disulfiram for covid-19 (disco) trial

Conditions: Covid19

Summary: disulfiram (dsf) a safe, easily dosed, fda-approved drug for the treatment of alcohol dependence has been identified to be a potential therapeutic target for sars-cov-2 infection. disulfiram may have both antiviral (inhibiting viral replication via blocking the mpro protease and zinc ejection) and anti-inflammatory effects (via inhibition of nf-kb-induced and nlrp inflammasome-induced cytokine release) on sars-cov-2. we will study oral disulfiram given for 5 consecutive days (1000 mg/day in cohort 1; 2000 mg/day in cohort 2) in 60 symptomatic covid+ individuals in a randomized (2:1) randomized, double blind placebo-controlled trial evaluating disulfiram's effect on covid-19 symptom severity, sars-cov-2 viral load, and biomarkers of inflammation and pyroptosis (aberrant pro-inflammatory cell death) over 31 days.

the identification of a safe, effective treatment for individuals with early mild-to-moderate symptomatic covid-19 that prevent progression to more severe disease would have immediate public health implications. a hallmark of severe covid-19 disease is immune system dysregulation called cytokine storm. multiple studies have reported that patients with severe disease demonstrate elevated levels of pro-inflammatory cytokines early in disease, and elevated il-6 plasma concentrations are predictive of poor clinical outcomes in covid-19. disulfiram, an fda-approved drug for the treatment of alcohol dependence disorder is an appealing therapeutic option for covid-19. it has a good safety profile, easy dosing schedule, and recent data suggesting multiple mechanisms by which disulfiram may act on covid-19 (both as a direct antiviral agent as well as indirect effects on reducing inflammation). in addition disulfiram has been studied extensively with detailed available pharmacokinetic data; disulfiram has a short half-life \~7.5 hours with \>90% of drug eliminated within 3 days post-dose, allowing quick reversal of any potential adverse effects. we will perform a phase 2 randomized (2:1), double blind placebo-controlled assessment of disulfiram in people with early mild-to-moderate symptomatic covid-19. a total of 60 symptomatic covid+ individuals will enrolled to receive active drug versus placebo (with equal distribution of mild or moderate/severe within each dosing cohort and within each randomization arm). for cohort 1, n=20 will receive dsf 1000 mg/n=10 placebo, and for cohort 2, n=20 will receive dsf 2000 mg/n=10 placebo. drug/placebo will be administered using strict infection control protocols designed to support the study of people with acute covid-19 infection per the center for diseases control (cdc) guidelines (https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html).

Eligibility criteria:
inclusion criteria: * willing and able to provide written informed consent, and * age \>= 18 years, and * sars-cov-2 positive pcr (nucleic acid) test within the preceding 7 days, and * not currently hospitalized, and * willing to abstain from any alcohol during the two week period in which disulfiram will be administered and during the two week period immediately after disulfiram administration. * both male and female subjects are eligible. females of childbearing potential must have a negative pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period. exclusion criteria: * pregnant, breastfeeding, or unwilling to practice birth control during participation in the study * active malignancy requiring systemic chemotherapy or surgery in the preceding 3 months or for whom such therapies are expected in the subsequent 6 months * decompensated liver disease as defined by the presence of ascites, encephalopathy, esophageal or gastric varices, or persistent jaundice * serious illness requiring systemic treatment and/or hospitalization in the 3 months prior to study enrollment * concurrent treatment with immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 4 weeks prior to study enrollment (e.g. corticosteroid therapy equal to or exceeding a dose of 15 mg/day of prednisone for more than 10 days, il-2, interferon-alpha, methotrexate, cancer chemotherapy). note: use of inhaled or nasal steroid is not exclusionary. * serious medical or psychiatric illness that, in the opinion of the site investigator, would interfere with the ability to adhere to study requirements or to give informed consent. * current alcohol use disorder or hazardous alcohol use (\>7 drinks per week for women or \> 14 drinks per week for men) as determined by clinical evaluation. * current use of any drug formulation that contains alcohol or that might contain alcohol * current use of warfarin. * clinically active hepatitis determined by the study physician; alt or ast \> 3 x the upper limit of normal or total bilirubin outside the normal range. * allergy to rubber or thiuram derivatives

Keywords: disulfiram covid-19 sars-cov-2