Questions about the JAMA study of ivermectin

Questions about the JAMA study of ivermectin

On March 4, JAMA published “Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19;A Randomized Clinical Trial” by Eduardo López-Medina et al. The main finding of the study was:

“In this randomized clinical trial that included 476 patients, the duration of symptoms was not significantly different for patients who received a 5-day course of ivermectin compared with placebo…”

The authors self-reported a change to the original primary endpoint after the initiation of the study. They also acknowledged that the study was not designed to detect a difference in the hazards ratio between the intervention and the control arms of less than 1.4. Other limitations they acknowledged were the lack of virological assessment, serum plasma measurement and observable differences between the treatment drug and the placebo during a part of the trial. The authors also self-report an incident during the trial in which study participants were given the study drug instead of the placebo.

However, other questions are raised by the publication, that may be more significant:

  1. On page 27 and 28 of Supplement 1 attached to the publication, the final secondary outcomes of the trial are listed. One of those outcomes is “The duration of supplemental oxygen in each arm of the study.” This outcome dose not appear in Table 2 “Outcomes in the Primary Analysis Population” or in Supplement 2 attached to the publication. Why was this outcome omitted from the publication?
  2. The study protocol was amended 4 times. The changes to the protocol at each amendment is given on page 43 of Supplement 1 attached to the publication. The changes are listed for amendments 2–4 but not for amendment 1. Were there substantive changes to the protocol with the first amendment?
  3. The final title to the protocol was “Double blind, randomized, controlled clinical trial to investigate the effectiveness of the D11AX22 molecule in adult subjects from Valle Del Cauca with initial stages of infection by SARS CoV2/COVID 19.” Were the subjects in this study informed that the purpose of the trial was to determine the effectiveness of ivermectin in COVID-19?


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  1. They didn’t measure symptom improvement, just symptom resolution.
    The average age is very low (37 years old) and insufficient to give any statistical relevance to symptom improvement
    They gave the medicine on an empty stomach, when Merck’s official label says that if the medicine is given after a high-fat meal, the bioavailability can increase up to 2.5x

  2. "The authors also self-report an incident during the trial in which study participants were given the study drug instead of the placebo"
    How many of the placebo group were given the study drug?
    If a significant number were given the drug, that is a major deal killer.

    1. During the time period when the control group was given the study drug, there were a total of 75 patients. All of those patients were then excluded from the primary analysis. They were included in the "as-treated" analysis.

  3. My thoughts are that if you include young, healthy patients you’ll need an order of magnitude more power to reach SS. This was seen in the COLCORONA trial and others. You can’t fault Ivermectin for not working when none of the IVM arm died and one died in the placebo group. Clinical deterioration 2% in IVM vs 3.5% placebo. Escalation of care needed was 2% in IVM vs 5% placebo. These percentage improvements are all positive and would likely be SS in a properly powered trial. They changed their endpoint mid-trial because their placebo group wasn’t sick enough. This is expected in a young, healthy population. Instead of changing their endpoint they should have changed their inclusion criteria to only high risk patients or increase their power. Unfortunately, they chose to do neither so their results are clinically worthless.
    Other issues with the study were that they used a proprietary formulation of Ivermectin. Since they didn’t use the standard oral form they should have validated absorption by checking sera levels to confirm their suspension formula reached therapeutic levels. There is no need to use a proprietary formula either. The major flaw in the "placebo" arm with IVM raises serious concerns regarding the quality controls for this study in general. What other errors were not caught? The final issue is the egregious conflict of interest disclosures which cast serious questions for the motivation behind this study. What I find the most troubling about this study is that of all the Ivermectin trials JAMA chose this one to publish. There are MANY other better designed trials without the major issues easily spotted in this one. This was conducted in Columbia so it’s not like they chose it because it was conducted in the USA or Europe. It’s clear they were waiting for a study that they felt could support their and Big Pharma’s desired narrative.

    1. Great commentary, Paul, as usual. I’d like to add that I lived in Colombia for four years. Currently, they have a government that when the USA says, “Jump!” Colombia says, “How high?” I suspect some “collusion” lol, with their government and ours to defame a perfectly efficacious drug for Covid-19 like ivermectin.

  4. I think the most disturbing is the "statistical analysis" section, which includes a long paragraph indicating a mixing up of treated and placebo (John Hainaut also notes this) – I think this might be much more worrying in terms of trying to take this study as worth considering very seriously than anything else ? – one might almost question whether it can be titled a "Randomised clinical trial" ….. :
    On October 20, 2020, the lead pharmacist observed that
    a labeling error had occurred between September 29 and
    October 15, 2020, resulting in all patients receiving ivermectin
    and none receiving placebo during this time frame. The
    study blind was not unmasked due to this error. The data and
    safety monitoring board recommended excluding these
    patients from the primary analysis but retaining them for
    sensitivity analysis. The protocol was amended to replace
    these patients to retain the originally calculated study power.
    The primary analysis population included patients who were
    analyzed according to their randomization group, but
    excluded patients recruited between September 29 and
    October 15, 2020, as well as patients who were randomized
    but later found to be in violation of selection criteria. Patients
    were analyzed according to the treatment they received in
    the as-treated population (sensitivity analysis).