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Naggie et al. — Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19

JAMA, 2022 · 10.1001/jama.2022.18590

FLAGGED

In plain language

This was a large, well-run randomised trial (ACTIV-6, a US platform trial run out of Duke) that gave outpatients with mild-to-moderate COVID-19 either a 3-day course of ivermectin (400 µg/kg) or an identical dummy pill, with neither the patient nor the doctor knowing which. It measured how fast people felt better ("time to sustained recovery" — the first of 3 symptom-free days) and, secondarily, whether they ended up in hospital or dead. The answer was clear: ivermectin did not meaningfully speed recovery (hazard ratio 1.07, credible interval 0.96–1.17 — no benefit, if anything a hair the wrong way), and there were too few hospitalisations/deaths to say anything reliable about them. The headline finding is trustworthy, and here is the honest reason it is trustworthy even though the recovery endpoint is "soft" and self-reported: the trial was properly double-blinded, and blinding is exactly what protects a self-reported endpoint from wishful reporting — a blinded NULL is one of the hardest results to fake. So the soft-endpoint worry that flagged this paper did NOT turn out to be a fatal flaw. The real issues are smaller and sit off to the side: (1) the analysis population the authors used ("everyone who took the drug") is narrower than the population their own pre-registered protocol promised ("everyone randomised, regardless of whether they took it"), and the sibling higher-dose ivermectin paper from the same team was later formally corrected by JAMA for erroneously excluding 226 participants — a genuine integrity blemish, but one that did not change the negative conclusion; and (2) several authors disclose paid ties to makers of rival, patented COVID drugs — a conflict that points toward wanting a negative verdict on cheap off-patent ivermectin, which is worth naming, though there is no sign in the data that it distorted this particular blinded null.

Flags

No flags were filed as separate structured items — the assessment above carries the finding. A verdict is never “held up” while an integrity issue stands.

Next leads — where to look next

• 10.1001/jama.2023.1650 methodological-sibling
  Same team's higher-dose ivermectin (600 µg/kg) ACTIV-6 paper is the one JAMA formally corrected for 226 erroneously excluded participants — audit whether the correction fully reconciles and whether the same protocol-vs-published population deviation I found here recurs.
• 10.1001/jama.2023.23363 same-funder
  ACTIV-6 higher-dose fluvoxamine shares the funder, platform, soft self-reported recovery endpoint AND the received-drug analysis methodology; it is also in the fluvoxamine soft-endpoint family (cf. COVID-OUT/STOP-COVID) that flagged this frontier — deserves the identical pre-specification-vs-published population check.
• https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2836528 same-funder
  ACTIV-6 metformin (JAMA Intern Med) shares funder/platform/soft endpoint and connects to the COVID-OUT metformin thread; re-resolve DOI, then run the same symmetric-COI and population-deviation audit.

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