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Ivermectin study #70 of 86
3/4 Early treatment study
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
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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.
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 actually 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 [1].
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 [2].
This study reportedly has an ethical issue whereby participants were told the study drug was "D11AX22" [3]. 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. Therefore this paper may be retracted (JAMA has not indicated their response yet) [4, 5, 6].
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, for example [7]. Additionally, the control group did about 5x better than anticipated for deterioration, also suggesting that the control patients used some kind of treatment. Patients which 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.
Most data was collected via surveys, without physical examination.
The trial protocol lists “the duration of supplemental oxygen” as an outcome but the results for this outcome are missing.
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.
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.
Other issues can be found in the comments of the article [8].
87% medication adherence. NCT04405843.

López-Medina et al., 3/4/2021, Double Blind Randomized Controlled Trial, Columbia, South America, peer-reviewed, median age 37.0, 19 authors, dosage 300μg/kg days 1-5.
risk of death, 66.8% lower, RR 0.33, p = 0.50, treatment 0 of 200 (0.0%), control 1 of 198 (0.5%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of escalation of care, 60.8% lower, RR 0.39, p = 0.10, treatment 4 of 200 (2.0%), control 10 of 198 (5.1%), odds ratio converted to relative risk.
risk of escalation of care with post-hoc <12h exclusion, 34.3% lower, RR 0.66, p = 0.51, treatment 4 of 200 (2.0%), control 6 of 198 (3.0%), odds ratio converted to relative risk.
risk of deterioration by >= 2 points on an 8-point scale, 43.1% lower, RR 0.57, p = 0.35, treatment 4 of 200 (2.0%), control 7 of 198 (3.5%), odds ratio converted to relative risk.
risk of fever post randomization, 24.8% lower, RR 0.75, p = 0.33, treatment 16 of 200 (8.0%), control 21 of 198 (10.6%), odds ratio converted to relative risk.
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%), odds ratio converted to relative risk, 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.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. For an individual study the most serious outcome may have a smaller number of events and lower statistical signficance, however this provides the strongest evidence for the most serious outcomes when combining the results of many trials.
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