Covid19
Conditions
Keywords
Disulfiram, COVID-19, SARS-CoV-2
Brief summary
Disulfiram (DSF) a safe, easily dosed, FDA-approved drug for the treatment of alcohol dependence has been identified to be a potential therapeutic target for SARS-CoV-2 infection. Disulfiram may have both antiviral (inhibiting viral replication via blocking the Mpro protease and zinc ejection) and anti-inflammatory effects (via inhibition of NF-kB-induced and NLRP inflammasome-induced cytokine release) on SARS-CoV-2. We will study oral disulfiram given for 5 consecutive days (1000 mg/day in cohort 1; 2000 mg/day in cohort 2) in 60 symptomatic COVID+ individuals in a randomized (2:1) randomized, double blind placebo-controlled trial evaluating disulfiram's effect on COVID-19 symptom severity, SARS-CoV-2 viral load, and biomarkers of inflammation and pyroptosis (aberrant pro-inflammatory cell death) over 31 days.
Detailed description
The identification of a safe, effective treatment for individuals with early mild-to-moderate symptomatic COVID-19 that prevent progression to more severe disease would have immediate public health implications. A hallmark of severe COVID-19 disease is immune system dysregulation called cytokine storm. Multiple studies have reported that patients with severe disease demonstrate elevated levels of pro-inflammatory cytokines early in disease, and elevated IL-6 plasma concentrations are predictive of poor clinical outcomes in COVID-19. Disulfiram, an FDA-approved drug for the treatment of alcohol dependence disorder is an appealing therapeutic option for COVID-19. It has a good safety profile, easy dosing schedule, and recent data suggesting multiple mechanisms by which disulfiram may act on COVID-19 (both as a direct antiviral agent as well as indirect effects on reducing inflammation). In addition disulfiram has been studied extensively with detailed available pharmacokinetic data; disulfiram has a short half-life \ 7.5 hours with \>90% of drug eliminated within 3 days post-dose, allowing quick reversal of any potential adverse effects. We will perform a phase 2 randomized (2:1), double blind placebo-controlled assessment of disulfiram in people with early mild-to-moderate symptomatic COVID-19. A total of 60 symptomatic COVID+ individuals will enrolled to receive active drug versus placebo (with equal distribution of mild or moderate/severe within each dosing cohort and within each randomization arm). For cohort 1, N=20 will receive DSF 1000 mg/N=10 placebo, and for cohort 2, N=20 will receive DSF 2000 mg/N=10 placebo. Drug/placebo will be administered using strict infection control protocols designed to support the study of people with acute COVID-19 infection per the Center for Diseases Control (CDC) guidelines (https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html).
Interventions
DRUGDisulfiram
This study will provide disulfiram. Participants in Cohort 1 receiving disulfiram will take 2 capsules of disulfiram (each capsule contains 500 mg DSF plus 27.75 mg microcrystalline cellulose powder) per day for a total of 5 consecutive days. Participants in Cohort 2 receiving placebo will take 4 capsules of disulfiram (each capsule contains 500 mg DSF plus 27.75 mg microcrystalline cellulose powder) per day for a total of 5 consecutive days.
DRUGPlacebo
This study will provide placebo. Participants in Cohort 1 receiving placebo will take 2 capsules of placebo (each capsule contains only microcrystalline cellulose powder) per day for a total of 5 consecutive days. Participants in Cohort 2 receiving placebo will take 4 capsules of placebo (each capsule contains only microcrystalline cellulose powder) per day for a total of 5 consecutive days
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind
Intervention model description
This is a dose escalation double blind randomized (2:1) placebo-controlled trial of disulfiram given as 1000 mg/day x 5 consecutive days (Cohort 1: N=20 drug/N=10 placebo) or 2000 mg/day x 5 consecutive days (Cohort 2: N=20 drug/N=10 placebo) among 60 acute symptomatic lab-confirmed (\<7 days) COVID+ individuals .
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide written informed consent, and * Age \>= 18 years, and * SARS-CoV-2 positive PCR (nucleic acid) test within the preceding 7 days, and * Not currently hospitalized, and * Willing to abstain from any alcohol during the two week period in which disulfiram will be administered and during the two week period immediately after disulfiram administration. * Both male and female subjects are eligible. Females of childbearing potential must have a negative pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
Exclusion criteria
* Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study * Active malignancy requiring systemic chemotherapy or surgery in the preceding 3 months or for whom such therapies are expected in the subsequent 6 months * Decompensated liver disease as defined by the presence of ascites, encephalopathy, esophageal or gastric varices, or persistent jaundice * Serious illness requiring systemic treatment and/or hospitalization in the 3 months prior to study enrollment * Concurrent treatment with immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 4 weeks prior to study enrollment (e.g. corticosteroid therapy equal to or exceeding a dose of 15 mg/day of prednisone for more than 10 days, IL-2, interferon-alpha, methotrexate, cancer chemotherapy). NOTE: use of inhaled or nasal steroid is not exclusionary. * Serious medical or psychiatric illness that, in the opinion of the site investigator, would interfere with the ability to adhere to study requirements or to give informed consent. * Current alcohol use disorder or hazardous alcohol use (\>7 drinks per week for women or \> 14 drinks per week for men) as determined by clinical evaluation. * Current use of any drug formulation that contains alcohol or that might contain alcohol * Current use of warfarin. * Clinically active hepatitis determined by the study physician; ALT or AST \> 3 x the upper limit of normal or total bilirubin outside the normal range. * Allergy to rubber or thiuram derivatives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immunologic Impact of 5 Days of Disulfiram, as Measured by the Fold-change in Plasma Levels of Pro-inflammatory Cytokines (e.g, Interleukin 6, Interleukin 1-beta, Etc.). | Day 0 and Day 31 | Change in plasma inflammatory biomarker levels (e.g., IL-6, IL-1b) at days 5, 15, and 31. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Virologic Impact of 5 Days of Disulfiram, as Measured by the Change in Copies of SARS-CoV-2 Virus Per mL Between Baseline and Day 31. | Day 0 and Day 31 | Change in copies of SARS-CoV-2 PCR virus per mL between Baseline and Day 31. |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Day 0 and Day 31 | The safety and tolerability of a 5 day course of disulfiram. The number of adverse events and their grade will be determined for each participant. |
| Change in COVID-19 Symptom Severity Score as Assessed by a 5-point Adapted Somatic Symptom Severity Score (SSS-8) | Day 0 and Day 31 | The severity of COVID-19 symptoms will be recorded on a 5-point symptom severity scale at each visit for each participant. A question about how much the symptoms bother the participants will be asked. The participant will rank 1 as not at all, 2 as a little bit, 3 as somewhat, 4 as quite a bit and 5 as very much. Higher values represent worse outcomes. Scales are combined to compute a total score at Day 0 and Day 31. A change of the median is reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Disulfiram 1000 mg This study will provide disulfiram. Participants in Cohort 1 receiving disulfiram will take 2 capsules of disulfiram (each capsule contains 500 mg DSF plus 27.75 mg microcrystalline cellulose powder) per day for a total of 5 consecutive days. | 7 |
| Cohort 1: Placebo This study will provide placebo comparator for disulfiram. Participants in Cohort 1 receiving placebo will take 2 capsules of placebo (each capsule contains only microcrystalline cellulose powder) per day for a total of 5 consecutive days. | 4 |
| Cohort 2: Disulfiram 2000 mg Participants in Cohort 2 receiving placebo will take 4 capsules of disulfiram (each capsule contains 500 mg DSF plus 27.75 mg microcrystalline cellulose powder) per day for a total of 5 consecutive days. | 0 |
| Cohort 2: Placebo Participants in Cohort 2 receiving placebo will take 4 capsules of placebo (each capsule contains only microcrystalline cellulose powder) per day for a total of 5 consecutive days. | 0 |
| Total | 11 |
Baseline characteristics
| Characteristic | Cohort 1: Disulfiram 1000 mg | Cohort 1: Placebo | Cohort 2: Disulfiram 2000 mg | Cohort 2: Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 4 Participants | 0 Participants | 0 Participants | 11 Participants |
| Age, Continuous | 38 years STANDARD_DEVIATION 12.5 | 43.5 years STANDARD_DEVIATION 8 | — | — | 40 years STANDARD_DEVIATION 11 |
| BMI | 25.6 kg/m^2 STANDARD_DEVIATION 5.5 | 33.3 kg/m^2 STANDARD_DEVIATION 2.2 | — | — | 28.4 kg/m^2 STANDARD_DEVIATION 5.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | — | — | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | — | — | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | — | — | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | — | — | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | — | — | 9 Participants |
| Region of Enrollment United States | 7 participants | 4 participants | — | — | 11 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | — | — | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | — | — | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 4 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 4 / 7 | 1 / 4 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 7 | 1 / 4 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Immunologic Impact of 5 Days of Disulfiram, as Measured by the Fold-change in Plasma Levels of Pro-inflammatory Cytokines (e.g, Interleukin 6, Interleukin 1-beta, Etc.).
Change in plasma inflammatory biomarker levels (e.g., IL-6, IL-1b) at days 5, 15, and 31.
Time frame: Day 0 and Day 31
Population: The trial stopped early so we were unable to enroll for Cohort 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Disulfiram 100 mg | Immunologic Impact of 5 Days of Disulfiram, as Measured by the Fold-change in Plasma Levels of Pro-inflammatory Cytokines (e.g, Interleukin 6, Interleukin 1-beta, Etc.). | Change in IL-6 (pg/mL) Day 0 to 31 | -0.1186 fold change |
| Cohort 1: Disulfiram 100 mg | Immunologic Impact of 5 Days of Disulfiram, as Measured by the Fold-change in Plasma Levels of Pro-inflammatory Cytokines (e.g, Interleukin 6, Interleukin 1-beta, Etc.). | Change in IL-1B (pg/mL) Day 0 to 31 | -0.1402 fold change |
| Cohort 1: Placebo | Immunologic Impact of 5 Days of Disulfiram, as Measured by the Fold-change in Plasma Levels of Pro-inflammatory Cytokines (e.g, Interleukin 6, Interleukin 1-beta, Etc.). | Change in IL-6 (pg/mL) Day 0 to 31 | -0.0215 fold change |
| Cohort 1: Placebo | Immunologic Impact of 5 Days of Disulfiram, as Measured by the Fold-change in Plasma Levels of Pro-inflammatory Cytokines (e.g, Interleukin 6, Interleukin 1-beta, Etc.). | Change in IL-1B (pg/mL) Day 0 to 31 | 0.0268 fold change |
Secondary
Change in COVID-19 Symptom Severity Score as Assessed by a 5-point Adapted Somatic Symptom Severity Score (SSS-8)
The severity of COVID-19 symptoms will be recorded on a 5-point symptom severity scale at each visit for each participant. A question about how much the symptoms bother the participants will be asked. The participant will rank 1 as not at all, 2 as a little bit, 3 as somewhat, 4 as quite a bit and 5 as very much. Higher values represent worse outcomes. Scales are combined to compute a total score at Day 0 and Day 31. A change of the median is reported.
Time frame: Day 0 and Day 31
Population: The trial stopped early so we were unable to enroll for Cohort 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Disulfiram 100 mg | Change in COVID-19 Symptom Severity Score as Assessed by a 5-point Adapted Somatic Symptom Severity Score (SSS-8) | -2.60 units on a scale |
| Cohort 1: Placebo | Change in COVID-19 Symptom Severity Score as Assessed by a 5-point Adapted Somatic Symptom Severity Score (SSS-8) | -2.14 units on a scale |
Secondary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
The safety and tolerability of a 5 day course of disulfiram. The number of adverse events and their grade will be determined for each participant.
Time frame: Day 0 and Day 31
Population: The trial stopped early so we were unable to enroll for Cohort 2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Disulfiram 100 mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | AE Grade 3 or Higher | 0 Participants |
| Cohort 1: Disulfiram 100 mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | AE Grade 1 or 2 | 4 Participants |
| Cohort 1: Placebo | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | AE Grade 1 or 2 | 1 Participants |
| Cohort 1: Placebo | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | AE Grade 3 or Higher | 1 Participants |
Secondary
Virologic Impact of 5 Days of Disulfiram, as Measured by the Change in Copies of SARS-CoV-2 Virus Per mL Between Baseline and Day 31.
Change in copies of SARS-CoV-2 PCR virus per mL between Baseline and Day 31.
Time frame: Day 0 and Day 31
Population: The trial stopped early so we were unable to enroll for Cohort 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Disulfiram 100 mg | Virologic Impact of 5 Days of Disulfiram, as Measured by the Change in Copies of SARS-CoV-2 Virus Per mL Between Baseline and Day 31. | -20.89 copies/mL | Standard Deviation 9.84 |
| Cohort 1: Placebo | Virologic Impact of 5 Days of Disulfiram, as Measured by the Change in Copies of SARS-CoV-2 Virus Per mL Between Baseline and Day 31. | -20 copies/mL | Standard Deviation 13.53 |