Probenecid as Pharmacotherapy for Alcohol Use Disorder
Phase: PHASE1
Conditions: Alcohol Use Disorder
Sponsor: Brown University

v. 08/07/2019
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Brown University  
Application for Full Board / Expedited IRB Review 
Protocol Title:  Probenecid as a pharmacotherapy for alcohol use disorder 
Principal Investigator:  Carolina Haass-Koffler  
Department:  CAAS, Psychiatry and Human Behavior 
Phone number: 401-836-6624 
Email address:  carolina_haass-koffler@brown.edu 
Is this a graduate student project?* ☐ Yes  ☒ No
If student PI, please provide the following: 
Advisor:     
Department:     
Phone number: 
Email address:  
Is this an undergraduate student project?* ☐ Yes  ☒ No
If yes, name of undergraduate student: 
Human Subjects CITI training is complete (PI, advisor (if student PI)): ☒  Yes ☐ No
Good Clinical Practice (GCP) training is complete (clinical trials only): ☒  Yes ☐ No ☐ N/A
HIPAA training is complete (if using PHI): ☐  Yes ☐ No ☒ N/A \
Are there multiple sites involved with this study?  ☐  Yes   ☒ No 
•
If “yes,” review the Application for IRB Authorization Agreement
Funding Source(s): 

If externally funded, provide the following:
Project title: Probenecid as pharmacotherapy for alcohol use disorder
Grant/Contract #: NIH R21 AA027614 – This protocol is in response to requested JIT

If there is no external funding for the project, write "University;" if funded by a specific internal funding
mechanism (e.g., Mellon Mays Fellowship, Royce Fellowship, UTRA, OVPR Seed funds, etc.) please
specify:
G1 CITI OK
GCP CITI OK

v. 08/07/2019                                                                                                                                                                    Page 2 of 28 
 
 
PART I. HUMAN SUBJECTS RESEARCH SCREENING 
 
Full Board/Expedited studies must meet the federal definition of “Human Subjects Research.” Answer the 
following questions to determine if your proposed study meets the federal definitions of both “Research” 
and “Human subjects.” 
  ☒ Yes   ☐ No 
Is this study a systematic investigation? 
  ☒ Yes   ☐ No 
Is the primary design intent of this study to contribute to generalizable knowledge? 
  ☒ Yes   ☐ No 
Is the information being obtained about living individuals? 
  ☒ Yes   ☐ No 
Will you collect information through some type of intervention or interaction? OR 
Will you have access to individually identifiable information? OR 
Will you have access to private information? 
If you answered “no” to any of the above questions, your study does not meet the definition of 
“Human Subjects Research.” You are not required to submit an Application for IRB review to the 
Brown HRPP. 
Before proceeding, be sure to review the revised Common Rule categories for Exemption to determine if 
your study meets criteria for Exempt review and the Application for Exemption. 
 
 
PART II.  RISK ASSESSMENT & EXPEDITED ELIGIBILITY SCREENER 
1. Minimal Risk means that the probability and magnitude of harm or discomfort anticipated in the 
research are not greater in and of themselves than those ordinarily encountered in daily life or during 
the performance of routine physical or psychological examination or tests. 
 
Using this definition, do you believe this research presents: 
  ☐ No greater than 
minimal risk 
(Expedited) 
Briefly justify this selection (and proceed to Question 2):  
 ☒ Greater than 
minimal risk (Full 
Board) 
Briefly justify this selection (and proceed to Part III): Potential risks of the study 
include discomfort from answering questionnaire items, breach of confidentiality, 
issues associated with coercion, discomfort from alcohol craving, side effects or drug 
interactions with probenecid. 
 
 
 
2. Below are Research Categories eligible for Expedited Review. Select one or more of the categories 
that are applicable to your proposed research, if any. 
  ☐ Category 1 
Clinical studies of drugs and medical devices only when condition (a) or (b) is met (please select 
one): 
 ☐ (a) research on drugs for which an IND application is not required. (Note: Research on 
marketed drugs that significantly increases the risks or decreases the acceptability of the risks 
associated with the use of the product is not eligible for expedited review); OR 
 
☐ (b) research on medical devices for which (i) an IDE exemption application is not required; or 
(ii) the medical device is cleared/approved for marketing and the medical device is being used in 
accordance with its cleared/approved labeling. 
 ☐ Category 2 
Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: 
STOP 

v. 08/07/2019
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☐(a) from healthy, non-pregnant adults who weigh at least 110 pounds. For these participants, the
amounts drawn must not exceed 550 ml in an 8-week period and collection may not occur more
frequently than 2 times per week; OR
☐(b) from other adults and children, considering the age, weight, and health of the participants,
the collection procedure, the amount of blood to be collected, and the frequency with which it will
be collected. For these participants, the amount drawn may not exceed the lesser of 50 ml or 3 ml
per kg in an 8-week period and collection may not occur more frequently than 2 times per week.
☐Category 3
Prospective collection of biological specimens for research purposes by noninvasive means. 
Examples may include: 
(a) hair and nail clippings in a non-disfiguring manner;
(b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction;
(c) permanent teeth if routine patient care indicated a need for extraction;
(d) excreta and external secretions (including sweat);
(e) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gum
base or wax or by applying a dilute citric solution to the tongue;
(f) placenta removal at delivery;
(g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor;
(h) supra- and subgingival dental plaque and calculus, provided the collection procedure is not
more invasive than routing prophylactic scaling of the teeth and the process is accomplished in
accordance with accepted prophylactic techniques;
(i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings;
(j) sputum collected after saline mist nebulization.
☐Category 4
Collection of data through noninvasive procedures (not involving general anesthesia or sedation) 
routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. 
Where medical devices are employed, they must be cleared/approved for marketing. (Studies 
intended to evaluate the safety and effectiveness of the medical device are not generally eligible for 
expedited review, including studies of cleared medical devices for new indications.) 
Examples may include: 
(a) physical sensors that are applied either to the surface of the body or at a distance and do not
involve input of significant amounts of energy into the subject or an invasion of the subject's
privacy;
(b) weighing or testing sensory acuity;
(c) magnetic resonance imaging;
(d) electrocardiography, electroencephalography, thermography, detection of naturally occurring
radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and
echocardiography;
(e) moderate exercise, muscular strength testing, body composition assessment, and flexibility
testing where appropriate given the age, weight, and health of the individual.
☐Category 5
Research involving materials (data, documents, records, or specimens) that have been collected, or 
will be collected solely for non-research purposes (such as medical treatment or diagnosis). NOTE: 
Some research in this category may be Exempt. Review the categories for Exemption before 
selecting this option. 
☐Category 6
Collection of data from voice, video, digital, or image recordings made for research purposes. 
☐Category 7
Research on individual or group characteristics or behavior (including, but not limited to, research 
on perception, cognition, motivation, identity, language, communication, cultural beliefs or 
practices, and social behavior) or research employing survey, interview, oral history, focus group, 
program evaluation, human factors evaluation, or quality assurance methodologies. NOTE: Some 
research in this category may be Exempt. Review the categories for Exemption before selecting 
this option. 

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PART III.  RESEARCH DESIGN & METHODS 
 
1. Introduction and Background.  
 
The proposed clinical trial advances a novel hypothesis of the potential relationship between pannexin 1 
channels and alcohol-related effects with the goal of elucidating novel pathophysiological mechanisms that could 
pave the way for new therapeutic targets for the treatment of alcohol use disorder (AUD). The premise prompting 
this investigation on testing probenecid as a novel medication for treating AUD is based on the direct evidence 
from our preliminary work with probenecid in a preclinical model of AUD. This work demonstrated that probenecid 
is able to reduce alcohol consumption in alcohol-dependent rats. The scientific rational for testing probenecid in 
AUD was derived by the well-known mechanism of action of probenecid as a pannexin 1 channel inhibitor, its 
role in alcohol-induced extracellular adenosine release, and that this process is promoted by a history of 
exposure to excessive alcohol. This application holds the potential to evaluate the role of pannexin 1 channels 
and provide the possibility to discover new AUD therapeutic opportunities, and will be the first to assess the 
efficacy of probenecid for AUD in an integrated behavioral and clinical setting. The data obtained from this 
exploratory, proof-of-concept clinical trial will demonstrate the safety and tolerability of probenecid while 
consuming alcohol and can pave the way for further testing probenecid in an appropriately-powered larger R01 
application. 
 
 
2. Specific Aims and Study Objectives.  
 
This proposed clinical trial is a proof-of-concept, within-subject, crossover, double-blind, placebo-controlled 
human alcohol laboratory study in non-treatment-seeking individuals with AUD (N = 34) randomized to 
probenecid or matched placebo. In a controlled alcohol laboratory session, randomized participants will receive 
one oral dose of 2 g probenecid or matched placebo, with a drink designed to raise the breath alcohol content 
(BrAC) to 0.08 g/dL. 
Particularly relevant for this application, pannexin 1 channels are expressed throughout the central nervous 
system (CNS), in neurons, astrocytes, and oligodendrocytes. They mediate the release of adenosine 5`-
triphosphate (ATP) and the excitatory neurotransmitter glutamate. They function primarily as a single-membrane, 
large-conductance channel. Dephosphorylation of ATP outside of cells contributes to the majority of extracellular 
adenosine, which is a potent neuromodulator involved in physiological and pathological processes. Adenosine 
levels, in the brain extracellular space, increase dramatically during metabolically stressful conditions (e.g. 
ischemia, seizures, or trauma) and alcohol use.  
Although some progress has been made in the advancement of our understanding of different neurobiological 
component of AUD, there are still many avenues which have not been explored. The contribution of pannexin 1 
channels and adenosine in alcohol and opioid use disorders has only been recently described and unlocking this 
relationship could hold the key to the development of new treatments. 
In cultured neurons, acute alcohol exposure increases extracellular adenosine. This spike in adenosine 
concentration contributes to the intoxicating and/or rewarding effect of alcohol. Furthermore, both high and low 
concentrations of alcohol could convert isolated neuronal bursts of activity into continuous activity. The loss of 
activity‐dependent adenosine release removes the negative feedback provided by adenosine (A1) receptor 
activation. The promoted continuous activity, may contribute to the alcohol’s tolerance with chronic alcohol use. 
Taken together, these observations prompt the hypothesis that probenecid (which is used in the clinic to treat 
hyperuricemia), may represent a valuable pharmacophore to evaluate the role of pannexin 1 channels in AUD. 
 
The goal of this research is to elucidate novel pathophysiological mechanisms that could pave the way for new 
therapeutic targets for the treatment of alcohol use disorder (AUD). 
 
The specific aims of this study will test the effects of probenecid, compared to placebo to: 
Aim 1: assess the safety and tolerability of probenecid, compared to placebo after alcohol administration 
using a battery of physiological/psychological assessments that measures potential adverse events. 

v. 08/07/2019                                                                                                                                                                    Page 5 of 28 
 
Aim 2: test the hypothesis that probenecid will reduce stimulant effect of alcohol by using the stimulation 
sub-score of Biphasic Alcohol Effects Scale (BAES). This hypothesis is based on the premise that probenecid, 
as pannexin 1 channel inhibitor, will reduce adenosine concentration, a contributor of the intoxicating and/or 
rewarding effect of alcohol. 
Aim 3: test the hypothesis that probenecid will reduce alcohol tolerance using the cued go/no-go reaction 
time. This hypothesis is based on the premise that probenecid, as a pannexin 1 channel inhibitor, may re-
establish the activity‐dependent adenosine release and facilitate the negative feedback provided by adenosine 
(A1) receptor activation, a mechanism that may contribute to the alcohol’s tolerance with chronic alcohol use. 
 
Exploratory Aim: test for medication effects on: alcohol craving by the alcohol urge questionnaire (AUQ), 
intoxication by the subjective intoxication rate and session preference (session they felt less/more drunk, and 
which they liked more). These objectives are exploratory and therefore we do not predict direction of these 
effects.  
 
Significance  
Probenecid as a candidate therapeutic for Alcohol Use Disorder (AUD) preclinical data  
The direct evidence that supports the possible role of pannexin 1 channels in alcohol use disorder (AUD) is 
provided by our published preclinical data (Probenecid Reduces Alcohol Drinking in Rodents. Is Pannexin1 a 
Novel Therapeutic Target for Alcohol Use Disorder? Alcohol and Alcoholism, 2019 on press).  
 
Probenecid pharmacological characteristics and relationship with pannexin 1 channels  
Probenecid was approved for therapy and prevention of gout and hyperuricemia in the United States in 1951. It 
is well-known that probenecid blocks organic anion transport and treats gout by its inhibition of renal reuptake of 
uric acid, by an anion transporter. Probenecid also inhibits pannexin 1 channels that have no known relationship 
with transporters. They exert their physiological role as non-junctional membrane channels, providing a pathway 
for exchange of molecules between the cytoplasm and extracellular space. 
 
Adenosine and Alcohol Use Disorder (AUD)  
Alcohol produces some of its multiple effects by interacting with adenosine signaling mechanisms. In particular, 
there is strong evidence that ethanol can increase the extracellular concentration of adenosine in the brain, and 
some of the effects of ethanol can be reduced by adenosine receptor antagonists. After repeated alcohol 
administrations, a fall in the increase of adenosine was observed, suggesting depletion of the intracellular 
adenosine stores in rats’ hippocampus. Adenosine is responsible for balancing neurotransmitter release, 
reducing neuronal excitability and regulating ion channel function through activation of four classes of adenosine 
receptor: A1, 2A, A2B and A3. Alcohol can also reduce the basal activity of A1 receptor, resulting in an 
enhancement of synaptic transmission. The mechanism could be a reduction in activity-dependent adenosine 
release. The decrease in A1 receptor activation may result from ethanol inhibiting ectonucleotidases (NTPDases, 
reducing conversion of ATP to adenosine.  
Acute alcohol exposure in cultured neurons is known to increase extracellular adenosine. This spike in adenosine 
contributes to the intoxicating and/or rewarding effect of alcohol. Both high and low concentrations of alcohol 
could convert isolated bursts of activity into continuous activity. The loss of activity‐dependent adenosine release 
removes the negative feedback provided by A1 receptor activation. This effect promotes continuous activity, 
which may contribute to the alcohol’s tolerance associated with chronic alcohol use. 
Mounting evidence supports a role for pannexin 1 in alcohol-induced adenosine release and this process is 
promoted by a history of exposure to excessive alcohol. Also interestingly, it was recently shown that pannexin 
1-mediated ATP releases from microglia during morphine withdrawal and that degrading endogenous spinal ATP 
contributes to withdrawal manifestation. Consistently, a pannexin 1-blocking peptide or probenecid suppressed 
ATP release during morphine withdrawal, and reduced the severity of withdrawal manifestations. Probenecid, 
as a pannexin 1 channel inhibitor, and an FDA-approved medication, could be an ideal candidate for the 
treatment for AUD. Also, the use a medication familiar to the practitioner community (not a psychoactive drug) 
may facilitate the incorporation of probenecid into clinical practice for the treatment of AUD. Taken together with 
the aforementioned observation that excessive alcohol promotes pannexin 1 opening and that probenecid 

v. 08/07/2019
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reduces alcohol drinking during acute withdrawal, these observations support the present hypothesis that 
inhibition of pannexin 1 channels may be beneficial for the treatment of AUD.  
Scientific Rigor and Reproducibility 
For this exploratory study, we will apply the utmost scientific rigor to ensure robust and unbiased experimental 
design, methodology, analysis, interpretation and reporting of results of the study. The PI and co-investigators 
will meet regularly to discuss methods for ensuring double blinded, unbiased, transparent, rigorous, and 
reproducible results and analyses. The proposal was designed based on the extensive clinical experience of the 
investigators. We will perform the data analyses in consideration of sex as a critical variable, because of the 
evidence that sex differences may be associated with significant differences in biological underpinnings related 
to women's greater physiological sensitivity to the effects of alcohol. 
 If your study ONLY involves the use of identifiable secondary data / biospecimens, including 
coded data from which you may be able to ascertain identity, 
skip to PART VI. Otherwise, please continue. 
3. Materials, Methods and Analysis. The study design, methods and procedures must be adequately described in
order for the IRB to understand all activities in which human subjects will participate. The IRB must also be
able to differentiate those procedures that are performed for research purposes from those that are performed
for routine care or evaluation.
NOTE: The focus of this section is on methods and procedures. Risks will be described later. 
This proposal meets the criteria for an NIH phase I clinical trial. The design is a randomized, within-subject, 
crossover, double-blind, placebo-controlled human alcohol laboratory study with one oral dose of 2g probenecid 
or placebo administered in two laboratory sessions. The pharmacological intervention is shown in Figure 1 
below, and the list of the assessments are in Table 2 (Appendix D, DSMP).  
Figure 1: Project design and pharmacological intervention. There will be a total of four study visits. Visit 
1 is the screening for eligibility (medical and physical examination). On Visits 2 and 3, participants will undergo 
an alcohol laboratory session with a one week washout period before administering the alternate therapy. The 
study will conclude at Visit 4. 
Visit 1 (Screening) Following a breath analyzer (BrAC=0.00), the informed consent process is conducted. 
Participants are assessed on demographics, medical history, a physical examination, vital signs and ECG. Blood 
and urine clinical assessments are performed to screen individuals for inclusion/exclusion criteria. A Licensed 
Clinician will conduct eligibility screening. The psychological/behavioral assessments are administered by a 
trained personnel. After the initial visit, a study medical provider reviews the medical history and lab results. 
When confirmed eligible for treatment by the medical provider, the participant is called with the results by the 
RA, and scheduled for Visit 2. Randomization is performed at Visit 2.  
STOP 
(Remind PI, if not already done, to contact the Institutional Biosafety 
Committee to review and approve the collection of blood in the study.)

v. 08/07/2019                                                                                                                                                                    Page 7 of 28 
 
Visits 2 and 3 (Probenecid/Alcohol Laboratory Session) Participants are instructed to not consume alcohol 
for 24-hrs (BrAC=0.00) prior to any assessment. We administer the CIWA-Ar to monitor alcohol withdrawal 
symptoms (Score>10) and vital signs (within normal limits) before confirming enrollment. The RA administering 
the CIWA will have thorough training on how to administer the assessments, and will be trained on how to alert 
the study clinician if the participant scores > an 8. The participants will then be randomized to receive either 
probenecid or placebo. After 1 hour, participants will begin the baseline assessments, and the cued go/no-go 
reaction time (RT) task powered by Inquisit 5 Lab. After 2 hours, according to probenecid pharmacokinetics, 
participants will receive two drinks designed to raise the BrAC to 0.08g/dL. Subjects will have 1 minute to finish 
each drink, and the drinks will be served 4 minutes apart. The next battery of physiological and psychological 
assessments will be administered to measure potential adverse events (Aim 1), stimulant effects of alcohol will 
be assessed using the Biphasic Alcohol Effects Scale (BAES) (Aim 2) and alcohol’s tolerance by the RT task 
(Aim 3). The BrAC will be collected at 10, 20, 30, 40, 50, 60, 70, 80, 90, 105, 140 and 180 min after alcohol 
administration. After a one week washout period, participants will be asked to return for the second lab session 
(administration of the other condition).  
 
Visits 4 (Follow-up) After one week, participants are asked to return to complete the final assessments and are 
given a Substance Use Resource List (Appendix F3).  
 
Assessments A list of assessments that will be administered during the study period are described in Table 1. 
Alcohol measures:  
• 
Alcohol consumption 90-days before the screening is assessed by the Timeline Follow-Back (TLFB). 
• 
Alcohol Withdrawal Assessment (CIWA-Ar) is a 10-item scale that determines the stage or severity of 
alcohol withdrawal. 
• 
Alcohol Urge Questionnaire (AUQ) consists of eight statements about the respondent’s feelings and 
thoughts about drinking as they are completing the questionnaire. 
• 
Alcohol Dependence Scale (ADS) is a 25 question assessments addresses participants’ reliance on 
alcohol. 
• 
Stimulant/sedative effects of alcohol are assessed using the Biphasic Alcohol Effects Scale (BAES). 
• 
The Drinker Inventory of Consequences (DrinC-2R) is a 23 question assessment asking participants 
personal consequences related to his/her/their alcohol intake. 
• 
The Family History of Alcoholism asks participants his/her/their family history of alcoholism- first and 
second degree relatives.  
• 
The Age of Onset of Alcoholism asks participants when drinking first had a negative effect on their life. 
• 
Alcohol tolerance will be measured by the cued go/no-go reaction time and subjective intoxication 
rate/session preference (session they felt less/more drunk, and which they liked more etc.). 
Mood, Anxiety, and Trauma: 
• 
The SCID 5 will be administered at the first session to measure any potential disorder/potentially 
traumatic event. 
• 
The NP will use the Suicide SAFETE as a way to access suicidal risk factors in participants. 
• 
Hamilton Anxiety & Depression Rating Scales (HAM-A and HAM-D) are 14-item scales that measure 
anxiety and depression symptoms (i.e., psychic anxiety, somatic anxiety and depression). 
• 
State-Trait Anxiety Inventory (STAI) is a 40-item measure that is split into state anxiety (20 items) and 
trait anxiety (20 items) symptoms, the scale measures worry, tension, apprehension and nervousness. 
• 
Life Events Checklist for DSM-5 (LEC-5) will be given as an identification of traumatic events index.  
• 
The PCL-5 is a 20 question self-report aimed at addressing potential PTSD symptoms.   
• 
The Brief Trauma Questionnaire asks about participants’ history of traumatic events. 
• 
The Perceived Stress Scale (PSS) asks about participants’ thoughts and feelings to assess stressful 
events within the past week. 
Additional Assessments  
• 
Sections 6-14 of the Menopause Health Questionnaire will be given to eligible female participants asking 
symptoms/concerns relating to menopause.  
• 
An Adverse Events Evaluation form will be given to each participant at each session to check for potential 
side effects or adverse events that could have occurred since the previous visit.  

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• 
Additional assessments include the Medical History Questionnaire and Probenecid Eligibility Checklist 
conducted by the NP to assess eligibility to enroll in the study.  
TABLE 1 
Assessments 
Visit 1 
Screening 
Visit 2 - 3 
Alcohol Lab I-II 
Visit 4 
Follow-up 
Done By 
Recorded 
On 
Informed Consent 
X 
 
 
RA/Participant 
    Paper 
Vitals  
X 
X 
X 
NP/Physician/PI/RA 
  Paper 
Urine toxicology 
X 
 
 
RA 
Paper 
Pregnancy test 
X 
X 
X 
RA 
Paper 
Blood collection 
X 
 
 
PI/NP 
Paper 
ECG 
X 
 
 
RA/PI/NP/Physician 
Paper 
Concomitant Medications 
X 
X 
X 
PI 
Paper 
Medical History Questionnaire* 
X 
 
 
NP/Physician 
Paper 
Physical Assessment 
X 
 
 
NP/Physician 
Paper 
Menopause Health Questionnaire* 
X 
 
 
NP/Physician 
Paper 
Probenecid Eligibility Checklist 
X 
 
 
PI/NP/Physician 
Paper 
Alcohol Timeline Followback 
(TLFB)* 
X 
X 
X 
RA 
Paper 
Adverse Events Evaluation (AEE)* 
X 
X 
X 
RA/NP/PI 
Paper 
Structured Clin Interview DSM-
5 (SCID-5) 
X 
 
 
RA/PI/NP 
Paper 
Alcohol Withdrawal Ass. (CIWA-
Ar)* 
X 
X 
X 
RA/NP/Physician 
Paper 
Biphasic Alcohol Effects Scale 
(BAES) 
 
X 
 
Participant 
Paper 
Brief Trauma Questionnaire (BTQ) 
X 
 
 
NP/Physician 
Paper 
Suicide SAFE-T 
X 
 
 
NP/Physician 
Paper 
Age of Onset of Alcoholism* 
X 
 
 
Participant 
Qualtrics 
Alcohol Depend. Scale (ADS)* 
X 
 
 
Participant 
Qualtrics 
Alcohol Urge Questionnaire (AUQ) 
 
X 
 
Participant 
Qualtrics 
Drinker Inv. 
Consequences (DrinC-2R)* 
 
X 
 
Participant 
Qualtrics 
Self-Eval. (STAI-y1) 
X 
 
 
Participant 
Qualtrics 
Self-Eval. (STAI-y2) 
X 
X 
X 
Participant 
Qualtrics 
Life Events (LEC-5) 
X 
 
 
Participant 
Qualtrics 
Perceived Stress Scale (PSS) 
X 
X 
X 
Participant 
Qualtrics 
PTSD Checklist (PCL-5) 
X 
 
 
Participant 
Qualtrics 
Family History Alcohol (FH)* 
X 
 
 
Participant 
Qualtrics 
Hamilton Anxiety & Depression 
(HAM-A/D) 
X 
X 
X 
Participant 
Qualtrics 
Subject Intoxication Report 
 
X 
 
Participant 
Qualtrics 
Go/no go task 
 
X 
 
Participant 
Inquisit 
Key: Assessments in blue and in green- performed on paper and secured in locked file cabinets in the 
laboratory; assessments in red- performed on Qualtrics and secured in the CAAS VPN Secured Sever; 
assessment in black performed with toolbox and secured in CAAS VPN Secured Sever;  
*matching assessments with treatment seeking clinical trials 
 
Due to the brevity of individual questionnaires, the surveys assessed via Qualtrics will accessed under one link. 
All data completed by the participant via the Qualtrics link and by Inquisit will be completed by the participant in 
real time. Data completed via paper assessment (either by the participant, RA, NP or PI) will be manually entered 
into Qualtrics (CAAS VPN Secured Sever) by the RA after that session has ended. Study coded participant 
assessments on paper will be kept in the participant binder in a locked filing cabinet at the RA desk during the 
duration of the sessions until the data is manually entered into Qualtrics. Once the participant has completed the 
study, the participant binder will then be moved to the PI’s locked office. For each data secured file location see 
the DSMP (Appendix D). 
 

v. 08/07/2019                                                                                                                                                                    Page 9 of 28 
 
THE BLUE TEXT IN THE FOLLOWING SECTIONS IS A GUIDE TO ENSURE ALL RELEVANT 
INFORMATION IS INCLUDED IN YOUR APPLICATION. YOU MAY DELETE THE BLUE TEXT 
BEFORE SUBMISSION 
 
4. Participant Population.  
 
Participants and Recruitment  
 
One hundred non-treatment-seeking individuals with AUD will be screened, 34 will be randomized (50% women). 
Drs. Haass-Koffler and Swift have extensive experience in successfully recruiting these participants in the 
Providence, RI area. Advertisements, such as paper flyers and ads, will be posted to recruit participants by the 
RA in the Providence, RI area (Appendix B). Participants will respond to the recruitment materials by 
telephone/email and will be pre-screened for initial eligibility and exclusion criteria (Appendix G). Eligible 
participants will be invited for an in-person screening, where they will provide written informed consent 
(Appendix H) and undergo a full physical examination. Participants will be enrolled in the study after confirmation 
of eligibility by the study’s medical provider (Table 2).  
 
Table 2 
Inclusionary Criteria 
• Male or female, 21-70 (inclusive) years; women >7 drinks/week; men >14 drinks/week;  
• meet any DSM-5 criteria score for AUD;  
• Breath alcohol Content (BrAC)=0.00 at each visit;  
• In good health as confirmed by medical history, physical examination and lab tests;  
• Willing to adhere to the study procedures;  
• Understand informed consent and questionnaires in English at an 8th grade level  
Exclusionary Criteria 
• Women who are breastfeeding or have a positive urine screen for pregnancy  
• CrCl < 60mL/min 
• Taking aspirin (salicylates may reduce effect of probenecid) 
• Taking penicillin 
• Taking methotrexate (may increase concentration) 
• Taking other medications that may interact with probenecid 
• History of suicide attempts in the last three years 
• Current diagnosis of another substance disorder(s) other than nicotine, as assessed by self-reports and 
urine toxicology screen at baseline 
• History of hypersensitivity to sulfa drugs 
NOTE:  
The exclusion criteria is based in enhancing participants’ safety. 
Participants need to speak English and be able to understand informed consent and questionnaires in 
English which will be written exclusively at an 8th grade level. 
 
Probenecid and alcohol: dose selection and administration protocol  
The medications will be prescribed by Dr. Swift. Eligible participants will receive a single oral dose of probenecid 
or matching placebo in two laboratory sessions. 
 
Sample Size Estimates 
This study is a randomized within group, crossover, double-blind, placebo-controlled Phase I Clinical Trial in 
non-treatment-seeking alcohol-dependent individuals in an alcohol laboratory setting. Primary Aim 1 focuses on 
the safety of administering probenecid with alcohol, as determined by descriptive effect estimates and a 
maintained level of non-significant difference (p>0.05) scores on the AEE throughout the trial. The AEE 
difference to be detected is based on a judgement concerning the minimal effect which has clinical relevance in 

v. 08/07/2019                                                                                                                                                                    Page 10 of 28 
 
the management of patients.  In aims of this nature, the exact sample size cannot be fixed in advance because 
it depends upon the chosen stopping guideline, see our Data and Safety Monitoring Plan (DSMP) in the Human 
Subject Form.  Therefore, the study is powered primarily on secondary aims.   
For Aim 2, the sample size was calculated using power analysis to detect differences in mean changes in the 
individual alcohol-related stimulation from the BAES of one of our pharmacological human laboratory studies. In 
this pilot study of 10 participants, randomized to either idazoxan or placebo in a double‐blind, crossover design, 
it was observed that the study medication significantly reduced the stimulant score (p<0.05) compared to placebo 
with a medium-to-large effect (d =0.75). To power the current trial, we selected the more conservative, lower 
bound of the anticipated effect size to power Aims 2 and 3 (i.e., medium). Therefore, assuming α (two-tailed) = 
0.05, N = 34 will provide β = 0.8 to detect a medium effect size for measuring the probenecid decreased alcohol-
related stimulation.  
For Aim 3, power analysis was conducted to detect differences in mean changes in the individual reaction time 
(RT) on the cued go/no go paradigm from a human laboratory study that measured the RT (ms) on the effect of 
alcohol compared to placebo. This pilot study of 20 participants, randomized in a double‐blind, crossover design, 
showed that, on the go task, alcohol (dose 0.08g/dL) slowed RT compared with placebo (p<0.01) with a medium-
to-large effect (d =0.626). Based on this pilot study, and assuming α (two-tailed) = 0.05, N = 34 will provide β = 
0.8 to detect at least a medium effect size for measuring if the probenecid significantly antagonizes the reduced 
alcohol RT compared to placebo. With 20% attriters, we predict that we need to enroll 41 participants to maintain 
an N of 34 completers. 
The outcomes of previous studies used to power the secondary Aims of this proposal speaks to the novelty of 
this proposal and the need for a Phase I Clinical trial using probenecid in non-treatment-seeking alcohol-
dependent individuals. In each statistical analyses conducted for the Aims, effect size estimates to determine 
power for a future clinical trial will be of primary interest in this Phase I study.   
 
5. Recruitment Methods 
 
Drs. Haass-Koffler and Swift have extensive experience in successfully recruiting these participants in the 
Providence, RI area. Participants will respond to the recruitment materials by telephone/email and will be pre-
screened for initial eligibility and exclusion criteria (Appendix G). Eligible participants will be invited for an in-
person screening, where they will provide written informed consent and undergo a full physical examination. 
Participants will be enrolled in the study after confirmation of eligibility by the study’s medical provider (Table 1). 
 
Potentially eligible participants will be invited for an in-person screening by the RA and the nurse practitioner, 
where they will provide written informed consent and undergo a physical examination, blood work and 
electrocardiogram (ECG). Various assessments will also be administered either by the RA or NP to check for 
eligibility criteria. After confirmation of eligibility by the study physician (Dr. Swift), participants will be enrolled in 
the study by the PI (Dr. Haass-Koffler), with the support of the RA.  
 
The biomedical assessments (urine test and ECG) will be performed by a trained RA under the supervision of 
the nurse practitioner and the blood will be collected by a phlebotomist or nurse practitioner.  
 
The RA will receive training to administer the screening assessments by trained research personnel (either by 
the PI or the nurse practitioner). Screening tests and procedures ensure that potential participants are eligible to 
participate. The nurse practitioner will administer the CIWA at the screening, and the RA administering the CIWA 
during the other visits will have thorough training on how to administer the assessments, and will be trained on 
how to alert the study clinician if the participant scores ≥ an 8. 
 
NOTE: The de-identified screening data (study code) will be kept after eligibility is determined for research 
purpose. The document that links the study code with identifiable information will be destroyed after conclusion 
of the trial. The screening consent process is fully described in Part V. All screening material will be in English. 
 
Participant Selection  

v. 08/07/2019                                                                                                                                                                    Page 11 of 28 
 
In this exploratory proposal, we selected to enroll non-treatment-seeking individuals with AUD because our 
primary goal is to assess health-related (alcohol/probenecid interaction) outcomes. The specific aims will assess 
the safety, tolerability and biobehavioral response of probenecid when co-administered with alcohol. As 
recommended by the FDA, these outcomes are critical for developing AUD pharmacotherapies, but ethically, 
can be accomplished only in a population that has not expressed intent to be treated. We recognize the 
importance of translating our outcomes to treatment seeking populations and we will consider demographic 
factors and clinical variables as recently recommended. To further control for discrepancies between treatment 
seekers vs non-treatment seekers in medication response, for this proposal, we have included matching 
assessments (Table 1) between ours and other larger clinical trials that have enrolled treatment-seeking 
participants. This strategy will help inform future AUD medication development. 
 
Standard care: none 
Intervention: 2 g of Probenecid or placebo 
 
6. Compensation / Reimbursement 
 
Visit # 
1 
2 
3 
4 
Type of Visit 
Screening 
Alcohol Lab I 
Alcohol Lab II 
Follow-Up 
Time Involved 
2-3 hours 
5 hours 
5 hours 
1 hour 
Amount Compensated 
$25  
$120  
$120  
$25  
+ bonus of $10 
 
Participants will receive $25 dollars at visit 2 (screening), $120 dollars at both lab sessions (Alcohol Lab I and 
Alcohol Lab II), and $25 dollars at visit 4 (follow-up). An additional $10 will be awarded at the follow-up visit for 
completion of the study. Therefore, maximum compensation for study completion is $300 cash.  
 
Participants will be compensated in cash and for the sessions that they complete. Participants who do not 
complete the study will be compensated for the sessions that they complete. The amount of compensation is 
based on the time spent in each session and based on other similar studies conducted by the PI or Dr. Swift at 
Brown University. Participants will receive parking validation or RIPTA tickets (both ways) as reimbursement for 
travel cost. Study procedures, such as a physical, ECG, urine tests, blood analysis, etc., will be provided for the 
participants.  
 
7. Potential Research Risks / Discomforts to Participants 
Risks of the study include:  
1) discomfort from answering questionnaire items 
2) breach of confidentiality  
3) issues associated with coercion 
4) discomfort from alcohol withdrawal 
5) side effects or drug interactions with probenecid 
6) craving for alcohol 
Participants will be protected against any potential risks and will be closely monitored throughout the study.  
1) Participants may experience some discomfort when answering questionnaires, however, we expect that the 
risks will be low. Based on past and current research by Drs. Haass-Koffler, Swift and Cioe, participants have 
not had any discomfort or issues that have arisen from questionnaires. 
2) The risk of breach of confidentiality is low and strict precautions will be taken to minimize the risk of breach 
of confidentiality. A Data Safety Monitoring Plan (DSMP) (Appendix D) is in place that follows Brown’s IRB 
guidelines. 
3) The risk of coercion is low. Monetary compensation for this study is commensurate with the amount of time 
and effort that is required for the study.  
4) Participants may experience some discomfort from alcohol withdrawal, but these should be minimal since 
this is a non-treatment seekers (non-abstinent) individuals with AUD and the withdrawal phase is in the 

v. 08/07/2019                                                                                                                                                                    Page 12 of 28 
 
controlled setting of the laboratory. As outlined below, several precautions will be taken to help minimize any 
alcohol withdrawal symptoms that participants may experience. 
5) A detailed procedure to minimize risk associated with probenecid is defined below.  
6) Participants may experience craving for alcohol after being exposed to alcohol cues. Past research by Drs. 
Swift and Haass-Koffler, have shown that participants do not have significant craving or subsequent drug 
use after cue exposure. Also, it was shown that cue reactivity elicits urge to drink in the first 6 minutes of 
alcohol exposure, followed by a gradual and significant decrease. Importantly, there were no differences in 
alcohol-related behavior in AUD individuals in their first or fourth week (after cue reactivity exposure). As 
such, running the laboratory phase before the naturalistic phase will not affect the results of the naturalistic 
phase.  
 
As detailed in the Description of Potential Risks, the following will be set forth to protect against risks of the study:  
1) To protect against or minimize discomfort from answering questionnaire items, participants may refuse to 
answer questions that they do not feel comfortable answering. Participants with discomfort may withdraw 
from the study with no penalty and will be referred to Dr. Swift for a clinical assessment if distress continues. 
2) To protect against a breach of confidentiality, all data acquired during the study will only be accessible to the 
research staff and used for research purposes only. All research data will be kept in a locked filing cabinet 
or on a password-protected computer database behind locked doors in the study office. Only participant code 
numbers will be used to identify participants. Consent forms and logs with participant’s names and codes will 
be locked in a separate cabinet in the PI’s office as an extra layer of security. All biological samples will be 
guarded in a similar manner. Only participant code numbers will be labeled on biological samples and will be 
locked in a laboratory suite. All interviews and assessments will be conducted in an interview room with a 
closed door to ensure participant privacy and confidentiality. We are also covered by the Certificate of 
Confidentiality at the NIH to protect against disclosing any identifying information/characteristics of 
participants in legal demands such as court orders or subpoenas. The Certificate will ensure further 
protection of participants’ confidentiality. 
3) To protect against issues associated with coercion, participants will be compensated appropriately for their 
time and effort. The study involves about a week of participation and given the considerable time commitment 
and involvement, compensating participants for their time and travel costs is appropriate and comparable to 
other study protocols. Those who drop out of the study early will be compensated for sessions that they 
completed. 
4) To protect against or minimize any discomfort from alcohol withdrawal, participants will be closely monitored 
throughout the study. Alcohol withdrawal will be assessed before each visit and since individuals with a 
CIWA-Ar ≥ 8 will be excluded from the study at screening, we do not expect withdrawal from alcohol to be 
severe. Dr. Swift will be accessible 24/7 during the study and participants will be instructed to call if they 
experience any withdrawal symptoms. Emergency medical services will be immediately called if a serious 
adverse event arises during the study.  
5) To protect against or minimize any risk of side effects associated with probenecid or any drug-drug or drug-
alcohol interactions, potential risks will be judiciously outlined to participants and thorough screening 
procedures will be in place to minimize recruitment of those that might be at a higher risk of adverse events. 
The study physician (Dr. Swift) will carefully review all participant screens and the PI (neuropharmacologist) 
will evaluate the individual medication profile to minimize any risk association with the medication. The 
participants will be instructed on the proper administration of the medication and they will return the 
medication bottle at the last visit.  
6) The safety of probenecid is supported by clinical practice since the medication was FDA-approved in 1951, 
and is still being used to treat gout and hyperuricemia in the United States today. Dr. Swift’s contact 
information will be provided to participants so that participants can contact him between visits if necessary.  
7) The protocol involves an intervention with a medication that has been prescribed since 1951. There are 
minimal risk for participants in their daily lives, however, they may feel discomfort during the laboratory 
procedures (alcohol administration).  See below additional consideration to prevent the additional risks: 
 
Dr. Swift will prescribe medication for eligible participants. The dose of probenecid was decided based on clinical 
work. We will administer probenecid (2 mg single dose) in the laboratory sessions (visits 2 and 3).  

v. 08/07/2019
 Page 13 of 28 
Medications (probenecid and matching placebo) 
Dose selection 
The 2g probenecid dose for this proposal was selected based on clinical practice (FDA-approved since 1951) 
and current research studies. In clinical practice, probenecid is administered up to 2g/day to treat chronic gout; 
to prolong penicillin serum level 500 mg/four times daily. In clinical research, probenecid was administered for: 
systolic heart failure, 2g/twice daily for seven days (NCT:01814319) and for calcium pyrophosphate deposition 
disease, 2g/day for five days (NCT02243631).  As such, the 2g administered in one dose is within in the safety 
range of the administration of probenecid in clinical practice. One single dose administration of probenecid 
should be sufficient to measure the outcome in this application since it has been shown in a rat model for opioid 
use disorder that one dose of probenecid was sufficient to alleviate morphine withdrawal in rats.  This approach 
is consistent with the preliminary and proof-of-concept nature of other early phase studies that have already 
taken place with other medications such as naltrexone, baclofen and gabapentin. A follow-up R01 study will be 
needed to look at chronic administration. 
The 0.08gr/dL alcohol dose was chosen based on prior research showing that it impairs the ability to quickly 
activate and inhibit responses, as measured by the cued go/no-go task. Doses will be calculated based on body 
weight and gender, and will be administered as absolute alcohol divided equally into two drinks, each containing 
one part alcohol and three parts mix. Subjects will have 1 min to finish each drink, and the drinks will be served 
4 min apart. This dosing procedure produces BrAC peak at ~60 min from the onset of drinking.  
Administration protocol As depicted in Fig. 2, the study drug-alcohol administration protocol for this application 
was derived by the pharmacokinetics profile of the administration of a single oral 2g probenecid (Fig. 2A) and of 
an alcohol dose to reach BrAC = 0.08g/dL (Fig. 2B). Probenecid is well absorbed after oral administration, with 
a half-life of 4-12 h and peak plasma levels reached within 2 h. Before probenecid reaches peak (Cmax), we will 
start the baseline assessments without the presence of alcohol (60 min). Probenecid remains at a steady-state 
for ~2 h, which will allows for the administration of alcohol and the battery of physiological and psychological 
assessments that measure potential adverse events (Aim 1), the stimulant effects of alcohol (Aim 2) and alcohol’s 
tolerance (Aim 3) during alcohol’s ascending and descending limb (Fig. 3B). The assessments post-experiment 
will be used to measure safety before discharge. We will also measure BrAC at this time to determine if it is safe 
for the participant to leave. 
Probenecid and matching placebo will be prepared as opaque capsules by JB Pharmacy, which has prepared 
medications for all of our other double-blind studies. Risks of medications will be minimized through careful and 
detailed screening of participants by the PI (Dr. Haass-Koffler) who is a pharmacologist and the Co-Is: the study 
physician, Dr. Swift, who is a practicing physician and psychiatrist and, Dr. Cioe, the nurse practitioner. Each 
investigator has extensive experience in addiction research. The medical team will act to minimize recruitment 
of those who might be at higher risk for adverse events or drug-drug interaction, as well as careful and detailed 
monitoring of adverse events and participant well-being during the study. 

v. 08/07/2019                                                                                                                                                                    Page 14 of 28 
 
 
Fig. 2 – Schematic representation of the administation of probenecid and alcohol in the laboratory. (A) 
Probenencid pharmacokinetic profile: Time 0 h corresponds to the time of probenencid administration and 
time 2 h corresponds to the Cmax. Probenecid remains at steady-state (constant concentration) for ~2 h after 
administration which will allow running the experiments during the alcohol phase. At Time 2 h, the alcohol 
administration starts (0.08g/dL, two drinks in 6 min). (B) Alcohol pharmacokinetic profile: Time 0 min 
corresponds to the time of alcohol administration and the peak concentration will be achieved after 60 min. 
Ascending limb (30-60 min) and descending limb (after 60 min). The graphs were adapted from (Selen, 
Amidon, & Welling, 1982) (oral 2g probenecid) and from (Fillmore, Marczinski, Bowman, 2005) (alcohol 
administration to reach BrAC = 0.08g/dL). 
 
 
Side Effects  
Common side effects of probenecid include headache, anorexia, nausea, and vomiting, joint pain, redness or 
swelling. Uncommon side effects include dizziness, flushing or redness of the face, frequent urge to urinate, 
alopecia, and sore gums. Rare side effects of probenecid include cloudy urine, cough or hoarseness, fast or 
irregular breathing, fever, pain in back and/or ribs, sores, ulcers, or white spots on lips or in mouth, sore throat, 
sudden decrease in the amount of urine, swollen and/or painful glands, unusual bleeding or bruising, unusual 
tiredness, yellow eyes or skin, and weight gain.  
 
Drug-drug interactions 
To protect against any risk of additional drug-drug interactions, participants will be thoroughly screened for any 
prescriptions or over-the-counter medications that may interact with Probenecid. Dr. Haass-Koffler will oversee 
the possible drug-drug interactions that may arise from the co-administration of existing medications taken by 
participants with the study medication. She will evaluate the medication profile for each screening visit and she 

v. 08/07/2019                                                                                                                                                                    Page 15 of 28 
 
will prepare a full pharmacokinetics/ pharmacodynamics (PK/PD) report for the final review by Dr. Swift using 
the Clinical Pharmacology database provided by Brown. Participants will be instructed to immediately call the PI 
if they start taking new medications. The PI will then contact Dr. Swift who will recommend next steps. 
Participants will be asked to avoid any medications that could interact with Probenecid. 
 
The following medications should be avoided when taking Probenecid: Avibactam, Cefotaxime, Doripenem, 
Ketorolac (nasal and systemic), Meropenem, Pegloticase, Methotrexate, aspirins, and those taking penicillin  
This list is not complete. Other drugs may interact with Probenecid, including prescription and over-the-counter 
medicines, vitamins, and herbal products. Not all possible interactions are listed. The PI will review specific drug-
drug interactions before enrolling participants in the study. 
 
Storage of Medication 
Probenecid tablets should be stored in well closed containers at temperatures between 15-30 deg C. 
Commercially available preparations containing probenecid and colchicine should be protected from light. 
Following the date of manufacture, commercially available probenecid tablets have an expiration date of 3-5 
years depending on the packaging. 
 
Adverse Events 
Adverse events (AEs) will be recorded and tracked for this protocol. Adverse events will be reported to Brown 
University IRB. An annual report will be submitted by the PI to the Project Officer summarizing all adverse events. 
An AE is defined as any reaction, side effect, or untoward event that occurs during the course of the study, 
whether or not the event is considered related to the investigational product. A new illness, symptom, sign or 
clinically significant clinical laboratory abnormality or worsening of a pre-existing condition or abnormality is 
considered an AE. Stable chronic conditions, such as arthritis, which are present prior to clinical trial entry and 
do not worsen are not considered AEs. 
Female participants in the study must not be pregnant or nursing; those who do not meet this criteria will be 
excluded. To verify the possibility of pregnancy, we will perform a pregnancy test at the start of each visit during 
the study. Should a female participant become pregnant during the study, she will be terminated from the study 
immediately and referred for obstetrical follow-up. If a woman has a positive or borderline pregnancy test after 
enrollment, the pregnancy will be recorded as an AE. The investigators will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been terminated or completed, also in order to verify 
if the definition of serious adverse event will apply (described below).  
All AEs regardless of severity, will be followed until satisfactory resolution. At the follow-up visit, AEs will be 
recorded and followed to resolution only if they are serious or unexpected, or if the study physician assesses 
them to be clinically significant. 
In accordance with FDA reporting requirements, all AEs occurring during the course of the study will be collected, 
documented, and reported by the investigators. The occurrence of AEs will be assessed starting on the day of 
randomization, after first dose of doxazosin. 
 
Unexpected Adverse Events.  
An unexpected AE is one that is not described with respect to nature, severity, or frequency in the current product 
package insert. 
 
Serious Adverse Events (SAEs) 
Each adverse event or reaction will be classified by a study physician as being serious or non-serious. Based 
on the seriousness of the adverse event or reaction, appropriate reporting procedures will be followed. The Code 
of Federal Regulations Title 21 part 312.32 and International Conference on Harmonization (ICH) Guideline for 
Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, ICH-E2A March 
1995, as implemented by the U.S. Food and Drug Administration, defines an SAE or serious adverse drug 
experience as any untoward medical occurrence at any dose that: 
• 
results in death; 

v. 08/07/2019                                                                                                                                                                    Page 16 of 28 
 
• 
is life-threatening;  (NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe). 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in persistent or significant disability/incapacity; or 
• 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug reaction, when based on appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in 
the above definition. If a study subject withdraws from the study or if an investigator decides to discontinue the 
subject from the study because of an SAE, the subject must have appropriate follow-up medical monitoring 
including, if necessary, hospitalization. Monitoring will continue until the problem prompting hospitalization has 
resolved or stabilized with no further change expected or is discovered to be clearly unrelated to study medication 
or progresses to death. 
 
Unexpected and Serious Adverse Events Reporting  
Any Unexpected AE or SAE, including death due to any cause, which occurs to any subject from the time of 
admission through discharge whether or not related to the investigational product, will be reported within 24 
hours of knowledge of the event to our local IRB and to the Project Officer of this project via fax or phone call. 
 
A detailed written documentation for all unexpected AEs/SAEs will be submitted to the Project Officer of this 
project within three (3) days of reporting the event and within seven (7) days to our local IRB. Required 
documents that must be submitted include the following information: 
• 
title of protocol;  
• 
description of the unanticipated adverse event;  
• 
a determination of whether the event was related to the research study;  
• 
name of the drug;  
• 
where and when the event occurred; and  
• 
to whom else has the event been reported.  
Upon receipt of a notification of an unanticipated adverse event or death, the IRB will determine whether further 
investigation of the event is required. Depending on the circumstances the investigator may be required to 
suspend the study pending the outcome of an IRB review. Also, the IRB may require modification of the risks 
section of the consent form. These documents may be submitted by facsimile, as email attachments, or via 
overnight courier.  
 
Follow-Up of All AEs/SAEs  
All adverse events must be followed until they are resolved, or until all attempts to determine the resolution of 
the AE/SAE are exhausted. This may require an extended hospitalization period or a change in status from 
outpatient to inpatient.  All treatments, outcomes and information regarding whether or not the subject was 
referred to their Primary Care Provider for additional follow-up must be recorded in the source document. Any 
unexpected AEs and/or SAEs occurring to study participants during the follow up period will be reported within 
24 hours of knowledge of the event to our local IRB and to the Project Officer of this project via fax or phone call. 
All follow-up AEs will be recorded and followed to resolution only if they are serious, or if the study physician 
assesses them to be clinically significant. 
 
Periodical Review of the Safety Data  
Dr. Haass-Koffler (PI), Dr. Swift (Co-I and Study Physician) and Dr. Cioe (Co-I and nurse practitioner), will meet 
prior to the enrollment of the first subject to review the research protocol, informed consent documents and plans 
for safety and data monitoring of the study. This review will determine the risks and benefits to research subjects, 

v. 08/07/2019                                                                                                                                                                    Page 17 of 28 
 
protection and safety of the subjects and to offer suggestions for improving the study design. Moreover, Drs 
Haass-Koffler, Swift and Cioe will meet on regular basis during the duration of the study. ‘Ad hoc’ and/or 
emergency meetings will take place if needed for specific and/or safety reasons. Minutes of these meetings will 
be taken and filed in the regulatory binder of this project.  
 
The goals of these meetings will be to: 
1. determine adherence to treatment plan; 
2. determine specific data to be analyzed; 
3. evaluate end point/stop point rules; 
4. review protocol violations and deviations to assess adequacy of study; 
5. ensure documentation of informed consent; 
6. Enrollment (followed eligibility criteria, enrollment numbers, visit compliance, screening failure 
information); 
7. discuss investigator or key personnel changes; 
8. review completeness and quality of data collection forms; 
9. evaluate the aggregate analysis of AEs/SAEs; 
10. review vital signs, clinical tests, etc.; 
11. review confidentiality. 
 
The major outcomes following data review include: (1) continuing the trial unchanged; (2) modifying the protocol 
and/or consent form; or (3) terminating the study. If the protocol and/or consent form should be changed, or the 
study should be terminated, Dr. Haass-Koffler will be responsible for all the necessary communications with the 
Project Officer and the IRB.  
 
Data and Safety Monitoring Plan (DSMP) is attached to this protocol (Appendix D). 
 
8. Potential Benefits of the Research. NOTE: Compensation for participation is not a benefit and should 
not be included in this section.  
 
• 
Potential benefits to human subjects and to others: There are no direct benefits to participants in this 
study. However, considering the potential benefits and the knowledge to be gained, we believe that the 
benefits outweigh the risks. The risk-benefit ratio provides a justification for conducting this study, which 
could ultimately lead to more effective treatment options for alcohol use disorder.   
 
• 
Importance of the knowledge to be gained: With the serious health and economic consequences 
associated with alcohol use disorder, this study provides a much needed understanding of the behavioral 
and biological factors involved with alcohol craving and use. This study aims to examine the potential 
efficacy of a novel pharmacological treatment for individuals with alcohol use disorder during stress 
conditions. If effective, the findings of this study could lay the groundwork for an effective treatment 
strategy for alcohol use disorder and individuals with other addictive disorders. 
 
 
 
PART IV.  APPENDICES SCREENER 
 
Please complete & attach the following Appendices to this Application, as applicable. 
 
Incl.      N/A  
☐ 
☒ 
Appendix A. Children as Subjects 
To be attached when minors are included as participants [please be aware of the age of 
majority for your specific research site(s)] 

v. 08/07/2019                                                                                                                                                                    Page 18 of 28 
 
☐ 
☒ 
Appendix B. Prisoners as Subjects 
To be attached when prisoners are included as participants. 
☒ 
☐ 
Appendix C. Use of Drugs 
To be attached when the research includes the use of FDA-regulated or unregulated drugs. 
☐ 
☒ 
Appendix D. Use of Devices 
To be attached when the research includes the use of FDA-regulated or unregulated devices. 
☒ 
☐ 
Appendix E. Prescription Drug / Medication Management 
To be attached when study procedures include administering prescription medications to 
study participants. 
☒ 
☐ 
Appendix F. Mental Health Safety Plan 
To be attached when participants may experience significant emotional distress, or be at risk 
of themselves or others. 
☐ 
☒ 
Appendix G. Use of protected health information (PHI) for Research 
To be attached when study procedures include a plan to access, use or disclose Protected 
Health Information (PHI) of participants.  
 
LIST OF ATTACHMENTS 
A. Probenecid Drug Manual 
B. Recruitment Material 
C. Use of Drugs 
D. Data and Safety Monitoring Plan 
E. Prescription Drug/Medication Management 
F. Mental Health Safety Plan 
 
F2. Mental Health Safety Plan Checklist 
 
F3. Substance Use Resources  
G. Pre-Study Telephone Screen 
H. Informed Consent Document  
I. Assessments & Measures 
 
PART V.  INFORMED CONSENT 
 
Informed consent is a process, not just a form. The IRB must ensure the informed consent process clearly 
discloses and facilitates the understanding of all information needed to make an informed decision to 
participate while promoting the voluntariness of participation. 
 
Please review the Consent/assent templates and related guidance on the HRPP Forms & Templates page 
before developing your consent forms. 
 
 
1. Describe the informed consent process, including: 
 
In a private room in Dr. Haass-Koffler’s laboratory, following a breath alcohol content (BrAC) = 0.00, participants 
will provide written informed consent to participate. Participants will be asked to read the document thoroughly 
and indicate that they have done so in order to proceed to the study. Potential participants have the option of 
refusing to participate in the study, withdrawing their participation at any time, and/or refusing to answer any 
questions that they feel uncomfortable responding to (Appendix H). 
 
 2. Facilitate Understanding 
 

v. 08/07/2019                                                                                                                                                                    Page 19 of 28 
 
To ensure that participants understand the informed consent, participants will read and signature each page. All 
participants will be informed of the study procedures, study rationale and any potential risks and benefits. The 
PI or Research Assistant will answer any questions about the informed consent and study that participants may 
have.   
 
Fluency in English is part of the study inclusion criteria and thus participants will not be permitted to enroll in 
the study unless they meet this criterion 
 
We will ensure ongoing consent by adding language to remind participants that they have the option to refuse 
to participate in the study, may withdraw their participation at any time, and/or refuse to answer any questions 
that they feel uncomfortable responding to. 
 
3. Documentation 
 
Participants will be asked to sign a copy of the consent form that the researcher will keep on file in a locked 
storage cabinet. A second copy of the consent form will be provided for study participants to keep. 
 
4. Additional Considerations 
 
All study participants will be consented. This study does not involve minors, any deception, and all data 
including biospeciments will be fully de-identified. 
 
 
 
Proceed to PART VII. DATA SECURITY ASSESSMENT 
 
PART VI. USE OF SECONDARY DATA / BIOSPECIMENS 
 
1. From what source(s) will you acquire or access the data / biospecimens? 
 
Research data collected from participants will include interviews, questionnaires, task responses, physiological 
responses (heart rate, blood pressure), and biological samples (breath, blood and urine). Breath samples will be 
taken at the start of each visit for BrAC. Urine samples will be taken to test for pregnancy (at each visit) and drug 
screening (the first visit and additional visits if deemed necessary). Blood samples will be obtained during the 
physical at the in-person screening. All data collected will be for research purposes only. Only authorized, trained 
research personnel certified by the Collaborative Institutional Training Initiative (CITI), will have access to the 
data. All data will be identified with numbers (labeled sequentially) with no personal identifiers 
 
 
2. Describe the type(s) of data and date range(s) of the data you will use and the characteristics of the study 
research population (e.g., age range, sex, and any other pertinent demographic information.) 
 
Research data collected from participants will include interviews, questionnaires, task responses, physiological 
responses (heart rate, blood pressure), and biological samples (breath, blood and urine). Breath samples will be 
taken at the start of each visit for BrAC (which must read 0.00) a urine sample will be collected at each visit to 
test for pregnancy, and at the first visit to conduct a toxicology screen, and at additional visits if necessary. Blood 
samples will be obtained during the physical at the in-person screening. All data collected will be for research 
purposes only. Only authorized, trained research personnel certified by the Collaborative Institutional Training 
Initiative (CITI), will have access to the data. A total of 100 individuals will be pre-screened by telephone, 50 will 
be screened in person in the CAAS laboratory, 41 will be randomized by urn randomization, and a total of 34 are 
expected to complete the study. The participants will be males or females ages 21-70 who fit the DSM-5 criteria 
for AUD (table 2). Participants must be in good health as deemed by his/her medical history, physical 
examination and lab tests conducted by research personnel, and must be willing to adhere to the study 

v. 08/07/2019                                                                                                                                                                    Page 20 of 28 
 
procedures with knowledge that he/she has the option to excuse his/herself from the study at any time (Appendix 
H). Participants will understand informed consent and questionnaires in English at an 8th grade reading level 
(table 2). 
 
4. HIPAA and Protected Health Information (PHI): NA 
 
5. Do any of the source(s) require a Data Use Agreement (DUA) or other Agreement that requires institutional 
signature to obtain, access or use the data / biospecimens? ☐ Yes   ☒ No 
 
If “yes,” please include a copy of the Agreement(s) with this submission and also follow the Data Use 
Agreement review and signature processes. 
 
 
Proceed to PART VII. DATA SECURITY ASSESSMENT 
 
 

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PART VII. DATA SECURITY ASSESSMENT 
 
1. Do the study data / biospecimens include identifiers? Video and audio recordings are considered 
identifiable. 
☒ Yes   ☐ No* 
*If “no,” I affirm that I have read and will abide by the Level 1 Risk Minimum Security 
Standards: ☐ Yes   ☐ No  
Proceed to Question #2. 
 
If “yes,” answer the following questions. 
 
A. Describe the identifiers associated with the data / biospecimens. 
Biospeciments will be coded by de-identified study numbers immediately after 
collection.  The file connecting the participant ID to their study code will be kept in a 
secured password protected department folder, which will be destroyed after 
conclusion of the trial.  
B. Justify why identifiers are required to conduct the research. 
This is a biomedical study that requires breath, urine, and blood collection for 
screening eligibility, safety measure and to answer research questions. 
 
C. Described the proposed research use of the identifiable data / biospecimens. 
The de-identified data will be used for the purpose of this study. 
D. Self-classify the Risk Level of these data / biospecimens (select the highest level of risk for 
all data / biospecimens being collected). 
     ☒ Level 2 Risk 
     ☐ Level 3 Risk 
2. How will study data / biospecimens be collected? 
   ☐ Brown desktop 
   ☐ Laptop 
   ☒ Departmental server 
   ☐ CIS managed server 
   ☒ Brown Qualtrics 
   ☐ REDCap; Please describe what instance of REDCap is being used (Brown does not have an instance of  
        REDCap):  
   ☐ MTurk (AMT) 
   ☐ Text messaging  You must complete the Text messaging section after completing Qs 3 – 5. 
   ☐ Mobile App (on tablet, iPad, Phone)  You must complete the Mobile App section after completing Qs 3-5. 
   ☐ Zoom  
   ☐ Other audio / videoconferencing tool; please describe the tool:  
   ☒ Paper records, including photographs. Please describe, including how you will securely store 
        the paper records:    
Subject’s identifiable information (i.e. screening questionnaires) will be stored separately from individual 
data. Paper records will be maintained in locked file cabinets in locked offices. The file connecting the 
participant ID to their study code will be kept in a secured password protected department folder, then 
destroyed after conclusion of the trial. 
 
   ☐ Web-based site / survey / other tool not listed above  You must complete the Web-based Other section after  
        completing Qs 3 – 5. 

v. 08/07/2019
 Page 22 of 28 
☐Other; please describe:
3. Who will have access to the study data / biospecimens?
☐A. Brown PI only. How will unauthorized access by others be prevented?
☒B. Brown PI and other Brown research team members. How will unauthorized access by others be
prevented? 
Data will be stored on a Brown University protected drive. Unauthorized access by others will be 
prevented by password protecting the folder that the file is located in, as well as the file itself. All 
computer and biospeciment information will be de-identified and referred to by a subject identification 
number following collection. All electronic records will be maintained on password protected fileservers 
in a locked office, further protected by firewalls and other security procedures. 
☐C. Data will be shared with research collaborators external to Brown. This data sharing intent
must be described as part of your consent process / form. Please describe how you will
securely share / transfer the data outside of Brown:
Note that an Outgoing Data Use Agreement is required when sharing identifiable data external to Brown. 
Please follow the procedures outlined here. You do not need to submit a copy of a DUA to the HRPP. This 
will be linked by the ORI administratively. 
4. Where will the study data / biospecimens be stored?
☒Departmental server
☐CIS managed server
☐Stronghold
☐Campus file storage
☐REDCap
☒Other. Please describe:
Data collected via Qualtrics will be kept within Brown University Qualtrics. 
5. If traveling with your data, describe how your data will be secured.
NA 
6. For how long will you retain identifiable data / biospecimens? How will you destroy identifiers when no
longer required?
We will be deleting the file connecting the participant ID to their study code at the completion of the 
study. 

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Text Messaging (only complete if instructed above.) 
1. Are you using the current text messaging service available on the device? 
☐ Yes   ☒ No 
 
If “no,” you must also complete the Mobile App section. 
2. Whose device will be used? ☐ Participant’s personal phone   ☐ Brown-issued phone NA 
3. Content of messaging: (If brief, insert here; otherwise, please provide as an attachment) NA 
4. Is the communication one-way or two-way? ☐ One-way   ☐ Two-way NA 
Mobile App (only complete if instructed above.) 
1. Name of the mobile app: NA 
2. Has this site / tool been reviewed by CIS IT Security?  NA 
☐ Yes   ☐ No 
If “no,” answer the following: 
a. Who created the site / tool (vendor name or off the-shelf app creator name)? 
b. Where is it hosted?  
c. Is the site / tool scanned for security vulnerabilities? ☐ Yes   ☐ No 
d. What version of software is being used, if applicable: ☐ N/A or  
e. How are the data encrypted?  
3. Whose device will be used? ☐ Participant’s personal phone   ☐ Brown-issued phone NA 
If Participant’s person phone: 
a. How is the app downloaded to the device?  
b. Is a password or PIN required for the app? ☐ Yes   ☐ No 
4. Will data be stored on the device for any period of time? NA 
☐ Yes   ☐ No 
 
a. If “yes,” please describe (i.e., queue on phone and then transmitted to server):  
 
 
b. Is the app data encrypted on the device? ☐ Yes   ☐ No 
5. Device features mobile app can access ☒ N/A 
   ☐ Device ID and call information 
   ☐ Identity 
   ☐ Contacts   
   ☐ Camera 
   ☐ SMS or chat 
   ☐ Storage 
   ☐ Device and application history 
   ☐ Phone 
   ☐ Photo / media / files 
   ☐ Microphone 
   ☐ Location 
   ☐ Other; please describe:  
 
6. Will a third-party have access to research data through this app? ☐ Yes   ☐ No NA 
7. Is data transmitted by the device? NA 
☐ Yes   ☐ No 
If “yes,” how is it encrypted in transit?  
 
8. Are phone numbers or mobile identification numbers stored with the data? ☐ Yes   ☐ No NA 
Web-based Other (only complete if instructed above.) 

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1. Name of the site / tool: NA 
2. Has this site / tool been reviewed by CIS IT Security? NA 
☐ Yes   ☐ No 
If “no,” answer the following: 
a. Who created the site / tool (vendor name or off the-shelf app creator name)? 
b. Where is it hosted?  
c. Is the site / tool scanned for security vulnerabilities? ☐ Yes   ☐ No 
d. What version of software is being used, if applicable: ☐ N/A or  
e. How are the data encrypted?  
☐ Yes   ☐ No 
If “no,” answer the following: 
a. Who created the site / tool (vendor name)?  
b. Where is it hosted?  
c. Is the site / tool scanned for security vulnerabilities? ☐ Yes   ☐ No 
d. What version of software is being used, if applicable: ☐ N/A or  
e. How are the data encrypted?  
3. Is informed consent being obtained via this site / tool? NA 
☐ Yes   ☐ No 
If “yes,” how is re-identification prevented?  
 
4. Does the technology allow for the explicit exclusion of the collection of IP address of the participant’s 
connection? NA 
☐ Yes   ☐ No 
If “yes,” will you use this option to exclude the collection of IP address? 
☐ Yes   ☐ No 
 
Brown Qualtrics: CIS has pre-vetted Brown Qualtrics for collection/storage of up to Risk Level III data. Qualtrics is the preferred 
survey tool for all Brown research data collection. 
 
REDCap: Brown does not currently have its own instance of REDCap. Access to REDCap through a Lifespan collaborator must be 
explicitly identified. 
 
Data collection: The expectation is that data collection devices will only store data during active data collection. Data must then be 
transitioned to more secure long-term storage solutions. 
 
Departmental/CIS managed servers: If data are collected/entered directly onto a Departmental or CIS managed server, you must 
ensure that the server meets the security standards described in the Minimum Security Standards for Servers based on the Risk Level 
of the data identified in 1D. 
 
 
 
 

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PART VIII. INTERNATIONAL RESEARCH 
 
1.  Does the research involve human subjects activities outside of the United States? 
☐ Yes   ☒ No 
If “yes,” please list the countries: 
 
 
 
If “no,” you are not required to complete this Part of the application. Proceed to PART IX. 
ATTACHMENTS. 
------------------------------------------------------------------------------------------------------------- 
b. What is the status of permissions / approvals from local ethics boards or committees? 
 ☐ Received; please append to this Application. 
 ☐ Pending  
 ☐ N/A. Please explain:  
------------------------------------------------------------------------------------------------------------- 
c. Will this research take place in a non-public setting (including a school, hospital or 
clinic) for which local permission is required? ☐ Yes   ☐ No 
If “yes,” please append a letter(s) of support or permission(s) to this Application.  
 
------------------------------------------------------------------------------------------------------------- 
d. Describe how you have taken into account any social, political, or cultural issues that 
may impact participants.  
 
 
 
 
 ☐ I have reviewed the current version of the International Compilation of Human Research 
Standards and agree to abide by relevant local laws, regulations and guidelines. 
☐ I have reviewed the General Data Protection Regulations guidance and will abide by any 
requirements. 
☐ I have reviewed ORI’s export control guidance on international travel, international 
collaborations, and international shipping (if applicable) 
 
 
 
 
Proceed to PART IX. ATTACHMENTS 
 
 

v. 08/07/2019                                                                                                                                                                    Page 26 of 28 
 
PART IX. ATTACHMENTS 
 
 
Please attach the following materials to this Application for Full Board / Expedited IRB Review, as 
applicable. 
 
Incl.      N/A  
☒ 
☐ 
Informed consent documents / scripts 
☒ 
☐ 
Data collection materials (questionnaires, surveys, interview scripts, etc.) 
☐ 
☒ 
Permissions, approval documents, and/or support letters identified in PART VII. 
☒ 
☐ 
Recruitment materials (emails, flyers, letters, scripts, posters, brochures, etc.) 
☐ 
☒ 
Application for IRB Authorization Agreement 
☐ 
☒ 
Data Use Agreement from data provider(s) 
☐ 
☒ 
HIPAA Authorization 
☒ 
☐ 
Data Safety Monitoring Plan 
☒ 
☐ 
Other: See complete list below 
 
 
PART X. CONFLICT OF INTEREST  
 
The Brown University Conflict of Interest Policy for Officers of Instruction and Research (“COI Policy”) 
defines the term “Investigator” as “the project director or principal investigator and any other person, 
regardless of title or position (e.g., full or part-time faculty member, staff member, student, trainee, 
collaborator, or consultant), who is responsible for the design, conduct, or reporting of sponsored 
research.” 
 
Using this definition of “Investigator,” please ensure that all Investigators on this protocol answer questions 
(1) and (2) below. Attach additional sheets for any Investigators who are not the PI; additional sheets are 
available on the HRPP website. 
 
1. Have you completed a conflict of interest disclosure (i.e. COI Reporting Form) within the past 12 months 
and is it accurate and up-to-date as of the time of this submission, as required by Brown’s COI Policy? (You 
may access the InfoEd system here to confirm.) 
☒ Yes   ☐ No 
If “no,” please do so before submitting this Application 
2. Do you have a significant financial interest (SFI) that is related to this research protocol?   
“Related” could mean the research involves products, technology, intellectual property, or services made, 
owned, or provided by the entity/ies in which you have an SFI. It could also mean that the SFI could be 
affected by the proposed research or its results.     
 
☐ Yes   ☒ No 
If “yes,” please identify the SFI and explain the relatedness:  
☐ Additional COI sheets for Investigators are attached to this Application. 
(Required for Advisors) 
 
PART XI. INVESTIGATOR & FACULTY ADVISOR AGREEMENTS / 
PRINCIPAL INVESTIGATOR RESPONSIBILITIES  

v. 08/07/2019                                                                                                                                                                    Page 27 of 28 
 
 
 
 A. Conduct of the Research 
1. I accept responsibility for the ethical conduct of this research and protection of participants as set 
forth in the Belmont Report, Common Rule, and Brown University policies. 
2. I accept responsibility for ensuring this research is conducted in accordance with: 
a) Sound research design and methods; 
b) The parameters of the research plan and activities described in this Application; 
c) The applicable terms of the grant, contract, or other signed funding agreements; 
d) Applicable laws and regulations, including those protecting the rights, safety and welfare of 
human subjects. 
3. I certify that I am, or my faculty advisor is, sufficiently qualified by education, training and 
experience to assume responsibility for the proper conduct of this research. I accept 
responsibility for ensuring that all member of the research team have or will complete human  
4. subjects CITI training before any work with participants or identifiable data / biospecimens 
begins. 
5. I accept responsibility to personally conduct and/or directly supervise this research. I certify that 
I have sufficient time and resources to properly conduct and/or supervise this research. 
 
B. Ensuring and Maintaining Compliance 
1. I will comply with relevant regulatory and institutional reporting requirements, including Brown 
University’s Reportable Events Policy.  
2. I understand that it is my responsibility to ensure that any research personnel, including myself, 
responsible for the design, conduct or reporting of the research declares any conflicts of interest 
related to this research. I will ensure that any changes that impact my or other research 
personnel’s answers to the questions in PART IX. Conflict of Interest, are reported promptly to 
Brown’s HRPP. 
3. I will ensure that prospective agreement and/or informed consent is obtained and a copy is 
provided to participants, when appropriate. 
4. If there are changes to the research described in this Application for Full Board / Expedited IRB 
Review that may impact the study’s classification as Full Board or Exepdited research, I will 
promptly notify the Brown HRPP of such changes. 
5. I will notify the Brown HRPP when I have completed all activities involving human subjects or 
identifiable participant data or identifiable biospecimens. 
6. I will maintain approval, as applicable, with collaborative parties, including approvals from other 
countries or jurisdictions. 
7. I will cooperate with any post-approval monitoring or auditing of study activities and/or study 
records as requested and/or required by the Brown ORI, the Brown IRB, funding entities, 
sponsors, and/or any federal or state regulatory agencies. 
 
C. Study records, Reports and Documentation 
1. I will maintain all research protocol materials and consent materials for the duration of this 
study. 
2. I will maintain research records for at least three years following the end of this research, or for a 
longer length of time if specified in applicable regulations or sponsor requirements. I will take 
measures to prevent accidental or premature destruction of these records. 
3. I will abide by all terms of any Data Use Agreement (or equivalent agreement) related to this 
study, including those agreed to electronically (through an online attestation). 
4. I will ensure that the data security measures for acquisition, collection, transfer and use of study 
data described in PART VI. of this Application are adhered to by all members of the research 

v. 08/07/2019                                                                                                                                                                    Page 28 of 28 
 
team.  
 
                
By my signature below, I certify that I have read and agree to uphold all of you and/or Advisor 
Responsibilities in PART XI. 
 
 
 
 
Principal Investigator signature:    
 
 
 
Date:  8/30/2019 
 
 
 
=============================================================================== 
 
An Advisor’s signature is required for all graduate/medical student projects 
 
Advisor certifies the following:  Advisor has read the complete protocol, approves this project, and will remain 
available to advise the student throughout the course of the proposed human subjects research, or will transfer 
responsibilities to another Advisor if unable to advise for the entirety of the project. 
 
Advisor’s name (please print):         
 
Advisor's signature:   
 
 
 
 
 
Date:  Click here to enter a date. 
 
 
 
 
 
 
For IRB Use Only 
 
Signature of the IRB:  
 
Date of IRB approval: Click here to enter a date.