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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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BackgroundThree randomized trials have been conducted indicating a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. We assessed the cost-consequences associated with the use of this early treatment in outpatient populations. MethodsUsing results from the three completed trials of fluvoxamine vs. placebo for the treatment of COVID-19, we performed a meta-analysis. We conducted a cost-consequence analysis using a decision-model to assess the health system benefits of the avoidance of progression to severe COVID-19. Outcomes of relevance to resource planning decisions in the US and elsewhere, including costs and days of hospitalization avoided, were reported. We constructed a decision-analytic model in the form of a decision tree to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19, from the perspective of a third-party payer:(1) treatment with a 10-day course of fluvoxamine (100mg twice daily); (2) current standard-of-care; (3) molnupiravir 5-day course. We used a time horizon of 28 days. ResultsAdministration of fluvoxamine to symptomatic outpatients with COVID-19 at high-risk of developing progression to severe COVID-19 complications is substantially cost-saving in the US, in the amount of $232 per eligible patient, and saves an average of 0.15 hospital days per patient treated is likely to be similarly beneficial in other settings. Fluvoxamine is cost saving in locations where total hospital costs are >$738. Molnupiravir had an additional cost to the healthcare system of $404 per patient treated. ConclusionsFluvoxamine is cost-saving for COVID-19 outpatient therapy. FundingFastGrants and Rainwater Charitable Foundation
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ImportanceWidely available and affordable options for the outpatient management of COVID-19 are needed, particularly therapies that prevent hospitalization. ObjectivePerform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19. Data SourcesWorld Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Study SelectionCompleted outpatient trials with available results which compared fluvoxamine to placebo. Data Extraction and SynthesisWe followed the PRISMA 2020 guidelines. We extracted study details in terms of inclusion criteria, trial demographics and the pre-specified outcome of all-cause hospitalization. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool. We conducted a frequentist random effects meta-analysis, as well as two sensitivity analyses using a Bayesian random effects meta-analysis with different estimates of prior probability: a weakly neutral prior (50% chance of efficacy with 95% confidence interval for Risk Ratio [RR] between 0.5 and 2) and a moderately optimistic prior (85% chance of efficacy). We contextualized the results by estimating the probability of any effect (RR [≤]1) and moderate effect (RR [≤]0.9) on reducing hospitalization. Main Outcome(s) and Measure(s)All cause hospitalization. Results2196 participants were included from 3 identified trials. The risk ratios for hospitalization were 0.75 (95%CI, 0.57-0.97) for the frequentist analysis, 0.78 (95%CI 0.58-1.08) for the Bayesian weakly neutral prior, and 0.73 (95%CI, 0.53-1.01) for the Bayesian moderately optimistic prior. Depending on the scenario, the probability of any effect on hospitalization ranged from 94.1% to 98.3% and a moderate effect from 81.6% to 91.1%. Conclusions and RelevanceUnder a variety of assumptions, fluvoxamine shows a high probability of preventing hospitalization in outpatients with COVID-19. While ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates, fluvoxamine could be recommended as a treatment option, particularly in resource-limited settings or persons without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals. Key PointsO_ST_ABSQuestionC_ST_ABSDoes early administration of fluvoxamine prevent hospitalization in symptomatic adult outpatients with confirmed COVID-19? FindingsIn this meta-analysis with Bayesian sensitivity analyses that accounted for varying prior probabilities, there was a high probability (94.1% to 98.3%) that fluvoxamine reduces hospitalization with frequentist risk ratio of 0.75 (95%CI 0.57-0.97). MeaningFluvoxamine is a widely available and inexpensive option that prevents hospitalization in patients with early COVID-19 based on randomized controlled trial evidence to date.
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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS CoV-2 in healthcare workers at high-risk of exposure. Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with Covid-19, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations. Results: We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16; P=0.18) and for twice weekly was 0.74 (95%CI 0.46 to 1.19; P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19 (154 ng/mL) versus participants without Covid-19 (133 ng/mL; P=0.08). Conclusions: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.
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IntroductionUse of hydroxychloroquine in hospitalized patients with COVID-19, especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from three outpatient randomized clinical trials. MethodsWe conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, post-exposure prophylaxis and early treatment for COVID-19. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings. ResultsWe enrolled 2,795 participants. The median age of research participants was 40 (IQR 34-49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2,324 (84%) participants reported side effect data, and 638 (27%) reported at least one medication side effect. Side effects were reported in 29% with daily, 36% with twice weekly, 31% with once weekly hydroxychloroquine compared to 19% with placebo. The most common side effects were upset stomach or nausea (25% with daily, 18% with twice weekly, 16% with weekly, vs. 10% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for daily, 16% twice weekly, 12% weekly, vs. 6% for placebo). Two individuals were hospitalized for atrial arrhythmias, one on placebo and one on twice weekly hydroxychloroquine. No sudden deaths occurred. ConclusionData from three outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials can safely investigate whether hydroxychloroquine is efficacious for COVID-19. Short SummaryData from three randomized clinical trials using hydroxychloroquine for the prevention and treatment of COVID-19 did not suggest significant safety concerns. Gastrointestinal side effects were common but arrhythmias were rare. There were no sudden deaths in any trial.
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BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease 2019 (COVID-19) pandemic. Currently, there are a lack of evidence-based therapies to prevent COVID-19 following exposure, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis and pre-emptive therapy for COVID-19. MethodsWe will conduct two nested multicenter international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) post-exposure prophylaxis (PEP) of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) pre-emptive therapy (PET) for symptomatic outpatients with COVID-19 with a total symptom duration of less than 4 days. We will recruit 1500 patients for each the PEP and PET trials. Participants will be randomized 1:1 to receive 5 days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19 disease. The primary PET trial outcome will be an ordinal scale of disease severity (not hospitalized; hospitalized without intensive care, hospitalization with intensive care, or death). Participant screening, informed consent, and follow up will be exclusively internet-based with appropriate regulatory and research ethics board approvals in Canada and the United States. DiscussionThese complementary randomized control trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted in order to facilitate social distancing strategies and reduce risks of exposure to study personnel. Innovative trial approaches are needed to urgently assess therapeutic options to mitigate the global impact of this pandemic. Trials Registrationclinicaltrials.gov (NCT04308668); 16 March 2020.
