Conditions: Covid19
Keywords: Disulfiram COVID-19 SARS-CoV-2
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 11
Healthy volunteers: no

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).

Arms:
arm 1: 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. arm 2: 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. 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.

Interventions: intervention 1: Disulfiram intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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

Protocol document:
Prot_SAP_000.pdf: 
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                                    Disulfiram COVID v 2.4 
Version Date: 08SEP2021 
 
  
 
 
 
DISulfiram for COvid-19 (DISCO) Trial: 
 
A Phase 2 Double-Blind, Randomized Placebo-Controlled Trial of  
Disulfiram Compared to Standard Care  
in Patients with Symptomatic COVID-19 
 
 
 
 
Clinical Protocol Co-Chairs: Sulggi Lee, Rada Savic 
 
IND: 151837 
 
 
 
 
 
 
 
 
 
 
NCT04485130 


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                                    Disulfiram COVID v 2.4 
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A Phase 2 Double-Blind, Randomized Placebo-Controlled Trial of  
Disulfiram Compared to Standard Care in Patients with Symptomatic COVID-19 
 
 
DISulfiram for COvid-19 (DISCO) Trial 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable U.S. Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements and institutional policies. 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________           Date: _____________ 
Name/Title 
 
 


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                                    Disulfiram COVID v 2.4 
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Contents 
1 
PROTOCOL TEAM ROSTER ....................................................................................................... 6 
2 
LIST OF ABBREVIATIONS .......................................................................................................... 7 
3 
PROTOCOL SYNOPSIS ............................................................................................................... 8 
4 
RATIONALE/BACKGROUND ..................................................................................................... 14 
4.1 
Background and scientific rationale .......................................................................................................... 14 
 
SARS-CoV-2-associated immune dysregulation ............................................................................................................... 15 
 
Disulfiram and putative SARS-CoV-2 antiviral activity ..................................................................................................... 16 
 
Disulfiram and mediation of aberrant inflammation in SARS-CoV-2 infection ................................................................ 18 
 
Clinical experience and safety of disulfiram .................................................................................................................... 19 
 
HIV clinical trials of disulfiram .......................................................................................................................................... 20 
 
Pharmacology of disulfiram ............................................................................................................................................. 20 
 
Table 1. Final PK model estimates for median AUC0-72 exposure to metabolites by dosing cohort. ............................... 22 
 
Disulfiram dose justification............................................................................................................................................. 23 
 
SARS-CoV-2 viral load quantification ............................................................................................................................... 23 
 
Preliminary data demonstrating the ability to enroll acute COVID+ patients ............................................................. 24 
5 
INVESTIGATIONAL PLAN: ........................................................................................................ 25 
5.1 
Study objectives ....................................................................................................................................... 25 
 
Primary objective ............................................................................................................................................................. 25 
 
Secondary objectives ....................................................................................................................................................... 25 
5.2 
Study Definitions ..................................................................................................................................... 25 
5.3 
Study Population ..................................................................................................................................... 25 
 
Inclusion Criteria .............................................................................................................................................................. 25 
 
Exclusion Criteria .............................................................................................................................................................. 26 
 
Participant Withdrawal .................................................................................................................................................... 27 
 
Treatment ........................................................................................................................................................................ 27 
 
Randomization ................................................................................................................................................................. 27 
 
Study drug administration ............................................................................................................................................... 27 
 
Concomitant medications ................................................................................................................................................ 27 
 
Prohibited medications .................................................................................................................................................... 28 
5.4 
Study procedures ..................................................................................................................................... 29 
5.4.2. Table 2: Schedule of Evaluations ......................................................................... Error! Bookmark not defined. 
5.5 
Study procedures by day .......................................................................................................................... 34 
 
Screen and Baseline (Day -3 to Day 1) ............................................................................................................................. 34 
 
Study Drug/ Placebo Administration (Day 1) ................................................................................................................... 34 
 
Study Drug/ Placebo Administration (Day 2) ................................................................................................................... 35 
 
Study Drug/ Placebo Administration (Day 3) ................................................................................................................... 35 
 
Study Drug/ Placebo Administration (Day 4) ................................................................................................................... 35 


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Study Drug/ Placebo Administration (Day 5) ................................................................................................................... 36 
 
Symptom/Adverse Event Telephone Follow-Up (Day 7) .................................................................................................. 36 
 
Symptom/Adverse Event Telephone Follow-Up (Day 9) .................................................................................................. 36 
 
Symptom/Adverse Event Telephone Follow-Up (Day 11) ................................................................................................ 37 
 
Follow-Up (Day 15) ...................................................................................................................................................... 37 
 
Follow-Up (Day 31) ...................................................................................................................................................... 37 
5.6 
Table 3. COVID-19 symptom severity questions adapted from the Somatic Symptom Scale (SSS-8). 3 ........ 39 
5.7 
Table 4. Adverse Event Log form............................................................................................................... 43 
6 
STATISTICAL PLAN ................................................................................................................... 44 
6.1 
Sample Size and Power Considerations ..................................................................................................... 44 
6.2 
Statistical Analysis ................................................................................................................................... 44 
 
Primary endpoint ............................................................................................................................................................. 45 
 
Secondary endpoint(s): .................................................................................................................................................... 46 
 
Other secondary endpoints ............................................................................................................................................. 46 
 
Analysis of AE data ........................................................................................................................................................... 46 
 
Analysis of plasma inflammatory biomarkers and SARS-CoV-2 antibody levels .............................................................. 46 
7 
HUMAN PARTICIPANTS PROTECTIONS ................................................................................. 47 
7.1 
Risks and Benefits .................................................................................................................................... 47 
 
Potential risks ................................................................................................................................................................... 47 
7.2 
Definitions ............................................................................................................................................... 48 
7.3 
Safety Reporting Requirements ................................................................................................................ 49 
 
Reporting Interval ............................................................................................................................................................ 49 
 
Investigator’s Assessment of Adverse Events .................................................................................................................. 49 
 
Assessment of Seriousness .............................................................................................................................................. 49 
 
Assessment of Association ............................................................................................................................................... 50 
7.4 
Safety Oversight ...................................................................................................................................... 50 
 
Monitoring Plan ............................................................................................................................................................... 50 
7.5 
Study compliance with clinical trial requirements ..................................................................................... 50 
8 
STUDY MODIFICATION ............................................................................................................. 52 
8.1 
Criteria for Discontinuation of the Study ................................................................................................... 52 
8.2 
Individual Criteria for Discontinuation ...................................................................................................... 52 
9 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS................................................................ 53 
9.1 
Ethical Standard ....................................................................................................................................... 53 
9.2 
Institutional Review Board ....................................................................................................................... 53 
9.3 
Informed Consent Process ........................................................................................................................ 53 
9.4 
Participant Confidentiality ....................................................................................................................... 53 
9.5 
Future Use of Stored Specimens ............................................................................................................... 54 
9.6 
Data management and monitoring ........................................................................................................... 54 
 
Source Documents ........................................................................................................................................................... 54 


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Data Management Plan ................................................................................................................................................... 55 
 
Data Capture Methods ..................................................................................................................................................... 55 
 
Study Record Retention ................................................................................................................................................... 55 
 
 
 


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1 
PROTOCOL TEAM ROSTER 
Protocol Chairs 
Sulggi Lee 
Associate Professor of Medicine 
Division of HIV, Infectious Diseases, & Global Medicine 
995 Potrero Ave, Box 0874 
San Francisco, CA 94110 
(415) 735-5127 
Fax (415) 476-6953 
Sulggi.Lee@ucsf.edu 
 
Rada Savic, PhD 
Professor of Bioengineering 
Department of Pharmacology 
University of California, San Francisco 
Rada.Savic@ucsf.edu 
 
Statistician 
Jingshen Wang 
Assistant Professor of Biostatistics 
School of Public Health 
University of California, Berkeley 
jingshenwang@berkeley.edu  
 
Investigators 
Mohamed Fayed 
University of California, San Francisco-Fresno 
Steven Deeks 
University of California, San Francisco 
Priscilla Hsue 
University of California, San Francisco 
 
 
 


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2 
LIST OF ABBREVIATIONS 
ADR: Adverse Drug Reaction 
ADE: Antibody-mediated enhancement of infection 
AE: Adverse Event/Adverse Experience 
CBC: Complete Blood Count 
CCP: COVID-19 Convalescent Plasm  
CDC: United States Centers for Disease Control and Prevention 
CFR: Code of Federal Regulations 
CLIA: Clinical Laboratory Improvement Amendment of 1988 
COI: Conflict of Interest 
COVID-19: Coronavirus Disease  
CRF: Case Report Form 
CRP: C-Reactive Protein 
DMC: Data Management Center 
DSF: Disulfiram 
DSMB: Data and Safety Monitoring Board 
EUA: Emergency Use Authorization 
FDA: Food and Drug Administration 
GCP: Good Clinical Practice 
ICF: Informed Consent (Informed Consent Form) 
ICH: International Conference on Harmonization 
ICU: Intensive Care Unit 
IEC: Independent Ethics Committee 
IND: Investigational New Drug Application 
IRB: Institutional Review Board 
LOS: Length of Stay 
MERS: Middle East Respiratory Syndrome  
NP: Nasopharyngeal 
OHRP: Office of Human Research Protections 
RT-PCR: Reverse Transcriptase Real-Time Polymerase Chain Reaction 
PK: Pharmacokinetic 
QC: Quality Control 
RDV: Remdesivir 
SAE: Serious Adverse Event 
SARS: Severe Acute Respiratory Syndrome 
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2 
SUSAR: Serious and Unexpected Suspected Adverse Reaction 
TACO: Transfusion-associated Circulatory Overload 
UAE: Unexpected Adverse Event  
UP: Unanticipated Problem 
 


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3 
PROTOCOL SYNOPSIS 
 
 
TITLE 
DISulfiram for COvid-19 treatment (DISCO) Trial 
SPONSOR 
University of California, San Francisco 
PRINCIPAL 
INVESTIGATOR(S) 
Sulggi Lee, MD PhD 
Rada Savic, PhD 
FUNDING 
ORGANIZATION 
Sulggi Lee, M.D. UCSF Departmental Discretionary Funds 
Mercatur International Fast Grant 
NUMBER OF SITES 
One (UCSF Fresno) 
RATIONALE 
The identification of a safe, effective treatment for individuals 
with early symptomatic COVID-19 that prevents 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. Several anti-inflammatory trials 
are now underway in hospitalized patients to determine whether 
blockade of these cytokines reduce COVID-19-associated 
mortality, including planned trials to inhibit IL-6/IL-1β signaling 
(e.g., NCT04320615, NCT04362813). However, even earlier 
treatment of symptomatic COVID-19 in patients might further 
reduce COVID-19 morbidity, such as in preventing 
hospitalizations and ICU admissions.  
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 


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~7.5 hours with >90% of drug eliminated within 3 days post-
dose, allowing quick reversal of any potential adverse effects. 
STUDY DESIGN 
This is a double-blind, placebo-controlled trial on a backbone of 
standard care of disulfiram in patients with early symptomatic 
COVID-19. Disulfiram 1000 mg (cohort 1) or 2000 mg (cohort) 
versus placebo will be given once daily for 5 consecutive days. 
A total of 60 participants will be randomized (2:1) to receive 
active drug versus placebo in a dose escalation study. The first 
30 participants will first be enrolled in the 1000 mg dosing 
cohort, randomized 2:1 to receive either disulfiram 1000 mg 
(N=20) or placebo (N=10) daily for 5 consecutive days. As long 
as safety monitoring criteria are met to proceed to the second 
dose, the next 30 participants will be enrolled in the 2000 mg 
dosing cohort, randomized 2:1 to receive either disulfiram 2000 
mg (N=20) or placebo (N=10) daily for 5 consecutive days.  
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). 
PRIMARY 
OBJECTIVE 
To determine the effect of oral disulfiram given as 1000 mg daily 
(cohort 1) or 2000 mg daily (cohort 2) versus placebo for 5 
consecutive days in adults with early symptomatic SARS-CoV-2 
infection on: 
Change in inflammatory biomarkers (plasma cytokine levels – 
e.g., IL-6, IL-1β) on days 5, 15, and 31.2 
SECONDARY 
OBJECTIVES 
To determine the effect of oral disulfiram (given as 1000 mg 
daily (cohort 1) or 2000 mg daily (cohort 2) versus placebo for 5 
consecutive days in adults with early symptomatic SARS-CoV-2 
infection on: 
• Safety and tolerability (Grade 2 or higher adverse events 
on days 5, 15, and 31). 
• Change in COVID symptom severity (five-point symptom 
scale3) on days 5, 15, and 31. 
• Change in SARS-CoV-2 PCR quantitative viral load4 on 
days 5, 15, and 31. 


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• The proportion of detectable versus not detectable levels 
of SARS-CoV-2 RNA from site-collected nasopharyngeal 
(NP) swabs at entry, day 5, and day 15 among a subset 
of participants.  
• Time to recovery (date of symptom onset to date of 
complete resolution of symptoms)  
• If applicable, the proportion of participants hospitalized at 
day 5, 15, and 31. 
• If applicable, the proportion of participant deaths at day 
5, 15, and 31. 
NUMBER OF 
PARTICIPANTS 
Total: N=60 patients ≥ age 18 with confirmed COVID-19 
infection diagnosed by molecular diagnostic assay 
• Cohort 1: N=20 disulfiram 1000 mg, N=10 placebo 
• Cohort 2: N=20 disulfiram 2000 mg, N=10 placebo 
PARTICIPANT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
• Willing and able to provide written informed consent, and 
• Age ≥ 18 years, and 
• Recent symptomatic COVID-19 disease (<14 days from 
symptom onset) 
• Recent SARS-CoV-2 positive test by molecular 
diagnostic assay 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 participants 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. 


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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 or unless if dexamethasone 
administered as part of inpatient COVID-19 standard of 
care treatment 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 oral lopinavir/ritonavir solution (and the 
inability to switch to a solid dosage form during the entire 
duration of the study). 
• Current use of warfarin. 
• ALT or AST > 2 x the upper limit of normal or total 
bilirubin outside the normal range. 


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• Creatinine clearance (CrCl) < 50 mL/min by Cockcroft-
Gault. 
• Allergy to rubber or thiuram derivatives 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF ADMINISTRATION 
Oral disulfiram given as 1000 mg daily (cohort 1) or 2000 mg 
daily (cohort 2) versus placebo for 5 consecutive days in adults 
with early symptomatic SARS-CoV-2 infection will be 
administered in a double-blind fashion.  
Placebo tablets will be administered in a double-blind fashion 
and given as a single oral administration on days 1-5. 
DURATION OF  
PARTICIPATION AND 
DURATION OF 
STUDY 
Study products will be administered at days 1-5. Participants 
will be observed on study at days 5, 15, and 31. 
Participants will be randomized to either of two treatment arms, 
oral disulfiram or placebo.  
Screening:  up to 7 days prior to treatment 
randomization. 
Treatment (for each arm):  5 days (participants to be 
observed for a total of 4 hours on the last treatment day, 
Day 5) 
Follow-up (for each arm): 31 days after the initial dose 
for that treatment arm. 
The total duration of the study is expected to be 31 days 
(approximately 1 month). 
CONCOMITANT 
MEDICATIONS 
The following medications are not allowed during the study 
because of potential interactions with disulfiram: warfarin; any 
over the counter drug, food or other product that contains or 
might contain alcohol; if HIV-positive, specific protease inhibitor 
preparations (oral amprenavir solution, ritonavir solution, 
lopinavir/ritonavir solution, soft gelatin form of ritonavir or 
lopinavir/ritonavir, tipranavir).  
EFFICACY 
EVALUATIONS 
• Change in plasma inflammatory biomarker levels2 
• Change in SARS-CoV-2 viral load4 
• Change in COVID-19 symptom severity3 (5-point scale) 
PRIMARY 
ENDPOINTS 
• Change in plasma inflammatory biomarker levels2 (e.g., 
IL-6, IL-1β) at days 5, 15, and 31. 


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SECONDARY 
ENDPOINTS 
• Safety and tolerability  
• Change in SARS-CoV-2 PCR quantitative viral load4 at 
days 5, 15, and 31. 
• Change in COVID-19 clinical stage (five-point symptom 
severity scale3) at days 5, 15, and 31. 
• Time to recovery (date of symptom onset to date of 
complete resolution of symptoms)  
• If applicable, the proportion of participants hospitalized at 
day 5, 15, and 31. 
• If applicable, the proportion of participant deaths at day 
5, 15, and 31 
OTHER 
EVALUATIONS 
• SARS-CoV-2 specific T- and B- cell responses5 
• Pyroptosis (aberrant proinflammatory cell death) assay6 
• High sensitivity SARS-CoV-2 antibody titer (IgM, IgE, 
IgA, IgG1, IgG2, IgG3, IgG4) 
• Changes in host gene and protein expression from 
matched blood and respiratory (NP) samples at the 
single cell level (B, T, natural killer, and myeloid cells).  
• Changes in T- and B-cell receptor (TCR/BCR) repertoire 
from matched blood and respiratory 
(nasal/oropharyngeal) samples.  
SAFETY 
EVALUATIONS 
All participants will be followed for possible adverse events 
(AEs) throughout their involvement in the study.  
PLANNED INTERIM 
ANALYSES  
A Safety Monitoring Committee (SMC) will be convened and 
will meet biannually to review all adverse events and the 
conduct of the study. Serious adverse events will be 
monitored by the committee on an ongoing basis throughout 
the study. All main analyses will be conducted on an 
intention-to-treat basis. Models will assess the relationship 
between the timing of disulfiram treatment initiation relative 
to symptom onset and study outcomes for key 
efficacy/activity endpoints. Stratified analyses will be 
performed based on symptom severity, as well as laboratory 
values (e.g., hs-CRP, ferritin, D-dimer levels at baseline). 
 
 


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4 
RATIONALE/BACKGROUND 
4.1 
Background and scientific rationale  
The coronavirus-2019 (COVID-19) pandemic has caused devastating morbidity and mortality 
worldwide.7-12 But the virus itself does not seem to explain the person-to-person variability in clinical 
course (ranging from asymptomatic carriage to severe lethal respiratory disease, as well as long-term 
inflammatory sequelae).13-15 Variation in host genetics and host-specific immune responses likely play 
a major role in determining the severity of COVID-19.13-15 Patients who progress to severe acute 
respiratory distress syndrome, for example, demonstrate increased expression of interleukin (IL)-6 and 
IL-1. 16-18 Several anti-inflammatory trials are now underway in hospitalized patients, to determine 
whether blockade of these pathways reduces COVID-19 associated mortality,18,19 including planned 
trials to inhibit IL-6/IL-1b signaling (NCT04320615, NCT04362813, NCT04346355, NCT04356937, 
NCT04341675).16 Yet early treatment of mild-to-moderate symptomatic severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection is likely to play an even greater role in public health 
efforts to control COVID-19 since over 80% of COVID-19 cases can be asymptomatic.20 This suggests 
that early treatment may potentially prevent hospitalizations/ICU admissions by reducing community 
viral transmission.  
Disulfiram is an FDA-approved drug and has been in clinical use for over 60 years. Recent data 
suggests that it may have both direct antiviral, as well as indirect (anti-inflammatory), effects on SARS-
CoV-2 infection (Figure 1).21-24 Disulfiram 
directly inhibits Mpro, the protease that 
processes the 2 main proteins, pp1a and 
pp1b, required for SARS-CoV-2 viral 
replication and transcription.23 Disulfiram 
can also act as a zinc ejector to inhibit viral 
replication.22 
Disulfiram 
may 
indirectly 
reduce inflammation via inhibition of the 
NF-κB pathway (upstream of IL-1β/IL-6 
signaling),25-27 
and 
recent 
data 
demonstrates 
that 
disulfiram 
inhibits 
gasdermin D pore formation (the final 
common step of NLRP3 inflammasome-
induced pyroptosis and cytokine release).24  
Given its relative safety, easy dosing 
schedule and putative antiviral and anti-
inflammatory effects associated with SARS-
CoV-2 infection, disulfiram is an appealing 
therapeutic option for COVID-19 treatment. 
Disulfiram 
is 
FDA 
approved 
for 
the 
treatment of alcohol dependence disorder 
(NCT01286259).28 More recently, disulfiram 
has been shown to be safe when 
administered in the setting of HIV cure (NCT01944371) 29 and cancer trials (NCT02715609, 
NCT02671890, NCT03323346, NCT00256230, NCT02678975).30,31Disulfiram is an oral daily 
administered drug. Disulfiram given at doses as high as 2000 mg has recently been shown to be safe 
Figure 1. Potential direct antiviral (inhibiting Mpro protease or zinc 
moiety to inhibit viral replication) and indirect anti-inflammatory 
(inhibition of NF-Kβ or NLRP3 inflammasome) effects of disulfiram on 
SARS-CoV-2 infection.  


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and well tolerated in HIV-infected individuals.29 Additionally, disulfiram has a short half-life (~7.5 hours) 
with over 90% of the drug eliminated within 3 days post dose.32,33,34 Now several drug screens have 
identified disulfiram as an effective antiviral against SARS-CoV and SARS-CoV-2.22,23  
 SARS-CoV-2-associated immune dysregulation 
Leveraging safe and readily available FDA-approved drugs that can potentially block inflammation and 
have antiviral activity against SARS-CoV-2 may help provide additional rationale and safety data for 
blocking inflammation, especially among mild-to-moderately symptomatic COVID-19 patients in whom 
early treatment is most likely to confer overall public health benefit. Unlike the first severe acute 
respiratory syndrome (SARS-CoV) virus, SARS-CoV-2, largely manifests as asymptomatic disease (in 
over 50-80% of infected individuals tested).20,35-37 However, the virus itself does not seem to explain 
the person-to-person variability in clinical course, ranging from asymptomatic carriage to severe lethal 
respiratory and/or cardiac disease.13-15 Higher levels of inflammation – e.g., plasma IL-6 levels, predict 
disease severity.1,16-18 Uncontrolled clinical trials suggest that blockade of IL-6 may improve COVID-19 
clinical outcomes,38-40 but controlled trial results are still pending.  
Hypercytokinemia is regarded as a hallmark of COVID-19. High levels of cytokines including TNF-α, 
IL-1β, IL-1Ra, sIL- 2Rα, IL-6, IL-10, IL-17, IL-18, IFN-
γ, MCP-3, M-CSF, MIP-1a, G-CSF, IP- 10 and MCP-
1 have been reported in patients with severe 
disease.41,42 Observational studies of COVID-19 
patients demonstrate increased levels of acute phase 
reactants during infection, e.g., elevated erythrocyte 
sedimentation rate (ESR), C-reactive protein (CRP), 
and ferritin levels, (these markers all have readily 
available clinical assays) that may represent 
underlying 
elevated 
cytokine 
levels.41-43 
Initial 
increases in cytokine levels can subsequently lead to 
“cytokine storm,” excessive cytokine release which 
can lead to multiple organ failure resulting in rapid 
deterioration and death, as observed in severe COVID-
19 patients.44,45  
Studies suggest that IL-1β and IL-6, in particular, are 
major driving factors of poor prognosis.1,43 A strong 
correlation was found between higher IL-6 levels and severe disease or the need for mechanical 
ventilation compared to patients with uncomplicated disease. 43-53 Indeed, IL-6 has been suggested as a 
predictive biomarker for respiratory failure and death (Figure 2), and randomized placebo-controlled 
clinical trials blocking this pathway are underway (e.g., NCT04320615, NCT04362813, NCT04346355, 
NCT04356937, NCT04341675).54 In a non-randomized, single-arm study, tocilizumab (soluble IL-6 
receptor monoclonal antibody) was given to patients with severe COVID-19, and demonstrated 
decreased oxygen requirements, resolution of radiographic abnormalities, and clinical improvement 
with no adverse events or deaths.50 Two other non-randomized studies found similar benefit as well.52,55 
Data from placebo-controlled IL-6 blocking trials are still pending. However, there are limited human 
data on the role of disulfiram on systemic cytokine levels. Prior studies have demonstrated that 
disulfiram may block IL-18 production in patients with glioblastoma, pancreatitis.56-58 IL-18 is closely 
linked to IL-6 as both IL-18 and IL-1β (the key upstream regulator of IL-6) are proteolytically cleaved 
Figure 2. Differences in plasma IL-6 levels between 
survivors (N=137) and non-survivors (N=54) in Wuhan, 
China. 
Non-survivors 
demonstrated 
statistically 
significantly higher plasma IL-6 levels as early as day 4 of 
symptom onset.1 


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via caspase-1 in response to innate immune sensing during pyroptosis.59 In fact, prior studies have 
used plasma IL-18 as a surrogate for inflammasome signaling/plasma IL-1β levels, given challenges in 
measure IL-1β from patient plasma samples (in the picogram/mL range) using older assays.60-63 Our 
group has recently demonstrated that IL-1β levels can now be reliably measured in plasma using newer 
chemiluminescent high sensitivity multiplex cytokine assay (Meso Scale Diagnostics, Rockland, MD) 
to discriminate differences within and between HIV+ antiretroviral therapy (ART)-suppressed 
individuals (Figure 3).64-66  
Additional immune pathways also likely contribute to the hypercytokinemia observed in SARS-CoV-2 
infection. For example, innate immune activation during SARS-CoV-2 infection can lead to activation 
of downstream signaling effectors such as NF-ĸB.67-69 NF-ĸB promotes the transcription of pro-
inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, 67,69 
further triggering Th1 and Th17 production with subsequent 
secretion of IFN-γ and IL-17. 50,67,69 While the exact mechanism 
by which SARS-CoV-2 triggers an innate immune response is 
unknown it is likely similar to that used by SAR-CoV. Previous 
studies have detailed that SARS-CoV is detected by pattern 
recognition receptions (PRR) such as melanoma differentiation-
associated protein 5 or retinoic acid-inducible gene 1 protein in 
the host.70 The PRRs then interact with mitochondrial antiviral-
signaling proteins (MAVS) triggering a kinase filled cascade 
which ultimately activates NF-ĸB. In turn NF-ĸB activates 
cytokine transcription leading to the elevated concentrations 
noted in COVID-19 patients.1,47,71 These kinases act to 
phosphorylate IFN-regulatory factors stimulating production of 
type 1 interferons (IFNs) which in turn active the JAK-STAT 
pathway.70 Both SARS-CoV and Middle Eastern respiratory virus 
(MERS-CoV) have developed mechanisms to interfere with the host innate response (using papain-
like protease (PLpro) and non-structural proteins) potentially leading to the dysregulation seen in severe 
cases.72-76  
 Disulfiram and putative SARS-CoV-2 antiviral activity 
Human coronaviruses, including the initial SARS-CoV, MERS-CoV, and the recent SARS-CoV-2, are 
all positive-sense single-stranded RNA viruses. Both SARS-CoV and MERS-CoV have developed 
mechanisms to interfere with the host innate response as described below .72-76  Similarly, SARS-CoV-
2 appears to promote immune dysregulation, as observed in severe COVID-19 patients who progress 
to severe acute respiratory distress syndrome (ARDS), with corresponding elevated plasma levels of 
IL-1 and IL-6.16-18 
For these coronaviruses, after the virus enters the host cell, two polyproteins, pp1a and pp1ab, are 
directly translated and then cleaved by two viral proteases, main protease (Mpro) and papain-like 
protease (PLpro).24,77,78 Both PLpro and Mpro play pivotal roles in mediating viral replication and 
transcription by cleavaging non-structural proteins (nsp) 1, 2 and 3 and Mpro cleaves all junctions 
downstream of nsp4, respectively.78 In a recent drug screen, disulfiram was shown to inhibit MERS-
CoV PLpro and SARS-CoV PLpro.18 Indeed, disulfiram acts as an allosteric inhibitor of MERS-CoV 
PLpro and as a competitive inhibitor of SARS-CoV PLpro, with a dose-dependent inhibitory effect on 
both proteases with IC50 values in the micromolar range (7.52 ± 2.13 μM).79 Disulfiram was also 
 
Figure 3. Plasma IL-1β and IL-18 levels 
performed using the MSD high sensitivity 
cytokine assay were correlated among 41 
HIV+ ART-suppressed participants from the 
UCSF SCOPE cohort.17 


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identified as a candidate for targeting SARS-CoV-2 Mpro by a high-throughput screen, demonstrating 
an IC50 value of 9.35±0.18 μM.23 In in vitro cell-based assays, disulfiram demonstrated its anti-SARS-
CoV-2 viral activity, reducing the absolute number of viral RNA copies (per mL) from 1.5 x109 to 1 x109 
compared to positive controls (SARS-CoV-2).23  
In addition to direct binding to the active site of human corona virus PLpro and Mpro, disulfiram may 
also act as a zinc ejector.22 There are four cysteines (Cys) bound to a zinc ion in PLpros 65-68 and 
disulfiram could inhibit PLpro by binding to the zinc site. Studies using a zinc release assay illustrated 
that disulfiram may bind not only to the active site but also to the zinc-binding sites in MERS-CoVpro 
and SARS-CoV PLpro.22 In addition, prior studies have shown that disulfiram may eject Zn2+ from the 
Zn-Cysteine-4 site in the hepatitis C virus NS5A protein, inhibiting viral replication.21 Finally, in one 
study to identify druggable Zn-sites in SARS-CoV-2, nsp3 in SARS-CoV-2 PLpro, nsp10 transcription 
factor, and nsp13 helicase were identified as the most attractive drug targets.79,80 Recent data now 
suggests that disulfiram may act synergistically with the nucleoside analog, remdesivir (an FDA-
approved SARS-CoV-2 antiviral agent shown to reduce time to recovery in severe81 and moderate82 
COVID-19 in the inpatient setting), by targeting conserved Zn2+-sites in SARS-CoV-2 nsp13 and nsp14 
and inhibiting nsp13 ATPase and nsp14 exoribonuclease activities.   


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 Disulfiram and mediation of aberrant inflammation in SARS-CoV-2 infection 
The mechanism by which SARS-CoV-2 leads to severe COVID-19 disease in some individuals may be 
due to aberrant, excessive inflammation caused by activation of the NOD-like receptor protein 3 
(NLRP3) inflammasome, a key player in antiviral responses.83 Disulfiram was recently shown to inhibit 
gasdermin D (GSDMD) pore 
formation, the final common 
step of NLRP3 inflammasome-
induced inflammatory cell death 
(“pyroptosis”) and subsequent 
release 
of 
proinflammatory 
cytokines such as IL-1β and IL-
6.6 
In 
addition, 
disulfiram 
inhibits NF-κB signaling, a 
transcription-factor 
mediated 
pathway that enhances NLRP3 
inflammasome activation.84 
The host antiviral response is 
triggered by highly conserved 
sensors 
called 
pattern 
recognition receptors (PRRs) 
that recognize “danger signals” 
caused by the pathogen (e.g., 
aberrant ion concentrations, 
mitochondrial 
damage, 
accumulation 
of 
misfolded 
protein aggregates, etc.). Some 
PRRs 
form 
inflammasomes 
(the most well-studied being the 
NLRP3 
inflammasome), 
cellular protein complexes that 
mediate 
host 
immune 
responses 
to 
pathogens.85 
Inflammasome 
assembly 
triggers ultimately leads to pyroptosis (inflammation-associated cell death) via auto-cleavage of pro-
caspase1 which mediates proteolysis of pro-IL-1β, and gasdermin D (GSDMD) (Figure 4). GSDMD 
membrane pore formation then promotes the secretion of IL-1β (which induces IL-6 expression) and 
IL-18 (which promotes cytotoxic activity of T and NK cells via interferon-γ production).86  
Unlike apoptosis, pyroptosis occurs faster and is accompanied by the release of large amounts of pro-
inflammatory cytokines and chemokines.87 In SARS-CoV-2 infection, a rise of IL-1β and lymphopenia 
were observed in patients, strongly suggesting the presence of cell pyroptotic activity.88 In SARS-CoV 
infection, a small viral protein which modifies host cell permeability, viroporin 3a, was shown to trigger 
the NLRP3 inflammasome and subsequent IL-1β release.89,90 Disulfiram may be able to reduce 
aberrant inflammation during SARS-CoV-2 infection via inhibition of NLRP3 inflamasome activation – 
either via inhibition of the final common step (GSDMD pore formation) or via inhibition of NF-κB-
mediated enhancement of NLRP3 inflammasome activation and  proinflammatory cytokine release.  
Figure 4. NLRP3 inflammasome activation during viral infections. Activation of the 
NLRP3 inflammasome requires 2 signals: (1) priming signal: activation of PRRs, TNFR, or 
IFNR induction of NF-kB activation, which triggers transcription of NLRP3, pro-caspase-1, 
pro-IL-1b, and pro-IL-18, and (2) activation signal: multiple DAMPs (damage-associated 
molecular patterns) and PAMPs (pathogen-associated molecular patterns) induce NRLP3 
inflammasome assembly and activation. Caspase-1 then mediates the proteolytic 
processing of pro-IL-1b, pro-IL-18, and gasdermin D (GSDMD, the final common step), to 
lead to proinflammatory cytokine production. (Zhao et. al., Front Immunol 2020) 


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Disulfiram has recently been shown to strongly inhibit GSDMD pore formation in a large high-throughput 
biochemical screen.24 Disulfiram had direct in vitro and in vivo effects on GSDMD pore formation, with 
inhibition of liposomal leakage and subsequent reduction of pyroptosis and inflammatory cytokine 
release. Disulfiram has also been shown to have inhibitory effects on NF-ĸB and IL-6/STAT3 signaling 
pathways in cancer cells.25-27 Therefore, disulfiram may mediate aberrant inflammasome activation via 
multiple potential mechanisms, a potential mechanism by which severe COVID-19 disease may be 
prevented if administered early in infection. 
 Clinical experience and safety of disulfiram 
Disulfiram was first advocated as a therapy for alcoholism in 1937 when it was noted that rubber factory 
workers exposed to the molecule became intolerant of alcohol. Disulfiram has been approved by the 
FDA since 1951 for the treatment of alcohol dependence. Given its unusual history and early drug 
development, the quality of evidence supporting its use is limited. Nonetheless, a recent multicenter 
observational study in Italy found that disulfiram statistically significantly reduced COVID-19-related 
symptoms (fever and dyspnea) in a cohort of 752 individuals taking disulfiram (dosing range 100-800 
mg daily) for the treatment of alcohol dependence compared to 542 COVID-19+ controls.91 There were 
a total of only 4 cases and 4 controls who were admitted to be able to determine whether disulfiram 
prevented hospitalizations due to COVID-19. Reviews of disulfiram outcome studies spanning several 
decades have found that only one of more than 40 clinical trials have met current adequate research 
design criteria and only five of 135 disulfiram clinical trials have had a controlled design.92 
The mechanism for the drug’s alcohol deterrent effects lie in its ability to inhibit liver mitochondrial 
aldehyde dehydrogenases (ALDH).93 This enzyme converts acetaldehyde to acetate in alcohol 
metabolism leading to an immediate uncomfortable reaction upon exposure to alcohol and when 
inhibited leads to the buildup of acetaldehyde. 94 The reaction to alcohol usually consists of symptoms 
such as flushing, heat sensation, nausea, vomiting, palpitations, headaches, and/or circulatory changes 
such as decreased blood pressure or increased pulse rate. The time to onset of ALDH inhibition which 
is sufficient to result in a reaction upon alcohol consumption is 12 hours and ALDH function is 
completely restored within 6 days of stopping disulfiram in alcoholics. 33,95  
The current recommended dose of disulfiram is 250 to 500 mg once daily. When disulfiram was first 
used clinically almost sixty years ago, it was common practice to use doses up to 1 to 3 grams.96 
However, these higher doses were associated with reports of severe adverse reactions, particularly in 
those individuals who continued to be exposed to alcohol.97 Many of the serious adverse effects of 
disulfiram, such as psychotic reactions, hypotension and neuropathy, are thought to be dose-related,96 
and most fatal reactions occurred in patients who were taking more than 500 mg a day of disulfiram 
and who consumed more than 28 grams of alcohol.98,99 
Given the variability in the clinical and biologic effect of disulfiram (see below), early recommendations 
by manufacturers and experts were to confirm that the drug was indeed active by challenging patients 
with alcohol. One recommended approach was to administer four 200 mg tablets (800 mg total) of 
disulfiram on the first day, reducing by one tablet each subsequent day until the fifth day, when patients 
were administered a single pill (200 mg) and then challenged with a dose containing 15-30 mL of pure 
ethanol. 100 In one study of 63 patients using this approach, 33 required 200 to 300 mg, 17 required 
400 to 500 mg, 6 required 600 to 700 mg and 7 required 800 to 1500 mg in order to develop a clinical 
reaction to ethanol. During longer-term dosing, significant side effects were uncommon, but included 
drowsiness and mild confused states; these side effects waned in one to three days after dose reduction 


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or cessation.100 Other approaches to deal with the patient-to-patient variability in activity were to 
administer very high doses. In one study, doses up to 6 grams per day were given.101 Disulfiram was 
reported to be safe, although with chronic dosing rare but significant liver complications occurred that 
may or may not have been drug-related.102  
 HIV clinical trials of disulfiram 
Our group has performed clinical trials of disulfiram in the setting of HIV cure trials, which have 
demonstrated safety and tolerability at doses as high as 2000 mg.103,104 In a phase 2b dose escalation 
trial in HIV-infected virally suppressed participants, we evaluated disulfiram given at 500 mg, 1000 mg 
or 2000 mg daily for 3 consecutive days (NCT01944371).29 Disulfiram was well tolerated at all doses 
studied; there were no drug discontinuations or grade 2-4 adverse events observed. These safety data 
were consistent with our prior phase 1 trial evaluating disulfiram 500 mg daily administered for 14 
consecutive days in HIV-infected virally suppressed participants (NCT01286259).104 A follow-up study 
in HIV-infected participants was performed, this time in combination with a histone deacetylase 
inhibitor, vorinostat (SAHA) (NCT03198559). In this phase 2b trial, HIV-infected virally suppressed 
participants received 2000 mg of oral disulfiram once daily for 28 days but this time, in combination with 
400 mg oral vorinostat once daily on days 8-10 and again on days 22-24 (for a total of 6 days total of 
vorinostat overlap).  Although there was evidence that this combination did reverse HIV latency, the 
study was halted due to two participants experiencing neurological adverse events including confusion, 
lethargy ataxia and paranoia. All symptoms resolved after discontinuation of both study drugs, 
disulfiram and vorinostat. Review of the participants’ clinical records was unable to completely rule out 
that disulfiram administration, in combination with vorinostat, was related to these adverse events. 
Therefore, for the proposed work, we will only be administering disulfiram alone, as was demonstrated 
to be safely given in our prior phase 2b dose escalation trial.29 
 Pharmacology of disulfiram 
Overview. The metabolism of disulfiram is complex (Figure 5).105-107 Disulfiram is metabolized to 
diethyldithiocarbamate (DDTC) and then to diethyldithiocarbamate methyl ester (DDTC-Me). DDTC-
Me is formed by thiol S-methyl ester transferase from DDTC. DDTC-Me is then metabolized to S-
methyl-N-N- diethylthiocarbamate (disulfiram carbamate, or DETC-Me), and then bioactivated to S-
methyl-N-N- diethylthiolcarbamate sulfoxide (DETC-MeSO). DETC-MeSO inhibits ALDH and hence is 
responsible for the anti-alcohol effect. 106,108 With regard to the anti-alcohol activity, most investigators—
including Dr. McCanz-Katz, who lead the PK study outlined below—focused on latter metabolites 
(DETC-Me and DETC-MeSO).  
Bioactivation of disulfiram to the active metabolite DETC-MeSO occurs principally via CYP 3A4/5, with 
contributions by CYP 1A2, 2A6 and 2D6.107,109 Faiman and colleagues reported that the reduced 


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metabolite of disulfiram, diethyldithiocarbamate 
(DDTC), inhibits several CYP enzymes including 
CYP 3A4/4, 2E1, and 2A6 which all play a role in 
bioactivation of disulfiram to DETC-MeSO.109 This 
effect has been postulated as a reason why 
disulfiram produces variable reactions when alcohol 
is co-consumed.109  
The pharmacokinetics and pharmacodynamics of 
disulfiram are highly variable between individuals. 
Up to 50% will not have a disulfiram-ethanol reaction 
on the recommended 250 mg dose.100 For some, 
doses up to 500 mg are insufficient to cause a 
disulfiram-ethanol reaction.100 This creates a clinical 
challenge in finding a dose of disulfiram that will be 
effective to elicit a mild disulfiram- ethanol reaction, 
while maintaining the safety of the patient should he 
or she drink alcohol while on the medication.110  
A formal study of the elimination 
kinetics of disulfiram was performed 
by Faiman and colleagues and 
reported 
in 
1984.111 
 
Fifteen 
alcoholics (all men) were given 250 
mg as a single dose on day 1 and 
day 12. The observed half-life of 
disulfiram, 
diethyldithiocarbamate 
(DDTC), 
diethyldithiocarbamate-
methyl 
ester 
(DDTC-Me), 
diethylamine (DEA), and carbon 
disulfide were found to be 7.3, 15.5, 
22.1, 
13.9, 
and 
8.9 
hours, 
respectively. Disulfiram is reported 
to be 90% eliminated in 3 days.112 
Peak plasma levels for disulfiram 
and its metabolites occurred at 
approximately 8 to 10 hours after the 
dose, while peak levels of carbon 
disulfide occurred 5 to 6 hours after 
the 
dose. 
There 
was 
marked 
variability 
in 
plasma 
levels 
of 
disulfiram and its metabolites (see 
Figure) which was attributed in part 
to plasma protein binding (disulfiram 
is 
95% 
protein 
bound) 
and/or 
differences in liver metabolism.113 It 
has also been suggested that 
 
 
Figure 5. Disulfiram metabolism. Disulfiram is rapidly 
metabolized to its metabolites, including DDTC, DDTC-Me, 
DETC-Me, DETC-MeSO, and carbamthione.   
      
 
 
Figure 6. Seven-compartment pharmacokinetic model of disulfiram (DSF) 
metabolism. CL, clearance (L/hour); DSFGUT, amount of disulfiram in gut (mg); 
DSFPLASMA, amount of disulfiram in plasma (mg); ka, absorption constant; knon-
lin, nonlinear elimination calculated using Km and maximum rate of metabolism 
(Vmax) terms; M1PLASMA, amount of N,N-diethyldithiocarbamate (DDTC) in 
plasma (mg); M2PLASMA, amount of diethyldithiocarbamate-methyl ester (DDTC-
Me) in plasma (mg); M3PLASMA, amount of S-methyl-N, N-diethylthiolcarbamate 
sulfoxide (DETC-MeSO) in plasma (mg); M3PERIPHERY, amount of DETC-
MeSO in plasma (mg); M4PLASMA, amount of carbamathione in plasma (mg); Q, 
blood flow (L/hour); V, volume of distribution (L).   


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disulfiram undergoes enteroheptic recycling. In a separate earlier study reported in 1979, a 600-fold 
variation in disulfiram plasma concentrations was reported.114 Other studies have noted high variability 
in levels of key metabolites. 
More recently, our group performed a 
detailed 
pharmacokinetic/ 
pharmacodynamic (PK/PD) modeling 
study based on our phase 2b dose 
escalation HIV cure clinical trial.29,34 
Parent drug (disulfiram) and four 
metabolites 
(DDTC, 
DDTC-Me, 
DETC-MeSO 
and 
carbamathione) 
were quantified and measured over 
the 31- day study period, as well as 
viral outcome measures for the PD 
analysis (cell-associated HIV RNA in 
CD4+ T cells and plasma HIV RNA). 
A 
comprehensive 
seven-
compartment PK/PD model was built 
to estimate disulfiram metabolism 
(Figure 
6). 
Higher 
doses 
of 
administered disulfiram were associated with higher plasma concentrations of parent drug and 
metabolites (Figure 7). A linear PK model simultaneously incorporating all metabolites underpredicted 
plasma concentrations in the 2000 mg group, which initially appeared to be due to supraproportional 
concentrations of disulfiram in the highest dosing group (Table 1). However, after fitting a PK model 
allowing for nonlinear elimination kinetics, the supraproportional concentrations seemed to be largely 
explained by reduced elimination (e.g., due to saturation of CYP enzymes at higher concentrations) 
rather than increased bioavailability at the 2000 mg dose. 
 Table 1. Final PK model estimates for median AUC0-72 exposure to metabolites by 
dosing cohort. 
 
Disulfiram concentrations were significantly associated with increases in HIV cell-associated RNA (with 
an Emax of 78% and AUC50 of 1600 mg-hr/L for the parent compound) for all of the dosing cohorts. 
Similarly, each of the four metabolites were also shown to significantly increase cell-associated RNA. 
Disulfiram concentrations were also associated with an increase in plasma HIV RNA levels, but only in 
the highest (2000 mg) dosing group.29,34  
 
 
Figure 7. Plasma disulfiram concentrations by dosing group. Elevated 
plasma drug concentrations were observed with higher administered dose of 
disulfiram, which was safe and well tolerated all doses studied. Supra-
proportional concentrations of disulfiram were observed in the 2000 mg dose, 
which was largely attributed to decreased elimination (rather than increased 
bioavailability) in the PK model. 


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 Disulfiram dose justification 
Disulfiram’s safety profile has been evaluated in several clinical trials. 
In an open-label clinical trial to determine short-term disulfiram on decay of the HIV reservoir in patients 
on highly active antiretroviral therapy (NCT01286259), patients received 500 mg disulfiram daily via 
oral administration for 14 days. The safety and tolerability of a two-week course of disulfiram was 
defined using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 1.0, December 2004 (Clarification, August 2009). A total of 16 patients were recruited, with no 
adverse event reported during the treatment course.  
In a phase 2 non-randomized trial focusing on short-term disulfiram to reverse latent HIV infection 
(NCT01944371),103 patients received disulfiram daily for 5 days at doses of 500 mg, 1000 mg or 2000 
mg. The safety and tolerability of disulfiram was defined using the Division of AIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events version 2.0, November 2014. Thirty patients were 
recruited, and all participants completed the study. There were no deaths, drug discontinuations, or 
grade 2-4 adverse events observed. No adverse events related to the study drug were reported in the 
500 mg group, which was consistent with the findings described in the previous trial above. Grade 1 
clinical adverse events related to study drug were more common in the higher dosing cohorts including 
10 events in the 1000 mg group, and 14 events in the 2000 mg group.  
The DIVA study (NCT03198559) was a phase 2b trial investigating whether disulfiram in combination 
with vorinostat could active HIV-1 viral replication. The proposed study design was to enroll 14 virally 
suppressed HIV-infected patients and to administer 2000 mg disulfiram orally once daily for 28 days 
and 400 mg vorinostat once daily orally on days 8-10 and again on days 22-24 (6 days total).  The 
primary outcome measure was plasma HIV RNA on day 11 normalize to each patients’ baseline value. 
The safety and tolerability of this combination was defined using the Division of AIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events version 2.0, November 2014. Although there was 
evidence that this combination did reverse HIV latency this study was stopped after recruiting two 
patients. Both patients experienced neurological adverse events including confusion, lethargy ataxia 
and paranoia. All symptoms resolved after discontinuation of study drugs. Upon review of the patients’ 
clinical records disulfiram was listed as possible and probably related to these adverse events 
respectively.  
 SARS-CoV-2 viral load quantification 
Serial SARS-CoV-2 viral load quantification will be performed using quantitative reverse transcription 
polymerase chain reaction (rtPCR) using the Roche MagNA Pure 96 (MP96) System.4 A modified CDC 
protocol was used to target the N1 and N2 gene of SARS-CoV-2 RNA, and this assay has been 
validated across multiple patient tissue types.115 The assay will be used to evaluate SARS-CoV-2 viral 
decline in those receiving or not receiving disulfiram. These assays will be performed on 
nasopharyngeal (NP) swabs, but also from blood samples. In addition, saliva will be collected and 
stored for potential future quantification of SARS-CoV-2 RNA and anti-SARS-CoV-2 IgA. 


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 Preliminary data demonstrating the ability to enroll acute COVID+ patients  
At the onset of the global COVID-19 pandemic, we rapidly developed the acute COVID-19 Host Immune 
Response Pathogenesis (CHIRP) study to evaluate clinical, demographic, behavioral, immunologic, 
and genetic risk factors associated with COVID-19 acquisition and severity. In order to minimize the 
potential risk of SARS-CoV-2 transmission to non-research patients, as well as household members to 
potentially infected research staff, we developed a study design for example, 
 allowing outpatient in-person visits using a mobile research van in order to abide by the Centers for 
Diseases 
Control 
guidelines 
for 
discontinuation 
of 
home 
isolation 
(https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html). In less than four 
weeks of cohort development, we obtained study protocol approval, set up the off-campus location and 
mobile study van, and implemented strict infection control protocols to enroll COVID+ individuals and 
close household contacts. In order to minimize exposure time during in-person visits, electronic 
informed consent and release of information are obtained by phone. Longitudinal biospecimen 
collection are performed at weeks 1, 2, 4, 8, and 24 from baseline visit, collecting blood, urine, stool, 
saliva, and home expectorated sputum. To date, a total of 13 (26%) of 50 prospective screened 
participants have been enrolled in the study after just three weeks from study initiation, including four 
individuals and four family clusters. Among the first 13 participants enrolled, 62% are female, with a 
median age of 42 years. We will now leverage this intensive sampling cohort infrastructure to rapidly 
enroll participants for the DISCO trial.  
 


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5 
INVESTIGATIONAL PLAN:  
5.1 
Study objectives  
 Primary objective 
• To determine the effect of oral disulfiram given at 1000 mg daily (cohort 1) or 2000 mg daily 
(cohort 2) versus placebo for 5 consecutive days in adults with early mild-to-moderate 
symptomatic SARS-CoV-2 infection on inflammation (plasma cytokine levels - e.g., IL-6, IL-1β) 
using the MesoScale Diagnostics high sensitivity plasma cytokine platform2 
 Secondary objectives 
 
• To determine the effect of oral disulfiram (2000 mg daily given for 5 consecutive days) in adults 
with early mild-to-moderate symptomatic SARS-CoV-2 infection on: 
o The safety and tolerability of oral disulfiram 2000 mg/day given for 5 consecutive days in 
adults with symptomatic SARS-CoV-2 infection. 
o SARS-CoV-2 PCR positivity and quantitative viral load using qRT-PCR on the Roche 
MagNA Pure 96 system.4  
o  COVID symptom severity (using an adapted SSS-8 five-point symptom scale for 
common COVID-19 symptoms3 which abide by the FDA Guidance: Assessing COVID-
19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials of 
Drugs and Biological Products for COVID-19 Prevention or Treatment.116 
o The proportion of participants hospitalized at day 5, 15, and 31. 
o The proportion of participant deaths at day 5, 15, and 31. 
 
5.2 
Study Definitions 
• Enrolled: From time consented to participate until designated as (i) ineligible based on the 
inclusion/exclusion criteria or withdraws, (ii) been discontinued from the study or (iii) completed the 
study.  
• Randomized: when a randomization number is assigned. 
• Screen Failures: signed informed consent, but then determined to be ineligible or withdraws before 
being randomized. 
• Discontinued: randomized, but then withdrawn by investigator or participant withdraws consent. 
• Completed: Participants are considered completed when they are followed through to day 31, had 
an adverse event or death occurred prior to day 31. 
5.3 
Study Population 
 Inclusion Criteria 
1. Willing and able to provide written informed consent, and 
2. Age ≥18 years, and 
3. Recent symptomatic COVID-19 disease (<14 days from symptom onset) 


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4. Recent SARS-CoV-2 positive test by molecular diagnostic assay within the preceding 7 days, 
and 
5. Not currently hospitalized, and 
6. 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. 
7. Both male and female participants 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 
1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study 
2. Active malignancy requiring systemic chemotherapy or surgery in the preceding 3 months or 
for whom such therapies are expected in the subsequent 6 months 
3. Decompensated liver disease as defined by the presence of ascites, encephalopathy, 
esophageal or gastric varices, or persistent jaundice 
4. Serious illness requiring systemic treatment and/or hospitalization in the 3 months prior to 
study enrollment 
5. 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. 
6. 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. 
7. 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. 
8. Current use of any drug formulation that contains alcohol or that might contain alcohol 
9. Current use of warfarin. 
10. Current use of oral lopinavir/ritonavir solution (and the inability to switch to a solid dosage 
form during the entire duration of the study). 
11. ALT or AST > 2 x the upper limit of normal or total bilirubin outside the normal range. 
12. Creatinine clearance (CrCl) < 50 mL/min by Cockcroft-Gault) 
13. Allergy to rubber or thiuram derivatives 
 
Note: Receipt of medications with potential anti-COVID activity that are considered standard-of-care at 
the study site (e.g., small molecules or monoclonal antibodies directed against SARS-CoV-2) is 
permitted during the trial. Prior receipt of current standard of care inpatient COVID-19 treatment, 
including remdesivir, convalescent plasma/sera, and dexamethasone,117 is also permitted and should 
be recorded as a prior medication.  


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 Participant Withdrawal 
Participants can terminate study participation and/or withdraw consent at any time without prejudice. 
Randomized participants who withdraw from the study will not be replaced. If a participant discontinues 
study dosing (for example, as a result of an AE), every attempt should be made to keep the participant 
in the study and continue to perform the required study-related follow-up and procedures (see Section 
8.1, Criteria for Discontinuation of Study Treatment). The investigator may withdraw participants if they 
are non-compliant with study procedures or if the investigator determines that continued participation 
in the study would be harmful to the participant or the integrity of the study data.  
 Treatment  
A total of 60 participants will be randomized (2:1) to receive active drug versus placebo in a dose 
escalation study. The first 30 participants will be enrolled in the 1000 mg dosing cohort, randomized 
2:1 to receive either disulfiram 1000 mg (N=20) or placebo (N=10) daily for 5 consecutive days. As long 
as safety monitoring criteria are met to proceed to the second dose, the next 30 participants will be 
enrolled in the 2000 mg dosing cohort, randomized 2:1 to receive either disulfiram 2000 mg (N=20) or 
placebo (N=10) daily for 5 consecutive days. 
 Randomization 
Participants enrolled in the study will be randomized using a web-based randomization procedure to 
receive active drug or no therapy at a 2:1 ratio within each dosing cohort.  
 Study drug administration 
Drug will be administered within 72 hours of randomization. 
 Concomitant medications  
Disulfiram is a substrate of CYP3A4, CYP2A6 and CYP2E1 and an inhibitor CYP2E1, CYP1A2 and 
CYP2C9, and therefore has potential drug-drug interactions.118 Concomitant medications will be 
documented on the Case Report Form (CRF) up to day 31. Most of these interactions can be managed 
clinically, as discussed below. 
1. Amprenavir oral solution: Amprenavir oral solution contains propylene glycol and should be 
avoided when using disulfiram.  
2. Benzodiazepines: Disulfiram may inhibit the metabolism of certain benzodiazepines.  Close 
monitoring for increased benzodiazepine effects is recommended.  
3. Metronidazole.  Metronidazole can have a disulfiram-like effect when administered with alcohol 
and should not be co-administered with this drug. 
4. Ritonavir: The gelatin capsule and liquid formulations of ritonavir contain alcohol. We will avoid the 
use of these formulations. The new ritonavir formulation has a small alcohol content, and thus co-
administered with disulfiram is not contraindicated.   
5. Sertraline:  The oral concentrate version of this drug contains alcohol. Thus, disulfiram should not 
be co-administered with this drug.  
6. Any drug which contains or may contain alcohol should be avoided. 
7. Theophylline Derivatives: Disulfiram may increase the serum concentration of theophylline.  
8. Tipranavir:  Disulfiram may enhance the adverse effect of tipranavir and should be avoided.  


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9. Vitamin K Antagonists (e.g., warfarin): Disulfiram may increase the serum concentration of Vitamin 
K.  We will exclude individuals who are receiving warfarin.  
10. Isoniazid: We will monitor for any potential side effects of isoniazid as the interactions between 
this drug and disulfiram are unknown 
11. Tricyclic antidepressants (TCAs): We will monitor for any potential side effects of TCAs as the 
interactions between these drugs and disulfiram are unknown. 
 
 Prohibited medications 
For study days 1-31, use of medications that are considered standard-of-care at the study site (including 
antiviral medications available under Emergency Use Authorization) is permitted. Use of other 
medications with potential anti-SARS-CoV-2 activity, including off-label, expanded access, or 
investigational agents, should be discussed with the team.  
Note: Participants who are hospitalized during the study are eligible to receive COVID-19 treatment per 
local standard of care, including remdesivir, immunomodulatory agents and/or convalescent 
sera/plasma and will not be excluded from the study if receiving this standard of care. Azithromycin 
administered for treatment of presumed or confirmed infection will be permitted.  
After study day 31, use of anti-COVID-19 treatments as salvage therapy for those with persistent severe 
COVID-19 are permitted but should be recorded.   


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5.4 
Study procedures  
5.4.1. Figure 1. SCHEDULE OF EVALUATIONS: 
 
Screen/ 
Baseline 
Day 1 
 
Clinic 
Day 2 
 
Clinic 
Day 3 
 
Phone 
Day 4 
 
Phone 
Day 5 
 
Pre dose  
Day 5 
2-hour  
Post dose 
Day 5 
4-hour 
Post dose 
Day 7 
 
Phone 
Day 9 
 
Phone 
Day 15 
 
Clinic 
Day 31 
 
Clinic 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
Release of information 
X 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Symptom diary/ AE check 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Vital signs (BP, HR, R, Temp, 
SP02)  
X 
Xa 
 
 
 
Xa 
Xb 
Xb 
 
 
X 
X 
Targeted Physical Exam  
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
SARS-COV-2 PCR TEST 
X 
 
 
 
 
 
 
 
 
 
 
 
Saliva 
 
X 
 
 
 
Xa 
 
 
 
 
X 
X 
Complete blood count with 
differential 
X 
 
Xb 
 
 
Xa 
 
 
 
 
X 
X 
Comprehensive Metabolic Panel 
X 
 
Xb 
 
 
Xa 
 
 
 
 
X 
X 
Erythrocyte Sedimentation Rate 
(ESR) 
X 
 
Xb 
 
 
Xa 
 
 
 
 
X 
X 
C-Reactive Protein (Inflammation) 
X 
 
Xb 
 
 
Xa 
 
 
 
 
X 
X 
D-Dimer 
X 
 
Xb 
 
 
Xa 
 
 
 
 
X 
X 
Lactate Dehydrogenase (LDH) 
X 
 
Xb 
 
 
Xa 
 
 
 
 
X 
X 


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Ferritin 
X 
 
Xb 
 
 
Xa 
 
 
 
 
X 
X 
Urine Pregnancy test (if WOCBP) 
X 
 
 
 
 
Xa 
 
 
 
 
 
 
CD4+/CD8+ T cell counts (if HIV 
positive) 
X 
 
 
 
 
 
 
 
 
 
 
X 
HIV RNA-standard Assay (if HIV 
positive) 
X 
 
 
 
 
 
 
 
 
 
 
X 
PK Samples 
 
 
Xb 
 
 
Xa 
Xb 
Xb 
 
 
X 
X 
PBMC 
 
X 
 
 
 
Xa 
Xb 
Xb 
 
 
X 
X 
Plasma 
 
X 
 
 
 
Xa 
Xb 
Xb 
 
 
X 
X 
Serum  
 
X 
 
 
 
Xa 
Xb 
Xb 
 
 
X 
X 
NP Swab  
 
X 
Xb 
 
 
Xa 
 
 
 
 
X 
X 
Study Drug/Placebo Administration 
(Given after blood collection on 
clinic visit days) 
• 
Cohort 1 = (N=20) 
1000mg/day; (N=10 placebo) 
• 
Cohort 2 = (N=20) 
2000mg/day; (N=10 placebo) 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
a=predose 
b=post-dose 
 
 
 
 


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The frequent time points are to detect both drug levels and human immune response. Red Cross limits 
are 500 mL per two months, which we do not exceed in this study. There is no stated guideline for 
blood volumes for this patient population, so we are utilizing the guidelines from interventional HIV cure 
trials, when often, serial blood sampling are completed in a single day. The total volume collected at 
each visit is as follows: 
 
Day 0 Screen/Baseline:  
15 mL 
Day 1: Pre-Dose 
 
65 mL 
Day 2: Post Dose 
 
19 mL 
Day 5 Hour -0.5 pre-dose: 59 mL 
Day 5 Hour 2 post dose: 
45 mL 
Day 5 Hour 4 post dose: 
45 mL 
Day 15: 
 
 
79 mL 
Day 31: 
 
 
79 mL 
 
The total volume collected during the study is 406 mL and does not exceed the Red Cross limit of 500 
mL. Safety labs collected during these visits will be monitored, and volume will be decreased at the 
discretion of the PI if needed. The blood volumes in this study were carefully calculated to stay within 
Red Cross Guidelines. This is the approach that is taken in HIV interventional trials, and indeed, the 
PK sampling days can be tricky. Even for observational (non-interventional trials), there are large 
volume protocols with separate Informed Consent, for example, the HIV SCOPE cohort that allows a 
much larger blood draw in a single day for the type of research assays being performed for DISCO. 
Indeed, most of the whole blood is processed and cryopreserved for several years to be applied 
towards future assays that have yet to be discovered at this time. In a recent project, 202 HIV+ 
samples were pulled, that were collected in the 1990s from the SCOPE cohort to be applied to 
advanced host whole genome sequencing assays that we now have available today. 
 
This trial is not only looking at clinical outcomes. The mechanism by which disulfiram acts is not well 
understood but based on Dr. Lieberman's recent data in Nature Immunology- this drug may have 
important implications not just for SARS-CoV-2, but other infectious pathogens that trigger an 
aberrant inflammatory response. If we are going to ask these study participants to take a study drug, 
we would like to understand HOW it is working, which may point to upstream novel drug targets that 
may be even more effective down the line in treating COVID-19. Each research assay requires 
approximately 10 cc of whole blood (Ficolled into PBMCs, peripheral blood mononuclear cells). Some 
assays require 2 aliquots. 
 
Red Cross Guidelines recommend staying with 480 cc over a 56-day period. We have tried to stay 
within that in order to draw the minimum samples needed to study host gene expression, host 
immune cell, PK changes after study drug; this includes changes in genes that are expressed in the 
hours after taking disulfiram. Although we are drawing this amount of blood in a 31-day period of time, 
the rationale for this is that in order to study an ACUTE viral illness, the first month of the host 
response is critical. Drawing blood later after the acute illness has passed makes those latter 
timepoint blood collections less informative. Moreover, even if the patient continues in clinical care, 
you can see from the attached blood volumes chart that the clinical lab draws make up a small 
proportion of the blood draws for these types of translational immunologic studies. 


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Prior to the DISCO trial, we conducted a pilot study titled COVID-19 Host Immune Response 
Pathogenesis study (CHIRP) and the amount of blood drawn during the study in 3 weeks was 486 
mL. There was no adverse event observed during the study. DISCO trial is designed to enroll patients 
with mild cases of COVID infection and further understand the immunogenicity of COVID-19 infection. 


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5.5 
Study procedures by day 
 Screen and Baseline (Day -3 to Day 1) 
1. Informed consent (obtained before performing study related activities) 
2. Questionnaire Evaluation to include the COVID-19 Index Initial General questionnaire, COVID-
19 Index Initial Substance Use, Reproductive Health survey, and Mental Health Supplemental 
Form  
• Demographics: Age, sex, race 
• Medical history: acute and chronic medical conditions that are risk factors for COVID – e.g., 
diabetes, cardiovascular disease, chronic obstructive pulmonary disease. 
• Transmission history: timing of exposure to COVID-19 source patient 
• Medications, allergies 
• Any medical condition arising after consent to be recorded as AE 
• Prior COVID-19 testing history (SARS-CoV-2 RT-PCR or antibody): positive test PCR 
required within 7 days of screening must be documented 
• COVID-19 symptom screen: 5-point ordinal adapted somatic symptom scale (SSS-8)3  
3. Targeted physical exam and vital signs (temperature, heart rate, blood pressure, respiratory rate, 
oxygen saturation by pulse oximetry) 
4. Clinical lab collection (run in real-time) 
a. Screening labs: complete blood count with differential, urea, electrolytes, creatinine, 
calcium, magnesium, phosphate, liver function tests 
b. Clinical labs associated with severe COVID: erythrocyte sedimentation rate (ESR), high 
sensitivity C-reactive protein (hs-CRP), D-dimer, lactate dehydrogenase (LDH), and ferritin. 
c. Clinical labs to confirm COVID+ status: SARS-CoV-2 NP swab PCR assay  
d. Females of childbearing potential: plasma beta-hCG urine pregnancy test 
e. HIV+ participants: a CD4+/CD8+ T cell count and standard plasma HIV RNA assay.  
5. Samples collected for research (run in batch at end of study enrollment) 
a. Saliva for host DNA sequencing and potential future SARS-CoV-2 quantification (RNA levels 
and anti-SARS-CoV-2 IgA) 
6. Randomization of those found to be eligible  
 
 Study Drug/ Placebo Administration (Day 1) 
5.5.2.1 Pre-Dose (Between Hour -0.5 and 0) 
1. Questionnaire Evaluation to include the Index Follow up Questionnaire 
2. Targeted physical exam and vital signs  
3. Clinical lab collection 


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4. Samples collected for research (storage) 
a. Blood: PBMC (CyTOF, single cell sequencing), plasma (plasma SARS-CoV-2 viral load), 
serum (SARS-CoV-2 serology) 
b. Nasopharyngeal swab for SARS-CoV-2 viral load 
c. Saliva for host DNA sequencing and potential future SARS-CoV-2 quantification (RNA 
levels and anti-SARS-CoV-2 IgA) 
5.5.2.2 Dose (Hour 0) 
Study staff to dispense the first dose of disulfiram or placebo to participant in person. The 
subsequent doses will be self-administered at home and the time noted as below. 
 
 Study Drug/ Placebo Administration (Day 2) 
Participant will come to the clinic for clinical laboratory to include complete blood count with 
differential, urea, electrolytes, creatinine, calcium, magnesium, phosphate, liver function tests, 
erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hs-CRP), D-dimer, 
lactate dehydrogenase (LDH), and ferritin, plasma PK testing, and Nasopharyngeal swab for 
SARS-CoV-2 viral load. Saliva for host DNA sequencing and potential future SARS-CoV-2 
quantification (RNA levels and anti-SARS-CoV-2 IgA) will be collected. 
 
The participant will be asked to hold the day 2 study medication until after the blood draw. After 
the blood has been collected, the participant will be asked to take their day 2 dose of study 
medication. The time of pre-dose blood draw and the study medication administration date and 
time will be recorded.  
 
The subject will complete a daily symptom check using the COVID-19 symptom severity 
questions adapted from the Somatic Symptom Scale (SSS-8) (table 3) while at the clinic and 
will be assessed for any adverse events.  
 
 Study Drug/ Placebo Administration (Day 3) 
Participant will self-administer the third dose of disulfiram or placebo at home. The participant 
will note the time of self-administration and will complete a daily symptom diary. Study 
coordinator will call patient to verify their symptoms, confirm self-administered dose, and 
evaluate for any adverse events. If any AEs are reported, an AE form will be completed by the 
study coordinator, and the PI will be notified for any Grade 3 or above AE. 
 
 Study Drug/ Placebo Administration (Day 4) 
Participant will self-administer the fourth dose of disulfiram or placebo at home. The participant 
will note the time of self-administration and will complete a daily symptom diary. Study 
coordinator will call patient to verify their symptoms, confirm self-administered dose, and 
evaluate for any adverse events. If any AEs are reported, an AE form will be completed by the 
study coordinator, and the PI will be notified for any Grade 3 or above AE. 
 


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 Study Drug/ Placebo Administration (Day 5)    
5.5.4.1 Pre-Dose (Hour -0.5 to Hour 0) 
1. Questionnaire Evaluation 
2. Targeted physical exam and vital signs  
3. Clinical lab collection to include; 
complete blood count with differential, urea, electrolytes, creatinine, calcium, magnesium, 
phosphate, liver function tests, erythrocyte sedimentation rate (ESR), high sensitivity C-
reactive protein (hs-CRP), D-dimer, lactate dehydrogenase (LDH), and ferritin. 
4. Samples collected for research (storage) 
a. Blood: PBMC (CyTOF, single cell sequencing), plasma (plasma SARS-CoV-2 viral load), 
serum (SARS-CoV-2 serology) 
b. Nasopharyngeal swab for SARS-CoV-2 viral load 
c. Saliva for host DNA sequencing and potential future SARS-CoV-2 quantification (RNA 
levels and anti-SARS-CoV-2 IgA) 
5.5.4.2 Dose (Hour 0) 
Study staff to dispense the fifth (last) dose of disulfiram or placebo to the participant.  
5.5.4.3 Post-Dose (Hour 2) 
1. Samples collected for research (storage) 
a. Blood: PBMC (CyTOF, single cell sequencing), plasma (PK, plasma SARS-CoV-2 viral 
load), serum (SARS-CoV-2 serology) 
5.5.4.4 Post-Dose (Hour 4) 
1. Samples collected for research (storage) 
a. Blood: PBMC (CyTOF, single cell sequencing), plasma (PK, plasma SARS-CoV-2 viral 
load), serum (SARS-CoV-2 serology)  
 
 Symptom/Adverse Event Telephone Follow-Up (Day 7) 
Participant will self-administer a daily symptom/adverse event diary. Study coordinator will call 
patient to verify their symptoms and evaluate for any adverse events. If any AEs are reported, 
an AE form will be completed by the study coordinator, and the PI will be notified for any Grade 
3 or above AE. 
 
 Symptom/Adverse Event Telephone Follow-Up (Day 9) 
Participant will self-administer a daily symptom/adverse event diary. Study coordinator will call 
patient to verify their symptoms and evaluate for any adverse events. If any AEs are reported, 
an AE form will be completed by the study coordinator, and the PI will be notified for any Grade 
3 or above AE. 
 


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 Symptom/Adverse Event Telephone Follow-Up (Day 11) 
Participant will self-administer a daily symptom/adverse event diary. Study coordinator will call 
patient to verify their symptoms and evaluate for any adverse events. If any AEs are reported, 
an AE form will be completed by the study coordinator, and the PI will be notified for any Grade 
3 or above AE. 
 
 Follow-Up (Day 15)  
1. Questionnaire Evaluation 
2. Targeted physical exam and vital signs  
3. Clinical lab collection 
a. Complete blood count with differential, urea, electrolytes, creatinine, calcium, magnesium, 
phosphate, liver function tests, erythrocyte sedimentation rate (ESR), high sensitivity C-
reactive protein (hs-CRP), D-dimer, lactate dehydrogenase (LDH), and ferritin. 
4. Samples collected for research (storage) 
a. Blood: PBMC (CyTOF, single cell sequencing), plasma (plasma SARS-CoV-2 viral load), 
serum (SARS-CoV-2 serology) 
b. Nasopharyngeal swab for SARS-CoV-2 viral load 
c. Saliva for host DNA sequencing and potential future SARS-CoV-2 quantification (RNA levels 
and anti-SARS-CoV-2 IgA) 
 
 Follow-Up (Day 31)  
5. Questionnaire Evaluation 
6. Targeted physical exam and vital signs  
7. Clinical lab collection 
a. Complete blood count with differential, urea, electrolytes, creatinine, calcium, magnesium, 
phosphate, liver function tests, erythrocyte sedimentation rate (ESR), high sensitivity C-
reactive protein (hs-CRP), D-dimer, lactate dehydrogenase (LDH), and ferritin. 
8. Samples collected for research (storage) 
a. Blood: PBMC (CyTOF, single cell sequencing), plasma (plasma SARS-CoV-2 viral load), 
serum (SARS-CoV-2 serology) 
b. Nasopharyngeal swab for SARS-CoV-2 viral load 
c. Saliva for host DNA sequencing and potential future SARS-CoV-2 quantification (RNA levels 
and anti-SARS-CoV-2 IgA) 
d. HIV+ participants: a CD4+/CD8+ T cell count and standard plasma HIV RNA assay.  
9. Samples collected for research (storage) 
a. Blood: PBMC (CyTOF, single cell sequencing), plasma (plasma SARS-CoV-2 viral load), 
serum (SARS-CoV-2 serology) 
b. Nasopharyngeal swab for SARS-CoV-2 viral load 


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c. Saliva for host DNA sequencing and potential future SARS-CoV-2 quantification (RNA levels 
and anti-SARS-CoV-2 IgA) 
 


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                                    Disulfiram COVID v 2.4 
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5.6 
Table 3. COVID-19 symptom severity questions adapted from the Somatic Symptom Scale (SSS-8). 3 
Symptom 
New 
occurrence 
or 
worsening 
of pre-
existing 
symptom 
during 
illness   
When did it start? 
(MMM/DD/YY) If day 
cannot be estimated 
within 3 days of true 
onset, include month 
and year and mark 
day not known. 
Skip if start 
date known. 
Was it present 
in the first 3 
days of 
illness? 
Are you still 
experiencing it, 
meaning in the 
past 2 days? For 
recovered phase, 
add: By this we 
mean that your 
initial symptoms 
you had when you 
first developed 
COVID-19 have not 
gone away. 
Skip if still 
experiencing the 
symptom. How 
many days did it 
last? This is 
defined as start 
date to last date 
experienced. 
When the symptom was at 
its worst, how much did it 
bother you? Please answer 
on a scale from 1 to 5, 
where 1 is NONE and 5 is 
VERY MUCH. 
Feeling feverish  
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Measured a 
temperature of 
>100.4ºF or 38ºC 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Chills, feeling unusually 
cold 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Fatigue or feeling tired 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Cough 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Shortness of breath or 
difficulty breathing 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Chest pain 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Runny nose or 
congestion  
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 


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Symptom 
New 
occurrence 
or 
worsening 
of pre-
existing 
symptom 
during 
illness   
When did it start? 
(MMM/DD/YY) If day 
cannot be estimated 
within 3 days of true 
onset, include month 
and year and mark 
day not known. 
Skip if start 
date known. 
Was it present 
in the first 3 
days of 
illness? 
Are you still 
experiencing it, 
meaning in the 
past 2 days? For 
recovered phase, 
add: By this we 
mean that your 
initial symptoms 
you had when you 
first developed 
COVID-19 have not 
gone away. 
Skip if still 
experiencing the 
symptom. How 
many days did it 
last? This is 
defined as start 
date to last date 
experienced. 
When the symptom was at 
its worst, how much did it 
bother you? Please answer 
on a scale from 1 to 5, 
where 1 is NONE and 5 is 
VERY MUCH. 
Sore throat  
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Muscle aches 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Loss of appetite 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Nausea 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Vomiting  
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Abdominal pain 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Diarrhea  
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Trouble with smell or 
taste  
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    
DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
 
 


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Symptom 
New 
occurrence 
or 
worsening 
of pre-
existing 
symptom 
during 
illness   
When did it start? 
(MMM/DD/YY) If day 
cannot be estimated 
within 3 days of true 
onset, include month 
and year and mark 
day not known. 
Skip if start 
date known. 
Was it present 
in the first 3 
days of 
illness? 
Are you still 
experiencing it, 
meaning in the 
past 2 days? For 
recovered phase, 
add: By this we 
mean that your 
initial symptoms 
you had when you 
first developed 
COVID-19 have not 
gone away. 
Skip if still 
experiencing 
the symptom. 
How many 
days did it 
last? This is 
defined as start 
date to last date 
experienced. 
When the symptom 
was at its worst, how 
much did it bother 
you? Please answer 
on a scale from 1 to 
5, where 1 is NONE 
and 5 is VERY MUCH. 
New spots or rash on 
your skin 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Trouble concentrating, 
trouble with your 
thinking, or trouble with 
your memory 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Headache 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Trouble with vision (e.g. 
double vision, blurry 
vision, or other visual 
issues) 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Dizziness, feeling like 
you are spinning, or the 
world is spinning 
around you 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Trouble with balance or 
feeling unsteady 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Numbness, tingling, or 
“pins and needles” in 
your arms or legs 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Difficulty falling or 
staying asleep 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 5 
 


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 Day not known 
 
 
Symptom 
New 
occurrence 
or 
worsening 
of pre-
existing 
symptom 
during 
illness   
When did it start? 
(MMM/DD/YY) If day 
cannot be estimated 
within 3 days of true 
onset, include month 
and year and mark 
day not known. 
Skip if start 
date known. 
Was it present 
in the first 3 
days of 
illness? 
Are you still 
experiencing it, 
meaning in the 
past 2 days? For 
recovered phase, 
add: By this we 
mean that your 
initial symptoms 
you had when 
you first 
developed 
COVID-19 have 
not gone away. 
Skip if still 
experiencing the 
symptom. How 
many days did 
it last? This is 
defined as start 
date to last date 
experienced. 
When the symptom 
was at its worst, how 
much did it bother 
you? Please answer 
on a scale from 1 to 
5, where 1 is NONE 
and 5 is VERY MUCH. 
Irritability, agitation, or 
difficulty controlling 
your emotions 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Decreased interest in 
activities or socializing 
with others 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Use the following instruction table to determine what to ask next based on previous responses. 
Reported symptoms in 
Q19?  
Symptoms uncovered in table 
above? 
Question to ask 
Yes 
Yes or No 
Were there other symptoms that you experienced? 
 Yes  Go to 23        No  SKIP to 24 
No 
Yes 
I’m glad we went through this list. Do any other symptoms come to 
mind? 
 Yes  Go to 23        No  SKIP to 24 
No 
No 
 SKIP to 26 
 
1. What other symptoms did you experience? Follow the instructions from question 22 for completing each row of the table. 
Other: Specify 
__________ 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 
Other: Specify 
__________ 
 Yes   
 No 
__ __ __/__ __/__ 
__ 
 Day not known 
 Yes    DK 
 No 
 Yes 
 No 
___ ___ 
 Don’t know 
 1      3 
 2      4 
 
 5 
 
 


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5.7 
Table 4. Adverse Event Log form.  
 


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6 
STATISTICAL PLAN 
6.1 
Sample Size and Power Considerations 
Based on a design with 20 patients per disulfiram treatment group within each dosing cohort (1000 
mg, 2000 mg) and a null hypothesis that there will be a differential change in plasma inflammatory 
cytokine levels (e.g., IL-6) in both groups (disulfiram treatment and placebo compared to baseline, we 
use reported ranges of plasma IL-6 levels in COVID-19 disease119 to estimate sample size and 
power. Based on a mean plasma IL-6 level of 36.7pg/mL (95% CI 21.6-62.3 pg/mL), we estimate that 
the study will have approximately 80% power to detect a 35% difference in plasma IL-6 levels 
between the disulfiram versus placebo groups. These measurements will be assessed at day 5, 15 
and 31 at the 0.05 significance level using a log-likelihood ratio test and non-linear mixed effect 
regression modeling. This estimate is based on the assumptions that plasma IL-6 levels are log 
normally distributed and that the standard deviation of the pre- and post-dose levels is is 12 ng/mL 
(derived from ref: DE Leisman et al. Cytokine elevation in severe and critical COVID-19: a rapid 
systematic review, meta-analysis, and comparison with other inflammatory syndromes). The adjustments 
will be made for pre-treatment plasma inflammatory cytokine (e.g., IL-6) levels. Safety endpoints will 
include the total number of Grade 2 or higher events; the number of Grade 2 or higher events 
possibly, probably or definitely related to study drug; the number of serious adverse events; and the 
number and cause for treatment or study discontinuation.  
 
6.2 
Statistical Analysis 
All main analyses will be conducted on an intention-to-treat basis. Models will assess the relationship 
between the timing of disulfiram treatment initiation relative to symptom onset and study outcomes for 
key efficacy/activity endpoints. The model will be fitted using generalized estimating equations (GEE) 
to handle the repeated measurements, where the comparison between randomized arms will use a 
two-sided Wald test. Levels of plasma inflammatory biomarker levels will be compared between arms 
using non-parametric Wilcoxon rank-sum tests (e.g., separately on days 5 and 15) considering results 
below the assay limit as the lowest rank. For the analysis of the SARS-CoV-2 viral loads, for the 
comparison of the proportion of participants with detectable SARS-CoV-2 RNA, we will use binary 
regression, with adjustment for risk stratum and pre-treatment SARS-CoV-2 RNA level. 
For longitudinal analyses, we will perform both statistical summaries at each time point and 
comprehensive regression modeling. For the regression model, a full non-linear mixed effects 
(NMLE) model will be developed for disulfiram including all 60 participants across the 5 dosing days. 
The pharmacokinetics of disulfiram and the measured metabolites will be described by 
compartmental models parameterized in terms of clearance from the central compartment, apparent 
central and peripheral Vd and intercompartmental clearance. This will be followed by a full covariate 
screening process and then inclusion into the pharmacokinetic model.  This may include covariates 
like drug interactions due to other therapy, weight, sex and other biologically plausible covariates 
collected during the study.  From the final model, we will provide the AUC0-72, Cmin, and Cmax for each 
patient. 
For the primary pharmacodynamics response (plasma inflammatory biomarker levels – e.g., IL-6) the 
PK and PD data will combined and analyzed simultaneously by nonlinear mixed-effects modelling 
(NONMEM version 7.1, Globomax LLC, Hanover, PA). Data will be analyzed using the first-order 
conditional estimation method with interaction, and ADVAN6 will be used to solve the differential 


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equations. Both empiric and mechanistic based pharmacodynamics models will be evaluated to 
describe the concentration effect relationship with the primary pharmacodynamics response.   
Model selection will be based on visual inspection of diagnostic scatter plots, the objective function 
value (OBJ) computed by NONMEM and biological plausibility of parameter estimates.  All final 
models will be evaluated by performing a visual predictive check (VPC). For this, 1000 data sets will 
be simulated from the final parameter estimates using the original data as a template. This approach 
has been successfully applied for the development of animal and human models. From the final 
model, Monte-Carlo simulations will be undertaken to evaluate if different dosing schedules (e.g. 
larger doses less often or a single dose) can optimize the dose-concentration-effect relationship. 
As this is an exploratory study, we will collect all possible trial outcomes, including those for participants 
who discontinue treatment. We will attempt to minimize the amount of missing data as much as possible 
to avoid bias in the interpretability of the findings. However, in the event that missing data is present 
we will follow standardized methods for handling these data. For time dependent covariates, if one 
covariate value of a participant is available, this will be carried forward unless the first value of the 
covariate is missing, then it will be carried backward to occasions with missing values of the respective 
covariate. The population median value at each time point will be used for missing data from a 
continuous variable (e.g. age and weight) for a particular participant. If a covariate, which can be 
classified as a categorical variable (e.g. sex and race), is recorded missing, the observation will be set 
to the mode. If either race or sex is found significant and there is missing data of the covariate in 
question in more than 10% of the population, then a sensitivity analysis will be performed, re-estimating 
the model with and without the covariate only in the participants that have information of the covariate 
in question. If a large proportion of participants (>15%) have a missing covariate this may be imputed 
from other covariates. The imputation will be based on a mixed effect linear regression model 
developed for the highly correlated covariates. Multiple imputation approach will be used to account for 
uncertainty in missing values. If any value is missing at baseline, screening values may be used for 
imputation, if available.  
From the time to treatment initiation to clinical recovery or improvement, all participants will be censored 
at the end of follow-up, not at the time of event (e.g., for mortality). Sensitivity analyses will be performed 
using imputation of missing data to differentiate discontinuation of participants from treatment versus 
study evaluations.  
Duration of fever, duration of symptoms and duration of time to self-reported return to usual health will 
be summarized with descriptive statistics. Participant-specific durations of fever and symptoms will be 
compared between study arms using a two-sided stratified Wilcoxon test with a 5% Type I error rate. 
Total symptom score will be calculated on each day and the participant-specific area under the curve 
(AUC) over time will also be compared using a two-sided stratified Wilcoxon test. Participants who do 
not have complete diary cards due to hospitalization or death will be ranked in these analyses as having 
poorer outcomes than participants who survived without hospitalization. 
 Primary endpoint 
•  Changes in plasma inflammatory biomarker levels2 (e.g., IL-6, IL-1β) at days 5, 15, and 31. 


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 Secondary endpoint(s): 
• Safety and tolerability (frequency of Grade 2 or higher adverse events) at days 2, 3, 4, 5, 7, 9, 
11, 15, and 31. 
  
• Change in SARS-CoV-2 PCR quantitative viral load4 at days 5, 15, and 31. 
• Change in COVID-19 clinical stage (five-point symptom severity scale3) at days 5, 15, and 31. 
• The proportion of detectable versus not detectable levels of SARS-CoV-2 RNA from site-
collected NP swabs at entry, day 5, and day 15 among a subset of participants. 
 Other secondary endpoints 
• SARS-CoV-2 specific T- and B- cell responses5 
• High sensitivity SARS-CoV-2 antibody titer (IgM, IgE, IgA, IgG1, IgG2, IgG3, IgG4) 
• Changes in host gene and protein expression from matched blood and respiratory (NP) 
samples at the single cell level (B, T, natural killer, and myeloid cells).  
• Changes in T- and B-cell receptor (TCR/BCR) repertoire from matched blood and respiratory 
(nasal/oropharyngeal) samples. 
• Pyroptosis (aberrant proinflammatory cell death) assays.6 
 Analysis of AE data 
Analysis of AE data will primarily be descriptive based on MedDRA coding of events. Rates of AE will 
be compared between randomized arms using Fisher’s Exact Test. 
 Analysis of plasma inflammatory biomarkers and SARS-CoV-2 antibody levels  
Analysis of titers will primarily be descriptive, comparing the geometric mean titers at days 0, 1, 5, 15, 
and 31 between the randomized arms. Furthermore, it is of interest to describe the entire distributions 
of plasma inflammatory cytokine levels or anti-SARS-CoV-2 antibody titers by randomized arms and 
contrast these distributions. Therefore, we will use quantile regression in order to describe whether 
there is a shift or change in the titer distribution between randomized arms. Given that repeated 
measures of titers will be obtained, we will account for the correlation in measures within individuals 
using a cluster bootstrap in order to properly estimate the p-value and 95% confidence intervals. Similar 
analysis will also be applied to lymphocyte counts on days 0, 1, 5, 15, and 31, hematological 
measurements (D-dimer, ferritin, LDH, hsCRP) on days 0, 1, 5, 15, and 31, and other lab measures 
showing right-skewed distributions 


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7 
HUMAN 
PARTICIPANTS 
PROTECTIONS 
7.1 
 Risks and Benefits 
Human participants’ involvement and characteristics. COVID-infected adults 18 years of age and older 
who are enrolled in the prospective COVID-19 Host Immune Response Pathogenesis (CHIRP) cohort 
for Aims 1 & 2, and acute COVID-positive individuals 18 years of age and older who completed a Phase 
2a trial of disulfiram (IND 151837, NCT04485130) from the UCSF CHIRP cohort. 
Sources of materials. Research materials include questionnaire and biospecimen data (serum, plasma, 
PBMCs, nasopharyngeal swabs, saliva) stored in the UCSF Core Immunology Lab and UCSF AIDS 
Specimen Bank CHIRP repository will be used to perform new assays as part of the experiments 
described in this proposal. Data will be identified by participants pre-existing de-identified study number.  
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by coded number so that participant confidentiality can be maintained. All records will be kept 
locked. All computer entry and networking programs will be performed with coded numbers only. 
There are no direct benefits to the study participants. However, there are some potential secondary 
benefits. However, the results from this study may eventually benefit other SARS-Cov-2-infected 
individuals in the future. This study may provide data to help identify novel therapeutic strategies for 
treating COVID-19. Participants will be reimbursed to cover costs related to the study (travel, loss of 
time). The knowledge gained from the proposed study has the potential to impact clinical care and 
research efforts with regard to individuals infected with SARS-CoV-2. 
 Potential risks 
Confidentiality: Participation in research may involve loss of privacy.  Participant’s records will be 
handled as confidentially as possible.  All research records will be coded with a four-digit study ID code.  
Only the study investigators and their staff will have access to study records and test results.  Study 
charts will be kept in a locked file cabinet in a locked office.  Electronic data will be protected with a 
password and kept on a secure network on the UCSF Fresno Network server..  All collaborators will 
receive specimens only identified by the four-digit study ID.  No individual identities will be used in any 
reports or publications resulting from this study. 
Disulfiram:  Disulfiram is an irreversible inhibitor of sulfhydryl-containing enzymes resulting in inhibition 
of ALDH and in the accumulation of acetaldehyde after ingestion of ethanol. It is FDA-approved as a 
pharmacotherapy for alcoholism. Side effects reported with disulfiram include drowsiness, peripheral 
neuropathy, hepatotoxicity, seizures, optic neuritis, hypertension, and metallic or garlic-like taste in the 
mouth. Adverse events associated with disulfiram administration are relatively infrequent occurrences 
with the proposed FDA approved doses, but we will mitigate against such events by thorough medical 
history-taking and examination as well as close clinical monitoring during the testing and by the brief 
duration of administration (up to 5 days total). We will repeat liver function tests at the conclusion of the 


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studies. Disulfiram produces an aversive reaction to ethanol due to the rapid accumulation of 
acetaldehyde in the blood.  This reaction is characterized by flushing, diaphoresis, palpitations, nausea, 
vomiting, and sometimes, hypotension. This may last for up to 5 hours and in some cases the reaction 
has been complicated by myocardial infarct, heart failure, and death. Such reactions will be minimized 
through education and close clinical monitoring of participants. Participants will also be instructed to 
abstain from alcohol during disulfiram administration and for two weeks after finishing these studies. 
They will also be instructed to avoid inadvertent alcohol exposure through various alcohol containing 
products.  Participants are given an Emergency Card that lists disulfiram as a current medication and 
provides contact information for study investigators. Participants have access to study investigators 24 
h/d, 7 d/week for any medical issues or questions that may arise. 
Risk of Pregnancy for Women of Childbearing Potential: Women of childbearing potential are not 
excluded from these studies. They must have a plan for avoiding pregnancy while on study protocol 
and this is discussed with each woman during the assessment process. We also test women for 
pregnancy in the medical workup for study entry. A woman would be discharged from the study if the 
test were to be positive and referred to standard prenatal care. The effects of disulfiram on an unborn 
baby are unknown.  All participants will be counseled to use two forms of birth control during the study.  
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. 
 Safety measures 
Recruitment and informed consent: Informed consent for phlebotomy will be obtained as part of the 
consent for enrollment into the disulfiram trial.  This study has been reviewed by Community Medical 
Centers Institutional Review Board. All participants will be informed of the discomforts, risks, and 
benefits of blood sampling 
Monitoring: Participants will be monitored carefully throughout the study.   At each visit, participants will 
be assessed for any new symptoms and vital signs will be obtained by a study coordinator.   
 
Protection against risks: Research records will be confidential to the extent permitted by law. 
Participants will be identified by a code, and personal information from study records will not be 
released without the participant’s permission. Study participants will not be identified in any publication 
about this study. 
 
7.2 
Definitions 
Adverse Event (AE): Any untoward medical occurrence in a clinical investigation participant who has 
received a study intervention and that does not necessarily have to have a causal relationship with the 
study product. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of the study 
product, whether or not considered related to the study product. 
Serious Adverse Event (SAE): Any adverse event that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• Prolongation of existing hospitalization 


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• Persistent or significant disability or incapacity 
• Important medical events that may not result in death, be life threatening, or require intervention 
or escalation of care may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
Unexpected Adverse Event (UAE): An adverse reaction, the nature or severity of which is not 
consistent with the investigator’s brochure. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): An adverse reaction, the nature 
of which is not consistent with the investigator’s brochure with severity as defined by SAE above. 
 
Unanticipated Problem (UP): Unanticipated Problem that is not an Adverse Event (e.g. breaches of 
confidentiality, accidental destruction of study records, or unaccounted-for study drug). 
 
Protocol Deviation: Deviation from the IRB-approved study procedures. Designated serious and non-
serious 
 
Serious Protocol Deviation: Protocol deviation that is also an SAE and/or compromises the safety, 
welfare or rights of participants or others 
 
7.3 
 Safety Reporting Requirements 
 Reporting Interval 
All AEs and SAEs will be documented from the first administration of study product. All AEs and SAEs 
will be followed until resolution even if AEs extend beyond the study-reporting period. Resolution of an 
adverse event is defined as the return to pre-treatment status or stabilization of the condition with the 
expectation that it will remain chronic. At any time after completion of the study, if the investigator 
becomes aware of a SAE that is suspected to be related to study product.  
 Investigator’s Assessment of Adverse Events  
The determination of seriousness, severity, and causality will be made by an on-site investigator who 
is qualified (licensed) to diagnose adverse event information, provide a medical evaluation of adverse 
events, and classify adverse events based upon medical judgment. This includes but is not limited to 
physicians, physician assistants, and nurse practitioners. 
 
Laboratory abnormalities will be reported as AEs if there is a 2 standard deviation increase above 
baseline. 
 
 Assessment of Seriousness 
Event seriousness will be determined according to the protocol definition of an SAE. 


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Event severity will be graded using the DAIDS toxicity table  
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 
 Assessment of Association 
The association assessment categories that will be used for this study are: 
• Associated – The event is temporally related to the administration of the study product and no 
other etiology explains the event. 
• Not Associated – The event is temporally independent of the study product and/or the event 
appears to be explained by another etiology.  
 
The investigator must provide an assessment of association or relationship of AEs to the study product 
based on: 
• 
Temporal relationship of the event to the administration of study product 
• 
Whether an alternative etiology has been identified 
• 
Biological plausibility 
• 
Existing therapy and/or concomitant medications. 
7.4 
 Safety Oversight 
 Monitoring Plan 
All AE and SAE will be reviewed by protocol team weekly, or more often if needed.  
 
We will develop an independent Safety Monitoring Committee (SMC) or Data Safety Monitoring Board 
(DSBM) prior to the initiation of of the study. We expect to recruit independent experts in infectious 
disease medicine, pulmonary medicine, emergency medicine and biostatistics without 
conflicts of interest.. Primary safety endpoints will be developed in collaboration with the study 
sponsor and reviewed with the SMC/DSMB before the study is initiated. The SMC/DSMB will first meet 
after the first 5 participants have completed 16 weeks of observation. The SMC or DSMB will meet 
quarterly during the study and at approximately 2 to 4 weeks after the last person’s follow-up are 
completed. The members of the SMC will be independent of the study team and free of any conflict of 
interest with the investigation and the sponsors.In order to monitor study participants for potential 
adverse events, the study coordinator will perform telephone symptom/adverse event visits on Days 2, 
3, 4, 7, 9, and 11, in addition to the in-person monitoring on Days 5, 15, and 31 (see Table 1 Schedule 
of Events). This is particularly important for Days 6-14 during which there are no scheduled in-person 
study visits after completion of the study treatment. Study staff will call the participant on these days to 
verify their symptoms and evaluate for any adverse events that need to be reported to the study 
investigators.  
7.5 
Study compliance with clinical trial requirements   
Study will be conducted in accordance with GCP and ICH. Specifically, regular QC will be conducted 
to document the following:  


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• There is documentation of the informed consent process and signed informed consent documents 
for each participant 
• There is compliance with recording requirements for data points 
• All SAEs are reported as required 
• Individual participant study records and source documents align 
• Investigators are in compliance with the protocol 
• Regulatory requirements as per Office for Human Research Protections (OHRP), FDA, and  
 
applicable guidelines (ICH-GCP) are being followed.  


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8 
STUDY MODIFICATION 
8.1 
Criteria for Discontinuation of the Study  
Two cohorts of participants (N=30 each) will be sequentially enrolled and receive disulfiram daily for 
five days at doses of 1000mg or 2000mg. The independent Safety Monitoring Committee will review 
the safety and tolerability data after the first cohort has completed dosing and determine whether it is 
safe to proceed with enrolling the final cohort using the below criteria. 
 
In addition, the study enrollment and dosing will be stopped and an ad hoc review by the SMC will be 
performed if any of the specific following events occur or, if in the judgment of the study physician, 
participant safety is at risk of being compromised: 
a. Death within one hour of drug administration 
 
b. Occurrence of a life-threatening allergic/hypersensitivity reaction (anaphylaxis), 
manifested by bronchospasm with or without urticaria or angioedema requiring 
hemodynamic support with pressor medications or mechanical ventilation, TRALI, TACO. 
 
c. One participant with an SAE associated with study product. 
 
d. Two participants with a Grade 3 or higher lab toxicity for the same parameter associated 
with study product. (Grading will be assessed using DAIDS Toxicity Table 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) 
 
e. An overall pattern of symptomatic, clinical, or laboratory events that the SMC considers 
associated with study product and that may appear minor in terms of individual events 
but that collectively may represent a serious potential concern for safety. 
 
f. Any other event(s) which is considered to be a serious adverse event in the good clinical 
judgment of the responsible physician. This will be appropriately documented. 
8.2 
Individual Criteria for Discontinuation 
A participant will be closely monitored if AST or ALT > 3 x ULN, and a participant should be removed 
from disulfiram treatment if AST or ALT > 5 x ULN (DAIDS Grade 3 toxicity). 
A participant whose treatment is terminated should remain in the study for appropriate follow up 
assessments as outlined in section 6.2. 
 


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9 
ETHICS/PROTECTION 
OF 
HUMAN PARTICIPANTS 
9.1 
Ethical Standard 
UCSF is committed to the integrity and quality of the clinical studies it coordinates and implements. 
UCSF will ensure that the legal and ethical obligations associated with the conduct of clinical research 
involving human participants are met. The information provided in this section relates to all UCSF sites 
participating in this research study 
This assurance commits a research facility to conduct all human participants’ research in accordance 
with the ethical principles in The Belmont Report and any other ethical standards recognized by OHRP. 
Finally, per OHRP regulations, the research facility will ensure that the mandatory renewal of this 
assurance occurs at the times specified in the regulations. 
9.2 
Institutional Review Board 
 
At UCSF main campus, this study will be reviewed by Advarra, under an intent to relay agreement via 
the UCSF IRB. At UCSF Fresno, this study will be reviewed by Community Medical Centers Institutional 
Review Board.  
9.3 
Informed Consent Process 
The informed consent process will be initiated before a volunteer agrees to participate in the study and 
should continue throughout the individual’s study participation. The California Subject’s Bill of Rights 
will be provided to the potential participant prior to the informed consent. Informed consent will be 
obtained in accordance with site SOP for COVID consenting and in compliance with current FDA 
guidance for consenting in setting of COVID pandemic https://www.fda.gov/media/136238/download. 
The method of consent includes both in person and telephone/electronic consent. A copy of the signed 
informed consent document will be given to the participant for their records prior to any study related 
procedures being completed. The consent will explain that participants may withdraw consent at any 
time throughout the course of the trial. Extensive explanation and discussion of risks and possible 
benefits of this investigation will be provided to the participants in understandable language. Adequate 
time will be provided to ensure that the participant has time to consider and discuss participation in the 
protocol. The consent will describe in detail the study interventions/products/procedures and 
risks/benefits associated with participation in the study. The rights and welfare of the participants will 
be protected by emphasizing that their access to and the quality of medical care will not be adversely 
affected if they decline to participate in this study. 
9.4 
 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsors and their agents. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. The results of the research study 
may be published, but participants’ names or identifiers will not be revealed. Records will remain 
confidential. To maintain confidentiality, the PI will be responsible for keeping records in a locked area 
and results of tests coded to prevent association with participants’ names. Data entered into 
computerized files will be accessible only by authorized personnel directly involved with the study and 


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will be coded. Participants’ records will be available to the FDA, investigators at the site involved with 
the study, and the IRB. 
9.5 
Future Use of Stored Specimens 
Participants will be asked for consent to use their samples for future testing before the sample is 
obtained. The confidentiality of the participant will be maintained. There will be no plans to re-contact 
them for consent or to inform them of results. The risk of collection of the sample will be the small risk 
of bruising or fainting associated with phlebotomy however these samples will be taken at the same 
time as other protocol required samples. These samples will be used to answer questions that may 
arise while the study is underway or after it is completed. If for instance, there were unanticipated AEs, 
blood samples could be used to run tests that might help determine the reason for the AEs.  
9.6 
Data management and monitoring 
Whole blood for local safety labs will be collected and processed by Community Medical Center 
laboratory. This will include complete blood count with differential, comprehensive metabolic panel, 
western sedimentation rate, C-reactive protein, D-Dimer, Ferritin, and urine pregnancy test.  If subject 
is known to be HIV positive, CD4/CD8 T cell count and HIV RNA standard assay will be completed. 
Local labs will be reviewed by the Investigator to monitor safety. Any abnormal values will be 
assessed for clinical significance by the Investigator. Any clinically significant laboratory results will be 
reported as an adverse event and assessed for causality. 
Research labs that include nasopharyngeal (NP) swab for PCR + IgG, IgM, IgA, cytokine 
quantification; Saliva for host genomics will be collected, labeled with the subject ID, visit number and 
collection date. Saliva and NP swab will be frozen and stored in the -80 freezer located in the UCSF 
Fresno Clinical Research Center until requested by UCSF Core Immunology Lab (CIL). The freezer is 
locked and requires badge access. All blood collected for research only purposes will be sent to 
UCSF CIL laboratory by courier on the same day as collection. 
 
 Source Documents 
The primary source documents for this study will be the participants’ medical records. If the 
investigators maintain separate research records, both the medical record and the research records 
will be considered the source documents for the purposes of auditing the study. The investigator will 
retain a copy of source documents. The investigator will permit monitoring and auditing of these data 
and will allow the IRB and regulatory authorities access to the original source documents. The 
investigator is responsible for ensuring that the data collected are complete, accurate, and recorded in 
a timely manner. Source documentation (the point of initial recording of information) should support the 
data collected and entered into the study database and must be signed and dated by the person 
recording and/or reviewing the data. All data submitted should be reviewed by the site investigator and 
signed as required with written or electronic signature, as appropriate. Data entered into the study 
database will be collected directly from participants during study visits or will be abstracted from 
participants’ medical records. The participants’ medical records must record their participation in the 


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clinical trial and what medications (with doses and frequency) or other medical interventions or 
treatments were administered, as well as any AEs experienced during the trial. 
 Data Management Plan 
Study data will be collected at the study site(s) and entered into the study database. Data entry is to be 
completed on an ongoing basis during the study. 
 Data Capture Methods 
Clinical data will be entered into a 21 CFR 11-compliant Internet Data Entry System (IDES). The data 
system includes password protection and internal quality checks to identify data that appear 
inconsistent, incomplete, or inaccurate. 
 
 Study Record Retention 
The PI is responsible for retaining all essential documents listed in the ICH GCP Guidelines. The FDA 
requires study records to be retained for up to 2 years after marketing approval or disapproval (21 CFR 
312.62), or until at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational agent for a specific indication. These records are also to be maintained in 
compliance with IRB/IEC, state, and federal medical records retention requirements, whichever is 
longest. All stored records are to be kept confidential to the extent provided by federal, state, and local 
law.  
No study document should be destroyed. Should the investigator wish to assign the study records to 
another party and/or move them to another location, the site investigator must provide written 
notification of such intent to sponsor with the name of the person who will accept responsibility for the 
transferred records and/or their new location. The sponsor must be notified in writing and written 
permission must be received by the site prior to destruction or relocation of research records. 
 
 
 
 
 
 
 
 
 


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Huffman JC, Stern TA. Disulfiram Use in an Elderly Man With Alcoholism and Heart Disease: A Discussion. Prim 
Care Companion J Clin Psychiatry 2003; 5(1): 41-4. 
100. 
Brewer C. How effective is the standard dose of disulfiram? A review of the alcohol-disulfiram reaction in 
practice. The British Journal of Psychiatry 1984; 144(2): 200-2. 
101. 
Talbott GD, Gander O. Antabuse, 1973. Md State Med J 1973; 22(7): 60-3. 
102. 
Talbott G, Gander O. Antabuse, 1973. Maryland state medical journal 1973; 22(7): 60. 
103. 
Elliott JH, McMahon JH, Chang CC, et al. Short-term administration of disulfiram for reversal of latent HIV 
infection: a phase 2 dose-escalation study. The lancet HIV 2015; 2(12): e520-e9. 
104. 
Spivak AM, Andrade A, Eisele E, et al. A pilot study assessing the safety and latency-reversing activity of 
disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin Infect Dis 2014; 58(6): 883-90. 
105. 
Madan A, Parkinson A, Faiman MD. Identification of the human and rat P450 enzymes responsible for the 
sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-ME). The terminal step in the bioactivation of disulfiram. 
Drug Metab Dispos 1995; 23(10): 1153-62. 
106. 
Madan A, Parkinson A, Faiman MD. Role of flavin-dependent monooxygenases and cytochrome P450 enzymes in 
the sulfoxidation of S-methyl N, N-diethylthiolcarbamate. Biochemical pharmacology 1993; 46(12): 2291-7. 
107. 
Madan A, Parkinson A, Faiman MD. Identification of the human P‐450 enzymes responsible for the 
sulfoxidation and thiono‐oxidation of diethyldithiocarbamate methyl ester: role of P‐450 enzymes in disulfiram 
bioactivation. Alcoholism: Clinical and Experimental Research 1998; 22(6): 1212-9. 
108. 
Madan A, Faiman MD. Characterization of diethyldithiocarbamate methyl ester sulfine as an intermediate in the 
bioactivation of disulfiram. Journal of Pharmacology and Experimental Therapeutics 1995; 272(2): 775-80. 
109. 
Madan A, Parkinson A, Faiman MD. Identification of the human and rat P450 enzymes responsible for the 
sulfoxidation of S-methyl N, N-diethylthiolcarbamate (DETC-ME). The terminal step in the bioactivation of disulfiram. 
Drug metabolism and disposition 1995; 23(10): 1153-62. 
110. 
Chick J, Gough K, Falkowski W, et al. Disulfiram treatment of alcoholism. The British Journal of Psychiatry 1992; 
161(1): 84-9. 
111. 
Faiman MD, Jensen JC, Lacoursiere RB. Elimination kinetics of disulfiram in alcoholics after single and repeated 
doses. Clinical Pharmacology & Therapeutics 1984; 36(4): 520-6. 
112. 
Peachey J, Sellers E. The disulfiram and calcium carbimide acetaldehyde-mediated ethanol reactions. 
Pharmacology & therapeutics 1981; 15(1): 89-97. 
113. 
Johansson B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta 
Psychiatr Scand Suppl 1992; 369: 15-26. 
114. 
Davidson WJ, Wilson A. Determination of Nanogram Quantities of Disulfiram in Human and Rat Plasma by Gas—
Liquid Chromatography. Journal of Studies on Alcohol 1979; 40(11): 1073-7. 
115. 
Perchetti GA, Nalla AK, Huang ML, et al. Validation of SARS-CoV-2 detection across multiple specimen types. J 
Clin Virol 2020; 128: 104438. 
116. 
Guidance F. Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials 
of Drugs and Biological Products for COVID-19 Prevention or Treatment. 2020. 
https://www.fda.gov/media/142143/download. 
117. 
Group RC. Dexamethasone in Hospitalized Patients with Covid-19—Preliminary Report. New England Journal of 
Medicine 2020. 
118. 
DISULFIRAM Monographs. 2020. https://www.wellrx.com/disulfiram/monographs/   
119. 
Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic 
review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med 2020; 8(12): 1233-44. 
 

ICF_001.pdf: 
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UNIVERSITY OF CALIFORNIA, SAN FRANCISCO-FRESNO 
CALIFORNIA EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
California law requires that any person asked to take part as a subject in research involving a 
medical experiment, or any person asked to consent to such participation on behalf of another, is 
entitled to receive the following list of rights written in a language in which the person is fluent. 
This list includes the right to: 
 
1. Be informed of the nature and purpose of the experiment. 
2. Be given an explanation of the procedure to be followed in the medical experiment and any 
drug or device to be utilized. 
3. Be given a description of any attendant discomforts and risks reasonably to be expected 
from the experiment. 
4. Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable. 
5. Be given a disclosure of any appropriate alternative procedures, drugs, or devices that 
might be advantageous to the subject, and their relative risks and benefits. 
6. Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise. 
7. Be given an opportunity to ask any questions concerning the experiment or the procedures 
involved. 
8. Be instructed that consent to participate in the medical experiment may be withdrawn at 
any time and the subject may discontinue participation in the medical experiment without 
prejudice. 
9. Be given a copy of the signed and dated written consent form. 
10. Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue 
influence on the subject’s decision. 
 
For questions about patient rights, contact the Chairman of the Institutional Review Board at 
Community Medical Centers at (559) 499-6553.   
 
I have carefully read the information contained above and I understand fully my rights as a 
potential subject in a medical experiment involving people as subjects. 
 
______________________________________________________________________________ 
Participant Printed Name: 
 
Participant Signature:  
 
Date:  
Time: 
 
 
______________________________________________________________________________ 
Witness Printed Name: 
 
Witness Signature: 
 
 
Date:  
Time: 
 
 


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UNIVERSITY OF CALIFORNIA, SAN FRANCISCO-FRESNO 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Study Title: DISulfiram for COvid-19 (DISCO) Trial: A Phase 2 Double-Blind, 
Randomized Placebo-Controlled Trial of Disulfiram Compared to Standard Care 
in Patients with Symptomatic COVID-19 
 
Lead Investigator at  
University of California, San 
Francisco 
Dr. Sulggi Lee 
Sulggi.Lee@ucsf.edu 
Local Principal Investigator: 
 
 
Sub Investigator: 
Mohamed Fayed, M.D. mohammed.fayed@ucsf.edu 
559-793-3501 option 1 extension 7304. 
 
 
Almira Opardjia, M.D. almira.opardjia@ucsf.edu 
786-280-8814 
Study Coordinators: 
Rebekah Garcia, CCRP rebekah.garcia2@ucsf.edu 
559-499-6636 
Ashley Gutierrez            ashley.gutierrez@ucsf.edu 
559-499-6678 
 
This is a medical research study. Dr. Mohamed Fayed or a member of the study staff will explain 
this study to you.   
 
Introduction   
We are asking you to take part in a research study being led by Dr. Sulggi Lee at University of 
California, San Francisco (Principal Investigator) and Dr. Mohamed Fayed at UCSF-Fresno 
(Local Principal Investigator) because you have tested positive for COVID-19. The first part of 
this form summarizes the study. We will give more details about the study later in the form. A 
study team member will also explain the study to you and answer your questions.  
 
Research studies only include people who choose to take part. It is your choice whether or not 
you want to participate in this study. Please take your time to make your decision about 
participating and if you would like, discuss your decision with your family, friends and health 
care team.  
 
Why is this study being done? This is a medical research study of the drug disulfiram. The drug 
is also called Antabuse. Disulfiram is a drug that is often used to prevent alcoholics from 
drinking alcohol. People who are taking this drug and who then drink alcohol develop flushing 
(suddenly feeling hot and reddening of the skin), headaches, nausea and vomiting. Disulfiram 
has been approved by the US Food and Drug Administration (FDA) for this purpose. The usual 
dose is between 250 and 500 milligrams once a day.  


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The use of disulfiram in the treatment of patients with COVID-19 is experimental. This study is 
being done to see if disulfiram may have a role in reducing the severity of Coronavirus Disease 
2019 (COVID-19) disease. Patients who become very ill with COVID-19 have been shown to 
have high levels of inflammation, and it is thought that the excess inflammation is what leads to 
worsening disease and death in some patients. Recent data suggests that disulfiram may 
potentially reduce the severity of COVID-19 disease by (1) directly preventing the virus from 
making more copies of itself and (2) reducing the abnormal inflammation that may lead to more 
severe COVID-19 disease. 
 
What will happen if I take part in the study?  
If you choose to be in the study, you will sign this Informed Consent Form, the California 
Experimental Subject’s Bill of Rights, a Use and Disclosure of Your Protected Health 
Information form, and a Release of Information for your medical provider (if you agree) so the 
researchers can review lab results or other relevant information in your medical record during the 
study. If you do not provide consent in person, you will complete a visit over the phone to 
provide consent and complete a questionnaire about your health.  You will be asked to complete 
up to five in-person study visits during the next 31 days.  
 
If you take part in the study, you will receive 5 days of study drug (disulfiram) or placebo (a pill 
that looks like disulfiram but contains no active ingredients); you are twice as likely to receive 
study drug than placebo since we will be randomly assigning 2 people to receive disulfiram for 
each person who is randomly assigned to placebo. Over the course of the study you will 
complete five additional visits over the phone to complete a questionnaire about your health. 
These visits will take place 1-2 days before each study visit that takes place in the clinic. You 
will also be asked to report your COVID-19 symptoms daily while on study treatment. During 
this period, you will be contacted by phone and asked about your symptoms. On in person visits, 
this information will be collected in person. 
 
At each in-person study visit, you will be asked to complete a questionnaire and we will collect 
blood from your vein, collect nasal and throat swabs, and collect saliva. You will be in this study 
for a total of 31 days, or 1 month, with a total of approximately 11hours of participation.  
 
Possible Risks: There are risks to taking part in any research study. The study medication 
disulfiram has limited information regarding its safety profile in patients with COVID-19. In 
addition, higher doses of disulfiram are associated with more frequent adverse events. The doses 
being evaluated in this study are higher than the doses prescribed for alcohol dependence 
disorder (approximately 250 mg to 500 mg daily). If you are randomized to receive disulfiram 
for this study, you will receive a total of 5 days of disulfiram at either 1000 mg or 2000 mg a 
day. These doses were found to be well tolerated without adverse events in a prior clinical trial 
when given for 3 days. You must not drink alcohol while taking part in this study. You will 
also need to be very careful not to eat foods such as wine vinegars, or use products such as 
cough syrups and mouthwashes that contain alcohol.  The study medication disulfiram can 


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cause a reaction to alcohol. This reaction can include flushing (suddenly feeling hot and 
reddening of the skin), nausea, vomiting, low blood pressure, chest pain, headache, and anxiety. 
Rarely people have died from these reactions.  
 
Less likely risks include slight drowsiness or tiredness, a skin rash, or a metallic or garlic-like 
taste in the mouth. More information about possible risks are listed in the main part of this 
consent form. 
 
There are also risks of discomfort from blood draws and from providing specimens, and loss of 
privacy if there is a breach of data security.  
 
Possible Benefits: Although there is a possibility that taking part in this study may reduce the 
severity of your illness, there may be no direct benefits to you from participating in this study. 
 
Your Other Options: You do not have to participate in this study. Your other choices may 
include getting treatment or care for your condition without being in a study or taking part in 
another study. Please talk to your doctor about your choices before agreeing to participate in this 
study. 
  
 
DETAILED STUDY INFORMATION 
This part of the consent form gives a detailed description of the study and what it involves. 
Please review the description carefully and ask any questions to help you decide whether to join 
the study.  
 
Why is this study being done? 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified 
coronavirus that causes an acute respiratory illness known as COVID-19. Early treatment of 
people with COVID-19, while their symptoms are still mild, may help reduce the number of 
people who become very ill from COVID-19. Reducing the number of people with severe 
COVID-19 disease may then help prevent the spread of the disease in the community as well as 
decrease the number of COVID-19 patients in the hospital. 
 
How many people will take part in this study? 
Up to 60 COVID-19 positive adults will be in this study. 
 
You are being asked to take part in this study because: 
1. You tested positive for COVID-19 by nasal or oral swab PCR test. 
2. You are able to attend the five in-person study visits over an approximately 31-day period of 
time. 
 
 


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Where will the study take place? 
The DISCO trial includes:  
1. Either an initial telephone visit or clinic visit to complete a Baseline Survey;  
2. Five in-person study visits for specimen collection;  
3. Daily Phone calls between each in-person visit to ask you about your current COVID-19 
symptoms while you are taking the study medication; and 
4. Five days of taking study drug (disulfiram or placebo). 
 
The in-person study visits will take place at East Medical Plaza Pulmonary Clinic located at 2335 
East Kashian Lane, Suite 260, Fresno CA  93701.  As the severity of the pandemic changes, and 
restrictions regarding COVID-19 change, you may be asked to come to the clinic at University of 
California, San Francisco-Fresno located at 155 N. Fresno Street Fresno CA  93701, if your illness 
is considered to be non-active (per the Centers for Disease Control guidelines), you have been 
cleared to return to work, and are no longer experiencing any symptoms. 
 
Who is paying for this study? 
This study is paid for by Dr. Sulggi Lee, UCSF, and Division of Acquired 
Immunodeficiency Syndrome (DAIDS). Dr. Fayed and the study coordinators are 
being paid by the sponsor for their work involved in the study procedures and the 
collection of study data. There is no financial conflict of interest concerning the 
Investigators or study staff at UCSF-Fresno. 
 
What will happen if I am in the study? 
If you decide you want to participate in this study and sign the Informed Consent Form and Use 
and Disclosure of Your Protected Health Information form, and a Release of Information for your 
medical provider (if you approve, and if applicable), the following things will happen:   
 
Screening/Baseline Visit: 
• You will first be asked to sign the informed consent. This may take place in 
the clinic, at the hospital if you were hospitalized, or over the phone using an 
electronic version of the consent form that you will sign electronically. After 
consent has been signed, you will be asked about any household members 
who have also been diagnosed with COVID-19, who may be interested in 
participating in the study. Family members who are interested will be invited 
to contact the study staff to discuss study participation.  
• 
If you are consented electronically, a questionnaire about your health will be 
completed. You will be asked about your COVID-19 symptoms and 
exposures, any hospitalizations you have had due to COVID-19, how you 
feel emotionally, and about your use of tobacco, alcohol, and any drug use. If 
you are female, we will ask some questions about your reproductive health 
history. This telephone call will take up to 30 minutes. If you are consented 
in person, this questionnaire will be completed at the clinic.   


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At the first in-person baseline visit:  This visit will take approximately one hour. 
• If you did not first complete a visit over the phone, you will complete a baseline questionnaire 
to ask about your health, COVID-19 symptoms and exposures, hospitalizations, how you feel 
emotionally, and about your use of tobacco, alcohol, and other drugs. If you are female, we 
will ask you some questions about your reproductive health history.  
• A study doctor will conduct a physical examination that is similar to those done for regular 
medical care. 
• A study staff member will take your vital signs, including your blood pressure, pulse rate, 
temperature, respirations and oxygen saturation.  
• A trained phlebotomist will draw approximately 68mL (about 1/3 of a cup) of blood by 
inserting a needle into a vein in your arm.  
• We will collect a saliva (spit) sample (if you are able to provide one) to test for proteins that 
may be responding to COVID-19.   
• If you are a female of child-bearing potential, you will be asked to provide a urine sample. 
Because being pregnant while you have COVID-19 could put you at higher risk of severe 
disease, some of your urine will be tested to see if you are pregnant. You will not be able to 
participate in this study if you are currently pregnant. The reason for this is because the 
amount of blood required for the research study exceeds the amount of blood that is 
considered safe for pregnant women. 
• The study doctor can share the clinical lab results that may be important for your medical 
care with you, and/or your medical provider, if you give permission. Information about your 
primary care physician will be collected at the end of this form. However, some of the tests 
are exploratory or experimental, so the relevance and accuracy of the results are not known. 
You can indicate at the end of this consent form if you want to have this done.   
 
Day 1, Day 15, and Day 31 visits: These visits will take approximately 1 hour each. 
At these visits, the following will take place: 
• You will complete a brief questionnaire about your current health. 
• A study doctor will conduct a physical examination similar to those done for regular medical 
care. 
• At your Day 1 visit, you will receive your first dose of study treatment (either disulfiram or 
placebo). If you are one of the first 30 people enrolled, you will get 1000 mg a day of 
disulfiram for 5 days or placebo for 5 days. If you are one of the second 30 people enrolled, 
you will get 2000 mg a day of disulfiram for 5 days or placebo for 5 days. 
• We will collect some fluid from your nose using cotton swabs to test for the COVID-19 virus 
and to study your respiratory tract immune cells.     
• A trained phlebotomist will draw approximately 65mL (about 1/3 of a cup) of blood by 
inserting a needle into a vein in your arm.  
• We will collect saliva (spit) samples (if you are able to provide them) to test for proteins that 
may be responding to COVID-19).   
• If you are female, because being pregnant while you have COVID-19 could put you at higher 


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risk of severe disease, some of your urine will be tested to see if you are pregnant. If you are 
currently pregnant, you will not be able to participate in this study. If you become pregnant 
during the course of the study, you will no longer be able to take part and no further research 
related procedures will be conducted.  
 
Day 2: 
Day 2 visit will take approximately 90 minutes. 
At this visit, the following will take place: 
• You will be asked not to take your study medication, and bring it with you to the study 
visit.  
• You will be asked not to have anything to eat for at least 2 hours prior to the visit. 
• You will complete a brief questionnaire about your current health. 
• A study staff member will take your vital signs, including your blood pressure, pulse 
rate, temperature, respirations and oxygen saturation. 
• You will be asked to take your study medication at the study visit.  
• A trained phlebotomist will draw approximately 19 mL(about 4 teaspoons) of blood by 
inserting a needle into a vein in your arm. About 14 mL of the blood will be used to 
assess your current physical condition, and the rest will be stored for research.  
• We will collect some fluid from your nose using cotton swabs to test for the COVID-19 
virus and to study your respiratory tract immune cells.     
• We will collect saliva (spit) samples (if you are able to provide them) to test for proteins 
that may be responding to COVID-19).   
 
 
 
 
Day 5 visit: This visit will take approximately 6 hours. 
At this visit, the following will take place: 
• You will complete a brief questionnaire about your current health. 
• A study doctor will conduct a physical examination similar to those done for regular medical 
care. 
• At this Day 5 visit, you will receive your last dose of study treatment (either disulfiram or 
placebo).  
• At this Day 5 visit, in addition to collecting blood at the beginning of the visit, we will also 
collect blood at 2 hours and 6 hours after your dose of study treatment. This is to measure the 
amount of the study treatment in your blood for us to determine how much of the study 
treatment is in your body. The total amount of blood that will be collected, by inserting a 
needle into your vein during this visit is 149 mL (2/3 cup of blood).  
• We will collect some fluid from your nose and throat using cotton swabs to test for the 
COVID-19 virus and to study your respiratory tract immune cells.     
• We will collect saliva (spit) to test for proteins that may be responding to COVID-19. 


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Telephone Visits: These visits will take approximately 30 minutes each. 
 
You will be contacted by phone on days 3 and 4 while you are taking the study medication to 
complete a brief questionnaire about how you are feeling. After you complete your study 
treatment, you will be contacted to complete this questionnaire on Day 7, Day 9 and Day 11.  
 
Participation in Future COVID-19-related research studies: 
 
Additional studies may be conducted in relation to the DISCO study as researchers continue to 
learn about COVID-19. You will be asked for permission to contact you for future participation 
in DISCO-related research studies. This is voluntary and your decision will have no effect on 
your participation in this study. You will be asked for your consent in another area of this 
consent form. 
 
How will my specimens and information be used?  
Researchers will use your specimens and information to conduct this study. When the study is 
done using your specimens and information, we may share them with other researchers to use 
them for other studies in the future. We will not share your name or any other personal 
information that would let the researchers know who you are. We will not ask your permission to 
share this de-identified information.  
Storage of de-identified blood and other specimens for future research studies  
As part of this study, some of the blood and other samples that we collect from you will be stored 
at a UCSF specimen bank, at UCSF specialty labs, and with our research collaborators for future 
studies to learn about COVID-19. We may also collect and save information from your medical 
record such as diagnostic test results, medical questionnaires, diagnoses, treatments, and genetic 
test results. We do not know if your stored specimens or information will be used for future 
research. Only Dr. Fayed and his collaborators, including Dr. Lee from University of California, 
San Francisco, will have access to your specimens at this time. In the future, it is possible that 
external researchers from Harvard University, Cold Springs Harbor Lab, and Emory University 
may collaborate with University of California, San Francisco and may have access to your de-
identified specimens. 
 
All stored specimens will be coded with a unique ID number and will not include your name. We 
may label the specimens with a testing date, your age or your sex at birth, but we will not give 
them your name, address, phone number, date of birth or any other information that would 
identify you. Your identifiable personal health information cannot be used for additional research 
without additional approval from either you or a review committee.  
 
Your specimens will be stored until they are used up or destroyed. Results from future research 
will not be given to you or your doctor. The research will not change the care you receive. Your 
stored specimens may be used to develop new discoveries, drugs, tests, treatments, or products. 


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In some instances, these may have potential commercial value. If this happens, you will not 
receive any payment or financial benefit from any products, tests, or discoveries. If you decide 
later that you do not want your specimens or information to be used for future research, you can 
notify Dr. Mohamed Fayed in writing at mohamed.fayed@ ucsf.edu or UCSF Fresno 155 N. 
Fresno Street, Suite 319 Fresno CA  93704, or by phone 559-793-3501 option 1 extension 7304), 
and any remaining identifiable specimens will be destroyed. We will not be able to eliminate 
data already collected.   
 
Genetic Testing: Researchers would like to use some of your specimens (for example, blood, 
etc.) to look at your RNA (the genetic information that comes from your DNA) and may look at 
your DNA in later studies. This is called “RNA sequencing” or “DNA sequencing.” DNA 
contain information that determines things like eye color, height, or disease risk that are passed 
on from parent to child. RNA can tell us which parts of the DNA are “active” and what cellular 
functions might be active in your body. You will be asked at the end of this consent form to 
indicate your willingness to participate in the genetic testing. 
 
How will my genetic information be shared? 
Genetic information (also known as genotype data) and the medical record data (also known as 
phenotype data) may be shared broadly in a coded form for future genetic research or analysis. 
Genetic information that results from this study does not have medical or treatment importance at 
this time.  However, there is a risk that information about taking part in a genetic study may 
influence insurance companies and/or employers regarding your health.  
 
Taking part in a genetic study may also have a negative impact or unintended consequences on 
family or other relationships.  It is possible that future research could one day help people of the 
same race, ethnicity, or sex as you. However, it is also possible through these kinds of studies 
that genetic traits might come to be associated with your group.  In some cases, this could 
reinforce harmful stereotypes. There will be no direct benefit to you from allowing your data to 
be kept and used for future research. However, we hope we will learn something that will 
contribute to the advancement of science and understanding of health and disease.  
 
We may give certain medical information about you (e.g. diagnosis, blood pressure, age) to other 
scientists or companies not at UCSF, including to a public government health research database, 
but we will not give them your name, address, phone number, or any other identifiable 
information. Research results from these studies will not be returned to you, as they are 
exploratory in nature.  
 
If the data or any new products, tests or discoveries that result from this research have potential 
commercial value, you will not share in any financial benefits.  If you decide later that you do 
not want your information used for future genetic research, you can notify Dr. Mohamed Fayed 
in writing at mohamed.fayed@ucsf.edu or UCSF Fresno 155 N. Fresno Street, Suite 319 Fresno 
CA  93704, or by phone 559-793-3501 option 1 extension 7304) and any remaining samples will 


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be destroyed, and no further data will be collected. However, we cannot retract any data has been 
shared with other researchers.  
 
What side effects or risks can I expect from being in the study? 
Side effects associated with taking disulfiram: Disulfiram (Antabuse) usually produces no 
effect in a person who does not have any alcohol in their bloodstream.  
 
It is not known what the risk is of taking disulfiram in the COVID-19 population. In patients 
without COVID-19, the following potential risks have been associated with disulfiram: 
 
Likely (Greater than 20%) 
 
Serious and more common effects (greater than 20%)(especially if you drink alcohol):  
• You must not drink alcohol during this study and for 2 weeks afterward because 
disulfiram can cause a reaction to alcohol. This reaction can include: 
• flushing (suddenly feeling hot and reddening of the skin) 
• nausea  
• vomiting,  
• low blood pressure,  
• chest pain, 
• headache,  
• anxiety.  
 
Rarely people have died from these reactions.  
 
This will not occur if you do not take alcohol or use alcohol-containing products (such as wine 
vinegars, salad dressing, mouthwash and cough syrup) while in this study and for at least 2 
weeks afterward.  
 
You should read labels and check ingredients of foods you eat and products you use to make sure 
that they do not contain alcohol while you take this medicine. We will provide you a list of 
commonly used medications to avoid, particularly over-the-counter medications (e.g., used for 
cough symptoms), that may interact with disulfiram and potentially cause adverse side effects. If 
you are in doubt about a product, call the study doctor who can advise you as to whether it is safe 
to use a product. 
 
Less Likely side effects (less than 20%):  
• Slight drowsiness or tiredness 
• Skin rash,  
• Metallic or garlic-like taste in the mouth can occur.  
 
Other side effects have rarely been reported by people taking this medicine and they include:  


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• Pain and tingling in arms/hands and/or legs/feet (also called peripheral neuropathy), 
• Inflammation of the liver  
• Liver failure  
• Seizures  
• Vision problems due to inflammation in the eye nerve (also called optic neuritis) 
• High blood pressure.  
• The use of disulfiram while also using some tricyclic antidepressant medications, 
tuberculosis (TB) medication (isoniazid), or medications associated with acid reflux 
(Prilosec, Nexium and Protonix) could have unexpected side effects including drowsiness 
and confusion. We will closely monitor your health while you are taking part in this 
study. 
 
Because the doses given in this study are higher than typically used or FDA approved, it is 
possible there will more side effects than expected or unusual side effects.  
 
Rare but serious side effects:  
• Although very rare, death from liver failure has been reported in retrospective 
population studies (1 in 32,000) for those who were on treatment for many weeks to 
months.  
• In HIV-infected patients also taking another drug called vorinostat, with disulfiram 2000 
mg for 28 days, led to some neurologic symptoms (paranoia, difficulty walking, lack of 
energy). These symptoms were reversed after stopping the drug, and levels of disulfiram 
drug in patients did not correlate with the symptoms. 
 
We will be monitoring your response to these drugs very closely. In the event of a serious 
adverse event, we will provide you appropriate medical care immediately. Many side effects go 
away shortly after the drugs are stopped, but in some cases, side effects may be serious, long 
lasting, life threatening or result in death. 
 
Reproductive risks  
• The effects of disulfiram on an unborn baby are unknown. Women of childbearing 
potential are not excluded from these studies. Women will be tested for pregnancy in the 
medical workup for study entry and excluded from participation if pregnant. Women of 
childbearing potential must have a negative serum pregnancy test at screening and agree 
to use a double-barrier method of contraception throughout the study period. Women 
will be counseled not to breast-feed during this study. Both male and female participants 
will be asked to use two forms of birth control during the study. 
• The use of the below mentioned birth control methods does not apply if the male partner 
has had a vasectomy at least two months prior to screening or if the female sexual 
partner has had a bilateral oophorectomy (surgical removal of both ovaries), a total 
hysterectomy (removal of the womb), a tubal ligation (commonly known as having 
tubes tied), other permanent birth control methods, or if she is post-menopausal (not 


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having monthly periods for at least 2 years). 
• If you are a woman who is able to have children, you should not become pregnant or 
nurse your child during the study. You must agree to use 2 effective methods of 
contraception during the study, such as a barrier method that prevents transmission of 
fluids and a hormonal contraceptive like the pill, patch, or vaginal ring. Barrier 
contraception includes male condoms OR female condoms (not to be used both 
simultaneously as friction between the two can result in damage or breakage of either 
product) diaphragm with spermicidal jelly, or cervical cap with spermicidal jelly. 
• If you are a man who has a female partner of child-bearing potential you must agree to 
use 2 effective methods of contraception. You and your female partner should use a 
male condom in combination with another effective method such as hormonal 
contraceptives (like the pill, patch or vaginal ring), intrauterine device, or diaphragm 
with spermicidal jelly or cervical cap with spermicidal jelly. 
• You must agree to inform your sexual partner that you are participating in a research 
study which requires you and your partner to use 2 methods of contraception. 
 
Blood Draw: Blood draws can cause some discomfort, bleeding or bruising where the needle 
enters the skin, and rarely, fainting or infection can occur. A total of 406 mL (about 1 3/4 cups) 
of blood will be drawn during the 31-day study period, which is within Red Cross Guidelines  
(which advise less than 500 mL every two months). Another risk of blood collection is anemia 
(low blood count). We will test you for anemia at each study visit. If investigators think you are 
at high risk for anemia, the amount of blood drawn at the next visits will be reduced. If you are 
currently anemic, the study doctor may exclude you from taking part in the study at his 
discretion. 
 
Nasal/Throat Swab: The nasal and throat swabs may be uncomfortable or cause slight bleeding. 
 
Pregnancy Testing (for females): You may worry about the results of a pregnancy test. We will 
give you the results as soon as possible and recommend you follow-up with your medical 
providers. 
 
Confidentiality: Participation in research can involve a loss of privacy. We will handle your 
records as confidentially as possible. All study questionnaires and samples are coded with a 
study ID, and no personal identifiers such as your name or date of birth are used for any 
specimens. Dr. Fayed and the research staff as well as the study staff at University of California 
San Francisco, who are also working on this project will have access to your study records and 
test results. No individual identities will be used in any reports or publications that may result 
from this study.  
 
Risk of genetic testing: Genetic information that results from this study does not have medical or 
treatment importance at this time. However, there is a risk that information about taking part in a 
genetic study may influence insurance companies and/or employers regarding your health. To 


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further safeguard your privacy, genetic information in this study will not be placed in your 
medical record. Although we will do our best to protect your genetic information, we cannot 
guarantee complete protection from potential computer security breaches that are relevant to 
maintaining data in an electronic format. 
 
Effect on participating in other studies: Every research study has different requirements for 
participation, which are known as eligibility criteria. If a participant agrees to take part in this 
study, the procedures required for this study may make him/her not eligible to participate in other 
studies for a period of time. How long that period of time is may be determined by the other 
study. 
 
Risks of randomization: You will be assigned to a treatment program by chance, and the 
treatment you receive may prove to be less effective or to have more side effects than the other 
study treatment(s) or other available treatments. 
 
Risks of placebo: If you are in the group that receives placebo, your condition will go without the 
active (study) treatment for 5 days. 
 
Unknown Risks: Any research study may result in side effects that we do not yet know about. 
The researchers will let you know if they learn anything that could change your mind about 
participation.  
 
Are there benefits to taking part in the study? 
While there is a chance that taking part in this study may reduce the severity of your illness, it 
may not provide you with any direct benefit. It may also help us understand how individuals 
experience and recover from COVID-19, to guide future diagnosis, prevention, and treatment of 
COVID-19.  
 
How long will I be in the study? 
Each of the five in-person research visits will last approximately one hour, with the exception of 
the Day 5 visit, which will take approximately six hours.  
 
Each of the five phone calls to complete Questionnaires will take anywhere from 10-30 minutes.   
 
At the Day 5 visit, which is the last day of your study treatment (disulfiram or placebo), you will 
be monitored for 6 hours and your blood will be drawn at the beginning of the visit, and after 2 
and 6 hours from taking your last dose of study treatment.  
 
Your total time in the study visits will be approximately 11 hours, and your overall time in the 
study is for 31 days, or 1 month.   
 
What does it cost to take part in this study? 


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There is no cost to you to take part in this research study.  All study required lab tests and 
procedures that are not being ordered as part of your regular standard of care will be paid for by 
the study sponsor. Neither you nor your insurance company are responsible for any research-
related costs. 
You will not be charged for the following research-related tests and procedures: 
 
• Saliva Collection and testing 
• Research-related blood collection and testing 
• Research-related physical exam 
• Completion of Questionnaires and Surveys 
• Research-related COVID-19 testing by throat or nose swabs 
• Research-related urine pregnancy testing 
• Study medication or placebo 
 
There may be times that your study visit will coincide with a regularly scheduled standard of care 
visit, and in this case, study related procedures will be charged to the study and standard of care 
procedures such as lab work or other tests that are not part of the study will be billed to you or to 
your insurance. You will be responsible for co-pays, deductibles, and any other charges that your 
insurer will not pay. Before you take part in this study, you should call your health insurer to find 
out if the cost of these tests and/or procedures will be paid for by the plan.  Some health insurers 
will not pay for these costs.  You will have to pay for any costs not covered by your health 
insurer.  Because there may be some costs which are not covered by the study sponsor or your 
health insurance, the study team can help you to determine if there are costs which may be billed 
directly to you. 
 
Will I be paid for taking part in this study? 
Yes. You will be paid $50.00 in cash for each regular single blood draw in-person study visit in 
return for your time and travel. There will be one pharmacokinetic (PK) day when we measure 
study treatment levels in your blood three times over a 6-hour period of time; you will paid 
$150.00 for this longer in-person study visit. This is a total of up to $400.00 for completion of all 
five visits that include the baseline visit, three regular in-person follow up visits, and one longer 
6-hour in-person visit. You will not be paid for the telephone follow-up calls. You will receive 
your payment at the end of each visit.  
 
What other choices do I have if I do not take part in this study? 
The alternative to this study is not to participate and to receive your regular standard of care or 
enroll into another research study for COVID-19 if available to you. Please talk to your doctor 
about your choices before agreeing to participate in this study. 
 
Can I stop being in the study? 
Your participation in the study is completely voluntary and you can withdraw at any time by 
telling any study team member. Withdrawing will not affect your ability to receive care at the 


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COVID-19 clinic or at any other care center. 
 
Additionally, the study team may end your participation at any time without your permission. 
This could be for your health or safety, because you have not followed instructions, or if for 
some reason your samples are no longer needed. If you leave the study before the last visit, you 
may be asked to attend a final visit for some of the end of study procedures. 
 
Will my medical information be kept private? 
We will do our best to make sure that personal information about you is kept private but cannot 
guarantee total privacy. In this study you will be asked about drug use and other possibly illegal 
activities. The researchers will keep information about you as confidential as possible, but 
complete confidentiality cannot be guaranteed. On rare occasions, research records have been 
subpoenaed by a court. The results of this study may be published in a medical book or journal or 
used for teaching purposes. However, your name or other identifiers will not be used in any 
publication or teaching materials without your specific permission.  
 
A research record is created when you participate in a clinical trial at UCSF Fresno. Some 
information from your medical records will be collected and used for this study. If you do not 
already have a medical record, one will be created for you because of your participation in this 
study. Your signed consent form and some of your research test results will be included in this 
record. Therefore, people involved with your future care and insurance may become aware of 
your participation and of any information added to your medical record as a result of your 
participation.  
 
Your personal information may be given out if required by law. For example, by California law, 
we are required to report 
• New cases of HIV, tuberculosis, hepatitis B, and hepatitis C infection to the county 
public health department.  
• New cases of COVID-19 disease are reportable to the county public health department. 
Newly diagnosed COVID-19 cases using the research (i.e., not yet validated) assays used in this 
study may not be shared with you since these assays are not yet approved for clinical use. Only 
COVID-9 testing results from clinical (CLIA-approved) assays – such as those tests performed as 
part of your regular clinical care outside of research are reportable to the county public health 
department. The reports include the patient’s name, social security number, and other identifying 
information. Additionally, identifiers might be removed from the identifiable private information 
or identifiable biospecimens and after such removal, the information or biospecimens could be 
used for future research studies or distributed to another investigator for future research studies 
without additional informed consent from the subject or the legally authorized representative. 
 
Information about these new infections is used to track diseases statewide and nationwide. Other 
than this required reporting, your results will be treated confidentially by the study staff. No 
personally identifying information will be shared to other departments or agencies. If information 


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from this study is published or presented at scientific meetings, your name and other personal 
information will not be used. Organizations that may look at and/or copy your medical records for 
research, quality assurance, and data analysis include:  
 
• The University of California 
• Community Medical Centers 
• Community Medical Centers Institutional Review board, involved in keeping research 
safe for people 
• UCSF Institutional Review Board involved in keeping research safe for people 
• The U.S. Food and Drug Administration (FDA) 
• The Office for Human Research Protections (OHRP) 
• Department of Health and Human Services (DHHS), and other government agencies 
involved in keeping research safe for people 
• Safety Monitoring Committee 
 
Research results: There may be times when researchers using your information and/or 
specimens may learn new information. The researchers may or may not share these results with 
you, depending on a number of factors. We can discuss those factors with you if you have 
questions. Your specimens may be used for commercial use. If this happens, you will not share 
in any profits. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell the study doctor, Dr. Mohamed Fayed, if you feel you are injured 
because of taking part in this study. You can tell the doctor in person or at (559)793-3501 
option 1 extension 7304. 
 
Treatment and Compensation for Injury: If you are injured as a result of being in this study, 
the University of California will provide necessary medical treatment. The costs of treatment may 
be billed to you or your insurer just like any other medical costs, or covered by the University of 
California, depending on a number of factors. Due to the coronavirus public health crisis, the 
federal government issued a Declaration under the public Readiness and Emergency Preparedness 
(PREP) Act. If the Declaration applies, it limits your right to sue and recover for losses from the 
researchers, healthcare providers, and study sponsor or manufacturer or distributor involved with 
the study, including the University of California, while participating in this COVID-19 clinical 
study. However, the federal government has a program that may provide compensation to you or 
your family for certain claims if you experience serious physical injuries or death and these costs 
are not covered by other payors. To find out more about this “Countermeasures Injury 
Compensation Program” go to https:///www.hrsa.gov/cicp/about/index.html or call 1-855-266-
2427. 
 
ClinicalTrials.gov is a website that provides information about clinical trials. A description of 
this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 


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This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part, you may leave the study at any time. Whatever 
decision you make, there will be no penalty and you will not lose any of your regular benefits. 
Leaving the study will not affect your medical care, which you can still receive from our 
institution. We will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. In the case of injury resulting from this 
study, you do not lose any of your legal rights to seek payment by signing this form. 
 
Who can answer my questions about the study? 
In the future, you may have questions about your study participation. You may have 
questions about your health, your test results, or about a research-related injury. If you have 
questions please contact Dr. Fayed at 559-793-3501 option 1 extension 7304. 
or email: mohamed.fayed@ucsf.edu  
 
For questions about your rights in this study, you can call the office of the Community 
Medical Centers Institutional Review Board (a group who reviews research to protect your 
rights) at (559) 499-6553. 
 
 
 
INFORMED CONSENT 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline 
participation and can withdraw at any point without penalty or loss of benefits to which you 
are otherwise entitled. You will receive a copy of this Consent Form and an Experimental 
Subject's Bill of Rights. You will be asked to sign a separate form to authorize access, use, 
creation, or disclosure of health information.  
 
By signing below, I affirm I have read this consent form, had a chance to ask questions, and have 
received satisfactory answers. I have been informed about the procedures, risks, and benefits and 
wish to participate.  
 
 Consent to Share Laboratory Results:  
____ (initials) YES, I want to receive laboratory results that might be important to my care.  
____ (initials) NO, I do not want to receive laboratory results that might be important to my care.  
 
____(initials) YES, I would like my primary care doctor to be informed of and receive laboratory 
results that might be important to my care. 
 


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________________________________________________________ 
Name and phone number of Primary Care Doctor 
 
_____(initials) NO, I would NOT like my primary care doctor to be informed of and receive 
laboratory results that might be important to my care. 
 
 
Consent for Genetic Testing: 
_____ (initials) YES, I agree to have genetic testing conducted on the samples collected for this              
study.         
_____ (initials) NO, I do not agree to genetic testing conducted on the samples collected for this 
study.         
 
 
Consent for Nasopharyngeal (NP) and Oropharyngal (OP) Swab Collection:  
_____ (initials) YES, I agree to have NP/OP swabs collected for this study. 
_____ (initials) NO, I do not agree to have NP/OP swabs collected for this study.  
 
 
Consent for Saliva Collection: 
_____ (initials) YES, I agree to have saliva collected for this study.  
_____ (initials) NO, I do not agree to have saliva collected for this study. 
 
 
 
Full Participant Name (Print) 
 
 
 
 
Participant Signature 
Date/Time 
 
_____________________________________ 
Medical Record Number 
 
 
 
Person Obtaining Consent Name (Print) 
 
 
 
 
Person Obtaining Consent Signature 
Date/Time 
 
 
 
Investigator Name (Print) 
 
 
 
 
Investigator Signature 
Date/Time 
 


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For remote/telephone/videoconference consent process: 
 
__________________________    __________________________     ___________ 
Print Name of Witness                     Signature of Witness                       Date/Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMC's Interpreter Statement: 
 
In the event that an interpreter is needed: 
 
I have accurately and completely read the foregoing document to: 
_______________________________________________________________ 
     (patient or legal representative's name) 
in ___________________________ the patient's (or legal representatives) primary language. 
     (identify language used) 
 
He/She understands all terminology/conditions, acknowledges his/her agreement by signing the 
document in my presence. 
______________________________      ____________________________ 
Signature of Interpreter                              Date/Time 
 
______________________________ 
Printed name of Interpreter 
 
 
_____________________________________________________________________________ 
 
 
 
 


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AUTHORIZATION FOR USE OF PROTECTED HEALTH INFORMATION FOR 
RESEARCH PURPOSES 
USE AND DISCLOSURE OF YOUR PROTECTED HEALTH INFORMATION 
 
Protected Health Information is any personal health information through which you can be 
identified. A decision to participate in this research means that you agree to the use of your 
health information for the purposes explained in this consent form. By signing this form, you are 
authorizing the use and disclosure of your health information collected in connection with your 
participation in this research study. Your information will only be used in accordance with the 
provisions of this consent form and applicable law. 
 
Your health information related to this study, including, demographics such as age, race, and sex, 
your health history, including chronic illnesses, illnesses related to COVID-19, information from 
hospital records if you were admitted to the hospital for COVID-19 including diagnosis, 
treatments, laboratory tests, imaging, medications, length-of-stay, physical examinations, and 
histories may be used or disclosed in connection with this research study. Study records that 
identify you will be kept confidential as required by law. Except when required by law, you will 
not be identified by name, SS#, date of birth, address, phone#, or any 
other direct personal identifier in study records disclosed outside of the Community Medical 
Centers (CMC). For records disclosed outside of CMC, you will be assigned a unique code 
number. The key to the code will be kept in a locked file in the office of the Principal 
Investigator, Dr. Mohamed Fayed. 
 
Representatives of the following groups are authorized to use and/or disclose your health 
information in connection with this research study: 
The Principal Investigator, Dr. Mohamed Fayed, the sub-investigator and the study coordinators 
working directly with this project. 
University of California and their affiliates working directly with this project 
Community Medical Centers  
Community Medical Centers Institutional Review Board 
 
The parties listed in the preceding paragraph may disclose your health information to the 
following persons and organizations for their use in connection with this research study: 
 
The Office for Human Research Protections (OHRP) 
Department of Health and Human Services (DHHS) 
The U.S. Food and Drug Administration (FDA) 


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Safety Monitoring Committee 
 
Your information may be re-disclosed if the recipients described above are not required by law 
to protect the privacy of the information. 
 
EXPIRATION DATE OR EVENT FOR THE RETENTION OF RECORDS 
 
The study results will be retained in your research record for at least six years after the 
completion of this study. At that time either the research information not already in your medical 
record will be destroyed or information identifying you will be removed from such study results 
at Community Medical Centers.  Any research information in your medical record will be kept 
indefinitely. 
 
VOLUNTARY PARTICIPATION 
 
Your participation is voluntary and you may choose not to participate in this research study or 
withdraw your consent or authorization for the use and disclosure of your health information at 
any time. Your choice will not at any time affect the commitment of your health care providers 
to administer care and there will be no penalty or loss of benefits to which you are otherwise 
entitled. If you decide to end your participation in the study, please notify the researcher(s) in 
writing. 
 
If you have questions or concerns regarding your privacy and the use of your personal health 
information, please contact the CMC Privacy Office, at 559-724-4400.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature (patient) 
 
 
Printed Name     
 
Date  Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature (parent/legal guardian/conservator) Printed Name 
Date   Time  
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If signed by other than patient, indicate relationship  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Signature  
 
 
Printed Name  
 
Date   Time