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

• ClinicalTrials.gov Identifier: NCT04594343
• Recruitment Status: Completed
• First Posted: October 20, 2020
• Last Update Posted: October 8, 2021
• Sponsor: ETICA
• Collaborator: Spring Research Foundation
• Information provided by (Responsible Party): Augusto Mota, ETICA

Study Description

Brief Summary:

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.

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

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Subjects will be randomized to receive either the active product (disulfiram) or placebo.

Disulfiram will be dosed 500 mg daily for a total of 14 days of treatment. A matching placebo will be given using the same dosing schedule.

• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: In order to minimize bias due to key baseline characteristics that can impact clinical outcomes, the randomization will be stratified 1:1 to placebo or active product based on age and comorbidities.
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Safety and Clinical Outcomes Study of Disulfiram in Subjects With Moderate COVID-19
• Actual Study Start Date: November 20, 2020
• Actual Primary Completion Date: September 10, 2021
• Actual Study Completion Date: September 25, 2021

Arms and Interventions

Arm	Intervention/treatment
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 Name: Antabuse
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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Mean number of days of supplemental oxygen (WHO score ≥4) [ Time Frame: Baseline to Day 28 ]
2. Time to discharge from the hospital [ Time Frame: From baseline to discharge, up to 28 days. ]
3. Percentage of subjects that are discharged by Day 8 [ Time Frame: At Day 8 ]
4. Percentage of subjects that worsened 1 or more points on the WHO Ordinal Scale, from baseline to any post baseline assessment through Day 28. [ Time Frame: Baseline to Day 28 ]
5. 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. [ Time Frame: Baseline to Day 28 ]
6. Mean number of days subjects were in the Intensive Care Unit (ICU) [ Time Frame: Baseline to Day 28 ]
7. 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. [ Time Frame: Baseline to Day 28 ]
8. 28-day mortality [ Time Frame: At Day 28 ]

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 35 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Brazil

ETICA

Salvador, Bahia, Brazil, CEP 41830-492

Sponsors and Collaborators

ETICA

Spring Research Foundation

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Augusto Mota, Principal Investigator, ETICA
• ClinicalTrials.gov Identifier: NCT04594343
• Other Study ID Numbers: SPR-001-201
• First Posted: October 20, 2020
• Last Update Posted: October 8, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• 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

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Disulfiram; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action