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0 0.5 1 1.5 2+ Mortality -195% Improvement Relative Risk Hospitalization -5% Progression, aggravated.. 68% Progression, C19 pneu.. 5% Progression -20% Clinical progression, day 7 24% Clinical progression, day.. 27% Clinical progression.. (b) 10% Recovery 7% post-hoc primary Recovery, severe 44% Recovery, moderate 3% Recovery, mild 11% Recovery, no symptoms -22% Recovery, onset 3 days 6% Recovery, onset 5 days 14% Recovery, onset 7 days 12% Recovery, onset 9 days 0% Recovery, onset 11 days -16% Recovery, onset 13 days -35% Naggie et al. NCT04885530 ACTIV-6 Ivermectin RCT LATE Favors ivermectin Favors control
Naggie, 1,591 patient ivermectin late treatment RCT: 5% higher hospitalization [p=1], 68% lower progression [p=0.36], and 24% improved recovery [p=0.07]
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Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial
Naggie, S., medRxiv, doi:10.1101/2022.06.10.22276252 (Preprint)
12 Jun 2022    Source   PDF   Share   Tweet
RCT low-risk outpatients with very late treatment (median 6 days, 25% ≥8 days) in the USA, showing 98% probability of efficacy for clinical progression at day 14, a treatment delay-response relationship, and significant efficacy for patients with severe symptoms at baseline. Efficacy was higher over calendar time, which may reflect higher efficacy with more recent variants. Efficacy was higher for vaccinated patients.
Design, presentation, and analysis shows a strong negative bias. While authors recommend and are performing further study, notably they are continuing with most flaws including a design focusing on very late monotherapy, while extensive research shows that early treatment is critical for antivirals, and a growing body of research shows greater and synergistic benefits from polytherapy protocols commonly used by physicians that treat COVID-19. Submit Updates or Corrections
There are many major issues as below.
SeverityIssue (most recent update 12 days ago)Author response
CRITICAL1. Superiority found, not reported (13 days ago) -
CRITICAL2. Very late treatment -
CRITICAL3. Primary outcome not reported, closest reported outcome shows superiority of ivermectin (13 days ago) -
CRITICAL4. Patients with symptoms >7 days included -
CRITICAL5. No response to data request (14 days ago) -
CRITICAL6. Outcomes reported do not match protocol (13 days ago) -
CRITICAL7. No COVID-19 mortality/hospitalization reported (14 days ago) -
CRITICAL8. Many pre-specified outcomes missing (12 days ago) -
CRITICAL9. Protocol unavailable (13 days ago) -
CRITICAL10. IDMC not independent (12 days ago) -
CRITICAL11. Reported primary outcome low relevance (13 days ago) -
CRITICAL12. Shipping and PCR delays largely enforce late treatment -
CRITICAL13. Blinding failure -
CRITICAL14. Extreme conflicts of interest -
CRITICAL15. Treatment delay-response relationship -
CRITICAL16. Asymptomatic patients included -
CRITICAL17. Disingenuous conclusion (14 days ago) -
CRITICAL18. Up to 6 days shipping delay (14 days ago) -
SERIOUS19. Randomization failure (15 days ago) -
SERIOUS20. Low risk patients (14 days ago) -
SERIOUS21. No adherence data (14 days ago) -
SERIOUS22. Subject to participant fraud (13 days ago) -
SERIOUS23. Not enough tablets provided -
SERIOUS24. Monotherapy with no SOC for most patients -
SERIOUS25. Over 2x greater severe dyspnea at baseline for ivermectin -
SERIOUS26. Authors suggest high-income country healthcare is better, however almost all patients received no active SOC -
SERIOUS27. Placebo unspecified -
SERIOUS28. No breakdown of severe outcomes -
MAJOR29. No subgroup counts for treatment delay -
MAJOR30. Skeptical prior not justified (12 days ago) -
Superiority found, not reported. Both day 7 and day 14 clinical progression results show superiority of ivermectin. The protocol states: "The Study Drug is found to have benefit (efficacy): A posterior probability of meaningful benefit (e.g. OR < 0.9) for a study drug in comparison to the placebo control of > 0.95 will result in a declaration of overall superiority" [].
Primary outcome not reported, closest reported outcome shows superiority of ivermectin. The protocol shows the primary outcome using a longitudinal statistical model with an ordinal variable based on symptom count and hospitalization/death measured daily until day 14 []. This outcome is not reported. The closest reported outcome is clinical progression at 14 days, which shows superiority of ivermectin, OR 0.73 [0.52-0.98], posterior probability of efficacy 98%, exceeding the pre-specified threshold.
Very late treatment. Patients were treated a median of 6 days late, with 25+% 8+ days late. Extensive research for COVID-19 and other viral diseases show that early antiviral treatment is critical. While authors recommend (and are performing) further study, they do not recommend or perform the obvious step of doing an early treatment trial, as is done for NIH recommended treatments like Paxlovid, suggesting a strong negative bias with a goal of maintaining late treatment and obtaining poor results.
Outcomes reported do not match protocol. The reported outcomes are very different to the trial registration [] and the protocol []. The trial registration shows three primary outcomes, of which zero are reported in the paper. The protocol shows the primary outcome using a longitudinal statistical model with an ordinal variable based on symptom count and hospitalization/death measured daily until day 14.
No response to data request. Authors have not responded to a request for the data.
No COVID-19 mortality/hospitalization reported. Authors only report all-cause mortality and hospitalization. Notably, the baseline hospitalization and mortality rate for non-COVID-19 causes may account for the death and many of the hospitalizations. This may also explain why authors report only 28 day mortality/hospitalization in violation of the protocol where the primary outcomes specify 14 days []. Additionally, adverse events show only one case of aggravated COVID-19 pneumonia for ivermectin, versus 3 for placebo.
Many pre-specified outcomes missing. Authors do not report []:
OR describing the overall difference in symptoms and clinical events over 14 days (primary outcome)
Overall clinical progression OR (only specific day 7, 14, 28 values are provided)
Time to first urgent care, emergency care, hospitalization or death
Risk and time to event for each component of the composite
Mean and median time to symptom freedom
Overall QOL OR
Day 7, 14, 28, 90 QOL OR
Mean difference in QOL scores at day 7, 14, 28, 90
Mean and median time to symptom resolution (only a new sustained resolution measure is reported, which is not in the protocol)
Day 90 mean and median symptom count
Protocol unavailable. No detailed protocol is available. For example, the Bayesian threshold for significance is not known and appears to be withheld. A typical posterior efficacy threshold of 97.6% is met by the clinical progression on the ordinal outcome scale at day 14, OR 0.73 [0.52-0.98] 0.98. Notably, the discussion includes vague and arbitrary "clinical relevance" and "substantial clinical benefit" rather than statistical significance. Update: partial protocol located [], threshold was exceeded. The protocol appendix is still unavailable which includes contraindications, exclusions, formulation, appearance, packaging, dispensing, dosing, and dose rationale.
Reported primary outcome low relevance. The reported primary outcome (which matches neither the trial registration or the protocol) is of relatively low relevance being based on sustained absence of all symptoms, where symptoms includes many things that may be found after viral clearance and may be unrelated to COVID-19, including fatigue, headache, and cough (which may remain for some time). Authors may have searched for the outcome that shows the least benefit. The 3-day sustained definition further adds two days for all participants, reducing efficacy. Authors should report data for more significant symptoms such as dyspnea, fever, and loss of sense of taste/smell.
Patients with symptoms >7 days included. The trial specifies symptoms ≤7 days, however subgroup results show symptoms ≤9, 11, and 13 days, and the Q3 for the ivermectin arm was 8 days, indicating 25% of patients with a treatment delay of ≥8 days. The difference is likely due to the authors not considering receipt of medication or treatment time in inclusion, i.e., due to shipping delays. However, ≤7 days treatment delay already makes the results inapplicable to real-world usage where antivirals are used early.
Asymptomatic patients included. Study inclusion required >2 symptoms, however the subgroup analysis includes 109 patients with no symptoms, where results favored placebo. The primary outcome may reach statistical significance without these patients.
Shipping and PCR delays largely enforce late treatment. Authors required positive PCR before randomization, and shipped medication to participants. The delay before PCR results become positive, delay in receiving PCR results, and the shipping delay largely ensure that patients will not be treated early.
Extreme conflicts of interest. This trial has extreme conflicts of interest, being funded by an organization that chose not to recommend treatment while providing no quantitative analysis, no reference to the majority of the research, and no updates for new research for a very long period []. Further, a majority of the panel providing the recommendation has major conflicts of interest []. Also see [, (B)].
Treatment delay-response relationship. Subgroup results for treatment delays 13, 11, 9, 7, and 5 show monotonically improving results (less than 1% probability due to chance). ≤3 days may have very few patients, and is within confidence limits for monotonically improving results. Improved efficacy for earlier treatment matches extensive results for ivermectin and other COVID-19 treatments [], however authors ignore this trend, claiming only a lack of statistical significance for one specific binary threshold (which may have few patients on one side), and authors have not initiated an early treatment trial.
Randomization failure. The placebo arm includes participants selected for other drugs, with drug specific exclusions. This breaks the randomization because the populations for each drug are different.
Blinding failure. The placebo arm included multiple regimens matching different treatment arms, hence some participants will know they are not in the ivermectin arm, and others will know that there is a higher probability of them being in the ivermectin arm than the placebo arm. This may be more important given the politicization in the study country. The fluticasone arm and matching placebo use an inhaler, the fluvoxamine arm uses 10 days treatment. Mached placebo analysis should be provided.
Disingenuous conclusion. The conclusion states that treatment did not lower mortality of hospitalization, however it is impossible to lower zero mortality. While authors do not indicate COVID-19 versus other hospitalization, statistically significant reduction in hospitalization would require at minimum 79% efficacy, but for COVID-19 hospitalization it is likely impossible based on expected non-COVID-19 hospitalizations. The trial is underpowered by design due to selection of a low-risk population. Note that among the 90 severe cases, statistically significant efficacy is reported.
Up to 6 days shipping delay. The ≤7 days inclusion criterion and the 13 days subgroup suggests there was up to 6 days shipping delay (in part due to no weekend shipping). COVID-19 is an acute disease (which may or may not be mild). Participants cannot be expected to wait 1-2 days or longer for treatment. Chances are that patients feel better by the time medication arrives and do not take the medication, which may explain why adherence is not reported, or their condition became worse and they found alternative immediate care elsewhere.
IDMC not independent. The IDMC vice chair was reportedly on the NIH panel that did not recommend treatment despite strong evidence, and provided no quantitative analysis, no reference to the majority of the research, and no updates for new research for a very long period [].
No adherence data. Authors provide no adherence data. Non-adherence may de-power the trial and may harm randomization.
Low risk patients. Authors focus on patients at low risk of COVID-19 severe outcomes, which ensures an underpowered trial, with only one death which may not be due to COVID-19. All-cause mortality and hospitalization become less meaningful, with a significant contribution from non-COVID-19 causes.
Subject to participant fraud. The self-reported design, partial blinding, and absence of professional medical examination opens the trial to participant fraud, which may be significant due to extreme politicization in the study country.
Not enough tablets provided. Participants were supplied 15 7mg tablets and instructed to take the number of tablets to approximate 400μg/kg, however not enough tablets were provided for patients with higher weights, indicating that higher risk patients received lower dosage. 41% of patients had BMI > 30 and subgroups include BMI 50.
Over 2x greater severe dyspnea at baseline for ivermectin. There was over 2x greater severe dyspnea in the ivermectin arm at baseline (1.65% vs. 0.71%), which may be very important for analyzing mortality and hospitalization.
Authors suggest high-income country healthcare is better, however almost all patients received no active SOC. Authors suggest the operation in a high-income country with an associated healthcare system is a notable strength, however the study country provided no active treatment for almost all patients in the study, in contrast to many lower income countries that provide multiple treatments. Remdesivir, monoclonal antibodies, and paxlovid are very difficult to obtain and rarely used for outpatients in the study country. High income countries also may have significantly higher conflicts of interest.
Placebo unspecified. Authors do not specify placebo details, only that packaging was identical. If the tablets were not identical, this would be an additional reason for blinding failure.
No breakdown of severe outcomes. Notably, no details are provided for the hospitalization and mortality events, which may have been more likely among patients with extremely late treatment, or influenced by the higher baseline severity in the ivermectin arm. No severe outcome results are provided for (relatively) early treatment.
Monotherapy with no SOC for most patients. Authors perform monotherapy and the standard of care for most patients in the study country included no active treatments. Other treatments were very rare - remdesivir 0.3%, monoclonal antibodies 3%, and paxlovid 0.1%. However, extensive and growing research shows greater and synergistic benefits from polytherapy. Many studies use polytherapy and/or the standard of care includes multiple active treatments.
No subgroup counts for treatment delay. Notably, no subgroup counts are provided for treatment delay, while they are provided for baseline symptoms and vaccination status. The number of patients with symptoms ≤3 days may have been very small given the design of the trial.
Skeptical prior not justified. The skeptical prior, which reduces the observed efficacy in the post-hoc primary outcome, is not justified based on the studies to date. The skeptical prior was pre-specified. Authors may argue that the prior is justified because the trial was designed to avoid showing efficacy.
What can be done better? This long list of issues details the flaws prohibiting any negative conclusion about early treatment. In fact, the results are extremely positive given the conditions. Despite extreme and obvious measures used to avoid showing efficacy, efficacy was still found. Running a better trial is a simple matter of avoiding the issues above. How do you ensure early treatment with high-risk patients? One example would be pre-enrolling nursing home patients, providing treatment packages in advance, and instructing local medical staff to initiate randomization, treatment, and monitoring immediately on symptoms. This would likely be cheaper to run, and easily extended to also study prophylaxis.
For additional issues see [ (C)].
risk of death, 194.7% higher, RR 2.95, p = 1.00, treatment 1 of 817 (0.1%), control 0 of 774 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 28.
risk of hospitalization, 5.3% higher, RR 1.05, p = 1.00, treatment 10 of 817 (1.2%), control 9 of 774 (1.2%), day 28.
risk of progression, 68.4% lower, RR 0.32, p = 0.36, treatment 1 of 817 (0.1%), control 3 of 774 (0.4%), NNT 377, aggravated C19 pneumonia, eTable 2.
risk of progression, 5.3% lower, RR 0.95, p = 1.00, treatment 4 of 817 (0.5%), control 4 of 774 (0.5%), NNT 3676, C19 pneumonia, eTable 2.
risk of progression, 20.0% higher, RR 1.20, p = 0.32, treatment 32 of 817 (3.9%), control 28 of 774 (3.6%), adjusted per study, urgent or emergency care visits, hospitalizations, or death.
clinical progression, 24.0% lower, OR 0.76, p = 0.07, treatment 817, control 774, mid-recovery, day 7, RR approximated with OR.
clinical progression, 27.0% lower, OR 0.73, p = 0.05, treatment 817, control 774, day 14, RR approximated with OR.
clinical progression, 10.0% lower, OR 0.90, p = 0.57, treatment 817, control 774, day 28, RR approximated with OR.
risk of no recovery, 6.5% lower, HR 0.93, p = 0.18, treatment 817, control 774, post-hoc primary outcome.
risk of no recovery, 44.1% lower, HR 0.56, p = 0.03, treatment 39, control 51, severe.
risk of no recovery, 2.9% lower, HR 0.97, p = 0.80, treatment 247, control 221, moderate.
risk of no recovery, 10.7% lower, HR 0.89, p = 0.12, treatment 434, control 490, mild.
risk of no recovery, 22.0% higher, HR 1.22, p = 0.33, treatment 54, control 55, no symptoms.
risk of no recovery, 5.7% lower, HR 0.94, p = 0.62, onset 3 days.
risk of no recovery, 13.8% lower, HR 0.86, p = 0.03, onset 5 days.
risk of no recovery, 12.3% lower, HR 0.88, p = 0.08, onset 7 days.
risk of no recovery, no change, HR 1.00, p = 1.00, onset 9 days.
risk of no recovery, 16.3% higher, HR 1.16, p = 0.40, onset 11 days.
risk of no recovery, 35.1% higher, HR 1.35, p = 0.28, onset 13 days.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Naggie et al., 6/12/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, North America, preprint, mean age 48.0, 1 author, study period 15 December, 2021 - 1 February, 2022, average treatment delay 6.0 days, dosage 400μg/kg days 1-3, trial NCT04885530 (ACTIV-6).
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