Which large randomized trials (names, sizes, designs) have most influenced WHO and PRINCIPLE conclusions about ivermectin?

1. PRINCIPLE: an open, adaptive platform in the community that reset expectations

The PRINCIPLE trial was a multicentre, open‑label, multi‑arm adaptive platform RCT enrolling adults aged ≥18 years in the community with positive SARS‑CoV‑2 tests and symptoms ≤14 days, randomising participants to usual care, usual care plus ivermectin (target dose 300–400 μg/kg once daily for 3 days), or other interventions, and using Bayesian models for co‑primary endpoints of time to self‑reported recovery and COVID‑19‑related hospitalisation/death within 28 days; the investigators report that their ivermectin findings align with three large placebo‑controlled trials and that their design choice (open‑label) was not thought to meaningfully bias hospital admission outcomes ^[1].

2. The Brazil double‑blind outpatient trial: a clean placebo‑controlled signal

A large, double‑blind, randomized, placebo‑controlled adaptive platform trial conducted at 12 public health clinics in Brazil tested ivermectin 400 μg/kg once daily for 3 days in symptomatic, SARS‑CoV‑2–positive outpatients (symptoms ≤7 days) and found no treatment benefit; the NEJM report notes that when trials judged to be of moderate or better quality are pooled, ivermectin did not show efficacy and that WHO’s recommendation against routine use was already based on very‑low‑certainty earlier evidence ^[2].

3. Other moderate‑sized placebo‑controlled trials that reinforced null findings

Several other randomized, double‑blind, placebo‑controlled community and hospital trials shaped the evidence base — for example, IVERCOR‑COVID19, a randomized, double‑blind, placebo‑controlled study in Corrientes, Argentina, which randomized 501 non‑hospitalized patients and aimed to assess prevention of hospitalization; such trials, collectively, contributed to systematic reviews that found little or no effect on recovery, hospital admission, ventilation, or mortality ^{[3] [1] [6]}.

4. How WHO and PRINCIPLE interpreted the totality: quality over quantity

WHO’s living guideline and PRINCIPLE both emphasized the low to very‑low certainty of evidence and recommended ivermectin only in clinical trials; that interpretation rested not on single dramatic positive trials but on the balance of higher‑quality RCTs and meta‑analyses that excluded or down‑weighted small, biased, or problematic studies ^{[2] [1] [6] [5]}.

5. Why earlier meta‑analyses looked more favorable — and why that changed

Early meta‑analyses that reported large mortality or recovery benefits included numerous small trials, some unpublished preprints, and a few studies later flagged for irregularities; methodological critiques and the withdrawal of at least one influential preprint exposed how a few suspect trials could disproportionately drive pooled effects, prompting reappraisal and uncertainty in guideline panels ^{[4] [7] [8]}.

6. The current balance: robust RCTs vs contested smaller studies

The decisive influence on policy has come from well‑designed, placebo‑controlled randomized trials (PRINCIPLE; the Brazil double‑blind trial; several other randomized trials including the 501‑patient Argentine study) plus systematic reviews that prioritized trial quality — together they produced the WHO and PRINCIPLE conclusions that ivermectin shows insufficient evidence of benefit and should be used only in trials, while acknowledging that lower‑quality meta‑analyses claim benefit but are compromised by bias concerns ^{[1] [2] [3] [4] [5]}.

7. Caveats and open questions still shaping research agendas

Guideline panels concede limitations in the evidence base — heterogeneity of dosing, timing, and patient risk, plus uneven trial quality and some unresolved reports — which is why several groups continue randomized investigations and why WHO restricts ivermectin use to trial settings pending further high‑quality data ^{[6] [2] [9]}.