Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19

Abstract

ImportanceThe effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown.ObjectiveTo evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19.Design, Setting, and ParticipantsACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US.InterventionsParticipants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774).Main Outcomes and MeasuresTime to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28.ResultsAmong 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]).Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

Effect of Ivermectin 600 μg/kg for 6 days vs Placebo on Time to Sustained Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial

“…17,18 Recent results from the current platform trial reported participants receiving ivermectin, with a 400 µg/kg, daily for 3 days had a an average ~12-hour shorter time spent unwell when compared with placebo, a secondary outcome for the trial. 15 This finding was not replicated here.…”

“…The notable difference in baseline characteristics between these 2 cohorts is the completed vaccination rate, which is 84% for this study and was 47% for the prior ivermectin 400 µg/kg group. 15 Hospitalizations and COVID-19-related clinical events were less common in this largely vaccinated cohort. The incidence of acute care visits, hospitalizations, or death was similar with ivermectin (5.7%) and placebo (6.0%); a result also observed in the two prior ivermectin 400 μg/kg randomized trials in the US.…”

“…The incidence of acute care visits, hospitalizations, or death was similar with ivermectin (5.7%) and placebo (6.0%); a result also observed in the two prior ivermectin 400 μg/kg randomized trials in the US. 6,15 This trial has several strengths. This was a double-blind, randomized, placebo-controlled nationwide trial with 93 enrolling sites and a call center that recruited participants from all 50 US states.…”

“…[11][12][13][14] Three large randomized outpatient trials in people with symptomatic mild or moderate COVID-19 failed to identify a clinical benefit of ivermectin when dosed at 400 µg/kg daily for 3 days. [15][16][17] One possibility is that the dose and duration studied was too low and too short, missing the therapeutic window for ivermectin. A proof-of-concept randomized controlled clinical trial in hospitalized patients showed that ivermectin, 600 µg/kg, for 5 days suggested possible anti-viral activity with increasing dose.…”

Outpatient regimens to reduce COVID-19 hospitalisations: a systematic review and meta-analysis of randomized controlled trials

“…Additionally, 15 repurposed drugs tested in 23 outpatient RCTs were included in our analysis for context: metformin 13 , fluvoxamine 13, 34, 35 , ivermectin 13, 36, 37, 38 , hydroxychloroquine 33, 39, 40, 41, 42 , nitazoxanide 43 , colchicine 44 , niclosamide 45 , four antithrombotics-aspirin, apixaban 46 , sulodexide 47 , enoxaparin 48, 49 , inhaled ciclesonide 50 , the herbal mixture Saliravira 51 , azithromycin 52, 53 , and resveratrol 54 .…”