The Effects of the Histamine-3 Receptor Inverse Agonist Pitolisant on Alcohol Self-Administration in Heavy Drinkers
Phase: PHASE1
Conditions: Alcohol Use Disorder, Alcohol Drinking
Sponsor: Boston Medical Center

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THE EFFECTS OF THE HISTAMINE-3 RECEPTOR INVERSE AGONIST PITOLISANT ON 
ALCOHOL SELF-ADMINISTRATION IN HEAVY DRINKERS  
 
ClinicalTrials.gov number:  
Protocol Version Number: 1.10 
Protocol Version Date: 7.7.2022 
Sponsor:  NIAAA/NIH 
Principal Investigator:  Eric G. Devine, Ph.D. 
Phone: 617-638-7888 
E-mail: eric.devine@bmc.org 
 
CONFIDENTIAL 
 
This document is confidential and the property of Boston Medical Center.   No part of it 
may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 
 
 

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TABLE OF CONTENTS 
1 List of Abbreviations .................................................................................................................3 
2 Protocol Summary .....................................................................................................................3 
3 Background/Rationale & Purpose..............................................................................................4 
3.1 
Background Information ..................................................................................................4 
3.2 
Rationale and Purpose ......................................................................................................6 
4 Objectives ..................................................................................................................................7 
4.1 
Study Objectives ..............................................................................................................7 
4.2 
Study Outcome Measures .................................................................................................7 
4.2.1 
Primary Outcome Measures ...............................................................................7 
4.2.2 
Secondary Outcome Measures ...........................................................................7 
5 Study Design ..............................................................................................................................7 
6 Potential Risks and Benefits ......................................................................................................8 
6.1 
Risks .................................................................................................................................8 
6.2 
Potential Benefits ...........................................................................................................11 
6.3 
Analysis of Risks in Relation to Benefits .......................................................................12 
7 Study Subject Selection ...........................................................................................................12 
7.1 
Subject Inclusion Criteria ...............................................................................................12 
7.2 
Subject Exclusion Criteria ..............................................................................................12 
8 Study Intervention ....................................................................................................................13 
9 Study Procedures .....................................................................................................................14 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) ...........................................18 
10.1 Definitions ......................................................................................................................18 
10.2 Safety Review ................................................................................................................19 
10.3 Reporting Plans ..............................................................................................................20 
10.4 Stopping Rules ...............................................................................................................21 
11 Data Handling and Record Keeping ........................................................................................21 
11.1 Confidentiality ................................................................................................................21 
11.2 Source Documents ..........................................................................................................22 
11.3 Case Report Forms .........................................................................................................22 
11.4 Study Records Retention ................................................................................................23 
12 Statistical Plan ..........................................................................................................................24 
12.1 Study Hypotheses and Proposed Analyses .....................................................................24 
12.2 Sample Size Determination ............................................................................................25 
13 Ethics/Protection of Human Subjects ......................................................................................25 
14 Literature References ...............................................................................................................26 
15.  Appendix A: Schedule of Events ............................................................................................30 

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1 
List of Abbreviations 
 
Abbreviation 
Abbreviation definition 
Alcohol Use Disorder 
AUD 
 
2 
Protocol Summary 
Title: 
The Effects of the Histamine-3 Receptor Inverse Agonist 
Pitolisant on Alcohol Self-Administration in Heavy Drinkers  
Population: 
The present study will involve 72 men and women aged 21 to 
55 who exceed safe levels of drinking.  Women and minorities 
who meet the study criteria will be eligible to participate. No 
vulnerable populations are being targeted for inclusion in this 
study. 
Intervention: 
Eligible subjects will receive a dose of 8.9 mg (two 4.45 mg 
pills) of pitolisant or a matched placebo once daily over a 7-
day period and a dose of 17.8 mg (one 17.8 mg pill) of 
pitolisant or matched placebo once daily over a 5-day period.  
A 25 mg riboflavin tracer will be added to each 4.45 mg 
capsule and 50 mg riboflavin tracer will be added to each 17.8 
mg capsule to serve as an objective measure of medication 
adherence. Subjects will take study medication by mouth.  
Subjects will receive alcohol in the laboratory on day 12 in an 
alcohol craving challenge.  Subjects will be presented with 
four drinks, each mixed to raise their BAL 0.0125g/dl. They 
will be told that they can either consume the desired number of 
drinks over the following 60 minutes or they will receive the 
equivalent in a cash reward.  This procedure will be repeated 
with an additional 4 drinks after 60 minutes has elapsed.  
Subjects will serve as their own controls.  The intervention will 
be repeated with a placebo/pitolisant after a washout period. 
The order of pitolisant and placebo dosing will be randomized.   
Objectives: 
The specific objective of this study is to determine whether 
pitolisant, an H-3 receptor inverse agonist that is FDA-
approved for treating narcolepsy, has effects on alcohol 
craving and consumption. Testing the effects of pitolisant on 
drinking is a compelling opportunity that is consistent with the 
mission of NIAAA to evaluate the efficacy of re-purposed 
compounds with novel mechanisms that have the potential to 
treat AUD.  If successful, this study could lead to a phase II 
randomized controlled trial to test pitolisant as a treatment for 
AUD.  The specific goal of this study is to evaluate the effects 
of pitolisant on drinking and craving among heavy drinkers in 
a human laboratory using an alcohol self-administration 
paradigm.   

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Design/Methodology: This is a double-blind, randomized, placebo-controlled, 
crossover design trial that will test the effect of pitolisant on 
alcohol self-administration and craving following a priming 
dose of alcohol.  An established human laboratory self-
administration procedure will be followed.  Each subject will 
complete 5 clinic visits over a period of up to 66 days of 
participation.  Study participation is comprised of a baseline 
assessment, randomization visit, alcohol self administration 
Trial 1, an assessment visit to verify continued eligibility and 
dispense medication, and a second alcohol self-administration 
Trial.  The volume of alcohol consumed during alcohol 
challenge trials 1 and 2 will be used to test the effect of 
pitolisant on alcohol consumption.  Craving measures (AUQ 
and VAS) collected during the self-administration trials will be 
used to test the effect of pitolisant on alcohol craving.   
Total Study 
Duration: 
The entire study will take 24 months to complete. 
Subject Participation 
Duration: 
Each subject’s length of participation will be up to 66 days.   
 
3 
Background/Rationale & Purpose 
 
3.1 
Background Information 
Current models of care for treating Alcohol Use Disorder (AUD) include both behavioral 
therapies and pharmacotherapy1.  Although pharmacotherapy for AUD in the US has been 
available since 1948 when disulfiram was approved, options for treatment are limited as there are 
only four medications which have been approved by the FDA for treating AUD.  Disulfiram, 
naltrexone, acamprosate, and long-acting naltrexone have all shown promise as agents to treat 
AUD2 but no single medication has proven to be effective across the heterogeneous groups of 
people with AUD3. Movement towards models of personalized care and pharmacogenetic 
treatment matching4-5 hold some promise for improving AUD treatment outcomes, but the 
limited number of unique mechanisms of action of the currently approved drugs presents a 
challenge to implementing this model of care.  Unfortunately, few novel compounds to treat 
AUD progress to phase II trials, and developing novel compounds is both costly and time-
consuming6.  One pathway of drug development efforts has been focused on re-purposing FDA 
approved medications that have promising mechanistic effects7 and some success data has 
supported the use of H3 receptor antagonists as haing potential to modulate craving and 
consumption8.  Identification of additional drugs with unique mechanisms of action that are 
found to reduce alcohol consumption could expand the treatment options and further the goal of 
personalized care for AUD.  The overarching goal of our research is to identify agents with 
unique mechanisms that hold promise for treating AUD.  The specific objective of this study is 
to determine whether pitolisant, an H-3 receptor inverse agonist that is FDA-approved for 
treating narcolepsy, has effects on alcohol craving and consumption.     
Alcohol Use Disorder as a national health problem 

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More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States9.  The 
economic burden of this is estimated to be 249 billion dollars and approximately 88,000 
Americans die from alcohol-related causes each year10.  Untreated AUD is associated with an 
increased risk of accidents, injuries, suicide, and worsening of other health comorbidities11 and it 
is the third most preventable cause of death in the US10.  Treating addiction more effectively has 
become a priority of national importance and the Surgeon General has urged researchers to 
undertake testing of new treatments to combat addiction12.  The present study is intended to 
answer the call for accelerating drug development for AUD by exploring the potential to re-
purpose an existing drug as a treatment for AUD6-7.    
 
Rationale for developing pitolisant as an agent to treat AUD 
H-3 histamine receptors are one of the four types of presently known histamine receptors. These 
G protein-coupled receptors are present predominately in the brain and are implicated in the 
regulation of a variety of behaviors including those related to cognitive function, locomotor 
activity and anxiety13-15.  The finding that the density of binding of an H-3 receptor ligand was 
lower in insular cortical, accumbal, and hippocampal brain regions in alcohol-preferring rats 
(AA) as compared to alcohol-avoiding rats provided some of the first evidence that brain H-3 
receptors may play an important role in the regulation of alcohol consumption16. Further 
evidence of this includes the observation that H-3 receptor knock-out mice derived from the 
C57B/6J strain consume less alcohol than wild type mice of this strain17. Numerous studies have 
shown that the administration of either H-3 receptor antagonists or H-3 inverse 
agonists/antagonists (i.e. ciproxifan clobenpropritor or thioperamide) reduces ethanol 
consumption in rats16,18 and mice 18, 19,20. In contrast, the administration of H-3 receptor agonists 
increases the self-administration of alcohol by AA rats16. Conditioned place preference studies 
indicate that H-3 receptor antagonists and inverse agonists/antagonists reduce alcohol-related 
reward17,19-21.  This may be a factor that explains the reduction of alcohol consumption produced 
by these agents.  It should be noted, however, that the administration of ciproxifan or the H-3 
receptor antagonist conessine, failed to block ethanol-induced place preference in certain strains 
of mice, namely C57BL/6Sca22 and Swiss mice23, respectively. Cue-induced reinstatement of 
responding by mice for alcohol is attenuated by the administration either of the H-3 receptor 
antagonist JNJ-39220675 or by ciproxifan, suggesting that these agents may decrease alcohol 
cue-induced craving24.  
 
While much of the research based on animal studies indicates that pharmacological 
blockade of H-3 receptors may lead to reductions in the drinking of alcohol, the degree to which 
these studies will translate to human alcohol consumption in individuals with AUD remains to be 
determined. Ligand binding studies do indicate that H-3 receptors are located in several areas of 
the human brain that are linked to the regulation of alcohol consumption including the nucleus 
accumbens, insular cortex, and anterior cingulate25-28. 
Recently the FDA has approved the H-3 receptor inverse agonist/antagonist pitolisant for 
the treatment of excessive daytime sleepiness and catalepsy in narcolepsy patients. The Ki of this 
drug as an antagonist of the recombinant human H-3 receptor is 0.16 nm, and its E50 for its 
action as an inverse agonist at these receptors is 1.5 nm13. In contrast, the Ki for pitolisant at H1, 
H2, and H4 receptors are in the micromolar range indicating that this drug has a high degree of 
selectivity for the H-3 receptor. The therapeutic effects of pitolisant in narcolepsy patients may 
be mediated by the activation of histaminergic neurons resulting from the blockade of 
presynaptic H-3 receptors. The presynaptic actions of this drug promote the release of 

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histamine13. Increased histamine release in the nucleus accumbens produced by the 
administration of ciproxifan was found to correlate with reductions in alcohol seeking 
behaviors24. Whether the histamine releasing actions of drugs that counteract H-3 receptor 
activation can account for their suppressant effects on alcohol consumption in rodents is still 
being studied.  Some authors have postulated that these effects may be related by the blockade of 
the effects of dopamine resulting from inhibition of H-3/dopamine heteroreceptors in the nucleus 
accumbens24. Pitolisant, in contrast to stimulants such as amphetamine that are abused, has not 
been found to elevate levels of mesolimbic dopamine29. 
In healthy volunteers who were moderate drinkers, enhanced bold signals in the striatal 
areas including the nucleus accumbens were found to correlate with stimulation ratings during 
alcohol infusion30. This finding suggests that alcohol-induced stimulation involves activation of 
the brain linked to the reinforcing effects of many drugs of abuse. One group of investigators has 
found that heavy drinkers may be more sensitive to the stimulant effects of alcohol than are light 
drinkers as measured on the ascending limb of the blood alcohol curve31-33 and suggest that 
continued sensitivity to the stimulant effects of alcohol may be one of the factors that contributes 
to the continued alcohol consumption in AUD.  Given the possible role of alcohol stimulant 
effects in facilitating drinking and that pitolisant has what can be construed as stimulant-like 
properties such as decreasing daytime sleepiness and in enhancing alertness, it is important to 
determine that this drug will not enhance the stimulating effects of alcohol in drinkers. We 
hypothesize that it will not for several reasons. Pitolisant as compared to psychomotor stimulants 
such as amphetamine does not increase the release of dopamine in the nucleus accumbens, which 
may play a key role in mediating the reinforcing effects of many drugs of abuse29.   Unlike 
psychomotor stimulants pitolisant is not self-administered by primates, an established animal 
model of abuse liability29. More importantly, among people who use stimulants, drug liking and 
willingness to use the drug did not differ significantly between pitolisant and placebo34. In this 
study we will examine whether pitolisant increases the stimulant effects of a priming drink of 
alcohol as assessed using the biphasic alcohol effects scale (BAES)35. 
In narcolepsy patients, pitolisant is well tolerated but may produce some adverse effects 
such as insomnia and sleep disturbance that may be related to its activation of the systems that 
mediate this drug’s therapeutic effects.  In healthy human subjects, single oral doses of pitolisant 
at doses several times above those currently recommended for therapeutic use were well 
tolerated with EEG evidence of increased vigilance and enhanced attention being detected at the 
end test days36. The H-3 receptor antagonist, ABT-288, also has been reported to be well 
tolerated when it was administered to healthy young adults37. Thus, it is anticipated that 
pitolisant should be well tolerated in subjects who do not have narcolepsy.   
 
 
3.2 
Rationale and Purpose  
 
This proposal holds significant innovation as there is strong evidence that medications 
that act as inverse agonists at the H-3 receptor decrease alcohol consumption and its rewarding 
effects. There are currently no published clinical studies concerning the effects of either H-3 
receptor inverse agonists/antagonists or of H-3 receptor antagonists on alcohol consumption. 
This proposed study answers the call for accelerating the development of medications for AUD 
by testing a commercially-available and well-tolerated agent at a fraction of the cost of 
developing novel therapies. This proposal is innovative as no other human studies have explored 

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the H-3 receptor systems as a target for medications to treat alcohol use disorder.  Given the 
compelling preclinical findings that H-3 inverse agonists/antagonists modulate craving and 
consumption, testing this mechanism in a human laboratory is the next logical step in drug 
development.  
 
 
 
4 
Objectives 
 
4.1 
Study Objectives 
 
The specific objective of this study is to determine whether pitolisant has effects on alcohol 
craving and consumption. Testing the effects of pitolisant on drinking is a compelling 
opportunity that is consistent with the mission of NIAAA to evaluate the efficacy of re-purposed 
compounds with novel mechanisms that have the potential to treat AUD.   
 
4.2 
Study Outcome Measures 
 
4.2.1 Primary Outcome Measures 
 
The primary outcomes are alcohol consumption and cravings during the alcohol self-
administration trials.  Drinking volume during the alcohol self-administration will be measured 
to evaluate the effects of pitolisant vs. placebo on the rate of alcohol consumption after a priming 
drink.  Alcohol craving will be measured using the Visual Analog Scale (VAS) and the Alcohol 
Urge Questionnaire (AUQ)38 during the alcohol self-administration trial.  These self-report 
measures of craving will be used to evaluate the effect of pitolisant on craving vs. placebo.   
 
4.2.2 Secondary Outcome Measures 
 
Secondary outcome measures for this study include the effect of pitolisant on 1) stimulant effects 
of alcohol, and 2) alcohol consumption and craving and sleep quality during the medication 
exposure period. The Biphasic Alcohol Effects Scale (BAES)35 will be used to assess the effects 
of pitolisant administration on the stimulant effects of alcohol. The Obsessive-Compulsive 
Drinking Scale (OCDS)39 and alcohol Visual Analog Scale (VAS) will be used to assess the 
effects of pitolisant on craving during the medication exposure period. Sleep Diaries will be used 
to assess the effects of pitolisant on sleep quality during the medication exposure period. 
 
5 
Study Design 
 
This is a double-blind, randomized, placebo-controlled, crossover design trial that will test the 
effect of pitolisant on alcohol self-administration and craving following a priming dose of 
alcohol.  An established human laboratory self-administration methodology developed by 
O’Malley and her colleagues will be followed40.  The O’Malley self-administration methodology 
entails subjects consuming a priming drink of alcohol and subsequently participating in two one-
hour self-administration sessions.  In each session subjects receive four alcoholic drinks which 

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they may either drink, or otherwise receive compensation for not consuming.  Confirmation of 
the validity of this approach as a method for screening for medications to treat AUD include the 
finding that pre-treatment with naltrexone significantly reduced alcohol consumption when the 
O’Malley methodology was used40. Using this method, our group has found that the 
anticonvulsant zonisamide reduces alcohol consumption in non-treatment seeking social 
drinkers41.  We later confirmed that the administration of zonisamide decreases alcohol 
consumption in subjects with AUD in a double-blind randomized clinical trial42 as have other 
investigators43. Testing pitolisant using this self-administration methodology is the next logical 
step in drug development given the strong evidence that the H-3 receptors are located in the 
pathways that regulate alcohol consumption in humans and that H-3 receptor inverse 
agonist/antagonists reduce drinking in animal models.  The human laboratory-based alcohol self-
administration methodology is cost effective and time-efficient for testing novel drug candidates 
for AUD treatment44. 
 
Subjects: Heavy-drinking subjects will be enrolled to increase the potential generalizability of 
these findings to a clinical AUD population.  Subjects will be recruited through advertising, 
study flyers, internet postings, and an established subject registry at Boston Medical Center.  
Interested subjects will be screened by telephone to determine initial eligibility prior to the 
baseline assessment.  
   
 
6 
Potential Risks and Benefits 
 
6.1 
Risks 
Risks of study medication  
To minimize the risk of adverse health events we will instruct subjects to contact study staff with 
any questions or concerns about changes in health effects after initiating study 
medication/placebo. Trained medical staff will evaluate any reported adverse effects and make a 
clinical determination about management through dosing methods, dose discontinuation, and/or 
referral for medical care. If subject cannot tolerate the escalation in dose of study medication 
during the medication exposure period, their participation in the study will be discontinued and 
they will be instructed to stop taking the study medication immediately Subjects will be given a 
wallet card that includes a phone number with 24/7 coverage for medical emergencies. As an 
added safety precaution, subjects will be contacted three times mid-week of the medication 
exposure period for an adverse effect assessment.    
Adverse events 
The following adverse reactions were observed in data collected for 266 patients with 
narcolepsy, 114 of which received a placebo45.  The incidence of the following adverse reactions 
of pitolisant versus placebo were as follows: Headache (18% vs 15%), Insomnia (6% vs 2%), 
Nausea (6% vs 3 %), Upper respiratory tract infection (5 % vs 3 %), Musculoskeletal pain (5% 
vs 3%), Anxiety (5 vs 1%), Heart rate increased (3% vs 0%).  In post marketing reports, the 
following adverse effects have been recorded: fatigue, weight gain, epilepsy, abnormal behavior 
and dreams, bipolar disorder, depression/depressed mood, sleep disorders, nightmares, 

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suicidality, and pruritus. Post marketing reports of side effects are uncertain in causality and 
because the population size is unknown, the rates of these effects cannot be 
determined. Although pitolisant has wakefulness effects, it has not been found to have a strong 
potential for misuse29.   
 
Pitolisant can reduce the reliability of hormonal contraceptives, and it’s dosing is altered by 
concomitant use of strong CYP2D6 inhibitors and CYP3A4 inducers. The pharmacodynamic 
effects of pitolisant may be blocked by the administration sedating histamine-1 receptor 
antagonists. Use of pitolisant can result in QT interval prolongation, especially when taken with 
other drugs that prolong the QT interval.  Preclinical studies have found a risk of exposure 
during pregnancy with doses four times greater than the maximum dose.  Given that the risk is 
unknown in humans, pregnant women should avoid exposure to pitolisant.   
 
To protect against the risk of altered drug metabolism for subjects taking strong CYP2D6 
inhibitors and CYP3A4 inducers, we will exclude subjects taking any of these medications.  
Subjects known to be poor CYP2D6 metabolizers (PMs) will also be excluded due to risk of 
higher pitolisant concentrations. Subjects who need to take sedating H-1 receptor antagonists 
will be excluded because these drugs may block the CNS effects of pitolisant. 
 
Given that pitolisant is largely metabolized by the liver, subjects will be excluded from this study 
who have any clinically significant hepatic disease.   Because the pharmacokinetics of pitolisant 
are unknown among people with renal disease, subjects will be excluded for renal insufficiency.   
 
To protect against the risk of QT prolongation, subjects taking other medications which have this 
adverse effect will be excluded and we will exclude subjects whose have QTc interval > 450 
msec.  Subjects will also be excluded if they have a history of any clinically significant cardiac 
disease or a family history of long-QT syndrome.   
 
Risks of Phlebotomy 
To minimize the risk of pain, bruising, lightheadedness, and on rare occasions, infection or 
fainting from a blood draw, we will used trained phlebotomists. 
 
Physical discomforts: 
The drawing of blood may cause pain, bruising, lightheadedness, and on rare occasions, 
infection. Subjects may briefly feel the prick of the needle when it is inserted.  Subjects may feel 
dizzy or faint when blood is drawn. Trained phlebotomists will be used to minimize these risks.    
ECGs may cause discomfort and/or irritation of the skin (redness and itching) from the adhesive 
electrodes. Hair on your chest may need to be removed in order to obtain the best electrical 
contact between the adhesive electrodes and subjects’ skin. Trained staff will be used to 
minimize these risks. 

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Risk to a developing fetus 
The administration of pitolisant in pregnant women has not established a known risk for major 
birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproductive studies, 
however, there is a known maternal and embryofetal toxicity in rats and rabbits.   
To protect against the risk of potential developmental toxicity to a fetus, women will be excluded 
from study entry if they have a positive urine pregnancy test or if they are of childbearing age 
and are either not using appropriate methods of contraception or not practicing abstinence. 
Pitolisant may reduce the efficacy of oral contraceptives. If the subject’s primary method of 
contraception is oral contraceptive, they will be required to use an approved back-up form of 
contraception beginning at first dose of pitolisant/placebo and continuing through 21 days 
following last dose. Urine pregnancy testing will also be completed at each study visit as a 
protection to the developing fetus.  Subjects with positive pregnancy test results will be 
discontinued form participation. 
 
Risks of alcohol self-administration 
Risk to recovery efforts 
Treatment-seeking drinkers will be excluded from this study to minimize the risk that drinking in 
the laboratory could worsen outcomes for a subject trying to reduce or abstain from alcohol. All 
subjects will undergo a medical screening and we will exclude subjects who have diagnosed 
medical or mental condition for which alcohol exposure in this study would be contraindicated.  
All subjects will receive the NIAAA self-help guide Rethinking Drinking at the end of study 
participation.  
Risk of overconsumption  
To minimize the risk of subjects reaching a level of intoxication that is uncomfortable to them, 
we will remind subjects that they may discontinue study participation at any time.  Subjects will 
be asked to drink to a target BAL (0.03 g/dl) that is customary for them given the minimum 
drinking criteria.  The alcohol self-administration paradigm that we have chosen does not include 
any coercion, inducements, or pressure to consume more alcohol than subjects feel comfortable 
consuming.  There are no experimental manipulations that would increase drinking (e.g., heavy 
drinking confederate, anxiety manipulation).  In fact, in this study design there are inducements 
for subjects to not drink beyond the initial priming dose.  Subjects will receive monetary 
incentives for each drink that they do not consume.  Access to medical backup services will be 
maintained throughout each alcohol challenge session.  Subjects will be monitored during the 
course of the study, both through direct assessment with study staff and by observation through a 
video camera.  Medical staff will evaluate subjects and may make a determination to halt study 
participation if the subject becomes too behaviorally impaired or if there are emergent safety 
issues.  Subjects who have a BAL greater than 0.04 g/dl or who appear to be too behaviorally 
impaired to leave our research center will be asked to remain in the clinic until their intoxication 
is reduced to a level that it is safe to discharge them from the research laboratory. BAL readings 
will be taken twice to confirm BAL is not greater than 0.04 g/dl prior to release.  Subjects will 

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not be released within 60 minutes of their last drink consumed to ensure that peak BAC has been 
reached prior to discharge.  During the descending BAL period, subjects will have access to a 
comfortable space with entertainment (streaming media), snacks, non-alcoholic beverages, and a 
nearby bathroom.       
 
Risks of suicidality 
Following consent at screening and during subsequent visits, suicidal ideation and behavior will 
be assessed using a validated measure (C-SSRS) by trained and credentialed staff including the 
study PI (PhD, Clinical Psychology), study physician (MD), study nurse (RN, MSN), and project 
manager (LMHC). All suicidality assessments are completed during in-person visits and are 
reviewed in real time. Staff who perform suicidality assessments are experienced in managing 
suicidal ideation and behavior. Clinical staff will work with subjects to ensure a plan for safety, 
and if this cannot be achieved will escalate to a higher level of care. Subjects will be escorted to 
the BMC Emergency Department in the case of emergent suicidal ideation. All subjects who 
have any suicidal ideation will be educated about the Boston Emergency Services Team and will 
be given the toll-free number for the BEST team. 
 
Risk of loss of confidentiality  
There is some risk that health information collected as part of this study could be seen by 
unauthorized individuals.  Every effort will be made to minimize this risk and protect subject 
confidentiality. Before a subject agrees to allow study staff to mail study materials to their home 
address, they will be asked to carefully consider the risk of others learning that they are 
participating in the study in the event that mail containing study materials is intercepted. 
Electronic data will be housed in the REDCap data management system.  REDCap is protected 
via Secure Sockets Layer (SSL) encryption that provides access restriction options.  Exported 
data from REDCap will be stored on a secure password-protected server behind the BMC 
firewall. Source and CRF binders will be stored in a double-locked area that is accessible to only 
study staff.  Subjects will be assigned a study identification number and this will be used to code 
any forms that do not require the subject’s direct identifiers (e.g., consent form, laboratory 
results, and contact information).  A linking key that associates study ID with direct identifiers 
will be stored in a double-locked cabinet accessible only by study team members.  Data will be 
stored on a password-protected computer accessible only to the study team.  Video of subjects 
during the drinking session will be stored on an encrypted drive with password protection.  
Video files will be deleted at the end of the study.  All study staff will receive appropriate 
training for the protection of human subjects (NIH Protecting Human Research Participants, 
CITI Training). A certificate of confidentiality will be sought to protect subjects from disclosure 
under court order or subpoena.  
 
6.2 
Potential Benefits 
 
There is no potential direct benefit to participation in this study.  This study presents a very 
strong potential for benefit to science.  Drug development for treating AUD is costly and few 
pharmaceutical companies are testing novel compounds as agents to treat AUD.  Re-purposing 

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compounds with FDA approval for other indications is the most promising route for rapid and 
cost-effective development of medications to treat AUD.   This study will bridge the gap in drug 
development by providing a test of pitolisant to see if it may be a candidate drug for treating 
AUD.  If successful, this could lead to the expansion of pharmacotherapy options to treat AUD 
and a broadening of our understanding of the mechanistic approach to treating AUD.  
 
6.3 
Analysis of Risks in Relation to Benefits 
 
Given that pitolisant has FDA approval for another indication and is well-tolerated in other 
populations, the risk to human subjects has been established through pre- and post-marketing 
data. With the protections we have in place, we believe the risks of this study are well 
minimized.  The study holds significant promise for informing new models of care given the 
novel mechanism of pitolisant.  We believe the risk/benefit ratio is favorable. 
 
 
7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
inclusion criteria: 
 
1. 21-55 years of age 
2. Able to verify age with a state or federal picture ID 
3.  Exceeds safe weekly drinking limits during the 28 days prior to consent (average of 14 
drinks for women or 21 drinks for men per week) 
4. Reports at least one episode of binge drinking (>3 drinks for women, >4 drinks for men) in 
the 28 days prior consent.   
5. Meets DSM-5 criteria for mild alcohol use disorder or greater severity. 
 
7.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Does not have a smartphone to complete medication exposure period study assessments   
2. Seeking treatment for alcohol problems  
3. Clinical Institute Withdrawal Assessment at ≥10  
4. DSM-5 diagnosis of current major depression, bipolar disorder, schizophrenia, 
bulimia/anorexia, insomnia disorder or a substance use disorder other than alcohol, nicotine, 
marijuana or caffeine 
5. If female, pregnant, nursing, have plans to become pregnant 
6. If female, does not agree to use an accepted form of birth control 
7. Has a medical contraindication to the use of pitolisant 
8. Has diagnosed medical or mental condition for which further alcohol exposure at the planned 
dose range would be contraindicated 
9. Current risk of suicidality (MINI suicidality score greater than 8 (low risk) or Yes to the 
ideation question #4 of the C-SSRS) 

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10. BMI is greater than 40 or less than 18 
11. Impaired renal function (GFR <80 mL/min) 
12. Has a history of any clinically significant renal or hepatic disease   
13. Child-Pugh Score equal to or greater than Class B (evaluated based on presence or absence 
of encephalopathy and ascites, INR, bilirubin, and albumin) [https://www.mdcalc.com/child-
pugh-score-cirrhosis-mortality]  
14. Has a clinically significant ECG as determined by the investigator or abnormal ECG heart 
rate (<45 or >100 bpm) or QTc interval corrected for heart rate using the Fridericia formula 
(QTcF) > 450 msec 
15. Has a history of cardiac arrhythmias or who for other reasons are at risk for developing 
Torsade de Pointes including those with bradycardia, hypokalemia, and congenital QT 
interval prolongation 
16. Has a history of dementia 
17. Has received alcohol counseling or other non-pharmacologic intervention to treat AUD in the 
past 90 days  
18. Has taken medications that are used to treat AUD in the past 90 days 
19. Is currently taking medication that is a sensitive CYP3A4 substrate 
20. Is currently taking a QTc prolongation agent 
21. Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, 
methadone, methamphetamines, oxycontin, barbiturates, or benzodiazepines.  
22. Subject is taking a medication which will significantly alter drug metabolism (e.g., strong 
CYP2D6 inhibitors, strong CYP3A4 inducers, or H1 receptor antagonists that cross the blood 
barrier (e.g. diphenhydramine or meclizine). 
23. Subject has known hypersensitivity to pitolisant and any of its components, riboflavin, and/or 
lactose. 
24. Subject is known to be a poor CYP2D6 metabolizer. 
25. Subject is unable to comfortably abstain from nicotine for a period of 8 hours.  
26. Has COPD, history of solid organ transplant, sickle cell disease, severe heart disease or other 
health condition for which exposure to COVID-19 represents an unreasonable risk as 
determined by the study staff physician using accepted COVID-19 guidance (e.g. Centers for 
Disease Control, etc.). 
 
8 
Study Intervention 
Study Medication 
Study medication will be packaged by the BMC Investigational Pharmacy Service. Pitolisant 
4.45 mg pills will be over-encapsulated with 25 mg of riboflavin and pitolisant 17.8 mg pills will 
be over-encapsulated with 50 mg of riboflavin which will serve as a tracer of medication 
compliance using urine obtained on the day of the alcohol challenge.  Matching placebo will also 
be packaged using lactose and 25 mg (4.45 mg pill) or 50 mg (17.8 mg pill) of riboflavin.  
Medication will be dispensed to each subject in two bottles. One bottle will contain 14 pills of 
pitolisant (4.45 mg) or placebo and the other bottle will contain 5 pills of pitolisant (17.8 mg) or 
placebo. Capsule size required will be determined by IPS with the goal of a minimum capsule 
size needed for over-encapsulation. If a subject reports losing (or destroying) study medication, a 
replacement prescription will be written by one of the study physicians and the BMC 
Investigational Pharmacy will dispense additional medication to replace the lost (or destroyed) 
medicine.  

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Dosing 
Subjects will take an 8.9 mg dose of pitolisant (two 4.45 mg pills) or placebo once per day on 
day 1 through 7, beginning 12 days prior to the alcohol challenge. Subjects will then take a 17.8 
mg dose of pitolisant (one 17.8 mg pill) or placebo once daily on days 8 through 12.  This dose 
was chosen because it is consistent with the clinical dose range of this drug when it is used for 
treating narcolepsy. 
 
 
Medication Storage 
Medication will be stored in the Investigational Pharmacy at room temperature (within the range 
of 59°F to 86°F) in a secured area until the time that medication is needed for study subjects.  
Stability and expiry will be monitored by IPS according to the labelling of the medication from 
the manufacturer.   
 
Medication Labeling 
The study number will be preprinted on each bottle label. The label will include the drug name 
(e.g., “Pitolisant 4.45 mg”, “Pitolisant 17.8 mg” or “placebo”).  The label will also have a 
randomization number, the number of tablets contained in the bottle, storage conditions, the 24/7 
phone number of the clinical site, and places to record the subject number and the date 
dispensed.  Additional fields may be added to this label to meet any regulatory requirements as 
determined by IPS.   
 
Medication Blinding and Unblinding 
Study medication and placebo capsules will be identically matched in appearance and the bottle 
labels will not reveal the drug identity. The Study PI and study physician(s) will make the 
decision to un-blind the identity of the study medication in the event that the study blind needs to 
be broken to make medical decisions regarding subject treatment. 
 
Medication accountability 
The site principal investigator (PI) or designated study personnel will maintain a log of all study 
medication and record of dispensing of all medication to the subject. The site PI or his staff will 
count the tablets remaining at the end of the study and record the tablet count on the appropriate 
drug accountability form. Subject compliance with study medication will be assessed by 
comparing unused capsule count to dispensing logs and dosing records (number of tablets 
dispensed, number of tablets prescribed, versus the number returned). Subjects will also be asked 
to account for any missing tablets. If the bottles are not returned, the subject will be asked to 
report daily drug self-administration. 
 
9 
Study Procedures 
Study Overview: Each subject will complete 5 clinic visits over a period of up to 66 days of 
participation.  Study participation is comprised of a baseline assessment, randomization visit, 
alcohol self administration Trial 1, an assessment visit to verify continued eligibility and 
dispense medication, and a second alcohol self-administration Trial (see figure 1 for an overview 
of study participation).     
 

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Baseline assessment:  Consenting subjects will undergo a general 
medical screen, physical examination, and electrocardiogram.  
Drinking will be assessed using the TLFB46, alcohol withdrawal 
using the Clinical Institute Withdrawal Assessment47, and 
suicidality using the Columbia-Suicide Severity Rating Scale (C-
SSRS)48.  Exclusionary mental health conditions will be assessed 
using the MINI Neuropsychiatric Interview and SCISD-R 
Interview for DSM-549.  Subjects will undergo laboratory testing 
that includes liver function and renal function, complete blood 
count, electrocardiogram recording, urine toxicology and a urine 
pregnancy test for women of child bearing potential.  
 
Study randomization (medication visit #1): Qualified subjects 
will return to the lab within 14 days for randomization to a 
crossover sequence of drug exposure.  Subjects will be assigned to 
one of 2 groups (n=18), with one group receiving pitolisant prior  
to the first alcohol challenge trial and the other receiving pitolisant 
prior to the second alcohol challenge trial.  Randomization of 
subjects will be accomplished using a stratified randomization 
procedure that will allow for between-group balance for drinking 
status (heavy vs. very heavy).  Heavy drinking is defined as ≥ 21 
and < 35 standard drinks per week for men, and ≥ 14 and < 28 
standard drinks per week for women.  Very heavy drinking is 
defined as ≥ 35 standard drinks per week for men, and ≥ 28 standard drinks per week for women.  
This stratified randomization will minimize the possibility that the order of study drug 
administration seems to influence outcomes when order effects are actually related to differences 
in severity of drinking between the two groups of subjects who are receiving the study 
medication in a different order. On the day of randomization, subjects will undergo an alcohol 
breath test, urine drug screening, urine pregnancy testing, assessment of concomitant 
medications, and the TLFB to ensure eligibility.  Subjects who have purposefully abstained from 
drinking and achieved 14 days of abstinence prior to the challenge will be discontinued from 
participation for ethical reasons50.  Eligible subjects will be randomized and will receive a 12-
day supply of over-encapsulated pitolisant or a matched placebo. Subjects will be scheduled for 
an alcohol challenge trial within 19 days of randomization.  Subjects will be contacted to remind 
them to start taking study medication twelve days prior to the scheduled alcohol challenge trial. 
Subjects will be allowed to delay start of medication for up to 7 days after randomization in 
order to accommodate scheduling for the alcohol challenge trial.   
 
Drug exposure period: 
Randomized subjects will receive 12 days of study medication at the time of randomization.  A 
riboflavin tracer (25 mg for 4.45 mg pill; 50 mg for 17.8 mg pill) will be added to each capsule 
to serve as an objective measure of medication adherence using urine obtained on the day of the 
alcohol challenge51. Two bottles will be dispensed to each subject. One bottle will contain 14 
pills of pitolisant (4.45 mg) or placebo and the other bottle will contain 5 pills of pitolisant (17.8 
mg) or placebo. All pills will be over-encapsulated with 25 mg (4.45 mg pill) or 50 mg (17.8 mg 
pill) of riboflavin. Subjects will take an 8.9 mg dose (two 4.45 mg pills) of pitolisant or placebo 
 

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once per day on day 1 through 7. Subjects will then take a 17.8 mg dose (one 17.8 mg pill) of 
pitolisant or placebo once per day on day 8 through 12. The 17.8 mg pill will be 
overencapsulated with 50 mg of riboflavin. Based on the published half-life for pitolisant, 
subjects should reach steady state levels after 5 days of taking the 17.8 mg dose.  This dosing 
plan is consistent with the FDA approved prescribing information for the treatment of 
narcolepsy.    
 
During the twelve-day period of drug exposure, subjects will be asked to answer a medication 
compliance question each day by smartphone using the REDCap data capture App52.  In addition 
to assessing medication compliance, subjects will also be asked to rate their craving for alcohol 
each day using the alcohol VAS. Subjects will receive a $5 reimbursement on each day they 
complete the VAS and answer the medication compliance question using the REDcap 
smartphone App.  Sleep quality during the drug exposure period will also be assessed by having 
subjects complete items from the National Sleep Foundation Sleep Diary each day. Items to be 
completed will include daily reports on the total number of hours slept per night and on the 
number of times and number of minutes for awakening during the night. 
 
Medication Visit #2 
After the 7-14 day washout period subjects will return to the lab to receive study medication 
prior to the alcohol challenge #2.  Subjects will complete the same tests and interviews 
completed during the randomization visit (See appendix A for schedule of events).  Based on the 
assessments at medication visit #2, subjects be discontinued for the following reasons: 
pregnancy, recreational drug use except for marijuana, evidence of non-compliance with study 
medication, suicidal thoughts or behavior, and use of a new medication that would make 
participation unsafe.  Subjects will receive a 12-day supply of study medication and will be 
scheduled for the alcohol challenge #2. Subjects will be allowed to delay start of medication for 
up to 7 days after randomization in order to accommodate scheduling for the alcohol challenge 
trial.   
 
Alcohol Challenge Trials 1 & 2:  Subjects will return to the laboratory on day 12 of drug 
exposure for each medication trial to complete the alcohol challenge. For safety reasons, subjects 
will be asked to arrange transportation plans (no driving) prior each of the alcohol challenge 
trials.  There will be a 7-14 day washout period between alcohol challenge Trial 1 and 
medication visit #2. The washout may extend to 14 days to accommodate the scheduling of the 
medication visit. Concomitant medications, urine drug screening, urine pregnancy testing, blood 
alcohol level will be assessed to determine eligibility to proceed with the challenge.  Blood 
alcohol level must be 0.000 to continue with the study procedures.  Urine collected for drug 
screening will be exposed to ultraviolet light as an objective test of medication compliance.  If no 
fluorescence is observed in the urine sample the subject will be excluded from continuing with 
the challenge.  Measures of drinking (TLFB) and cravings (OCDS, VAS and AUQ) will be 
collected to inform secondary outcomes.  Subjects will be observed taking the morning dose of 
pitolisant (or placebo) on the day of the challenge (after compliance is confirmed via a urine 
screening).  The peak plasma concentration of pitolisant should be reached approximately 60 
minutes after administration.  The alcohol self-administration session will begin no sooner than 
one hour after the administration of the observed 17.8 mg morning dose. The alcohol self-
administration will be conducted in the GCRU.  The room will be a carpeted and furnished with 

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a lounge chair, side table and television which allows access to popular streaming entertainment 
(e.g., Netflix, YouTube). A small unobtrusive camera is placed in the room to allow for 
monitoring without study staff being present in the room. The room has ready access to a 
bathroom.  The alcohol self-administration is divided into four segments: 1) a 5-minute segment 
for the priming dose, 2) a 40-minute segment for observing alcohol’s effects, 3) a 60-minute 
segment of alcohol self-administration (Block1) and, 4) a second 60-minute segment of alcohol 
self-administration (Block2) [see figure 2 for the alcohol self-administration Procedure].   
 
Priming dose.  Subjects will be given 
a priming drink designed to increase 
the subject’s blood alcohol level 
(BAL) to 0.03g/dl, using the alcohol 
of their choice that is 24% Alcohol 
By Volume (ABV) or greater.  The 
volume of alcohol will be calculated 
using an online tool developed by UW-Madison 
(http://dionysus.psych.wisc.edu/WebCMS/baccalc.htm) based on a formula described by 
Watson53. The subjects will be asked to drink the priming drink over a period of 5 minutes. Part 
of the purpose of the priming drink is to normalize drinking in the laboratory.  
 
Observation period. Subjects will be observed for 40 minutes following the priming dose of 
alcohol to allow for absorption of the alcohol. Cravings will be assessed using the AUQ and 
VAS and effect of pitolisant on stimulant effects of alcohol swill be assessed using the BAES 
every 10 minutes during the observation period. 
 
Alcohol self administration Blocks 1 and 2.  In each of the alcohol self-administration Blocks, 
subjects will be presented with four drinks, each mixed to raise their BAL 0.0125g/dl. They will 
be told that they can either consume the desired number of drinks over the following 60 minutes 
or they will receive the equivalent dollar amount of the cost of each drink ($3.00) they did not 
consume before leaving the clinic. At the end of each 1 hour session the tray with the remaining 
drinks will be removed and the amount of alcohol remaining will be measured.  Cravings will be 
assessed using the AUQ and VAS and effect of pitolisant on stimulant effects of alcohol will be 
assessed using the BAES every 30 min during the self-administration blocks. Based on the rate 
of alcohol metabolism over the time of the trial, we anticipate that subjects who consumed every 
drink could reach a BAC of 0.09 to 0.13 g/dl depending upon differences in alcohol metobolism.  
Safety assessments will be completed (intoxication, sedation, adverse effects) prior to subjects 
leaving the laboratory. Subjects will be required to have a plan for transportation home that does 
not involve driving.  Subjects will not be released until their blood alcohol level is ≤ 0.04 g/dl 
and they are not behaviorally impaired.  After the second alcohol self-administration trial has 
been completed subjects will receive a copy of the NIAAA publication Rethinking Drinking54 
and will be encouraged to review rethinking drinking materials online.   
 
Subject compensation 
Subjects will be compensated up to $543 for completion of all study activities.  Subjects will 
Figure 2: Alcohol Self-Administration Procedure 
 Priming Dose 
5 minutes  
Drink mixed to 
achieve BAL= 
0.03g/dl 
Observation  
40 minutes 
Craving and 
intoxication 
measured in 10-
minute intervals 
Self-Administration 
Blocks 1 & 2 
60 minutes each 
4 drinks per block 
Each drink mixed to 
raise BAL 0.0125 g/dl 

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receive a reimbursement of $50 for the screening visit, $100 for alcohol Challenge Trial #1, $100 
for alcohol Challenge Trial #2 and a $75 completion bonus if they complete both challenges.  
Subjects will also receive $20 on each of the two visits during which medication is dispensed.  
Subjects will receive a $5 payment each on day during the two drug exposure periods that they 
respond to the REDcap smartphone app to rate their alcohol craving, medication compliance, and 
sleep quality. Subjects will also receive a $10 completion bonus in each challenge if they 
complete the craving scale and medication log on all days. Subjects may receive up to $48 
dollars in payments for drinks not consumed during the two alcohol self-administration trials.      
 
In addition to this $543 of compensation, subject may also be reimbursed up to an additional $60 
for distributing study recruitment materials to other people who may want to take part in this 
study.  Distributing recruitment materials is completely optional.  subjects may take part in the 
study and decline to hand out flyers to people they know.   
 
Subjects who report no recreational drug use other than marijuana at the time of phone screening 
but then test positive for recreational drug use other than marijuana at the first in-clinic visit will 
not be reimbursed.  Subjects will be informed of this policy at the time of telephone screening.  
This measure is in place to prevent subjects from lying about no recreational drug use in order to 
receive compensation for a single visit in this study.   
 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
10.1 Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject's health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the 
event as it occurred.  
 

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Unanticipated Problem is defined as an event, experience or outcome that meets all three of the 
following criteria:  
 
is unexpected; AND 
 
is related or possibly related to participation in the research; AND 
 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
Possibly related means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
 the known or foreseeable risk of adverse events associated with the procedures involved in 
the research that are described in (a) the protocol–related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant sources of information, such 
as product labeling and package inserts; or 
 the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile 
for the adverse event. 
 
10.2 Safety Review 
 
Both the risks listed in Section 6.1 and unknown risks will be monitored as follows:  
 
Adverse events will be monitored from the time of study enrollment until the end of 
participation.  Adverse events will be monitored by medical staff using the “adverse events” 
CRF.  Adverse event monitoring will be conducted at three mid-week calls during both titration 
periods.  Adverse events will also be assessed on the alcohol self-administration challenge days.  
Subjects will be given a wallet card with a 24/7 telephone number in the event that there are 
adverse effects which the subject would like to consult with medical staff prior to the next 
scheduled visit.  Adverse events will be assessed if at any point in the study a subject uses this 
24/7 emergency phone contact. If a subject has an ongoing SAE or unanticipated problem at the 
time that the subject completes all study procedures, Adverse Event assessment will continue 
until satisfactory resolution (either resolved or stabilized and is not expected to resolve in the 
near term) of the event or problem. 
 
For each recorded AE or SAE, the study MD staff or study nurse will assess expectedness based 
on the known published side effect profile for pitolisant.  The study MD staff or study nurse will 
also assess severity based on the following criteria: 
Mild: 
An event that is usually transient, requiring no special treatment, and 
does not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 

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Mild: 
An event that is usually transient, requiring no special treatment, and 
does not generally interfere with the subject’s daily activities. 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention.  
Severe: 
 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
Life-threatening 
An event that puts the subject into imminent risk of death without 
intervention. 
 
The study MD staff or study nurse will assess AE/SAE relationship to the investigational product 
based on the following criteria: 
 
Unrelated: 
The subject did not receive the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is not reasonable, or there is another obvious cause of 
the AE/SAE. 
Unlikely: 
There is evidence of exposure to the investigational product or there is 
another more likely cause of the AE/SAE. 
Possible: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, but the AE/SAE could have been due 
to another equally likely cause. 
Probable: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, and the AE/SAE is more likely 
explained by the investigational product than by any other cause. 
Definite 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, the AE/SAE is more likely explained 
by the investigational product than by any other cause, and the AE/SAE 
shows a pattern consistent with previous knowledge of the investigational 
product or investigational product class. 
 
10.3 Reporting Plans 
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems and 
Adverse Events to the BMC/BU Medical Center IRB in accordance with IRB policies: 
 Unanticipated Problems occurring at BMC/BU Medical Campus will be reported to the 
IRB within 7 days of the investigator learning of the event. 
 Adverse Events (including Serious Adverse Events) will be reported in summary at the 
time of continuing review, along with a statement that the pattern of adverse events, in 

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total, does not suggest that the research places subjects or others at a greater risk of harm 
than was previously known. 
 
10.4 Stopping Rules 
 
There are no interim analyses planned that would allow for a determination of futility or 
overwhelming benefit.  Study enrollment will be suspended under the following circumstances: 
 
1.  Severe and Serious Adverse Events.  Study enrollment will be suspended in the event of a 
single severe adverse event or a single serious adverse event if that is determined to be 
unexpected and at least “possibly related.” If suspended, study recruitment will not continue until 
a determination has been made about whether the known risks of participation have changed 
and the Boston Medical Center IRB has made a finding that the risk/benefit ratio remains 
favorable given the possible newly identified risks. 
 
2.  Risk of intoxication.  Subject recruitment will also be suspended if more than one subject of 
the first ten subjects enrolled is discontinued by the investigator due to intoxication during the 
alcohol self administration trial.  Due to differences in alcohol tolerance, BAL is not a reliable 
measure of subjects potentially posing a safety risk.  Medical staff will make a subjective 
determination of risk based on the subject’s behavior.  After 10 subjects have been enrolled, the 
trial will be suspended if there are more than 10% of subjects whose participation has been 
halted by the study team due to concerns about physical safety because of intoxication during the 
alcohol self-administration trial. If suspended for this reason, the study team will consider design 
changes to reduce the likelihood of this as a potential risk to study subjects.  Recruitment would 
resume when the BU Medical Campus/Boston Medical Center IRB has made a determination 
that proposed changes to the study design have an acceptable risk/benefit ratio. 
 
11 Data Handling and Record Keeping 
 
11.1 Confidentiality 
 
All staff will be fully trained in the procedures for protection confidential health information.  To 
maintain subject confidentiality, study data will be coded on CRFs that are identified by a subject 
number only. Source records with identifying information and CRFs will be stored in double-
locked space with access only by authorized staff.  Data stored in the REDcap system have 
strong protections including file encryption and password access.  Subject information will not 
be released without written permission.  Upon approval of the study by an IRB, NIH will furnish 
a Certificate of Confidentiality.  
 
Deidentified data from this study will be submitted to the NIAAA Data archive 
(https://nda.nih.gov/).   
￼￼￼￼￼￼￼￼￼ 

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11.2 Source Documents 
 
Source documents in this study include: 
Laboratory test results 
Photocopies of the urine drug screening test result 
ECG tracings 
Subject locator form 
Subject contact form 
 
Data generated by the methods described in the protocol will be recorded in the subjects' source 
binder. Data may be transcribed legibly on CRFs for each subject or directly inputted into an 
electronic system or any combination thereof. 
 
11.3 Case Report Forms 
 
The study case report form (CRF) will be the primary data collection instrument for the study. 
All data requested on the CRF will be recorded. All missing data will be explained. If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, a 
written explanation will be included to detail why the data was not recorded.  If the item is not 
applicable to the individual case, a notation will be made.  All entries on will be printed legibly 
in black ink. If any entry error has been made, to correct such an error, a single straight line will 
be drawn through the incorrect entry and the correct data will be entered closely to the original 
data. All such changes will be initialed and dated.  There will be no erasures or white-out on 
CRFs.  For clarification of illegible or uncertain entries, the clarification will be printed near the 
item, then initialed and dated. Electronic CRFs in the REDcap system will include an audit trail.   
 
The CRFs that will be used in this study are: 
Demographics 
Concomitant Medications 
Adverse Events 
Birth Control Assessment 
Urine Drug Screening  
Vital Signs 
Blood Alcohol Level 
Time-line Follow-back 
Pregnancy test 
Birth control assessment 
Medical History 
Physical Examination 
MINI diagnoses summary 
Medication Compliance log 
Eligibility 
ECG 
C-SSRS 
CIWA-AR 
OCDS 

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AUQ 
VAS 
BAES 
 
11.4 Study Records Retention 
Study records will be retained for at least seven years after completion of the study.  
 
 

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12 Statistical Plan 
 
12.1 Study Hypotheses and Planned Analyses 
 
For our primary outcomes, separate analyses will be conducted on data collected during the 
Priming and Self-Administration periods of the test session.  
Hypothesis 
Proposed Analyses 
1. Subjects will consume 
less alcohol during an 
alcohol self-
administration trial when 
receiving pitolisant 
compared to when they 
are receiving placebo.     
The volume of alcohol consumed during alcohol challenge trials 
1 and 2 will be used to test the effect of pitolisant on alcohol 
consumption.  We will use a mixed models repeated measures 
approach to test for differences between alcohol consumed 
between the pitolisant and placebo self-administration trials45-
46.  This data will be divided into first and second-hour blocks of 
self-administration. Within-subject factors for this analysis will 
include treatment and Time Block. Trial order will be used as 
covariate in these analyses to allow evaluation as to whether the 
order of treatments had a significant effect on the outcome. 
Appropriate covariance structures will be determined using 
Akaikes information criteria to evaluate the best model fit. 
Results analysis will be examined for both treatment effects and 
the Treatment x Time Block interaction results. 
2.  Subjects will report 
lower levels of craving as 
measured by the Visual 
Analog Scale (VAS) and 
the Alcohol Urge 
questionnaire (AUQ) 
during the pitolisant self-
administration trial 
compared to the placebo 
self-administration trial.   
Craving measures (AUQ and VAS) collected at 30-minute 
intervals during the self-administration trials will be used to test 
the effect of pitolisant on alcohol craving.  A mixed models 
approach will be used to test for differences in craving between 
the pitolisant and placebo self-administration trials. Within-
subject factors for this analysis will include Treatment and Time 
Block. Trial order will be used as covariate in these analyses to 
allow evaluation as to whether the order of treatments has a 
significant effect on the outcome. 
3.  Subjects will 
experience no difference 
in alcohol-induced 
stimulation, as measured 
on the BAES,  after the 
consumption of the 
priming dose of alcohol 
when they are receiving 
pitolisant as compared to 
when they are receiving 
placebo. 
BAES scores and BALs obtained during the 40-minute 
observation period and both of the 60-minute self-administration 
blocks will be used to test the effect of pitolisant on the 
stimulating effects of alcohol.  A mixed model for repeated 
measures approach will be used to test for differences between 
pitolisant and placebo on the stimulant BAES scores at each of 
the 10-minute observation intervals and 30-minute self-
administration intervals.  This data will be analyzed with 
Treatment and Time used as within-subject factors.  
5.  Subjects will report 
lower levels of alcohol 
craving and consumption 
The alcohol VAS, OCDS, and the TLFB measurements during 
the twelve-day period of drug exposure will be used to determine 
the effect of pitolisant on craving and consumption.   Mixed 

Pitolisant effects on alcohol self administration and craving in heavy drinkers   
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during pitolisant exposure 
period as compared to 
placebo exposure period.     
models repeated measures approach will be used to test for 
differences in craving and consumption between the pitolisant 
and placebo trials.  Treatment will be used as within-subject 
factor. VAS measures taken on each of the twelve days of drug 
exposure, repeated measures mixed models analysis will be 
conducted with Day and Treatment as within-subject factors.   
6. Subjects will not report 
significant differences in 
the number of hours sleep 
per night and minutes 
spent awake during the 
pitolisant exposure period 
as compared to the 
placebo exposure period 
Daily hours of sleep and number of minutes spent awake during 
the twelve-day period of drug exposure will be used to determine 
the effect of pitolisant on craving and consumption.   Mixed 
Models repeated measures approach will be used to test for 
differences in sleep quality between the pitolisant and placebo 
trials.  Treatment will be used as within-subject factor. Sleep 
measures taken on each of the twelve days of drug exposure, 
repeated measures mixed models analysis will be conducted with 
Day and Treatment as within-subject factors.   
 
12.2 Sample Size Determination 
 
A group size of 28 completers was selected for use in this study based on an assumed effect size 
of 0.7 suggested by similar alcohol self-administration studies with amount consumed as the 
primary outcome.  This effect size is in the range we found for the anticonvulsant zonisamide 
used in a similar alcohol self-administration study.  The sample size for this study is based on an 
estimated reduction of 1.5 standard drinks with an estimated standard deviation (2.1) of the 
between Challenge Trial differences in alcohol self-administration, with an effect size of this 
magnitude (i.e. 0.7).  This requires a sample size of 28 to allow for detection of a significant 
within-subject difference in alcohol consumption with an alpha value of 0.01 and power value of 
0.81.  Based on an estimated 15-20% rate of non-completion for randomized subjects, we 
anticipate randomizing 36 subjects to achieve a sample of 28 completers.  Given our experience 
with recruiting AUD populations into clinical trials, we expect a screening exclusion rate of 
roughly 50%.  Approximately 72 subjects will be consented and screened in clinic to yield a 
sample of 36 eligible subjects.  Given that this a laboratory based experiment we do not plan to 
conduct any planned interim analyses in this study. 
 
 
13 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional 
policies (which are based in federal regulations, guidance, and ICH Good Clinical Practice 
guidelines). 
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston 
University Medical Campus IRB, for formal approval of the study conduct. The decision of the 
IRB concerning the conduct of the study will be made in writing to the investigator. A copy of 
the initial IRB approval letter will be provided to the sponsor before commencement of this 
study.  
 

Pitolisant effects on alcohol self administration and craving in heavy drinkers   
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All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The consent form will be submitted with the protocol for review and approval by the IRB. 
The consent of a subject, using the IRB-approved consent form, must be obtained before that 
subject is submitted to any study procedure. Consent will be documented as required by the IRB.   
 
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15.  Appendix A: Schedule of Events 
 
Baseline 
(May be 
split over 
2 visits) 
Randomization 
Trial 1 
Dispense 
Trial 2 
Clinic Visit # 
0 
1 
2 
3 
4 
Informed Consent 
X 
 
 
 
 
Urine Drug ScreenA, B 
XX 
X 
X 
X 
X 
Locator Form  
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
MINI V 6.0 
X 
 
 
 
 
SCISD-R 
X 
 
 
 
 
Metabolic panel (Alb, Tbil, 
Ca, CO2, Cl, CRG, G, ALP, 
K, TP, Na, ALT, AST, BUN) 
14.1.1 
PT/INR 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Vital Signs, weight, Blood 
Alcohol LevelB 
XX 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
Prior and Concomitant Meds 
X 
X 
X 
X 
X 
CIWA-AR 
X 
X 
X 
X 
X 
Eligibility Checklist 
 
X 
 
 
 

Pitolisant effects on alcohol self administration and craving in heavy drinkers   
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Baseline 
(May be 
split over 
2 visits) 
Randomization 
Trial 1 
Dispense 
Trial 2 
Clinic Visit # 
0 
1 
2 
3 
4 
Drug 
compliance/accountability 
 
 
X 
 
X 
Urine Pregnancy Test   
X 
X 
X 
X 
X 
Birth control assessment 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
Dispense medication/placebo 
 
X 
 
X 
 
Brief Telephone Interview 
 
Mid-week call 
3-4 days, 6-7 
days, and 9-10 
days after 
starting 
medication  
 
Mid-week call 
3-4 days, 
6-7 days and 9-
10 days after 
starting 
medication 
 
Treatment Referral 
 
 
 
 
X 
TLFB (28 day at baseline) 
X 
X 
X 
X 
X 
VAS 
 
X 
Daily during 12-
day medication 
exposure period 
X 
X 
Daily during 12-
day medication 
exposure period 
X 
OCDS 
 
X 
Days 7 and 11 
of medication 
exposure period 
X 
X 
Days 7 and 11 
of medication 
exposure period 
X 
AUQ 
 
X 
X 
X 
X 
BAES 
 
 
X 
 
X 
National Sleep Foundation 
Sleep Diary 
 
Daily during 12-
day medication 
exposure period 
 
Daily during 12-
day medication 
exposure period 
 
 
A)  Test for opioids, cocaine, amphetamines, methamphetamine, tetrahydrocannabinol (THC), 
barbiturates, oxycodone, buprenorphine, methadone and benzodiazepines.  
B) If the baseline visit is split between two days, UDS, vitals, breathalyzer, and weight are to be 
taken at each visit.    
 

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16.  Appendix B: Schedule of assessments during the alcohol challenge 
 
 
 
Observation 
Self-admin 
Block1 
Self-admin 
Block2 
Assessment 
 
 
 
BAC 
Every 10 
minutes 
Every 30 
minutes 
Every 30 
minutes 
VASa) 
Every 10 
minutes 
Every 30 
minutes 
Every 30 
minutes 
AUQ  
 
Every 30 
minutes 
Every 30 
minutes 
BAES 
Every 10 
minutes 
Every 30 
minutes 
Every 30 
minutes