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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Covid19

Intervention / Treatment
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* Drug: Disulfiram
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects may be enrolled in the study only if all the inclusion criteria are met. Male and female subjects, age 35 or older. Female subjects of childbearing potential must have a negative hCG (in urine or blood) pregnancy test. An International Ethics Committee (IEC) approved informed consent is signed and dated prior to any study-related activities. 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. Have the ability to understand the requirements of the study and is willing to comply with all study procedures and visits. Respiratory rate: ≤ 30 per minute. Use supplemental O2 via nasal cannula or equivalent. Currently hospitalized ≤ 5 days. PCR test or rapid antigen test confirming SARS-CoV-2. 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. Admission into the Intensive Care Unit (ICU) at screening and baseline. Clinically active Hepatitis. ALT or AST > 3 times the upper limit of normal. Need for invasive or non-invasive ventilation at screening and baseline. Stage 4 severe chronic kidney disease or requiring dialysis or estimated GFR < 30. Known allergy to disulfiram. 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. Participation in any other interventional trial within 30 days prior to enrollment. 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). 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. Fully vaccinated for COVID-19 (number of doses as per manufacturer recommendation.

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Disulfiram<br> | Drug: Disulfiram<br>* The subject will receive 500 mg of disulfiram orally or enterally through NG tube if in mechanical ventilation once daily for 14 days<br>* Other names: Antabuse;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* The subject will receive a matching placebo orally or enterally through NG tube if in mechanical ventilation once daily for 14 days<br>|

What is the study measuring?
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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 | Measure Description | 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 |