Clinical trial NCT04485130: DISulfiram for COvid-19 (DISCO) Trial
Official title: DISulfiram for COvid-19 (DISCO) Trial: A Phase 2 Double-Blind, Randomized Placebo-Controlled Trial of Disulfiram Compared to Standard Care in Patients With Symptomatic COVID-19
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Covid19
Keywords: Disulfiram
COVID-19
SARS-CoV-2
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2020-07-24
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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 .
Primary purpose: TREATMENT

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.

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).

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

Primary outcomes:
measure: 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.).
timeFrame: Day 0 and Day 31
Secondary outcomes:
measure: 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.
timeFrame: Day 0 and Day 31
measure: Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
timeFrame: Day 0 and Day 31
measure: Change in COVID-19 Symptom Severity Score as Assessed by a 5-point Adapted Somatic Symptom Severity Score (SSS-8)
timeFrame: Day 0 and Day 31
Other outcomes:
Locations:
city: Fresno
country: United States
facility: University of California San Francisco, Fresno
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
Study officials:
affiliation: University of California, San Francisco
name: Sulggi A Lee, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.