DISulfiram for COvid-19 (DISCO) Trial

Phase 2TerminatedNCT04485130

University of California, San Francisco11 enrolled

Overview

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).

Interventions

DisulfiramDRUG

This study will provide disulfiram. Participants in Cohort 1 receiving disulfiram will take 2 capsules of disulfiram (each capsule contains 500 mg DSF plus 27.75 mg microcrystalline cellulose powder) per day for a total of 5 consecutive days. Participants in Cohort 2 receiving placebo will take 4 capsules of disulfiram (each capsule contains 500 mg DSF plus 27.75 mg microcrystalline cellulose powder) per day for a total of 5 consecutive days.

PlaceboDRUG

This study will provide placebo. Participants in Cohort 1 receiving placebo will take 2 capsules of placebo (each capsule contains only microcrystalline cellulose powder) per day for a total of 5 consecutive days. Participants in Cohort 2 receiving placebo will take 4 capsules of placebo (each capsule contains only microcrystalline cellulose powder) per day for a total of 5 consecutive days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Immunologic Impact of 5 Days of Disulfiram, as Measured by the Fold-change in Plasma Levels of Pro-inflammatory Cytokines (e.g, Interleukin 6, Interleukin 1-beta, Etc.).

Change in plasma inflammatory biomarker levels (e.g., IL-6, IL-1b) at days 5, 15, and 31.

Time frame: Day 0 and Day 31

Secondary Outcomes

Virologic Impact of 5 Days of Disulfiram, as Measured by the Change in Copies of SARS-CoV-2 Virus Per mL Between Baseline and Day 31.

Change in copies of SARS-CoV-2 PCR virus per mL between Baseline and Day 31.

Time frame: Day 0 and Day 31

Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0

The safety and tolerability of a 5 day course of disulfiram. The number of adverse events and their grade will be determined for each participant.

Time frame: Day 0 and Day 31

Change in COVID-19 Symptom Severity Score as Assessed by a 5-point Adapted Somatic Symptom Severity Score (SSS-8)

The severity of COVID-19 symptoms will be recorded on a 5-point symptom severity scale at each visit for each participant. A question about how much the symptoms bother the participants will be asked. The participant will rank 1 as "not at all," 2 as "a little bit," 3 as "somewhat," 4 as "quite a bit" and 5 as "very much." Higher values represent worse outcomes. Scales are combined to compute a total score at Day 0 and Day 31. A change of the median is reported.

Time frame: Day 0 and Day 31

DISulfiram for COvid-19 (DISCO) Trial

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes