Clinical trial NCT04594343: Clinical Study to Evaluate the Effects of Disulfiram in Patients With Moderate COVID-19
Official title: A Randomized, Double-blind, Placebo-controlled Safety and Clinical Outcomes Study of Disulfiram in Subjects With Moderate COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Covid19
Lead sponsor: ETICA
Sponsor class: OTHER
Collaborators: name: Spring Research Foundation
First posted: 2020-10-20
Enrollment: 140
Sex: ALL
Minimum age (years): 35
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Time to clinical improvement
timeFrame: From enrollment to clinical improvement (1 point or more in the WHO score), up to 28 days
Secondary outcomes:
measure: Mean number of days of supplemental oxygen (WHO score ≥4)
timeFrame: Baseline to Day 28
measure: Time to discharge from the hospital
timeFrame: From baseline to discharge, up to 28 days.
measure: Percentage of subjects that are discharged by Day 8
timeFrame: At Day 8
measure: Percentage of subjects that worsened 1 or more points on the WHO Ordinal Scale, from baseline to any post baseline assessment through Day 28.
timeFrame: Baseline to Day 28
measure: 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.
timeFrame: Baseline to Day 28
measure: Mean number of days subjects were in the Intensive Care Unit (ICU)
timeFrame: Baseline to Day 28
measure: 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.
timeFrame: Baseline to Day 28
measure: 28-day mortality
timeFrame: At Day 28
Other outcomes:
measure: Change from baseline to Day 8 and Day 15 for cytokine IL-18
timeFrame: Baseline, Day 8 and Day 15
measure: Percentage of subjects requiring supplemental oxygen (WHO Score ≥4) by Day 8, 15, and 28.
timeFrame: Baseline, Day 8, Day 15 and Day 28
measure: Percentage of subjects that are discharged by Day 15 and Day 28.
timeFrame: Day 15 and Day 28
measure: Percentage of subjects that worsened 1 or more points on the WHO Ordinal Scale from baseline through Day 8 and Day 15.
timeFrame: Baseline to Day 8, 15
measure: Percentage of subjects admitted to the Intensive Care Unit.
timeFrame: Baseline to Day 28
measure: Percentage of subjects that improved 1 or more points on the WHO Ordinal Scale from baseline to Day 8, 15, and 28.
timeFrame: Baseline to Day 8, 15, and 28
measure: Change in total neutrophil count from baseline to Day 8 and 15.
timeFrame: Baseline, Day 8 and Day 15
measure: Percent change in total lymphocyte count from baseline to Day 8 and Day 15
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for neutrophil-derived circulating free DNA (cf-DNA/NETs)
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for Cytokine TNF-α
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for cytokine IL-1β
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for cytokine IL-1RA
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for cytokine IL-6
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for cytokine IL-8
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for cytokine IL-10
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for Lactate Dehydrogenase (LDH)
timeFrame: Baseline, Day 8 and Day 15
measure: Change from baseline to Day 8 and Day 15 for D-dimer
timeFrame: Baseline, Day 8 and Day 15
measure: Association between baseline and worst post-baseline WHO score
timeFrame: Baseline to Day 28
Locations:
city: Salvador
country: Brazil
facility: ETICA
state: Bahia
Study officials:
affiliation: ETICA
name: Augusto Mota, MD/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spring Research Foundation
name: Wendy Cousin, PhD
role: STUDY_DIRECTOR
References:
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.