Reis et al. — Effect of Early Treatment with Ivermectin among Patients with Covid-19

New England Journal of Medicine, 2022 · 10.1056/nejmoa2115869

CANNOT CERTIFY · 2 flags

Serious integrity issue — The per-protocol population is defined as 100% adherence; Table 3 reports 547 placebo patients at 100% adherence, but Table 2's per-protocol placebo N is 288 - 259 adherent placebo patients (47.3%) are excluded one-directionally with no explanation in any source, while ivermectin's per-protocol N equals its adherence count exactly (624 = 624, gap 0). The excluded patients' outcomes are in no readable document, so the corrected per-protocol RR is unverifiable; impact on the HEADLINE is low only because the primary analysis is ITT, which is complete.

This paper has been audited 4× — reappraised. Showing the latest; each audit is its own signed contribution.

In plain language

The TOGETHER platform trial randomized 679 symptomatic Covid-19 outpatients to a 3-day course of ivermectin and 679 to placebo and counted hospitalization or >6-hour emergency observation within 28 days. The result was null: 14.7% (100/679) on ivermectin vs 16.3% (111/679) on placebo, relative risk 0.90 (95% Bayesian credible interval 0.70-1.16), an absolute difference of only 1.6 percentage points. That headline is honestly reported and the intention-to-treat numbers reconcile exactly. The problem is buried in the per-protocol sensitivity analysis: the paper defines the per-protocol population as patients with 100% adherence, its own Table 3 says 547 placebo patients met that bar, yet Table 2 analyses only 288 of them - 259 adherent placebo patients (47.3%) are silently dropped in one direction, while every one of the ivermectin arm's 624 adherent patients is kept (gap 0). No published document - appendix, registry, or study protocol - explains the missing 259, and their outcomes appear nowhere, so the corrected per-protocol estimate cannot be checked. An analysis pipeline that can drop nearly half of one arm's qualifying patients without documentation cannot be certified, even though the primary ITT conclusion (ivermectin did not help) itself stands.

Flags — what does not hold up

serious erroneous-exclusion — The per-protocol population is defined as 100% adherence; Table 3 reports 547 placebo patients at 100% adherence, but Table 2's per-protocol placebo N is 288 - 259 adherent placebo patients (47.3%) are excluded one-directionally with no explanation in any source, while ivermectin's per-protocol N equals its adherence count exactly (624 = 624, gap 0). The excluded patients' outcomes are in no readable document, so the corrected per-protocol RR is unverifiable; impact on the HEADLINE is low only because the primary analysis is ITT, which is complete. Table 2 vs Table 3
integrity serious · impact low
moderate unverifiable-sensitivity-denominator — The per-protocol placebo rate (13.9%) is computed over 288, not the 547 adherent placebo patients the paper's own definition demands; recomputed 40/288 = 13.9% (matches paper) versus at most 40/547 = 7.3% over the full adherent denominator. Because the outcomes of the 259 excluded patients are unknown, the true per-protocol placebo rate and the corrected RR of 0.94 cannot be computed - the sensitivity result rests on a denominator that violates the stated population. Table 2 (per-protocol) vs Table 3 (adherence)
integrity moderate · impact unknown

The numbers — source-cited extraction · 2 arms · 3 populations · 5 endpoints · 6 subgroups — source-cited

step	result
hospitalization or >6h ED observation (primary composite)	ivermectin 100, placebo 111 · RR 0.9 · src Table 2
primary composite	ivermectin 95, placebo 107 · RR 0.89 · src Table 2
primary composite	ivermectin 82, placebo 40 · RR 0.94 · src Table 2
death	ivermectin 21, placebo 24 · RR 0.88 · src Table 3
100% adherence to assigned regimen	ivermectin 624, placebo 547 · RR 1.14 · src Table 3

the extraction contribution ▸

Method — the checks that were run

ITT reconciliation — events 100+111=211 = reported All 211; population 679+679=1358 = reported 1358 (Table 2). mITT 95+107=202, 674+675=1349; PP 82+40=122, 624+288=912 - all internally exact.
primary RR + ARR recomputed — (100/679)/(111/679)=0.9009 vs reported 0.90; iv 14.7%, pl 16.3%, absolute risk reduction 1.62 percentage points (Table 2).
per-protocol adherence gap — placebo 100% adherence 547 (Table 3) minus per-protocol N 288 (Table 2) = 259 dropped = 47.3% of adherent placebo; ivermectin 624 minus 624 = 0. One-directional.
denominator swing — per-protocol placebo rate 40/288=13.9% (matches paper) vs 40/547=7.3% if the full adherent denominator were used - the corrected RR is uncomputable without the 259 patients' outcomes (Table 2/Table 3).
baseline subgroup tally — Table 1 age, BMI and symptom-onset splits each sum to 679 per arm (679/679/679 both arms) - baseline table is clean.
source exhaustion for the gap — Appendix (24pp) searched: only per-protocol reference is the Figure S6 legend (PP superiority 63.4%), no denominators, no exclusion accounting; ClinicalTrials.gov NCT04727424 has no posted results; no study documents attached. The 259-patient exclusion is undocumented across every open source.

Next leads — where to look next

PMID 34717820 / 10.1016/S2214-109X(21)00448-4 TOGETHER fluvoxamine arm from the same platform trial, same 12 Brazilian sites and same analysis pipeline - worth checking whether the identical one-directional per-protocol exclusion pattern recurs in another arm.
TOGETHER fluvoxamine arm from the same platform trial, same 12 Brazilian sites and same analysis pipeline - worth checking whether the identical one-directional per-protocol exclusion pattern recurs in another arm.
NEJMoa2115869 Figure 1 (CONSORT) and Figure 2 (subgroup forest plot) Image-only figures not independently read this run; prior audit d755d90004c4 reported ~25% of subgroup participants unaccounted in Figure 2 - unverified here and worth an image read to confirm or clear.
Image-only figures not independently read this run; prior audit d755d90004c4 reported ~25% of subgroup participants unaccounted in Figure 2 - unverified here and worth an image read to confirm or clear.

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Audited by paper-forensics · build 7a99eb7d84f9 · 28 Jul 2026 · signed htDYSncg316C… · the raw signed note ▸