Ivermectin for COVID-19: real-time analysis of all 126 studies

Covid Analysis (Preprint) (meta analysis)

Ivermectin for COVID-19: real-time meta analysis of 64 studies

• Meta analysis using the most serious outcome reported shows 67% [53‑76%] and 86% [75‑92%] improvement for early treatment and prophylaxis, with similar results after exclusion based sensitivity analysis (which excludes all of the GMK/BBC team studies), with primary outcomes, and after restriction to peer-reviewed studies or Randomized Controlled Trials.

• Statistically significant improvements are seen for

mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance. All remain statistically significant after exclusions. 31 studies show statistically significant improvements in isolation.

• Results are very robust — in worst case exclusion sensitivity analysis 53 of 64 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 25% of ivermectin studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments could be more effective, including monoclonal antibodies which may be available in countries not recommending ivermectin (sotrovimab, casirivimab/imdevimab, and bamlanivimab/etesevimab).

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer, TrialSiteNews]. Denying the efficacy of treatments increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.

	Studies	Prophylaxis	Early treatment	Late treatment	Patients	Authors
All studies	64	86% [75‑92%]	67% [53‑76%]	36% [21‑48%]	48,661	627
Peer-reviewed	44	86% [74‑93%]	71% [54‑82%]	38% [16‑55%]	17,126	466
With GMK/BBC exclusions	47	84% [69‑91%]	73% [63‑80%]	45% [22‑61%]	37,558	518
RCTs	30	84% [25‑96%]	63% [44‑75%]	20% [-6‑39%]	6,368	357
Percentage improvement with ivermectin treatment

• There is evidence of a negative publication bias, and the probability that an ineffective treatment generated results as positive as the 64 studies is estimated to be 1 in 222 billion.

• 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
Budesonide (UK)	1	1,779	17%
Remdesivir (USA EUA)	1	1,063	31%
Casirivimab/i.. (USA EUA)	1	799	66%
Ivermectin evidence	64	48,637	66% [57‑73%]

Low et al., Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, doi:10.1016/j.bbadis.2021.166294 (Review) (Peer Reviewed)

Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication

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.

Borody et al., TrialSite News (Preprint)

Combination Therapy For COVID-19 Based on Ivermectin in an Australian Population

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%), relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 92.9% lower, RR 0.07, p < 0.001, treatment 5 of 600 (0.8%), control 70 of 600 (11.7%).

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, 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.

Segatori et al., Viruses, doi:10.3390/v13102084 (Peer Reviewed) (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

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.

Jitaboam et al., Research Square, doi:10.21203/rs.3.rs-941811/v1 (Peer Reviewed) (In Vitro)

Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2

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.

Jitaboam et al., 10/14/2021, peer-reviewed, 8 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Goodkin, M. (News)

Are Major Ivermectin Studies Designed for Failure?

Discussion of flaws in ivermectin trials creating a bias towards not finding an effect.

Goodkin et al., 10/14/2021, preprint, 1 author.

Fordham et al., OSF Preprints, doi:10.31219/osf.io/mp4f2 (Review) (Preprint)

The uses and abuses of systematic reviews

Analysis of defects in the Popp et al. meta analysis.

Fordham et al., 10/7/2021, preprint, 4 authors.

Francés-Monerris et al., Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C (Peer Reviewed)

Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection

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.

TrialSite News (News)

Committed to Medical Evidence, a Prominent Ivermectin Group is Eradicated from the Memories of Cyberspace

Report on Twitter's censorship of the British Ivermectin Recommendation Development group.

TrialSite News et al., 10/2/2021, preprint, 1 author.

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

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.

Mayer et al., Zenodo, doi:10.5281/zenodo.5525362 (Preprint)

Safety and efficacy of a MEURI Program for the use of high dose ivermectin in COVID-19 patients

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.

risk of death, 55.1% lower, RR 0.45, p < 0.001, treatment 3,266, control 17,966, adjusted, OR converted to RR, multiple logistic regression, Figure 3.

risk of ICU admission, 65.9% lower, RR 0.34, p < 0.001, treatment 3,266, control 17,966, adjusted, OR converted to RR, multiple logistic regression, Figure 3.

risk of death, 27.6% lower, RR 0.72, p = 0.03, treatment 3,266, control 17,966, OR converted to RR, unadjusted.

risk of ICU admission, 26.0% lower, RR 0.74, p = 0.13, treatment 3,266, control 17,966, OR converted to RR, unadjusted.

Mayer et al., 9/23/2021, retrospective, Argentina, South America, preprint, 14 authors, dosage 540μg/kg days 1-5, mean prescribed dose.

Scheim, D., TrialsSite News (News)

Merck’s deadly Vioxx playbook, redux: a debunked smear campaign against its competing drug—the FDA-approved, Nobel prize-honored ivermectin

Discussion of Merck's ivermectin statements and past actions related to Vioxx raising significant concerns.

Scheim et al., 9/7/2021, preprint, 1 author.

Buonfrate et al., SSRN, doi:10.2139/ssrn.3918289 (Preprint)

High Dose Ivermectin for the Early Treatment of COVID-19 (COVIER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

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. 3 patients were hospitalized in the very high dose ivermectin arm (and 1 in the high dose arm) versus 0 in the control arm. While this result is not statistically significant, it may be in part due to randomization failure because 9 patients were randomized at the hospital for very high dose ivermectin versus 4 in the control arm, suggesting higher baseline severity. Supplementary data is not currently available. COVIER. NCT04438850.

risk of hospitalization, 600.0% higher, RR 7.00, p = 0.30, treatment 4 of 58 (6.9%), control 0 of 29 (0.0%), continuity correction due to zero event.

relative change in viral load, RR 0.69, p = 0.10, treatment 30, control 29, day 7, arm C.

relative change in viral load, RR 0.86, p = 0.12, treatment 28, control 29, day 7, arm B.

Buonfrate et al., 9/6/2021, Double Blind Randomized Controlled Trial, Italy, Europe, preprint, 18 authors, dosage 1200μg/kg days 1-5, arm B 600µg/kg, arm C 1200µg/kg.

Okogbenin et al., Nigerian Postgraduate Medical Journal, doi:10.4103/npmj.npmj_532_21 (Peer Reviewed)

Clinical characteristics, treatment modalities and outcome of coronavirus disease 2019 patients treated at thisday dome isolation and treatment centre, federal capital territory Abuja, Nigeria

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.

Marik et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001443 (Peer Reviewed) (meta analysis)

Ivermectin, A Reanalysis of the Data

Updated meta analysis showing no significant change if Elgazzar et al. is excluded.

Marik et al., 9/2/2021, peer-reviewed, 2 authors.

Neil et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001450 (Peer Reviewed) (meta analysis)

Bayesian Hypothesis Testing and Hierarchical Modeling of Ivermectin Effectiveness

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.

González-Paz et al., Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677 (Peer Reviewed)

Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

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.

González-Paz et al., Journal of Molecular Liquids, doi:10.1016/j.molliq.2021.117284 (Peer Reviewed)

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

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.

Kory, P., Substack (Review) (Preprint)

Summary of the Evidence for Ivermectin in COVID-19

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.

Elavarasi et al., medRxiv, doi:10.1101/2021.08.10.21261855 (Preprint)

Clinical features, demography and predictors of outcomes of SARS-CoV-2 infection in a tertiary care hospital in India - a cohort study

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%), unadjusted.

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.

Pedroso et al., The Brazilian Journal of Infectious Diseases, doi:10.1016/j.bjid.2021.101603 (Peer Reviewed)

Self-prescribed Ivermectin use is associated with a lower rate of seroconversion in health care workers diagnosed with COVID, in a dose-dependent response

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 [1]). Authors combine no dose and one dose. Clinical outcomes and timing of treatment are not provided.

[1] c19ivermectin.com/caly.html

Pedroso et al., 8/12/2021, peer-reviewed, 11 authors.

La Pampa, Argentina (News)

La Pampa expondrá a la comunidad científica los resultados del Programa de Intervención Monitoreado de Ivermectina

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.

risk of combined death/ICU, 38.0% lower, RR 0.62, treatment 3,269, control 18,149.

risk of death, 33.4% lower, RR 0.67, treatment 3,269, control 18,149, >40yo.

risk of death, 44.0% lower, RR 0.56, treatment 3,269, control 18,149, >40yo including comorbidities.

Excluded in after exclusion results of meta analysis: detail too minimal.

La Pampa et al., 8/10/2021, retrospective, Argentina, South America, preprint, 1 author, dosage 600μg/kg days 1-5.

Kow et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001441 (Review) (Peer Reviewed)

Pitfalls in Reporting Sample Size Calculation Across Randomized Controlled Trials Involving Ivermectin for the treatment of COVID-19

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.

Together Trial (News)

Early Treatment of COVID-19 with Repurposed Therapies: The TOGETHER Adaptive Platform Trial

Preliminary report from the Together Trial showing mortality RR 0.82 [0.44-1.52] and combined extended ER observation or hospitalization RR 0.91 [0.69-1.19].

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 — RR 0.76 [0.30-1.88] [jamanetwork.com].

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.

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 excluson criteria.

Time from symptom onset to randomization is specified as within 7 days. However the schedule of study activities specifies treatment administration only one day after randomization, suggesting that treatment was delayed an additional day for all patients.

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.

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].

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.

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]. Prior statements: [odysee.com].

There are two 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."

The trial is associated with:

MMS Holdings - a company 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].

Cytel Inc. - another statistical modelling company that helps pharmaceutical companies get approval - they work very closely with Pfizer [cytel.com].

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].

If you are a trial participant please contact us below. For other issues see: [twitter.com, twitter.com (B)].

1. ajtmh.org, https://www.ajtmh.org/view/journals/tpmd/104/1/article-p35.xml.

2. Amrhein et al., Nature, 567:305-307, Scientists rise up against statistical significance, https://www.nature.com/articles/d41586-019-00857-9.

3. certara.com, https://www.certara.com/pressrelea..ientific-data-access-and-analysis/.

4. cytel.com, https://www.cytel.com/blog/an-interview-with-pfizers-chris-conklin.

5. drive.google.com, https://drive.google.com/file/d/1RewIbMErzo0ALy3au9NbTy6DHBeRd7D2/view.

6. Faria et al., Science, doi:10.1126/science.abh2644, Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil, https://www.science.org/lookup/doi/10.1126/science.abh2644.

7. gatesopenresearch.org, https://gatesopenresearch.org/articles/5-117.

8. Guzzo et al., J. Clinical Pharmacology, doi:10.1177/009127002237994, Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects, https://accp1.onlinelibrary.wiley...7/009127002237994?sid=nlm%3Apubmed.

9. jamanetwork.com, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779044.

10. mmsholdings.com, https://www.mmsholdings.com/pfizer..-language-summary-writing-support/.

11. Nonaka et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.08.003, SARS-CoV-2 variant of concern P.1 (Gamma) infection in young and middle-aged patients admitted to the intensive care units of a single hospital in Salvador, Northeast Brazil, February 2021, https://www.sciencedirect.com/science/article/pii/S1201971221006354.

12. odysee.com, https://odysee.com/@FrontlineCovid..ents-defeating-the-delta-variant:a.

13. otempo.com.br, https://www.otempo.com.br/interess..eocupa-por-risco-a-saude-1.2466432.

14. ourworldindata.org, https://ourworldindata.org/grapher/covid-variants-area?country=~BRA.

15. reddit.com, https://www.reddit.com/r/ivermecti..trial_was_not_randomized_possible/.

16. Sabino et al., Lancet, doi:10.1016/S0140-6736(21)00183-5, Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence, https://www.thelancet.com/article/S0140-6736(21)00183-5/fulltext.

17. twitter.com, https://twitter.com/Covid19Crusher/status/1426612910579757059.

18. twitter.com (B), https://twitter.com/Covid19Crusher/status/1427255119800848386.

19. Yeh et al., BMJ, doi:10.1136/bmj.k5094 , Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial, https://www.bmj.com/content/363/bmj.k5094.

20. Zavascki et al., Research Square, doi:10.21203/rs.3.rs-910467/v1, Advanced ventilatory support and mortality in hospitalized patients with COVID-19 caused by Gamma (P.1) variant of concern compared to other lineages: cohort study at a reference center in Brazil, https://www.researchsquare.com/article/rs-910467/v1.

risk of death, 18.0% lower, RR 0.82, p = 0.54, treatment 18 of 677 (2.7%), control 22 of 678 (3.2%).

extended ER observation or hospitalization, 9.0% lower, RR 0.91, p = 0.51, treatment 86 of 677 (12.7%), control 95 of 678 (14.0%).

Excluded in after exclusion results of meta analysis: preliminary report with minimal details.

Together Trial et al., 8/6/2021, Double Blind Randomized Controlled Trial, Brazil, South America, preprint, 1 author, dosage 400μg/kg days 1-3.

Rana et al., Research Square, doi:10.21203/rs.3.rs-755838/v1 (Preprint)

A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection

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.

1. ajtmh.org, https://www.ajtmh.org/view/journals/tpmd/104/1/article-p35.xml.

2. Amrhein et al., Nature, 567:305-307, Scientists rise up against statistical significance, https://www.nature.com/articles/d41586-019-00857-9.

3. certara.com, https://www.certara.com/pressrelea..ientific-data-access-and-analysis/.

4. cytel.com, https://www.cytel.com/blog/an-interview-with-pfizers-chris-conklin.

5. drive.google.com, https://drive.google.com/file/d/1RewIbMErzo0ALy3au9NbTy6DHBeRd7D2/view.

6. Faria et al., Science, doi:10.1126/science.abh2644, Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil, https://www.science.org/lookup/doi/10.1126/science.abh2644.

7. gatesopenresearch.org, https://gatesopenresearch.org/articles/5-117.

8. Guzzo et al., J. Clinical Pharmacology, doi:10.1177/009127002237994, Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects, https://accp1.onlinelibrary.wiley...7/009127002237994?sid=nlm%3Apubmed.

9. jamanetwork.com, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779044.

10. mmsholdings.com, https://www.mmsholdings.com/pfizer..-language-summary-writing-support/.

11. Nonaka et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.08.003, SARS-CoV-2 variant of concern P.1 (Gamma) infection in young and middle-aged patients admitted to the intensive care units of a single hospital in Salvador, Northeast Brazil, February 2021, https://www.sciencedirect.com/science/article/pii/S1201971221006354.

12. odysee.com, https://odysee.com/@FrontlineCovid..ents-defeating-the-delta-variant:a.

13. otempo.com.br, https://www.otempo.com.br/interess..eocupa-por-risco-a-saude-1.2466432.

14. ourworldindata.org, https://ourworldindata.org/grapher/covid-variants-area?country=~BRA.

15. reddit.com, https://www.reddit.com/r/ivermecti..trial_was_not_randomized_possible/.

16. Sabino et al., Lancet, doi:10.1016/S0140-6736(21)00183-5, Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence, https://www.thelancet.com/article/S0140-6736(21)00183-5/fulltext.

17. twitter.com, https://twitter.com/Covid19Crusher/status/1426612910579757059.

18. twitter.com (B), https://twitter.com/Covid19Crusher/status/1427255119800848386.

19. Yeh et al., BMJ, doi:10.1136/bmj.k5094 , Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial, https://www.bmj.com/content/363/bmj.k5094.

20. Zavascki et al., Research Square, doi:10.21203/rs.3.rs-910467/v1, Advanced ventilatory support and mortality in hospitalized patients with COVID-19 caused by Gamma (P.1) variant of concern compared to other lineages: cohort study at a reference center in Brazil, https://www.researchsquare.com/article/rs-910467/v1.

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.

Santin et al., New Microbes and New Infections, doi:10.1016/j.nmni.2021.100924 (Review) (Peer Reviewed)

Ivermectin: a multifaceted drug of Nobel prize-honored distinction with indicated efficacy against a new global scourge, COVID-19

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.

Sathi et al., Journal of Cardiovascular Disease Research, doi:10.31838/jcdr.2021.12.05.11 (Peer Reviewed)

Clinical Effect of the Combination Therapy of Hydroxychloroquine, Azithromycin and Ivermectin in Patients with COVID-19

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.

Popp et al., Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD015017.pub2 (Preprint) (meta analysis)

Ivermectin for preventing and treating COVID‐19

This meta analysis is designed to exclude almost all studies. Authors select a small subset of studies, with a majority of results based on only 1 or 2 studies, showing positive (non-statistically significant) results for 8 of 9 outcomes across a total of 13 studies. 5 outcomes are based on a single study, and 4 are based on 2 studies.

Authors split up studies in order to dilute the effects and avoid statistical significance. However, we can consider the probability of 8 of 9 positive effects occurring due to chance for an ineffective treatment, which is very unlikely (0.02 with an independence assumption).

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 (Gonzalez et al. "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.

[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].

Bias due to funding is ignored for both analyzed studies and Cochrane. For Cochrane funders see [cochrane.org, cochrane.org (B)].

1. blogs.bmj.com, https://blogs.bmj.com/bmj/2018/11/..ochrane-no-longer-a-collaboration/.

2. bmj.com, https://www.bmj.com/content/364/bmj.k5302.

3. Butler et al., The Lancet Respiratory Medicine, doi:10.1016/S2213-2600(21)00310-6, Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial, https://www.sciencedirect.com/science/article/pii/S2213260021003106.

4. cochrane.org, https://www.cochrane.org/news/cochrane-announces-support-new-donor.

5. cochrane.org (B), https://www.cochrane.org/about-us/our-funders-and-partners.

6. ebm.bmj.com, https://ebm.bmj.com/content/23/5/165.

7. en.x-mol.com, https://en.x-mol.com/paper/article/947631.

8. Fordham et al., OSF Preprints, doi:10.31219/osf.io/mp4f2, The uses and abuses of systematic reviews, https://osf.io/mp4f2/.

9. gcgh.grandchallenges.org, https://gcgh.grandchallenges.org/a..n-opens-new-european-office-berlin.

Popp et al., 7/28/2021, preprint, 8 authors.

Ontai et al., medRxiv, doi:10.1101/2021.07.21.21260223 (Preprint)

Early multidrug treatment of SARS-CoV-2 (COVID-19) and decreased case fatality rates in Honduras

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.

1. blogs.bmj.com, https://blogs.bmj.com/bmj/2018/11/..ochrane-no-longer-a-collaboration/.

2. bmj.com, https://www.bmj.com/content/364/bmj.k5302.

3. Butler et al., The Lancet Respiratory Medicine, doi:10.1016/S2213-2600(21)00310-6, Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial, https://www.sciencedirect.com/science/article/pii/S2213260021003106.

4. cochrane.org, https://www.cochrane.org/news/cochrane-announces-support-new-donor.

5. cochrane.org (B), https://www.cochrane.org/about-us/our-funders-and-partners.

6. ebm.bmj.com, https://ebm.bmj.com/content/23/5/165.

7. en.x-mol.com, https://en.x-mol.com/paper/article/947631.

8. Fordham et al., OSF Preprints, doi:10.31219/osf.io/mp4f2, The uses and abuses of systematic reviews, https://osf.io/mp4f2/.

9. gcgh.grandchallenges.org, https://gcgh.grandchallenges.org/a..n-opens-new-european-office-berlin.

Ontai et al., 7/25/2021, preprint, 6 authors.

World Ivermectin Day (News)

World Ivermectin Day

Joint event by 22 worldwide organizations.

World Ivermectin Day et al., 7/24/2021, preprint, 1 author.

Mansour et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.108004 (Peer Reviewed)

Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study

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.

FLCCC Alliance and British Ivermectin Recommendation Development Group (News)

Joint Statement of the FLCCC Alliance and British Ivermectin Recommendation Development Group on Retraction of Early Research on Ivermectin

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.

Neil et al., ResearchGate, doi:0.13140/RG.2.2.31800.88323 (Preprint) (meta analysis)

Bayesian Meta Analysis of Ivermectin Effectiveness in Treating Covid-19 Disease

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.

Muthusamy et al., Journal of Virology & Antiviral Research (Peer Reviewed)

Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein

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.

Together Trial (News)

Together Trial removes mortality and adverse event outcomes, and sublingual administration mid-trial

Together Trial removes mortality and adverse event outcomes, and sublingual administration mid-trial.

Together Trial et al., 7/8/2021, preprint, 1 author.

Hazan et al., medRxiv, doi:10.1101/2021.07.06.21259924 (Preprint)

Effectiveness of Ivermectin-Based Multidrug Therapy in Severe Hypoxic Ambulatory COVID-19 Patients

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, 85.9% lower, RR 0.14, p = 0.04, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 93.3% lower, RR 0.07, p = 0.001, relative risk is not 0 because of continuity correction due to zero events.

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, 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.

Open Letter, Statement of Concern and Request for Retraction, re: Roman et al. (News)

Open Letter, Statement of Concern and Request for Retraction

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.

Adegboro et al., African Journal of Clinical and Experimental Microbiology, doi:10.4314/ajcem.v22i3.2 (Review) (Peer Reviewed)

A review of the anti-viral effects of ivermectin

Review of the antiviral effects of ivermectin.

Adegboro et al., 7/2/2021, peer-reviewed, 4 authors.

Vallejos et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06348-5 (Peer Reviewed)

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial

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 [Vallejos], 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.

There were no serious adverse events. NCT04529525.

1. Canga et al., AAPS J., doi:10.1208/s12248-007-9000-9, The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751445/.

2. scidev.net, https://www.scidev.net/america-lat..ta-saber-si-sirve-contra-covid-19/.

3. Vallejos et al., Preliminary Results, Ivermectina en agentes de salud e IVERCOR COVID19, https://twitter.com/Covid19Crusher/status/1365420061859717124.

4. Yeh et al., BMJ, doi:10.1136/bmj.k5094 , Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial, https://www.bmj.com/content/363/bmj.k5094.

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.

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.

risk of hospitalization, 33.0% lower, RR 0.67, p = 0.23, treatment 14 of 250 (5.6%), control 21 of 251 (8.4%), OR converted to RR.

risk of no virological cure, 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.

risk of no virological cure, 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.

Vallejos et al., 7/2/2021, Double Blind Randomized Controlled Trial, Argentina, South America, peer-reviewed, 29 authors, dosage 12mg days 1-2, <80kg 12mg, 80-110kg 18mg, >110kg 24mg.

Turkia, M., ResearchGate, doi:10.13140/RG.2.2.16973.36326 (Review) (Preprint)

A Continuation of a Timeline of Ivermectin-Related Events in the COVID-19 Pandemic [June 30, 2021]

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.

1. Canga et al., AAPS J., doi:10.1208/s12248-007-9000-9, The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751445/.

2. scidev.net, https://www.scidev.net/america-lat..ta-saber-si-sirve-contra-covid-19/.

3. Vallejos et al., Preliminary Results, Ivermectina en agentes de salud e IVERCOR COVID19, https://twitter.com/Covid19Crusher/status/1365420061859717124.

4. Yeh et al., BMJ, doi:10.1136/bmj.k5094 , Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial, https://www.bmj.com/content/363/bmj.k5094.

Turkia et al., 6/30/2021, preprint, 1 author.

Roman et al., Clinical Infectious Diseases, doi:10.1093/cid/ciab591 (preprint 5/25/21) (Peer Reviewed) (meta analysis)

Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials

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 PubMed search strategy provided is syntactically incorrect. For additional errors, see [pubpeer.com]. Also see [roundingtheearth.substack.com].

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.

1. bird-group.org, https://bird-group.org/rebuttal-to-roman-et-al/.

2. cellohealth.com, https://cellohealth.com/.

3. pubpeer.com, https://pubpeer.com/publications/955418F3D4D39742CFFA8C1B023AA3.

4. roundingtheearth.substack.com, https://roundingtheearth.substack...ta-analytical-fixers-an-ivermectin.

5. trialsitenews.com, https://trialsitenews.com/statemen..iseases-acceptance-of-roman-et-al/.

Roman et al., 6/28/2021, peer-reviewed, 6 authors.

Jagiasi et al., The International Journal of Clinical Practice, doi:10.1111/ijcp.14574 (Review) (Peer Reviewed)

Variation in therapeutic strategies for the management of severe COVID-19 in India- A nationwide cross-sectional survey

Survey of medication use for severe COVID-19 in India, showing 33% adoption of ivermectin as of January 2021.

1. bird-group.org, https://bird-group.org/rebuttal-to-roman-et-al/.

2. cellohealth.com, https://cellohealth.com/.

3. pubpeer.com, https://pubpeer.com/publications/955418F3D4D39742CFFA8C1B023AA3.

4. roundingtheearth.substack.com, https://roundingtheearth.substack...ta-analytical-fixers-an-ivermectin.

5. trialsitenews.com, https://trialsitenews.com/statemen..iseases-acceptance-of-roman-et-al/.

Jagiasi et al., 6/25/2021, peer-reviewed, 19 authors.

Misiones Ministry of Public Health (News)

Results from ivermectin use from the Misiones Ministry of Public Health

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.

Lind et al., Journal of General Internal Medicine, doi:10.1007/s11606-021-06948-6 (Review) (Peer Reviewed)

Increase in Outpatient Ivermectin Dispensing in the US During the COVID-19 Pandemic: A Cross-Sectional Analysis

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.

Krolewiecki et al., EClinicalMedicine, doi:10.1016/j.eclinm.2021.100959 (Peer Reviewed)

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

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: [1].

[1] sciencedirect.com/science/article/pii/S2589537021003990

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.

risk of disease progression, 3.7% higher, RR 1.04, p = 1.00, treatment 2 of 27 (7.4%), control 1 of 14 (7.1%).

viral decay rate, 65.6% lower, RR 0.34, p = 0.09, treatment 20, control 14, relative mean viral decay rate (corrigendum table 2).

Krolewiecki et al., 6/18/2021, Randomized Controlled Trial, Argentina, South America, peer-reviewed, 23 authors, dosage 600μg/kg days 1-5.

Bryant et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001402 (preprint 3/11/21) (Peer Reviewed) (meta analysis)

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Systematic review, meta analysis, and trial sequential analysis of 24 RCTs finding mortality RR 0.38 [0.19-0.73].

risk of death, 62.0% lower, RR 0.38, p = 0.005.

Bryant et al., 6/17/2021, peer-reviewed, 7 authors.

Zaidi et al., The Journal of Antibiotics, doi:10.1038/s41429-021-00430-5 (Review) (Peer Reviewed)

The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article

Extensive review of 20 mechanisms of action of ivermectin for SARS-CoV-2.

This paper was censored by the editor for reasons unrelated to the review of mechanisms of action. The editor required the authors to change the paper to include false statements, which the authors declined [1].

[1] facebook.com/groups/3595465843801899/permalink/5132874373394364

Zaidi et al., 6/15/2021, peer-reviewed, 2 authors.

Aref et al., International Journal of Nanomedicine, doi:10.2147/IJN.S313093 (Peer Reviewed)

Clinical, Biochemical and Molecular Evaluations of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Reducing Upper Respiratory Symptoms of Mild COVID-19

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.

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.

relative duration of cough, 64.3% lower, relative time 0.36, p < 0.001, treatment 57, control 57.

risk of no virological cure, 78.6% lower, RR 0.21, p = 0.004, treatment 3 of 57 (5.3%), control 14 of 57 (24.6%).

time to viral-, 35.7% lower, relative time 0.64, p < 0.001, treatment 57, control 57.

Aref et al., 6/15/2021, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 7 authors, dosage not specified.

Hariyanto et al., Reviews In Medical Virology, doi:10.1002/rmv.2265 (Peer Reviewed) (meta analysis)

Ivermectin and outcomes from Covid-19 pneumonia: A systematic review and meta-analysis of randomized clinical trial studies

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.

Hariyanto et al., 6/6/2021, peer-reviewed, 5 authors.

Wang et al., medRxiv, doi:10.1101/2021.06.01.21258147 (Review) (Preprint)

Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19

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.

Abd-Elsalam et al., Journal of Medical Virology, doi:10.1002/jmv.27122 (Peer Reviewed)

Clinical Study Evaluating the Efficacy of Ivermectin in COVID-19 Treatment: A Randomized Controlled Study

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%), OR converted to RR, logistic regression.

risk of mechanical ventilation, no change, RR 1.00, p = 1.00, treatment 3 of 82 (3.7%), control 3 of 82 (3.7%).

hospitalization time, 19.6% lower, relative time 0.80, p = 0.09, treatment 82, control 82.

Abd-Elsalam et al., 6/2/2021, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 16 authors, dosage 12mg days 1-3.

Mondal et al., Journal of the Indian Medical Association, 119:5 (Peer Reviewed)

Prevalence of COVID-19 Infection and Identification of Risk Factors among Asymptomatic Healthcare Workers: A Serosurvey Involving Multiple Hospitals in West Bengal

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, OR converted to RR, multivariate logistic regression, control prevalence approximated with overall prevalence.

Mondal et al., 5/31/2021, retrospective, India, South Asia, peer-reviewed, 11 authors, dosage not specified.

Mountain Valley MD (Preprint) (In Vitro)

Mountain Valley MD Receives Successful Results From BSL-4 COVID-19 Clearance Trial on Three Variants Tested With Ivectosol™

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.

FLCCC Public Statement (News)

FLCCC Alliance Statement on the Irregular Actions of Public Health Agencies and the Widespread Disinformation Campaign Against Ivermectin

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.

Faisal et al., The Professional Medical Journal, doi:10.29309/TPMJ/2021.28.05.5867 (Peer Reviewed)

Potential use of azithromycin alone and in combination with ivermectin in fighting against the symptoms of COVID-19

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%), 6-8 days, mid-recovery.

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%), 3-5 days.

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%), 9-10 days.

Faisal et al., 5/10/2021, Randomized Controlled Trial, Pakistan, South Asia, peer-reviewed, 3 authors, dosage 12mg days 1-5.

Zatloukal et al. (News) (In Vitro)

News report on In Vitro results from the research institute of Prof. Zatloukal

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.

Qureshi et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1906750 (Peer Reviewed)

Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications

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.

Karale et al., medRxiv, doi:10.1101/2021.04.30.21256415 (Preprint) (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

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.

Merino et al., SocArXiv Papers, doi:10.31235/osf.io/r93g4 (Preprint)

Ivermectin and the odds of hospitalization due to COVID-19: evidence from a quasi-experimental analysis based on a public intervention in Mexico City

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.

risk of hospitalization, 74.4% lower, RR 0.26, p < 0.001, model 7, same time period, patients receiving kit.

risk of hospitalization, 68.4% lower, RR 0.32, p < 0.001, model 1, different time periods, administrative rule.

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.

Kory et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001377 (Review) (Peer Reviewed)

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

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.

Kory et al., 4/30/2021, peer-reviewed, 5 authors.

Ahsan et al., Cureus, doi:10.7759/cureus.14761 (Peer Reviewed)

Clinical Variants, Characteristics, and Outcomes Among COVID-19 Patients: A Case Series Analysis at a Tertiary Care Hospital in Karachi, Pakistan

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%).

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.

DiNicolantonio et al., Open Heart, doi:10.1136/openhrt-2021-001655 (Review) (Peer Reviewed)

Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors

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.

Loue et al., J. Infectious Diseases and Epidemiology, doi:10.23937/2474-3658/1510202 (Peer Reviewed)

Ivermectin and COVID-19 in Care Home: Case Report

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%).

risk of COVID-19 severe case, 55.0% lower, RR 0.45, p = 0.11, treatment 3 of 10 (30.0%), control 10 of 15 (66.7%).

Loue et al., 4/17/2021, retrospective quasi-randomized (patient choice), France, Europe, peer-reviewed, 2 authors, dosage 200μg/kg single dose.

Morgenstern et al., Cureus, doi:10.7759/cureus.17455 (preprint 4/16/2021) (Peer Reviewed)

Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study

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%), relative risk is not 0 because of continuity correction due to zero events, PSM.

risk of COVID-19 case, 74.0% lower, RR 0.26, p = 0.008, treatment 5 of 271 (1.8%), control 18 of 271 (6.6%), adjusted, PSM, multivariate Cox regression.

Morgenstern et al., 4/16/2021, retrospective, propensity score matching, Dominican Republic, Caribbean, peer-reviewed, 16 authors, dosage 200μg/kg weekly.

Schöning et al., Research Square, doi:10.21203/rs.3.rs-379291/v1 (Preprint)

Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains

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.

Seet et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035 (Peer Reviewed)

Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial

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 = 0.01, treatment 32 of 617 (5.2%), control 64 of 619 (10.3%).

risk of COVID-19 case, 5.8% lower, RR 0.94, p = 0.61, treatment 398 of 617 (64.5%), control 433 of 619 (70.0%), adjusted, OR converted to RR, model 6.

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.

Bello et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857 (Peer Reviewed)

Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets

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.

Turkia, M., Research Gate (Review) (Preprint)

A timeline of ivermectin-related events in the COVID-19 pandemic

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.

Mourya et al., Int. J. Health and Clinical Research (Peer Reviewed)

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

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 virological cure, 89.4% lower, RR 0.11, p < 0.001, treatment 5 of 50 (10.0%), control 47 of 50 (94.0%).

Mourya et al., 4/1/2021, retrospective, India, South Asia, peer-reviewed, 5 authors, dosage 12mg days 1-7.

Wehbe et al., Front. Immunol., doi:10.3389/fimmu.2021.663586 (Review) (Peer Reviewed)

Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities

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.

Chahla et al., Research Square, doi:10.21203/rs.3.rs-495945/v1 (original preprint 3/30) (Preprint)

Cluster Randomised Trials - Ivermectin Repurposing For COVID-19 Treatment Of Outpatients With Mild Disease In Primary Health Care Centers

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%), adjusted, OR converted to RR, logistic regression.

Chahla et al., 3/30/2021, Cluster Randomized Controlled Trial, Argentina, South America, preprint, 9 authors, dosage 24mg days 1, 8, 15, 22.

Kow et al., Pharmacological Reports, doi:10.1007/s43440-021-00245-z (Peer Reviewed) (meta analysis)

The association between the use of ivermectin and mortality in patients with COVID-19: a 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.

Tanioka et al., medRxiv, doi:10.1101/2021.03.26.21254377 (Preprint)

Why COVID-19 is not so spread in Africa: How does Ivermectin affect it?

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.

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.

Udofia et al., Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2 (Peer Reviewed)

In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV

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.

Choudhury et al., Future Medicine, doi:10.2217/fvl-2020-0342 (Peer Reviewed)

Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach

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.

Huvemek Press Release (Preprint)

Kovid-19 - Huvemek® Phase 2 clinical trial

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 [1]. Limited data has been reported currently. No serious adverse events were observed. EudraCT 2020-002091-12.

[1] twitter.com/Covid19Crusher/status/1367854845340844039

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%), day 7, patients with improvement on WHO scale.

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%), day 4, patients with improvement on WHO scale.

Huvemek et al., 3/25/2021, Double Blind Randomized Controlled Trial, Bulgaria, Europe, preprint, 1 author, dosage 400μg/kg days 1-3.

Yagisawa et al., The Japanese Journal of Antibiotics, 74-1, Mar 2021 (Review) (Peer Reviewed)

Global trends in clinical studies of ivermectin in COVID-19

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 [1].

[1] en.wikipedia.org/wiki/Satoshi_%C5%8Cmura

Yagisawa et al., 3/24/2021, peer-reviewed, 4 authors.

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

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.

Del Franco et al., Journal of Biomedical Research and Clinical Investigation, doi:10.31546/2633-8653.1008 (Peer Reviewed)

Ivermectin in Long-Covid Patients: A Retrospective Study

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.

Kumar et al., bioRxiv, doi:10.1101/2021.05.17.444467 (Preprint) (In Vitro)

Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells

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 [1]. 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. [2] note that the absence of systemic inflammation, circulatory factors, and other paracrine systemic influences is a potential limitation of the isolated cell system.

[1] journals.physiology.org/doi/pdf/10.1152/ajplung.1994.266.5.L493

[2] journals.physiology.org/doi/pdf/10.1152/ajplung.1994.266.5.L493

Kumar et al., 3/17/2021, preprint, 14 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Roy et al., medRxiv, doi:10.1101/2021.03.08.21252883 (Preprint)

Outcome of Different Therapeutic Interventions in Mild COVID-19 Patients in a Single OPD Clinic of West Bengal: A Retrospective study

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.

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.

Nardelli et al., Signa Vitae, doi:10.22514/sv.2021.043 (Peer Reviewed) (meta analysis)

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?

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%), OR converted to RR.

Nardelli et al., 3/11/2021, peer-reviewed, 8 authors.

Scheim et al., OSF Preprints (Preprint) (meta analysis)

Ivermectin sales in Valle del Cauca, Colombia, patterns of AEs, and other background re López-Medina et al. 2021

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.

Scheim et al., OSF Preprints (Preprint) (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

Report on protocol violations in López-Medina et al.

Scheim et al., 3/11/2021, preprint, 3 authors.

Kern et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678 (Peer Reviewed)

Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

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.

Yesilbag et al., Virus Research, doi:10.1016/j.virusres.2021.198384 (Peer Reviewed) (In Vitro)

Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) 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.

Pott-Junior et al., Toxicology Reports, doi:10.1016/j.toxrep.2021.03.003 (Peer Reviewed)

Use of ivermectin in the treatment of Covid-19: a pilot trial

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.

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%).

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%).

relative improvement in Ct value, 0.8% lower, RR 0.99, p = 1.00, treatment 27, control 3.

risk of no virological cure, 11.1% higher, RR 1.11, p = 1.00, treatment 10 of 27 (37.0%), control 1 of 3 (33.3%).

time to viral-, 16.7% lower, relative time 0.83, treatment 27, control 3.

Pott-Junior et al., 3/9/2021, Randomized Controlled Trial, Brazil, South America, peer-reviewed, 10 authors, dosage 200μg/kg single dose, dose varies in three arms 100, 200, 400μg/kg.

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

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.

Guzman et al., medRxiv, doi:10.1101/2021.03.04.21252084 (Preprint)

Factors associated with increased mortality in critically ill COVID-19 patients in a Mexican public hospital: the other faces of health system oversaturation

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, RR 0.81, p = 0.35.

Guzman et al., 3/8/2021, retrospective, Mexico, North America, preprint, 11 authors.

Galan et al., Pathogens and Global Health, doi:10.1080/20477724.2021.1890887 (Peer Reviewed)

Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 infection

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 [1] 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.

[1] sciencedirect.com/science/article/pii/S2214109X20302850

Galan et al., 3/8/2021, peer-reviewed, 19 authors.

Descotes, J., ImmunoSafe Consultance (Preprint)

Medical Safety of Ivermectin

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.

López-Medina et al., JAMA, doi:10.1001/jama.2021.3071 (Peer Reviewed)

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial

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 (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].

Most data was collected via surveys, without physical examination. 87% medication adherence. NCT04405843.

1. francesoir.fr, https://www.francesoir.fr/societe-..-participants-letude-est-confirmee.

2. Guzzo et al., J. Clinical Pharmacology, doi:10.1177/009127002237994, Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects, https://accp1.onlinelibrary.wiley...7/009127002237994?sid=nlm%3Apubmed.

3. jamaletter.com, https://jamaletter.com/.

4. jamanetwork.com, https://jamanetwork.com/journals/jama/fullarticle/2777389.

5. osf.io, https://osf.io/6m3ch/.

6. osf.io (B), https://osf.io/bvznd.

7. trialsitenews.com, https://trialsitenews.com/jama-ive..ceived-participants-on-study-drug/.

9. trialsitenews.com (C), https://trialsitenews.com/jama-ive..articipants-is-publicly-confirmed/.

10. trialsitenews.com (D), https://trialsitenews.com/is-there..g-the-trial-site-during-the-study/.

11. Yeh et al., BMJ, doi:10.1136/bmj.k5094 , Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial, https://www.bmj.com/content/363/bmj.k5094.

risk of death, 66.8% lower, RR 0.33, p = 0.50, treatment 0 of 200 (0.0%), control 1 of 198 (0.5%), relative risk is not 0 because of continuity correction due to zero events.

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%), OR converted to RR.

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%), OR converted to RR.

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%), OR converted to RR.

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%), OR converted to RR.

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%), OR converted to RR, Cox proportional-hazard model.

hazard ratio for lack of resolution of symptoms, 6.5% lower, RR 0.93, p = 0.53, treatment 200, control 198.

relative median time to resolution of symptoms, 16.7% lower, relative time 0.83, treatment 200, control 198.

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, dosage 300μg/kg days 1-5.

Saha et al., Structural Chemistry, doi:10.1007/s11224-021-01776-0 (preprint 3/1) (Preprint)

The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2

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.

1. francesoir.fr, https://www.francesoir.fr/societe-..-participants-letude-est-confirmee.

2. Guzzo et al., J. Clinical Pharmacology, doi:10.1177/009127002237994, Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects, https://accp1.onlinelibrary.wiley...7/009127002237994?sid=nlm%3Apubmed.

3. jamaletter.com, https://jamaletter.com/.

4. jamanetwork.com, https://jamanetwork.com/journals/jama/fullarticle/2777389.

5. osf.io, https://osf.io/6m3ch/.

6. osf.io (B), https://osf.io/bvznd.

7. trialsitenews.com, https://trialsitenews.com/jama-ive..ceived-participants-on-study-drug/.

9. trialsitenews.com (C), https://trialsitenews.com/jama-ive..articipants-is-publicly-confirmed/.

10. trialsitenews.com (D), https://trialsitenews.com/is-there..g-the-trial-site-during-the-study/.

11. Yeh et al., BMJ, doi:10.1136/bmj.k5094 , Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial, https://www.bmj.com/content/363/bmj.k5094.

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.

Gonzalez et al., medRxiv, doi:10.1101/2021.02.18.21252037 (Preprint)

Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial

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 [web.archive.org] (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%

Although the data from this study is reported to be available, a researcher has been unable to obtain the data for verification [twitter.com].

1. gob.mx, https://www.gob.mx/salud/documentos/datos-abiertos-152127.

2. Guzman et al., medRxiv, doi:10.1101/2021.03.04.21252084, Factors associated with increased mortality in critically ill COVID-19 patients in a Mexican public hospital: the other faces of health system oversaturation, https://www.medrxiv.org/content/10.1101/2021.03.04.21252084v1.

3. twitter.com, https://twitter.com/Data_is_Louder/status/1447387394408321026.

4. web.archive.org, http://web.archive.org/web/2021091..jchamie/status/1438631284163715074.

risk of death, 14.4% lower, RR 0.86, p = 1.00, treatment 5 of 36 (13.9%), control 6 of 37 (16.2%).

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%).

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%).

hospitalization time, 20.0% higher, relative time 1.20, p = 0.43, treatment 36, control 37.

Gonzalez et al., 2/23/2021, Double Blind Randomized Controlled Trial, Mexico, North America, preprint, mean age 53.8, 13 authors, dosage 12mg single dose, 18mg for patients >80kg.

BIRD Meeting 20th February 2021 (News)

BIRD Meeting 20th February 2021

The British Ivermectin Recommendation Development (BIRD) panel, with dozens of multi-national scientists & doctors, issued sweeping recommendations for the immediate global use of ivermectin.

1. gob.mx, https://www.gob.mx/salud/documentos/datos-abiertos-152127.

2. Guzman et al., medRxiv, doi:10.1101/2021.03.04.21252084, Factors associated with increased mortality in critically ill COVID-19 patients in a Mexican public hospital: the other faces of health system oversaturation, https://www.medrxiv.org/content/10.1101/2021.03.04.21252084v1.

3. twitter.com, https://twitter.com/Data_is_Louder/status/1447387394408321026.

4. web.archive.org, http://web.archive.org/web/2021091..jchamie/status/1438631284163715074.

BIRD et al., 2/20/2021, preprint, 1 author.

Elalfy et al., J. Med. Virol., doi:10.1002/jmv.26880 (Peer Reviewed)

Effect of a combination of Nitazoxanide, Ribavirin and Ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-1

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 virological cure, 86.9% lower, RR 0.13, p < 0.001, treatment 7 of 62 (11.3%), control 44 of 51 (86.3%), day 15.

risk of no virological cure, 58.1% lower, RR 0.42, p < 0.001, treatment 26 of 62 (41.9%), control 51 of 51 (100.0%), day 7.

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.

Behera et al., Cureus 13:8, doi:10.7759/cureus.16897 (preprint 2/15/21) (Peer Reviewed)

Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers

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 COVID-19 case, 83.0% lower, RR 0.17, p < 0.001, treatment 45 of 2,199 (2.0%), control 133 of 1,147 (11.6%), two doses.

risk of COVID-19 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.

Behera et al., 2/15/2021, prospective, India, South Asia, peer-reviewed, 14 authors, dosage 300μg/kg days 1, 4.

Biber et al., medRxiv, doi:10.1101/2021.05.31.21258081 (results 2/12/21) (Preprint)

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

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%).

risk of no virological cure, 44.8% lower, RR 0.55, p = 0.04, treatment 13 of 47 (27.7%), control 21 of 42 (50.0%), adjusted, OR converted to RR, multivariable logistic regression, day 6, Ct>30.

risk of no virological cure, 70.2% lower, RR 0.30, p = 0.14, treatment 2 of 47 (4.3%), control 6 of 42 (14.3%), day 10, non-infectious samples (Ct>30 or non-viable culture).

risk of no virological cure, 82.1% lower, RR 0.18, p = 0.01, treatment 2 of 47 (4.3%), control 10 of 42 (23.8%), day 8, non-infectious samples (Ct>30 or non-viable culture).

risk of no virological cure, 75.6% lower, RR 0.24, p = 0.02, treatment 3 of 47 (6.4%), control 11 of 42 (26.2%), day 6, non-infectious samples (Ct>30 or non-viable culture).

risk of no virological cure, 65.1% lower, RR 0.35, p = 0.05, treatment 4 of 28 (14.3%), control 9 of 22 (40.9%), day 4, non-infectious samples (Ct>30 or non-viable culture).

risk of no virological cure, 51.9% lower, RR 0.48, p = 0.08, treatment 7 of 47 (14.9%), control 13 of 42 (31.0%), day 10, Ct>30.

risk of no virological cure, 57.9% lower, RR 0.42, p = 0.02, treatment 8 of 47 (17.0%), control 17 of 42 (40.5%), day 8, Ct>30.

risk of no virological cure, 44.7% lower, RR 0.55, p = 0.05, treatment 13 of 47 (27.7%), control 21 of 42 (50.0%), day 6, Ct>30.

risk of no virological cure, 31.9% lower, RR 0.68, p = 0.16, treatment 13 of 28 (46.4%), control 15 of 22 (68.2%), day 4, Ct>30.

Biber et al., 2/12/2021, Double Blind Randomized Controlled Trial, Israel, Middle East, preprint, 10 authors, dosage 12mg days 1-3, 15mg for patients >= 70kg.

Lima-Morales (Peer Reviewed)

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

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%), adjusted, OR converted to RR, multivariate.

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%).

risk of hospitalization, 67.4% lower, RR 0.33, p < 0.001, treatment 44 of 481 (9.1%), control 89 of 287 (31.0%), adjusted, OR converted to RR, multivariate.

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%), adjusted, OR converted to RR, recovery at day 14 after symptoms, multivariate.

Lima-Morales et al., 2/10/2021, prospective, Mexico, North America, peer-reviewed, 9 authors, 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.

Mohan et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.08.021 (preprint 2/2/2021) (Peer Reviewed)

Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): a single-centre randomized, placebo-controlled trial

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%), ivermectin 24mg.

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%), ivermectin 12mg.

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%), ivermectin 24mg.

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%), ivermectin 12mg.

risk of no virological cure, 23.8% lower, RR 0.76, p = 0.18, treatment 21 of 40 (52.5%), control 31 of 45 (68.9%), ivermectin 24mg, day 5.

risk of no virological cure, 5.6% lower, RR 0.94, p = 0.82, treatment 26 of 40 (65.0%), control 31 of 45 (68.9%), ivermectin 12mg, day 5.

risk of no virological cure, 10.3% lower, RR 0.90, p = 0.65, treatment 20 of 36 (55.6%), control 26 of 42 (61.9%), ivermectin 24mg, day 7.

risk of no virological cure, 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.

Mohan et al., 2/2/2021, Double Blind Randomized Controlled Trial, India, South Asia, peer-reviewed, 27 authors, dosage 400μg/kg single dose, 200μg/kg also tested.

Cobos-Campos et al., Clin. Res. Trials, 2021, doi:10.15761/CRT.1000333 (Peer Reviewed) (meta analysis)

Potential use of ivermectin for the treatment and profilaxis of SARS-CoV-2 infection: Efficacy of ivermectin for SARS-CoV-2

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.

Castaneda-Sabogal et al., medRxiv, doi:10.1101/2021.01.26.21250420 (Preprint) (meta analysis)

Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis

Student-written 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: [1, 2]

Authors on Twitter: [3, 4, 5, 6]

[1] twitter.com/Covid19Crusher/status/1354463260599328778

[2] twitter.com/joshuanbarbozam/status/1354471295690403840

[3] twitter.com/DiegoMichilot

[4] twitter.com/carlostoro_29

[5] twitter.com/christiansr96

[6] twitter.com/joshuanbarbozam

Castaneda-Sabogal et al., 1/27/2021, preprint.

Eweas et al., Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908 (Peer Reviewed)

Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2

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 M^pro 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.

Errecalde et al., Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017 (Peer Reviewed)

Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model

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.

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

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.

Mody et al., Communications Biology, doi:10.1038/s42003-020-01577-x (Peer Reviewed) (In Vitro)

Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

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.

Shahbaznejad et al., Clinical Therapeutics, doi:10.1016/j.clinthera.2021.04.007 (partial results available 1/19) (Peer Reviewed)

Effect of ivermectin on COVID-19: A multicenter double-blind randomized controlled clinical trial

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 [1] and the author response [2].

[1] sciencedirect.com/science/article/pii/S0149291821002502

[2] clinicaltherapeutics.com/article/S0149-2918(21)00251-4/fulltext

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.

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%).

recovery time, 31.6% lower, relative time 0.68, p = 0.05, treatment 35, control 34, duration of dsypnea.

recovery time, 19.2% lower, relative time 0.81, p = 0.02, treatment 35, control 34, duration of all symptoms.

hospitalization time, 15.5% lower, relative time 0.85, p = 0.02, treatment 35, control 34.

Shahbaznejad et al., 1/19/2021, Double Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, dosage 200μg/kg single dose.

Hill et al., Research Square, doi:10.21203/rs.3.rs-148845/v1 (Preprint) (meta analysis)

Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection

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 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) [1, 2, 3]. Note that one of the 18 studies in this analysis has since been withdrawn (Elgazzar).

[1] francesoir.fr/videos-les-debriefings/le-scandale-de-livermectine-tess-lawrie-le-retour

[2] youtube.com/watch?v=y2FWPQm6sxw&t=3s

[3] reddit.com/r/ivermectin/comments/m5kr7b/dr_tess_lawrie_discusses_her_ivermectin/

risk of death, 75.0% lower, RR 0.25, p < 0.001.

Hill et al., 1/19/2021, preprint, 40 authors.

Samaha et al., Viruses, doi:10.3390/v13060989 (results 1/16) (Peer Reviewed)

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

This study has been reported as pending retraction and has been removed.

Samaha et al., 1/16/2021, peer-reviewed, 16 authors.

Bukhari et al., medRxiv, doi:10.1101/2021.02.02.21250840 (results 1/16) (Preprint)

Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease

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 virological cure, 82.4% lower, RR 0.18, p < 0.001, treatment 4 of 41 (9.8%), control 25 of 45 (55.6%), day 7.

risk of no virological cure, 38.7% lower, RR 0.61, p < 0.001, treatment 24 of 41 (58.5%), control 43 of 45 (95.6%), day 3.

Bukhari et al., 1/16/2021, Randomized Controlled Trial, Pakistan, South Asia, preprint, 10 authors, dosage 12mg single dose.

Kory et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.643369 (Review) (Peer Reviewed)

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

Meta analysis of ivermectin clinical studies and natural experiments where ivermectin has been widely used, showing efficacy of ivermectin in prophylaxis and treatment of COVID-19. This paper was censored by the journal after acceptance [1].

[1] the-scientist.com/news-opinion/frontiers-removes-controversial-ivermectin-paper-pre-publication-68..

Kory et al., 1/13/2021, peer-reviewed, 10 authors.

Okumuş et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06104-9 (preprint 1/12) (Peer Reviewed)

Evaluation of the Effectiveness and Safety of Adding Ivermectin to Treatment in Severe COVID-19 Patients

Small RCT for severe COVID-19 comparing the addition of ivermectin to SOC (low dose HCQ+AZ+favipiravir), with 30 treatment and 30 control patients in Turkey, showing lower mortality and faster clinical recovery. Authors also investigate the presence of gene mutations that alter ivermectin metabolism, predicting that ivermectin can be used safely without serious side effects in patients without MDR-1/ABCB1 and/or CYP3A4 gene mutation, and recommending monitoring and appropriate treatment if necessary when sequencing is unavailable. NCT04646109.

risk of death, 33.3% lower, RR 0.67, p = 0.55, treatment 6 of 30 (20.0%), control 9 of 30 (30.0%).

risk of no improvement at day 10, 42.9% lower, RR 0.57, p = 0.18, treatment 8 of 30 (26.7%), control 14 of 30 (46.7%).

risk of no improvement at day 5, 15.8% lower, RR 0.84, p = 0.60, treatment 16 of 30 (53.3%), control 19 of 30 (63.3%).

risk of no virological cure, 80.0% lower, RR 0.20, p = 0.02, treatment 2 of 16 (12.5%), control 5 of 8 (62.5%), day 10.

Okumuş et al., 1/12/2021, Double Blind Randomized Controlled Trial, Turkey, Europe, peer-reviewed, 15 authors, dosage 200μg/kg days 1-5, 36-50kg - 9mg, 51-65kg - 12mg, 66-79kg - 15mg, >80kg 200μg/kg.

Chahla et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001433 (Peer Reviewed)

A randomized trial - intensive treatment based in ivermectin and iota-carrageenan as pre-exposure prophylaxis for COVID-19 in healthcare agents

Prophylaxis RCT for ivermectin and iota-carrageenan in Argentina, 117 healthcare workers treated with ivermectin and iota-carrageenan, and 117 controls, showing significantly lower cases with treatment. There were no moderate/severe cases with treatment vs. 10 in the control group. There were 4 cases with treatment (all mild) vs. 25 for the control group. NCT04701710.

risk of moderate/severe case, 95.2% lower, RR 0.05, p = 0.002, treatment 0 of 117 (0.0%), control 10 of 117 (8.5%), relative risk is not 0 because of continuity correction due to zero events, moderate/severe COVID-19.

risk of COVID-19 case, 84.0% lower, RR 0.16, p = 0.004, treatment 4 of 117 (3.4%), control 25 of 117 (21.4%), adjusted, OR converted to RR, all cases.

Chahla et al., 1/11/2021, Randomized Controlled Trial, Argentina, South America, peer-reviewed, 11 authors, dosage 12mg weekly, this trial uses multiple treatments in the treatment arm (combined with iota-carrageenan) - results of individual treatments may vary.

Bousquet-Melou et al., Preprint, doi:10.22541/au.161047848.80388481/v1 (Preprint)

Large Impact of obesity on the disposition of ivermectin, moxidectin and eprinomectin in a canine model: relevance for COVID-19 patients

Animal dosing study with an obese dog model concluding that ivermectin maintenance doses should be based on lean body weight and not the total body weight in obese subjects, while the loading dose should be based on the total body weight.

Bousquet-Melou et al., 1/11/2021, preprint, 5 authors.

Formiga et al., J. Control Release, doi:10.1016/j.jconrel.2020.10.009 (Review) (Peer Reviewed)

Ivermectin: an award-winning drug with expected antiviral activity against COVID-19

Review hypothesizing that micro- and nanotechnology-based formulations of ivermectin for the pulmonary delivery of ivermectin may be beneficial for use with COVID-19.

Formiga et al., 1/10/2021, peer-reviewed, 6 authors.

Ravikirti et al., Journal of Pharmacy & Pharmaceutical Sciences, doi:10.18433/jpps32105 (Peer Reviewed)

Ivermectin as a potential treatment for mild to moderate COVID-19: A double blind randomized placebo-controlled trial

RCT with 112 mild and moderate COVID-19 patients in India, showing lower mortality, ventilation, and ICU admission, although not statistically significant due to the small number of events. There was no mortality in the treatment arm (55 patients) versus 7% (4 of 57) in the control arm. The PCR result is subject to confounding by biased loss of followup, with 23 lost in the treatment group and 13 in the control group, and 8 more people in the treatment group discharged before day 6.

risk of death, 88.7% lower, RR 0.11, p = 0.12, treatment 0 of 55 (0.0%), control 4 of 57 (7.0%), relative risk is not 0 because of continuity correction due to zero events.

risk of mechanical ventilation, 79.3% lower, RR 0.21, p = 0.10, treatment 1 of 55 (1.8%), control 5 of 57 (8.8%).

risk of ICU admission, 13.6% lower, RR 0.86, p = 0.80, treatment 5 of 55 (9.1%), control 6 of 57 (10.5%).

risk of no hospital discharge, 88.7% lower, RR 0.11, p = 0.12, treatment 0 of 55 (0.0%), control 4 of 57 (7.0%), relative risk is not 0 because of continuity correction due to zero events.

risk of no virological cure, 11.6% higher, RR 1.12, p = 0.35, treatment 42 of 55 (76.4%), control 39 of 57 (68.4%).

Ravikirti et al., 1/9/2021, Double Blind Randomized Controlled Trial, India, South Asia, peer-reviewed, 11 authors, dosage 12mg days 1, 2.

Chamie, J. (News)

COVID-19 in Mexico

Comparison of COVID-19 death rates in Mexico showing that the only state using ivermectin has a dramatically lower rate.

Chamie et al., 1/8/2021, preprint, 1 author.

Babalola et al., QJM: An International Journal of Medicine, doi:10.1093/qjmed/hcab035 (preprint 1/6) (Peer Reviewed)

Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double-blind, dose-response study in Lagos

Small RCT comparing ivermectin 6mg & 12mg q84hr with lopinavir/ritonavir, showing a statistically significant and dose dependent effect of ivermectin on reducing the time to PCR-.

The study does not report mortality, hospitalization, progression, recovery, etc. The paper does report change in SpO₂ (Figure 3, ∆SpO₂), where a similar improvement with a smaller p value is seen with ivermectin, however this result is unadjusted and there are large differences between groups. Specifically, baseline SpO₂ is lower in the control group, giving the control group more room to improve, therefore the actual benefit of ivermectin is likely to be even larger than the benefit in ∆SpO₂ shown.

adjusted risk of viral+ at day 5, 63.9% lower, RR 0.36, p = 0.11, treatment 40, control 20, adjusted.

relative ∆SpO₂, 41.5% lower, RR 0.59, p = 0.07, treatment 38, control 18, figure 3.

risk of no virological cure, 58.0% lower, RR 0.42, p = 0.01, treatment 20, control 20, 12mg - Cox proportional hazard model.

risk of no virological cure, 40.5% lower, RR 0.60, p = 0.12, treatment 20, control 20, 6mg - Cox proportional hazard model.

time to viral-, 49.2% lower, relative time 0.51, p = 0.02, treatment 20, control 20, 12mg.

time to viral-, 34.4% lower, relative time 0.66, p = 0.08, treatment 20, control 20, 6mg.

Babalola et al., 1/6/2021, Double Blind Randomized Controlled Trial, Nigeria, Africa, peer-reviewed, baseline oxygen requirements 8.3%, 10 authors, dosage 12mg or 6mg q84h for two weeks, this trial compares with another treatment - results may be better when compared to placebo.

Hirsch et al., Microbiology & Infectious Diseases (Peer Reviewed)

Ivermectin as Prophylaxis Against COVID-19 Retrospective Cases Evaluation

Report on ivermectin prophylaxis for healthcare workers in a hospital in Argentina, showing 0 cases in the 162 participants. Dosage was 0.2mg/kg weekly for eight weeks, followed by 4 months rest.

Hirsch et al., 1/6/2021, peer-reviewed, 2 authors.

Lawrie et al., Preprint (Preprint) (meta analysis)

Ivermectin reduces the risk of death from COVID-19 – a rapid review and meta-analysis in support of the recommendation of the Front Line COVID-19 Critical Care Alliance

Meta analysis confirming the effectiveness of ivermectin for COVID-19, showing ivermectin treatment mortality relative risk RR 0.17 [0.18-0.35] and prophylaxis cases RR 0.12 [0.08-0.18].

risk of death, 83.0% lower, RR 0.17, p < 0.001, treatment 8 of 585 (1.4%), control 44 of 522 (8.4%).

Lawrie et al., 1/3/2021, preprint, 1 author.

Wijaya et al., Cermin Dunia Kedokteran, 47:7 (Peer Reviewed)

Ivermectin as a Potential Therapeutic Agent for COVID-19 – case studies

Case report on 3 confirmed cases of COVID-19 with significant clinical and radiological improvement after a single dose of ivermectin.

Wijaya et al., 12/31/2020, peer-reviewed, 2 authors.

Madrid et al., Heliyon, doi:10.1016/j.heliyon.2020.e05820 (Peer Reviewed)

Safety of oral administration of high doses of ivermectin by means of biocompatible polyelectrolytes formulation

In vivo analysis of the safety of high dose ivermectin with a Corydoras fish animal model.

Madrid et al., 12/31/2020, peer-reviewed, 8 authors.

McCullough et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.264 (Review) (Peer Reviewed)

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

Review urging early treatment of COVID-19 with sequential multidrug treatment that has been shown to be safe and effective. Proposed treatment includes zinc, vitamin D & C, quercetin, and depending on age, comorbidities, and symptoms may include >=2 of HCQ, ivermectin, favipiravir; AZM/DOXY; corticosteroids; colchicine; bamlanivimab; aspirin; LMWH; and supplemental oxygen.

McCullough et al., 12/30/2020, peer-reviewed, 58 authors.

Procter et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.260 (Peer Reviewed)

Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection

Retrospective 922 outpatients, with 320 treated early due to age>50 or comorbidities, showing 2.2% hospitalization and 0.3% death, which authors note is considerably lower than reported in other studies in their region.

At least two of zinc, HCQ, and ivermectin were used, along with one antibiotic, and budesonide and/or dexamethasone.

Procter et al., 12/30/2020, peer-reviewed, 6 authors.

Hill, A., Preprint (Preprint) (meta analysis)

Meta-analysis of clinical trials of ivermectin to treat COVID-19 infection

WHO-funded meta analysis showing ivermectin treatment mortality relative risk RR 0.17 [0.08-0.35] for RCTs and RR 0.28 [0.13-0.62] for RCTs and observational studies, and confirming a dose-response effect.

Hill et al., 12/27/2020, preprint, 1 author.

Jeffreys et al., bioRxiv, doi:10.1101/2020.12.23.424232 (Preprint) (In Vitro)

Remdesivir-Ivermectin combination displays synergistic interaction with improved in vitro antiviral activity against SARS-CoV-2

In Vitro study showing enhanced antiviral activity of ivermectin and remdesivir in combination.

Jeffreys et al., 12/24/2020, preprint, 15 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Vallejos et al., Preliminary Results (Preprint)

Ivermectina en agentes de salud e IVERCOR COVID19

Report on ivermectin prophylaxis in a hospital in Argentina showing lower cases for healthcare workers taking ivermectin. Preliminary results from: [1]. Note that this prophylaxis trial is a different study to the early treatment Vallejos trial.

[1] twitter.com/Covid19Crusher/status/1365420061859717124

risk of COVID-19 case, 73.4% lower, RR 0.27, p < 0.001, treatment 13 of 389 (3.3%), control 61 of 486 (12.6%).

Excluded in after exclusion results of meta analysis: detail too minimal.

Vallejos et al., 12/20/2020, retrospective, Argentina, South America, preprint, 1 author, dosage 12mg weekly.

Kory et al., FLCCC Alliance (Preprint) (meta analysis)

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

Meta analysis of ivermectin clinical studies and natural experiments where ivermectin has been widely used, showing efficacy of ivermectin in prophylaxis and treatment of COVID-19.

risk of death, 69.0% lower, RR 0.31, p < 0.001, treatment 35 of 1,551 (2.3%), control 191 of 1,957 (9.8%), OR converted to RR.

Kory et al., 12/18/2020, preprint, 10 authors.

Alam et al., European Journal ofMedical and Health Sciences, doi:10.24018/ejmed.2020.2.6.599 (Peer Reviewed)

Ivermectin as Pre-exposure Prophylaxis for COVID-19 among Healthcare Providers in a Selected Tertiary Hospital in Dhaka – An Observational Study

91% reduction in COVID-19 cases with ivermectin prophylaxis. 118 healthcare workers in Bangladesh, 58 receiving ivermectin 12mg monthly, showing RR 0.094, p < 0.0001.

risk of COVID-19 case, 90.6% lower, RR 0.09, p < 0.001, treatment 4 of 58 (6.9%), control 44 of 60 (73.3%).

Alam et al., 12/15/2020, prospective, Bangladesh, South Asia, peer-reviewed, 13 authors, dosage 12mg monthly.

Ghauri et al., International Journal of Clinical Studies & Medical Case Reports, doi:10.46998/IJCMCR.2021.13.000320 (preprint 12/15/2020) (Peer Reviewed)

Ivermectin Use Associated with Reduced Duration of Covid-19 Febrile Illness in a Community Setting

Retrospective 95 outpatients in Pakistan with strong clinical suspicion of COVID-19 (testing was not widely available), with 40 patients treated with ivermectin, showing significantly shorter duration of febrile illness with treatment. Most patients also received HCQ, AZ, zinc, and aspirin. Authors note that there was a treatment delay-response relationship.

duration of fever, 98.0% lower, relative time 0.02, p < 0.001, treatment 37, control 53, adjusted, logistic regression.

Ghauri et al., 12/15/2020, retrospective, Pakistan, South Asia, peer-reviewed, 6 authors, dosage 12mg days 1-6.

Hussain et al., International Journal of Molecular and Immuno Oncology, doi:10.25259/IJMIO_30_2020 (Preprint)

Outcome of ivermectin and doxycycline in cancer patients with COVID-19: A positive experience in Bangladesh

Small case study of ivermectin + doxycycline with 8 cancer patients, with all patients becoming PCR- by day 6 when tested again.

Hussain et al., 12/11/2020, preprint, 3 authors.

Chaccour et al., EClinicalMedicine, doi:10.1016/j.eclinm.2020.100720 (preprint 12/7) (Peer Reviewed)

The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial

Tiny RCT for early treatment of mild COVID-19 in low risk patients, with 12 400mcg/kg single dose ivermectin patients and 12 control patients, showing significantly faster viral load reduction and symptom improvement with ivermectin. Average median viral load for gene E and gene N mid-viral recovery at day 7: Ivermectin: 1637, control: 30175 (supplementary appendix). NCT04390022.

risk of symptoms, 96.0% lower, RR 0.04, p < 0.05, treatment 12, control 12, logistic regression, chance of presenting any symptom, RR approximated with OR.

viral load, 94.6% lower, relative load 0.05, p < 0.01, treatment 12, control 12, day 7 mid-recovery, average of gene E and gene N, data in supplementary appendix.

risk of no virological cure, 8.0% lower, RR 0.92, p = 1.00, treatment 12, control 12.

Chaccour et al., 12/7/2020, Double Blind Randomized Controlled Trial, Spain, Europe, peer-reviewed, 23 authors, dosage 400μg/kg single dose.

Kalfas et al., medRxiv, doi:10.1101/2020.11.30.20236570 (Preprint) (meta analysis)

The therapeutic potential of ivermectin for COVID-19: a systematic review of mechanisms and evidence

Review of ivermectin mechanisms and 8 trials, showing positive mortality benefit, reduced time to clinical recovery, reduced incidence of disease progression, and decreased duration of hospital admission in patients across all stages of clinical severity.

Kalfas et al., 12/4/2020, preprint, 4 authors.

Surnar et al., ACS Pharmacol. Transl. Sci., doi:10.1021/acsptsci.0c00179 (Peer Reviewed) (In Vitro)

Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19

In Vitro analysis of ivermectin with orally administrable nanoparticles showing efficacy for decreasing expression of the viral spike protein and ACE2. Inhibition of nuclear transport activities mediated through proteins such as importin α/β1 heterodimer are also considered as a possible mechanism of action. The technology may work for other coronaviruses as well.

Surnar et al., 12/4/2020, peer-reviewed, 4 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Ahmed et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.11.191 (Peer Reviewed)

A five day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness

Small 72 patient RCT of ivermectin and ivermectin + doxycycline showing faster recovery with ivermectin. The ivermectin + doxycycline group uses only a single dose of ivermectin vs. 5 daily doses for the ivermectin group.

Hospitalization time in this study does not indicate symptomatic recovery time - discharge was related to PCR- status (with tests only done weekly after day 7).

Ivermectin group: 12mg daily for 5 days
Ivermectin + doxycycline: 12mg ivermectin single dose, 200mg doxycycline + 100mg bid 4 days

risk of unresolved symptoms, 85.0% lower, RR 0.15, p = 0.09, treatment 0 of 17 (0.0%), control 3 of 19 (15.8%), relative risk is not 0 because of continuity correction due to zero events, day 7, fever, ivermectin (5 days).

risk of unresolved symptoms, 62.7% lower, RR 0.37, p = 0.35, treatment 1 of 17 (5.9%), control 3 of 19 (15.8%), day 7, fever, ivermectin (1 day) + doxycycline.

risk of no virological cure, 75.6% lower, RR 0.24, p = 0.03, treatment 11 of 22 (50.0%), control 20 of 23 (87.0%), adjusted, day 7, ivermectin (5 days).

risk of no virological cure, 56.5% lower, RR 0.43, p = 0.22, treatment 16 of 23 (69.6%), control 20 of 23 (87.0%), adjusted, day 7, ivermectin (1 day) + doxycycline.

risk of no virological cure, 63.0% lower, RR 0.37, p = 0.02, treatment 5 of 22 (22.7%), control 14 of 23 (60.9%), adjusted, day 14, ivermectin (5 days).

risk of no virological cure, 41.2% lower, RR 0.59, p = 0.19, treatment 9 of 23 (39.1%), control 14 of 23 (60.9%), adjusted, day 14, ivermectin (1 day) + doxycycline.

time to viral-, 23.6% lower, relative time 0.76, p = 0.02, treatment 22, control 23, ivermectin (5 days).

time to viral-, 9.4% lower, relative time 0.91, p = 0.27, treatment 23, control 23, ivermectin (1 day) + doxycycline.

hospitalization time, 1.0% lower, relative time 0.99, ivermectin, not symptomatic recovery time, PCR- with tests only weekly after day 7.

hospitalization time, 4.1% higher, relative time 1.04, ivermectin + doxycycline, not symptomatic recovery time, PCR- with tests only weekly after day 7.

Ahmed et al., 12/2/2020, Double Blind Randomized Controlled Trial, Bangladesh, South Asia, peer-reviewed, mean age 42.0, 15 authors, dosage 12mg days 1-5, the ivermectin + doxycycline group took only a single dose of ivermectin.

Chamie, J. (News)

The effect of using ivermectin to control COVID-19 in Chiapas

After starting to distribute ivermectin in drug kits in July, the Mexican state of Chiapas has seen a dramatic divergence from other states with much lower mortality [1, 2].

[1] twitter.com/Covid19Crusher/status/1334448128922165248

[2] sie7edechiapas.com/post/repartir%C3%A1n-10-mil-kits-con-ivermectina-para-combatir-covid-19-en-tuxtla

Chamie et al., 12/2/2020, preprint, 1 author.

Alonso et al., (Preprint)

COVID-19: Uso de ivermectina

Observational study in Argentina showing significantly lower mortality in the 60 days after adopting ivermectin compared to the 60 days before, relative risk RR 0.082, p=0.003.

risk of death, 91.8% lower, RR 0.08, p = 0.009, treatment 1 of 311 (0.3%), control 5 of 128 (3.9%).

Alonso et al., 12/1/2020, retrospective, Argentina, South America, preprint, 1 author, dosage not specified.

Bernigaud et al., Annals of Dermatology and Venereology, doi:10.1016/j.annder.2020.09.231 (Peer Reviewed)

Ivermectin benefit: from scabies to COVID-19, an example of serendipity

69 residents of a French care home, median age 90, were treated with ivermectin for a scabies outbreak. 3,062 residents in 45 nearby comparable homes were used as controls. 7 of 69 treated patients had probable or certain COVID-19, with no serious cases and no deaths. In comparable care homes in the same district, matched by age and socio-economic level, there was 22.6% COVID-19 and 5% death.

risk of death, 99.4% lower, RR 0.006, p = 0.08, treatment 0 of 69 (0.0%), control 150 of 3,062 (4.9%), relative risk is not 0 because of continuity correction due to zero events.

risk of COVID-19 case, 55.1% lower, RR 0.45, p = 0.01, treatment 7 of 69 (10.1%), control 692 of 3,062 (22.6%).

Bernigaud et al., 11/28/2020, retrospective, France, Europe, peer-reviewed, 12 authors, dosage 200μg/kg days 1, 8, 15, 400μg/kg days 1, 8, 15, two different dosages.

Hellwig et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106248 (Peer Reviewed)

A COVID-19 Prophylaxis? Lower incidence associated with prophylactic administration of Ivermectin

Analysis of COVID-19 cases vs. widespread prophylactic use of ivermectin for parasitic infections showing significantly lower incidence of COVID-19 cases.

risk of COVID-19 case, 78.0% lower, RR 0.22, p < 0.02, African countries, PCTI vs. no PCT, relative cases per capita.

risk of COVID-19 case, 80.0% lower, RR 0.20, p < 0.001, worldwide, PCTI vs. no PCT, relative cases per capita.

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.

Hellwig et al., 11/28/2020, retrospective, ecological study, multiple countries, multiple regions, peer-reviewed, 2 authors, dosage 200μg/kg, dose varied, typically 150-200μg/kg.

Niaee et al., Asian Pacific Journal of Tropical Medicine, doi:10.4103/1995-7645.318304 (preprint 11/24/20) (Peer Reviewed)

Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial

82% lower mortality with ivermectin. RCT with 180 hospitalized patients showing reduced mortality and hospital stay with ivermectin, with a wide margin of safety. All patients received SOC including low dose HCQ. Analysis suggests randomization failure [1]. This study was reported as pending retraction, however the journal has indicated that this is incorrect and no retraction is pending.

[1] twitter.com/Covid19Crusher/status/1447193460046548992

risk of death, 81.8% lower, RR 0.18, p = 0.001, treatment 4 of 120 (3.3%), control 11 of 60 (18.3%), All IVM vs. all control.

risk of death, 94.3% lower, RR 0.06, p = 0.01, treatment 0 of 30 (0.0%), control 11 of 60 (18.3%), relative risk is not 0 because of continuity correction due to zero events, IVM single dose 200mcg/kg vs. all control.

risk of death, 45.5% lower, RR 0.55, p = 0.37, treatment 3 of 30 (10.0%), control 11 of 60 (18.3%), IVM three dose 200mcg/kg vs. all control.

risk of death, 94.3% lower, RR 0.06, p = 0.01, treatment 0 of 30 (0.0%), control 11 of 60 (18.3%), relative risk is not 0 because of continuity correction due to zero events, IVM single dose 400mcg/kg vs. all control.

risk of death, 81.8% lower, RR 0.18, p = 0.06, treatment 1 of 30 (3.3%), control 11 of 60 (18.3%), IVM three dose 400/200/200mcg/kg vs. all control.

Excluded in after exclusion results of meta analysis: analysis suggests randomization failure.

Niaee et al., 11/24/2020, Double Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, mean age 56.0, 14 authors, dosage 400μg/kg single dose, dose varies in different groups.

de Melo et al., EMBO Mol. Med., doi:10.15252/emmm.202114122 (preprint 11/22/20) (Peer Reviewed)

Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin

Animal study showing that standard doses of ivermectin prevented clinical deterioration, reduced olfactory deficit, and limited the inflammation of the upper and lower respiratory tracts in SARS-CoV-2-infected hamsters.

de Melo et al., 11/22/2020, peer-reviewed, 11 authors.

Budhiraja et al., medRxiv, doi:10.1101/2020.11.16.20232223 (Preprint)

Clinical Profile of First 1000 COVID-19 Cases Admitted at Tertiary Care Hospitals and the Correlates of their Mortality: An Indian Experience

Retrospective 976 hospitalized patients with 34 treated with ivermectin showing ivermectin mortality relative risk RR 0.13, p = 0.04 in unadjusted results.

risk of death, 99.1% lower, RR 0.009, p = 0.04, treatment 0 of 34 (0.0%), control 103 of 942 (10.9%), relative risk is not 0 because of continuity correction due to zero events, unadjusted.

Budhiraja et al., 11/18/2020, retrospective, India, South Asia, preprint, 12 authors, dosage not specified.

Carvallo et al., Journal of Biomedical Research and Clinical Investigation, doi:10.31546/2633-8653.1007 (Peer Reviewed)

Study of the Efficacy and Safety of Topical Ivermectin + Iota-Carrageenan in the Prophylaxis against COVID-19 in Health Personnel

Prophylaxis study using ivermectin and iota-carrageenan showing 0 of 788 cases from treated healthcare workers, compared to 237 of 407 control.

The authors later reported that carrageenan is not necessary in this protocol [1].

[1] youtube.com/watch?v=CB6Bvi_g-w8

risk of COVID-19 case, 99.9% lower, RR 0.001, p < 0.001, treatment 0 of 788 (0.0%), control 237 of 407 (58.2%), relative risk is not 0 because of continuity correction due to zero events.

Excluded in after exclusion results of meta analysis: concern about potential data issues.

Carvallo et al., 11/17/2020, prospective, Argentina, South America, peer-reviewed, 4 authors, dosage 12mg weekly, this trial uses multiple treatments in the treatment arm (combined with iota-carrageenan) - results of individual treatments may vary.

Spoorthi et al., IAIM, 2020, 7:10, 177-182 (Peer Reviewed)

Utility of Ivermectin and Doxycycline combination for the treatment of SARSCoV-2

100 patient prospective trial of ivermectin + doxycycline showing reduced time to symptom resolution and shorter hospital stay with treatment.

recovery time, 21.1% lower, relative time 0.79, p = 0.03, treatment 50, control 50.

hospitalization time, 15.5% lower, relative time 0.84, p = 0.01, treatment 50, control 50.

Spoorthi et al., 11/14/2020, prospective, India, South Asia, peer-reviewed, 2 authors, dosage not specified, this trial uses multiple treatments in the treatment arm (combined with doxycycline) - results of individual treatments may vary.

Elgazzar et al., Research Square, doi:10.21203/rs.3.rs-100956/v2 (Preprint)

Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic

This study was withdrawn.

Elgazzar et al., 11/13/2020, preprint, 6 authors.

Camprubí et al., PLoS ONE, 15:11, doi:10.1371/journal.pone.0242184 (Peer Reviewed)

Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients

Tiny 26 patient retrospective study of very late treatment with ivermectin 200 μg/kg, median 12 days after symptoms, not showing significant differences. Authors suggest the dose is too low and recommend evaluation of higher doses. All patients received HCQ which may reduce the potential benefit for adding ivermectin.

risk of mechanical ventilation, 40.0% lower, RR 0.60, p = 0.67, treatment 3 of 13 (23.1%), control 5 of 13 (38.5%).

risk of ICU admission, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 13 (15.4%), control 3 of 13 (23.1%), ICU at day 8.

risk of no improvement at day 8, 33.3% higher, RR 1.33, p = 1.00, treatment 4 of 13 (30.8%), control 3 of 13 (23.1%).

risk of no virological cure, 25.0% higher, RR 1.25, p = 1.00, treatment 5 of 13 (38.5%), control 4 of 13 (30.8%), tests done between days 3-5.

Camprubí et al., 11/11/2020, retrospective, Spain, Europe, peer-reviewed, 9 authors, dosage 200μg/kg single dose.

Turkia, M., ResearchGate (Review) (Preprint)

FLCCC Alliance MATH+ ascorbic acid and I-MASK+ ivermectin protocols for COVID-19 — a brief review

Review suggesting that ivermectin should be used based on existing data suggesting significant benefits, and that waiting for additional data may result in significant harm.

Turkia et al., 11/10/2020, preprint, 1 author.

Cadegiani et al., New Microbes and New Infections, doi:10.1016/j.nmni.2021.100915 (preprint 11/4/2020) (Peer Reviewed)

Early COVID-19 Therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in Outpatient Settings Significantly Improved COVID-19 outcomes compared to Known outcomes in untreated patients

Comparison of HCQ, nitazoxanide, and ivermectin showing similar effectiveness for overall clinical outcomes in COVID-19 when used before seven days of symptoms, and overwhelmingly superior compared to the untreated COVID-19 population, even for those outcomes not influenced by placebo effect, at least when combined with azithromycin, and vitamin C, D and zinc in the majority of the cases. 585 patients with mean treatment delay 2.9 days. There was no hospitalization, mechanical ventilation, or mortality with treatment. Control group 1 was a retrospectively obtained group of untreated patients of the same population.

risk of death, 78.3% lower, RR 0.22, p = 0.50, treatment 0 of 110 (0.0%), control 2 of 137 (1.5%), relative risk is not 0 because of continuity correction due to zero events, control group 1.

risk of mechanical ventilation, 94.2% lower, RR 0.06, p = 0.005, treatment 0 of 110 (0.0%), control 9 of 137 (6.6%), relative risk is not 0 because of continuity correction due to zero events, control group 1.

risk of hospitalization, 98.0% lower, RR 0.02, p < 0.001, treatment 0 of 110 (0.0%), control 27 of 137 (19.7%), relative risk is not 0 because of continuity correction due to zero events, control group 1.

Excluded in after exclusion results of meta analysis: control group retrospectively obtained from untreated patients in the same population.

Cadegiani et al., 11/4/2020, prospective, Brazil, South America, peer-reviewed, 4 authors, dosage 200μg/kg days 1-3, this trial uses multiple treatments in the treatment arm (combined with AZ, nitazoxanide (82), HCQ (22), spironolactone (66), dutasteride (4)) - results of individual treatments may vary.

Morgenstern et al., J. Clinical Trials (preprint 11/3) (Peer Reviewed)

The Use of Compassionate Ivermectin in the Management of SymptomaticOutpatients and Hospitalized Patients with Clinical Diagnosis of Covid-19 at theCentro Medico Bournigal and at the Centro Medico Punta Cana, GrupoRescue, Dominican Republic, from May 1 to August 10, 2020

Retrospective 3,099 outpatients treated with ivermectin in an ER. Of 2,706 treated on an outpatient basis, 18 were subsequently hospitalized, 2 in the ICU, and there was one death (0.04%).

The average treatment delay for patients treated on an outpatient basis was 3.6 days, compared to 6.9 days for hospitalized patients, and 7.8 days for ICU patients.

For the 300 late treatment hospitalized patients there was 3 deaths. For the 111 very late treatment ICU patients there was 34 deaths.

Morgenstern et al., 11/3/2020, peer-reviewed, 14 authors.

Behera et al., PLoS ONE, doi:10.1371/journal.pone.0247163 (preprint 11/3) (Peer Reviewed)

Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study

Retrospective matched case-control prophylaxis study for HCQ, ivermectin, and vitamin C with 372 healthcare workers, showing lower COVID-19 incidence for all treatments, with statistical significance reached for ivermectin.

HCQ OR 0.56, p = 0.29
Ivermectin OR 0.27, p < 0.001
Vitamin C OR 0.82, p = 0.58

risk of COVID-19 case, 53.8% lower, RR 0.46, p < 0.001, treatment 41 of 117 (35.0%), control 145 of 255 (56.9%), adjusted, OR converted to RR, model 2 2+ doses conditional logistic regression.

risk of COVID-19 case, 44.5% lower, RR 0.56, p = 0.007, treatment 41 of 117 (35.0%), control 145 of 255 (56.9%), OR converted to RR, matched pair analysis.

Behera et al., 11/3/2020, retrospective, India, South Asia, peer-reviewed, 13 authors, dosage 300μg/kg days 1, 4.

Arévalo et al., Scientific Reports, doi:10.1038/s41598-021-86679-0 (preprint 11/2/20) (Peer Reviewed)

Ivermectin reduces in vivo coronavirus infection in a mouse experimental model

Mouse study showing ivermectin reducing MHV viral load and disease. MHV is a type 2 family RNA coronavirus similar to SARS-CoV2.

Arévalo et al., 11/2/2020, peer-reviewed, 12 authors.

Chang et al., ResearchGate (Preprint)

COVID-19: Effectiveness of pre-exposure prophylaxis with ivermectin in exposed persons

Pre-exposure prophylaxis study with 129 people split into high/low exposure groups, with each group split into different dosing regimens, showing higher effectivess with more frequent doses.

High-exposure group:

every 7 days dosing: 0 of 20 cases, 100% effective
every 14 days dosing: 1 of 47 cases, 98% effective
every 30 days dosing: 2 of 20 cases, 90% effective

Low-exposure group:

every 14 days dosing: 0 of 21 cases, 100% effective
every 30 days dosing: 1 of 20 cases, 95% effective

Chang et al., 10/31/2020, preprint, 2 authors.

Szente Fonseca et al., Travel Medicine and Infectious Disease, doi:10.1016/j.tmaid.2020.101906 (Peer Reviewed)

Risk of Hospitalization for Covid-19 Outpatients Treated with Various Drug Regimens in Brazil: Comparative Analysis

Retrospective 717 patients in Brazil showing OR 1.17 [0.72-1.90] for ivermectin. This paper focuses on HCQ, event counts for ivermectin are not provided. With significant correlation between the variables used, including overlap in the prescription of multiple treatments that show efficacy alone, and limited data for the model size, the model used here may be inaccurate due to multicollinearity [1].

[1] statisticsbyjim.com/regression/multicollinearity-in-regression-analysis/

risk of hospitalization, 13.9% higher, RR 1.14, p = 0.53, treatment 340, control 377, adjusted, OR converted to RR, control prevalence approximated with overall prevalence.

Excluded in after exclusion results of meta analysis: result is likely affected by collinearity across treatments in the model.

Szente Fonseca et al., 10/31/2020, retrospective, Brazil, South America, peer-reviewed, mean age 50.6, 10 authors, dosage 12mg days 1-2.

Hashim et al., Iraqi Journal of Medical Science, 19:1 (Peer Reviewed)

Controlled randomized clinical trial on using Ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq

RCT 70 ivermectin+doxycycline patients and 70 control patients showing reduced time to recovery and reduced mortality with treatment. Earlier treatment was more successful. For ethical reasons, critical patients were all in the treatment group. NCT04591600.

risk of death, 91.7% lower, RR 0.08, p = 0.03, treatment 0 of 59 (0.0%), control 6 of 70 (8.6%), relative risk is not 0 because of continuity correction due to zero events, excluding non-randomized critical patients.

risk of death, 67.1% lower, RR 0.33, p = 0.16, treatment 2 of 70 (2.9%), control 6 of 70 (8.6%), OR converted to RR, including critical patients that were always allocated to treatment.

risk of disease progression, 83.1% lower, RR 0.17, p = 0.07, treatment 1 of 59 (1.7%), control 7 of 70 (10.0%), excluding non-randomized critical patients.

risk of disease progression, 57.4% lower, RR 0.43, p = 0.20, treatment 3 of 70 (4.3%), control 7 of 70 (10.0%), OR converted to RR, including critical patients that were always allocated to treatment.

recovery time, 40.7% lower, relative time 0.59, p < 0.001, treatment 70, control 70.

Hashim et al., 10/26/2020, Single Blind Randomized Controlled Trial, Iraq, Middle East, peer-reviewed, 7 authors, dosage 200μg/kg days 1-2, some patients received a third dose on day 8, this trial uses multiple treatments in the treatment arm (combined with doxycycline) - results of individual treatments may vary.

Guerrero et al., Colombia Médica, doi:10.25100/cm.v51i4.4613 (Peer Reviewed)

COVID-19: The Ivermectin African Enigma

Study of African Programme for Onchocerciasis Control (APOC) countries, which used ivermectin, with non-APOC countries in Africa, showing 28% lower mortality for APOC countries, relative risk RR = 0.72 [0.67-0.78]. See also [1] and the author's response [2].

[1] colombiamedica.univalle.edu.co/index.php/comedica/article/view/4816

[2] colombiamedica.univalle.edu.co/index.php/comedica/article/view/4833

Guerrero et al., 10/22/2020, peer-reviewed, 5 authors.

Carvallo et al., NCT04425850 (Preprint)

Usefulness of Topic Ivermectin and Carrageenan to Prevent Contagion of Covid 19 (IVERCAR)

Prophylaxis study using ivermectin and carrageenan showing 0 of 131 cases from treated healthcare workers, compared to 11 of 98 control.

The effect is likely to be primarily due to ivermectin - the author has later reported that carrageenan is not necessary [1].

[1] youtube.com/watch?v=CB6Bvi_g-w8

risk of COVID-19 case, 96.3% lower, RR 0.04, p < 0.001, treatment 0 of 131 (0.0%), control 11 of 98 (11.2%), relative risk is not 0 because of continuity correction due to zero events.

Excluded in after exclusion results of meta analysis: concern about potential data issues.

Carvallo et al., 10/19/2020, prospective, Argentina, South America, preprint, 1 author, dosage 1mg days 1-14, this trial uses multiple treatments in the treatment arm (combined with iota-carrageenan) - results of individual treatments may vary.

Chaccour et al., Scientific Reports, doi:10.1038/s41598-020-74084-y (Peer Reviewed)

Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats

Study showing that nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats. Authors note that additional experiments are required to assess the safety of this formulation in larger animals.

Chaccour et al., 10/13/2020, peer-reviewed, 8 authors.

Rajter et al., Chest, doi:10.1016/j.chest.2020.10.009 (Peer Reviewed)

Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID-19 (ICON study)

Retrospective 280 hospitalized patients showing lower mortality with ivermectin (13.3% vs 24.5%), propensity matched odds ratio OR 0.47 [0.22-0.99], p=0.045.

risk of death, 46.0% lower, RR 0.54, p = 0.04, treatment 13 of 98 (13.3%), control 24 of 98 (24.5%), adjusted, OR converted to RR, PSM.

risk of death, 66.9% lower, RR 0.33, p = 0.03, treatment 26 of 173 (15.0%), control 27 of 107 (25.2%), adjusted, OR converted to RR, multivariate.

risk of mechanical ventilation, 63.6% lower, RR 0.36, p = 0.10, treatment 4 of 98 (4.1%), control 11 of 98 (11.2%), matched cohort excluding intubated at baseline.

Rajter et al., 10/13/2020, retrospective, propensity score matching, USA, North America, peer-reviewed, 6 authors, dosage 200μg/kg single dose.

Mahmud et al., Journal of International Medical Research, doi:10.5061/dryad.qjq2bvqf6 (preprint 10/9/20) (Peer Reviewed)

Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial

RCT for ivermectin+doxycycline showing improvements in mortality, recovery, progression, and virological cure. 183 treatment and 183 control patients with no deaths in the treatment arm vs. 3 in the control arm (the 3 control deaths are not included in the analysis of other outcomes). NCT04523831.

risk of death, 85.7% lower, RR 0.14, p = 0.25, treatment 0 of 183 (0.0%), control 3 of 183 (1.6%), relative risk is not 0 because of continuity correction due to zero events.

risk of disease progression, 57.0% lower, RR 0.43, p < 0.001, treatment 16 of 183 (8.7%), control 32 of 180 (17.8%), adjusted, Cox regression.

risk of no recovery, 94.0% lower, RR 0.06, p < 0.001, treatment 72 of 183 (39.3%), control 100 of 180 (55.6%), adjusted, day 7, Cox regression.

risk of no recovery, 38.5% lower, RR 0.61, p = 0.005, treatment 40 of 183 (21.9%), control 64 of 180 (35.6%), day 11.

risk of no recovery, 96.0% lower, RR 0.04, p < 0.001, treatment 42 of 183 (23.0%), control 67 of 180 (37.2%), adjusted, day 12, Cox regression.

time to recovery, 27.0% lower, RR 0.73, p = 0.003, treatment 183, control 180, Cox regression.

risk of no virological cure, 39.0% lower, RR 0.61, p = 0.002, treatment 14 of 183 (7.7%), control 36 of 180 (20.0%), adjusted, Cox regression.

Mahmud et al., 10/9/2020, Double Blind Randomized Controlled Trial, Bangladesh, South Asia, peer-reviewed, 15 authors, dosage 12mg single dose, this trial uses multiple treatments in the treatment arm (combined with doxycycline) - results of individual treatments may vary.

Francés-Monerris et al., ChemRxiv, doi:10.26434/chemrxiv.12782258.v1 (Preprint)

Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent

In silico study showing that ivermectin is capable of interfering in different key steps of the SARS-CoV-2 replication cycle.

Francés-Monerris et al., 10/8/2020, preprint, 8 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Soto-Becerra et al., medRxiv, doi:10.1101/2020.10.06.20208066 (Preprint)

Real-World Effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: Results of a target trial emulation using observational data from a nationwide Healthcare System in Peru

Retrospective database study of 5683 patients, 692 received HCQ/CQ+AZ, 200 received HCQ/CQ, 203 received ivermectin, 1600 received AZ, 358 received ivermectin+AZ, and 2630 received standard of care.

This study 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. The last day available for ivermectin shows RR 0.83, p = 0.01. 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.

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 state that outcomes within 24 hours were excluded, however KM curves show significant mortality at day 1 (only for the treatment groups).

Several protocol violations and missing data have also been reported in this study: [1, 2].

Aspirin	Metformin
Bamlanivimab	Molnupiravir
Bromhexine	Nigella Sativa
Budesonide	Nitazoxanide
Casirivimab/i..	Povidone-Iod..
Colchicine	Probiotics
Conv. Plasma	Proxalutamide
Curcumin	Quercetin
Favipiravir	Remdesivir
Fluvoxamine	Sotrovimab
Hydroxychloro..	Vitamin A
Iota-carragee..	Vitamin C
Ivermectin	Vitamin D
Melatonin	Zinc

Other	Adoption