A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder
Phase: PHASE2
Conditions: Alcohol Use Disorder
Sponsor: University of Maryland, Baltimore

 
HP-00061575, Pharmacogenetic Treatments for Alcoholism 
Version 11.1 09-05-2018 
 
Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder 
NCT02354703 
 
Responsible Party David A. Gorelick, MD, PhD 
 
September 5, 2018 
 
 
 

  
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CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
       David A. Gorelick, MD, PhD, DLFAPA 
 
 
 
 
       Clinical Neurobehavioral Center 
 
 
 
 
       University of Maryland, Baltimore School of Medicine  
 
 
 
 
       Department of Psychiatry 
 
 
 
 
       5900 Waterloo Rd. 
 
 
 
 
       Columbia, MD 21045 
 
 
 
 
       Tel : (667) 214-2111 
 
 
 
 
        Email: dgorelick@som.umaryland.edu 
 
 
Henry R. Kranzler, M.D. 
Treatment Research Center 
University of Pennsylvania 
3535 Market Street 
Philadelphia, PA 19104 
Tel: (215) 386-6662 
Email: kranzler@mail.med.upenn.edu 
Funding Sponsor: 
National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
National Institutes of Health 
Division of Treatment and Recovery Research 
5635 Fishers Lane 
Bethesda MD 20892 
Study Product: 
Ondansetron 
 
 
IND Number: 
IND #45,228  
 
 
 
 
 
 

  
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Table of Contents 
 
 
STUDY SUMMARY 
1 
1 
INTRODUCTION 
2 
1.1 
BACKGROUND 
2 
1.2 
INVESTIGATIONAL AGENT 
3 
1.3 
PRECLINICAL DATA 
4 
1.4 
CLINICAL DATA TO DATE 
4 
1.5 
DOSE RATIONALE AND RISK/BENEFITS 
7 
2 
STUDY OBJECTIVES 
11 
3 
STUDY DESIGN 
12 
3.1 
GENERAL DESIGN 
12 
3.2 
PRIMARY STUDY ENDPOINTS 
13 
3.3 
SECONDARY STUDY ENDPOINTS 
13 
3.4 
PRIMARY SAFETY ENDPOINTS 
14 
4 
SUBJECT SELECTION AND WITHDRAWAL 
16 
EXCLUSION CRITERIA 
 
4.1 
SUBJECT RECRUITMENT AND SCREENING 
20 
4.2 
EARLY WITHDRAWAL OF SUBJECTS 
21 
5 
STUDY DRUG 
22 
5.1 
DESCRIPTION 
22 
5.2 
TREATMENT REGIMEN 
22 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS 
22 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG 
23 
5.5 
SUBJECT COMPLIANCE MONITORING 
23 
5.6 
PRIOR AND CONCOMITANT THERAPY 
25 
5.7 
PACKAGING 
27 
5.8 
BLINDING OF STUDY DRUG 
27 
5.9 
RECEIVING, STORAGE, DISPENSING, AND RETURN 
27 
6 
STUDY PROCEDURES 
28 
6.1 
INITIAL TELEPHONE SCREEN (APPROXIMATELY 20 MINUTES) 
28 
6.2   SCREEN PART-1 VISIT (V0-1; STUDY WEEK -1) 
29 
6.3 SCREENING PART-2 VISIT (WEEK 0) 
31 
6.4 ON-TREATMENT VISITS (WEEKS 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, AND 20) 
32 
6.5 END OF STUDY VISIT (WEEK 16)/EARLY TERMINATION VISIT 
32 
6.6. 
SAFETY FOLLOW-UP PHONE VISIT (WEEK 20) 
33 
6.8  GENETIC EVALUATION 
37 
7 
STATISTICAL PLAN 
38 
7.1 
SAMPLE SIZE DETERMINATION 
38 
7.2 
STATISTICAL METHODS 
38 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS 
40 
8 
SAFETY AND ADVERSE EVENTS 
40 
8.1 
DEFINITIONS 
40 
8.2 
RECORDING OF ADVERSE EVENTS 
42 

  
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8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS 
43 
8.4 
UNBLINDING PROCEDURES 
45 
8.5 
MEDICAL MONITORING 
46 
9 
DATA HANDLING AND RECORD KEEPING 
 
9.1 
CONFIDENTIALITY 
 
9.2 
SOURCE DOCUMENTS 
 
9.3 
CASE REPORT FORMS 
49 
9.4 
RECORDS RETENTION 
49 
10 
STUDY MONITORING, AUDITING, AND INSPECTING 
 
10.1   STUDY MONITORING PLAN 
 
11 
ETHICAL CONSIDERATIONS 
53 
12 
STUDY FINANCES 
 
12.1 
FUNDING SOURCE 
 
12.2 
CONFLICT OF INTEREST 
 
12.3 
SUBJECT STIPENDS OR PAYMENTS 
53 
13 
REFERENCES 
 
 
 
 

 
HP-00061575, Pharmacogenetic Treatments for Alcoholism 
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Study Summary 
Title 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Pharmacogenetic Study of Ondansetron in Alcohol Use Disorder 
Short Title 
Ondansetron for Alcohol Use Disorder (AUD) 
Protocol Number 
HP 00061575   
Phase 
Phase 2 
Methodology 
This is a randomized, two-center, double-blind, parallel-group, placebo-
controlled study. Comparable, but not identical studies will be conducted at 
the two sites 
Study Duration 
5 years 
Study Center(s) 
University of Pennsylvania (Penn) and University of Maryland Baltimore 
(UMB) 
Objectives 
Primary specific aim: to test the hypothesis that alcohol-dependent 
individuals of European ancestry (EAs) or of African American ancestry (AAs) 
carrying any one or a combination of specific genotypes will have a 
significantly lower number of drinks/drinking day (DDD) in response to 
ondansetron 0.33 mg twice daily, compared to those who are not carrying 
any of the selected genotypes or those who were treated with the placebo.  
Secondary exploratory aim): We further hypothesize that specific 
genotypes (which differ for AAs and EAs) will moderate the response to 
ondansetron. The genotypes of interest reflect polymorphisms in the genes 
encoding the serotonin transporter (SLC6A4) and the 5-HT3A (HTR3A) and 
5-HT3B (HTR3B) receptor subunits. 
 
We also will test the additional secondary predictions that the differences 
seen in our primary specific aim (above) will extend to secondary drinking 
measures and measures of quality of life. Additionally, we will use genome-
wide expression studies of total RNA and miRNA- from blood samples and 
supported by supplemental funding-to compare the 15 most responsive 
subjects (whose drinking is reduced most significantly) and the 15 least 
responsive subjects on DDD and the 15 subjects with the greatest number of 
adverse events and the 15 with the fewest to identify changes that mediate 
ondansetron’s efficacy and adverse events profile, respectively. 
Number of Subjects 
366 at two sites (183 at each site) 
Diagnosis and Main 
Inclusion Criteria 
Current DSM-5 diagnosis of Alcohol Use Disorder; AUDIT score  8; >6 
Heavy Drinking Days (HDDs)- define as a day with alcohol consumption of >5 
standard drinks for men, and >4 standard drinks for women in the last 28 
days; currently drinking an average of 14 standard drinks/week (women) 
and 21 standard drinks/week (men) in the last 28 days (and have met these 
criteria for the 7 days prior to randomization); and expressed a wish to reduce 
or stop drinking. 
Study Product, Dose, 
Route, Regimen 
Ondansetron 0.33 mg or matching placebo by mouth twice daily. 
Duration of 
administration 
16weeks 
Reference therapy 
Placebo 

  
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Statistical 
Methodology 
All randomized subjects will be included in the analysis using the intent-to-
treat principle.  We will use a mixed-models approach, adjusting for baseline 
covariates (when significantly different by group) and the same drinking 
variables for baseline.  For the drinking variables, the baseline value is the 
average for the 30-day period prior to the screening visit.  Other potential 
covariates shall include age, race, and sex.  The primary outcome measure 
will be DDD during the 16-week treatment period.   
1 Introduction 
 
This document is a protocol for a human research study. This clinical trial will be 
conducted according to US and international standards of Good Clinical Practice (FDA Title 21 
part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and institutional research policies and procedures.  
1.1 Background 
 
Alcohol use disorder (AUD) is a heterogeneous and chronic relapsing disorder that 
includes both acute (binge drinking) and chronic (frequent heavy drinking) dimensions.  Globally 
and in the United States, AUD ranks 5th and 3rd, respectively, among the most common 
preventable causes of morbidity and mortality. 
 
Approximately 7.2 percent or 17 million adults in the United States ages 18 and older 
had an AUD in 2012. This includes 11.2 million men and 5.7 million women. AUD can cause 
serious health, family, and economic problems. Finding treatments that are effective in 
decreasing heavy drinking among individuals with AUD is, therefore, an important scientific and 
health goal. Only a fraction of the people who could benefit from AUD treatment receives 
treatment. In 2012, for example, 1.4 million adults received treatment for an AUD at a 
specialized facility (8.4 percent of adults in need).        
 
A novel and important strategy to improve AUD treatment outcomes uses a personalized 
medicine approach to optimize treatment response. This approach matches a subject   with 
specific genotypes to an appropriate medication with a high probability of a positive treatment 
outcome while also potentially minimizing adverse events. Despite the development of new 
medications to treat AUD, pharmacotherapy remains an underutilized approach. This is, in large 
measure, a function of modest effect sizes associated with the FDA-approved medications for 
AUD.  
Personalized medicine offers the prospect of greater efficacy and safety by matching subjects 
with optimal treatments. 
 
This proposed study will address important limitations in a previously published Phase ΙΙ 
study (Johnson et al. 2011) conducted in a sample of European Americans (EA). In the first 
study12, Johnson et al. reported that 5-HTTLPR:LL genotype in the gene that encodes the 
serotonin transporter molecule (SLC6A4) either alone or in combination with rs1042173:TT of 
the same gene predicted response to ondansetron.  In a secondary analysis of the same 
sample, the authors reported three additional genotypes in the two genes that encode the 
primary binding site of ondansetron – the 5-HT3 sub unit genes HTR3A and HTR3B1. As the 
primary aim of this study, we will test the replicability of these findings with following 
modifications to address several limitations of the prior studies.  First, we will stratify the 
population into two main groups of participants based on whether a participant is carrying any of 
the responsive genotypes (Genotype responsive group vs. Genotype non-responsive group). 
There are three main differences between the Genotype-responsive group defined by Johnson 
et al 2013 and the present study. 
(1) 
In this study, we will use the tri-allelic classification for 5-HTTLPR of SLC6A4, the gene 
encoding the serotonin transporter (LA, LG or S alleles) to avoid the underestimation of 
pharmacogenetic effects associated with the use of the bi-allelic classification (L or S alleles). 

  
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We will limit the LL group to include only those who are LALA, will be considered as Genotype-
responsive as the LG allele has been shown to be associated with lower expression levels of 5-
HTT mRNA similar to the S allele (2). 
(2) 
Carriers of rs1042173:TT (without 5-HTTLPR:LALA) will be included in the Genotype 
responsive group, based on the findings that indicated a significant risk effect of rs1042173:TT 
on heavy drinking3. 
(3) 
Treatment assignment within Genotype Responsive group will be balanced at 
randomization according to genotype subgroups listed below, to accurately characterize the 
degree to which ondansetron’s therapeutic effect is enhanced by either one of SLC6A4 or any 
of the HTR3A/B genotypes. 
a. 
LALA in the absence of rs1042173:TT and regardless of presence/absence of HTR3A/B 
genotypes 
b. 
rs1042173:TT in the absence of  LALA and regardless of presence/absence of HTR3A/B 
genotypes 
c. 
LALA together with rs1042173:TT and regardless of presence/absence of HTR3A/B 
genotypes 
d. 
Any one or more HTR3A/B genotypes in the absence of  both LALA and rs1042173:TT   
Number of participants in the two main groups (Genotype responsive vs. non-responsive) as 
well as the four subgroups will represent population frequencies of constituent genotypes. This 
approach, as opposed to having equal numbers in each group, was adopted in order to include 
all participants who are otherwise qualified to be enrolled in this study.  At the UMB site, we will 
enroll both African Americans (AAs) and EAs. Because of differences in population frequencies 
and linkage disequilibrium structures, in AAs, we will explore the moderating effect of a non-
synonymous, functional SNP (rs1176744) that has been shown to be associated with alcohol 
dependence in AAs (Enoch et al. 2011).  This SNP is in HTR3B, a gene in which variation was 
shown in the published Phase II study (Johnson et al. 2013) to moderate the response to 
ondansetron. (3) We will use the tri-allelic classification for 5-HTTLPR of SLC6A4, the gene 
encoding the serotonin transporter (LA, LG or S alleles) to avoid the underestimation of 
pharmacogenetic effects associated with the use of the bi-allelic classification (L or S alleles). 
We will limit the LL group to include only those who are LALA, as the LG allele has been shown to 
be associated with lower expression levels of 5-HTT mRNA similar to the S allele and will 
balance individuals within genotype (LALA vs. non- LALA between the ondansetron and placebo 
groups in the primary randomization (4) We will also balance individuals in the primary 
randomization within the two genotype groups of the SLC6A4 3′-UTR SNP rs1042173 (TT vs 
TG/GG). This will make it possible to characterize accurately the degree to which ondansetron’s 
therapeutic effect is moderated by rs1042173 and determine the independent therapeutic effect 
of ondansetron in individuals with the TT genotype. Finally, we will examine mRNA expression 
in a subset of individuals from the study to test whether the observed moderating effects of 
genotype are evident also in the expression of HTR3B and SLC6A4. 
  
In addition to conducting analyses separately using genotypes that are relevant to each  
racial group, we will examine the findings from the two sites in a joint analysis. 
 
1.2 Investigational Agent 
Ondansetron, a specific serotonin-3 (5-HT3) antagonist is FDA approved to treat 
chemotherapy-induced nausea and vomiting, radiation-induced nausea and vomiting, and 
postoperative nausea and vomiting.  In the present study, subjects will be given ondansetron 
0.33 mg or matching placebo capsules twice daily.  

  
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The active ingredient in ondansetron tablets is ondansetron hydrochloride (HCl) as the 
dihydrate, the racemic form of ondansetron.  Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-
[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate.  
Ondansetron’s empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 
365.9. 
1.3 Preclinical Data 
Ondansetron’s effects are mediated through 5-HT3 receptors in the brain. Transgenic 
mice over-expressing 5-HT3 receptors in the forebrain have been used to study alterations in 5-
HT current induced by ethanol within the brain (Engel & Allan, 1999; Engel, Lyons, & Allan, 
1998; Sung, Engel, Allan, & Lovinger, 2000). These studies have shown that 5-HT3 over-
expression reduced ethanol consumption, improved contextual fear conditioning, reduced 
anxiety, increased inspective behavior toward a novel object and increased dopamine release in 
the nucleus accumbens (Allan, Galindo, Chynoweth, Engel, & Savage, 2001; Engel & Allan, 
1999; Engel, Lyons, & Allan, 1998; Sung, Engel, Allan, & Lovinger, 2000; Metz, Chynoweth, & 
Allen; 2006). Using a transgenic mouse model lacking the gene for the 5-HT3A receptor subunit, 
Hodge and colleagues (2004) showed that the reduction of alcohol drinking produced by 5-HT3 
antagonism is dependent on the presence of 5-HT3A subunit-containing receptor complexes. 
While these data, especially the directional effect, cannot be extrapolated directly to studies in 
wild-type animals that can differ in the density and neuroanatomical distribution of 5-HT3 
receptors or to human studies, they do provide a framework which suggests that differential 5-
HT3 expression can influence alcohol consumption. 
1.4 Clinical Data to Date 
Serotonin (5-HT) function is an important regulator of alcohol consumption. The 
serotonin transporter (5-HTT), which is encoded by the gene SLC6A4, is the major modulator of 
neuronal 5-HT function. Variation in SLC6A4 has been associated in humans with differences in 
alcohol craving and consumption. Specifically, in some studies, alcohol-dependent individuals 
who are homozygous for the long (L) allele of an insertion deletion polymorphism in the 5′-
regulatory region of SLC6A4 (5-HTTLPR) or the T allele of the single nucleotide polymorphism 
(SNP) rs1042173 in the 3′-untranslated region (3′-UTR) of that gene report increased craving 
and consumption of alcohol.   
SLC6A4, which is located on chromosome 17q11.1–q12, is the only known gene 
encoding the serotonin transporter (5-HTT) in the human genome The SLC6A4 promoter 
contains a functional insertion-deletion polymorphism (5′-regulatory region of the 5-HTT; 5- 
HTTLPR) that results in a long (L) form, which possesses 44 base pairs that are absent in the 
short (S) allele. The 5-HTTLPR polymorphism has been investigated extensively for a possible 
association with a wide range of psychiatric disorders including alcohol dependence. Recent 
research suggests a gene-by environment interaction. A neuroimaging study showed that 
alcohol-dependent LL genotype individuals had lower binding of the radioligand 123β-CIT (2 
beta-carbomethoxy-3 beta-(4-iodophenyl) tropane) to the 5-HTT in the raphe nuclei of the brain 
than did healthy LL genotype individuals (Heinz et al., 2000). In contrast, within S-carriers 5-
HTT availability did not differ significantly between control and alcoholic subjects. Previous 
studies conducted by our own research team have also shown similar patterns of 5-HTTLPR 
genotype-based differences in 5-HTT availability and function. Specifically, among individuals 
with the L allele, a greater quantity of lifetime alcohol consumption was associated with lower 
levels of 5-HT uptake and binding (Javors et al., 2005; Johnson et al., 2008).  Taken together, 
these findings suggest a potential selective susceptibility of L-allele carrying individuals to the 
neurotoxic effects of chronic excessive alcohol consumption. Johnson et al. (2013) discovered 
that another functional allelic variant, the SNP rs1042173 (T/G) in the 3′- untranslated region (3′-
UTR) of SLC6A4, is associated with the intensity of alcohol consumption measured by the 

  
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number of standard drinks (1 standard drink = about 14g of 100% alcohol) consumed per 
drinking day (Seneviratne, Huang, Ait-Daoud, & Johnson, 2009). TT homozygotes at this locus, 
compared with G-allele carriers, had a significantly greater intensity of alcohol consumption. T-
allele-transfected HeLa cells had lower levels than their G allele counterparts of expression of 
both 5-HTT mRNA and protein. Because rs1042173 is located at or near a potential binding site 
for several microRNAs in the 3′-UTR of the gene, the variant may alter expression levels by 
reducing the stability of mRNA.  
Lowered 5-HTT expression would, paradoxically, be associated with reduced rather than 
increased 5-HT synaptic neurotransmission and consequent upregulation of postsynaptic 5-HT 
receptors. This is because the 5-HTT in the raphe nuclei is somatodendritic, and, therefore, 
negative feedback mechanisms would decrease 5-HT neuron firing rates and upregulate 
postsynaptic 5-HT receptors. In sum, these findings suggest that blockade of upregulated 5-HT3 
receptors by ondansetron (a specific 5-HT3 receptor antagonist) would reduce heavy drinking. 
We hypothesize that, among individuals with an AUD, the alcohol consumption-promoting 
effects of the 5-HTTLPR and 3′-UTR variants are due to lower 5-HTT function and decreased 5-
HTT expression through reduced stability of mRNA, respectively—effects that individually lead 
to substantial postsynaptic 5-HT upregulation and, when combined, a supra-additive effect. 
 
In a phase 2, randomized, double-blind clinical trial of 283 alcohol-dependent individuals 
of EA or AA ancestry, treatment with the specific serotonin-3 (5-HT3) antagonist ondansetron, 
presumably through its neuromodulatory effects at postsynaptic 5-HT receptors, significantly 
reduced drinking among those who were homozygous for the L allele of the 5-HTTLPR—an 
effect that was enhanced in individuals who were T-allele homozygotes for the 3′-UTR SNP 
(Johnson et al., 2011). Further analysis of this data set revealed additional polymorphisms 
located on the genes for the A and B subunits of the serotonin 5-HT3 receptor that were also 
associated with a therapeutic response to ondansetron (Johnson, Seneviratne, Wang, Ait-
Daoud, & Li, 2013 
The proposed study is designed to address several important limitations of the above 
mentioned phase 2 clinical trials that tested the efficacy of ondansetron in AUD. Addressing 
these limitations (listed below), would further establish the use of ondansetron as an efficacious 
pharmacotherapy for AUD utilizing a personalized genetic (pharmacogenetic) approach.  The 
current study is a proof-of-concept, double-blind, randomized clinical trial to test whether, 
treatment-seeking, alcohol-dependent AA and EA adults  carrying specific genotypes show  a 
significantly greater and more robust treatment response to ondansetron than placebo and/or 
non-carriers of the genotypes, as reflected in greater reductions in DDD. 
 
Genetic association studies: An examination of 360 treatment-seeking AA male subjects 
with DSM-IV lifetime diagnoses of alcohol, cocaine, and heroin dependence and   187 showed a 
significant association between alcohol dependence and the functional SNP rs1176744 in  
HTR3B which encodes a subunit of the 5-HT3AB receptor (Enoch et al., 2011).  These findings 
were supported by earlier work from the same group that showed an association between a 5-
HT3B genotype and alcohol dependence with antisocial behaviors (Ducci et al., 2009).  A recent 
candidate gene association analysis in EAs also showed a strong interactive effect of 5-
HTTLPR, rs1042173 and 5-HT3AB variants associated with AUD (Seneviratne et al., 2013). 
Taken together, these studies suggest that variation in the genes encoding the 5-HT3 receptor 
and serotonin transporter may contribute to the development of alcoholism and lay the 
foundation for an examination of how certain polymorphic variants in the genes may 
differentially influence response to ondansetron treatment.  Nevertheless, because polymorphic 
variants associated with alcoholism may differ from those that moderate the ondansetron 
treatment response, effects of polymorphisms on treatment response will have to be 
demonstrated in a clinical study of ondansetron, rather than only in disease risk association 
studies. 

  
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Clinical Study: Based on the expectation that allelic variants within either homomeric or 
heteromeric 5-HT3 receptors could impact the response to ondansetron, Johnson et al. (2011) 
conducted an additional analysis on the same sample included in the phase 2 ondansetron 
study described above that considered multiple SNPs located on genes for the 5-HT3A and 5-
HT3B subunits of the 5-HT3 receptor. The latter analysis (Johnson et al. 2013) investigated the 
associations between drinking severity and 18 SNPs across HTR3A and HTR3B genes using 
blood samples for genetic testing and ondansetron response data from the Phase 2 trial of 
ondansetron (4 μg/kg, twice daily) versus placebo in 283 alcohol-dependent individuals with or 
without the LL/TT genotypes of the 5-HTT (described above: Johnson et al., 2011).  The 
analysis focused on 18 SNPs selected based on their minor allele frequency (≥ 0.05), their 
physical distribution on the HTR3A and HTR3B genes to obtain uniform physical coverage, and 
results from previous genetic association studies. 
This analysis identified three HTR3A and HTR3B genotypes that were significantly 
associated with a positive response to ondansetron in the EA sample (see Table 1).  Because of 
population differences in allele frequencies and linkage disequilibrium structure, the study of 
AAs will examine ondansetron response in relation to genetic variants that overlap, but are not 
identical, with those being examined in the EA sample (see section 3.1 below).  
Table 1: HTR3A and HTR3B genotype associations with response to ondansetron in EAs 
 
    Use of a larger ancestry-informative SNP panel for assessment of population admixture 
between samples in the two treatment groups: 
Allelic differences among populations are potential confounders in genetic association 
analyses, which may result in spurious associations. The differences in population admixture 
between subjects included in ondansetron and placebo groups of the Phase 2 study described 
above were tested using the program STRUCTURE   
(http://pritch.bsd.uchicago.edu/software/structure2_2.html), which revealed no statistically 
significant difference between the two groups.  As the subjects consisted of two groups, 
Caucasians and Hispanics, individual genetic ancestry proportions were calculated for all 
283 subjects and were used as covariates in all of the above-mentioned statistical models that 
tested HTR3A, HTR3B and SLC6A4 genotype effects.  Genetic ancestry proportions are 
increasingly being used as covariates in genetic association analyses as a strategy to limit type 
I error (Piwkham et al., 2011; Sucheston et al., 2011) 1-3.  In this Phase 2 trial, to prevent 
spurious associations resulting from population stratification, genetic ancestry proportions will 
be assessed using a panel of 186 ancestry informative SNPs described by Hodgkinson et al., 
(2008) as opposed to the 24-marker panel that we used in the phase 2 study. Genetic ancestry 
proportions will be calculated for each individual subject during data analysis, using the 
statistical software package Structure (Pritchard, Stephens, & Donnelly, 2000) 4 and genetic 
ancestry proportions for each individual subject will be used as covariates in statistical analyses. 
 

  
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1.5 Dose Rationale and Risk/Benefits 
 
Dose Selection: Selection of the 0.33 mg dose is based on the results of prior Phase 2 
studies (Johnson et al., 2011; Johnson et al., 2000; Sellers et al., 1994)). Johnson et al. (2011) 1-
3 showed that ondansetron at a dose equivalent of 0.33 mg twice daily was well tolerated and 
effective in reducing alcohol consumption in subjects with targeted genotypes vs. subjects 
without the targeted genotypes. Based on that study, we chose a dosage of 0.33 mg twice daily 
of ondansetron for use in the present trial. 
 
Each subject will receive ondansetron doses at the CNC under direct observation during 
the baseline visit (first dose at study Week 0) and on study Weeks 4 and 8 (first dose of the 
week). All other doses will be take-home. The investigator will closely monitor the subject for 
any adverse events or lack of tolerability.  Subjects will continue twice-daily dosing at home, and 
will be counseled to take the study medication at approximately the same times each day. 
 
Subjects will be asked to return all unused study medication and packaging to the study 
staff.  Throughout the study, the staff will closely monitor the subject for dosing compliance and 
adverse events or lack of tolerability to the study medication.  If the subject stops taking study 
medication for any reason and later, upon discussion with the investigator, wishes to restart the 
study medication, he/she will be provided with that opportunity no later than the study visit 
immediately following the request.  Interruption in study medication will be documented on the 
case report form.  If the subject wishes not to restart the medication, he/she will be encouraged 
to continue to participate in all scheduled study visits and assessments.  The case report form 
will document the duration through which the subject took study medication. 
 
Contraindications:  The concomitant use of apomorphine with ondansetron is 
contraindicated based on reports of profound hypotension and loss of consciousness when 
apomorphine was administered with ondansetron. Ondansetron is also contraindicated for 
patients known to have hypersensitivity to the drug. 
 
Warnings:  
 
Hypersensitivity reactions have been reported in patients who have exhibited 
hypersensitivity to other selective 5-HT3 receptor antagonists.  
ECG changes including QT interval prolongation has been seen in patients receiving 
ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in 
patients using ondansetron.  Ondansetron should not be administered to patients with 
congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte 
abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, 
bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation. 
High-dose, intravenous ondansetron (32 mg) has been associated with prolongation of 
the QTc interval. Freedman et al. (2014) reviewed the risk of cardiac arrhythmia associated with 
ondansetron).  Over the 22 years since ondansetron has been approved, no one case of an 
arrhythmia following a single oral dose of ondansetron has been reported. Furthermore, the 
maximal QTc lengthening from a 32 mg IV dose (100 x the dose proposed in the study) of 
ondansetron is 17-20 msec but only 5.8 msec after an 8 mg oral dose (24 x the dose proposed 
in this study).  Additionally, the peak serum level of oral ondansetron is only 3 to 35% of IV 
ondansetron.  Individuals identified by Freedman et al. (2014) to be most at risk of developing 
an arrhythmia were treated with ondansetron IV and had either an underlying arrthymogenic 
condition or were receiving other pro-arrthymic medications. As a precaution, we have 
incorporated appropriate exclusion criteria (long QTc syndrome) even though it would require 
that approximately 16,000 people be screened by ECG to find one case of asymptomatic long-
QT syndrome.  A 12-lead ECG assessment will be performed prior to the initiation of drug 
therapy and at visit 5, week 5 to assess possible effects of the currently proposed chronic low 
dose of ondansetron (0.66 mg/day) on the QTc interval.  Subjects will also be screened for 

  
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electrolyte abnormalities, which are not uncommon in this patient population and could lead to 
cardiac arrhythmias. 
           Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone. Most 
reports have been associated with concomitant use of serotonergic drugs (e.g., selective 
serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), 
monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous 
methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with 
overdose of ondansetron alone has also been reported. The majority of reports of serotonin 
syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an 
infusion center. Serotonin syndrome may include the following combination of signs and 
symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), 
autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, 
hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, 
incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, 
diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially 
with concomitant use of ondansetron and other serotonergic drugs. If symptoms of serotonin 
syndrome occur, discontinue ondansetron and initiate supportive treatment. Patients should be 
informed of the increased risk of serotonin syndrome, especially if ondansetron is used 
concomitantly with other serotonergic drugs.   
 
Drug Interactions: Ondansetron does not appear to induce or inhibit the cytochrome P-
450 drug-metabolizing enzyme system of the liver but is metabolized by this system. 
Theoretically, inducers or inhibitors of these enzymes may change the clearance and, hence, 
the half-life of ondansetron. On the basis of available data, however, no dosage adjustment is 
recommended for patients on these drugs. Thus, we will inform patients being treated with 
serotonergic antidepressants that the potential exists for an interaction with the study 
medication and we will monitor their progress accordingly.  It should be noted, however, that the 
low dose of ondansetron that is being used in this study (0.66 mg/day), is unlikely to contribute 
to serotonin syndrome. Notably, the dosage of ondansetron that is commonly prescribed to 
prevent nausea and vomiting is 16 mg/day, thus the dosage used in the current study is less 
than 1/24 the anti-emetic dosage. 
 
Apomorphine: Based on reports of profound hypotension and loss of consciousness  
when apomorphine was administered with ondansetron, concomitant use of apomorphine 
with ondansetron is contraindicated. 
 
Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers  
of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron 
was significantly increased and ondansetron blood concentrations were decreased. 
However, on the basis of available data, no dosage adjustment for ondansetron is 
recommended for patients on these drugs. 
 
Tramadol: Although no pharmacokinetic drug interaction between ondansetron and  
tramadol has been observed, data from 2 small studies indicate that ondansetron may be 
associated with an increase in patient controlled administration of tramadol. 
 
Serotonergic Drugs: Serotonin syndrome (altered mental status, autonomic  
instability, and neuromuscular abnormalities) has been associated with the concomitant use of 5-
HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake 
inhibitors (SSRIs; e.g. fluoxetine, sertraline, and citalopram,) and serotonin and noradrenaline 
reuptake inhibitors (SNRIs; e.g. venlafaxine). As indicated above, the likelihood of such an 
interaction is very small given the very low dosage of ondansetron being used in this study.  To 
ensure the safety of participants, we will monitor the appearance of signs and symptoms of the 
serotonin syndrome at every study visit after screening, using a standardized Serotonin Syndrome 
Symptom Checklist. Two or more positive responses on the Serotonin Syndrome Symptom Checklist will 
trigger further clinical evaluation. If there is clinical suspicion of the serotonin syndrome, the study 

  
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medication will be immediately stopped and the participant told to also immediately stop taking the 
serotonergic concomitant medication. (See section 5.6). 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility: Ondansetron was not mutagenic 
in standard tests for mutagenicity.  
 
Pregnancy: Teratogenic Effects: Pregnancy Category B. Should a woman become 
pregnant at any point in the study, we will immediately discontinue the treatment and refer her 
to an obstetrician for evaluation. We will also maintain contact with her via phone for the 
duration of the pregnancy to obtain self-reported safety information and, with her permission 
and that of her physician, will obtain information from her medical chart. 
 
Adverse Reactions: Studies examining adverse events associated with ondansetron 
(at a dosage much higher than the one being used in the present study) have focused on two 
patient groups: individuals receiving high-dose chemotherapy and subjects being treated for 
post-operative nausea and vomiting. Ondansetron was well tolerated in the postoperative 
nausea and vomiting population (n = 1081), which is more representative of our proposed 
population.  In this group, adverse events were similar between ondansetron and placebo (see 
Table 2) 
 
Post-marketing reports: Post-marketing reports are voluntary, therefore the frequency of 
the following adverse events are unknown: transient ECG changes (rare and predominantly with 
intravenous ondansetron); flushing; hypersensitivity reactions (rare), sometimes severe (e.g., 
anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, shortness of breath, 
hypotension, laryngeal edema, stridor); allergic reactions, including laryngospasm, shock, and 
cardiopulmonary arrest (predominantly the injectable formulation). Also reported: liver enzyme 
abnormalities, hiccups, oculogyric crisis (alone, as well as with other dystonic reactions), 
urticaria, and transient blindness (predominantly with the intravenous formulation and resolved 
within a few minutes up to 48 hours). 
 
 
 
 
Table 2: Adverse Events Associated with ondansetron and placebo 
Adverse Event  
ondansetron 16 mg   
Placebo  
Wound problem  
152 (28%)  
162 (31%)  
Drowsiness/sedation  
112 (20%)  
122 (23%)  
Headache  
49 (9%)  
27 (5%)  
Hypoxia  
49 (9%)  
35 (7%)  
Pyrexia  
45 (8%)  
34 (6%)  
Dizziness  
36 (7%)  
34 (6%)  
Gynecological disorder  
36 (7%)  
33 (6%)  
Anxiety/agitation  
33 (6%)  
29 (5%)  
Bradycardia  
32 (6%)  
30 (6%)  
Shiver(s)  
28 (5%)  
30 (6%)  
Urinary retention  
28 (5%)  
18 (3%)  
Hypotension  
27 (5%)  
32 (6%)  
Pruritus  
27 (5%)  
20 (4%)  
 
Physical Risks: Peripheral venipuncture poses a small risk of bruising and local infection at 
the needle puncture site. 
 

  
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Minimization of the risks: This risk of bruising and local infection at the needle site will be 
minimized by adherence to sterile techniques and standard, simple procedures to ensure 
hemostasis. 
 
    Psychological Risks: Psychological risks can include distress and heightened sensitivity, 
which can occur as part of the behavioral treatments, clinical interviews, or completion of self-
reported ratings and questionnaires. While the possibility of such events is low, we will monitor 
these situations and provide an appropriate level of support. 
Such events will be documented fully in the case records. 
 
Minimization of the risks: The potential for psychological harm will be reduced by adherence to 
FDA guidelines for Good Clinical Practice and by formal supervision and training of clinical 
personnel. Subjects will be allowed to take session breaks at any time, or reschedule a session 
(consistent with the overall study schedule).  Experienced clinical personnel are available at the 
CNC to evaluate subjects who express distress or discomfort over study procedures. We have 
surveyed our subjects and found good satisfaction with the quality of care that they have 
received. 
Overall, the development of carefully standardized and supervised SOP has allowed us to 
develop a high standard of care 
  
   Social and Legal Risks: Social and legal risks can include the disclosure of sensitive 
information about a subject to some other agency or an employer. 
 
Minimization of the risks: The likelihood of information from our clinic being disseminated 
without the subject’s consent to an outside source is remote. No information about a subject is 
disclosed without his or her written authority. Case records also are kept at a secure location in 
locked files. Access to these files is restricted to known personnel, who must fill out an entry 
form to receive any subject’s records. Computer based information contains subject numbers 
and codes that cannot be traced directly back to the original records. The computer records are 
protected by passwords and encrypted files that meet the C2 security standards of the U.S. 
Department of Defense. 
 
     Risk of participation becoming part of the medical record:  If a participant needs to be 
seen by a non-study physician and/or admitted to the hospital during the study, in order to provide 
medical treatment; it may be necessary to inform treatment providers (medical staff) of his/her 
participation in this study. This may include information regarding the use of alcohol in this study. 
This information can become part of the participant’s medical records. When insurance 
companies review medical record information, they might see the documentation of alcohol use 
and/or abuse as justification for denying coverage or charging higher premiums. Also it is possible 
for medical records to be entered as evidence in court. 
 
   Risks associated with questionnaires:   Participants will be asked questions of a sensitive 
nature concerning their medical, psychiatric, drug, and personal history, which some may find 
anxiety-provoking.  
 
Minimization of risk: To minimize this risk, research personnel are highly trained to be sensitive 
and responsive. All answers will be strictly confidential. In addition, a federal Certificate of 
Confidentiality will be obtained pending IRB approval of the protocol. 
 
 

  
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    Risk associated with pregnancy:   The safety of ondansetron to an unborn child is not 
established. For these reasons, pregnant women will not be allowed to participate.  
 
Minimization of risk: Women of childbearing potential must be using an acceptable form of birth 
control to participate in this study and have no intention of becoming pregnant. 
 
   Risk of alcohol withdrawal:  Alcohol withdrawal may occur from suddenly stopping the use of 
alcohol after chronic or prolonged ingestion.  
 
Minimization of risk: Presence and severity of acute alcohol withdrawal will be assessed at 
baseline and subjects who are experiencing significant alcohol withdrawal symptoms will be 
referred for treatment. 
 
   Risk of breach of confidentiality:  The research team is highly experienced providing care 
and doing research of this nature.  
 
Minimization of risk: All subject contact will occur in a private room. All study staff are well-trained 
and experienced in practices to protect confidentiality. 
 
 
The risks to subjects in this study are low. The medication, ondansetron, is well tolerated, and 
we have experience with its use in alcohol-dependent subjects for whom no serious adverse 
events were reported. We will minimize the risks to subjects participating in this study by 
adhering carefully to the eligibility criteria and our SOP. 
 
An alternative to participation in the study is for subjects to seek treatmet for alcohol use 
disorder from a treatment facility.  Alternative treatment may include taking a medication (other 
than ondansetron) that is FDA-approved for the treatment of AUD (disulfiram, naltrexone, and 
acamprosate), or psychosocial treatment without any medication 
 
 
2 Study Objectives 
The primary study objective is to determine the efficacy of ondansetron 0.33 mg twice 
daily, administered orally for a period of 16 weeks in reducing heavy drinking ( characterized by 
DDD) in carriers of specific SLC6A4, HTR3A and HTR3B “responsive” genotypes and 
secondary measures of drinking and quality of life among current drinking subjects. We will also 
compare ondansetron with placebo in subgroups of the sample based on alcohol intake. We 
also will test the additional secondary predictions that the differences seen in our primary 
specific aim will extend to secondary drinking measures and measures of quality of life. 
Additionally, we will use genome-wide expression studies of total RNA and miRNA- from blood 
samples and supported by supplemental funding-to compare the 15 most responsive subjects 
(whose drinking is reduced most significantly) and the 15 least responsive subjects on DDD and 
the 15 subjects with the greatest number of adverse events and the 15 with the fewest to 
identify changes that mediate ondansetron’s efficacy and adverse events profile, respectively. 
AUD is a heterogeneous and chronic relapsing disorder that includes both acute (binge 
drinking) and chronic (frequent heavy drinking) dimensions. Perhaps because of this 
heterogeneity, the therapeutic effect size of the approved medicines for the treatment of AUD 
has been small (Johnson & Ait-Daoud, 2011).  In an effort to overcome the heterogeneity of 
response to a particular medication, recent studies have instituted a personalized approach to 
therapy (Kranzler and McKay 2012). Major breakthroughs in pharmacogenetics have made it 
possible to identify discrete subgroups of the AUD population according to genetic profiles in 

  
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order to target the subjects who are most likely to respond to treatment with a particular agent. 
In addition, genetic variation contributing to the risk of alcohol dependence may be differentially 
associated with treatment response (Johnson et al., 2011; Kranzler et al., 2014; Oslin et al., 
2003). Thus, a successful personalized pharmacologic approach should ensure that targeted 
subgroups achieve an optimal treatment response with high predictability.  Such an approach 
holds the potential to identify not only robust responders to treatment but also those who might 
have minimal or modest adverse effects from the putative therapeutic medication.  From a 
practical clinical standpoint, a personalized medicine approach starts with a screen to identify 
the subject’s salient genotypes, in order to match the subject with the appropriate medication to 
ensure a high probability of a positive treatment outcome. This approach has the potential to 
exert  a substantial positive impact on public health (Kranzler and McKay, 2012). 
Hypothesis: 
Our overarching hypothesis is that, in both AAs and EAs, ondansetron 0.33 mg twice 
daily will decrease the intensity of drinking (i.e., the number of DDD) more than placebo. We 
further hypothesize that the effect will be greater in specific genotype groups in the two 
populations and we will balance the randomization on this genetic variation separately by 
population group to explore this prediction. 
Other exploratory aims will be examined in separate strata across both study sites, with 
treatment assignment at randomization balanced based on the genotypes that are relevant to 
each population:  to test the hypothesis that alcohol-dependent individuals with 5-HTTLPR LALA 
genotype in SLC6A4 (which encodes the serotonin transporter protein). We also will test the 
secondary predictions that the differences in our primary specific aims will extend to secondary 
drinking measures and measures of quality of life.  
Finally, we will use  
genome-wide expression studies of total RNA and miRNA- from blood samples and 
supported by supplemental funding- to compare the most responsive subjects (whose 
drinking is reduced most significantly) and 15 least responsive subjects on DDD as well as 
the 15 subjects with the greatest number of adverse events and the 15 with the fewest to 
identify changes that mediate ondansetron’s efficacy and adverse events profile, 
respectively. 
 
3 Study Design 
3.1 General Design 
 
This is a, randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial to 
explore the safety and efficacy of ondansetron to reduce drinking intensity in AA and EA adult 
subjects with AUD who commonly engage in heavy drinking . We will use selected genotype 
polymorphisms of the serotonin transporter and 5-HT3B receptor genes to examine ondansetron 
effects in subgroups based upon genotype. Analyses based on genotype will be conducted 
separately in EA and AA because different, but overlapping, genetic variants are relevant as 
potential moderators of ondansetron response in the two populations. The UPENN site is 
conducting a parallel study with both EAs and AAs. 
Probability of group assignment and potential for subjects to be randomized to placebo 
group:   
European Americans 
Participants with EA race will be selected based on absence/presence of any one of the 
combination of the following genotypes and will have equal probability (i.e., 50-50 chance) of 
being assigned to receive ondansetron (active medication) or placebo.  

  
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Subjects will be balanced based on their SLC6A4 genotypes, • 
5-HTTLPR:LL together with 
rs25531:AA (LALA genotype) in SLC6A4 gene; 
• 
SLC6A4-rs1042173: TT; 
• 
HTR3A-rs1150226: AG; 
• 
HTR3A-rs1176713: GG; 
• 
HTR3B-rs17614942: AC 
 
 
African Americans 
 
Participants with AA will be selected based on having a CC or TC genotype at rs176744, 
with each participant having an equal probability (i.e., 50-50 chance) of being assigned to 
receive ondansetron (active medication) or placebo.  
Participants will be balanced based on their SLC6A4 genotypes: 
 
5-HTTLPR-LALA vs. non- LALA genotypes 
 
rs1042173*TT vs. TG/GG genotypes.  
…. 
  
 
Eligible subjects will be stratified into two groups (Genotype responsive vs. non-responsive). 
Genotype responsive group will include the carriers of the above mentioned genotypes and the 
non-responsive group will include those who do not carry any of the above genotypes.  
 
 
Genotypes will be determined within one week of the Screen Visit. Primary Study 
Endpoints 
 
Drinking variables will be derived from the data collected by the Timeline Follow-back 
Interview (TLFB). Baseline for the drinking variables is defined as the 90 days preceding the 
baseline visit. One month is defined as 4 weeks (28 days). 
 
Primary Efficacy Variable: Change from baseline in the number of drinks per drinking 
day (DDD) during the last 8 weeks of the 16 week treatment period. 
3.2 Secondary Study Endpoints 
 
Key Secondary Variables 
o Responder analysis: Number of subjects with no HDDs during the last 8 weeks of the 
16-week treatment period. 
o Change from baseline in the total alcohol consumption, defined as mean daily alcohol 
consumption in standard drinks/day over the last 4 weeks of the 16-week treatment 
period.  
 
 
.   
Change from baseline in the percentage of heavy drinking days (PHDDs) defined as a 
day on which men drink >5 
drinks and women drink >4 drinks. 
   

  
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3.3 Primary Safety Endpoints 
Safety evaluations, including laboratory assessments, physical examination, vital signs, 
12-lead ECG and assessment of alcohol withdrawal, depression and suicidal risk, and querying 
for adverse events will be performed to identify safety issues in the study.   
 
Hematology, clinical chemistry, urinalysis, urine drug screen, medical history, psychiatric 
history, and physical examination will be performed at baseline and at varying intervals during 
the 16-week treatment, as described in detail in Table 3 below. 
Body weight and    
vital signs (including temperature, systolic and diastolic blood pressure, heart rate and 
respiratory rate) will be measured at screening/baseline and at every study visit. 
The Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) is a reliable 
and well-validated, 10-item scale to assess the severity of alcohol withdrawal symptoms. 
Alcohol withdrawal symptoms at the screening visit constitute a screen failure.  Any post-
screening physical finding from the CIWA-Ar that is considered to be clinically significant will be 
reported as an adverse event. 
The 21-item Beck Depression Inventory (BDI) will be used to measure depressive 
symptoms. Questions focus on topics such as mood, suicidal thoughts, sleep habits, and eating 
behaviors. The BDI will be administered at every study visit.  At screening/baseline, subjects 
with severe, untreated depression or who endorse suicidal intent will be excluded from the study 
and referred for treatment or immediate intervention.  At each post-baseline visit, the staff will 
review the findings on the BDI to ensure that the subject’s safety is not compromised by 
changes in depression symptoms. 
 
Careful screening using the MINI International Neuropsychiatric Interview 6.0 (MINI) 
Suicide Risk Assessment Scale (module B) will serve to exclude individuals with significant 
suicidal risk.  Ongoing monitoring using that instrument throughout the study will serve to reduce 
the risk of intentional overdose or other suicidal behavior. The MINI B   will also be used to 
assess suicide risk at each study visit, and if rated equal to or greater than 9 (i.e., clinically 
significant suicidal ideation), a study physician will be consulted to decide the appropriate 
clinical management. 
 
Table 3: Schedule of Study Procedures 
Assessments 
Study Visit 
V0-1 (Screen) 
V0-2 (Baseline) 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7  (Midpoint) 
 
V8 
 
V9 
 
 
 
V10(endpoint) 
V11 
Study Week 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
BrACa  
X X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Weight, vital signs, heightb 
X X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
TLFBc  
X X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENIING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SORT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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 Race/Ethnicity 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Psychiatric 
History, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-IV, AUDITd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SSADDA Nicotine  
Dependence Module 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUD criteria and clinical 
status (DSM-5) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Names and contact 
information for two locators 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY TESTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
hematology & clin. chem. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for %dCDT 
and GGTP 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Blood sample for mRNA and 
miRNA expression studies 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Urine pregnancy test 
X X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Urine specimen for riboflavin 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Drug Use 
questionnaire 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
SF-12, SIP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
OCDS, PSQI 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
ADS 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
STUDY VISIT 
V0-1 (Screen Part-1) 
V0-2 (baseline) 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
 
V8 
 
V9 
 
 
 
V10 
V11 
STUDY WEEK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NON-LABORATORY 
CLINICAL MONITORING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECG 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CIWA-Ar 
X X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
BDI 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
MINI Suicide Risk 
Assessment Scale 
X X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Clinical Global Impression 
Scales (CGI) 
(CGI-I, CGI-S) 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 

  
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BBCET 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
SSS Checklisth 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY MEDICATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of Study 
Drug (witnessed ingestion) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Dispensing of study drug 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
 
 
Compliance and drug 
accountability 
 
 
X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Adverse eventse 
 
 
X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
Xi 
, Concomitant medications 
and treatments 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
 
 
X 
Xg 
 
a. 
BrAC will be the first procedure at all visits; 
b. 
Height measured at screen part-1 visit only; 
c. 
At screen part-1 visit, subjects will complete the TLFB for the preceding 90 days.  At subsequent visits, the 
TLFB will span the time since the prior visit; 
d. 
AUDIT ( at phone screen) 
e. 
Subjects will be monitored for the occurrence of adverse events from the date the informed consent is 
signed; 
f. 
Final visit can be a telephone call unless an SAE has occurred since the last visit. Safety follow-up should 
include subjects who withdrew their consent but the safety follow-up data must only be included in the 
medical records and not in the CRF. 
g. 
Adverse events only 
h. 
Only for participants taking a serotonergic concomitant medication 
Abbreviations in the table:  ADS=Alcohol Dependence Scale; AUD=Alcohol Use Disorder; AUDIT=Alcohol Use Disorders 
Identification Test; BBCET=Brief Behavioral Compliance Enhancement Treatment; BDI=Beck Depression Inventory; CGI-I & 
CGI-S=Clinical Global Impression Scales (Improvement & Severity); CIWA-Ar=Clinical Institute Withdrawal Assessment for 
Alcohol-revised; GGTP=gamma-glutamyltranspeptidase; dCDT=disialotransferrin; MINI=Mini International Neuropsychiatric 
Interview; PSQI=Pittsburgh Sleep Quality Index; SCID=Structured Clinical Interview for DSM-IV; SF-12=Short Form Health 
Survey; SIP=Short Index of Problems; SORT= Slosson Oral Reading Test; SSS Checklist = Serotonin Syndrome Symptom 
Checklist  
 
4 
Subject Selection and Withdrawal 
 
Men and women, 18 to 70 years old, will b recruited: 183 AA and 183 EA. EAs will be 
self-identified as White, non-Hispanic or Hispanic individuals. Approximately 30% of the total 
cohort will be women.  Minorities and women will, therefore, be well represented in this trial. 
Children between the ages of 18 years and 21 years will be included in this study. This is in 
accordance with NIH guidelines for the inclusion of children in clinical studies, if appropriate. 
The inclusion of children enhances the generalizability of the results of clinical studies to the 
general population. 
 
The ethnic group commonly known as “Hispanic” or “Latino” is an admixed population 
that primarily resulted from two-way admixture between Native American and European 
populations or three-way admixture among Native American, European, and West African 
populations. In admixed individuals with a disease, chromosomal segments harboring 
susceptibility variants will show an excess of ancestry from the parental population in which the 
risk alleles are more frequent (Mao et al., 2007), leading to genetic subgroups within a 
population. The existence of genetic subgroups or substructure in a population may lead to 
spurious associations if the subgroups are not equally represented in cases and controls (Lai et 
al., 2009). Balancing for subgroups in a genetic association study examining a common disorder 
such as AUD will require a large number of subjects to permit an analysis of the subtle effects of 
multiple polymorphisms with sufficient statistical power.  For this reason, the current study will 

  
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be limited to subjects of predominantly (>75%) European and African ancestry.  This will include 
Hispanic/Latino individuals who self-report being of African or European ancestry.   
Number of subjects (at each site) needed to complete the protocol:  128 subjects of 
African-American ancestry and 128 subjects of European ancestry are needed to complete the 
protocol. Also, each site will aim to have a total of 128 completing subjects (from either race). 
 
Expected rate of screen failure/ dropouts/withdrawals from all sites:  Allowing for a 30% 
drop-out rate (during the course of the study, which is about 4 months), as seen in previous 
studies conducted by the PI’s research team, we will need to randomize about 183 subjects at 
each site in order to have 128 subjects complete the protocol.    
 
  Inclusion Criteria 
 Men and women who have given written informed consentAged 18 to 70. 
 The subject has a breath alcohol concentration (BrAC) = 0.00% at the screening visit 
 Self-reported African-American or European ancestry (mixed ancestry individuals will not be 
included in this study) 
 The subject has a breath alcohol concentration (BrAC) = 0.00% at the screening visit 
 Diagnosis of alcohol use disorder (AUD) using Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition (DSM-5) criteria 
 Able to provide TLFB alcohol consumption information for the 90-day period prior to the 
Screen Part-1 Visit. 
 During the 4 weeks preceding the Screening Visit, the subject reports: 
o >6 Heavy Drinking Days (HDDs) – defined as a day with alcohol consumption of > 5 
standard drinks (i.e., 12 g of ethanol) for men, and > 4 standard drinks for women 
o <14 consecutive abstinent days 
o Total alcohol consumption of an average of >21 standard drinks/week for men and 
>14 standard drinks/week for women in past 30 days and have met these criteria 
during the 7 days prior to randomization 
 An expressed wish to reduce or stop drinking 
 Willingness to participate in a research study with  behavioral treatment and medicinal 
treatments or placebo study medication  for Alcohol Use Disorder 
 Stable residence in the 28 days prior to the Baseline Visit and no plans to move in the next 9 
months.  A stable residence is a domicile in which an individual can operate as if it were his 
or her own homestead and does not include shelters or halfway houses.  
 Provides contact information for 1 or 2 "locators" who can be used to contact the subject 
 Able to read and understand English and accurately complete the rating scales and 
questionnaires, follow instructions, and make use of the behavioral treatments.  This will be 
assessed with the Slosson Oral Reading Test-Revised, on which the subject must 
demonstrate at least a 6th grade reading level. 
 If the subject is a woman of child-bearing age, she must: 
 
Agree not to try to become pregnant during the study, and use adequate contraception 
(defined as oral/ systemic contraception, such as Norplant, Depo-Provera, or birth 
control pills or patches, an intrauterine device, a combination method such as a 
diaphragm  or male condom combined with spermicide, jellies or foam, withdrawal, a 
sponge, the rhythm method, or a cervical cap) or 

  
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 
Be postmenopausal, (i.e., have had her last natural menstruation at least 24 months 
prior to baseline) or  
 
Have had a hysterectomy or been surgically sterilized prior to the Baseline Visit, or 
 
Plan not to be sexually active vaginally with men during the entire duration of the trial. 
 
Weight >110 Kg (242 lb) 
 
Exclusion Criteria 
A subject presenting with any of the following criteria will be excluded from the study: 
 
o The subject has fewer than 6 heavy drinking days (HDD) (defined as >5 standard 
drinks for men and >4 or greater standard drinks for women) in the 4 weeks 
preceding the Screening Visit.  
o The subject has greater than 14 consecutive abstinent days in the 4 weeks 
preceding the Baseline Visit. 
o The subject has a Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-
Ar), Revised, score >10 at Baseline visit. 
o The subject has a current diagnosis of any of the following psychiatric disorders: 
schizophrenia, bipolar disorder, other psychotic disorder, severe major depressive 
disorder, post-traumatic stress disorder, panic disorder, eating disorder, or substance 
use disorder (except alcohol, tobacco, or cannabis).  
o Current or recent (within 4 weeks prior to Baseline Visit) treatment with 
antipsychotics  or any medications likely to interact with ondansetron to produce 
adverse effect, as judged by a study physician . 
o Treatment with any investigational medicinal product within 30 days or 5 half-lives 
(whichever is longer) prior to the Randomization 
o Currently participating or has recently (4 weeks prior to the Randomization) 
participated in a treatment program for alcohol use disorders. 
o MINI 6.0 Suicide Risk Assessment (module B) will be used to assess subjects’ risk of 
suicide. Subjects who receive a score of >9 on this assessment will be evaluated by 
the PI or designee to determine their eligibility.  Subjects who are deemed by the PI 
or designee to be at risk of suicide will be excluded. 
o Clinically significant, unstable physical illness (e.g., hematologic disorders, hepatic or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, 
neurological, infectious, neoplastic, or metabolic disturbance), as judged by the PI or 
designee to be exclusionary 
o Clinically significant abnormal vital signs, as judged by the PI or designee 
o Clinically significant abnormal 12-lead ECG at the Screen Visit, clinically significant 
cardiovascular disease requiring regular or intensive clinical monitoring,  or a current 
or past history of clinically significant QT prolongation, including: QTcF > 450 ms 
(average of 3 12-lead measurements) 
 Serum potassium, magnesium or calcium levels outside the central laboratory's 
reference range that are deemed clinically significant by the PI or designee. 
 
Taking medication (within the last 7 days prior to the Baseline Visit) that has the potential 
to clinically significantly prolong the QT interval, as judged by a study physician. or may 
require such medications during the course of the study (see Table  below for a list of 
medications).  For patients taking these medications, a study physician will evaluate the 
potential for ondansetron to interact with the medication to produce a clinically significant 
risk for the participant.  

  
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 Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic 
bradycardia, unstable congestive heart failure, active myocardial ischemia or indwelling 
cardiac pacemaker 
 Complete left bundle branch block 
 History of Long QT Syndrome or a first-degree biological family member with this 
condition 
o Evidence of hepatic failure and/or ascites, prolonged prothrombin time (International 
Normalized Ratio [INR] >1.7), bilirubin >10% above the upper limit of the central lab's 
normal range and/or esophageal variceal disease 
o Active hepatitis and/or serum glutamic oxaloacetic transaminase (SGOT), serum 
glutamic pyruvic transaminase (SGPT) or lactate dehydrogenase (LDH) > 3x the 
upper limit of normal  
o Treatment, either current or within 28 days prior to the Randomization, with any 
medications having a potential effect on alcohol consumption and related behaviors.  
These include opioid antagonists (e.g., naltrexone, Vivitrol®, Selincro®), glutamate 
antagonists (e.g., acamprosate), anticonvulsants (e.g., topiramate, gabapentin), 
dopamine antagonists (e.g., haloperidol), and disulfiram (Antabuse®) 
o At the Screen visit, the subject's urine contains opiates, cocaine, 
methamphetamines, benzodiazepines, or opiates that cannot be explained by 
appropriate use of a prescribed medication. 
o History of severe or life-threatening adverse reactions to ondansetron 
o Female subjects of childbearing potential who have a positive pregnancy test at 
Baseline Visit or are pregnant, breast feeding, not adhering to an acceptable form of 
contraception at screening or any time during the study, or unwilling to maintain an 
acceptable form of contraception throughout the study  
o Prior to randomization, the subject is compelled to participate in an alcohol treatment 
program to maintain his/her liberty 
o As of Screen Visit, the subject is sharing a household with a subject randomized to 
any investigational trial of ondansetron 
o Any other condition or therapy that, in the investigator's opinion, may pose a risk to 
the subject, prevent the subject from completing the required study procedures or 
interfere with the study objectives 
o Less than 75% European ancestry proportions or African-American ancestry 
proportions. If ancestry is determined by a 24-marker ancestry panel, the participant 
will not start treatment until after the results are known. 
 
 
Table 4  
 
 
Some drugs associated with QTc prolongation 
 
 
Antibiotics 
azithromycin 
clarithromycin 
erythromycin 
roxithromycin 
metronidazole 
(with alcohol) 
moxifloxan 
 
Antifungals 
Anaesthetics 
halothane 
 
Antiarrhythmics 
disopyramide 
procainamide 
quinidine 
Antipsychotics 
risperidone 
fluphenazine 
haloperidol 
clozapine 
thioridiazine 
ziprasidone 
pimozide 
droperidol 
 

  
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fluconazole 
(in cirrhosis) 
ketoconazole 
 
Antivirals 
nelfinavir 
 
Antimalarials 
chloroquine 
mefloquine 
amiodarone 
sotalol 
 
Antidepressants 
amitriptyline 
clomipramine 
imipramine 
dothiepin 
doxepin 
Antihistamines 
terfenadine* 
astemizole* 
 
Other 
probucol 
cisapride 
 
4.1 Subject Recruitment and Screening 
Subjects will be recruited at research centers at the Clinical Neurobehavioral Center 
(CNC) at UMB.  Advertisements for the study will state clearly that there will be no cost to the 
subject for participation.  Only recruitment materials and methods approved by the UMB IRB will 
be utilized.  We recognize that our recruitment efforts may yield individuals in need of treatment 
who do not qualify for the present study.  We will try to enroll these individuals in other ongoing 
studies at our sites.  Should subjects fail to qualify or decline to participate in other ongoing 
treatment studies at our research centers, we will assist with a referral to another treatment 
facility.  
 
Subjects will be recruited through local advertisements, possibly including posters, flyers, 
newspaper, radio, television, electronic communications (including email and social media), 
Craigslist, advertisements on mass transit, referrals from local treatment programs and centers, 
and commercial sites such as such as gambling casinos, race tracks (horse, auto), hunting and 
fishing supply stores, auto supply stores, and stores selling alcoholic beverages. 
 University health systems, community agencies, and local college campuses that offer 
services and means of posting and distributing recruitment materials in the community settings 
with public posting areas or providing community access to materials ( such as hospitals, town 
halls, public libraries, YMCAs, health fairs, etc.) We will obtain permission at selected locations 
before distributing or posting the approved recruitment materials (ensuring compliance with 
other institution guidelines, including seeking IRB approval as needed). We will also screen 
patient databases as permitted by the institution and approved by the IRB. We will search the 
University of Maryland Medical Center and FPI EPIC medical record databases to identify 
potential subjects based on demographics, medical diagnosis codes related to AUD and 
exclusionary comorbid diagnoses, and residence within commuting distance of CNC. We will 
contact the individuals with IRB-approved outreach letters from the study PI. About a week 
after sending the letter, we will make a follow-up phone call to these individuals if no response 
has been received.  
Subjects who express interest will be invited to participate in a telephone screening interview. 
Prior to initiating screening, we will describe the nature of the study to the subject, including the 
number of visits to the center, subject protections, and confidentiality. If the caller remains 
interested, we will obtain oral consent for the phone screening. Screening questions cover 
general health, psychiatric history and alcohol consumption (AUDIT, see section 6.7 below). If 
we determine the applicant to be eligible based on this screening, s/he will be asked whether 
they wish to participate.  If so, s/he will be scheduled for an initial in-person appointment, at 
which informed consent will be obtained.  
 We will request a partial waiver of HIPAA Authorization from the IRB to allow for 
preliminary telephone screening for calls initiated or invited (e.g., following our having contacted 
them by letter)  by potential subjects.  Individuals deemed eligible for in-person screening will 

  
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sign a HIPAA Authorization and study consent form at their first visit. These procedures have 
been approved by the Institutional Review Boards of both UMB and UPenn to ensure 
compliance with HIPAA requirements.  The telephone screening interview will include: a) 
demographic data; b) medical status; c) a brief psychiatric history; d) a brief TLFB for alcohol 
consumption; e) drug use history and e) questions to assess motivation to engage in treatment.  
Prospective participants will contact the CNC by telephone. On the telephone, recruiting staff 
will provide information about the trial and will provide the caller with the eligibility criteria. 
Recruitment staff will follow an IRB approved telephone script. If the caller remains interested in 
participation, he or she will be informed about a time to come to the CNC for medical screening. 
Our intake interviewers have been trained specifically in these tasks.  This enhances data 
quality and increases the likelihood of suitable subjects being invited for intake.  Collection of 
these data, which are identical to some of the measures in the proposed study, will allow for 
comparison of the target and study populations.  Additionally, it will improve the efficiency of the 
study and reduce the likelihood of unsuitable subjects having to undergo a full screening before 
being excluded.  The telephone screening interviews will be conducted only by trained study 
staff.  Once subjects pass this telephone screen, we will schedule an intake examination within 
14 days.  
4.2 Early Withdrawal of Subjects 
4.2.1 When and How to Withdraw Subjects 
It is recognized that subjects are free to withdraw from the study at any time.  However, 
if a subject wishes to withdraw from the study before completing all study visits during the 
treatment phase, the study staff will ask him or her to schedule an early termination visit.  The 
early termination visit will include all Week 16 procedures and assessments.  Following an early 
termination, an effort will be made to interview the subject at the previously scheduled study 
endpoint, either in person or by telephone.  This will make it possible to record drinking history 
during the period between early termination and the scheduled endpoint.  
The following efforts will be made to contact subjects who discontinue treatment prior to 
completing the 16-week treatment period: 2 telephone calls by the research coordinator or 
technician resulting in contact (either with the subject or by leaving a message on voicemail or a 
person answering the subject’s telephone), followed by 2 telephone calls by a study physician, 
followed by calls to the 2 locators nominated by the subject, followed by a letter. Only if all of 
these efforts are unsuccessful in obtaining follow-up information (either during an in-person visit 
or a telephone interview), will the subject be considered to be lost to follow-up.  
An investigator may discontinue medication and withdraw the subject from the study if 
he or she deems it clinically appropriate or for any of the following reasons: 1) significant side 
effects from the medication, 2) serious or unexpected adverse events, 3) inability to comply with 
the study protocol, 4) protocol violation, or 5) serious intercurrent illness.  A subject may 
withdraw from the study anytime he or she wishes.  In the event that a subject is discontinued 
from receiving the research medication but may be able to continue with the psychosocial 
intervention, the subject will be allowed to continue the psychosocial intervention visits with the 
approval of the investigator.   
At week 16, subjects that request ongoing care will be given a referral to an alcohol 
treatment facility or may be given a list of alcohol treatment facilities to contact.  
4.2.2 Data Collection and Follow-up for Withdrawn Subjects 
Any subject who discontinues treatment prematurely, regardless of the reason, will be 
requested to return for a final visit to do the necessary procedures and obtain data for end-of-
study/early-termination and follow-up visits.  Following an early termination, an effort will be 

  
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made to interview the subject at the previously scheduled study endpoint, either in person or by 
telephone.  This will make it possible to record drinking history during the period between early 
termination and the scheduled endpoint. 
5 Study Drug  
5.1 Description 
 
The only investigational agent to be used in this study is ondansetron, a specific 
serotonin-3 (5-HT3) antagonist that is FDA approved to treat chemotherapy-induced nausea and 
vomiting, radiation-induced nausea and vomiting, and postoperative nausea and vomiting.  In 
the present study, subjects will be given ondansetron at a dosage of 0.33 mg or matching 
placebo capsules by mouth twice daily.  
 
The active ingredient in ondansetron tablets is ondansetron hydrochloride (HCl) as the 
dihydrate, the racemic form of ondansetron.  Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-
[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate.  
Ondansetron’s empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 
365.9. 
5.2 Treatment Regimen 
 
Ondansetron 0.33 mg or matching placebo by mouth twice daily for 16 weeks. 
5.3 Method for Assigning Subjects to Treatment Groups 
 
Randomization: Subjects within each of the 2 above-mentioned genotype groups will be 
randomly assigned to receive ondansetron or placebo. The clinical coordinator will collate intake 
data essential to assign subjects to a treatment group, including genotype information, which 
will be used to complete a Subject Randomization Form. The Randomization List Form 
records the subject’s ID number and UMB Investigational Drug Service (IDS) randomization to 
ondansetron or placebo. The UMB pharmacist is responsible to keep the treatment assignments 
recorded on the Randomization List Forms confidential and completely blinded from the staff 
involved in the trial, except as specified under the emergency conditions for which both sites 
have written Standard Operating Procedures (SOPs). Upon receipt of the Subject 
Randomization Form for a particular participant, the pharmacist shall communicate to the 
research staff which of the medication kits provided to the site is to be used for that subject. All 
clinical staff members directly involved with the assessment of subjects are always blind to the 
medication condition. These procedures have been designed to avoid delay. An IDS staff 
person, who is not otherwise involved in the study, will perform the randomization and 
assignment of eligible subjects into treatment groups. All participants and other investigators will 
be blinded.  
 
Only subjects who meet all inclusion criteria and no exclusion criteria will be randomized 
to treatment.  One hundred eighty-three subjects with a DSM-5 AUD will be randomized into two 
medication groups (ondansetron or placebo; N=~91/group).  Randomization will be stratified by 
site, race, gender and genotype.  There will be 8 genotype strata (based on all combinations of 
3 loci or SNP’s) for AAs and 2 genotype strata (“responsive”  vs. “non-responsive” genotype 
combinations) for EAs,  based on the race-specific genotypes defined in section 3.1 above). 
Treatment group assignment will be  assigned using a block randomization procedure that 
balances the treatment groups within the above defined strata.    
 
The IDS at UMB will implement the randomization for both participating sites.  The 
clinical coordinator will collate intake data essential for assignment to a treatment group, 
including genotype information that will be used to complete a Subject Randomization Form.  A 
study physician or nurse practitioner must sign the Subject Randomization Form.  This signature 

  
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functions as a prescription for the UMB IDS to distribute medication to the participating sites at 
both universities.  A copy of the form is kept in the Case Report Form (CRF), and the original is 
provided to the pharmacist at UMB.  The UMB pharmacist will then complete all identifying 
information required on the Subject Dose Record Form.  The Subject Dose Record Form 
records the subject ID number.   The pharmacist is responsible to keep the dose assignments 
recorded on the Subject Dose Record Form confidential and completely blinded from the local 
investigative research staff, except as specified under the emergency conditions for which all 
the sites have written Standard Operating Procedures (SOPs).  Upon receipt of the faxed 
Subject Randomization Form for a particular participant (which will be faxed to the UMB IDS 
Monday through Friday, from 8 AM to 4 PM), the UMB pharmacist will fax back to the site the 
identity of the medication kit to be dispensed to the subject.  Medication starter kits for the first 
three weeks of treatment will be shipped in a batch to UPenn from the UMB IDS. Once the 
subject has been randomized, the UMB IDS will provide medication for subsequent weeks of 
treatment in batches, as described below. The UMB IDS will track the number of starter kits 
dispensed at UPenn and will replenish them to ensure that medication is available for ongoing 
enrollment.  All clinical staff members directly involved with the assessment of subjects will 
always be blind to the medication condition.  These procedures have been designed to avoid 
delay. 
5.4 Preparation and Administration of Study Drug 
 
Ondansetron will be purchased commercially and formulated by the UMB School of 
Pharmacy Good Manufacturing Practices facility in opaque capsules.  Placebo capsules will be 
formulated to match the active medication, so that inspection of the capsules will not allow them 
to be differentiated. The UMB IDS will be responsible to blind study medication according to the 
protocol outlined by the study statistician. 
5.5 Subject Compliance Monitoring 
 
Compliance with ondansetron will be assessed using the methods below: 
 Pill Count: An account of dispensed and returned study drug will be kept at the study 
center for each subject.  Subject reports of discrepancies (e.g., lost or discarded capsules) will 
be documented in the case report form (CRF). 
 Presence of urinary riboflavin (an internal tracer for assessing medication compliance):  
Both the active and placebo drug will be packaged with the internal tracer, 12.5 mg of crushed 
riboflavin tablets. At screening, a research team member will query subjects as to whether they 
are taking any vitamins that contain riboflavin. If so, the subject will be asked to provide the 
name of the vitamin, and if the daily dose of riboflavin taken exceeds 2 mg, the subject will be 
asked to replace the formulation with a low-riboflavin formulation. Urine samples will be 
collected at each visit following the initiation of medication to measure riboflavin amounts in 
urine. Percentage of optical density of riboflavin in samples will be compared to that of a control 
sample containing a set amount of riboflavin to objectively determine medication compliance. 
Optical densities will be measured using a urinary fluorescence assay to be conducted at UMB 
using frozen urine samples sent from both sites. 
 Dosing Diary: The clinician will use a calendar-based TLFB-style technique to elicit this  
information, which increases precision for the exact times of medication ingestion.  
 BBCET: Brief Behavioral Compliance Enhancement Treatment (BBCET). Subjects in  
both medication groups will receive BBCET (described below). BBCET emphasizes maintaining 
compliance and avoiding early discontinuation of the medication. Adverse events are monitored 
and protocol-permitted remedies or over-the-counter medications are provided if necessary to 
deal with them. 

 
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Figure 1: Stratification and Randomization Scheme:

 
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                                                     EA 
 
 
Genotype Non-Responsive Group 
Genotype Responsive Group 
5-HTTLPR: L′L′ 
And 
rs1042173:TT 
 
With or without 
HTR3A-rs1150226:AG; 
HTR3A-rs1176713:GG; 
HTR3B-rs17614942:AC 
 
(Apr. Population 
frequency =0.13 of total 
sample) 
5-HTTLPR: L′L′ 
And 
rs1042173:TG/GG 
 
With or without 
HTR3A-rs1150226:AG; 
HTR3A-rs1176713:GG; 
HTR3B-rs17614942:AC 
 
(Apr. Population 
frequency =0.18 of total 
sample) 
 
5-HTTLPR: L′LG/LGLG/LS/SS 
And 
rs1042173:TT 
 
With or without 
HTR3A-rs1150226:AG; 
HTR3A-rs1176713:GG; 
HTR3B-rs17614942:AC 
 
(Apr. Population frequency 
=0.17 of total sample) 
 
5-HTTLPR: L′LG/ LGLG/LS/SS 
And 
rs1042173:TG/GG 
And 
HTR3A-rs1150226:AA/GG; 
HTR3A-rs1176713:AA/AG; 
HTR3B-rs17614942:AA/CC 
 
(Population frequency =0.39 of total sample) 
 
ONDANSETRON 
 
N=32 
PLACEBO 
 
N=32 
ONDANSETRON 
 
N=32 
PLACEBO 
 
N=32 
5-HTTLPR: L′LG/LGLG/LS/SS 
And 
rs1042173:TG/GG 
And 
One/more of the following: 
HTR3A-rs1150226:AG; 
HTR3A-rs1176713:GG; 
HTR3B-rs17614942:AC 
 
(Apr. Population frequency 
=0.13 of total sample) 
 

 
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5.6 Prior and Concomitant Therapy 
Subjects who enter this study must not be on any medication that may affect alcohol 
consumption.  We also will avoid the prescription of medications with potentially clinically 
significant interactions with ondansetron.  It is, however, recognized that concomitant 
medication may be prescribed or self-administered to treat minor physical ailments during the 
study.  Such appropriate medications will be allowed and documented in the concurrent 
medications section, and the physical ailment recorded in the adverse events section, of the 
subject’s study book.  A list of allowable concomitant medications will be compiled and placed in 
the appendix section of each case study book for easy reference (see the table 5 below). 
 
 
Table 5: Allowed and disallowed concomitant medications  
 
Drug Class 
Episodic 
Use 
Chronic  
Use 
Analgesics 
Yi 
N 
Anorexics 
N 
N 
Antacids 
Y 
Y 
Anti-anginal drugs 
N 
N 
Anti-anxiety/alcohol withdrawal agentsii 
N 
N 
Anti-arrhythmics 
N 
N 
Anti-asthma agents 
Y 
Y 
Antibiotics 
Y 
Y 
Anticoagulantsiii 
N 
N 
Anticonvulsants 
N 
N 
Anti-dependence drugs (e.g., bupropion or naltrexone) 
N 
N 
Anti-diarrheal agents 
Y 
N 
Antihistamines 
Y 
Y 
Antihypertensives 
N 
Y 
Anti-psychotics 
N 
N 
Cough/cold preparations iv 
Y 
N 
 Diabetes medications (oral hypoglycemics, insulin) 
N 
Y 
Dietary supplementsv 
N 
N 
Digitalis preparations 
N 
N 
Hormones/steroidsvi 
N 
Y 
Laxatives 
Y 
N 
Nicotine replacement therapy 
N 
N 
Non-steroidal anti-inflammatory agents vii 
Y 
Y 
Tricyclic Antidepressants 
N 
N 
     
Y=allowed, N=not allowed 
 
Definitions 
Chronic use: 4 days per week or more, for a month or more.  Additionally, the medication must have been 
started and stabilized for at least 2 weeks prior to study enrollment.  Periodic or episodic use: 3 days per 
week or less, or more frequent use for less than a month’s duration. 
 
 
 
Key 
I Episodic use of Opiate-containing analgesics will be allowed if there is a clear indication and the time of 
administration is noted relative to the timing of the urine drug screen.  
ii Benzodiazepine use will not be allowed 
iii  Aspirin up to 325 mg/day  for cardiovascular prophylaxis will be allowed. 
iv Episodic use of opiate-containing formulations will be allowed 

  
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v Riboflavin is not allowed. We will allow multi-vitamins that contain less than 2 mg of riboflavin. 
vi Topical steroid preparations for episodic use will be allowed. 
viiChronic NSAID use is not allowed for participants with a history of gastritis or ulcers. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
 
 
 
 
5.7 Packaging 
 
The UMB School of Pharmacy Good Manufacturing Practice facility will package bulk 
drug on-site.  The bottle will contain an extra two days of medication to ensure that subjects 
have adequate medication to continue the prescribed regimen if a visit needs to be rescheduled. 
Half of the participants will receive an inactive placebo. Placebo will be opaque, gelatin capsules 
of the same size, color, and shape packaged with cornstarch. All capsules (active and placebo) 
will be packaged with 12.5 mg of riboflavin for detection of urinary riboflavin to measure 
medication adherence.  
5.8 Blinding of Study Drug 
 
All subjects and research staff will be blinded as to whether the subject is in the 
ondansetron or placebo group until the decision to break the study blind is determined at the 
end of the study (after study database lock). Codes linking randomization number for each 
subject to actual treatment will be secured in a sealed, opaque envelope and maintained in a 
locked drawer in the IDS. Research subjects will be given the emergency contact number for 
the study during the consenting process. See section 8.4 (Unblinding Procedures) for a 
description of the process for unblinding a study subject.  
5.9 Receiving, Storage, Dispensing, and Return 
5.9.1 Receipt of Drug Supplies:   
 
There is no industry sponsor for this study. The UMB School of will prepare the study 
medication using commercially available product. The IDS will dispense coded, blinded study 
drug kits to the research coordinator at each site.  Starter kits containing three weeks of study 
medication will be following by three other kits, 2 of which will contain 4 weeks of study 
medication ( for week 4-7 and for weeks 8-11)and one of which will contain 5 weeks of study 
medication (for weeks 12-16). Each kit will contain medication divided into weekly prescriptions 
that contain 9 days of medication (i.e., an extra two days of medication (i.e., 4 capsules) to 
ensure that subjects have adequate medication to continue the prescribed regimen if a visit 
needs to be rescheduled).   The research coordinator will maintain 100% drug accountability at 
the clinic for the duration of the study. The research coordinator will document all medication 
using a drug accountability log to track the study medication from time it leaves the IDS until the 
time that it is returned to the IDS for reconciliation and disposal.  

  
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5.9.2 Storage 
 
Study drug will be stored at the IDS at controlled room temperature (36-86 F). Study 
drug kits dispensed from the UMB IDS to the clinics at UPenn and UMB will be stored in a 
locked cabinet in a room that is temperature controlled and double locked until dispensed. Any 
returned study medication will also be kept under locked conditions until returned to the UMB 
IDS for disposal. 
5.9.3 Dispensing of Study Drug 
 
Upon receipt of the Subject Randomization Form for a particular participant, the study 
staff will have the medication for that subject ready for dispensing.  Medication will be dispensed 
to subjects at each study visit, with enough medication provided to last until the next scheduled 
visit (with two days of additional medication to ensure that the subject has adequate medication 
if the appointment is not scheduled for the exact number of weeks or has to be rescheduled).  
All clinical staff members directly involved with the assessment of subjects are always blind to 
the medication condition. These procedures have been designed to avoid delay. The 
randomization and assignment of eligible subjects into groups will be conducted at by an 
individual who is not otherwise involved in the study. All participants and other investigators will 
be blinded.  
 
The study nurse and study coordinator will maintain a dispensing record, documenting 
the amount of medication dispensed to the subject, the amount returned, and the amount taken. 
A log will be used to document the amount of study drug returned to the IDS and the date it was 
returned. 
5.9.4 Return or Destruction of Study Drug 
 
A final reconciliation of all remaining study medication will be made at the end of the 
study. All unused kits and medications dispensed and later returned by the subjects will be 
returned to the UMB IDS, which will be responsible for the disposal/ destruction of all unused 
study medication. The study coordinator will reconcile all remaining study medication for each 
subject as they complete the study and return all unused study medication and empty 
medication bottles to the UMB IDS for reconciliation in batches on a quarterly basis.  All 
attempts will be made to collect the study medication and bottles from subjects at the end of the 
study and during follow-up sessions as needed. 
6 Study Procedures 
6.1 Initial Telephone Screen (approximately 20 minutes) 
Subjects will be recruited through local advertisements in print and broadcast media, through 
leaflets and posters distributed throughout the Greater Baltimore regions, and by advertising on-
line and through social media, and by communicating with them by mail ( as described in 
section 4.1). Subjects who express interest by responding to this advertising will be contacted to 
participate in a telephone screening interview. Prior to eliciting any information, we will describe 
the nature of the study, including the number of visits to the center, subject protections and 
confidentiality. If the caller is still interested, we will obtain oral consent for the phone screening. 
Screening questions cover general health, psychiatric history and alcohol consumption. If, in 
consultation with the principal investigator or his designee, we determine that the applicant is 
eligible based on this screening, s/he will be invited to come to the clinic for an in-person screen 
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6.2   Screen Visit (V0-1; Study Week -1)  
 
This visit is designed for genetic screening to allow stratification on the tested genotypes 
Upon arriving to the visit, which will be conducted at the CNC in Columbia, MD, subjects will be 
asked to show legal photo identification and to provide informed consent. They will then 
undergo a breathalyzer test to ensure a breath alcohol concentration (BrAC) of 0.00%, which 
will be used to assess alcohol intoxication at every visit.  The allowable alcohol concentration at 
all visits following the screening visit is less or equal to 0.02. The informed consent will be 
considered valid and no assessments will be performed at the screening or any subsequent visit 
unless subjects have BrAC readings of 0.00% 
 
If the subject attends the clinic and records a BrAC greater than this level, the study staff 
will encourage the subject to wait in the clinic for a sufficient time to permit testing.  If a subject 
coming to the UMB site records a BrAC level >0.02 mg/dl , and does not agree to wait, or it is 
impractical for the subject to wait until the BrAC falls to the desired level for testing, he or she 
should be advised not to leave until the BrAC is below the legal level.  If the subject insists on 
leaving at a level at or above the legal limit, this should be documented in the appropriate 
section of the CRF.  The investigator should make a reasonable effort to reach the subject after 
he or she leaves the clinic to ascertain his or her safety and to encourage him or her to attend 
the next clinic visit.    
 
The screening visit can be done in one or more visits, depending on participant’s 
availability and convenience. If necessary, because of technical issues preventing a valid test or 
for clinical considerations, we will allow repeating any screening clinical laboratory test at least 
twice (at the same or future visit). 
 
 

 
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Subjects will be given the informed consent form to read, after which a study staff member will 
review it with the subject, providing an explanation of the study protocol, its risks, potential 
benefits, and alternative treatments. Following resolution of any questions, subjects will be 
asked to sign the study informed consent form.  An entire signed copy of the informed consent 
form will be given to the subject, who will be reminded that the consent addresses his or her 
willingness to participate but that the subsequent screening process will determine his or her 
eligibility to do so. Further, the subject will be reminded that participation is voluntary, and at any 
time, he or she may withdraw from the study. 
 
The study personnel will inform the subject that the purpose of this visit is to determine 
Eligibility based on whether or not it is medically safe for them to participate. The study 
personnel will also describe the Brief Behavioral Compliance Enhancement Treatment (BBCET; 
see section 6.8, below), the psychosocial treatment that will be employed for this study. 
 
 
 
The Screen Part-1 Visit will consist of the following: 
 BrAC, vital signs ,body weight, and height 
 Obtain informed consent (signature by subject) 
 Race/Ethnicity questionnaire 
 Demographics  
 Names and addresses of one or two locators (people who will know the whereabouts of 
the subject to assist in locating him/her during treatment, if needed) 
 Medical/Psychiatric history and physical exam  
 Electrocardiogram (ECG) 
o Blood collection – 45 mL for:  
o Hematology and clinical chemistry tests, DNA extraction and genotyping 
o Gamma-glutamyl transferase (GGT) to assess the validity of self-reported 
drinking. 
o Carbohydrate-deficient transferrin (%dCDT; to assess the validity of self-reported 
drinking) 
o RNA and miRNA expression studies(To be stored at -800C for future studies) 
 Urine collection for  
o Urine toxicology (presence of psychoactive drugs) 
o Urinalysis 
o Urine pregnancy test (for women of child bearing potential) 
 Complete assigned questionnaires and rating scales (see section 6.7, below) 
o SORT 
o AUDIT 
o SCID-IV with the Alcohol Use Disorder module to include DSM-5 criteria  
o SSADDA Nicotine Dependence Module 
o TLFB (for 90 days prior to the visit) 
o CIWA-Ar 
o MINI Suicide Risk Assessment Scale (every visit) 
 

  
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If the Principal Investigator (or designee) deems it necessary, all or part of any screening 
assessment or laboratory test may be repeated up to two times (at the same or a future visit), if 
needed because of technical issues preventing a valid result or for clinical considerations.  
 
6.3 Baseline Visit (Week 0) 
 
Subjects who have one of the specific desired genotype combinations will be notified of 
that fact within one week and asked to return to the CNC within 30 days from screening  visit for 
additional screening procedures.  If the subject continues to be eligible, he/she will be 
randomized and will receive the first dose of ondansetron or placebo based on their assigned 
randomization schedule. The baseline visit can be spread out over 2 visits, depending on 
participant’s availability and convenience. 
 
 
The Baseline Visit will consist of the following: 
Before the first dose of ondansetron: 
 BrAC, weight and vital signs 
 Urine collection for: 
o Riboflavin measurement for compliance 
o Urine pregnancy test 
 Complete assigned questionnaires and rating scales(see section 6.7 below) 
o TLFB 
o CIWA-Ar 
o Other Drug Use questionnaire 
o SF-12 
o SIP 
o ADS 
o OCDS 
o BDI 
o PSQI 
o MINI Suicide Risk Assessment Scale ( every visit) 
o CGI-I and CGI-S 
o Administer BBCET 
 Names and addresses of two locators (people who will know the whereabouts of the 
subject to assist in locating the subject during treatment, if needed 
 Review of eligibility 
 Record medication changes and treatment history since screening 
NB: If an abnormality is found during screening that could pose a risk to the subject, prevent the 
subject from completing study procedures, or interfere with study results, the investigator may 
decide not to administer study medication. 
Once it has been determined that the subject meets all inclusion and no exclusion criteria, the 
study nurse or physician will administer first dose of study medication and dispense first week of 
medication to subject, giving instructions on how to take the medication twice daily for 16 
weeks. Study nurses will instruct subjects to call at any time to discuss any problems or 
concerns that they may have while taking the study medication.   
 
 
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 BBCET (see section 6.8 below) will be administered. 
6.4 On-Treatment Visits (Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 20) 
Subjects will be seen at every week (+ 4 days) for the first six weeks, every two weeks (+ 4 
days) from weeks 6-12 and 4 weeks following week 12, at week 16. At the baseline, week 4, 
and week 8 visits, a dose of the study medication will be administered in the clinic. The following 
study procedures will be performed at the on-treatment visits.  
 BrAC , body weight, and vital signs (every visit) 
 Blood sample: 15 mL for GGT, %dCDT (Week 8) and 15 ml for future RNA and miRNA 
expression studies (weeks 4, 8 and 12) as close as possible to the same time of day  
 Urine to screen for drugs of abuse (Week 8), pregnancy test (for women of child bearing 
potential) (Weeks 4, 8, 16, and 12) and riboflavin measurement for compliance (every 
visit)  
 ECG (visit 5 only) 
 Other Drug Use questionnaire 
 Administer a scheduled dose of medication (first or second of the day) in the clinic 
(weeks 4 and 8) 
 Complete questionnaires and rating scales (see section 6.7 below) 
o TLFB (every visit) 
o CIWA-Ar (every visit) 
o MINI Suicide Risk Assessment Scale ( every visit) 
o OCDS ( every visit) 
o BDI (every visit) 
o PSQI (every visit) 
o CGI-I and CGI_S (every visit) 
o SF-12 ( week 8) 
o SIP ( week 8) 
o ADS (week 8) 
 Administer BBCET (every visit) 
 Record concomitant medication and treatment use since last visit (every visit) 
 Document study medication compliance (every visit) 
 Record adverse events 
 
If a subject stops study medication at any time during the study, he/she will be 
encouraged to continue to attend study visits and participate in all non-study-drug-related 
procedures of the study. 
6.5 End of Study Visit (Week 16)/Early Termination Visit 
The subject will return to the CNC at Week 16 (±4 days) for the End of Study visit.  Subject will 
have completed 16 weeks. 
of study medication prior to the last visit.  
 
 
The following procedures will be performed at the Week 24 (End of Study) visit: 
 BrAC, body weight and vital signs  

  
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 Blood sample – 15 mL for GGT, %dCDT, hematology and clinical chemistry tests and 15 
ml for RNA and miRNA extractions (this sample will not be obtained at an early 
termination visit)  
 Physical examination 
 Urine pregnancy test (for women of child bearing potential) and urinalysis 
 DSM-5 AUD criteria 
 Complete all assigned questionnaires and rating scales (see section 6.7 below) 
o CIWA-Ar 
o TLFB 
o SIP 
o OCDS 
o BDI 
o PSQI 
o CGI-I and CGI-S 
o SF-12 
o ADS 
o MINI Suicide Risk Assessment Scale 
 BBCET session 
 Record concomitant medication and treatment use since screening 
 Document compliance 
Record adverse eventsThis visit should be conducted not only for all subjects who 
complete the treatment but those who discontinue from the study early as well. 
  
6.6. 
Safety Follow-up Visit (Week 20) 
At this visit, a BrAC and vital signs will be measured and study personnel will assess persistent 
adverse events following the cessation of study medication. If the subject discontinues the study 
early, the visit can be by telephone unless an SAE occurred during the study and it has not 
been fully resolved by Week 16.  Individuals who complete the study medication period will be 
invited to give an optional blood draw for mRNA and miRNA expression studies.      
                   6.7.   Assessments 
 Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental  
Disorders, 4th Edition (SCID-IV).  Diagnosis by trained clinicians will be based on DSM-IV 
diagnoses (American Psychiatric Association, 1994) except for the alcohol use disorder 
diagnosis, which will be based on the 5th edition of the Diagnostic and Statistical Manual of 
Mental Disorders (DSM-5) (American Psychiatric Association, 2013). For the AUD diagnosis, we 
will adapt the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental 
Disorders (SCID-IV) (First, Spitzer, Gibbon, & Williams, 1994), to ensure that subjects meet at 
least two of the 11 diagnostic criteria. The SCID will also be used to exclude subjects with 
exclusionary psychiatric diagnoses. 
 
The Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). The 
SSADDA is a polydiagnostic instrument developed for use in genetic studies of alcohol 
and drug dependence. Because the SCID-IV does not assess nicotine dependence, the 
Nicotine dependence module of SSADDA interview will be used to characterize the 
study sample with respect to a DSM-IV diagnosis of nicotine independence. 
 Alcohol Dependence Scale (ADS total score). The ADS was designed to provide a  
quantitative measure of the severity of alcohol dependence consistent with the concept of the 
alcohol dependence syndrome.  The Alcohol Dependence Scale is a rater-administered, 25-

  
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item questionnaire covering alcohol withdrawal symptoms, impaired control over drinking, 
awareness of a compulsion to drink, increased tolerance to alcohol, and drink seeking behavior.  
The ADS will be administered by a trained member of the research team. 
 The Alcohol Use Disorders Identification Test (AUDIT) will be used to screen potential  
study participants for alcohol use and related problems.  The AUDIT is a 10-item self-report 
questionnaire that measures alcohol consumption, dependence symptoms, and personal and 
social harm reflective of drinking.  The AUDIT has demonstrated good content, criterion and 
construct validity (Babor, de la Fuente, Saunders, & Grant, 1992), and reliability (Cronbach’s 
alphas ranging from 0.77 to 0.83) (Bohn, Babor, & Kranzler, 1995).  The AUDIT will be 
administered at the site as part of the telephone screening interview. 
 The Timeline Follow-back (TLFB) method to quantify alcohol consumption will be  
administered at every study visit by a trained member of the study team. The TLFB is a daily 
calendar for alcohol consumption that employs memory aids, such as a calendar, to help 
subjects provide retrospective estimates of their daily drinking as the number of standard drinks 
for each day. A day is defined as a 24-hour period starting at 6.00 a.m. and ending at 6.00 a.m. 
the following morning. A month is a period of 28 consecutive days.  The TLFB can be completed 
in a reasonable length of time (approximately 10-15 min) and has been used extensively in 
pharmacotherapy trials for alcohol dependence. At the Baseline Visit, the TLFB will be used to 
measure alcohol consumption for the prior 28 days.  At each subsequent visit, the TLFB will be 
used to obtain alcohol consumption since the prior visit.  If the subject misses a scheduled visit 
and returns for a later visit, the TLFB will be administered to document alcohol consumption 
during the missed period.  For example, if the subject attends Visit 6 (Week 4), does not attend 
Visit 7 (Week 5) and returns to the study center for Visit 8 (Week 6), the TLFB administered at 
Visit 8 will elicit consumption data for the period of time since the Visit 6 TLFB administration.  If 
the subject has not withdrawn consent for participation in the study, every effort should be made 
to conduct a Week 28 visit.  If the subject refuses to participate in an on-site study visit, the 
study center may administer the TLFB via phone, at Week 20 to obtain the missing data. 
 Mini International Psychiatric Interview (MINI) Suicide Risk Assessment Scale (Module 
B) is a subscale of the MINI neuropsychiatric interview. It has been shown to help 
identify patients at risk for self-harm. 
 Obsessive Compulsive Drinking Scale (OCDS) is a 14-item, self-report measure that 
assesses aspects of alcohol craving, including obsessive thoughts about alcohol use and 
compulsive behaviors toward drinking. 
 Revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar)  
consists of 10 items, 9 of which (nausea and vomiting, tremor, paroxysmal sweats, anxiety, 
agitation, tactile disturbances, auditory disturbances, visual disturbances, headache, fullness in 
head) are rated on a scale of from 0 to 7. The 10th item (orientation and clouding of sensorium) 
is rated on a scale of from 0-4. It takes approximately 2 minutes to administer and score the 
CIWA-Ar.  The CIWA-Ar scale must be administered by the investigator or another qualified 
member of the research team.  The research team member who administers the CIWA-Ar 
assessment will be trained in the scoring conventions for the scale. 
 Clinical Global Impression-Improvement Scale (CGI-I The CGI-I is rated on a 7-point  
scale: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 
5=minimally worse; 6=much worse; or 7=very much worse and permits a global evaluation of 
the subject’s improvement (or worsening) over time. The clinician is required to assess the 
subject's condition relative to baseline at every study visit. In all cases, the assessment should 
be made independent of whether the rater believes the improvement is drug-related or not. CGI-
1 will be administered by the investigator or other qualified member of the research team, after 
training. Due to the simplicity of the scale, the CGI will be used in the original English version.   

  
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 Clinical Global Impression-Severity Scale (CGI-S)  The CGI-S assesses the  
clinician's impression of the subject's current clinical condition, and is rated on a 7-point scale: 
1= normal, not at all ill; 2= borderline ill; 3= mildly ill; 4= moderately ill; 5= markedly ill; 6= 
severely ill; 7= among the most extremely ill subjects. The clinician should use his/her total 
clinical experience with this subject population and rate the current severity of the subject's 
clinical condition on a 7-point scale. CGI-S will be administered by the investigator or other 
trained, qualified member of the research team. Short Index of problems (SIP) is a 15-item self-
report instrument  
that will be administered at the screening, baseline, Week 4, Week 8, Week 12and Week 16 
(End of Study) visits. The SIP measures specific and direct harmful consequences of drinking.  
Each item is assessed on a 3-point scale ranging from “never or once or a few times” to “daily or 
almost every day.”  A lower score indicates fewer adverse consequences of drinking. The 
DrInC, which contains items that measure a wide range of alcohol-related problems (including 
alcohol dependence symptoms and medical, psychological, social, occupational, and legal 
problems), has been shown to be a reliable and valid measure of alcohol-related problems.  The 
SIP is simpler to administer and, like the DrInC, has been shown to measure a single factor of 
alcohol-related problems.  
 Beck Depression Inventory (BDI) The 21-item BDI will be used to measure  
depressive symptoms. Questions focus on topics such as mood, thoughts of suicide, sleep 
habits, and eating behaviors. The BDI will be used to assess the severity of any depressive 
symptoms, particularly suicidal risk. The BDI will be administered at every study visit.  At 
screening/baseline, subjects with severe, untreated depression or who endorse suicidal intent 
will be excluded from the study and referred for treatment or immediate intervention.  At each 
post-baseline visit, the staff will review the findings on the BDI to ensure that the subject’s safety 
is not compromised by changes in depression symptoms. 
 Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire assessing  
sleep quality and disturbances during a 1-month period.  It contains 19 items that generate 7 
component scores on subjective sleep quality, sleep latency, sleep duration, habitual sleep 
efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction, all of which 
add up to a global score.  Because sleep disturbance is common in alcoholism, recovery may 
be associated with improved sleep.  
 Other Drug Use questionnaire is a brief self-report questionnaire on which the  
subject is asked to list his/her use of any prescribed or non-prescribed drug use occurring since 
the last study visit.  Upon its completion, a study staff member reviews the questionnaire and 
obtains details about any reported drug use. 
 RAND 12-Item Health Survey (SF-12), a self-report measure of life functioning in  
various domains.  It yields an overall health-related quality of life score and physical and mental 
health component summary scales. 
 6.8  Brief Behavioral Compliance Enhancement Treatment (BBCET) 
 
Delivery of BBCET: BBCET is the psychosocial adjunct intervention for the study. A 
BBCET manual has been developed by the UMB group. A BBCET-trained staff member from 
UMB will train the BBCET provider(s) at the UPenn site and will meet monthly by telephone with 
the staff members who administer the BBCET to address any issues.  BBCET sessions shall 
occur at every study visit and will be delivered by a trained nurse or masters level clinician.  
All BBCET sessions will be audiotaped. Study staff will not use names or disclose PHI 
during the audio-taped sessions. Study staff will identify the subject by study ID and the audio 
recording will be uploaded to a secure server until reviewed by study staff (exclusively) and then 
deleted. The BBCET supervisors will review 10% of these tapes to ensure adherence to its 

  
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uniform delivery. Including the pre-randomization and termination BBCET sessions, there will be 
a total of 11 BBCET sessions for the 16-week trial. Each BBCET session lasts about 10–15 
minutes and is delivered contemporaneously with the accounting of the amount of study 
medication taken from the last visit and the ascertainment of adverse events. BBCET sessions 
focus on compliance with the medication and reinforce adherence to the protocol. BBCET 
sessions also reinforce the importance of taking study medication and provide general 
motivation, encouragement, and support for continuing in treatment. BBCET provides education 
on the negative effects of excessive alcohol use on physical and mental health. The rationale for 
using the medication is discussed in simple language. Physical examination and laboratory 
results are discussed with each participant. BBCET helps subjects to overcome ambivalence, 
which may interfere with their desire to change. Adherence to medication and compliance with 
the protocol are praised and reinforced. 
BBCET emphasizes that alcohol dependence is a disease process that can be tackled 
by compliance with the study regimen. BBCET mimics a naturalistic doctor/patient relationship 
in function and duration and will feel familiar to most participants. BBCET does not allow for the 
interpretation of feelings, psychological interpretations about the nature of alcohol dependence, 
or applying problem-solving techniques to matters other than medication compliance. One 
hallmark of BBCET is that subjects set their target drinking goal for the next period at each 
session. BBCET can be more readily generalized than formal psychotherapies for use in 
generic treatment or family practitioner settings because it is much briefer. General health care 
workers can be trained to deliver it, thereby increasing greatly clinical access to care for the 
treatment of alcohol dependence. BBCET has been used successfully in previous 
pharmacotherapy trials. 
BBCET is delivered in 3 phases.  
In Phase 1 (Baseline and Weeks 1–3), the BBCET provider builds rapport with the 
subject to inspire confidence, trust, and warmth, discusses medication effects, instructs on the 
importance of taking the medication regularly, provides a basic and easily understandable 
model of how the medication(s) might work, addresses concerns about taking medication, 
adverse events, and compliance barriers with the subject in understandable terms, and clearly 
conveys his or her knowledge and experience with the pharmacotherapy of alcohol problems. 
The BBCET provider allows the subject to air prejudices, corrects any misconceptions (which 
may include “all or none” expectations), and provides a medication information sheet with an 
emergency contact card that describes the possible medication being taken and appropriate 
contact numbers for the investigator or study staff.  
In Phase 2 (Weeks 4–10), the emphasis is on maintaining compliance and avoiding 
early discontinuation of the medication. Adverse events are monitored and protocol-permitted 
remedies or over-the-counter medications are provided if necessary to deal with them. 
In Phase 3 (Weeks 12 and 16), the BBCET provider and the subject discuss the 
subject’s experience throughout the study. Typically, the subject will be offered referrals, and 
the termination visit will take place. 
The BBCET provider will discuss plans regarding how to discontinue the medication and 
will provide a rationale of how the medication may have helped the participant to achieve his or 
her goal. It is expected that a significant provider-subject relationship has been developed 
during the study, and care should be taken in the termination of this relationship. 
Subject Compliance with BBCET Administration: BBCET is the only allowed 
psychosocial treatment.  Subject participation in BBCET sessions will be tracked.  Evidence of 
non-compliance could result in discontinuation of the subject from the study.  
Practitioner Adherence to BBCET: BBCET sessions will be audiotaped. A random 
selection of 10% of the tapes will be reviewed at each site to ensure adherence to the protocol. 
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protocol deviations. A provider checklist (PSC) will be administered as an additional check on 
compliance. 
6.9  Genetic Evaluation 
Blood sample collection: Two vaccutainer tubes containing ACD buffer (to prevent 
coagulation) will be used to collect a total of 15 ml of peripheral venous whole blood from each 
subject as shown in Table 1 .  All blood samples collected for DNA, mRNA and miRNA 
extraction will be processed and stored at 4C to be sent to Dr. Seneviratne’s laboratory at the 
UMB Institute for Genome Sciences (IGS). 
Genotyping for subject stratification and randomization:  All genotyping for the subjects 
enrolled at both UMB and UPenn will be performed at the IGS.  Genomic DNA will be extracted 
from whole blood samples using established procedures from Dr. Seneviratne’s previous work 
(Ait-Daoud et al., 2009; Johnson et al., 2011; Seneviratne et al., 2009).  
The 5-HTTLPR genotypes LL, LS and SS and the rs25531 genotypes AA, AG and GG will be 
will be performed simultaneously using restriction fragment-length polymorphism (RFLP) 
method. Genotyping for the SNPs of interest (listed below) will be performed with commercially 
available TaqMan® allelic discrimination assays (Applied Biosystems, Foster City, California). 
Applied Biosystems 7900HT Fast Real-Time PCR system will be used for amplification and 
capture of the resulting florescent signals. 
 
 
rs1042173 (TT, TG, and GG genotypes) in the 3′-untranslated region of SLC6A4 that 
encodes the serotonin transporter; 
 
rs1150226 (AA, AG and GG genotypes) in the 5′UTR of HTR3A gene that encodes 
subtype A of the serotonin-3 receptor; 
 
rs1176713 (GG, GA and AA genotypes), a synonymous SNP in exon 9 of HTR3A 
gene that encodes subtype A of the serotonin-3 receptor; 
 
rs17614942 (AA, AC and CC genotypes), an intron 8 SNP in HTR3B gene that 
encodes subtype B of the serotonin-3 receptor 
 
rs1176744 (AA, AC, CC genotypes), an exon 5SNP in HTR3B gene that encodes 
subtype B of the serotonin-3 receptor ( for UPENN site only) 
All samples will be genotyped in duplicate and any discrepancies will be repeated to ensure the 
accuracy of the procedure.  No results of genetic testing (including ancestry genetic panel, if 
done) will be provided to participants, even if they request it. A requesting participant will be 
reminded that the informed consent form stated that no genetic test results would be provided to 
participants. 
mRNA and miRNA expression studies:  The total RNA extractions will be performed after 
completing the entire proposed study, using supplemental funding. Until then, the blood 
samples will be stored securely in -800C freezers. The genome-wide expression levels of mRNA 
and miRNA in WBC (cellular mRNA and miRNA) as well as circulating miRNA in serum will be 
quantified with next generation sequencing based technologies available at the sequencing core 
of the IGS.   
 
6.10 
Missed Visit 
If a subject anticipates missing a study visit (e.g., due to a vacation), the study nurse will provide 
the subject with enough study medication to ensure the maintenance of the daily dosage of 
study medication until the next scheduled visit as per the dosing schedule, either in person or 
via mail. Subjects will be instructed to call the UPENN study staff at any time to discuss 
problems or concerns that they may have while participating in the study.  They will be provided 
with phone numbers to contact the study staff during office hours and a pager number for off-

  
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hours contact. Subjects will be asked to come in for their next study visit as soon as possible. A 
subject unable to attend an in-person visit will be asked to provide all scheduled assessment 
information by telephone.  A study physician will approve all study medication mailed to the 
subjects. 
If a subject calls to cancel a scheduled study visit due to an unforeseen event, the study visit will 
be rescheduled to occur as soon thereafter as possible. Study staff will send study medication 
to the subject via overnight mail under the supervision of a study nurse to avoid having the 
subject run out of study medication. Subjects will be given only enough study medication to 
ensure that they maintain their daily dosage of study medication until their next scheduled visit. 
The subject will be asked to record any adverse events that may have occurred since the last 
study visit. Study nurses will instruct subjects to call at any time to discuss any problems or 
concerns that they may have while taking the study medication. A study physician will determine 
how many additional weeks of study medication a subject will be allowed to receive without 
attending a study visit and will approve the mailing of all study medication.  
 
 
7 Statistical Plan 
7.1 Sample Size Determination 
 
 
For the 2 EA genotype groups discussed above (section 3.1), we are expecting that 61% of the 
EA sample will be in the responsive genotype strata and 29% of the EA sample will be in the 
non- responsive genotype strata based on prior studies5. Block randomization will balance 
allocation of the 2 treatment conditions (within each racial group) with the responsive and non-
responsive genotype strata. Hence, after 30% dropout, the expected cell frequency for the 2 
treatment arms for EAs will each be 39 in the responsive strata and 25 in the non-responsive 
strata. For two of the AA genotype grouping discussed above (section 3.1), we are expecting 
that the 5-HTTLPR LALA group, which in the randomized sample is estimated to include 55 AAs 
subjects (i.e., ~30% of the total randomized sample based on the frequency of the LALA 
genotype in AAs) and subjects with rs1042173*TT genotype (which is estimated to include 106 
subjects, i.e., 58% of AAs have the TT genotype). Power analysis was done using the methods 
in Section 8.3 in Cohen (1988).  For the power calculations, we estimated that the effect size for 
reduction of DDD between the ondansetron and placebo groups in the responsive genotype 
group would be 0.595.  Assuming an alpha level of 0.05 and a sample size of 39 in each arm we 
will have power equal to 0.84.  Because the intent-to-treat principle on which our analysis is 
based includes all randomized subjects in the statistical analyses, and because we will use 
enhanced techniques to ensure that we obtain most of the drinking data, our study has more 
than adequate power to test the stated hypotheses.  
 
 
We will also test whether ondansetron is better than placebo overall (i.e. regardless of 
genotype). For this comparison we expect to have 64 EA subjects in each treatment arm and 64 
AA subjects in each treatment arm. With alpha=.05, we have power equal to .81 to detect effect 
sizes down to .44. 
 
 
7.2 Statistical Methods 
 
We expect to have n=128 treatment-seeking alcohol dependent individuals who 
complete the 16 week trial at each site. However, we will include all randomized subjects in the 

  
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main intent-to-treat analyses. Stratified randomization will ensure approximate balance between 
the 2 treatment conditions ( ondansetron and placebo) within genotype strata (as discussed 
above)  Group assignment will be achieved using a permuted block randomization 
procedure that further balances the treatment groups on study site, race and gender.  
Statisticians who will have no contact with subjects or with clinical staff involved in direct patient 
care have created the randomization list which will be used by the UMB Investigational Drug 
Services. Subjects also will receive Brief Behavioral Compliance Enhancement Treatment 
(BBCET) as their psychosocial adjunct weekly in weeks 1–8 and then every 2 weeks in weeks 
8-16.  
 
Descriptive summaries and group comparisons:  Data will be summarized for the 
primary and secondary outcome measures, demographics, and baseline characteristics.  
Generally, quantitative variables will be summarized with standard descriptive statistics (e.g., 
range, quartiles, means, and standard deviations), while frequency tables will summarize 
categorical variables.  Group comparison for quantitative variables will be done using standard 
two-sample t-tests or analysis of variance as appropriate.  Highly skewed variables may be 
transformed before inferential comparison, or non-parametric methods may be used.  Group 
comparison for categorical variables will be analyzed with two-sample proportional comparisons 
or chi-square tests as appropriate. 
 
Analyses of primary and secondary outcomes:  The primary efficacy variable will be 
change from baseline in DDD.  Secondary outcome variables will include other measures of 
drinking—percent heavy drinking days (PHDD) and the percentage of days abstinent.  
Exploratory drinking outcomes will include the novel measure—percentage of subjects with no 
heavy drinking days (Falk et al., 2010), which presently is the standard identified by the FDA as 
an outcome measure for registration trials in alcohol dependence.  
 
The general approach to statistical analyses will be the same as that utilized in our 
previous studies (Johnson et al., 2011; Johnson et al., 2000).  All randomized subjects will be 
included in the analysis using the intent-to-treat principle.  We will use a mixed-models 
approach, adjusting for baseline covariates (when significantly different by group) and the 
same drinking variables for baseline.  For the drinking variables, the baseline value is the 
average for the 90-day period prior to the screening visit.  Other potential covariates shall 
include age, race, and sex.   In the first model, we will assess whether individuals who are 
hypothesized to be in the responsive genotype group and treated with ondansetron will have 
greater reduction in DDD than the corresponding placebo group.  In the second model, we will 
test whether EA subjects who are treated with ondansetron will show fewer DDD than the 
corresponding placebo group overall (regardless of genotype).  We also will explore the 
‘difference in differences’ hypothesis that the difference in DDD will be greater in the 
hypothesized responsive genotype group than the difference in the hypothesized non-
responsive genotype group, however the study is not powered for this. The residuals from our 
analyses will be checked for normality by computing their skewness and kurtosis and will be 
checked for homogeneity of variance by plotting them in a histogram and against predicted 
outcomes.  Standard (i.e., square root or log) transformations will be employed to improve the 
distributions when required.   
 
Before we conduct the analyses, the groups will be compared to verify balance on the 
age, gender, and drinking severity variables, as well as other important baseline demographics 
and clinical characteristics.  If, as expected, there are no significant group differences, these 
baseline and balancing variables will be dropped from further analyses.  Possible (though 
unexpected) group differences will be further examined and interpreted as to their clinical 
meaning and whether they may confound the interpretation of planned comparisons.  Since this 
is a simple factorial model, the interpretation of main effects and their interaction is 
straightforward.  Where there is a significant main effect for an independent variable with three 
or more levels or an interaction, post-hoc comparisons will be done.  

  
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The mixed-models approach is our first analytic choice as it assumes a random effect for 
missing data.  If, however, there is a differential attrition rate (i.e., if dropout is informative), we 
shall consider other approaches (e.g., joint models of longitudinal drinking outcome and time to 
dropout) to account for informative dropout to obtain valid results (Liu, 2009; Wulfsohn & Tsiatis, 
1997).  Statistics will be run using SAS 9.1 (SAS Institute Inc., Cary, NC).  
 
In secondary analyses we will conduct analyses similar to the main analyses only with 
change from baseline in number of heavy drinking days (HDDs) during the last 8 weeks of 
treatment as the outcome variable.  We will also conduct a responders analysis on this 
secondary outcome with endpoint: no heavy drinking days over the last 8 weeks of treatment 
versus one or more heavy drinking days in the last 8 weeks of treatment.  For this outcome we 
will use an ordinary logistic regression model to compare the treatment groups in the whole 
sample and within the hypothesized responsive genotype adjusting for the same covariates as 
in the main model.  One additional alternative endpoint that we will examine is mean daily 
alcohol consumption (in standard drinks/day) over the last 4 weeks of the 16-week treatment 
period.  This will be analyzed with ordinary linear regression for a continuous outcome. 
 
As an exploratory procedure, we also will use the more advanced two-part random 
effects model (Olsen & Schafer, 2001; Tooze, Grunwald, & Jones, 2002) to analyze the daily 
drinking record.  This model can simultaneously characterize the frequency (odds of daily 
drinking being zero) and quantity (the number of drinks on a drinking day) of drinking.  It is more 
efficient and can tackle non-normality in the drinking level.  We also will do trajectory analyses 
of different treatments over time to capture differences in drinking outcomes (Chen et al., 2011).  
Such an analysis is more clinically intuitive and could be more powerful than the analysis based 
on endpoints. 
 
Furthermore, as an additional exploratory step to provide information on whether 
ondansetron treatment has differential efficacy for specific genotypes in a “relapse prevention” 
model rather than with the “currently drinking” approach, we will do secondary analyses on 
those who quit drinking during the study to determine whether, and by how much, these results 
differ from our primary analyses.  We will report and discuss these secondary analyses along 
with the primary approach in our publications.   
7.3 Subject Population(s) for Analysis 
 
The primary efficacy analysis will be conducted with the intent-to-treat population 
consisting of all individuals who are randomized to treatment and take at least one dose of study 
medication.  This will require at least one post-randomization measurement of outcomes.  
Similarly, all safety evaluations will include all available subjects on whom any safety 
information is obtained. 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others:  Any incident, experience, or 
outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc) 
 Related or possibly related to participation in the research (i.e. 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) 

  
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 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
An Adverse Event (AE): is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study.  Intercurrent illnesses or injuries should be regarded 
as adverse events.  Abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
A Serious Adverse Event (SAE): Any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period:  The study period during which adverse events must be 
reported is normally defined as the period from the initiation of any study procedures to the end 
of the study treatment follow-up.  For this study, the study treatment follow-up is defined as 30 
days following the last administration of study treatment.  
 
Preexisting Condition: A pre-existing condition is one that is present at the start of the study.  
A preexisting condition should be recorded as an adverse event if the frequency, intensity, or 
the character of the condition worsens during the study period. 
 
General Physical Examination Findings: At screening, any clinically significant abnormality 
should be recorded as a preexisting condition.  At the end of the study, any new clinically 
significant findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
 
Post-study Adverse Event:  All unresolved adverse events should be followed by the 
investigator until the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study.  The investigator should notify the 
study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study.  The 

  
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sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study.  
 
Abnormal Laboratory Values: A clinical laboratory abnormality should be documented as an 
adverse event if any one of the following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery: Any adverse event that results in 
hospitalization or prolonged hospitalization should be documented and reported as a serious 
adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 Recording of Adverse Events 
 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the appropriate 
adverse event module of the case report form (CRF).  All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should recorded in the source document, though should 
be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse events 
that are still ongoing at the end of the study period must be followed up to determine the final 
outcome.  Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be recorded and reported 
immediately. 

  
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8.3 Reporting of Serious Adverse Events and Unanticipated 
Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a 
minimum those events that must be reported are those that are: 
 
related to study participation, 
 
unexpected, and  
 
serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as 
serious 
 
Investigator assessment of the association 
between the event and study treatment 
8.3.1 Investigator reporting: notifying the study sponsor 
 
Each study site will be responsible for reporting any study-related unanticipated problem 
posing risk of harm to subjects or others, and any type of serious adverse event, and all other 
adverse events as required by the UMB/UPENN IRB sites (see sections 8.3.2) to the study 
sponsor (NIAAA) and FDA. Both IRB sites will be notified of all reported events and outcomes at 
both sites.  The investigator will keep a copy of these reportson file at the study site.  
 
 
Within the following 48 hours, the investigator must provide further information on the 
serious adverse event or the unanticipated problem in the form of a written narrative.  This 
should include a copy of the completed Serious Adverse Event form, and any other diagnostic 
information that will assist the understanding of the event.  Significant new information on 
ongoing serious adverse events should be provided promptly to both sites. 
 
 
    8.3.2. Investigator reporting: notifying the Institutional Review  
 
 
              Board 
 
This section describes the requirements for safety reporting by investigators who are 
UMB/Penn faculty, affiliated with a UMB/Penn research site, or otherwise responsible for safety 
reporting to the IRB. The Institutional Review Boards at UPenn and UMB require expedited 
reporting of those events related to study participation that are unforeseen and indicate that 
participants or others are at increased risk of harm.  The IRB will not acknowledge safety 
reports or bulk adverse event submissions that do not meet the criteria outlined below.  The IRB 
requires researchers to submit reports of the following problems within 5 business days from the 
time the investigator becomes aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-site or 
off-site) that occurs any time during or after the research study, which in the opinion of 
the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and 
package inserts.) 

  
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AND 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the principal investigator or sponsor, the event was more likely than not to 
be caused by the research procedures.) 
 
Reporting Process:  Unanticipated problems posing risks to subjects or others as noted above 
will be reported to the UMB IRB in CICERO under reportable new information within 5 business 
days.   
 
Copies of each report and documentation of IRB notification and receipt will be kept in 
the Clinical Investigator’s study file. 
Reporting Deaths:  more rapid reporting requirements 
Deaths that occur during the course of a research study and that are:  
1) Unexpected; AND  
2) Related to the research study; AND  
3) When other participants are believed to be at an increased risk of harm 
Must be reported to the IRB within 3 business days from the time the investigator becomes 
aware of the death.  
Other Reportable events: For clinical drug trials, the following events are also reportable to the 
IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 
 Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
 An interim analysis indicates that participants have a lower rate of response to treatment 
than initially expected. 
 Safety monitoring indicates that a particular side effect is more severe, or more frequent 
than initially expected. 
 A paper is published from another study that shows that an arm of your research study is 
of no therapeutic value. 
– Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
– Breach of confidentiality 
– Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
– Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to 
remain on the study. 
– Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
– Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more 
participants at increased risk, or affects the rights or welfare of subjects. 

  
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8.3.3 Sponsor reporting: Notifying the FDA:   
The study sponsor is required to report certain study events in an expedited 
fashion to the FDA.  These written notifications of adverse events are referred 
to as IND safety reports. The following describes the safety reporting 
requirements by timeline for reporting and associated type of event: 
   
 
 
– Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening, and  
 
– Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
 a previous adverse event that was not initially deemed reportable but is later found to fit 
the criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
Any finding from tests in laboratory animals that:  
– suggests a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
Additional reporting requirements:  Sponsors are also required to identify in IND safety 
reports all previous reports concerning similar adverse events and to analyze the significance of 
the current event in light of the previous reports. 
Reporting Process:  Adverse events may be submitted on FDA Form 3500A or in a narrative 
format. If supplied as in a narrative format, the minimum information to be supplied is noted 
above at the beginning of section 8.3.  
8.3.4 Sponsor reporting: Notifying participating investigators 
 
It is the responsibility of the study sponsor to notify all participating investigators, in a 
written IND safety report, of any adverse event associated with the use of the drug that is both 
serious and unexpected, as well as any finding from tests in laboratory animals that suggest a 
significant risk for human subjects.  Additionally, sponsors are also required to identify in IND 
safety reports all previous reports concerning similar adverse events and to analyze the 
significance of the current event in light of the previous reports. 
8.4 Unblinding Procedures 
 
On the day of randomization, participants are given an emergency notification card.  The 
emergency notification card has a 24-hour emergency number by which to contact a PI or 

  
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physician co-investigator in case of an after-hours emergency.  At UPenn, the number is a 
pager that is in the possession of one of the study physicians.  The coverage physician will then 
be responsible to contact the participant to determine the nature of the emergency and to 
provide reassurance, advice, or treatment referrals as appropriate.  In the morning, the study 
physician is responsible to inform the PI, document the event, and follow-up with the participant.  
 
Only the PI or another study physician is authorized to break the blind dose code, which 
will be done in collaboration with the IDS at UMB, where the randomization information will be 
retained.  The decision to break the study blind for an individual subject lies with the study PI (or 
a designated co-investigator if a PI is not available) and would be resorted to only in cases of 
anemergency when knowledge of the treatment arm investigational agent will influence clinical 
management. 
8.5 Medical Monitoring 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
8.5.1 Data and Safety Monitoring Board 
 
The DSMB will include relevant experts at UPenn.  The DSMB members will include 
James McKay, Ph.D. (chair), Kevin Lynch, Ph.D. (biostatistician), Richard Feinn, Ph.D., David 
Metzger, Ph.D., Daniel Weintraub, M.D., Deb Dunbar, MSN, CRNP, and Cynthia Clark, Ph.D. 
The DSMB will meet by teleconference annually or more often if warranted to review progress 
pursuant to presentation of a summary report from the principal investigator, ensuring that 
policies on the identification and reporting of adverse events to the appropriate regulatory 
bodies, which can include the local IRB, the FDA, and the project officer at the NIH, have been 
implemented diligently and promptly.  Prompt and due diligence reporting of adverse events 
(i.e., within 24 hours during the week and on the next working day following a weekend) to the 
regulatory bodies remains the express duty of the principal investigator.  The DSMB will retain 
the right to make independent representation to the regulatory bodies if there has been a failure 
or lapse in reporting by the principal investigator.  The DSMB also will have the capacity to 
instruct the principal investigator to pause or terminate pursuance of research if regulatory body 
guidelines are contravened.  The DSMB will provide regular independent reports to the IRB 
concerning the protection of human subjects in this study.  These DSMB procedures have been 
approved previously by the NIH for our ongoing clinical studies.   
 
Frequency of data and safety monitoring reviews:  These investigators have extensive 
experience with clinical trials using pharmacotherapy for the treatment of substance abuse and 
with the recruitment and retention of substance-dependent subjects.  In the past, such trials 
have been done with minimal risks to participants.  Therefore, the DSMP will include two items: 
The research members at each site, including the PI, co-investigators, research nurses, and 
project coordinators, will meet weekly to discuss progress on the study and to address any 
issues related to the research procedures.  The DSMB will meet annually and will generate a 
report that is sent to the PI at each site.  The report will summarize the Board’s review of 
cumulative serious and unexpected adverse events and any other concerns that may arise. 
 

  
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Content of data and safety monitoring report:  The PI at each university will be responsible to 
monitor the safety and efficacy of this trial, executing the DSMP, providing the DSMB with the 
needed information, and complying with the reporting requirements.  The overall PI will provide 
a summary of the data and safety monitoring report to staff at the NIAAA on an annual basis as 
part of the progress report.  
9 
Data Handling and Record Keeping 
9.1 Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
Records, filed in the IRB office, verify that all research project personnel have completed 
training in the protection of human research subjects in accordance with the guidelines of the 
U.S. Department of Health and Human Services (DHHS) and the Office for Human Research 
Protection (OHRP).  The study staff (PI, Clinical research coordinator, etc.) will keep all study 
medical records (including any codes to de-identified data) under lock and key in a secure 
location, as required by law. Only date and time of the research visit and lab specimen data will 
be placed in the client’s existing electronic medical record. All electronic data and files (e.g., 
database, spreadsheet, etc.) containing identifiable subject information shall be password 
protected.  Any computer hosting such files shall have a BIOS password to prevent access by 
un-authorized users.  If subject data are to be exchanged with others, the data will be coded. If 
identification is necessary, then the data will be encrypted while en route to the recipient with 
strong encryption levels (≥ 128 bits for symmetric encryption (DES) and ≥ 1024 bits for 
asymmetric encryption (RSA).    
All data and blood specimens will be stored without direct identifiable information, but will 
be identifiable via a linking code. The secured research records are labeled with code numbers 
only (names and other identifying information are kept separate from research records). Access 
to data is only given to staff members working on the study. Only staff members designated to 
handle or analyze study samples will have access to the samples and their storage. Coded 
blood samples are stored in clinic-specific refrigerators and freezers, which are located in 
secure rooms. As per routine in the UPenn Center for Studies of Addiction (CSA), all electronic 
files (e.g., database, spreadsheet) will be password protected. Any computer hosting such files 
will have a BIOS password to prevent access by un-authorized users. Further information 
concerning the CSA’s Data Management Unit (DMU) is provided below.  
Blood will be collected for DNA analysis. The information derived from analysis of the 
subjects’ DNA will not be provided to the subject, since at the present time the existing 
preliminary genetic data for predicting response to ondansetron do not provide a basis for 
genetic counseling. Should that situation change over the course of the study, procedures will 

  
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be developed in conjunction with the UPenn and UMB IRBs to provide subjects with relevant 
information on their genotypes and to counsel them in relation to that information. While the 
study is open, DNA samples will be coded with a number that provides an indirect link to the 
subject’s identity (samples will be accessible only by the researchers and staff involved with this 
study). Upon completion of the study, the sample will be kept in storage indefinitely. However, 
the sample will forever be separated from all identifiers. These de-identified samples may be 
shared with other researchers and used in other projects. The lab procedures for storage 
include a passcode-protected locked room, and secure storage freezers.  All samples will be 
retained securely as per lab protocols.  
A certificate of confidentiality has been obtained for this study. The following conditions 
apply to the protection provided under this certificate: 
(l) This certificate does not authorize the University of Maryland, Baltimore, School 
of Medicine, their contractors or cooperating agencies to refuse to reveal identifying 
information concerning research subjects if any of the following conditions exist: 
 
(a) The research subject (or, if he or she is legally incompetent, his or her guardian) 
consents in writing to disclosure of the subject's own identifying information; 
 
(b) Authorized personnel of the United States Department of Health and Human 
Services request such information for an audit or program evaluation of the research project, 
or for an investigation of the University of Maryland, Baltimore, School of Medicine, or their 
contractors or cooperating agencies in carrying out the research project; 
 
(c) Release is required by the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 
et seq.) or regulations promulgated  thereunder (Title 21, Code of Federal Regulations). 
 
(2) This certificate is issued with the expectation that there will be no disclosures of 
identifying characteristics of research subjects in any Federal, State, or local civil, criminal, 
administrative, legislative, or other proceedings to compel disclosure of the identifying 
characteristics of research subjects, except as provided for in paragraph (1), above. 
 
(3) The confidentiality certificate does not govern the voluntary disclosure of 
identifying characteristics of research subjects, but only protects subjects from compelled 
disclosure of identifying characteristics. Sponsors/investigators are therefore not prevented 
from the voluntary disclosure of such matters as child abuse or a subject's threatened 
violence to self or others; however, the consent form should indicate clearly the 
investigators’ intention to make any such voluntary disclosures. 
 
(4) This certificate does not represent an endorsement of the research project by the 
Department of Health and Human Services, or the Food and Drug Administration. 
 

  
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(5) All research subjects in the project will be given a fair, clear explanation of the 
protection which this certificate affords, and of the limitations and exceptions to the 
protection. 
 
(6) This authority granted to the sponsors/investigators by this certificate is effective 
upon issuance, and will expire on the date on which the IND application is terminated or 
withdrawn, or sooner if the sponsor/investigator is notified of cancellation by the Food and 
Drug Administration.   However, regardless of any subsequent expiration or cancellation of 
the sponsors/investigators’ authority under this certificate of confidentiality, the privacy 
protection afforded to the individual subjects by this certificate of confidentiality is permanent 
(including after the death of a subject) and will continue for all persons who were research 
subjects in the study during any time the sponsor/investigator held this certificate of 
confidentiality. 
 
 
9.2 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the IDS, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
9.3 Case Report Forms 
 
The study will use the web-based direct entry data management system of the CSA’s 
DMU, with data stored on secure servers located in the Perelman School of Medicine’s Data 
Center. Interview data and self-report data from both UPenn and UMB will be entered directly 
onto computers by research staff and/or patients under supervision by staff.  A range of checks 
for the validity of responses (including field validation to ensure that no out-of-range or 
otherwise invalid responses are accepted), and form validation to ensure that logically 
impossible responses to different questions are not accepted) are built into this entry 
process.  After entry, the research staff performs a brief review to ensure that the form has been 
completed.  On completion of this review, the technician will transmit the data (in 128-bit 
encrypted form) over the Internet to the DMU data servers.  After a series of online reviews, the 
data are archived on the servers.  Protected health information will not be included in these 
research data.  Permission to modify the archived data is limited to designated DMU 
personnel.  Audit logs record any modification to the original entry.  Various levels of password 
protection, determined by the UPenn PI, Dr. Kranzler, will allow different members of the 
research team access to the data.  Once the dataset is complete, it will be exported to the 
biostatistical group for use in modeling. 
9.4 Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 
years after the last approval of a marketing application in their country and until there are no 

  
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pending or contemplated marketing applications in their country or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period if required by an agreement with the sponsor.  
In such an instance, it is the responsibility of the sponsor to inform the investigator/institution as 
to when these documents no longer need to be retained.  
10 Study Monitoring, Auditing, and Inspecting 
                   10.1   Study Monitoring Plan 
This study will be monitored according to the monitoring plan described below. The 
Principal Investigator will allocate adequate time for such monitoring activities. The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the above noted study-related documents and study related facilities (e.g., 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
The Principal Investigator and research staff will monitor the study. Written monitoring 
procedures for monitoring clinical investigations will be implemented to assure the quality of the 
study and to assure that each person involved in the monitoring process carries out his or her 
duties.  
The Principal Investigator will maintain a record of the findings, conclusions, and action 
taken to correct errors noted by the monitor for each visit.  
Monitoring Responsibilities: The monitor, in accordance with local and NIH 
requirements, should ensure that the study is conducted and documented properly by carrying 
out the following activities:  
 Verifying that the investigator has adequate qualification and resources and that these 
remain adequate throughout the study period, and that the staff and facilities, including 
laboratories and equipment, are adequate to safely and properly conduct the study and 
these remain adequate throughout the study period.  
 Verifying that the investigator follows the approved protocol and all approved 
amendment(s), if any.  
 Verifying that written informed consent was obtained before each subject's participation 
in the study.  
 Verifying that the investigator is enrolling only eligible subjects.  
 Reporting the subject recruitment rate.  
 Verifying that source data/documents and other study records are accurate, complete, 
kept up to date, and maintained.  
 Verifying that the investigator provides all the required reports, notifications, applications, 
and submissions, and that these documents are accurate, complete, timely, legible, 
dated and identify the study.  
 Checking the accuracy and completeness of the CRF entries, source data/documents, 
and other study related records against each other.  
 Informing the investigator of any CRF entry error, omission, or illegibility. The monitor 
should ensure that appropriate corrections, additions, or deletions are made, dated, 
explained, and initialed by the investigator or by a member of the study staff who is 
authorized to initial CRF changes for the investigator. This authorization should be 
documented.  

  
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 Determining whether all adverse events (AE's) are appropriately reported within the time 
periods required by GCP, the protocol, the IRB/IEC, the applicable regulatory 
requirement(s).  
 Determining whether the investigator is maintaining the essential documents.  
 Communicating deviations from the protocol, SOP's, GCP, and the applicable regulatory 
requirements to the investigator and taking appropriate action designed to prevent 
recurrence of the detected deviations.  
 Following the University’s SOP's, GCP, and the applicable regulatory requirements.  
 
Study Monitoring  
The study Principal Investigator and research staff have prepared a case record form (CRF) that 
is designed to reduce coding errors and promote data quality. Each page of the CRF will contain 
a header that includes the title of the protocol, the protocol number, the subject randomization 
number, subject screening number, and visit number. The technicians are responsible for data 
entry. The research charts will be maintained separately from the CRF and will contain subject 
information that is not entered in the study CRF database.  
Regulatory Binder:  A detailed Regulatory Binder will be assembled.  Any changes to 
procedures are documented in this section. This binder is the backbone of quality assurance.  
We use this binder to train any new study personnel and for reference so that our policies and 
procedures are standard throughout all phases of the protocol. The ‘Measures’ section of the 
binder addresses, specifically all forms and instruments that comprise the CRF. A Table of 
Contents has been prepared that contains all the forms used in the study.  
The study manual will include: 
 study protocol research team names, titles, roles and responsibilities, work and home 
phone numbers  
 purpose of study, study intent and rationale 
 all study procedures for each team member (PIs, technicians, study coordinator, 
pharmacists, nurses, nurse practitioner, physicians, etc.)  
 recruitment and screening procedures 
 intake procedures 
 study phase procedures  
 completion/discontinuation procedures 
Data Collection Training  
The CNC provides comprehensive data collection training for the study staff. Study staff receive 
training on how to proceed with problematic subjects. Study staff is trained to follow the general 
data collection guidelines listed below.   
 Study staff should be present when subject is completing instruments. 
 Research interviews and evaluations should be administered in a private, quiet office or 
area. 
 Instruments are introduced and explained the same way each time to each subject. 
 Order of research assessments should be maintained, as much as possible. 
 Order of specimens obtained should be maintained as much as possible. 
 Study staff should show an interested, polite, appropriate, and helpful demeanor. 
 
Quality assurance (QA) procedures  

  
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Changes to the CRF and the study database are strictly monitored.  After a single line is drawn 
through the corrected data point, the study staff documents the change by placing his or her 
initials and the date of the change adjacent to the correction. Typical QA responsibilities of the 
study staff include: 
 Checking all data during or immediately after study visits. 
 Checking charts at predetermined points during the study (initials and date of checker 
are required on each form checked). 
 Performing the initial data check after a few charts have been entered. 
 Performing a 10% data check when all data have been entered. 
 
Typical responsibilities of the PI include: 
 Monitoring and reporting on study staff interviewing and data collection proficiency at 
subject study visits. 
 Checking charts at predetermined points during the study (initials and date of PI are 
required on each form checked). 
 Supervising study database checks. 
 When databases, in Filemaker Pro or other applications, are developed by the research 
staff, only the data checked by the study staff are entered.  Data sets are double 
checked in pairs by UPENN technicians.  The PI supervises any corrections to the data 
set and reviews the completed database before the information is used in any reports or 
analyses. 
 The PI holds meetings with the study staff to report and review the project and data entry 
status.  
 PI reviews lab results and screening information for potential subjects.  
 PI reviews adverse events on at least a weekly basis. 
 
 
Study Logs and Reports  
Study logs are routinely maintained in order to keep computerized back up records of identifying 
and socio-demographic characteristics and experimental group status.  The study subject log 
usually includes subjects’ initials, study number, CRF number, date of birth, race, medication 
start dates, subject status (active, drop-out, completer, follow-up) and relevant dates and 
comments. 
 
Data Storage on Site   
The CRFs and research charts are stored in file rooms specifically designed for data 
storage.  All study data are housed in locked file cabinets.  Only designated members of the 
research team have access to the file cabinets containing research data.  Data are kept on site 
for not less than three years after the subject has completed the final assessment.  Data are 
then eligible for archiving.  
 
The Principal Investigator will permit study-related monitoring, audits, and inspections by 
the IRB, government regulatory bodies, and University compliance and quality assurance 
groups of all study-related documents (e.g., source documents, regulatory documents, data 
collection instruments, study data).  The investigator will ensure that inspections can be made of 
applicable study-related facilities (e.g., Data Management Unit). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 

  
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11 Ethical Considerations 
 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted  
Institutional Review Board (IRB), in agreement with local legal prescriptions, 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 and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of EC/IRB members and 
their affiliate to the sponsor. 
 
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 for the study.  The formal consent of a subject, using the IRB-approved 
consent form, must be obtained before that subject undergoes any study procedure.  The 
consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
 
This study is funded by a grant from the US National Institute on Alcohol Abuse and 
Alcoholism. 
12.2 Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor prior to participation in this study.  All University of Pennsylvania investigators will 
follow the University conflict of interest policy. 
12.3 Subject Stipends or Payments 
 
Subjects will receive payments of $25 for each screening visit(s) and baseline visit(s), $20 
each for Visits 1-9 and $50 for the last treatment visit (Visit 10), $10 for returning all medication 
bottles at each visit ($100 for all 10 medication visits), and $25 if you complete the follow-up 
visit. Subjects who can not complete the follow-up visit in person can do the assessments by 
telephone, for which they will be paid $10 when they come to the study clinic. A $100 
completion bonus will be given to the participant if he/she completes all study visits and returns 
all medication bottles. The total amount that subjects can receive for full participation in the 
research study is up to $555.00. Subjects will receive payment prorated on the basis of the 
number of visits completed and for incomplete visits, the portion of the visit completed.  If a 
participant does not have transportation to come to a study visit, we can provide transportation 
at no cost; for example a taxi, bus pass, or providing a car and driver hired through a UMB-
approved vendor. If a study visit extends over a mealtime, we will provide them with a meal or 
snacks at no cost. 
 
Ondansetron Study Participants Payments 

  
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Study 
Visit 
Study 
Week 
Payment for Visit 
Payment for 
medication’s 
bottles 
TOTAL 
MAX 
V 
0-1 
Screen 
(SV) 
 
$ 25 for each visit 
0 
Up to $ 50 
V 
0-2 
Baseline 
(BL) 
0 
$ 25 for each  
0 
Up to $ 50 
V 1 
1 
$ 20 
$ 10 
$ 30 
V 2 
2 
$ 20 
$ 10 
$ 30 
V 3 
3 
$ 20 
$ 10 
$ 30 
V 4 
4 
$ 20 
$ 10 
$ 30 
V 5 
5 
$ 20 
$ 10 
$ 30 
V 6 
6 
$ 20 
$ 10 
$ 30 
V 7 
8 
$ 20 
$ 10 
$ 30 
V 8 
10 
$ 20 
$ 10 
$ 30 
V 9 
12 
$ 20 
$ 10 
$ 30 
V 10 
16 
$ 50 
$ 10 
$ 60 
V 11 
20 
$ 10 – by phone 
$ 25 – in person (with blood draw) 
$ 100 – completion bonus 
 
 
TOTAL 
 
If V11 by phone $ 10 + $ 280 (or $305 if 2 SV or $330 if 2 SV 
and 2 BL) = $ 290 (or $315 if 2 SV or $340 if 2 BL)  
If V11 in person $ 25 + $ 280 (or $305 if 2 SV or 330 if 2 SV 
and 2 BL) = $ 305 (or $330 if 2 SV or $355 if 2 SV and 2 BL) 
$ 100 bonus – if all study visits completed and all med. bottles 
returned 
MAX $ 100 
MAX 
payment 
UP to:   
 $ 355 + $ 
100 + $ 100 
= $ 555 
 
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