What large randomized trials of ivermectin for COVID‑19 have reported since 2022 and what were their results?

1. The big platform trials: PRINCIPLE and platform arms that stopped for futility

The UK PRINCIPLE adaptive platform randomized 8,811 SARS‑CoV‑2–positive community participants and randomized 2,157 to ivermectin, but the ivermectin arm was stopped on 1 July 2022 because a pre‑specified futility criterion for hospitalization/death was met; the trial concluded there was no meaningful benefit on primary outcomes in this large community sample ^{[2] [8]}. This stopping decision and its sample size make PRINCIPLE one of the largest randomized datasets against routine ivermectin use in community COVID‑19 ^[2].

2. High‑dose, placebo‑controlled outpatient trials: JAMA and ACTIV‑6 results

A large randomized platform trial testing higher‑dose ivermectin (600 μg/kg daily for six days) versus placebo found no improvement in time to sustained recovery among outpatients with early mild‑to‑moderate COVID‑19; that JAMA report represents a rigorously conducted dose‑finding randomized trial that failed to show clinical benefit ^[1]. Independently, decentralized platform trials such as ACTIV‑6 and other NIH‑funded randomized studies enrolled thousands and, in preliminary and final analyses, reported no meaningful clinical benefit of ivermectin for early outpatient COVID‑19 ^{[3] [4]}.

3. TOGETHER and other large randomized trials reported in 2022

The TOGETHER trial investigators presented ivermectin results in 2022 to clinical audiences and the study—alongside other multicenter randomized efforts—contributed to the dataset showing no reliable effect on key clinical endpoints such as hospitalization or disease progression in outpatients ^{[9] [10]}. Multiple well‑conducted multicenter randomized, double‑blind, placebo‑controlled clinical trials published in 2022 likewise reported non‑effectiveness for inpatient and outpatient cohorts ^[11].

4. Systematic reviews, meta‑analyses and contested prior evidence

Systematic reviews and meta‑analyses have been divided: some meta‑analyses that included many small RCTs and observational studies reported large effect sizes, while higher‑quality reviews and the Cochrane assessment warned the evidence is low quality and subject to bias, with randomized trials overall failing to demonstrate a consistent, clinically meaningful benefit ^{[5] [12] [6]}. Fact‑checking and public health agencies concluded that, after hundreds of studies and several large RCTs, evidence remains insufficient to recommend ivermectin for COVID‑19 outside trials, and large trials have not shown benefit ^{[7] [3]}.

5. Why the controversy persists: study quality, heterogeneity and activism

Disagreement endures because early positive signals came from small or observational studies later criticized for methodological flaws or potential bias, and advocates have amplified those results even as larger, more rigorous trials failed to replicate them; fact‑checkers and mainstream medical journals emphasize that large, double‑blind randomized trials carry greater weight and have not found clinically meaningful benefit ^{[5] [3] [7]}. Reporting also notes political and social movements promoting ivermectin despite the evolving RCT evidence, which complicates public understanding ^[4].

6. What this reporting cannot show from the supplied sources

The supplied reporting catalogs several large randomized trials and reviews through 2024 and early 2025 and consistently reports null findings in the best‑designed studies, but the available sources do not provide a single exhaustive list of every large RCT since 2022, nor do they allow a patient‑level pooled reanalysis beyond the published meta‑analyses cited; therefore definitive assertions about every trial worldwide or subgroup effects not reported in these sources cannot be made here ^{[2] [6] [12]}.