Clinical Study to Evaluate the Effects of Disulfiram in Patients With Moderate COVID-19

A Randomized, Double-blind, Placebo-controlled Safety and Clinical Outcomes Study of Disulfiram in Subjects With Moderate COVID-19

This clinical trial evaluates the safety, efficacy, and biomarker levels of FDA-approved drug disulfiram in the treatment of adult subjects hospitalized with moderate COVID-19. Disulfiram may limit the hyperinflammatory response associated with COVID-19 and reduce the risk of progression to severe illness.

Subjects will be screened and randomized to receive either daily administration of oral disulfiram or placebo for 14 days. Subjects will be followed up on Day 28.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Disulfiram; Drug: Placebo

Detailed Description

COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. There is currently no vaccine to prevent COVID-19 or infection with SARS-CoV-2 or therapeutic agent to treat COVID-19. The ongoing COVID-19 pandemic has demonstrated increased risk to those with an aging immune system. The elderly and those with comorbidities are reported as being the most susceptible to COVID-19, which may be due to a higher basal state of inflammation ("inflammaging") and a primed inflammasome pathway. Disulfiram, an FDA-approved drug for the treatment of alcohol dependence, has a potential for limiting the hyperinflammatory response associated with COVID-19. Specifically, the drug inhibits gasdermin D pore formation, reducing pyroptosis and netosis and could target the root cause of hyperinflammation, weakening the cytokine storm and therefore reducing the risk of progression to severe illness.

This is a stratified, randomized, double-blind, placebo-controlled study of disulfiram in hospitalized subjects over the age of 50 diagnosed with moderate COVID-19. Up to 200 subjects are planned to be enrolled and randomized (1:1) to either receive 500 mg of disulfiram (active product) or placebo, orally (po) or enterally (only in patients that require mechanical ventilation) once daily for fourteen (14) days in addition to standard of care. Stratification will be done at randomization based on age and comorbidities.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Bahia
    • Salvador, Bahia, Brazil, CEP 41830-492
      • ETICA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Subjects may be enrolled in the study only if all the inclusion criteria are met.

1. Male and female subjects, age 35 or older.
2. Female subjects of childbearing potential must have a negative hCG (in urine or blood) pregnancy test.
3. An International Ethics Committee (IEC) approved informed consent is signed and dated prior to any study-related activities.
4. Willing to abstain from any alcohol or substances containing alcohol (including medications, personal hygiene products, salad dressing) within 24 hours prior to treatment and for 14 days after treatment concludes.
5. Have the ability to understand the requirements of the study and is willing to comply with all study procedures and visits.
6. Respiratory rate: ≤ 30 per minute.
7. Use supplemental O2 via nasal cannula or equivalent.
8. Currently hospitalized ≤ 5 days.
9. PCR test or rapid antigen test confirming SARS-CoV-2.
10. In the opinion of the investigator, able to participate in the study.

Exclusion Criteria:

Subjects may not be enrolled in the study if any of the exclusion criteria apply.

1. Admission into the Intensive Care Unit (ICU) at screening and baseline.
2. Clinically active Hepatitis.
3. ALT or AST > 3 times the upper limit of normal.
4. Need for invasive or non-invasive ventilation at screening and baseline.
5. Stage 4 severe chronic kidney disease or requiring dialysis or estimated GFR < 30.
6. Known allergy to disulfiram.
7. Treatment with any of the medications listed below within 7 days prior to the baseline visit 1: Amprenavir, Dronabinol, Hydantoins, Metronidazole, Ritonavir, Benznidazole, Dyphylline, Idelalisib, Naltrexone, Sertraline, Chloral Hydrate, Ethanol, Immuno-modulatory drugs, Paclitaxel, Tinidazole, Cocaine, Ethotoin, Ixabepilone, Phenytoin, Tipranavir, Cyclosporine, Fosphenytoin, Lithium, Pimozide, Tranylcypromine, Dasabuvir, Guaifenesin, Mesoridazine, Pirfenidone.
8. Participation in any other interventional trial within 30 days prior to enrollment.
9. Active malignancy (excluding basal cell carcinoma, squamous cell carcinoma, in situ cervical cancer, or adenocarcinoma of the prostate with low or very low-risk categories by NCCN criteria).
10. Any surgical or medical condition which in the opinion of the investigator may interfere with participation in the study or which may affect the outcome of the study.
11. Fully vaccinated for COVID-19 (number of doses as per manufacturer recommendation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; The subject will receive a matching placebo orally or enterally through NG tube if in mechanical ventilation once daily for 14 days
EXPERIMENTAL: Disulfiram	Drug: Disulfiram; The subject will receive 500 mg of disulfiram orally or enterally through NG tube if in mechanical ventilation once daily for 14 days; Other Names: Antabuse

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to clinical improvement	Defined as the time from baseline to the first post-baseline assessment with an improvement in WHO score of ≥1 point.	From enrollment to clinical improvement (1 point or more in the WHO score), up to 28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Mean number of days of supplemental oxygen (WHO score ≥4)	Baseline to Day 28
Time to discharge from the hospital	From baseline to discharge, up to 28 days.
Percentage of subjects that are discharged by Day 8	At Day 8
Percentage of subjects that worsened 1 or more points on the WHO Ordinal Scale, from baseline to any post baseline assessment through Day 28.	Baseline to Day 28
Mean number of days of non-invasive ventilation or high flow oxygen devices or invasive mechanical ventilation (WHO Score 5 or 6) over the 28-day period.	Baseline to Day 28
Mean number of days subjects were in the Intensive Care Unit (ICU)	Baseline to Day 28
Percentage of subjects that were on non-invasive ventilation or high flow oxygen devices or invasive mechanical ventilation (WHO Score 5 or 6) over the 28-day period.	Baseline to Day 28
28-day mortality	At Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline to Day 8 and Day 15 for cytokine IL-18	Mean change and percent change	Baseline, Day 8 and Day 15
Percentage of subjects requiring supplemental oxygen (WHO Score ≥4) by Day 8, 15, and 28.		Baseline, Day 8, Day 15 and Day 28
Percentage of subjects that are discharged by Day 15 and Day 28.		Day 15 and Day 28
Percentage of subjects that worsened 1 or more points on the WHO Ordinal Scale from baseline through Day 8 and Day 15.		Baseline to Day 8, 15
Percentage of subjects admitted to the Intensive Care Unit.		Baseline to Day 28
Percentage of subjects that improved 1 or more points on the WHO Ordinal Scale from baseline to Day 8, 15, and 28.		Baseline to Day 8, 15, and 28
Change in total neutrophil count from baseline to Day 8 and 15.	Mean change and percent change	Baseline, Day 8 and Day 15
Percent change in total lymphocyte count from baseline to Day 8 and Day 15		Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for neutrophil-derived circulating free DNA (cf-DNA/NETs)	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for Cytokine TNF-α	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for cytokine IL-1β	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for cytokine IL-1RA	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for cytokine IL-6	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for cytokine IL-8	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for cytokine IL-10	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for Lactate Dehydrogenase (LDH)	Mean change and percent change	Baseline, Day 8 and Day 15
Change from baseline to Day 8 and Day 15 for D-dimer	Mean change and percent change	Baseline, Day 8 and Day 15
Association between baseline and worst post-baseline WHO score		Baseline to Day 28

Collaborators and Investigators

• Sponsor: ETICA
• Collaborators: Spring Research Foundation
• Investigators: Principal Investigator: Augusto Mota, MD/PhD, ETICA; Study Director: Wendy Cousin, PhD, Spring Research Foundation

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 20, 2020
• Primary Completion (ACTUAL): September 10, 2021
• Study Completion (ACTUAL): September 25, 2021

Study Registration Dates

• First Submitted: October 18, 2020
• First Submitted That Met QC Criteria: October 19, 2020
• First Posted (ACTUAL): October 20, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 8, 2021
• Last Update Submitted That Met QC Criteria: September 30, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Disulfiram
• Other Study ID Numbers: SPR-001-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No