DISulfiram for COvid-19 (DISCO) Trial

NCT04485130 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: DSF151837
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

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.

Conditions

Covid19

Keywords

Disulfiram; COVID-19; SARS-CoV-2

Outcome Measures

Primary Outcomes (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.).

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

  Day 0 and Day 31

Secondary Outcomes (3)

• 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.

  Day 0 and Day 31

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

  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)

  Day 0 and Day 31

Study Arms (2)

Disulfiram

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Disulfiram DRUG

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.

Also known as: Antabuse

Disulfiram

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (2)

University of California San Francisco, Fresno

Fresno, California, 93701, United States

Location

San Francisco General Hospital

San Francisco, California, 94110, United States

Location

Related Publications (7)

• Lee SA, Elliott JH, McMahon J, Hartogenesis W, Bumpus NN, Lifson JD, Gorelick RJ, Bacchetti P, Deeks SG, Lewin SR, Savic RM. Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase IIb Trial. Clin Pharmacol Ther. 2019 Mar;105(3):692-702. doi: 10.1002/cpt.1220. Epub 2018 Oct 9.

  PMID: 30137649 BACKGROUND

• Elliott JH, McMahon JH, Chang CC, Lee SA, Hartogensis W, Bumpus N, Savic R, Roney J, Hoh R, Solomon A, Piatak M, Gorelick RJ, Lifson J, Bacchetti P, Deeks SG, Lewin SR. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV. 2015 Dec;2(12):e520-9. doi: 10.1016/S2352-3018(15)00226-X. Epub 2015 Nov 17.

  PMID: 26614966 BACKGROUND

• Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, Duan Y, Yu J, Wang L, Yang K, Liu F, Jiang R, Yang X, You T, Liu X, Yang X, Bai F, Liu H, Liu X, Guddat LW, Xu W, Xiao G, Qin C, Shi Z, Jiang H, Rao Z, Yang H. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020 Jun;582(7811):289-293. doi: 10.1038/s41586-020-2223-y. Epub 2020 Apr 9.

  PMID: 32272481 BACKGROUND

• Lin MH, Moses DC, Hsieh CH, Cheng SC, Chen YH, Sun CY, Chou CY. Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes. Antiviral Res. 2018 Feb;150:155-163. doi: 10.1016/j.antiviral.2017.12.015. Epub 2017 Dec 28.

  PMID: 29289665 BACKGROUND

• Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, Ruan J, Luo X, Lou X, Bai Y, Wang J, Hollingsworth LR, Magupalli VG, Zhao L, Luo HR, Kim J, Lieberman J, Wu H. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020 Jul;21(7):736-745. doi: 10.1038/s41590-020-0669-6. Epub 2020 May 4.

  PMID: 32367036 BACKGROUND

• Lobo-Galo N, Terrazas-Lopez M, Martinez-Martinez A, Diaz-Sanchez AG. FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication. J Biomol Struct Dyn. 2021 Jun;39(9):3419-3427. doi: 10.1080/07391102.2020.1764393. Epub 2020 May 14.

  PMID: 32364011 BACKGROUND

• Saifi MA, Shaikh AS, Kaki VR, Godugu C. Disulfiram prevents collagen crosslinking and inhibits renal fibrosis by inhibiting lysyl oxidase enzymes. J Cell Physiol. 2022 May;237(5):2516-2527. doi: 10.1002/jcp.30717. Epub 2022 Mar 13.

  PMID: 35285015 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Disulfiram

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Ditiocarb; Thiocarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Disulfides; Sulfides; Sulfur Compounds

Results Point of Contact

• Title: Dr. Sulggi Lee
• Organization: University of California, San Francisco

sulggi.lee@ucsf.edu

415-735-5127

Study Officials

• Sulggi A Lee, MD PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: 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 .

Study Record Dates

• First Submitted: July 22, 2020
• First Posted: July 24, 2020
• Study Start: August 18, 2021
• Primary Completion: February 28, 2022
• Study Completion: February 28, 2022
• Last Updated: September 13, 2023
• Results First Posted: September 13, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: After publication of study results
• Access Criteria: De-identified data

Locations

US (2)