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

Primary Purpose

Covid19

Status

Completed

Phase

Phase 2

Locations

Brazil

Study Type

Interventional

Intervention

Disulfiram

Placebo

About this trial

This is an interventional treatment trial for Covid19

Eligibility Criteria

35 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

ETICA

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Disulfiram

Placebo

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Mean number of days of supplemental oxygen (WHO score ≥4)

Time to discharge from the hospital

Percentage of subjects that are discharged by 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.

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.

Mean number of days subjects were in the Intensive Care Unit (ICU)

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.

28-day mortality

Full Information

NCT ID

NCT04594343

First Posted

October 18, 2020

Last Updated

September 30, 2021

Sponsor

ETICA

Collaborators

Spring Research Foundation

1. Study Identification

Unique Protocol Identification Number

NCT04594343

Brief Title

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

2. Study Status

Record Verification Date

September 2021

Overall Recruitment Status

Completed

Study Start Date

November 20, 2020 (Actual)

Primary Completion Date

September 10, 2021 (Actual)

Study Completion Date

September 25, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

ETICA

Collaborators

Spring Research Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Covid19

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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

ParticipantCare ProviderInvestigatorOutcomes 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.

Allocation

Randomized

Enrollment

140 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Disulfiram

Arm Type

Experimental

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Disulfiram

Other Intervention Name(s)

Antabuse

Intervention Description

The subject will receive 500 mg of disulfiram orally or enterally through NG tube if in mechanical ventilation once daily for 14 days

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

The subject will receive a matching placebo orally or enterally through NG tube if in mechanical ventilation once daily for 14 days

Primary Outcome Measure Information:

Title

Time to clinical improvement

Description

Defined as the time from baseline to the first post-baseline assessment with an improvement in WHO score of ≥1 point.

Time Frame

From enrollment to clinical improvement (1 point or more in the WHO score), up to 28 days

Secondary Outcome Measure Information:

Title

Mean number of days of supplemental oxygen (WHO score ≥4)

Time Frame

Baseline to Day 28

Title

Time to discharge from the hospital

Time Frame

From baseline to discharge, up to 28 days.

Title

Percentage of subjects that are discharged by Day 8

Time Frame

At Day 8

Title

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

Title

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

Title

Mean number of days subjects were in the Intensive Care Unit (ICU)

Time Frame

Baseline to Day 28

Title

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

Title

28-day mortality

Time Frame

At Day 28

Other Pre-specified Outcome Measures:

Title

Change from baseline to Day 8 and Day 15 for cytokine IL-18

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

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

Title

Percentage of subjects that are discharged by Day 15 and Day 28.

Time Frame

Day 15 and Day 28

Title

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

Title

Percentage of subjects admitted to the Intensive Care Unit.

Time Frame

Baseline to Day 28

Title

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

Title

Change in total neutrophil count from baseline to Day 8 and 15.

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Percent change in total lymphocyte count from baseline to Day 8 and Day 15

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for neutrophil-derived circulating free DNA (cf-DNA/NETs)

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for Cytokine TNF-α

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for cytokine IL-1β

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for cytokine IL-1RA

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for cytokine IL-6

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for cytokine IL-8

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for cytokine IL-10

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for Lactate Dehydrogenase (LDH)

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Change from baseline to Day 8 and Day 15 for D-dimer

Description

Mean change and percent change

Time Frame

Baseline, Day 8 and Day 15

Title

Association between baseline and worst post-baseline WHO score

Time Frame

Baseline to Day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Augusto Mota, MD/PhD

Organizational Affiliation

ETICA

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Wendy Cousin, PhD

Organizational Affiliation

Spring Research Foundation

Official's Role

Study Director

Facility Information:

Facility Name

ETICA

City

Salvador

State/Province

Bahia

ZIP/Postal Code

CEP 41830-492

Country

Brazil

12. IPD Sharing Statement

Plan to Share IPD

Yes

Citations:

PubMed Identifier

35285015

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.

Results Reference

derived

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

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