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BackgroundWhether ivermectin, with a maximum targeted dose of 600 g/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) remains unknown. Our objective was to evaluate the effectiveness of ivermectin, dosed at 600 g/kg, daily for 6 days compared with placebo for the treatment of early mild to moderate COVID-19. MethodsACTIV-6, an ongoing, decentralized, randomized, double-blind, placebo-controlled, platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1206 participants age [≥]30 years with confirmed COVID-19, experiencing [≥]2 symptoms of acute infection for [≤]7 days, were enrolled from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022, at 93 sites in the US. Participants were randomized to ivermectin, with a maximum targeted dose of 600 g/kg (n=602), daily vs. placebo daily (n=604) for 6 days. The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. ResultsAmong 1206 randomized participants who received study medication or placebo, median (interquartile range) age was 48 (38-58) years; 713 (59%) were women; and 1008 (84%) reported [≥]2 SARS-CoV-2 vaccine doses. Median time to recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (HR) (95% credible interval [CrI], posterior probability of benefit) for improvement in time to recovery was 1.02 (0.92-1.13; P[HR>1]=0.68). In those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (HR 1.0, 0.6- 1.5; P[HR<1]=0.53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. ConclusionsAmong outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 g/kg daily for 6 days, compared with placebo did not 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.
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BackgroundThe effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic coronavirus disease 2019 (COVID-19) is unclear. DesignACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial testing repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 non-hospitalized adults aged [≥]30 years with confirmed COVID-19 experiencing [≥]2 symptoms of acute infection for [≤]7 days prior to randomization were randomized to receive fluvoxamine 50 mg or placebo twice daily for 10 days. The primary outcome was time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Secondary outcomes included composites of hospitalization or death with or without urgent or emergency care visit by day 28. ResultsOf 1331 participants randomized (mean [SD] age, 48.5 [12.8] years; 57% women; 67% reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (n=614 placebo, n=674 fluvoxamine). Median time to recovery was 13 days (IQR 12-13) in the placebo group and 12 days (IQR 11-14) in the fluvoxamine group (hazard ratio [HR] 0.96, 95% credible interval [CrI] 0.86-1.07; posterior probability for benefit [HR>1]=0.22). Twenty-six participants (3.9%) in the fluvoxamine group were hospitalized or had urgent or emergency care visits compared with 23 (3.8%) in the placebo group (HR 1.1, 95% CrI 0.6-1.8; posterior probability for benefit [HR<1]=0.340). One participant in the fluvoxamine group and 2 in the placebo group were hospitalized; no deaths occurred. Adverse events were uncommon in both groups. ConclusionsTreatment with fluvoxamine 50 mg twice daily for 10 days did not improve time to recovery, compared with placebo, among outpatients with mild to moderate COVID-19. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.
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BackgroundThe effectiveness of inhaled corticosteroids to shorten time to symptom resolution or prevent hospitalization or death among outpatients with mild-to-moderate coronavirus 2019 (Covid-19) is unclear. MethodsACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial testing repurposed medications in outpatients with confirmed SARS-CoV-2 infection. Non-hospitalized adults aged [≥]30 years, experiencing [≥]2 symptoms of acute infection for [≤]7 days were randomized to inhaled fluticasone furoate 200 g once daily for 14 days or placebo. The primary outcome was time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Secondary outcomes included composites of hospitalization or death with or without urgent care or emergency department visit by day 28. ResultsOf those eligible for the fluticasone arm, 656 were randomized to and received inhaled fluticasone; 621 received concurrent placebo. There was no evidence of improvement in time to recovery with fluticasone compared with placebo (hazard ratio [HR] 1.01, 95% credible interval [CrI] 0.91-1.12; posterior probability for benefit [HR>1]=0.56). Twenty-four participants (3.7%) in the fluticasone arm had urgent care or emergency department visits or were hospitalized compared with 13 (2.1%) in the pooled, concurrent placebo arm (HR 1.9, 95% CrI 0.8-3.5; posterior probability for benefit [HR<1]=0.03). Three participants in each arm were hospitalized, and no deaths occurred. Adverse events were uncommon in both arms. ConclusionsTreatment with inhaled fluticasone furoate for 14 days did not result in improved time to recovery among outpatients with Covid-19 in the United States during the delta and omicron variant surges. Trial RegistrationClinicalTrials.gov (NCT04885530).
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BackgroundThe effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the United States with mild-to-moderate symptomatic coronavirus disease 2019 (COVID-19) is unknown. ObjectiveWe evaluated the efficacy of ivermectin 400 {micro}g/kg daily for 3 days compared with placebo for the treatment of early mild-to-moderate COVID-19. MethodsACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial to evaluate repurposed therapies in outpatients with mild-to-moderate COVID-19. Non-hospitalized adults age [≥]30 years with confirmed COVID-19, experiencing [≥]2 symptoms of acute infection for [≤]7 days were randomized to receive ivermectin 400 {micro}g/kg daily for 3 days or placebo. The main outcome measure was time to sustained recovery, defined as achieving at least 3 consecutive days without symptoms. Secondary outcomes included a composite of hospitalization or death by day 28. ResultsOf the 3457 participants who consented to be evaluated for inclusion in the ivermectin arm, 1591 were eligible for this study arm, randomized to receive ivermectin 400 {micro}g/kg (n=817) or placebo (n=774), and received study drug. Of those enrolled, 47% reported receiving at least 2 doses of SARS-CoV-2 vaccination. The posterior probability for any improvement in time to recovery was 0.91 (hazard ratio 1.07, 95% credible interval 0.96-1.17). The posterior probability of this benefit exceeding 24 hours was less than 0.01, as measured by the difference in mean time unwell. Hospitalizations or deaths were uncommon (ivermectin [n=10]; placebo [n=9]). Ivermectin at 400 {micro}g/kg was safe and without serious adverse events as compared with placebo (ivermectin [n=10]; placebo [n=9]). ConclusionsIvermectin dosed at 400 {micro}g/kg daily for 3 days resulted in less than one day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 in the United States during the delta and omicron variant time periods. Trial registrationClinicalTrials.gov Identifier: NCT04885530.
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ObjectiveTo determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCW). DesignMulticenter, 1:1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial. Setting34 clinical centers in the United States. Participants1360 HCW at risk for COVID-19 infection enrolled between April and November 2020. InterventionsA loading dose of HCQ 600 mg twice on Day 1 followed by 400 mg daily for 29 days or matching placebo taken orally. Main Outcome MeasureComposite of confirmed or suspected COVID-19 clinical infection by Day 30 defined as new onset fever, cough, or dyspnea and either a positive SARS-CoV-2 PCR test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected). ResultsEnrollment for the study was closed before full accrual due to difficulties recruiting additional participants. The primary composite endpoint occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No statistically significant difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6% to 0.9%, p=0.20). We identified no significant safety issues. ConclusionOral HCQ taken as prescribed appeared to be safe in a group of HCW. No significant clinical benefits were observed. The study was underpowered to rule out a small but potentially important reduction in COVID-19 infections. Trial RegistrationNCT04334148
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Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We conducted a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine was 1.11 (95% CI: 1.02, 1.20; I2=0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I2=0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine was associated with increased mortality in COVID-19 patients, and there was no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
