Which randomized trials specifically report adverse event rates for ivermectin doses above 400 µg/kg and what were those rates?
Executive summary
Randomized trials testing ivermectin above 400 µg/kg do exist — most notably the COVER dose‑finding trial (600 and 1200 µg/kg arms), the ACTIV‑6 platform trial with a 600 µg/kg‑per‑day arm, and at least one placebo‑controlled trial that randomized participants to 400–600 µg/kg/day — but the provided reporting does not give clear, single‑trial adverse‑event (AE) percentages for those high‑dose arms in its snippets [1] [2] [3]. What the available systematic reviews and pooled analyses do report is that across many randomized trials of ivermectin (various doses), the overall proportion of participants with reported adverse events was roughly 29% in ivermectin arms versus 29% in control arms [4], and other meta‑analyses conclude no convincing increase in AEs with ivermectin overall [5] [6].
1. Trials that randomized participants to doses above 400 µg/kg and how they were dosed
The COVER study randomized outpatients to placebo, ivermectin 600 µg/kg for 5 days, or ivermectin 1200 µg/kg for 5 days, explicitly designed as a high‑dose, dose‑finding trial with serious adverse drug reactions (SADRs) and viral‑load change as primary endpoints [1]. The ACTIV‑6 platform included a randomized arm with a maximum targeted dose of 600 µg/kg daily for 6 days versus placebo in outpatients with early COVID‑19 [2]. A randomized, double‑blind trial at Siriraj Hospital used a regimen that delivered ivermectin in the range 400–600 µg/kg/day for 3 days [3]. Background reporting also notes that some studies and nonrandomized uses have explored doses up to 2 mg/kg in various contexts, but the randomized trials highlighted above are the clearest examples of >400 µg/kg dosing in RCTs [3] [1].
2. What those trials reported about adverse events (what is and isn’t available in the sources)
In the summarized snippets, the COVER trial’s primary safety endpoint was SADRs, and 93 participants were randomized across arms, but the provided text does not include arm‑specific AE rates or counts in the excerpted report [1]. The ACTIV‑6 trial reports that adverse events were “uncommon in both groups” and provides composite counts for hospitalization/death/urgent care visits (ivermectin 34 events vs placebo 36 events) and notes rare hospitalizations and one death in the ivermectin arm, but the snippet does not give a per‑arm percentage of all adverse events or a breakdown by severity for the 600 µg/kg dosing arm [2]. The Siriraj trial’s summary states that a high dose of 400–600 µg/kg/day for 3 days showed no significant benefit, but the provided excerpt does not quantify AEs by arm in the snippet [3]. Therefore, the supplied reporting does not permit extraction of precise, trial‑specific AE rates for the >400 µg/kg arms except where bundled into broader safety statements [1] [2] [3].
3. What pooled evidence says about adverse events across randomized trials (context for safety at higher doses)
A pooled safety meta‑analysis of COVID‑19 ivermectin RCTs found 371 adverse events among 1,261 participants in ivermectin arms (29%) and 376 events among 1,284 controls (29%), yielding no significant difference in overall AE reporting across the included trials [4]. Larger systematic reviews and meta‑analyses likewise conclude that ivermectin did not increase adverse events or serious adverse events overall in the randomized trial literature to date [5] [6]. These pooled findings cover many dosing regimens and are useful context, but they do not isolate the high‑dose (>400 µg/kg) randomized arms as a separate subgroup in the provided excerpts [4] [5] [6].
4. Bottom line, uncertainty, and why precise per‑trial AE percentages matter
The evidence shows randomized high‑dose ivermectin trials exist (COVER, ACTIV‑6 high‑dose arm, Siriraj trial), and pooled analyses of many RCTs report no overall increase in adverse events [1] [2] [3] [4] [5]. However, the supplied reporting excerpts do not include clear, per‑trial numerical AE rates specifically for the >400 µg/kg arms, so a definitive list of trial‑by‑trial AE percentages cannot be produced from these snippets alone [1] [2] [3]. Independent agendas — proponents emphasizing tolerability and critics emphasizing potential neurotoxicity at supratherapeutic doses — make it important to consult full trial reports, supplementary appendices, and DSMB statements to obtain arm‑level AE counts and severity grading before drawing final safety conclusions [1] [4].