NCT04510194.

Study name	COVID‐OUT: Early outpatient treatment for SARS‐CoV‐2 infection (COVID‐19)
Methods	Trial design: quadruple‐blind RCT with 6 parallel arms, only 2 arms relevant; the other 4 arms investigate metformin and fluvoxamin in various combinations Sample size: 1160 Setting: outpatient Country: USA Language: English Number of centres: 7 Study purpose (treatment, prevention): treatment Trial registration number: NCT04510194 Date of registration: 12 August 2020
Participants	Inclusion criteria Positive laboratory test for active SARS‐CoV‐2 viral infection based on local laboratory standard (i.e. positive PCR result) within 3 days of randomization No known history of confirmed SARS‐CoV‐2 infection BMI ≥ 25 kg/m2 by self‐report or ≥ 23 kg/m2 in patients who self‐identify in South Asian or Latinx background Willing and able to comply with study procedures (i.e. swallow pills) Has an address and electronic device for communication GFR > 45 mL/min within 2 weeks for patients > 75 years old, or with history of heart, kidney, or liver failure Exclusion criteria Hospitalized, for COVID‐19 or other reasons Symptom onset greater than 7 days before randomization (symptoms not required for inclusion) Immune compromized state (solid organ transplant, bone marrow transplant, AIDS, on high‐dose steroids) Hepatic impairment (Child‐Pugh B and C) or other condition that, in the opinion of the investigator, would affect safety Inability to obtain informed consent Enrolment in another blinded RCT for COVID‐19 Already received an effective (Food and Drug Administration approved/emergency use authorization) therapy for COVID‐19 (currently monoclonal antibody treatment) Alcohol use disorder Other unstable medical condition or combination of home medications that in the view of the PI make it unsafe for the individual to participate History of severe kidney disease Unstable heart failure (stage 3 or 4 heart failure) Allergic reaction to metformin, fluvoxamine, or ivermectin in the past Bipolar disease: individuals who report they have bipolar disorder or are taking medication for bipolar disorder (lithium, valproate, high‐dose antipsychotic), unless the investigator concludes that the risk for mania is unlikely Current Loa loa or onchocerciasis infection Typhoid, BCG, or cholera vaccination within 14 days or 3 days after enrolment Co‐medication specified in protocol
Interventions	Details of intervention of relevant arms Type and dose: ivermectin 0.4 mg/kg, once daily for 3 days Route of administration: oral Treatment details of control group Placebo Concomitant therapy: NA
Outcomes	Primary study outcome Decreased oxygenation (SpO2 ≤ 93% on home monitoring) within 14 days Emergency department use for COVID‐19 symptoms within 14 days Relevant review outcomes planned None Additional study outcomes Maximum symptom severity within 14 and 28 days Clinical progression scale within 14 and 28 days Time to meaningful recovery within 14 and 28 days Laboratory outcome subsidy ‐ viral load, CRP, albumin, microbiome at several time points Post‐acute sequelae of SARS‐CoV‐2 infection (PASC) questionnaire at 6 and 12 months
Starting date	1 January 2021, postponed fromSeptember 2020
Contact information	University of Minnesota 3 Morrill Hall 100 Church St. SE Minneapolis MN 55455 United States
Notes	Recruitment status: recruiting Prospective completion date: January 2022 (date provided by trialist via personal communication) Planned completion date more than 6 months ago: no Date last update posted: 18 November 2021 Sponsor/funding: University of Minnesota