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Review 2: "Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial"

Both reviewers are in agreement that this study provides strong support for its claim that ivermectin does not seem to provide any clinically significant improvement in treatment outcomes.

Published onAug 15, 2022
Review 2: "Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial"
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key-enterThis Pub is a Review of
Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial
Description

AbstractBackgroundThe 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.ObjectiveWe 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.MethodsACTIV-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.ResultsOf 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]).ConclusionsIvermectin 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.Trial registrationClinicalTrials.gov Identifier: NCT04885530.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The main study findings are supported by the well-conducted study enrolling the largest number of study participants in an out-patient ivermectin placebo-controlled trial. In the context of this and other emerging trials from outside of the United States, the evidence is now overwhelming that ivermectin is not an important drug for the treatment of COVID-19.

ACTIV- 6 is a full decentralized trial evaluating repurposed drugs for outpatient COVID-19 treatments. This trial is based on a master protocol of the ACTIV-6 intended platform trial. The exact meaning of platform trials is not well established and, although intended to offer the opportunity to evaluate multiple arms at the same time using a shared placebo, this is not necessary. Herein, the use of a master protocol guides what can be used in any intended future evaluation.

The investigators used a novel primary outcome as well as the well-established composite endpoint of “hospitalization or death.” The novel outcome of “time to sustained recovery” defined as 3 or more consecutive days of recovery is quickly becoming a customary outcome. However, for any outcome, the outcome needs to be important to patients or society in general. Most people would agree that faster recovery is important. But how exactly recovery is defined is important; in particular, what would be the minimally important difference for a patient to determine it is worth taking a drug that may (or may not) have costs and risks associated with it?

It is important to note that this study was conducted somewhat late in the pandemic when clinical events were becoming rarer and thus, the emphasis on time to recovery as a primary endpoint. The uptake of vaccination in the United States and the inclusion of both lower and higher risk populations in the trial mean that detecting clinical events would be increasingly difficult. While clinical endpoints are desired by guideline groups and decision-makers, it is now virtually impossible to sufficiently detect these effects in the outpatient setting.

The trial enrolled patients at lower and higher risk of serious illness defined as >2 symptoms beginning no longer than 7 days from enrollment. This is somewhat standard in outpatient trials as any longer than this and a patient may already be expected to be improving. In this case, the average duration of symptoms was 6 days, but some longer (IQR 5-8). This is really the only notable limitation in the trial.

Trials that applied decentralized approaches have many strengths in the context of this pandemic, but are also limited by the lack of direct clinical observation. In this case, as the primary outcomes are self-reported rather than clinical, this limitation does not matter that importantly. The finding that patients in the treatment group had a small improvement in time to sustained recovery needs to be tempered by whether the effect is clinically useful. In this case, it appears to not be. The other outcomes, such as hospitalization, death, emergency room visits and adverse events, were predictably low The study did not find any useful signal of a treatment effect on clinical outcomes.

The subgroup analysis is useful and indicates that trends towards favorable recovery may be affected by the subgroup status. While the evidence for the dose used in this trial appears to now be conclusive, the ACTIV-6 group are now conducting a higher and longer dose of ivermectin vs placebo (600ug/Kg daily for 6 days).

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