Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

Effect of Coronavirus Disease 2019 Lockdowns on Identification of Advanced Human Immunodeficiency Virus Disease in Outpatient Clinics in Uganda.

Using data from 67 Ugandan human immunodeficiency virus (HIV) clinics (July 2019-January 2022), we report a 40% (1005/1662) reduction in the number of people with HIV presenting to care after August 2021 compared to prepandemic levels, with a greater proportion presenting with advanced HIV disease (20% vs 16% in the pre-coronavirus disease 2019 period).

Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Feasibility of SARS-CoV-2 Antibody Testing in Remote Outpatient Trials.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, clinical trials necessitated rapid testing to be performed remotely. Dried blood spot (DBS) techniques have enabled remote HIV virologic testing globally, and more recently, antibody testing as well. We evaluated DBS testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody testing in outpatients to assess seropositivity. Methods: In 2020, we conducted 3 internet-based randomized clinical trials and offered serologic testing via self-collected DBS as a voluntary substudy. COVID-19 diagnosis was based on the Centers for Disease Control and Prevention case definition with epidemiological link to cases. A minority reported polymerase chain reaction (PCR) testing at an outside facility. We tested for anti-SARS-CoV-2 immunoglobulin via antibody detection by agglutination-PCR (ADAP) and compared the results with enzyme-linked immunosorbent assay (ELISA). Results: Of 2727 participants in the primary studies, 60% (1648/2727) consented for serology testing; 56% (931/1648) returned a usable DBS sample. Of those who were asymptomatic, 5% (33/707) had positive ADAP serology. Of participants with a positive PCR, 67% (36/54) had positive SARS-CoV-2 antibodies. None of those who were PCR-positive and asymptomatic were seropositive (0/7). Of 77 specimens tested for concordance via ELISA, 83% (64/77) were concordant. The challenges of completing a remote testing program during a pandemic included sourcing and assembling collection kits, delivery and return of the kits, and troubleshooting testing. Self-collection was successful for >95% of participants. Delays in US mail with possible sample degradation and timing of DBS collection complicated the analysis. Conclusions: We found remote antibody testing during a global pandemic feasible although challenging. We identified an association between symptomatic COVID-19 and positive antibody results at a similar prevalence as other outpatient cohorts.

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 µg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19. Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022. Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 µg/kg (n = 602) daily, or placebo (n = 604) for 6 days. Main Outcomes and Measures: 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. Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .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. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model.

To date, two published randomized trials have indicated a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. Using the results of the largest of these trials, the TOGETHER trial, we conducted a cost-consequence analysis to assess the health system benefits of preventing progression to severe COVID-19 in outpatient populations in the United States. A decision-analytic model in the form of a decision tree was constructed to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19 in the primary analysis: treatment with a 10-day course of fluvoxamine (100 mg twice daily) and current standard-of-care. A secondary analysis comparing a 5-day course of nirmatrelvir-ritonavir was also conducted. We used a time horizon of 28 days. Reported outcomes included cost-savings and hospitalization days avoided. The results of our analysis indicated that administration of fluvoxamine to symptomatic outpatients at high risk of progressing to severe COVID-19 was substantially cost-saving, in the amount of $232 per eligible patient and prevented an average of 0.15 hospital days per patient treated, compared with standard of care. Nirmatrelvir-ritonavir was also shown to be cost-saving despite its higher acquisition cost and provided savings to the healthcare system of $625 per patient treated. These findings suggest that fluvoxamine is likely to be a cost-effective addition to frontline COVID-19 mitigation strategies in many settings, particularly where access to nirmaltrevir-ritonavir or monoclonal antibodies is limited.

Impact of SARS-CoV-2 vaccination and booster on COVID-19 symptom severity over time in the COVID-OUT trial.

BACKGROUND: SARS-CoV-2 vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe COVID-19. The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < 0.001). Individual symptoms were least severe in the vaccine-boosted group including: cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over delta and omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19 which abated the quickest over time.

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Hydroxychloroquine for treatment of non-hospitalized adults with COVID-19: A meta-analysis of individual participant data of randomized trials.

Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID-19). Conventional meta-analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID-19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID-19. We evaluated the overall treatment group effect by log-likelihood ratio test (-2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (-2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614-1.610; -2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta-analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome-coronavirus 2 viral clearance and COVID-19 hospitalization did not show a clinical benefit of HCQ. Our meta-analysis provides evidence to support the interruption in the use of HCQ in mild COVID-19 outpatients to reduce progression to severe disease.

Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease.

This cohort study examines the prevalence of contraindications to nirmatrelvir-ritonavir in patients hospitalized with COVID-19.

Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown. Objective: To 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 Participants: ACTIV-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. Interventions: Participants were randomized to receive ivermectin, 400 µg/kg (n = 817), daily for 3 days or placebo (n = 774). Main Outcomes and Measures: Time 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. Results: Among 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 Relevance: Among 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 Registration: ClinicalTrials.gov Identifier: NCT04885530.

Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19.

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19. We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP-HP (Assistance Publique-Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482). Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35-0.41, p < 0.001). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41-0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents. Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations. These treatments may reduce SARS-CoV-2 infections and COVID-19-related mortality in inpatients, and may be appropriate for prophylaxis and/or COVID-19 therapy for outpatients or inpatients.

Prevalence of Medical Contraindications to Nirmatrelvir/Ritonavir in a Cohort of Hospitalized and Nonhospitalized Patients With COVID-19.

This analysis describes the prevalence of contraindications to nirmatrelvir/ritonavir among 66 007 patients with coronavirus disease 2019 in a large health care system. A possible contradiction was present in 9830 patients (14.8%), with the prevalence of contraindications increasing with higher acuity of illness.

Prevalence of medical contraindications to nirmatrelvir/ritonavir in a cohort of hospitalized and non-hospitalized patients with COVID-19

This analysis describes the prevalence of contraindications to nirmatrelvir/ritonavir among 66,007 patients with COVID-19 in a large health care system. A possible contradiction was present in 9,830 patients (14.8%), with the prevalence of contraindications increasing with higher acuity of illness.

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Technical procedures and REDCap tools for internet-based clinical trials.

In March of 2020 our team of researchers developed and opened three clinical trials to investigate hydroxychloroquine as prophylaxis or treatment for the coronavirus disease 2019 (COVID-19). We simultaneously built corresponding Research Electronic Data Capture (REDCap) projects for these low-touch, remote trials that relied on participant-reported data. REDCap has built-in features that support pragmatic, internet-based studies, and REDCap is flexible enough to allow creative solutions for specific trials. We describe challenges, choices, and suggestions based on our experience with REDCap for our COVID-19 trials.