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DISulfiram for COvid-19 (DISCO) Trial (DISCO)

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ClinicalTrials.gov Identifier: NCT04485130
Recruitment Status : Not yet recruiting
First Posted : July 24, 2020
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
Sulggi A. Lee, MD, PhD, University of California, San Francisco

Brief 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.

Condition or disease Intervention/treatment Phase
Covid19 Drug: Disulfiram Drug: Placebo Phase 2

Detailed Description:
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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This is a dose escalation double blind randomized (2:1) placebo-controlled trial of disulfiram given as 1000 mg/day x 5 consecutive days (Cohort 1: N=20 drug/N=10 placebo) or 2000 mg/day x 5 consecutive days (Cohort 2: N=20 drug/N=10 placebo) among 60 acute symptomatic lab-confirmed (<7 days) COVID+ individuals .
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double blind
Primary Purpose: Treatment
Official Title: DISulfiram for COvid-19 (DISCO) Trial: A Phase 2 Double-Blind, Randomized Placebo-Controlled Trial of Disulfiram Compared to Standard Supportive Care in Outpatients With Symptomatic COVID-19
Estimated Study Start Date : December 1, 2020
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : June 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Disulfiram

Arm Intervention/treatment
Experimental: Disulfiram
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.
Drug: Disulfiram
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.
Other Name: Antabuse

Placebo Comparator: Placebo
This study will provide placebo comparator for disulfiram. 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.
Drug: Placebo
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




Primary Outcome Measures :
  1. 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.). [ Time Frame: 31 days ]
    Change in plasma inflammatory biomarker levels (e.g., IL-6, IL-1b) at days 5, 15, and 31.


Secondary Outcome Measures :
  1. Virologic impact of 5 days of disulfiram, as measured by the fold-change in copies of SARS-CoV-2 virus per million cells between Baseline and Day 31. [ Time Frame: 31 days ]
    Change in SARS-CoV-2 PCR quantitative viral load at days 3, 5, 7, 15, and 31

  2. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 31 days ]
    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.

  3. Change in COVID-19 symptom severity score as assessed by a 5-point adapted somatic symptom severity score (SSS-8) [ Time Frame: 31 days ]
    The severity of COVID-19 symptoms will be recorded on a 5-point symptom severity scale at each visit for each participant.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04485130


Contacts
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Contact: Sulggi A Lee, MD PhD 415-735-5127 Sulggi.Lee@ucsf.edu
Contact: Rada Savic, PhD 415-502-0640 Rada.Savic@ucsf.edu

Locations
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United States, California
University of California San Francisco, Fresno
Fresno, California, United States, 93701
Contact: Mohamed A Fayed, MD    559-499-6500    mfayed@fresno.ucsf.edu   
San Francisco General Hospital
San Francisco, California, United States, 94110
Contact: Sulggi A Lee, MD PhD       Sulggi.Lee@ucsf.edu   
Contact: Rada Savic, PhD       Rada.Savic@ucsf.edu   
Sub-Investigator: Steven G Deeks, MD         
Sub-Investigator: Priscilla Hsue, MD         
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Sulggi A Lee, MD PhD University of California, San Francisco
Publications of Results:

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Responsible Party: Sulggi A. Lee, MD, PhD, Associate Professor of Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04485130    
Other Study ID Numbers: DSF151837
First Posted: July 24, 2020    Key Record Dates
Last Update Posted: November 17, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Planned sharing of de-identified individual participant data for the purposes of collaboration and meta-analyses.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: After publication of study results
Access Criteria: De-identified data

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sulggi A. Lee, MD, PhD, University of California, San Francisco:
Disulfiram
COVID-19
SARS-CoV-2
Additional relevant MeSH terms:
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Disulfiram
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action