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0 0.5 1 1.5 2+ Mortality -200% Improvement Relative Risk Mortality (b) -195% Death/hospitalization -152% Hospitalization -5% Progression, aggravated C.. 68% Progression 0% Progression (b) -20% Clinical progression, day 7 -61% Clinical progression, day 14 -114% Clinical progression, day 28 -161% Clinical progression.. (b) 24% Clinical progression, d.. (b) 27% Clinical progression, d.. (b) 10% Time to recovery 2% post-hoc primary Limited activity 30% Time to recovery (b) 7% post-hoc primary Time to recovery, severe 46% recovery Ivermectin  ACTIV-6  LATE TREATMENT  DB RCT Is late treatment with ivermectin beneficial for COVID-19? Double-blind RCT 1,591 patients in the USA (June 2021 - February 2022) This trial has multiple critical issues, see analysis Naggie et al., JAMA, June 2022 Favors ivermectin Favors control

Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial

Naggie et al., JAMA, doi:10.1001/jama.2022.18590, ACTIV-6, NCT04885530
Jun 2022  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Extreme COI, data inconsistencies, uncorrected errors, no response from authors, participant fraud, refusal to release data
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. The posterior probability ivermectin is effective was 99%, 98%, 97% for mean time unwell and clinical progression @14 and 7 days. All exceed the pre-specified threshold for superiority Note that the clinical progression results exceeding the superiority threshold in the preprint changed in the journal version for the 400µg/kg arm, with no explanation for over 530 days). The 600µg/kg arm was reported separately Naggie. When not specified, comments refer to the 400µg/kg arm. We provide more detailed analysis of this study due to widespread incorrect press.
There was one death reported in each of the 400µg/kg and 600µg/kg ivermectin arms. For 400µg/kg, the patient did not take ivermectin. For 600µg/kg, authors note that the death was accidental.
There are many critical issues as below. Design, presentation, and analysis shows a strong negative bias. Submit Updates or Corrections
CRITICAL1. Impossible data
CRITICAL2. Adverse event count mismatch
CRITICAL3. Randomization failure - higher severity in ivermectin arms
CRITICAL4. Adverse events consistent with potential medication error
CRITICAL5. Adverse events similar for active and placebo
CRITICAL6. Participant fraud
CRITICAL7. Superiority found, not reported
CRITICAL8. Interim analyses not reported, likely showed superiority
CRITICAL9. Death reported in mITT, however participant not in mITT, did not receive study drug
CRITICAL10. Ivermectin source unknown, specified for other trial medications
CRITICAL11. Non-identical placebo
CRITICAL12. Post-hoc protocol
CRITICAL13. Clinical progression results changed
CRITICAL14. Primary outcome not reported, closest reported outcome shows superiority
CRITICAL15. Pre-specified primary 14 day outcomes not reported, clinical status shows 30% benefit
CRITICAL16. Hospitalization/death mismatch
CRITICAL17. 90 day followup results not provided
CRITICAL18. Very late treatment
CRITICAL19. Key clinical question consistent with unreported pre-specified primary outcome but not the reported outcome
CRITICAL20. Patients with symptoms >7 days included
CRITICAL21. Data unavailable over 660 days from publication
CRITICAL22. Outcomes reported do not match protocol
CRITICAL23. Primary outcomes changed after publication
CRITICAL24. Different hospitalization/urgent care numbers between paper and presentation
CRITICAL25. Post-hoc primary outcome measured on day 3
CRITICAL26. Dose below 400μg/kg
CRITICAL27. Effective dose ~130μg/kg, administration on empty stomach
CRITICAL28. Clinical progression details for fluticasone/fluvoxamine but not ivermectin
CRITICAL29. COVID-19 mortality/hospitalization not reported
CRITICAL30. Many pre-specified outcomes missing
CRITICAL31. Full protocol unavailable before October 2022
CRITICAL32. IDMC not independent, extreme conflict of interest
CRITICAL33. Reported primary outcome low relevance
CRITICAL34. Shipping and PCR delays largely enforce late treatment
CRITICAL35. Very slow shipping
CRITICAL36. Blinding failure
CRITICAL37. Extreme conflicts of interest
CRITICAL38. Treatment delay-response relationship
CRITICAL39. Asymptomatic patients included
CRITICAL40. Disingenuous conclusion
CRITICAL41. Significant missing data, not mentioned in paper
CRITICAL42. Statistically significant efficacy for severe patients removed
CRITICAL43. Statistical analysis plan dated after trial end
CRITICAL44. 31% more severe cases in the ivermectin arm
CRITICAL45. Population incorrect
CRITICAL46. Early treatment incorrect
CRITICAL47. Author claims results from 628 researchers should be censored for false information
SERIOUS48. Bias due to false positive antigen tests
SERIOUS49. Participant pickup delay
SERIOUS50. Randomization failure
SERIOUS51. Low risk patients
SERIOUS52. No adherence data or per-protocol analysis
SERIOUS53. Skeptical prior not justified
SERIOUS54. Not enough tablets provided
SERIOUS55. Monotherapy with no SOC for most patients
SERIOUS56. Over 2x greater severe dyspnea at baseline for ivermectin
SERIOUS57. Safety conclusion removed, suggests bias
SERIOUS58. Authors suggest high-income country healthcare is better, however almost all patients received no active SOC
SERIOUS59. Placebo unspecified
SERIOUS60. No breakdown of severe outcomes
SERIOUS61. Missing subgroup counts
MAJOR62. Overlapping fluticasone placebo shows very different event numbers
MAJOR63. Overlapping fluticasone placebo shows unexpected baseline numbers
MAJOR64. Inconsistent calendar time subgroups
UNKNOWN65. Outcome graph presented does not match either medication tested
Responses: authors have not responded to any of these issues.
Impossible data. There are major data mismatches For the ivermectin 600 arm (CT) indicates that 718 patients started and 708 completed the arm, while the paper claims that only 668 were randomized to ivermectin, of which 66 did not even receive the medication Baseline age, ethnicity, and race data all differ between CT and the paper, for example CT indicates 3 patients in the ivermectin arm were American Indian or Alaska Native, whereas the paper shows 9, despite reporting on a much smaller number of patients. Many results also differ between CT and the paper.
Adverse event count mismatch. The paper reports 44 of 604 placebo patients had an adverse event in the 600µg/kg arm, whereas clinicaltrials shows 5 of 724 placebo patients had an adverse event
Randomization failure - higher severity in ivermectin arms. The most severe baseline symptom reported is severe dyspnea. For both 600μg/kg and 400μg/kg, the ivermectin arm has higher incidence of severe dyspnea, which is statistically significant across both arms (p = 0.02). This suggests that known and potentially unknown blinding failures are material.
Adverse events consistent with potential medication error. Placebo adverse events are expected to be similar for the 400μg/kg and 600μg/kg arms. The populations are similar and patients are not taking any study treatments. The 600μg/kg arm has a lower overall hospitalization rate. However, the 600μg/kg placebo arm reports 44/604 (7.3%) adverse events, while the 400μg/kg arm reports only 27/774 (3.5%), over 2 times higher. This is a significant increase in adverse events, p = 0.002, without explanation or discussion. Comparing 400μg/kg and 600μg/kg, adverse events are over 2x higher for both the active and placebo arms. The overall increase in adverse events with the higher dosage (total 3x higher) matches expectations, however we expect the increase in the active treatment arm, not both active and placebo arms. One hypothesis is that patient arm classifications are incorrect, i.e., many patients received the opposite of their designated arm. This kind of error is possible in all placebo controlled trials and happened for example in López-Medina (discovered and excluded in that case). This hypothesis is consistent with both the adverse events and the 600μg/kg results, with the very small remaining effect explainable by the 10% non-matching placebo patients. We recommend that participants retain any leftover tablets for analysis.
Adverse events similar for active and placebo. For the 600μg/kg arm authors report that 9% of patients experienced an adverse event, similar to placebo (7%, no significant difference). However significantly more side effects are expected at this dosage (the total dosage is 3x greater due to the longer duration). The 600μg/kg arm in Buonfrate reports much higher adverse events. Overall reporting is higher in this trial, which may include lower severity items, especially within "general disorders". However looking specifically at eye disorders, a known side effect of higher doses of ivermectin, Buonfrate show 46% vs. 3% for ivermectin vs. control. The lack of higher side effects for ivermectin in ACTIV-6 suggests that patients may not have taken authentic ivermectin at the dosage reported. GMK notes that data was self-reported by patients in ACTIV-6. Highly inaccurate reporting by patients would also apply to the symptomatic results, similarly invalidating the trial.
Participant fraud. A paper on the operation of the trial Lindsell reveals that there was participant fraud - authors identified participants that signed up repeatedly, and participants that withdrew when not randomized to their preferred arm. Authors indicate that they tried to prevent repeat signups but provide no details on the algorithms or the evaluation thereof. It is possible that they only caught a small fraction of the fraud, and possible that improvements to detection were added only later in the trial during or after the ivermectin arms. It is likely that individuals were gaming the system related to the politicization and extreme financial implications. This information was not disclosed previously. Patients were allowed to specify treatments that they accept or decline to be a part of. One author indicates this was most commonly used by patients to specify only ivermectin (B), which may be related to fraud targeting ivermectin. There are known paid groups of individuals targeting ivermectin, and it would be simple to bias results towards null without having to break the blinding. Participant fraud has also been reported for a similar remote trial where known fake surveys were submitted. The self-reported design and absence of professional medical examination opens these kind of trials to participant fraud, which may be significant due to extreme politicization in the study country.
Superiority found, not reported. Day 7 and day 14 clinical progression results and mean time unwell show superiority of ivermectin (note: 400μg/kg arm, preprint version, clinical progression results were changed without explanation in the journal version). The protocol indicates superiority for OR < 0.9 and posterior probability > 0.95 In the presentation, author shows a slide containing these results while stating "this was, um, not statistically significant" (@22:36). These results were seen despite 107 patients having no symptoms at baseline and the use of the skeptical prior
Interim analyses not reported, likely showed superiority. The original protocol specified interim analyses every 200 patients, this was later modified to every 300 patients. However the paper claims "Because the rate of enrollment was so rapid, it was not possible to complete the interim analyses". This is not realistic — the analysis code is written and tested in advance for trials like ACTIV-6 which have professional statisticians. Based on the clinical progression results showing superiority, it is likely that one or more of the interim analyses showed superiority on the original primary outcome.
Death reported in mITT, however participant not in mITT, did not receive study drug. Authors report one death in the ivermectin 400µg/kg arm in the mITT population (817 patients that received the drug within 7 days), however in the presentation (@21:15) author reports that the patient that died did not receive the drug because they were admitted prior to receipt. The reported mITT death is therefore incorrect. Similarly, at least one and potentially many or all hospitalizations may have occurred before receiving the drug.
Ivermectin source unknown, specified for other trial medications. Authors do not specify who provided the ivermectin and ivermectin placebo tablets. This information is specified for the other ACTIV-6 medications (fluticasone and fluvoxamine). For both other medications, active and placebo were provided by the same source.
Non-identical placebo. The protocol states that the ivermectin placebo tablets will be identical to the ivermectin tablets. However, the papers state only that packaging was identical, suggesting that a decision was made at some point to use non-identical tablets. This was only done for ivermectin, both fluvoxamine and fluticasone papers report using identical placebos. The protocol changelist notes that ivermectin and matched placebo information was updated in version 2.0 (version 2.0 is not available).
Post-hoc protocol. An incorrect post-hoc protocol is included with the paper published October 21, 2022 which differs significantly from the pre-specified protocol The post-hoc protocol is dated December 20, 2021, long after the trial started and after scheduled interim analyses that likely showed superiority as above. Metadata shows the author of the protocol files to be Jenny Jackman. The protocol for the ivermectin arm is included with the fluticasone NEJM paper, and is dated May 25, 2021. Neither protocol matches the reported outcomes, however the post-hoc version has been modified to be closer.
Clinical progression results changed. The preprint and journal version show very different clinical progression results, with no acknowledgement or explanation. See also (C).
Primary outcome not reported, closest reported outcome shows superiority. The protocol shows the primary symptom outcome using a longitudinal statistical model with an ordinal variable based on symptom count and hospitalization/death measured daily until day 14 (see section 10.6.1). 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%, which exceeds the pre-specified threshold for superiority (note: changed without explanation as above).
Pre-specified primary 14 day outcomes not reported, clinical status shows 30% benefit. The pre-specified primary 14 day outcomes are still not reported in the journal version. However, authors now show the clinical status graphs in eFigure 2, which shows 30% benefit for ivermectin for limited activity at 14 days.
Hospitalization/death mismatch. Results show 10 and 9 events for hospitalization/death, however eFigure 1A shows 4 and 3.
90 day followup results not provided. Authors do not provide the PROMIS-29 results, stating that this is due to the 90 day followup. The 90 day followup period ended 169 days before publication (38 days before the preprint publication). The protocol also specifies 7, 14, and 28 day PROMIS-29 results.
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.
Key clinical question consistent with unreported pre-specified primary outcome but not the reported outcome. Authors report the key clinical questions for ACTIV-6 as being "How to help someone feel better faster with newly diagnosed mild-moderate COVID-19?" and "How to prevent hospitalizations or death in someone with newly diagnosed mild-moderate COVID-19?" The pre-specified but unreported primary symptom outcome provides a measure for feeling better faster, however the reported post-hoc primary outcome is very poorly matched. For example, a treatment that resolves serious symptoms 10x faster, but does not speed up 100% resolution of cough for three consecutive days, would show zero benefit in the post-hoc primary outcome. Cough may persist long after viral clearance Note also that the trial does not address "newly diagnosed" patients, but rather very late treatment a median of 6 days after symptoms. The very late treatment also minimizes the chance of preventing the initiation of viral cough.
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.
Data unavailable over 660 days from publication. Data for the study is unavailable over 660 days after publication.
Outcomes reported do not match protocol. The reported outcomes are very different to the trial registration (B) and the pre-specified protocol The trial registration shows three primary outcomes, of which zero are reported in the paper. The pre-specified 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.
Primary outcomes changed after publication. The primary outcomes were changed from day 14 to day 28 on June 25, 2022, after publication (C). Two of the three primary outcomes were changed to match what was reported, while the third remains unreported, and none of the pre-specified primary outcomes have been reported to date.
Different hospitalization/urgent care numbers between paper and presentation. The paper and the later presentation show different numbers for hospitalization and urgent care/ER. In the presentation, a hospitalization was moved from the placebo arm to the ivermectin arm (@21:44). The HRs did not change.
Post-hoc primary outcome measured on day 3. The new primary outcome of sustained 100% recovery for 3 days is measured on day 3 rather than day 1 (@19:10). We are unaware of any reason to use day 3 rather than the day of 100% recovery, other than to reduce the observed efficacy. Both the pre-specified and post-hoc protocols include a secondary outcome of "symptom resolution, defined as first of at least three consecutive days without symptoms".
Dose below 400μg/kg. The abstract states that patients received 400μg/kg. This is incorrect, section 16.3.3 in the protocol shows that the actual dose was always below 400μg/kg, unless patients weighed exactly 35kg or 70kg, as shown below Dosage was as low as 269μg/kg for 52kg. When considering administration as below, the average dose administered is equivalent to ~130μg/kg as used in practice. Authors state: "ivermectin was dosed by weight to achieve a goal dose of 400μg/kg, but the maximum dose of ivermectin provided by the study was 35mg. While almost 42% of participants had a weight of more than 88kg and thus did not achieve the goal dose, more than 75% of participants had a weight of less than 100kg and so received at least 90% of the target dose". This is incorrect - the goal dose varied between ~300-400μg/kg, and the percentage that received 90+% of 400μg/kg is likely < 40%.
Effective dose ~130μg/kg, administration on empty stomach. Authors instructed patients to take ivermectin on an empty stomach (not done for fluvoxamine). Guzzo show that the plasma concentration of ivermectin is much higher when administered with food (geometric mean AUC 2.6 times higher). "Ivermectin should be taken on an empty stomach with water" (protocol section 16.3.3). This is not mentioned in the paper or the supplementary appendix, only in the protocol. This makes the average effective dose administered equivalent to ~130μg/kg for administration with a meal (as used in clinical protocols).
Clinical progression details for fluticasone/fluvoxamine but not ivermectin. Authors provide clinical progression details for fluticasone (Table S3, Figure S5) and fluvoxamine (eFigure 3), but not for ivermectin. This may be related to authors not reporting any of the pre-specified primary outcomes — the same table would reveal 2 of the 3 pre-specifed primary outcome results.
COVID-19 mortality/hospitalization not 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 (B). 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
Full protocol unavailable before October 2022. The pre-specified protocol is missing the appendix which includes contraindications, exclusions, formulation, appearance, packaging, dispensing, dosing, and dose rationale.
IDMC not independent, extreme conflict of interest. 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 (B). While not reviewing most of the evidence, the panel concluded that there was "insufficient evidence".
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.
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.
Very slow shipping. While one day or faster shipping should have been possible (~$11,000 funding per patient (B)), the shipping delays in this trial appear to be very long based on the ≤7 days inclusion criterion and subgroup analysis up to 13 days. One participant in the ivm-600 arm shared their experience showing 6 days from signing up until arrival of the medication, resulting in a total of 11 days treatment delay (C). 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.
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. Matched placebo analysis should be provided.
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 (B). Further, a majority of the panel providing the recommendation has major conflicts of interest (B). Also see (B), (C). The ACTIV executive committee was chaired by employees of J&J and NIH, and is now chaired by employees of Pfizer and NIH. Other members of the committee are from NIAID (Dr. Fauci), FDA, and Pfizer,
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.
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.
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.
Significant missing data, not mentioned in paper. The paper does not mention missing data, however in the presentation (@44:20) authors report close to 10% missing survey data. One author indicates there was less then 10% missing survey data through day 14. However, the presentation also shows clinical progression graphs (@22:10) that contradict this, showing 650/614 patients at day 14, which is over 20% missing data.
Statistically significant efficacy for severe patients removed. The statistically significant HR 1.86 [1.10-3.16] efficacy for severe patients at baseline (using the post-hoc primary outcome) was noted in the text of the preprint, but has been deleted in the journal version (only seen in the appendix eFigure 3).
Statistical analysis plan dated after trial end. The statistical analysis plan included with the journal paper is dated after the end of the trial.
31% more severe cases in the ivermectin arm. There were 31% more severe cases in the ivermectin arm at baseline (39 control vs. 51 ivermectin).
Population incorrect. The visual abstract reports the population as patients experiencing two or more symptoms for 7 days or less. This is incorrect and refers to the time of enrollment, not the time of intervention. The study actually includes a subgroup of patients 13 days from onset, and 107 patients that had no symptoms at baseline (eFigure 3).
Early treatment incorrect. The abstract and paper claim to study "treatment of early mild to moderate COVID-19." This is incorrect, treatment was very late, median 6 days, 25+% 8+ days, and with subgroup results up to 13 days. For influenza and oseltamivir or baloxavir, treatment is typically considered early within 24-48 hours (C).
Author claims results from 628 researchers should be censored for false information. 62 studies by 628 scientists report statistically significant positive results for ivermectin treatment of COVID-19 (D). One author claimed that a report of positive results is "disinformation" and distributed a request to report and censor the author (D), (E), (F). While discussion is warranted for all studies, a call for censorship of results is extreme and raises questions. Author provides no basis for the results of the 628 scientists being wrong and warranting of censorship, and there is no indication that author has even read most of the studies. Author cherry-picked two of 102 studies, (COVID-OUT and ACTIV-6 Bramante, Naggie (B), both very high COI studies with an extensive list of issues and very delayed treatment) and claimed that "no benefit of ivermectin was observed" (G). In addition to ignoring the 62 studies reporting statistically significant positive results, ACTIV-6 (E) reported a posterior probability that ivermectin is effective of 99%, 98%, and 97% for mean time unwell, clinical progression @14 days, and clinical progression @7 days (even though none of the pre-specified primary outcomes were reported, and noting that these preprint results were changed without explanation), and COVID-OUT showed 61% lower hospitalization with ivermectin vs. placebo (not including metformin), although this was not reported.
Bias due to false positive antigen tests. Authors accept positive antigen tests for enrollment, where the false positive rate varies depending on the prevalence of COVID-19. If the false positive rate significantly affects the results, we would expect the observed efficacy to vary with COVID-19 prevalence, with lower prevalence leading to higher false positives leading to lower observed efficacy (as more patients did not actually have COVID-19). The change in COVID-19 prevalence and efficacy over time follows this pattern in both the 400μg/kg and 600μg/kg arms. Results may be significantly affected by the inclusion of patients that do not have COVID-19 but had false positive antigen tests (H).
Participant pickup delay. A paper on the operation of the trial Lindsell reveals that delivery was increasingly made to centralized pickup locations and not directly to the participant. Authors indicate they use shipping logs and participant notification of drug receipt. This is unclear because if delivery was based on participant confirmation there would be no need to determine delivery based on shipping logs. This suggests that in at least some cases, delivery time may not have accounted for the time for participant pickup. Therefore, the actual treatment delay may be even longer than reported. This information was not disclosed previously.
Randomization failure. The treatment and control groups were drawn from different populations. Patients were allowed to select which medication they would like to test, while the control group contains patients assigned to other medications, some of which specifically requested that medication (D). Additionally, drug-specific exclusions further modify the populations.
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.
No adherence data or per-protocol analysis. Authors provide no adherence data. Non-adherence may de-power the trial and may harm randomization.
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.
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. In the journal version authors confirm that 42% of patients exceeded 88kg and did not receive the intended dose.
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.
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. Notably, the opposite is the case for fluticasone. The ivermectin placebo arm has less severe dyspnea than fluticasone, despite being larger.
Safety conclusion removed, suggests bias. Authors included the conclusion "Ivermectin at 400 μg/kg was safe and without serious adverse events as compared with placebo" in the abstract This was deleted in the JAMA paper (I).
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.
Missing subgroup counts. No subgroup counts are provided for several subgroups including 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. Authors suggest that there are no discrete categories to count the number of participants. While the graph shows estimates from a smoothed model, there are discrete numbers of participants in each group, for example patients treated within 3 days.
Overlapping fluticasone placebo shows very different event numbers. The ivermectin and fluticasone arms have 79% overlap in time (Jun 23, 2021 - Feb 4, 2022 vs. Aug 10, 2021 - Feb 12, 2022). The ivermectin placebo arm is 20% larger, suggesting approximately 20% more events. However, hospitalization is 3x larger (9 vs. 3), and combined hospitalization, urgent care, ER, and death is 2.2x larger (28 vs. 13).
Overlapping fluticasone placebo shows unexpected baseline numbers. The ivermectin and fluticasone arms have 79% overlap in time (Jun 23, 2021 - Feb 4, 2022 vs. Aug 10, 2021 - Feb 12, 2022). The ivermectin placebo arm is 20% larger, suggesting approximately 20% more patients for each characteristic. However, ivermectin placebo has less Latino patients than fluticasone and over 2x COPD patients.
Inconsistent calendar time subgroups. The calendar time subgroups for ivermectin and fluticasone are identical, from Oct 15, 2021 to Feb 1, 2022, however these do not match the reported recruitment periods.
Outcome graph presented does not match either medication tested. In the ACTIV-6 presentation (@9:22) an outcome graph is shown, however there is no indication what treatment it is for. The deaths and hospitalizations do not match those reported for either ivermectin or fluticasone.
Efficacy was higher over calendar time, which may reflect higher efficacy with more recent variants. Efficacy was higher for vaccinated patients.
Posterior probability ivermectin is effective:

Mean time unwell: 99%
Clinical progression @14 days: 98%
Clinical progression @7 days: 97%

All exceed the pre-specified threshold for superiority (Clinical progression results showing superiority in the preprint have been changed without explanation).
Team comments:
“No differences were observed in relief of mild-to-moderate COVID-19 symptoms” (@24:22)

“No evidence of improvement in time to recovery”

"The posterior probability for treatment benefit did not meet prespecified thresholds for clinical events or on the COVID Clinical Progression Scale" (in the preprint)
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
This is the 36th of 49 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000038.
This is the 85th of 102 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 560 quintillion).
16. (C),
risk of death, 200.3% higher, RR 3.00, p = 0.50, treatment 1 of 602 (0.2%), control 0 of 604 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), 600µg/kg, day 28.
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), 400µg/kg, day 28.
risk of death/hospitalization, 151.7% higher, RR 2.52, p = 0.29, treatment 5 of 600 (0.8%), control 2 of 604 (0.3%), 600µg/kg, 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%), 400µg/kg, 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, 400µg/kg, aggravated C19 pneumonia, eTable 2.
risk of progression, no change, RR 1.00, p = 0.53, treatment 34 of 600 (5.7%), control 36 of 604 (6.0%), NNT 341, adjusted per study, urgent or emergency care visits, hospitalizations, or death, 600µg/kg.
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, 400µg/kg.
clinical progression, 61.0% higher, OR 1.61, p = 0.07, treatment 600, control 604, mid-recovery, 600µg/kg, day 7, RR approximated with OR.
clinical progression, 114.0% higher, OR 2.14, p = 0.04, treatment 600, control 604, 600µg/kg, day 14, RR approximated with OR.
clinical progression, 161.0% higher, OR 2.61, p = 0.04, treatment 600, control 604, 600µg/kg, day 28, RR approximated with OR.
clinical progression, 24.0% lower, OR 0.76, p = 0.07, treatment 817, control 774, mid-recovery, 400µg/kg, day 7, RR approximated with OR.
clinical progression, 27.0% lower, OR 0.73, p = 0.05, treatment 817, control 774, 400µg/kg, day 14, RR approximated with OR.
clinical progression, 10.0% lower, OR 0.90, p = 0.57, treatment 817, control 774, 400µg/kg, day 28, RR approximated with OR.
time to recovery, 2.0% lower, HR 0.98, p = 0.72, treatment 600, control 604, inverted to make HR<1 favor treatment, 600µg/kg, post-hoc primary outcome.
risk of limited activity, 30.5% lower, RR 0.70, p = 0.14, treatment 30 of 805 (3.7%), control 41 of 765 (5.4%), NNT 61, eFigure 2, 400µg/kg, day 14.
time to recovery, 6.5% lower, HR 0.93, p = 0.18, treatment 817, control 774, inverted to make HR<1 favor treatment, 400µg/kg, post-hoc primary outcome.
time to recovery, 46.2% lower, HR 0.54, p = 0.02, treatment 39, control 51, inverted to make HR<1 favor treatment, 400µg/kg, severe, recovery.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Naggie et al., 12 Jun 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 28 authors, study period 23 June, 2021 - 4 February, 2022, average treatment delay 6.0 days, dosage 600μg/kg days 1-6, trial NCT04885530 (history) (ACTIV-6). Contact:
This PaperIvermectinAll
Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial
MD, MHS Susanna Naggie
Background: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the United States with mild-to-moderate symptomatic coronavirus disease 2019 (COVID-19) is unknown. Objective: We evaluated the efficacy of ivermectin 400 µg/kg daily for 3 days compared with placebo for the treatment of early mild-to-moderate COVID-19. Methods: ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial to evaluate repurposed therapies in outpatients with mild-to-moderate COVID-19. Non-hospitalized adults age ≥30 years with confirmed COVID-19, experiencing ≥2 symptoms of acute infection for ≤7 days were randomized to receive ivermectin 400 µg/kg daily for 3 days or placebo. The main outcome measure was time to sustained recovery, defined as achieving at least 3 consecutive days without symptoms. Secondary outcomes included a composite of hospitalization or death by day 28. Results: Of the 3457 participants who consented to be evaluated for inclusion in the ivermectin arm, 1591 were eligible for this study arm, randomized to receive ivermectin 400 µg/kg (n=817) or placebo (n=774), and received study drug. Of those enrolled, 47% reported receiving at least 2 doses of SARS-CoV-2 vaccination. The posterior probability for any improvement in time to recovery was 0.91 (hazard ratio 1.07, 95% credible interval 0.96-1.17). The posterior probability of this benefit exceeding 24 hours was less than 0.01, as measured by the difference in mean time unwell. Hospitalizations or deaths were uncommon (ivermectin [n=10]; placebo [n=9]). Ivermectin at 400 µg/kg was safe and without serious adverse events as compared with placebo (ivermectin [n=10]; placebo [n=9]). Conclusions: Ivermectin dosed at 400 µg/kg daily for 3 days resulted in less than one day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 in the United States during the delta and omicron variant time periods.
Author Contributions Author and collaborator contributions, including responsibility for decision to submit the manuscript, drafting of the initial manuscript, study conceptualization, investigation, data curation, formal analysis, study supervision, and review and editing of the manuscript, are provided in the Online Supplement. CL and TS directly accessed and verified the underlying study data. SN and AFH had access to all the study data and had final responsibility for the decision to submit the paper for publication.
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Bmi, >30 kg/m 2
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Late treatment
is less effective
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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