previous trials shows a benefit of 16%, so the actual benefit of ivermectin, HCQ, and PVP-I may be higher. Cluster RCT with 40 clusters.There were no hospitalizations and no deaths. NCT04446104.
risk of symptomatic case, 49.8% lower, RR 0.50, p < 0.001, treatment 32 of 617 (5.2%), control 64 of 619 (10.3%), NNT 19.
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risk of case, 5.8% lower, RR 0.94, p = 0.61, treatment 398 of 617 (64.5%), control 433 of 619 (70.0%), NNT 18, adjusted, OR converted to RR, model 6, primary outcome.
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Seet et al., 4/14/2021, Cluster Randomized Controlled Trial, Singapore, Asia, peer-reviewed, 15 authors, dosage 12mg single dose, 200µg/kg, maximum 12mg, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04446104.
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Submit Corrections or Comments
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In Silico |
Bello et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857 |
In Silico |
Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets |
Details
In Silico analysis finding that the in vitro activity of ivermectin may explained by acting as an inhibitor of importin-α, dimeric 3CLpro, and Nsp9. |
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Details
Source
PDF
In Silico
In Silico
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Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets |
Bello et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857 |
In Silico analysis finding that the in vitro activity of ivermectin may explained by acting as an inhibitor of importin-α, dimeric 3CLpro, and Nsp9.
Bello et al., 4/10/2021, peer-reviewed, 1 author.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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|
Review |
Turkia, M., Research Gate (Review) (Preprint) |
review |
A timeline of ivermectin-related events in the COVID-19 pandemic |
Details
An extensive timeline of ivermectin-related events from April 2020 to March 2021 including studies, news, health authority decisions, biased news coverage, and censorship. The author concludes that in a broader historical perspective, the.. |
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Details
Source
PDF
Review
Review
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A timeline of ivermectin-related events in the COVID-19 pandemic |
Turkia, M., Research Gate (Review) (Preprint) |
An extensive timeline of ivermectin-related events from April 2020 to March 2021 including studies, news, health authority decisions, biased news coverage, and censorship.The author concludes that in a broader historical perspective, the timeline depicts rather dysfunctional societies unable to properly communicate and organize themselves, leading to misallocation of resources and decisions that may have conflicted with elementary ethical considerations, with this behavior rationalized by claiming adherence to mental paradigms that may have poorly matched the situation.
Turkia et al., 4/3/2021, preprint, 1 author.
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Submit Corrections or Comments
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Early |
Mourya et al., Int. J. Health and Clinical Research |
viral+, ↓89.4%, p<0.0001 |
Comparative Analytical Study of Two Different Drug Regimens in Treatment of Covid 19 Positive Patients in Index Medical College Hospital and Research Center, Indore, India |
Details
Retrospective 100 patients in India with 50 treated with ivermectin, and SOC for all patients including HCQ+AZ, showing much higher viral clearance with ivermectin. Baseline clinical status was worse in the control group. Time of testing .. |
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Details
Source
PDF
Early treatment study
Early treatment study
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Comparative Analytical Study of Two Different Drug Regimens in Treatment of Covid 19 Positive Patients in Index Medical College Hospital and Research Center, Indore, India |
Mourya et al., Int. J. Health and Clinical Research |
Retrospective 100 patients in India with 50 treated with ivermectin, and SOC for all patients including HCQ+AZ, showing much higher viral clearance with ivermectin. Baseline clinical status was worse in the control group. Time of testing after treatment initiation was longer in the control group (mean 7.24 days versus 5.22 days).
risk of no viral clearance, 89.4% lower, RR 0.11, p < 0.001, treatment 5 of 50 (10.0%), control 47 of 50 (94.0%), NNT 1.2, primary outcome.
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Mourya et al., 4/1/2021, retrospective, India, South Asia, peer-reviewed, 5 authors, dosage 12mg days 1-7.
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Submit Corrections or Comments
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Review |
Wehbe et al., Front. Immunol., doi:10.3389/fimmu.2021.663586 (Review) |
review |
Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities |
Details
Review of how ivermectin was identified for use in COVID-19, mechanisms of action, and selected clinical trials. |
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Details
Source
PDF
Review
Review
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Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities |
Wehbe et al., Front. Immunol., doi:10.3389/fimmu.2021.663586 (Review) |
Review of how ivermectin was identified for use in COVID-19, mechanisms of action, and selected clinical trials.
Wehbe et al., 3/30/2021, peer-reviewed, 7 authors.
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Submit Corrections or Comments
|
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Early |
Chahla et al., Research Square, doi:10.21203/rs.3.rs-495945/v1 (original preprint 3/30) (Preprint) |
no disch., ↓86.9%, p=0.004 |
Cluster Randomised Trials - Ivermectin Repurposing For COVID-19 Treatment Of Outpatients With Mild Disease In Primary Health Care Centers |
Details
Cluster RCT outpatients in Argentina showing significantly faster recovery with ivermectin. There were no deaths. Cluster RCT where outpatients in Tucumán were assigned to the ivermectin group and outpatients from San Miguel de Tucumán an.. |
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Early treatment study
Early treatment study
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Cluster Randomised Trials - Ivermectin Repurposing For COVID-19 Treatment Of Outpatients With Mild Disease In Primary Health Care Centers |
Chahla et al., Research Square, doi:10.21203/rs.3.rs-495945/v1 (original preprint 3/30) (Preprint) |
Cluster RCT outpatients in Argentina showing significantly faster recovery with ivermectin. There were no deaths. Cluster RCT where outpatients in Tucumán were assigned to the ivermectin group and outpatients from San Miguel de Tucumán and Gran San Miguel de Tucumán were assigned to the control group. All comorbidities, percentage of male patients, and age were higher in the ivermectin group, favoring the control group. NCT04784481.
risk of no discharge, 86.9% lower, RR 0.13, p = 0.004, treatment 2 of 110 (1.8%), control 20 of 144 (13.9%), NNT 8.3, adjusted, OR converted to RR, logistic regression, primary outcome.
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Chahla et al., 3/30/2021, Cluster Randomized Controlled Trial, Argentina, South America, preprint, 9 authors, dosage 24mg days 1, 8, 15, 22, trial NCT04784481.
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Meta |
Kow et al., Pharmacological Reports, doi:10.1007/s43440-021-00245-z (meta analysis) |
meta-analysis |
The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis |
Details
Small meta analysis of 6 RCTs showing mortality OR 0.21 [0.11-0.42]. Authors do not include two more recent RCTs with mortality results, 10 other studies with mortality results, and a total of 42 other studies including other outcomes. Au.. |
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Meta
Meta
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The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis |
Kow et al., Pharmacological Reports, doi:10.1007/s43440-021-00245-z (meta analysis) |
Small meta analysis of 6 RCTs showing mortality OR 0.21 [0.11-0.42]. Authors do not include two more recent RCTs with mortality results, 10 other studies with mortality results, and a total of 42 other studies including other outcomes. Authors do not distinguish between studies with very different treatment delays (earlier treatment is more successful).
Kow et al., 3/29/2021, peer-reviewed, 4 authors.
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PrEPPEP |
Tanioka et al., medRxiv, doi:10.1101/2021.03.26.21254377 (Preprint) |
death, ↓88.2%, p=0.002 |
Why COVID-19 is not so spread in Africa: How does Ivermectin affect it? |
Details
Retrospective study of the 31 onchocerciasis-endemic countries using the community-directed treatment with ivermectin (CDTI) and the 22 non-endemic countries in Africa, showing significantly lower mortality per capita in the countries us.. |
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Prophylaxis study
Prophylaxis study
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Why COVID-19 is not so spread in Africa: How does Ivermectin affect it? |
Tanioka et al., medRxiv, doi:10.1101/2021.03.26.21254377 (Preprint) |
Retrospective study of the 31 onchocerciasis-endemic countries using the community-directed treatment with ivermectin (CDTI) and the 22 non-endemic countries in Africa, showing significantly lower mortality per capita in the countries using ivermectin.
risk of death, 88.2% lower, RR 0.12, p = 0.002, relative mean mortality per million.
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Excluded in after exclusion results of meta analysis:
not a typical trial, analysis of African countries that used or did not use ivermectin prophylaxis for parasitic infections.
Tanioka et al., 3/26/2021, retrospective, ecological study, multiple countries, multiple regions, preprint, 3 authors, dosage 200μg/kg, dose varied, typically 150-200μg/kg.
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In Silico |
Udofia et al., Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2 |
In Silico |
In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV |
Details
In Silico analysis finding that ivermectin had the highest binding energy against the 3CLpro of SARS-CoV-2 and RdRps of both SARS-CoV and SARS-CoV-2. |
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In Silico
In Silico
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In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV |
Udofia et al., Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2 |
In Silico analysis finding that ivermectin had the highest binding energy against the 3CLpro of SARS-CoV-2 and RdRps of both SARS-CoV and SARS-CoV-2.
Udofia et al., 3/25/2021, peer-reviewed, 5 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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In Silico |
Choudhury et al., Future Medicine, doi:10.2217/fvl-2020-0342 |
In Silico |
Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach |
Details
In Silico analysis finding that ivermectin has high binding affinity for the SARS-CoV-2 viral spike protein, main protease, replicase, and human TMPRSS2 receptors. |
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In Silico
In Silico
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Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach |
Choudhury et al., Future Medicine, doi:10.2217/fvl-2020-0342 |
In Silico analysis finding that ivermectin has high binding affinity for the SARS-CoV-2 viral spike protein, main protease, replicase, and human TMPRSS2 receptors.
Choudhury et al., 3/25/2021, peer-reviewed, 7 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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Late |
Huvemek Press Release (Preprint) |
no improv., ↓31.6%, p=0.28 |
Kovid-19 - Huvemek® Phase 2 clinical trial |
Details
Phase 2 results from a multicenter RCT of hospitalized patients in Bulgaria showing faster viral clearance, greater clinical improvement, and improved biomarkers with treatment. Ivermectin was taken on an empty stomach, potentially reduci.. |
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Late treatment study
Late treatment study
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Kovid-19 - Huvemek® Phase 2 clinical trial |
Huvemek Press Release (Preprint) |
Phase 2 results from a multicenter RCT of hospitalized patients in Bulgaria showing faster viral clearance, greater clinical improvement, and improved biomarkers with treatment. Ivermectin was taken on an empty stomach, potentially reducing lung tissue concentration by ~2.5x []. Limited data has been reported currently. No serious adverse events were observed. EudraCT 2020-002091-12.
risk of no improvement, 31.6% lower, RR 0.68, p = 0.28, treatment 13 of 50 (26.0%), control 19 of 50 (38.0%), NNT 8.3, day 7, patients with improvement on WHO scale.
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risk of no improvement, 34.5% lower, RR 0.66, p = 0.07, treatment 19 of 50 (38.0%), control 29 of 50 (58.0%), NNT 5.0, day 4, patients with improvement on WHO scale.
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Huvemek et al., 3/25/2021, Double Blind Randomized Controlled Trial, Bulgaria, Europe, preprint, 1 author, average treatment delay 7.0 days, dosage 400μg/kg days 1-3.
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Review |
Yagisawa et al., The Japanese Journal of Antibiotics, 74-1, Mar 2021 (Review) |
review |
Global trends in clinical studies of ivermectin in COVID-19 |
Details
Review of ivermectin for COVID-19. Authors note that Kitasato University's project was expanded in response to the results of Caly et al. which had left questions regarding in vivo therapeutic levels, and the results of those studies were.. |
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Review
Review
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Global trends in clinical studies of ivermectin in COVID-19 |
Yagisawa et al., The Japanese Journal of Antibiotics, 74-1, Mar 2021 (Review) |
Review of ivermectin for COVID-19. Authors note that Kitasato University's project was expanded in response to the results of Caly et al. which had left questions regarding in vivo therapeutic levels, and the results of those studies were positive. Early in the pandemic, Kitasato University requested Merck to conduct clinical trials in Japan because they have priority for an expansion of ivermectin's indications, however Merck declined.Since large companies have declined to study ivermectin for COVID-19, trials have been mostly doctor-initiated with relatively little funding. Authors discuss these, noting that the physicians involved are enthusiastic about avoiding bias, and strive to treat and prevent COVID-19 witn non-profit motives.Authors discuss the trials, epidemiological data, and inaccurate statements made by certain authorities.Authors note that regulations make it challenging for doctor-initiated trials to enroll many participants in a timely manner.Authors conclude that ivermectin may turn out to be comparable to the benefits achieved from the discovery of penicillin - said to be one of the greatest discoveries of the twentieth century.Authors include the nobel prize winning biochemist who discovered ivermectin, Satoshi Ōmura [en.wikipedia.org].
Yagisawa et al., 3/24/2021, peer-reviewed, 4 authors.
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Early |
Emmerich et al., Int. J. Environ. Res. Public Health, doi:10.3390/ijerph18073371 (Preprint) |
Comparisons between the Neighboring States of Amazonas and Pará in Brazil in the Second Wave of COVID-19 Outbreak and a Possible Role of Early Ambulatory Treatment |
Details
Comparison between the two largest neighboring states in Brazil, Amazonas and Pará, showing more than 5 times lower mortality in Pará during the second wave when the Pará government supported early treatment and Amazonas did not, compared.. |
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Early treatment study
Early treatment study
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Comparisons between the Neighboring States of Amazonas and Pará in Brazil in the Second Wave of COVID-19 Outbreak and a Possible Role of Early Ambulatory Treatment |
Emmerich et al., Int. J. Environ. Res. Public Health, doi:10.3390/ijerph18073371 (Preprint) |
Comparison between the two largest neighboring states in Brazil, Amazonas and Pará, showing more than 5 times lower mortality in Pará during the second wave when the Pará government supported early treatment and Amazonas did not, compared to similar results in the first wave when treatment protocols were similar.
Emmerich et al., 3/21/2021, preprint, 1 author.
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Submit Corrections or Comments
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Late |
Del Franco et al., Journal of Biomedical Research and Clinical Investigation, doi:10.31546/2633-8653.1008 |
Ivermectin in Long-Covid Patients: A Retrospective Study |
Details
Retrospective 856 patients previously admitted to hospital for COVID-19 in Argentina, finding that ivermectin improved recovery from "long covid" symptoms. |
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Late treatment study
Late treatment study
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Ivermectin in Long-Covid Patients: A Retrospective Study |
Del Franco et al., Journal of Biomedical Research and Clinical Investigation, doi:10.31546/2633-8653.1008 |
Retrospective 856 patients previously admitted to hospital for COVID-19 in Argentina, finding that ivermectin improved recovery from "long covid" symptoms.
Del Franco et al., 3/18/2021, peer-reviewed, 3 authors.
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Submit Corrections or Comments
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In Vitro |
Dinesh Kumar et al., Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.01543-21 (preprint 3/17/2021) (In Vitro) |
In Vitro |
Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells |
Details
In Vitro study showing moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Authors indicate that no statistically significant effect was seen in Calu-3/PBEC cells, however Figure 3 shows a dose dependent reduction wit.. |
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In Vitro
In Vitro
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Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells |
Dinesh Kumar et al., Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.01543-21 (preprint 3/17/2021) (In Vitro) |
In Vitro study showing moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Authors indicate that no statistically significant effect was seen in Calu-3/PBEC cells, however Figure 3 shows a dose dependent reduction with ivermectin and moxidectin, and the actual values are not provided. Calu-3 is one of many cell lines derived from human lung carcinomas [journals.physiology.org]. Calu-3 cells resemble serous gland cells. They do not express 15-lipoxygenase, an enzyme specifically localized to the surface epithelium, but they do express secretory component, secretory leukocyte protease inhibitor, lysozyme, and lactoferrin, all markers of serous gland cells. [journals.physiology.org] note that the absence of systemic inflammation, circulatory factors, and other paracrine systemic influences is a potential limitation of the isolated cell system.
Dinesh Kumar et al., 3/17/2021, peer-reviewed, 14 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Early |
Roy et al., medRxiv, doi:10.1101/2021.03.08.21252883 (Preprint) |
recov. time, ↓5.6%, p=0.87 |
Outcome of Different Therapeutic Interventions in Mild COVID-19 Patients in a Single OPD Clinic of West Bengal: A Retrospective study |
Details
Retrospective database analysis of 56 mild COVID-19 patients, all treated with vitamin C, vitamin D, and zinc, comparing ivermectin + doxycycline (n=14), AZ (n=13), HCQ (n=14), and SOC (n=15), finding that all groups recover quickly, and .. |
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Early treatment study
Early treatment study
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Outcome of Different Therapeutic Interventions in Mild COVID-19 Patients in a Single OPD Clinic of West Bengal: A Retrospective study |
Roy et al., medRxiv, doi:10.1101/2021.03.08.21252883 (Preprint) |
Retrospective database analysis of 56 mild COVID-19 patients, all treated with vitamin C, vitamin D, and zinc, comparing ivermectin + doxycycline (n=14), AZ (n=13), HCQ (n=14), and SOC (n=15), finding that all groups recover quickly, and there was no significant difference between the groups. Subject to the usual limitation of a database study, very small size, and limited evaluation of patients.
relative time to clinical response of wellbeing, 5.6% lower, relative time 0.94, p = 0.87, treatment 14, control 15, primary outcome.
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Excluded in after exclusion results of meta analysis:
no serious outcomes reported and fast recovery in treatment and control groups, there is little room for a treatment to improve results.
Roy et al., 3/12/2021, retrospective, database analysis, India, South Asia, preprint, 5 authors, dosage not specified, this trial uses multiple treatments in the treatment arm (combined with doxycycline) - results of individual treatments may vary.
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Submit Corrections or Comments
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Meta |
Nardelli et al., Signa Vitae, doi:10.22514/sv.2021.043 (meta analysis) |
death, ↓79.5%, p<0.0001 |
Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use? |
Details
Meta analysis of RCT mortality results showing RR 0.19, p < 0.00001. |
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Meta
Meta
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Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use? |
Nardelli et al., Signa Vitae, doi:10.22514/sv.2021.043 (meta analysis) |
Meta analysis of RCT mortality results showing RR 0.19, p < 0.00001.
risk of death, 79.5% lower, RR 0.21, p < 0.001, treatment 14 of 703 (2.0%), control 57 of 620 (9.2%), NNT 14, OR converted to RR.
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Nardelli et al., 3/11/2021, peer-reviewed, 8 authors.
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Submit Corrections or Comments
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Meta |
Scheim et al., OSF Preprints (Preprint) (meta analysis) |
meta-analysis |
Ivermectin sales in Valle del Cauca, Colombia, patterns of AEs, and other background re López-Medina et al. 2021 |
Details
Analysis of several issues with López-Medina et al. including the atypical adverse effects in the control arm and population use of ivermectin. |
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Meta
Meta
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Ivermectin sales in Valle del Cauca, Colombia, patterns of AEs, and other background re López-Medina et al. 2021 |
Scheim et al., OSF Preprints (Preprint) (meta analysis) |
Analysis of several issues with López-Medina et al. including the atypical adverse effects in the control arm and population use of ivermectin.
Scheim et al., 3/11/2021, preprint, 1 author.
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Submit Corrections or Comments
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Meta |
Scheim et al., OSF Preprints (Preprint) (meta analysis) |
meta-analysis |
Protocol violations in López-Medina et al.: 38 switched ivermectin (IVM) and placebo doses, failure of blinding, widespread IVM sales OTC in Cali, and nearly identical AEs for the IVM and control groups |
Details
Report on protocol violations in López-Medina et al. |
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Details
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Meta
Meta
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Protocol violations in López-Medina et al.: 38 switched ivermectin (IVM) and placebo doses, failure of blinding, widespread IVM sales OTC in Cali, and nearly identical AEs for the IVM and control groups |
Scheim et al., OSF Preprints (Preprint) (meta analysis) |
Report on protocol violations in López-Medina et al.
Scheim et al., 3/11/2021, preprint, 3 authors.
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Submit Corrections or Comments
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In Silico |
Kern et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678 |
In Silico |
Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing |
Details
Modeling study analyzing timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. The greatest benefits were seen when treatments were given immediately at the time of diagnosis. Au.. |
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Details
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In Silico
In Silico
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Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing |
Kern et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678 |
Modeling study analyzing timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. The greatest benefits were seen when treatments were given immediately at the time of diagnosis. Authors state that "For IVM, no results of clinical trials regarding its effectiveness in COVID-19 have been published yet", which is inaccurate - there were 19 peer-reviewed trials published as of Mar 10, 2021 (43 including preprints).
Kern et al., 3/10/2021, peer-reviewed, 4 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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In Vitro |
Yesilbag et al., Virus Research, doi:10.1016/j.virusres.2021.198384 (In Vitro) |
In Vitro |
Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro |
Details
In Vitro study showing that ivermectin can inhibit infection of bovine respiratory disease viral agents BCoV, BPIV-3, BVDV, BRSV and BoHV-1 at the concentrations of 2.5 and 5 μM and in a dose-dependent manner. |
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Details
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In Vitro
In Vitro
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Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro |
Yesilbag et al., Virus Research, doi:10.1016/j.virusres.2021.198384 (In Vitro) |
In Vitro study showing that ivermectin can inhibit infection of bovine respiratory disease viral agents BCoV, BPIV-3, BVDV, BRSV and BoHV-1 at the concentrations of 2.5 and 5 μM and in a dose-dependent manner.
Yesilbag et al., 3/10/2021, peer-reviewed, 3 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Submit Corrections or Comments
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Late |
Pott-Junior et al., Toxicology Reports, doi:10.1016/j.toxrep.2021.03.003 |
ventilation, ↓85.2%, p=0.25 |
Use of ivermectin in the treatment of Covid-19: a pilot trial |
Details
Very small RCT with 4 control patients and 28 ivermectin patients split across 3 different dosage levels, showing lower (non-statistically significant) ICU admission with treatment. Authors suggest that ivermectin for SARS-CoV-2 is safe a.. |
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Late treatment study
Late treatment study
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Use of ivermectin in the treatment of Covid-19: a pilot trial |
Pott-Junior et al., Toxicology Reports, doi:10.1016/j.toxrep.2021.03.003 |
Very small RCT with 4 control patients and 28 ivermectin patients split across 3 different dosage levels, showing lower (non-statistically significant) ICU admission with treatment. Authors suggest that ivermectin for SARS-CoV-2 is safe and reduces symptoms and viral load, and that the antiviral effect appears to be dose-dependent. NCT04431466.Retraction/censorship: this paper appears to have been censored at the request of the journal's founding editor [pubmed.ncbi.nlm.nih.gov]. An external review is mentioned but is not provided, and there is no reply from the authors, or indication that the authors were notified. Conclusions in this study are limited due to the small size, however we should consider all information in the context of the full body of research.
risk of mechanical ventilation, 85.2% lower, RR 0.15, p = 0.25, treatment 1 of 27 (3.7%), control 1 of 4 (25.0%), NNT 4.7.
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risk of ICU admission, 85.2% lower, RR 0.15, p = 0.25, treatment 1 of 27 (3.7%), control 1 of 4 (25.0%), NNT 4.7.
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relative improvement in Ct value, 0.8% better, RR 0.99, p = 1.00, treatment 27, control 3.
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risk of no viral clearance, 11.1% higher, RR 1.11, p = 1.00, treatment 10 of 27 (37.0%), control 1 of 3 (33.3%), primary outcome.
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time to viral-, 16.7% lower, relative time 0.83, treatment 27, control 3.
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Pott-Junior et al., 3/9/2021, Randomized Controlled Trial, Brazil, South America, peer-reviewed, 10 authors, average treatment delay 8.0 days, dosage 200μg/kg single dose, dose varies in three arms 100, 200, 400μg/kg, trial NCT04431466.
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Submit Corrections or Comments
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Early |
Chamie-Quintero et al., OSF Preprints (Preprint) |
Ivermectin for COVID-19 in Peru: 14-fold reduction in nationwide excess deaths, p=.002 for effect by state, then 13-fold increase after ivermectin use restricted |
Details
Analysis of ivermectin use in Peru concluding that ivermectin most likely caused a 14 times reduction in excess deaths in Peru, prior to a 13 times increase after reversal of ivermectin use. Authors conclude that the results strongly sugg.. |
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Early treatment study
Early treatment study
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Ivermectin for COVID-19 in Peru: 14-fold reduction in nationwide excess deaths, p=.002 for effect by state, then 13-fold increase after ivermectin use restricted |
Chamie-Quintero et al., OSF Preprints (Preprint) |
Analysis of ivermectin use in Peru concluding that ivermectin most likely caused a 14 times reduction in excess deaths in Peru, prior to a 13 times increase after reversal of ivermectin use. Authors conclude that the results strongly suggest that ivermectin can complement vaccination. They note that the potential mechanism of action, competitive binding with the SARS-CoV-2 spike protein, is likely to be non-epitope specific, possibly maintaining efficacy against emerging mutant strains.
Chamie-Quintero et al., 3/8/2021, preprint, 3 authors.
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Submit Corrections or Comments
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Late |
Guzman et al., medRxiv, doi:10.1101/2021.03.04.21252084 (Preprint) |
death, ↓19.0%, p=0.35 |
Factors associated with increased mortality in critically ill COVID-19 patients in a Mexican public hospital: the other faces of health system oversaturation |
Details
Retrospective 196 critically ill patients in Mexico. Patients overlap with the existing RCT by Beltran-Gonzalez (NCT04391127). This preprint shows a larger treated population and greater (non-statistically significant) improvement with iv.. |
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Late treatment study
Late treatment study
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Factors associated with increased mortality in critically ill COVID-19 patients in a Mexican public hospital: the other faces of health system oversaturation |
Guzman et al., medRxiv, doi:10.1101/2021.03.04.21252084 (Preprint) |
Retrospective 196 critically ill patients in Mexico. Patients overlap with the existing RCT by Beltran-Gonzalez (NCT04391127). This preprint shows a larger treated population and greater (non-statistically significant) improvement with ivermectin, RR 0.81 [0.53-1.24].
risk of death, 19.0% lower, HR 0.81, p = 0.35.
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Guzman et al., 3/8/2021, retrospective, Mexico, North America, preprint, 11 authors, trial NCT04391127.
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Submit Corrections or Comments
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Late |
Galan et al., Pathogens and Global Health, doi:10.1080/20477724.2021.1890887 |
Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 infection |
Details
RCT 168 very late stage severe condition hospitalized patients comparing CQ, HCQ, and ivermectin not showing significant differences. Authors were unable to add a control arm due to ethical issues. Authors claim that "the mortality r.. |
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Late treatment study
Late treatment study
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Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 infection |
Galan et al., Pathogens and Global Health, doi:10.1080/20477724.2021.1890887 |
RCT 168 very late stage severe condition hospitalized patients comparing CQ, HCQ, and ivermectin not showing significant differences. Authors were unable to add a control arm due to ethical issues.Authors claim that "the mortality rates of the three groups are very similar to historical reports of other studies that used placebo in hospitalized patients", without providing any reference. However [sciencedirect.com] shows 43% hospital mortality in the northern region of Brazil, where the study was performed, from which we can estimate the mortality with ivermectin in this study is 47% lower, RR 0.53. Further, the study is restricted to more severe cases, hence the expected mortality may be higher.
Galan et al., 3/8/2021, peer-reviewed, 19 authors.
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Submit Corrections or Comments
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Safety |
Descotes, J., ImmunoSafe Consultance (Preprint) |
safety analysis |
Medical Safety of Ivermectin |
Details
Safety analysis of >350 articles showing that ivermectin has an excellent safety profile. The author notes that "no severe adverse event has been reported in dozens of completed or ongoing studies involving thousands of participants.. |
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Safety
Safety
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Medical Safety of Ivermectin |
Descotes, J., ImmunoSafe Consultance (Preprint) |
Safety analysis of >350 articles showing that ivermectin has an excellent safety profile. The author notes that "no severe adverse event has been reported in dozens of completed or ongoing studies involving thousands of participants worldwide to evaluate the efficacy of ivermectin against COVID-19".
Descotes et al., 3/5/2021, preprint, 1 author.
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Submit Corrections or Comments
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Early |
López-Medina et al., JAMA, doi:10.1001/jama.2021.3071 |
death, ↓66.8%, p=0.50 |
Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial |
Details
An open letter, signed by >100 physicians, concluding this study is fatally flawed can be found at [ jamaletter.com ] . This is a phone survey based RCT with low risk patients, 200 ivermectin and 198 control, showing lower mortality, lowe.. |
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Early treatment study
Early treatment study
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Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial |
López-Medina et al., JAMA, doi:10.1001/jama.2021.3071 |
An open letter, signed by >100 physicians, concluding this
study is fatally flawed can be found at [jamaletter.com].
This is a phone survey based RCT with low risk patients, 200
ivermectin and 198 control, showing lower mortality, lower disease
progression, lower treatment escalation, and faster resolution of symptoms
with treatment, without reaching statistical significance. Authors find the
results of this trial alone do not support the use of ivermectin. However the
effects are all positive, especially for serious outcomes which are unable to
reach statistical significance with the very small number of events in the
low risk population.
RCTs have a fundamental bias against finding an effect for
interventions that are widely available — patients that believe they
need treatment are more likely to decline participation and take the
intervention [Yeh], i.e., RCTs are more likely to enroll low-risk
participants that do not need treatment to recover (this does not apply to
the typical pharmaceutical trial of a new drug that is otherwise
unavailable). This trial was run in a community where ivermectin was
available OTC and very widely known and used.
With the low risk patient population, there is little room for
improvement with an effective treatment - 59/57% (IVM/control) recovered
within the first 2 days to either "no symptoms" or "not hospitalized and no
limitation of activities"; 73/69% within 5 days. Less than 3% of all patients
ever deteriorated.
The primary outcome was changed mid-trial, it was originally
clinical deterioration, which is more meaningful, and shows greater benefit.
The new outcome of resolution of symptoms includes "not hospitalized and no
limitation of activities" as a negative outcome and is not very meaningful in
terms of assessing how much treatment reduces serious outcomes. Using this
measure could completely invalidate results - for example a treatment that
eliminates all COVID-19 symptoms but has a temporary minor adverse event
could be seen as worse.
Authors state that "preliminary reports of other randomized
trials of ivermectin as treatment for COVID-19 with positive results have not
yet been published in peer-reviewed journals", however there were 8
peer-reviewed RCTs with positive effects published prior to this paper(and 19
total peer-reviewed studies with positive effects).
Authors advised taking ivermectin on an empty stomach, reducing
lung tissue concentration by ~2.5x [Guzzo].
76 patients were excluded due to control patients receiving
ivermectin. However, there was a similar percentage of adverse events like
diarrhea, nausea, and abdominal pain in both treatment and control groups.
These are potential non-serious side effects of treatment and suggest that it
is possible that many more control patients received some kind of
treatment.
Ivermectin was widely used in the population and available OTC
at the time of the study. The study protocol only excluded patients with
previous ivermectin use within 5 days, however other trials often monitor
effects 10+ days after the last dose [osf.io].
This study reportedly has an ethical issue whereby participants
were told the study drug was "D11AX22"
[trialsitenews.com].
The editor-in-chief of JAMA initially offered to help with this issue, but
later indicated that "JAMA does not review consent forms", however the lead
author reportedly confirmed the issue [francesoir.fr, trialsitenews.com (B), trialsitenews.com (C)].
The study protocol specifically allows "the use of other
treatments outside of clinical trials". The paper provides no information on
what other treatments were used, but other treatments were commonly used at
the time. Additionally, the control group did about 5x better than
anticipated for deterioration, also suggesting that the control patients used
some kind of treatment. Patients that enroll in such a study may be more
likely to learn about and use other treatments, especially since they do not
know if they are receiving the study medication.
The study protocol was amended 4 times. Amendments 2-4 are
provided but amendment 1 is missing. Amendment 2 increased the inclusion
criteria to within 7 days of onset, including more later stage patients and
reducing the expected effectiveness. The trial protocol lists “the duration
of supplemental oxygen” as an outcome but the results for this outcome are
missing.
Grants and/or personal fees, including in some cases during the
conduct of the study, were provided by Sanofi Pasteur, GlaxoSmithKline,
Janssen, Merck, and Gilead. For more details see [trialsitenews.com (D)].
For other confounding issues see [osf.io (B)] and additional
issues can be found in the comments of the article [jamanetwork.com].
Re-analysis of the raw data has been reported to show a significant positive effect
[twitter.com].
Most data was collected via surveys, without physical
examination. 87% medication adherence. NCT04405843.
risk of death, 66.8% lower, RR 0.33, p = 0.50, treatment 0 of 200 (0.0%), control 1 of 198 (0.5%), NNT 198, relative risk is not 0 because of continuity correction due to zero events.
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risk of escalation of care, 60.8% lower, RR 0.39, p = 0.11, treatment 4 of 200 (2.0%), control 10 of 198 (5.1%), NNT 33, OR converted to RR.
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risk of escalation of care with post-hoc <12h exclusion, 34.3% lower, RR 0.66, p = 0.52, treatment 4 of 200 (2.0%), control 6 of 198 (3.0%), NNT 97, OR converted to RR.
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risk of deterioration by >= 2 points on an 8-point scale, 43.1% lower, RR 0.57, p = 0.37, treatment 4 of 200 (2.0%), control 7 of 198 (3.5%), NNT 65, OR converted to RR, primary outcome.
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risk of fever post randomization, 24.8% lower, RR 0.75, p = 0.38, treatment 16 of 200 (8.0%), control 21 of 198 (10.6%), NNT 38, OR converted to RR.
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risk of unresolved symptoms at day 21, 15.3% lower, RR 0.85, p = 0.53, treatment 36 of 200 (18.0%), control 42 of 198 (21.2%), NNT 31, OR converted to RR, Cox proportional-hazard model.
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lack of resolution of symptoms, 6.5% lower, HR 0.93, p = 0.53, treatment 200, control 198, post-hoc primary outcome.
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relative median time to resolution of symptoms, 16.7% better, relative time 0.83, treatment 200, control 198.
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Excluded in after exclusion results of meta analysis:
strong evidence of patients in the control group self-medicating, ivermectin widely used in the population at that time, and the study drug identity was concealed by using the name D11AX22.
López-Medina et al., 3/4/2021, Double Blind Randomized Controlled Trial, Colombia, South America, peer-reviewed, median age 37.0, 19 authors, average treatment delay 5.0 days, dosage 300μg/kg days 1-5.
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In Silico |
Saha et al., Structural Chemistry, doi:10.1007/s11224-021-01776-0 (preprint 3/1) (Preprint) |
In Silico |
The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2 |
Details
In Silico analysis predicting that ivermectin has a large binding affinity for the SARS-CoV-2 spike protein. Three different computer modeling techniques show that ivermectin can inhibit SARS-CoV-2 entrance via hACE2. |
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In Silico
In Silico
|
The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2 |
Saha et al., Structural Chemistry, doi:10.1007/s11224-021-01776-0 (preprint 3/1) (Preprint) |
In Silico analysis predicting that ivermectin has a large binding affinity for the SARS-CoV-2 spike protein. Three different computer modeling techniques show that ivermectin can inhibit SARS-CoV-2 entrance via hACE2.
Saha et al., 3/1/2021, preprint, 2 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Late |
Beltran Gonzalez et al., Infectious Disease Reports, doi:10.3390/idr14020020 (preprint 2/23/2021) |
death, ↓14.4%, p=1.00 |
Efficacy and Safety of Ivermectin and Hydroxychloroquine in Patients with Severe COVID-19: A Randomized Controlled Trial |
Details
RCT late stage severe condition (93% SOFA ≥ 2, 96% APACHE ≥ 8) high comorbidity hospitalized patients in Mexico with 36 low dose ivermectin and 37 control patients not finding significant differences. NCT04391127. Another study reports re.. |
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Late treatment study
Late treatment study
|
Efficacy and Safety of Ivermectin and Hydroxychloroquine in Patients with Severe COVID-19: A Randomized Controlled Trial |
Beltran Gonzalez et al., Infectious Disease Reports, doi:10.3390/idr14020020 (preprint 2/23/2021) |
RCT late stage severe condition (93% SOFA ≥ 2, 96% APACHE ≥ 8) high
comorbidity hospitalized patients in Mexico with 36 low dose ivermectin and
37 control patients not finding significant differences. NCT04391127.
Another study reports results on a larger group of patients in
the same hospital, showing ivermectin mortality RR 0.81 [0.53-1.24] [Guzman].
Questions have been raised about this study and the early
termination of the study and discontinuation of treatments, because the
hospital statistics show a dramatically lower (~75%) case fatality rate
during the period of the study [] (data from [gob.mx]).
Date | Cases | Deaths | CFR |
3/2020 | 2 | 1 | 50% |
4/2020 | 4 | 1 | 25% |
5/2020 | 13 | 1 | 8% |
6/2020 | 37 | 2 | 5% |
7/2020 | 65 | 5 | 8% |
8/2020 | 79 | 23 | 29% |
9/2020 | 54 | 12 | 22% |
10/2020 | 62 | 21 | 34% |
11/2020 | 80 | 26 | 33% |
12/2020 | 41 | 13 | 32% |
Several other inconsistencies have been reported
[Chamie].
Although the data from this study is reported to be available
and has been shared with an anti-treatment group, independent researchers have
been unable to obtain the data for verification [Chamie, ].
risk of death, 14.4% lower, RR 0.86, p = 1.00, treatment 5 of 36 (13.9%), control 6 of 37 (16.2%), NNT 43.
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risk of respiratory deterioration or death, 8.6% lower, RR 0.91, p = 1.00, treatment 8 of 36 (22.2%), control 9 of 37 (24.3%), NNT 48.
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risk of no hospital discharge, 37.0% higher, RR 1.37, p = 0.71, treatment 4 of 36 (11.1%), control 3 of 37 (8.1%).
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hospitalization time, 20.0% higher, relative time 1.20, p = 0.43, treatment 36, control 37, primary outcome.
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Excluded in after exclusion results of meta analysis:
major inconsistencies reported and the data is no longer available, although the authors state that it is available, and have shared it with an anti-treatment group.
Beltran Gonzalez et al., 2/23/2021, Double Blind Randomized Controlled Trial, Mexico, North America, peer-reviewed, mean age 53.8, 13 authors, average treatment delay 7.0 days, dosage 12mg single dose, 18mg for patients >80kg.
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|
News |
BIRD Meeting 20th February 2021 (News) |
news |
BIRD Meeting 20th February 2021 |
Details
The British Ivermectin Recommendation Development (BIRD) panel, with dozens of multi-national scientists & doctors, issued sweeping recommendations for the immediate global use of ivermectin. |
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News
News
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BIRD Meeting 20th February 2021 |
BIRD Meeting 20th February 2021 (News) |
The British Ivermectin Recommendation Development (BIRD) panel, with dozens of multi-national scientists & doctors, issued sweeping recommendations for the immediate global use of ivermectin.
BIRD et al., 2/20/2021, preprint, 1 author.
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Early |
Elalfy et al., J. Med. Virol., doi:10.1002/jmv.26880 |
viral+, ↓86.9%, p<0.0001 |
Effect of a combination of Nitazoxanide, Ribavirin and Ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-1 |
Details
Non-randomized controlled trial with 62 mild and early moderate patients with home treatment with ivermectin + nitazoxanide + ribavirin + zinc, showing significantly faster viral clearance. |
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Details
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Early treatment study
Early treatment study
|
Effect of a combination of Nitazoxanide, Ribavirin and Ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-1 |
Elalfy et al., J. Med. Virol., doi:10.1002/jmv.26880 |
Non-randomized controlled trial with 62 mild and early moderate patients with home treatment with ivermectin + nitazoxanide + ribavirin + zinc, showing significantly faster viral clearance.
risk of no viral clearance, 86.9% lower, RR 0.13, p < 0.001, treatment 7 of 62 (11.3%), control 44 of 51 (86.3%), NNT 1.3, day 15, primary outcome.
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risk of no viral clearance, 58.1% lower, RR 0.42, p < 0.001, treatment 26 of 62 (41.9%), control 51 of 51 (100.0%), NNT 1.7, day 7.
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Elalfy et al., 2/16/2021, retrospective, Egypt, Africa, peer-reviewed, 15 authors, dosage 18mg days 1, 4, 7, 10, 13, <90kg 18mg, 90-120kg 24mg, >120kg 30mg, this trial uses multiple treatments in the treatment arm (combined with nitazoxanide, ribavirin, and zinc) - results of individual treatments may vary.
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PrEPPEP |
Behera et al., Cureus 13:8, doi:10.7759/cureus.16897 (preprint 2/15/21) |
cases, ↓83.0%, p<0.001 |
Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers |
Details
Prospective prophylaxis study with 3,532 healthcare workers, 2,199 receiving two-dose ivermectin prophylaxis, showing adjusted relative risk of confirmed COVID-19 with treatment 0.17 [0.12-0.23] p<0.001. 186 patients took only the first d.. |
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Details
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Prophylaxis study
Prophylaxis study
|
Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers |
Behera et al., Cureus 13:8, doi:10.7759/cureus.16897 (preprint 2/15/21) |
Prospective prophylaxis study with 3,532 healthcare workers, 2,199 receiving two-dose ivermectin prophylaxis, showing adjusted relative risk of confirmed COVID-19 with treatment 0.17 [0.12-0.23] p<0.001. 186 patients took only the first dose, and no significant difference was observed for this group. The same group published an earlier small study with 117 ivermectin patients. There were no serious adverse events. T/IM-NF/CM&FM/20/142.
risk of case, 83.0% lower, RR 0.17, p < 0.001, treatment 45 of 2,199 (2.0%), control 133 of 1,147 (11.6%), NNT 10, two doses, primary outcome.
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risk of case, 4.0% higher, RR 1.04, p = 0.85, treatment 23 of 186 (12.4%), control 133 of 1,147 (11.6%), patients only receiving the first dose.
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Behera et al., 2/15/2021, prospective, India, South Asia, peer-reviewed, 14 authors, dosage 300μg/kg days 1, 4.
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Early |
Biber et al., medRxiv, doi:10.1101/2021.05.31.21258081 (results 2/12/21) (Preprint) |
hosp., ↓70.2%, p=0.34 |
Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19, A double-blind, randomized placebo-controlled trial |
Details
Double blind RCT for mild-moderate COVID-19 outpatients in Israel showing significantly faster reduction in viral load with treatment, and lower hospitalization with treatment. The one treatment hospitalization was a few hours after treat.. |
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Details
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Early treatment study
Early treatment study
|
Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19, A double-blind, randomized placebo-controlled trial |
Biber et al., medRxiv, doi:10.1101/2021.05.31.21258081 (results 2/12/21) (Preprint) |
Double blind RCT for mild-moderate COVID-19 outpatients in Israel showing significantly faster reduction in viral load with treatment, and lower hospitalization with treatment. The one treatment hospitalization was a few hours after treatment and the patient improved and was discharged quickly. Authors also examine culture viability on days 2-6, with 13% positive in the ivermectin group vs. 48% in the control group. There were no safety issues. Sheba IRB-7156/20. NCT04429711.
risk of hospitalization, 70.2% lower, RR 0.30, p = 0.34, treatment 1 of 47 (2.1%), control 3 of 42 (7.1%), NNT 20.
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risk of no viral clearance, 44.8% lower, RR 0.55, p = 0.04, treatment 13 of 47 (27.7%), control 21 of 42 (50.0%), NNT 4.5, adjusted, OR converted to RR, multivariable logistic regression, day 6, Ct>30, primary outcome.
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risk of no viral clearance, 70.2% lower, RR 0.30, p = 0.14, treatment 2 of 47 (4.3%), control 6 of 42 (14.3%), NNT 10.0, day 10, non-infectious samples (Ct>30 or non-viable culture).
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risk of no viral clearance, 82.1% lower, RR 0.18, p = 0.01, treatment 2 of 47 (4.3%), control 10 of 42 (23.8%), NNT 5.1, day 8, non-infectious samples (Ct>30 or non-viable culture).
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risk of no viral clearance, 75.6% lower, RR 0.24, p = 0.02, treatment 3 of 47 (6.4%), control 11 of 42 (26.2%), NNT 5.0, day 6, non-infectious samples (Ct>30 or non-viable culture).
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risk of no viral clearance, 65.1% lower, RR 0.35, p = 0.05, treatment 4 of 28 (14.3%), control 9 of 22 (40.9%), NNT 3.8, day 4, non-infectious samples (Ct>30 or non-viable culture).
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risk of no viral clearance, 51.9% lower, RR 0.48, p = 0.08, treatment 7 of 47 (14.9%), control 13 of 42 (31.0%), NNT 6.2, day 10, Ct>30.
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risk of no viral clearance, 57.9% lower, RR 0.42, p = 0.02, treatment 8 of 47 (17.0%), control 17 of 42 (40.5%), NNT 4.3, day 8, Ct>30.
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risk of no viral clearance, 44.7% lower, RR 0.55, p = 0.049, treatment 13 of 47 (27.7%), control 21 of 42 (50.0%), NNT 4.5, day 6, Ct>30.
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risk of no viral clearance, 31.9% lower, RR 0.68, p = 0.16, treatment 13 of 28 (46.4%), control 15 of 22 (68.2%), NNT 4.6, day 4, Ct>30.
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Biber et al., 2/12/2021, Double Blind Randomized Controlled Trial, Israel, Middle East, preprint, 10 authors, average treatment delay 4.0 days, dosage 12mg days 1-3, 15mg for patients >= 70kg, trial NCT04429711.
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Late |
Lima-Morales |
death, ↓77.7%, p<0.001 |
Effectiveness of a multidrug therapy consisting of ivermectin, azithromycin, montelukast and acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico |
Details
Prospective trial of 768 COVID-19 outpatients in Mexico, 481 treated with ivermectin, AZ, montelukast, and aspirin, and 287 control patients with various treatments, showing significantly lower mortality and hospitalization, and significa.. |
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Details
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Late treatment study
Late treatment study
|
Effectiveness of a multidrug therapy consisting of ivermectin, azithromycin, montelukast and acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico |
Lima-Morales |
Prospective trial of 768 COVID-19 outpatients in Mexico, 481 treated with ivermectin, AZ, montelukast, and aspirin, and 287 control patients with various treatments, showing significantly lower mortality and hospitalization, and significantly higher recovery at 14 days with treatment.
risk of death, 77.7% lower, RR 0.22, p < 0.001, treatment 15 of 481 (3.1%), control 52 of 287 (18.1%), NNT 6.7, adjusted, OR converted to RR, multivariate.
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risk of mechanical ventilation, 51.9% lower, RR 0.48, p = 0.15, treatment 8 of 434 (1.8%), control 11 of 287 (3.8%), NNT 50.
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risk of hospitalization, 67.4% lower, RR 0.33, p < 0.001, treatment 44 of 481 (9.1%), control 89 of 287 (31.0%), NNT 4.6, adjusted, OR converted to RR, multivariate.
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risk of no recovery, 58.6% lower, RR 0.41, p < 0.001, treatment 75 of 481 (15.6%), control 118 of 287 (41.1%), NNT 3.9, adjusted, OR converted to RR, recovery at day 14 after symptoms, multivariate.
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Lima-Morales et al., 2/10/2021, prospective, Mexico, North America, peer-reviewed, 9 authors, average treatment delay 7.2 days, dosage 12mg single dose, this trial uses multiple treatments in the treatment arm (combined with azithromycin, montelukast, and aspirin) - results of individual treatments may vary.
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Early |
Mohan et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.08.021 (preprint 2/2/2021) |
no recov., ↓62.5%, p=0.27 |
Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): a single-centre randomized, placebo-controlled trial |
Details
RCT in India with low risk patients, comparing 24mg ivermectin, 12mg ivermectin, and placebo showing non-statistically significant improvements in recovery and PCR+ status (day 5 both arms, day 7 24mg only) with treatment, and showing gre.. |
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Details
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Early treatment study
Early treatment study
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Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): a single-centre randomized, placebo-controlled trial |
Mohan et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.08.021 (preprint 2/2/2021) |
RCT in India with low risk patients, comparing 24mg ivermectin, 12mg ivermectin, and placebo showing non-statistically significant improvements in recovery and PCR+ status (day 5 both arms, day 7 24mg only) with treatment, and showing greater improvement for the higher dose arm. Viral load decline was similar in all arms - absolute values are lower for ivermectin in a dose-dependent manner, however the baseline value for the ivermectin groups was lower, leaving less room for change. There were no deaths or use of mechanical ventilation. There were no serious adverse events. Note that our pre-specified protocol prioritizes clinical outcomes over PCR results. The supplementary appendix is not currently available.
risk of no discharge at day 14, 62.5% lower, RR 0.38, p = 0.27, treatment 2 of 40 (5.0%), control 6 of 45 (13.3%), NNT 12, ivermectin 24mg.
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risk of no discharge at day 14, 43.8% lower, RR 0.56, p = 0.49, treatment 3 of 40 (7.5%), control 6 of 45 (13.3%), NNT 17, ivermectin 12mg.
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risk of clinical worsening, 32.5% lower, RR 0.68, p = 0.72, treatment 3 of 40 (7.5%), control 5 of 45 (11.1%), NNT 28, ivermectin 24mg.
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risk of clinical worsening, 55.0% lower, RR 0.45, p = 0.44, treatment 2 of 40 (5.0%), control 5 of 45 (11.1%), NNT 16, ivermectin 12mg.
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risk of no viral clearance, 23.8% lower, RR 0.76, p = 0.18, treatment 21 of 40 (52.5%), control 31 of 45 (68.9%), NNT 6.1, ivermectin 24mg, day 5, primary outcome.
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risk of no viral clearance, 5.6% lower, RR 0.94, p = 0.82, treatment 26 of 40 (65.0%), control 31 of 45 (68.9%), NNT 26, ivermectin 12mg, day 5.
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risk of no viral clearance, 10.3% lower, RR 0.90, p = 0.65, treatment 20 of 36 (55.6%), control 26 of 42 (61.9%), NNT 16, ivermectin 24mg, day 7.
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risk of no viral clearance, 3.2% higher, RR 1.03, p = 1.00, treatment 23 of 36 (63.9%), control 26 of 42 (61.9%), ivermectin 12mg, day 7.
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Mohan et al., 2/2/2021, Double Blind Randomized Controlled Trial, India, South Asia, peer-reviewed, 27 authors, average treatment delay 5.0 days, dosage 400μg/kg single dose, 200μg/kg also tested.
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Submit Corrections or Comments
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Meta |
Cobos-Campos et al., Clin. Res. Trials, 2021, doi:10.15761/CRT.1000333 (meta analysis) |
meta-analysis |
Potential use of ivermectin for the treatment and profilaxis of SARS-CoV-2 infection: Efficacy of ivermectin for SARS-CoV-2 |
Details
Review finding that there appears to be sufficient evidence to recommend ivermectin for the treatment of COVID-19, especially in the early stages of the disease. |
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Details
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Meta
Meta
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Potential use of ivermectin for the treatment and profilaxis of SARS-CoV-2 infection: Efficacy of ivermectin for SARS-CoV-2 |
Cobos-Campos et al., Clin. Res. Trials, 2021, doi:10.15761/CRT.1000333 (meta analysis) |
Review finding that there appears to be sufficient evidence to recommend ivermectin for the treatment of COVID-19, especially in the early stages of the disease.
Cobos-Campos et al., 1/29/2021, peer-reviewed, 9 authors.
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Submit Corrections or Comments
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Meta |
Castaneda-Sabogal et al., medRxiv, doi:10.1101/2021.01.26.21250420 (Preprint) (meta analysis) |
meta-analysis |
Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis |
Details
Meta analysis of a very small subset of studies exhibiting very high bias and significant flaws. Some of the problems: - As of the publication date, there are 35 studies, authors include only 4. (They list 5, but two are the same study, p.. |
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Details
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PDF
Meta
Meta
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Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis |
Castaneda-Sabogal et al., medRxiv, doi:10.1101/2021.01.26.21250420 (Preprint) (meta analysis) |
Meta analysis of a very small subset of studies exhibiting very high bias and significant flaws. Some of the problems:- As of the publication date, there are 35 studies, authors include only 4. (They list 5, but two are the same study, preprint and published version).- From the 17 RCTs, authors include 0.- Authors include only late treatment studies, excluding all 10 early treatment studies and all 10 prophylaxis studies.- Authors did not locate 13 studies, despite this being trivial from existing meta analyses.- There is no logic in the exclusion reasons. For example, they include the most biased study to date, Soto-Becerra, and assign the highest weight to it.- Authors randomly exclude letters but include preprints (excluding letters to help avoid positive results, including preprints to include Soto-Becerra).- Soto-Becerra has clear evidence of extreme bias. The study presents 30 day results and extended KM curves up to day 43 for ivermectin. At 30 days the result is negative but reverts (as do all treatments in the study) and becomes positive before day 43. Authors of this meta analysis ignore the extended followup. Soto-Becerra is a database analysis that includes anyone with ICD-10 COVID-19 codes which includes asymptomatic PCR+ patients, therefore many patients in the control group are likely asymptomatic with regards to SARS-CoV-2, but in the hospital for another reason. For those that had symptomatic COVID-19, there is also likely significant confounding by indication. In this study all medications show higher mortality at day 30, which is consistent with asymptomatic (for COVID-19) or mild condition patients being more common in the control group. For ivermectin they show 30 day mortality aHR = 1.39 [0.88 - 2.22]. KM curves show that the treatment groups were in more serious condition, and also that after about day 35 survival became better with ivermectin. More than the total excess mortality happened on the first day. This is consistent with treated patients being in more serious condition, and with many of the control group patients being in hospital for something unrelated to COVID-19. Authors use a machine learning based propensity scoring system that appears over-parameterized and likely to result in significant overfitting and inaccurate results. Essentially they test for all interactions between two and three covariates. The nature and large number of covariates means many random correlations may be found. COVID-19 severity is not used. In summary, this is the lowest quality ivermectin study to date. This study also does not compare treatments with a control group not receiving the treatment - authors put patients receiving treatments after 48 hours in the control group. Authors also state that outcomes within 24 hours were excluded, however KM curves show significant mortality at day 1 (only for the treatment groups).- We checked the reported results for the mortality outcome and found they do not appear to match the actual papers.- Rajter: authors list mortality as 13/85 (treatment), 24/74 (control), the paper shows (for the matched cohort) 13/98 (treatment), 24/98 (control). The adjusted result in the paper is OR 0.27 [0.09-0.80] (multivariate) or OR 0.47 [0.22-0.99] (PSM). These correspond to RR 0.33 and 0.54 respectively, or logRR -1.1 and -0.62. However authors here show logRR 0.54 and 0.85 - they include the study twice (preprint and published). The preprint and published papers have the same multivariate result, the PSM result was added in the published paper. Neither of the two results the authors use match the actual results.- Khan: the paper shows RR 0.13, logRR -2.0. Authors show logRR 0.13.- Soto-Becerra at day 30 shows wHR 1.39 [0.88-2.22], and day 43 weighted KM 0.82 [0.76-0.88]. These correspond to logRR 0.33 and -0.19. Authors show logRR 1.75.- Gorial: there is zero mortality with treatment in this paper. Using the typical continuity correction, the paper shows RR 0.29 when accounting for the different group sizes, or 0.86 when using naive continuity correction that does not account for the very different group sizes. These correspond to logRR -1.24 or -0.15. Authors show logRR 0.60.- Authors did not locate and reference the existing widely known meta-analyses from well-known researchers - Kory et al., Hill et al., Lawrie et al.For more issues see: [, ]. Authors on Twitter: [, , , ].
Castaneda-Sabogal et al., 1/27/2021, preprint, 6 authors.
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In Silico |
Eweas et al., Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908 |
In Silico |
Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2 |
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Molecular docking analysis showing that ivermectin efficiently binds to the viral S protein as well as the human cell surface receptors ACE-2 and TMPRSS2; therefore, it might be involved in inhibiting the entry of the virus into the host .. |
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In Silico
In Silico
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Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2 |
Eweas et al., Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908 |
Molecular docking analysis showing that ivermectin efficiently binds to the viral S protein as well as the human cell surface receptors ACE-2 and TMPRSS2; therefore, it might be involved in inhibiting the entry of the virus into the host cell. It also binds to Mpro and PLpro of SARS-CoV-2; therefore, it might play a role in preventing the post-translational processing of viral polyproteins. The highly efficient binding of ivermectin to the viral N phosphoprotein and nsp14 is suggestive of its role in inhibiting viral replication and assembly.
Eweas et al., 1/25/2021, peer-reviewed, 3 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Animal |
Errecalde et al., Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017 |
animal study |
Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model |
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Animal study of a novel spray formulation of ivermectin, showing an advantage of the spray formulation in terms of fast attainment of high and persistent ivermectin concentrations in nasopharyngeal tissue. |
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Animal study
Animal study
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Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model |
Errecalde et al., Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017 |
Animal study of a novel spray formulation of ivermectin, showing an advantage of the spray formulation in terms of fast attainment of high and persistent ivermectin concentrations in nasopharyngeal tissue.
Errecalde et al., 1/23/2021, peer-reviewed, 15 authors.
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Early |
Chamie-Quintero et al., Preprint, doi:10.2139/ssrn.3765018 (Preprint) |
Sharp Reductions in COVID-19 Case Fatalities and Excess Deaths in Peru in Close Time Conjunction, State-By-State, with Ivermectin Treatments |
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Analysis of ivermectin usage within states in Peru showing sharp reductions in COVID-19 deaths corresponding to the usage of ivermectin treatment. |
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Early treatment study
Early treatment study
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Sharp Reductions in COVID-19 Case Fatalities and Excess Deaths in Peru in Close Time Conjunction, State-By-State, with Ivermectin Treatments |
Chamie-Quintero et al., Preprint, doi:10.2139/ssrn.3765018 (Preprint) |
Analysis of ivermectin usage within states in Peru showing sharp reductions in COVID-19 deaths corresponding to the usage of ivermectin treatment.
Chamie-Quintero et al., 1/21/2021, preprint, 3 authors.
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In Vitro |
Mody et al., Communications Biology, doi:10.1038/s42003-020-01577-x (In Vitro) |
In Vitro |
Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents |
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Computational molecular modeling screening and in vitro analysis for inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme, showing that ivermectin blocked more than 85% of 3CLpro activity of SARS-CoV-2. Antiviral activity of ivermectin.. |
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In Vitro
In Vitro
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Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents |
Mody et al., Communications Biology, doi:10.1038/s42003-020-01577-x (In Vitro) |
Computational molecular modeling screening and in vitro analysis for inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme, showing that ivermectin blocked more than 85% of 3CLpro activity of SARS-CoV-2. Antiviral activity of ivermectin mediated through the blocking of α/β1 importin has been previously established, this analysis suggests an additional antiviral mechanism of ivermectin for SARS-CoV-2 via inhibitory effects on 3CLpro.
Mody et al., 1/20/2021, peer-reviewed, 9 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Late |
Shahbaznejad et al., Clinical Therapeutics, doi:10.1016/j.clinthera.2021.04.007 (partial results available 1/19) |
death, ↑197.1%, p=1.00 |
Effect of ivermectin on COVID-19: A multicenter double-blind randomized controlled clinical trial |
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RCT in Iran showing shorter time to recovery and shorter hospitalization time with ivermectin. There were no adverse effects. There was one death in the treatment group, the patient was in critical condition at baseline and died within 24.. |
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Late treatment study
Late treatment study
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Effect of ivermectin on COVID-19: A multicenter double-blind randomized controlled clinical trial |
Shahbaznejad et al., Clinical Therapeutics, doi:10.1016/j.clinthera.2021.04.007 (partial results available 1/19) |
RCT in Iran showing shorter time to recovery and shorter hospitalization time with ivermectin. There were no adverse effects. There was one death in the treatment group, the patient was in critical condition at baseline and died within 24 hours of admission. IRCT20111224008507N3. Also see [sciencedirect.com] and the author response [clinicaltherapeutics.com].
risk of death, 197.1% higher, RR 2.97, p = 1.00, treatment 1 of 35 (2.9%), control 0 of 34 (0.0%), continuity correction due to zero event, patient died within 24 hours of admission.
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risk of mechanical ventilation, 94.3% higher, RR 1.94, p = 1.00, treatment 2 of 35 (5.7%), control 1 of 34 (2.9%).
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recovery time, 31.6% lower, relative time 0.68, p = 0.048, treatment 35, control 34, duration of dsypnea.
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recovery time, 19.2% lower, relative time 0.81, p = 0.02, treatment 35, control 34, duration of all symptoms, primary outcome.
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hospitalization time, 15.5% lower, relative time 0.85, p = 0.02, treatment 35, control 34.
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Shahbaznejad et al., 1/19/2021, Double Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, average treatment delay 6.29 days, dosage 200μg/kg single dose.
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Meta |
Hill et al., Research Square, doi:10.21203/rs.3.rs-148845/v1 (Preprint) (meta analysis) |
death, ↓75.0%, p=0.0002 |
Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection |
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Meta analysis of 18 ivermectin RCTs with 2,282 patients showing faster viral clearance (dose and duration dependent), improved clinical recovery, and lower hospitalization and mortality. In six RCTs of moderate or severe infection, there .. |
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Meta
Meta
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Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection |
Hill et al., Research Square, doi:10.21203/rs.3.rs-148845/v1 (Preprint) (meta analysis) |
Meta analysis of 18 ivermectin RCTs with 2,282 patients showing faster viral clearance (dose and duration dependent), improved clinical recovery, and lower hospitalization and mortality. In six RCTs of moderate or severe infection, there was a 75% reduction in mortality, RR 0.25 [0.12-0.52], p = 0.0002.A documentary about the external influences changing the conclusions of this study, and the resulting negative impacts, can be found at [drtesslawrie.substack.com].A sponsor reportedly required the conclusion of this paper to be changed against the wishes of the authors (to suggest that more trials should be done as opposed to the existing evidence being sufficient) [francesoir.fr, , youtube.com]. Reportedly, Unitaid had influence over the conclusions [trialsitenews.com, worldcouncilforhealth.org]. See also [roundingtheearth.substack.com].Note that one of the 18 studies in this analysis has since been withdrawn (Elgazzar).
risk of death, 75.0% lower, RR 0.25, p < 0.001.
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Hill et al., 1/19/2021, preprint, 40 authors.
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Early |
Samaha et al., Viruses, doi:10.3390/v13060989 (results 1/16) |
Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon |
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This study was retracted. |
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Early treatment study
Early treatment study
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Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon |
Samaha et al., Viruses, doi:10.3390/v13060989 (results 1/16) |
This study was retracted.
Samaha et al., 1/16/2021, peer-reviewed, 16 authors.
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Early |
Bukhari et al., medRxiv, doi:10.1101/2021.02.02.21250840 (results 1/16) (Preprint) |
viral+, ↓82.4%, p<0.0001 |
Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease |
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RCT of relatively low risk hospitalized patients with 50 ivermectin and 50 control patients showing significantly faster viral clearance with treatment. 9 patients in the treatment arm were lost to followup compared with 5 in the control .. |
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Early treatment study
Early treatment study
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Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease |
Bukhari et al., medRxiv, doi:10.1101/2021.02.02.21250840 (results 1/16) (Preprint) |
RCT of relatively low risk hospitalized patients with 50 ivermectin and 50 control patients showing significantly faster viral clearance with treatment. 9 patients in the treatment arm were lost to followup compared with 5 in the control arm, which could be in part due to faster recovery with treatment. There were no safety concerns. No mortality was reported. The numbers in Table 3 are the number of patients that became negative on that day, i.e., non-cumulative. SOC included vitamin C and vitamin D. NCT04392713.
risk of no viral clearance, 82.4% lower, RR 0.18, p < 0.001, treatment 4 of 41 (9.8%), control 25 of 45 (55.6%), NNT 2.2, day 7, primary outcome.
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risk of no viral clearance, 38.7% lower, RR 0.61, p < 0.001, treatment 24 of 41 | |