Randomized, Double Blind, Placebo-Controlled Trial of the Safety and Efficacy of HORIZANT (Gabapentin Enacarbil) Extended-Release Tablets for the Treatment of Alcohol Use Disorder
Phase: PHASE2
Conditions: Alcohol Use Disorder
Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

HORIZANT for Alcohol Use Disorder 
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Protocol Number: NCIG-006 
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IND Number: 123220 
 
Protocol Number: NCIG-006 
 
Randomized, Double Blind, Placebo-Controlled Trial of the Safety and Efficacy of 
HORIZANT® (Gabapentin Enacarbil) Extended-Release Tablets for the Treatment of 
Alcohol Use Disorder 
 
Sponsor: 
National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
National Institutes of Health 
Division of Medications Development 
5635 Fishers Lane 
Bethesda MD 20892 
NIAAA Principal Investigator: 
(Sponsor’s Representative) 
Raye Z. Litten, Ph.D. 
NIAAA 
5635 Fishers Lane, room 2041 
Rockville, MD 20852-1705 
Phone: 301-443-0636 
Fax: 301-443-8774 
E-mail: rlitten@mail.nih.gov 
 
NIAAA Co-Investigators: 
Joanne Fertig, Ph.D. 
 
NIAAA (address above) 
Tel: (301) 443-0635 
Email: jfertig@mail.nih.gov 
Daniel E. Falk, Ph.D.  
NIAAA (address above) 
Tel: (301) 443-0788 
Email: falkde@mail.nih.gov 
NIAAA Clinical Program 
Manager: 
Megan Ryan, M.B.A, CCRP 
NIAAA (address above) 
Tel: (301) 443-4225 
Email: mryan1@mail.nih.gov 
XenoPort Representative: 
Richard Kim, M.D., Sr. VP, Chief Medical Officer 
XenoPort, Inc.  
3410 Central Expressway 
Santa Clara, CA 95051 
Tel: 408-616-7151 
Email: Richard.kim@xenoport.com 

HORIZANT for Alcohol Use Disorder 
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Protocol Number: NCIG-006 
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Study Coordinating Center: 
Fast-Track Drugs & Biologics, LLC 
5 Paramus Ct. 
North Potomac, Maryland 20878 
Janet H. Ransom, Ph.D.  
Project Director 
Tel: (301) 762-5787 
Email: jransom@fasttrackresearch.com  
Charles Scott, Ph.D. 
Tel: (240) 421-7826 
Biostatistician 
Email: cscott@fasttrackresearch.com 
Medical Monitor: 
Roberta Kahn, M.D. 
5 Paramus Ct. 
North Potomac, Maryland 20878 
Mobile: (240) 506-6385 
Email: rkahn@fasttrackresearch.com 
 
Alternative Medical Monitor: 
Ivan Montoya 
National Institute on Drug Abuse 
6001 Executive Blvd 
Rockville, MD 20892-9551 
Tel: (301) 443-8639 
Mobil: (240) 460-5101 
Email: imontoya@mail.nih.gov 
 
This document is a confidential communication of NIAAA. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without NIAAA’s prior written approval, except that this document may 
be disclosed to appropriate Institutional Review Boards under the condition that they are 
requested to keep it confidential. 
 
 

HORIZANT for Alcohol Use Disorder 
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Protocol Number: NCIG-006 
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STATEMENT OF COMPLIANCE 
 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CRF Part 46, 21 CFR Part 50, 21 CFR Part 56 and 21 CFR Part 312) 
• International Conference on Harmonisation (ICH) E6 
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 

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Protocol Number: NCIG-006 
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1. 
Protocol Synopsis 
Name of Sponsor/Company: National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
Name of Investigational Product: HORIZANT® Extended-Release Tablets 
Name of Active Ingredient: Gabapentin enacarbil 
Protocol Number: NCIG-006 
Study Title: Randomized, Double Blind, Placebo-Controlled Trial of the Safety and Efficacy of HORIZANT® 
(Gabapentin Enacarbil) Extended-Release Tablets for the Treatment of Alcohol Use Disorder 
NIAAA Principal Investigator: Raye Litten, Ph.D. 
Study Centers: 10 sites in the United States 
Study Period: 
Phase of Development: 
Estimated date first subject enrolled: May 2015 
Estimated date last subject completed: October  2016 
2 
Objectives: 
Primary: The primary objective of the study is to compare the efficacy of HORIZANT (gabapentin enacarbil) 
Extended-Release Tablets 600 mg twice daily (BID) with matched placebo on the primary alcohol consumption 
outcome endpoint, percentage of subjects with no heavy drinking days (PSNHDD) during the last 4 weeks of 
treatment, among patients with Alcohol Use Disorder (AUD).  
Secondary: Secondary objectives are separated into two categories: key secondary objectives and supportive 
secondary objectives. The key secondary objective is to compare HORIZANT to placebo on the percentage of 
subjects abstinent from alcohol during the last 4 weeks of treatment. The supportive secondary study objectives are 
to assess other treatment benefits including: reduction in other alcohol consumption endpoints, alcohol-related 
craving and consequences, mood, sleep quality, smoking quantity and frequency, and safety. 
Methodology: This study is a double-blind, randomized, placebo-controlled, parallel group, multi-site study 
designed to assess the efficacy of HORIZANT Extended-Release Tablets compared with placebo to reduce drinking 
in 346 subjects (173 in each group) who report 4 or more Diagnostic and Statistical Manual of Mental Disorders – 
Fifth Edition (DSM-5™) symptoms of AUD and who meet the drinking criteria outlined hereafter. This study will be 
conducted at 10 clinical sites. If eligible for the study, subjects will be randomized using a stratified permuted block 
randomization procedure with “clinical site” as the stratification variable in an approximate 1:1 ratio (targeting 173 
subjects per group) to receive either HORIZANT Extended-Release Tablets or placebo for 26 weeks (1 week 
escalation; 24 weeks maintenance; 1 week taper). 
Subjects will be seen in the clinic at screening, at randomization and 11 other times during the study. During the 
Week 1 dose escalation period (midway through the week) and during the maintenance period (Weeks 2 to 25), 
subjects will be contacted once per week by telephone at non-clinic visit weeks to encourage study drug compliance 
and to assess withdrawal, adverse events (AEs), and concomitant medications. A final follow-up telephone interview 
will occur during Weeks 28 to 29 (1 to 2 weeks after the end of dosing). 
Number of Subjects (Planned): 346 
Main Inclusion/Exclusion Criteria: Subjects will be male and female at least 21 years of age with 4 or more 
DSM-5™ symptoms of AUD. They must also be seeking treatment for alcohol dependence and if male, report 
drinking an average of 28 drinks per week or if female report drinking an average of 21 drinks per week and at least 
one heavy drinking day per week for the 28-day period prior to consent, and be abstinent for the 3 consecutive days 
prior to the day of randomization. A “heavy drinking day” is 4 or more drinks per drinking day for women and 5 or 
more drinks per drinking day for men. 

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Investigational Product, Dosage and Mode of Administration: 
Dose titration, maintenance and taper will occur as scheduled below. The target maintenance dose of HORIZANT 
Extended-Release Tablets is 600 mg BID. Subjects in the placebo group will take the equivalent number of placebo 
tablets. 
Study Period 
Time Period 
AM Dose 
(# of tablets) 
PM Dose 
(# of tablets) 
Titration 
Week 1, Days 1-3 
600 mg (1) 
None 
Titration 
Week 1, Days 4-7 
600 mg (1) 
600 mg (1) 
Maintenance 
Weeks 2-25 
600 mg (1) 
600 mg (1) 
Taper 
Week 26 
600 mg (1) 
 None 
Reference Therapy, Dosage and Mode of Administration: Identically debossed placebo tablets will be 
administered according to the same schedule as HORIZANT Extended-Release Tablets. 
Duration of Study: Each subject will participate in the study for up to approximately 30 weeks, including up to 2 
weeks of screening, 26 weeks of treatment, one follow-up visit after completing treatment, and a final telephone 
contact 1 to 2 weeks after completing treatment. 
Criteria for Evaluation: 
Primary: The primary outcome measure examines the hypothesis that HORIZANT Extended-Release Tablets will 
increase the PSNHDD compared to placebo during the last 4 weeks of the maintenance period (Study Weeks 22-25). 
A “heavy drinking day” is 4 or more drinks per drinking day for women and 5 or more drinks per drinking day for 
men. Drinking data will be collected by the Timeline Followback (TLFB) method. If during the last 4 weeks of the 
maintenance period of the study, the subject does not come back for clinic visits or provide TLFB data but agrees to 
telephone contact, then the subject will be asked if there were any heavy drinking days during the final study period. 
These data will be used to determine the primary efficacy endpoint when TLFB data are missing, otherwise the data 
will be imputed as having a heavy drinking day during this period. 
Secondary: Secondary efficacy endpoints will also be analyzed over the last 4 weeks of treatment. 
1. Percentage of subjects abstinent from alcohol (key secondary endpoint) 
2. Percentage of subjects with a World Health Organization (WHO) drinking risk category decrease of: 
a. 
at least 1-level  
b. at least 2-levels  
3.    Percentage of days abstinent per week 
4.    Percentage of heavy drinking days per week 
5.    Weekly mean number of drinks per week 
6.    Weekly mean drinks per drinking day 
7.    Cigarettes smoked per week among smokers 
8.    Alcohol craving score [Alcohol Craving Scale – Short Form (ACQ-SR-R)] 
9.    Alcohol related consequences (ImBIBe) score 
10.  Pittsburg Sleep Quality Index (PSQI) score 
11.  Beck Anxiety Inventory (BAI) score 
12.  Beck Depression Inventory Scale – II  (BDI-II) score 
Safety Endpoints Safety endpoints will be evaluated over the entire treatment and follow-up periods. 
1.   Vital signs 
2.   Blood chemistries  
3.   Urine drug screen results 
4.   Blood alcohol concentration (BAC) by breathalyzer  
5.   AEs 
6.   Electrocardiogram (ECG) results 

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Protocol Number: NCIG-006 
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7.   Clinical Institute of Withdrawal – Alcohol Revised (CIWA-AR) scores 
8.   Profile of Moods States (POMS) scores 
9.   Frequency of subjects with suicidal ideation at any time during the treatment period –Columbia-Suicide   
      Severity Rating Scale (C-SSRS) 
Compliance: Self report of compliance with investigational products and gabapentin plasma levels. 
Pharmacokinetics (PK): A population PK/pharmacodynamics (PD) analysis will be performed using gabapentin 
plasma levels determined from blood samples collected at Weeks 12, 20, and 24 from subjects in the HORIZANT 
Extended-Release Tablets group. Blood will be collected from all subjects at different times at each PK visit (pre-
dose and up to 12 hours post dose). 
Exploratory Analysis: An exploratory analysis of the primary and secondary efficacy endpoints will test treatment 
effects over varying time intervals (e.g., weekly, monthly, and by grace periods) and by the use of imputation; in 
addition, these endpoints will be analyzed within the evaluable population. The MINI AUD number of symptoms, 
blood phosphatidylethanol (PEth) levels, and abstinence from cigarette smoking will also be tested as endpoints. 
Potential moderators of the treatment effect will be tested using the primary endpoint, PSNHDD. 
Statistical Methods (Data Analysis):  
Analysis Populations: 
Modified intention-to-treat (mITT) Analysis Set: The mITT set is defined as subjects randomized to participate in 
the study who took at least one dose of investigational product. 
Evaluable Analysis Set: The evaluable analysis set is defined as those subjects randomized to the study who took at 
least 80% of the per-protocol prescribed dose of tablets during the maintenance period (Weeks 2-25) and did not 
have a major protocol violation.  
The primary and secondary efficacy analyses will be conducted on both the mITT and evaluable analysis sets. 
Exploratory analyses will be performed on the mITT analysis set, unless otherwise specified. Safety analyses will be 
conducted on the mITT analysis set. 
Analysis of the Primary Efficacy Endpoint: 
The primary analysis will be conducted via a fully covaried logistical regression of the PSNHDD during Study 
Weeks 22 to 25 (last 4 weeks of the maintenance period) on the mITT population. The model includes treatment 
group, clinical site, pre-randomization drinking goal (abstinence versus not abstinent), and baseline percent heavy 
drinking days as covariates.  Subjects with any missing drinking data during Weeks 22 to 25 will be considered 
heavy drinkers. Treatment group differences will be tested for significance using the Wald statistic and will be 
considered statistically significant at a two-tailed p <0.05. 
Analysis of the Key Secondary Endpoint: 
The key secondary endpoint is the percentage of subjects abstinent during Weeks 22 through 25 on the mITT 
population. The analysis will be performed using a fully covaried logistic regression that includes treatment group, 
clinical site, pre-randomization drinking goal (abstinence versus not abstinent), and baseline percent days abstinent 
as covariates; however, fewer covariates may be included given a limited number of observed events. Subjects with 
any missing drinking data during Weeks 22 to 25 will be considered non-abstinent. Statistical significance will be 
evaluated if and only if the primary endpoint (PSNHDD) is statistically significant (p<0.05). The testing procedure 
utilizes serial gate keeping methodology (Dmitrienko and Tamhane 2009). If statistical significance for the primary 
endpoint of PSNHDD is met then the Wald statistic from the fully covaried logistic regression will be used to test 
treatment differences in the percentage of subjects abstinent with statistical significance identified with a two-tailed 
p-value below 0.05. 
Analysis of the Supportive Secondary Endpoints: 
Secondary endpoints will compare the HORIZANT Extended-Release Tablets group with the placebo group using 
mixed-effects models. Covariates for continuous secondary efficacy endpoints include the baseline equivalent of the 
endpoint, clinical site, treatment, time and the treatment by time interaction. Additional covariates for the secondary 
efficacy endpoints may include baseline characteristics with a theoretical and/or empirical basis for a relationship 
with a particular secondary endpoint. In general, every continuous secondary efficacy endpoint is analyzed using a 
repeated measures mixed effects model where subjects are random effects; factors and covariates are fixed effects. 
The overall least squares means and least square means for each time point along with the 95% confidence intervals 
will be presented for the untransformed endpoint only, while two-tailed p-values and Cohen’s d will be presented for 
both the untransformed and transformed data.  Inference and Cohen’s d will be based upon the results using 

HORIZANT for Alcohol Use Disorder 
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Protocol Number: NCIG-006 
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appropriately transformed data. Percent subjects with a WHO 1-level decrease in alcohol consumption and a WHO 
2-level decrease in alcohol consumption will be analyzed via a fully covaried logistic regression of the endpoint 
measured during the last 4 weeks of the maintenance period. No imputation will be used for the analysis of 
secondary endpoints. 
PK Analyses: Population PK/PD analyses will be conducted under a separate population PK/PD SAP. 
Safety Analyses: 
The severity, frequency, and relationship of AEs to investigational product will be presented by Medical Dictionary 
for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT) grouping. Listings of 
each individual AE including start date, stop date, severity, relationship, outcome, and duration will be provided. 
Clinical chemistry, urine drug screen results, pregnancy test results, and BAC results, will be reported as summary 
statistics. Vital signs will be presented as summary statistics and change from baseline. The proportions of ECG 
results considered clinically significant will also be provided. CIWA-AR scores will be analyzed in a manner similar 
to the efficacy endpoints: mixed effects models with and without baseline characteristics. In addition, change from 
baseline (shift tables) will also be presented for clinical chemistry data. The numbers and proportion of subjects who 
reported CIWA-AR scores ≥ 10 at any time after the start of dosing will be presented. 
Compliance and Retention Analyses: 
Medication compliance, defined as the amount of investigational product taken as a proportion of the total amount 
prescribed per protocol, will be evaluated for the HORIZANT Extended-Release Tablets and placebo groups. Self-
reported compliance with HORIZANT Extended-Release Tablets will be compared against plasma samples 
collected at Weeks 12, 20, and 24 having detectable levels of gabapentin when drug exposure was reported. Average 
amounts of investigational product taken overall and weekly will be reported for the HORIZANT Extended-Release 
Tablets and placebo groups. The research participation rate, defined as percentage of subjects with complete 
drinking data, will be compared between treatment groups. In addition, the percentage of subjects discontinuing 
medication or early withdrawal from the study and a listing of these reasons for discontinuation will be provided. 
Baseline Descriptive Statistics: 
Summaries of the characteristics of the subjects in each of the study groups at baseline will be prepared for both the 
mITT and evaluable analysis sets. Baseline characteristics will be compared between the HORIZANT 
Extended-Release Tablets and placebo groups using appropriate statistical methods. 

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2. 
Table of Contents, List of Tables, and List of Figures 
 Table of Contents 
1. 
Protocol Synopsis .................................................................................................................. 4 
2. 
Table of Contents, List of Tables, and List of Figures .......................................................... 8 
3. 
List of Abbreviations and Definition of Terms ................................................................... 13 
4. 
Introduction ......................................................................................................................... 16 
4.1. 
Alcohol Use Disorder ............................................................................................. 16 
4.2. 
Current Treatments for Alcohol Use Disorder ....................................................... 16 
4.3. 
HORIZANT (Gabapentin Enacarbil) Extended-Release Tablets ........................... 17 
4.3.1. Rationale for Studying HORIZANT Extended-Release Tablets ............... 18 
4.3.2. HORIZANT Extended-Release Tablets Pharmacodynamics .................... 18 
4.3.3. Pharmacokinetics and Metabolism ............................................................ 18 
4.3.4. Drug Interactions ....................................................................................... 20 
4.3.5. Contraindicated Medications ..................................................................... 20 
4.3.6. Warnings and Precautions for Subjects Taking HORIZANT Extended-
Release Tablets .......................................................................................... 20 
4.3.7. Clinical Studies of Gabapentin in Alcohol Use Disorder .......................... 21 
4.3.8. Safety of HORIZANT Extended-Release Tablets in Clinical Studies of 
Restless Legs Syndrome ............................................................................ 22 
4.3.9. Safety of HORIZANT Extended-Release Tablets in Clinical Studies of 
Postherpetic Neuralgia .............................................................................. 22 
4.3.10. Subjects with Renal Impairment ............................................................... 23 
4.3.11. Risk of Suicidal Thoughts or Behaviors in Patients Taking Antiepileptic 
Drugs ......................................................................................................... 23 
4.3.12. Drug Reaction with Eosinophilia and Systemic Symptoms ...................... 23 
4.3.13. Overdose Information ................................................................................ 24 
4.3.14. HORIZANT Extended-Release Tablets in Pregnant Women ................... 24 
4.3.15. Summary of Safety in Restless Legs Syndrome and Postherpetic Neuralgia24 
4.3.16. Rationale for Selection of Doses for this Study ........................................ 25 
4.4. 
Discussion of the Study Design .............................................................................. 25 
5. 
Study Objectives .................................................................................................................. 28 
5.1. 
Primary Objective ................................................................................................... 28 
5.2. 
Secondary Objective ............................................................................................... 28 
6. 
Investigational Plan ............................................................................................................. 29 
7. 
Study Interventions .............................................................................................................. 33 
7.1. 
Investigational Products: HORIZANT Extended-Release Tablets and Placebo .... 33 
7.2. 
Investigational Product Packaging, Labeling, and Distribution of Drug Kits to Sites33 
7.3. 
Investigational Product Storage .............................................................................. 33 
7.4. 
Investigational Product Dispensing ........................................................................ 33 
7.5. 
Investigational Product Accountability .................................................................. 34 
7.6. 
Used/Unused Investigational Product Supplies ...................................................... 34 
7.7. 
Investigational Product Administration .................................................................. 34 
7.8. 
Take Control Behavioral Platform ......................................................................... 35 
7.9. 
Concomitant Medications ....................................................................................... 35 

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Protocol Number: NCIG-006 
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8. 
Study Procedures ................................................................................................................. 37 
8.1. 
Recruitment of Subjects ......................................................................................... 37 
8.2. 
Informed Consent ................................................................................................... 37 
8.3. 
Selection and Withdrawal of Subjects .................................................................... 37 
8.3.1. Inclusion Criteria ....................................................................................... 37 
8.3.2. Exclusion Criteria ...................................................................................... 39 
8.4. 
Eligibility Screening ............................................................................................... 41 
8.5. 
Baseline and Final Eligibility Assessments ............................................................ 42 
8.6. 
Measures Taken to Minimize/Avoid Bias .............................................................. 43 
8.6.1. Randomization (Day -1) ............................................................................ 43 
8.6.2. Blinding ..................................................................................................... 44 
8.7. 
Interventions on Day -1 and Day 1 ......................................................................... 44 
8.8. 
Weeks 1 and 2 Safety Telephone Contact .............................................................. 45 
8.9. 
Maintenance Phase ................................................................................................. 45 
8.10. 
Telephone Assessments .......................................................................................... 46 
8.11. 
Final Clinic Visit .................................................................................................... 46 
8.12. 
Telephone Follow-up ............................................................................................. 47 
8.13. 
Duration of Subject Participation ........................................................................... 47 
8.14. 
Dose-adjustment Criteria ........................................................................................ 47 
8.14.1. Safety Criteria for Dose Adjustment or Stopping Doses ........................... 47 
8.14.1.1. 
Investigational Product Dose Reduction ................................ 47 
8.14.1.2. 
Investigational Product Discontinuation ................................ 47 
8.15. 
Subject Withdrawal or Discontinuation Procedures ............................................... 48 
8.16. 
Situations Requiring Discontinuation from the Study as well as from 
Investigational Product ........................................................................................... 48 
8.17. 
Study Termination Criteria ..................................................................................... 49 
9. 
Study Endpoints .................................................................................................................. 50 
9.1. 
Efficacy Endpoints ................................................................................................. 50 
9.1.1. Primary Efficacy Endpoint ........................................................................ 50 
9.1.2. Secondary Efficacy Endpoints .................................................................. 50 
9.2. 
Safety Endpoints ..................................................................................................... 50 
9.3. 
Compliance ............................................................................................................. 51 
9.4. 
Pharmacokinetics .................................................................................................... 51 
10. 
Safety Monitoring Plan........................................................................................................ 52 
11. 
Assessment Methods ........................................................................................................... 54 
11.1. 
Alcohol Breathalyzer .............................................................................................. 54 
11.2. 
Adverse Events and Serious Adverse Events ......................................................... 54 
11.2.1. Adverse Event Definition .......................................................................... 54 
11.2.2. Serious Adverse Events and Serious Unexpected Adverse Events 
Definition .................................................................................................. 54 
11.2.3. Methods/Timing for Assessing, Recording, and Analyzing Safety 
Endpoints ................................................................................................... 55 
11.2.4. Clinical Laboratory Abnormalities and Other Abnormal Assessments .... 55 
11.2.5. Classification of Adverse Event Intensity and Relationship to 
Investigational Product .............................................................................. 55 
11.2.6. Outcomes and Actions Taken .................................................................... 56 
11.2.7. Reporting Serious Adverse Events ............................................................ 57 
11.2.7.1. 
24 hour Reporting Requirements (Initial Report) .................. 57 

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11.2.7.2. 
3-Day Supporting Documentation Requirements (Follow-up 
Report) ................................................................................... 57 
11.2.7.3. 
Reporting to the IRB .............................................................. 58 
11.3. 
Alcohol Craving Scale ............................................................................................ 58 
11.4. 
Barratt Impulsiveness Scale ................................................................................... 58 
11.5. 
Beck Anxiety Inventory ......................................................................................... 58 
11.6. 
Beck Depression Inventory – II .............................................................................. 59 
11.7. 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) ........ 59 
11.8. 
Clinical Chemistry .................................................................................................. 59 
11.9. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................... 60 
11.10. Demographics ......................................................................................................... 60 
11.11. Drinking Question .................................................................................................. 60 
11.12. ECG ........................................................................................................................ 61 
11.13. Exit Interview ......................................................................................................... 61 
11.14. Fagerström Test for Nicotine Dependence ............................................................. 61 
11.15. Cigarette Smoking Quantity-Frequency ................................................................. 61 
11.16. Family History of Alcohol Problems ..................................................................... 61 
11.17. Genetic Analysis ..................................................................................................... 61 
11.18. ImBIBe ................................................................................................................... 62 
11.19. Locator Form/Mobile Phone Contact ..................................................................... 62 
11.20. Medical History ...................................................................................................... 62 
11.21. MINI ....................................................................................................................... 63 
11.22. Other Services Used for Alcohol Use Problems .................................................... 63 
11.23. Phosphatidylethanol Determination ....................................................................... 63 
11.24. Pittsburg Sleep Quality Index (PSQI) .................................................................... 64 
11.25. Procedures for Monitoring Subject Compliance .................................................... 64 
11.25.1. Drug Accountability/Compliance .............................................................. 64 
11.25.2. Gabapentin Plasma Levels ........................................................................ 64 
11.26. Profile of Mood State (POMS) ............................................................................... 65 
11.27. Pregnancy Test and Birth Control Record .............................................................. 65 
11.28. Prior and Concomitant Medications ....................................................................... 65 
11.29. Physical Examination ............................................................................................. 65 
11.30. Screen Failures Documentation .............................................................................. 65 
11.31. Subject Disposition ................................................................................................. 65 
11.32. Drinking Goal ......................................................................................................... 66 
11.33. TLFB Interview ...................................................................................................... 66 
11.33.1. World Health Organization Drinking Risk Categorical Scale ................... 67 
11.34. Urine Drug Screen .................................................................................................. 68 
11.35. Vital Signs .............................................................................................................. 68 
12. 
Statistical Methods and Determination of Sample Size ...................................................... 69 
12.1. 
Statistical and Analytical Plans .............................................................................. 69 
12.2. 
Statistical Hypotheses ............................................................................................. 69 
12.3. 
Analysis Populations .............................................................................................. 69 
12.4. 
Description of Statistical Methods ......................................................................... 70 
12.4.1. General Approach ...................................................................................... 70 
12.4.2. Analysis Addressing the Primary Efficacy Endpoint ................................ 70 
12.4.3. Secondary Efficacy Endpoints Analysis ................................................... 71 
12.4.3.1. 
Key Secondary Endpoint: Percentage of Subjects Abstinent 
from Alcohol .......................................................................... 71 
12.4.3.2. 
Supportive Secondary Efficacy Endpoints ............................ 71 

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12.4.4. Safety Analyses ......................................................................................... 72 
12.4.5. Compliance and Retention Analyses ......................................................... 73 
12.4.6. PK Analysis ............................................................................................... 73 
12.4.7. Baseline Descriptive Statistics .................................................................. 73 
12.4.8. Exploratory Analyses ................................................................................ 73 
12.4.9. Adjustment for Covariates ......................................................................... 74 
12.4.10. Interim Analyses and Data Monitoring ..................................................... 74 
12.4.11. Multiple Comparison/Multiplicity............................................................. 74 
12.4.12. Tabulation of Individual Response Data ................................................... 75 
12.5. 
Determination of Sample Size ................................................................................ 75 
13. 
Quality Control and Quality Assurance............................................................................... 76 
13.1. 
Study Monitoring ................................................................................................... 76 
13.2. 
Audits and Inspections ........................................................................................... 76 
14. 
Ethics ................................................................................................................................... 77 
14.1. 
Ethics Review ......................................................................................................... 77 
14.1.1. Review/Approval of Study Protocol ......................................................... 77 
14.1.2. Protocol Modifications .............................................................................. 77 
14.1.3. Protocol Deviation Reporting Procedures ................................................. 77 
14.2. 
Ethical Conduct of the Study .................................................................................. 77 
14.2.1. Confidentiality ........................................................................................... 78 
14.2.1.1. 
Confidentiality of Data .......................................................... 78 
14.2.1.2. 
Confidentiality of Subject Records ........................................ 78 
14.2.2. Compensation for Participation ................................................................. 78 
14.2.3. Written Informed Consent ......................................................................... 78 
14.2.4. Delegation of Responsibilities and Adequate Resources .......................... 79 
14.2.5. Financial Disclosure .................................................................................. 79 
15. 
Data Handling and Record Keeping .................................................................................... 80 
15.1. 
Subject Identification and Confidentiality .............................................................. 80 
15.2. 
Inspection of Records ............................................................................................. 80 
15.3. 
Retention of Records .............................................................................................. 80 
15.4. 
Trial Registration .................................................................................................... 81 
16. 
Publication Policy ................................................................................................................ 82 
17. 
Protocol Signature Page ...................................................................................................... 83 
18. 
References ........................................................................................................................... 84 
19. 
Appendices .......................................................................................................................... 89 
19.1. 
Example Drug Card ................................................................................................ 89 
19.2. 
Medication Guide to Be Given to Subjects ............................................................ 90 
19.3. 
Common Terminology Criteria for Adverse Events for Clinical Laboratory and 
Blood Pressure Elevation Adverse Events ............................................................. 91 
19.4. 
Certificate of Confidentiality .................................................................................. 92 
 
List of Tables 
Table 1: 
Drugs Approved in the US or European Union for Alcohol Dependence .......................... 16 
Table 2: 
Pharmacokinetics of Gabapentin in Postherpetic Neuralgia Patients Taking Gabapentin and 
HORIZANT Extended-Release Tablets .............................................................................. 19 

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Table 3: 
Normative Status on ASI Severity Scores at Twelve-Months by Three-Month Drinking 
Status ................................................................................................................................... 26 
Table 4: 
ASI Severity Scores at Twelve Months by Six-Month Drinking Status ............................. 27 
Table 5: 
Schedule of Assessments ..................................................................................................... 30 
Table 6: 
Schedule for Dispensing Study Drug Bottles ...................................................................... 34 
Table 7: 
Schedule of Administration of Investigational Products ..................................................... 35 
Table 8: 
Standard Drink Unit Definitions ......................................................................................... 67 
Table 9: 
CTCAE Criteria for Clinical Laboratory and Blood Pressure Elevation Adverse Events .. 91 
 
List of Figures 
Figure 1: 
Comparison of Gabapentin Concentrations in Patients Dosed with Gabapentin and 
HORIZANT Extended-Release Tablets .............................................................................. 19 
Figure 2:  
Overview of Study Design .................................................................................................. 29 
 
 

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3. 
List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
5-HT 
 
Serotonin 
AA 
Alcoholics anonymous 
ACQ-SR-R 
Alcohol Craving Scale – Short Form  
AE 
Adverse event 
AEDs 
Antiepileptic drugs 
ALT 
Alanine aminotransferase 
ASI 
Addition severity index. 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
AUD 
Alcohol Use Disorder 
BAC 
Blood alcohol concentration 
BAI 
Beck Anxiety Inventory 
BDI-II 
Beck Depression Inventory-II 
BID 
Twice daily 
BIS 
Barratt Impulsiveness Scale 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Act 
CYP 450 
Cytochrome P450 
CI 
Confidence interval 
CIWA-AR 
Clinical Institute Withdrawal Assessment for Alcohol-revised 
CrCl 
Creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
Css,avg 
Concentration at steady state average 
Cmax 
Maximum concentration 
Css,max 
Concentration at steady state maximum 
eCRF 
Electronic Case Report Form 
CTCAE 
Common terminology criteria for adverse events 
dL 
Deciliter 
DNA 
Deoxyribonucleic acid 
DRESS 
Drug Reaction with Eosinophilia and Systemic Symptoms 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDMS 
Electronic data management system 
EDTA 
Ethylenediaminetetraacetic acid 
EMA 
European Medicines Agency 
EOS 
End of study 

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Abbreviation 
Definition 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
g 
Gram 
GABA 
Gamma aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HIPAA 
Health Insurance Portability Accountability Act 
hr 
Hour 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
L 
Liter 
LC–MS/MS 
liquid chromatography–mass spectrometry/mass spectrometry 
MAOI 
Monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCT-1 
Monocarboxylate transporter-1 
mg 
Milligram 
μg 
Microgram 
min 
Minutes 
MINI 
MINI Neuropsychiatric Interview 
mITT 
Modified intention-to-treat 
mL 
Milliliter 
mm 
Millimeter 
mmol 
Millimole 
NIAAA 
National Institutes on Alcohol Abuse and Alcoholism 
OTC 
Over-the-counter 
oz 
Ounce 
PD 
Pharmacodynamic 
PEth 
Phosphatidylethanol 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
POMS 
Profile of Mood State 
PSNHDD 
Percentage of subjects with no heavy drinking days 
PSQI 
Pittsburg Sleep Quality Index 
PT 
Preferred Term 
QTcF 
QT interval with Fridericia’s correction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDU 
Standard drinking unit 

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Abbreviation 
Definition 
SOC 
System Organ Class 
SOS 
Secular organizations for sobriety 
SNRI 
Serotonin-norepinephrine reuptake inhibitors 
SSRI 
Selective serotonin reuptake inhibitors 
T1/2 
Terminal elimination half-life 
THC 
Tetrahydrocannabinol 
TLFB 
Timeline followback  
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 

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4. 
Introduction 
4.1. 
Alcohol Use Disorder 
Alcohol use disorder (AUD) (alcohol dependence and abuse) affects 76 million adults world-
wide, including 18 million Americans, and is responsible for a myriad of medical, psychological, 
social, economic and personal problems (Litten et al-2012). Tragically, more than 2.5 million 
individuals including 80,000 Americans die each year from alcohol-related events. The total 
economic cost to society is a staggering $224 billion each year in the United States (US) 
(NIAAA-2014).  
4.2. 
Current Treatments for Alcohol Use Disorder 
Pharmacologic treatment of AUD has mostly focused on altering the reinforcing effects of 
alcohol use. Medication development has focused on several neurotransmitter systems that 
interact with the corticomesolimbic dopamine pathway, which can mediate reinforcement. Many 
available or promising compounds appear to act by modulating the function of opioids, 
glutamate (with or without gamma aminobutyric acid, GABA), and serotonin (5-HT) (Heilig and 
Egli-2006). 
During the past decade, advances have been made in medications development. Currently, there 
are four medications approved by the US Food and Drug Administration (FDA) to treat alcohol 
dependence:  disulfiram, oral naltrexone, long-acting injectable (depot) naltrexone, and 
acamprosate. Last year, nalmefene was approved by the European Medicines Agency (EMA) to 
treat alcohol dependence. The indications and efficacy of the drugs for the treatment of alcohol 
dependence is shown in Table 1. 
Table 1: 
Drugs Approved in the US or European Union for Alcohol Dependence 
Drug Name 
Target 
Receptor 
Putative 
Mechanism of 
Action 
Randomized 
Controlled Trial 
Design 
Outcomes 
Reference 
Oral 
naltrexone 
(Revia, 
Depade) 
μ-opioid 
antagonist 
Reduce positive 
reinforcement of 
drinking and 
increase unpleasant 
effects 
Meta analysis of 50 
randomized trials of 
7793 subjects 
Compared with 
placebo relative risk 
was 0.8 (95% CIa 
0.76-0.90) 
Rasner et al- 
2010 
Oral 
naltrexone 
(Revia, 
Depade) 
μ-opioid 
antagonist 
Reduce positive 
reinforcement of 
drinking and 
increase unpleasant 
effects 
Meta analysis of 53 
randomized trials of 
9120 subjects 
Numbers needed to 
prevent return to any 
drinking was 20 
(95% CI, 11 to 500), 
risk difference 
-0.05%  (95% CIa -
0.10 to -0.002) 
Jonas et al-
2014 

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Table 1: 
Drugs Approved in the US or European Union for Alcohol Dependence 
(Continued) 
Drug Name 
Target 
Receptor 
Putative 
Mechanism of 
Action 
Randomized 
Controlled Trial 
Design 
Outcomes 
Reference 
Depot 
naltrexone 
(Vivitrol) 
μ-opioid 
antagonist 
Reduce positive 
reinforcement of 
drinking and 
increase 
unpleasant 
effects 
Randomized 
placebo controlled 
trial of two doses of 
depot naltrexone in 
624 subjects  
Vivitrol had a 
25% greater 
reduction in rate 
of heavy drinking 
days after 24 
weeks (relative 
risk 0.75, 95% CI 
0.60 to 0.94) 
Garbutt et al- 
2005 
Disulfiram 
(Antabuse) 
Inhibits 
aldehyde 
dehydrogenase 
and prevents the 
metabolism of 
alcohol's 
primary 
metabolite, 
acetaldehyde 
Maintain 
abstinence (leads 
to adverse effects 
when given with 
alcohol) 
Only effective when 
given under regular 
supervision. 
Randomized trial vs 
naltrexone or 
acomprosate over 12 
weeks 
Patients taking 
disulfiram 
experienced a 
greater reduction 
in heavy drinking 
days and average 
weekly 
consumption, and 
a longer time to 
first drink 
Laaksonen et 
al-2008 
Acamprosate 
(Campral) 
Glutamate 
system and the 
gamma-
aminobutyric 
acid system 
Prevent relapse – 
should be given 
when abstinence 
is achieved. 
Meta analysis 
Compared with 
placebo, relative 
risk was 0.84, 
(95% CI 0.71-
0.91) 
Rasner et al-
2008 
Nalmefene 
(Selincro) 
Opioid 
antagonist (all 3 
subtypes of 
receptors) 
Reduce positive 
reinforcement of 
drinking 
Meta analysis of two 
randomized placebo 
controlled trials of 
403 subjects over 28 
weeks 
Reduction in 
relapse rate 
compared with 
placebo relative 
risk 0.62 (95% CI 
0.41-0.93) 
Srisurapanont 
& Jarusuraisin- 
2005 
a CI=confidence interval. 
As these medications do not work for everyone or in all situations, additional research is vital to 
develop more efficacious and safe medications to treat AUD. 
4.3. 
HORIZANT (Gabapentin Enacarbil) Extended-Release Tablets 
Gabapentin is a GABA analog that was originally developed to treat epilepsy (Neurontin®) and 
more recently has been approved for the treatment of postherpetic neuralgia (Neurontin and 
Gralise®). HORIZANT Extended-Release Tablets is an actively transported prodrug of 
gabapentin that undergoes rapid post absorption hydrolysis to gabapentin that was designed to 
produce dose proportional gabapentin blood level exposure. HORIZANT Extended-Release 
Tablets is approved for the treatment of moderate-to-severe primary Restless Legs Syndrome in 
adults and management of postherpetic neuralgia in adults. HORIZANT overcomes some of the 
limitations of oral gabapentin including highly variable and dose dependent bioavailability 
among patients and fluctuations in gabapentin blood levels over 24 hours. 

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4.3.1. 
Rationale for Studying HORIZANT Extended-Release Tablets 
Recent research findings have shown gabapentin to be a promising medication to treat alcohol 
dependence. Mason et al (2014) conducted a 12-week, double-blind, placebo-controlled 
randomized trial of gabapentin (900 mg or 1800 mg/day) in 150 alcohol dependent patients. 
Gabapentin significantly improved rates of abstinence and no heavy drinking as well as 
alleviated relapse-related symptoms of insomnia, dysphoria, and alcohol craving. Patients treated 
with gabapentin exhibited no serious adverse events (SAEs) with a favorable safety profile. The 
results of this randomized controlled trial are supported by the following earlier studies. 
Mason et al (2009) demonstrated in a human laboratory paradigm that gabapentin (1200 mg/day) 
was effective in reducing alcohol craving and improving measures of sleep quality. Gabapentin 
was also effective in reducing alcohol withdrawal symptoms (Myrick et al- 2009). In addition, 
several single-site clinical trials have also yielded promising results for gabapentin in treating 
alcohol dependence. In a small clinical trial, Brower et al (2008) reported that gabapentin (1500 
mg/day) significantly delayed the onset to heavy drinking and improved the symptoms of 
insomnia in alcohol dependent patients. Furieri and Nakamura-Palacios (2007) conducted a 
double-blind, placebo-controlled trial of gabapentin (600 mg/day) in 60 alcohol dependent 
patients and found gabapentin effective in reducing alcohol consumption and alcohol craving. 
Anton et al (2009) reported that a combination of gabapentin (1200 mg/day) and flumazenil was 
efficacious in increasing percent days abstinent and time to first heavy drinking in alcohol 
dependent patients with pretreatment alcohol withdrawal symptoms. In another clinical trial, 
Anton et al (2011) found that the addition of gabapentin (1200 mg/day) to naltrexone improved 
drinking outcomes over naltrexone alone. With these positive efficacy and safety results from the 
single site studies above, gabapentin is now ready to be tested in a multi-site clinical trial. 
HORIZANT Extended-Release Tablets was selected over other oral gabapentin products due to 
more uniform bioavailability, faster time to titrating to full therapeutic dose, and less fluctuating 
gabapentin blood levels with twice daily administration. 
4.3.2. 
HORIZANT Extended-Release Tablets Pharmacodynamics 
Gabapentin is structurally related to the neurotransmitter GABA but has no effect on GABA 
binding, uptake, or degradation. HORIZANT Extended-Release Tablets and gabapentin have 
been tested in radioligand binding assays, and neither exhibited affinity for a number of other 
common receptor, ion channel, or transporter proteins. In vitro studies have shown that 
gabapentin binds with high affinity to the α2δ subunit of voltage-activated calcium channels; 
however, the relationship of this binding to the therapeutic effects of HORIZANT Extended-
Release Tablets in Restless Legs Syndrome and postherpetic neuralgia is unknown. 
4.3.3. 
Pharmacokinetics and Metabolism 
Gabapentin pharmacokinetic (PK) parameters were compared within the same postherpetic 
neuralgia patients taking gabapentin and HORIZANT Extended-Release Tablets by Backonja et 
al (2011). As shown in Table 2 and Figure 1, average steady-state gabapentin concentrations in 
plasma when patients received 1468 mg-equivalents in divided doses of 1200 mg tablets twice 
daily of HORIZANT Extended-Release Tablets were increased 17% when compared with 1800 
mg of gabapentin given as 600 mg tablets 3 times per day (p = 0.005; paired t-test).  

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Table 2: 
Pharmacokinetics of Gabapentin in Postherpetic Neuralgia Patients Taking 
Gabapentin and HORIZANT Extended-Release Tablets 
 
Treatment 
PK Parameter 
Gabapentin (N=42) 
HORIZANT Extended-Release Tablets 
(N=42) 
Gabapentin equivalent dose 
1,800 mg 
1,248 mg 
Css,avg μg/mL 
6.93 (2.25) 
8.10 (2.91) 
F, % 
43.3 (19.8) 
76.8 (26.4) 
AUC(0-24), μg·h/mL 
166 (54.1) 
194 (69.9) 
Css, max μg/mL 
9.07 (3.00) 
11.00 (3.99) 
Tmax, hours 
2.31 (1.13) 
4.63 (2.45) 
T1/2, hours 
7.23 (3.22) 
7.37 (2.97) 
Figure 1: 
Comparison of Gabapentin Concentrations in Patients Dosed with 
Gabapentin and HORIZANT Extended-Release Tablets 
 
Legend: Data are mean ± SD steady-state concentrations of gabapentin in plasma of 42 patients with postherpetic 
neuralgia after repeated dosing of either gabapentin (600 mg three times daily) or HORIZANT Extended-Release 
Tablets (1,200 mg twice daily). GEn = gabapentin enacarbil. From Backonja et al (2011). 
 
For subjects with postherpetic neuralgia taking HORIZANT Extended-Release Tablets 600 mg 
twice daily, the estimated steady state mean Cmax was 5.35 µg/mL, mean AUC(0-24) was 
approximately 109 µg*hr/mL, mean Cmin was 3.63 µg/mL, and mean peak trough ratio was 1.5 
(HORIZANT Extended-Release Tablets Product Label). 
Absorption: The pathway for absorption of HORIZANT Extended-Release Tablets is believed 
to include active transport via a proton-linked monocarboxylate transporter, MCT-1. This 
transporter is expressed at high levels in the intestinal tract and is not saturated by administration 
of high doses of HORIZANT Extended-Release Tablets. Mean bioavailability of gabapentin 

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(based on urinary recovery of gabapentin) for HORIZANT Extended-Release Tablets in the fed 
state is about 75%. Bioavailability under fasting conditions has been estimated by gabapentin 
urinary recovery to be 42% to 65%. In a food effect study, the exposure of gabapentin increased 
by 24%, 34%, and 44% with low, moderate, and high fat meals, respectively. The Tmax of 
gabapentin after administration of 600 mg of HORIZANT Extended-Release Tablets was 5.0 
hours in fasted subjects and 7.3 hours in fed subjects. Steady state is reached in 2 days with daily 
administration. 
Metabolism: Neither HORIZANT Extended-Release Tablets nor gabapentin are substrates, 
inhibitors, or inducers of the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). HORIZANT Extended-
Release Tablets is neither a substrate nor an inhibitor of P-glycoprotein in vitro. 
4.3.4. 
Drug Interactions 
Alcohol: Gabapentin enacarbil is released faster from HORIZANT Extended-Release Tablets in 
the presence of alcohol. This was determined in an in vitro dissolution study which was 
conducted to evaluate the impact of ethanol (5, 10, 20, and 40%) on the extended-release 
characteristics of HORIZANT Extended-Release Tablets. The in vitro study showed that about 
63% of the total gabapentin dose was released at 1 hour at the highest alcohol level (40%), and 
about 43% of total drug was released at 1 hour with 5% alcohol. Ethanol causes a more rapid 
release of gabapentin enacarbil from the Extended-Release Tablets that may increase the risk for 
AEs associated with HORIZANT Extended-Release Tablets. Based on this data, consumption of 
alcohol is not recommended when taking HORIZANT Extended-Release Tablets. 
Morphine: HORIZANT Extended-Release Tablets taken in conjunction with morphine causes 
increased somnolence/ sedation, dizziness, and nausea when compared with either drug alone. 
This was determined via the administration of a single 600 mg dose of HORIZANT Extended- 
Release Tablets 2 hours after a single 60 mg dose of extended-release morphine sulfate in 18 
subjects and was associated with increased somnolence/sedation, dizziness and nausea for the 
combination compared to HORIZANT Extended-Release Tablets or morphine alone as measured 
by the visual analog scale. No changes in Cmax and AUC of gabapentin, morphine or its active 
metabolite morphine-6-glucuronide were observed. 
4.3.5. 
Contraindicated Medications 
No medications are contraindicated in patients taking HORIZANT Extended-Release Tablets. 
4.3.6. 
Warnings and Precautions for Subjects Taking HORIZANT Extended-Release 
Tablets 
HORIZANT Extended-Release Tablets is not recommended for patients who are required to 
sleep during the daytime and remain awake at night. 
Driving impairment: Patients should be warned not to drive until they have gained sufficient 
experience with HORIZANT Extended-Release Tablets to assess whether it will impair their 
ability to drive. 
Somnolence/sedation and dizziness: HORIZANT Extended-Release Tablets may impair the 
patient’s ability to operate complex machinery.  

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Suicidal thoughts or behaviors: HORIZANT Extended-Release Tablets is a prodrug of 
gabapentin, an antiepileptic drug. Antiepileptic drugs increase the risk of suicidal thoughts or 
behaviors. Subjects will be monitored for suicidal thoughts or behaviors in this study. 
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): This is also known as 
multiorgan hypersensitivity and has been reported in patients taking antiepileptic drugs, 
including gabapentin. HORIZANT Extended-Release Tablets is a prodrug of gabapentin, and 
therefore carries this risk. 
4.3.7. 
Clinical Studies of Gabapentin in Alcohol Use Disorder 
Three randomized double-blind placebo controlled trials have evaluated the effects of gabapentin 
on heavy alcohol drinking in alcohol dependent subjects.  
In the study by Brower et al (2008), 21 subjects with a diagnosis of alcohol dependence and 
insomnia underwent a 1-2 week single-blind placebo lead-in period, a 6-week randomized 
double-blind, parallel group period of gabapentin (1500 mg/day) vs placebo, then were followed 
by a 6-week post trial follow-up visit. The primary drinking outcome variable was survival in 
days to first episode of heavy drinking. Heavy drinking was defined as more than 4 standard 
drinks in a day for women and more than 5 standard drinks in a day for men, or presenting to any 
study visit with a blood alcohol level > .08% as measured by breathalyzer. Altogether, among the 
gabapentin group, 3 (30.0%) of 10 were categorized as having relapsed to heavy drinking during 
the 6-week trial vs 9 (81.8%) of 11 in the placebo group (Fisher’s exact test, p = 0.03). A 
survival analysis of time to heavy drinking by treatment group revealed a statistically significant 
difference (log rank p= 0.03) favoring the gabapentin group. Insomnia improved in both 
treatment groups during the medication phase, but gabapentin had no differential effects on sleep 
as measured by either subjective report or polysomnography. 
Furieri and Nakamura-Palacios (2007) conducted a double-blind, placebo-controlled trial of 
gabapentin in 60 alcohol dependent Brazilian males who received 7 days of diazepam for acute 
withdrawal then were randomized to gabapentin (600 mg/day) or placebo for 28 days. The 
gabapentin group showed a significant reduction in both number of drinks per day and mean 
percentage of heavy drinking days (p = 0.02 for both), and an increase in the percentage of days 
of abstinence (p = 0.008), compared to the placebo group. Additionally, some improvement in 
obsessive-compulsive symptoms was noted in both groups after the treatment, but it resulted in a 
more pronounced decrease in automaticity of drinking and aspects of craving in the gabapentin 
group than in the placebo group. 
Mason et al (2014) conducted a 12-week, double-blind, placebo-controlled randomized trial of 
gabapentin (900 mg or 1800 mg/day) in 150 alcohol dependent patients who had to be abstinent 
for 3 days prior to randomization. The co-primary endpoints were rates of complete abstinence 
and no heavy drinking days over the 12-week period. A heavy drinking day was defined as 4 or 
more drinks per day for women and 5 or more drinks per day for men. Gabapentin significantly 
improved rates of abstinence and no heavy drinking in a dose dependent manner. The rate of 
sustained abstinence was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 
5.2%-22.2%) in the 900 mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800 mg group. The 
no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% 
CI, 19.1%-42.8%) in the 900 mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800 mg 
group. Gabapentin also had a significant linear dose effect on reduction in log-transformed 

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gamma-glutamyl transferase (GGT) values (p = 0.02). Beneficial effects included alleviation of 
relapse-related symptoms including insomnia [Pittsburg Sleep Quality Index total score: 
gabapentin 1800 mg vs placebo: -1.5 (95% CI, -2.1 to -0.8); p < .001), dysphoria [Beck 
Depression Inventory – II (BDI-II)], gabapentin 1800 mg vs placebo: -1.1 (95% CI, -2.0 to -0.3); 
p = 0.01), and alcohol craving (ACQ-SR-R: gabapentin1800 mg vs placebo: -6.8 (95% CI,-1.5 to 
-12.1); p = 0.01]. Subjects reported experiencing sleep disturbance and related daytime 
dysfunction that significantly improved with gabapentin relative to placebo. No evidence of drug 
substitution or misuse of gabapentin was detected.  
4.3.8. 
Safety of HORIZANT Extended-Release Tablets in Clinical Studies of Restless 
Legs Syndrome 
The safety of HORIZANT Extended-Release Tablets in doses ranging from 600 to 2,400 mg has 
been evaluated in 515 patients with restless leg syndrome in 3 double-blind, placebo-controlled, 
12-week clinical trials. The 600-mg dose was studied in 2 of the 3 studies. Eleven out of 163 
(7%) patients treated with 600 mg of HORIZANT Extended-Release Tablets discontinued 
treatment due to adverse reactions compared with 10 of the 245 (4%) patients who received 
placebo. The most commonly observed adverse reactions (≥5% and at least 2 times the rate of 
placebo) in these trials for the 600-mg BID dose of HORIZANT Extended-Release Tablets were 
somnolence/sedation (27%) and dizziness (22%). 
4.3.9. 
Safety of HORIZANT Extended-Release Tablets in Clinical Studies of 
Postherpetic Neuralgia  
The safety of HORIZANT Extended-Release Tablets in doses ranging from 1,200 to 3,600 mg 
has been evaluated in 417 patients with postherpetic neuralgia in 3 clinical studies. The principal 
study evaluating the efficacy and safety of HORIZANT Extended-Release Tablets in the 
management of postherpetic neuralgia was a 12-week, double-blind, multicenter study 
comparing 1,200 mg/day, 2,400 mg/day and 3,600 mg/day to placebo. Six out of 107 (6%) 
patients treated with 1,200 mg of HORIZANT Extended-Release Tablets discontinued treatment 
due to AEs compared with 12 of the 95 (13%) patients who received placebo. 
During the 12-week, controlled study in patients with postherpetic neuralgia, somnolence was 
reported in 10% of patients treated with 1,200 mg of HORIZANT Extended-Release Tablets per 
day compared with 8% of patients receiving placebo. Fatigue/asthenia was reported in 6% of 
patients treated with 1,200 mg of HORIZANT Extended-Release Tablets per day compared with 
1% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT 
Extended-Release Tablets per day who reported somnolence (10%), the somnolence persisted 
during treatment in about 27%. In the remaining patients, symptoms resolved within 4 to 5 
weeks. Dizziness was reported in 17% of patients receiving 1,200 mg of HORIZANT Extended-
Release Tablets per day compared with 15% of patients receiving placebo. In those patients 
treated with 1,200 mg of HORIZANT Extended-Release Tablets per day who reported dizziness, 
symptoms persisted during treatment in about 6%.  
Somnolence led to withdrawal in <1% of patients receiving 1,200 mg of HORIZANT Extended-
Release Tablets per day compared with 2% of patients receiving placebo. Dizziness led to 
withdrawal in 2% of patients receiving 1,200 mg of HORIZANT Extended-Release Tablets per 
day compared with 3% of patients receiving placebo. 

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4.3.10. 
Subjects with Renal Impairment 
Gabapentin is known to be almost exclusively excreted by the kidney, and the risk of adverse 
reactions to this drug may be greater in patients with impaired renal function. Subjects with 
abnormal creatinine clearance will be excluded for this study, and creatinine will be monitored 
monthly during treatment. 
4.3.11. 
Risk of Suicidal Thoughts or Behaviors in Patients Taking Antiepileptic Drugs 
HORIZANT Extended-Release Tablets is a prodrug of gabapentin, an antiepileptic drug (AED). 
AEDs increase the risk of suicidal thoughts or behaviors in patients taking these drugs for any 
indication. Because HORIZANT Extended-Release Tablets is a prodrug of gabapentin, 
HORIZANT Extended-Release Tablets also increases this risk. 
Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) 
of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately 
twice the risk (adjusted relative risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior 
compared with patients randomized to placebo. In these trials, which had a median treatment 
duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 
AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, 
representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 
patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-
treated patients, but the number is too small to allow any conclusion about drug effects on 
suicide. 
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week 
after starting drug treatment with AEDs and persisted for the duration of treatment assessed. 
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal 
thoughts or behavior beyond 24 weeks could not be assessed. 
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data 
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a 
range of indications suggests that the risk applies to all AEDs used for any indication. The risk 
did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.  
4.3.12. 
Drug Reaction with Eosinophilia and Systemic Symptoms 
DRESS, also known as multiorgan hypersensitivity, has been reported in patients taking 
antiepileptic drugs, including gabapentin. HORIZANT Extended-Release Tablets is a prodrug of 
gabapentin, and therefore carries this risk. Some of these events have been fatal or life-
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or 
lymphadenopathy, in association with other organ system involvement, such as hepatitis, 
nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute 
viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, 
other organ systems not noted here may be involved. 
It is important to note that early manifestations of hypersensitivity, such as fever or 
lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are 
present, the patient should be evaluated immediately. HORIZANT Extended-Release Tablets 
should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 

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4.3.13. 
Overdose Information 
The highest single dose of HORIZANT Extended-Release Tablets administered to date is 6,000 
mg in healthy subjects. At this supratherapeutic dose there were no SAEs. The incidence of 
central nervous system adverse reactions, particularly dizziness and somnolence/ sedation, is 
increased with doses greater than 600 mg daily. 
In the event of an overdose, the patient should be treated supportively with appropriate 
monitoring as necessary. Gabapentin derived from HORIZANT Extended-Release Tablets can 
be removed from plasma by hemodialysis. The mean percentage of gabapentin recovered 
following hemodialysis in patients with end-stage renal disease was 29% (expressed as a 
proportion of the gabapentin released from HORIZANT Extended-Release Tablets). Further 
management should be as clinically indicated or as recommended by a poison control center. 
4.3.14. 
HORIZANT Extended-Release Tablets in Pregnant Women 
HORIZANT Extended-Release Tablets is considered a Pregnancy Category C drug and should 
only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. 
There are no adequate and well-controlled studies with HORIZANT Extended-Release Tablets 
in pregnant women. In nonclinical studies in rat and rabbits, administration of HORIZANT 
Extended-Release Tablets was developmentally toxic when administered to pregnant animals at 
doses and gabapentin exposures greater than those used clinically. 
4.3.15. 
Summary of Safety in Restless Legs Syndrome and Postherpetic Neuralgia 
In all controlled and uncontrolled trials across various patient populations with Restless Legs 
Syndrome or postherpetic neuralgia, more than 2,300 patients have received HORIZANT 
Extended-Release Tablets orally in daily doses ranging from 600 to 3,600 mg. The most 
commonly observed adverse reactions in 12-week studies of patients with Restless Legs 
Syndrome (≥2% of patients and numerically greater than placebo) in trials for the 1200-mg total 
daily dose of HORIZANT Extended-Release Tablets were somnolence/sedation (27% vs 6% for 
placebo), dizziness (22% vs 4% for placebo), and headache (15% vs 11%). Adverse reactions 
reported in these studies in <2% of patients treated with 600 mg of HORIZANT Extended-
Release Tablets and numerically greater than placebo were balance disorder, blurred vision, 
disorientation, feeling drunk, lethargy, and vertigo. Eleven out of 163 (7%) patients treated with 
600 mg of HORIZANT Extended-Release Tablets discontinued treatment due to adverse 
reactions compared with 10 of the 245 (4%) patients who received placebo. 
In studies of HORIZANT Extended-Release Tablets for the treatment of postherpetic neuralgia 
(600 mg BID), 6 out of 107 (6%) patients treated with HORIZANT Extended-Release Tablets 
discontinued treatment due to AEs compared with 12 of the 95 (13%) patients who received 
placebo. The most commonly observed adverse reactions (≥2% and numerically greater than 
placebo) in this trial for the 1,200 mg dose of HORIZANT Extended-Release Tablets compared 
with placebo were dizziness (17% vs 15%), somnolence (10% vs 8%), and headache (10% vs 
9%). The following adverse reactions were also reported as ≥2% at 2,400 mg/day and/or 3,600 
mg/day and appeared to be dose-related but were <2% at 1,200 mg/day: balance disorder, 
confusional state, depression, dry mouth, flatulence, increased appetite, irritability, and vertigo. 
Dizziness, somnolence, fatigue, and insomnia appeared to show a dose relationship. 

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In the randomized controlled trial of 150 alcohol dependent subjects receiving 900 mg (54 
subjects) or 1800 mg of gabapentin per day (47 subjects) or placebo (49 subjects), gabapentin 
was well tolerated, with no deaths and no drug-related SAEs (Mason et al-2014). Nine 
participants discontinued the study due to AEs. Of these, 5 were rated as drug related by blinded 
study physicians: 2 complaints of headache (900 mg), 2 complaints of fatigue (1 in the 900-mg 
group and 1 in the 1800-mg group), and 1 complaint of euphoria and feeling “on speed” (placebo 
group). No differences were found among groups in type of AEs with10% or more of the sample 
complaining of fatigue (23%), insomnia (18%), and headache (14%). Groups also were similar in 
the number and severity of AEs reported.  
At a dose of 6,000 mg, HORIZANT Extended-Release Tablets does not prolong QTc to a 
clinically relevant extent. 
4.3.16. 
Rationale for Selection of Doses for this Study 
The recommended dose of HORIZANT Extended-Release Tablets in the product label is 600 mg 
once daily for the treatment of moderate-to-severe primary Restless Legs Syndrome in adults and 
600 mg BID for the management of postherpetic neuralgia in adults. In contrast, the 
recommended dose of Neurontin (immediate release gabapentin) for the treatment of 
postherpetic neuralgia is 1800 mg per day given as 3 daily divided doses of 600 mg (Neurontin 
Product Insert). Based on the product prescribing information, the proportion of postherpetic 
neuralgia patients responding at the recommended doses of HORIZANT Extended-Release 
Tablets and Neurontin were similar. Higher doses of Neurontin or HORIZANT Extended-
Release Tablets were not more effective in treating postherpetic neuralgia, suggesting that both 
recommended dose regimens achieved essentially equivalent maximum levels of efficacy. The 
systemic exposure to gabapentin at the recommended HORIZANT dose in postherpetic neuralgia 
is approximately 20 to 30% lower than that from the recommended dose of Neurontin. However, 
HORIZANT Extended-Release Tablets achieves a similar level of efficacy to Neurontin despite 
this lower systemic exposure, presumably as a result of its more sustained plasma profile. 
In the Phase 2 randomized controlled trial in alcohol dependent patients reported by Mason et al 
(2014), two doses of the immediate release form of gabapentin were studied (900 mg per day and 
1800 mg per day). There was a dose dependent efficacy response with 1800 mg per day favoring 
the higher response. Therefore, based on the optimal dose of 1800 mg of immediate release 
gabapentin in the treatment of alcohol dependence and the fact that 600 mg BID HORIZANT 
Extended-Release Tablets produces equivalent efficacy to 1800 mg gabapentin in postherpetic 
neuralgia, a dose of 600 mg BID of HORIZANT Extended-Release Tablets was selected for 
evaluation in this study. 
4.4. 
Discussion of the Study Design 
The primary efficacy endpoint for this study is PSNHDD during the last 4 weeks of the 
maintenance period. We propose a grace period of 5 months and a responder analysis during the 
last 4 weeks (month 6) because of the highly variable baseline amounts and unstable drinking 
patterns observed during alcohol trials during the initial months of the treatment period. Several 
studies have indicated that drinking patterns over the first 3 months are not stable or 
representative of future experience when reported at 6 months. For example, in the Project 
MATCH study, Zweben and Cisler (2003) reported that 47% of the subjects experienced 

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abstinence or moderate drinking without problems at the three month follow-up interval, but 
decreased to 38% at the six month follow-up and 29% at the one year follow-up interval, 
indicating that subjects were returning to heavy drinking and alcohol-related problems over time.  
Recently, using patients with alcohol use disorders from Kaiser Permanente, Kline-Simon et al 
(2013; 2014) reported that compared with heavy drinkers, abstinent or low-risk drinkers at 6  
months post-treatment (looking back at the 1 month period before the 6 month follow-up) were 
more likely to be abstinent or low-risk drinkers at 12 months post-treatment. Moreover, 
compared to heavy drinkers, abstinent and low-risk drinkers at 6 months were similarly 
associated with lower 12-month psychiatric severity and family/social problem severity. 
Furthermore, abstainers and low-risk drinkers had lower inpatient (hospitalization) treatment 
utilization over the next 5 years compared to that of heavy drinkers. Heavy drinkers had 
increased emergency department and inpatient costs during this period. Based on this data, we 
chose a 5-month grace period with the primary analysis being conducted during Month 6 of the 
treatment period as a clinically meaningful primary outcome. Treatment effects during earlier 
months will be explored. 
In the analysis by Kline-Simon and Weisner (2014), three month post-treatment was compared to 
6 month post-treatment in predicting consequences at 12 months (see Table 3 and Table 4). 
Compared with the heavy drinkers, the abstinent and low-risk drinkers at 6 months post-
treatment had improved social/family and employment consequences at 12 months post-
treatment, whereas in the 3 month post-treatment group, the psychosocial outcomes did not differ 
among the abstinent, low-risk, and heavy drinking groups at 12 month post-treatment. 
The drinking pattern appears to be more stable at 6 months than 3 months, thus more 
representative of the patient’s drinking pattern going forward in time. The responder analysis 
was selected for month 6 because of this stable period in the 4 weeks prior to Month 6. Months 4 
and 5 were not selected because the available data supported the last 4 weeks of the treatment 
period.  
Table 3: 
Normative Status on ASI Severity Scores at Twelve-Months by Three-Month 
Drinking Status 
  
  
Abstinence 
(n=294) 
Low-risk 
Drinking 
(n=47) 
Heavy Drinking 
(n=53) 
p-Value 
Alcohol (%) 
ASIa  ≤  Norm 
76.2 
42.6 
28.3 
<0.0001 
Medical (%) 
ASI  ≤  Norm 
61.2 
59.6 
58.5 
nsb 
Psychiatric (%) 
ASI  ≤  Norm 
45.9 
44.7 
34.0 
ns 
Social/Family (%) 
ASI  ≤  Median 
66.3 
59.6 
50.9 
ns 
Employment (%) 
ASI  ≤  Median 
59.5 
48.9 
43.4 
ns 
a ASI=addition severity index. 
b ns = not significant. 

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Table 4: 
ASI Severity Scores at Twelve Months by Six-Month Drinking Status 
 
  
Abstinence 
(N=660) 
  Low-risk drinking 
(N=137) 
Heavy drinking 
(N=198) 
p-value 
Alcohol (%) 
ASIa   ≤   Norm 
          80.3 
             51.8 
           31.3 
<0.0001 
Medical (%) 
ASI   ≤   Norm 
65.2 
73.7 
67.2 
ns 
Psychiatric (%) 
ASI   ≤   Norm 
58.6 
62.0 
53.5 
ns 
Social/family (%) 
ASI   ≤   Median 
68.0 
65.7 
48.5 
0.0003 
Employment (%) 
ASI   ≤   Median 
55.2 
54.0 
41.4 
0.0070 
a Addiction Severity Index (ASI) score values: Alcohol Norm = 0.11; Medical Norm = 0.24; Psychiatric Norm = 
0.03; Social/Family Median = 0; Employment Median = 0.19; (Normed to the general population on ASI scores 
(Weisner et al-2000); Median based on full sample scores). Six month data relies on the 4 week period prior to this 
time point. 
 

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5. 
Study Objectives 
5.1. 
Primary Objective 
The primary objective of this study is to compare the efficacy of HORIZANT Extended-Release 
Tablets 600 mg BID compared with matched placebo on the primary alcohol consumption 
outcome endpoint, PSNHDD during the last 4 weeks of the maintenance phase, among subjects 
with AUD. PSNHDD will also be analyzed during other time periods (i.e., the last 8, 12, 16, 20, 
and 24 weeks of the maintenance period) in exploratory analyses. 
5.2. 
Secondary Objective 
Secondary objectives are separated into two categories: key secondary objectives and supportive 
secondary objectives. The key secondary objective is to compare HORIZANT to placebo on the 
percentage of subjects abstinent from alcohol during the last 4 weeks of treatment. The 
supportive secondary study objectives are to assess other treatment benefits, including: reduction 
in other alcohol consumption endpoints, alcohol-related craving and consequences, mood, 
smoking, sleep quality, safety, and tolerability. 

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6. 
Investigational Plan 
This study is a double-blind, randomized, placebo-controlled, parallel group, multi-site study 
designed to assess the efficacy of HORIZANT Extended-Release Tablets compared with placebo 
to reduce drinking in 346 subjects (173 in each group) who report 4 or more Diagnostic and 
Statistical Manual of Mental Disorders – Fifth Edition (DSM-5™) symptoms of AUD and who 
meet the drinking criteria outlined hereafter. This study will be conducted at 10 clinical sites. If 
eligible for the study, subjects will be randomized using a stratified permuted block 
randomization procedure with “clinical site” as the stratification variable in an approximate 1:1 
ratio (targeting 173 subjects per group) to receive either HORIZANT Extended-Release Tablets 
or placebo for 26 weeks (1 week escalation; 24 weeks maintenance; 1 week taper). 
Subjects will be seen in the clinic at screening, at randomization and 11 other times during the 
study. During the Week 1 dose escalation period (midway through the week) and during the 
maintenance period (Weeks 2 to 25), subjects will be contacted once per week by telephone at 
non-clinic visit weeks to encourage study drug compliance and to assess withdrawal, AEs, and 
concomitant medications. A final follow-up telephone interview will occur during Weeks 28 to 
29 (1 to 2 weeks after the end of dosing). 
An overview of the study design is provided in Figure 2. Study assessments and procedures will 
be performed at the visits and time points outlined in the Schedule of Assessments (Table 5). 
 
Figure 2:  
Overview of Study Design 
 
Weeks -2 to -1
Day -1
Week 1
Weeks 2 to 25
Week 26
Week 28-29
Screening
Dose Titration
Maintenance
Dose Taper
Follow-up Telephone Call
Randomization
Gabapentin Enacarbil
N=173
Placebo
N=173
Week 27
End of Study (EOS) Assessments
11 In-clinic visits &
17 Telephone contacts

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Table 5: 
Schedule of Assessments  
 
Screen 
Ti-
trate 
Maintenance 
Taper 
 
Safety 
Follow-
up 
Clinic Visit # 
0 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
12 
 
Study Week 
-2 to -1 
Day 
-1 
1 
2 
Mid 
week 2 
& 3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 -
15 
16 
17-
19 
20 
21-
23 
24 
25 
26 
EOSa
/27 
28-
29 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breathalyzer 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Urine Drug Screenb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Locator Form  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MINI V 7.0 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
 
 
Clinical Chemistryd 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital Signse 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Prior and Concomitant 
Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CIWA-AR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Eligibility Checklist 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA 
Genomics Testingf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for RNA 
Expression Testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Blood for PK/Medication 
Complianceg 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Blood spot for PEth 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Drug compliance/ 
accountability 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Pregnancy Test  + birth 
control 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 

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Screen 
Ti-
trate 
Maintenance 
Taper 
 
Safety 
Follow-
up 
Clinic Visit # 
0 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
12 
 
Study Week 
-2 to -1 
Day 
-1 
1 
2 
Mid 
week 2 
& 3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 -
15 
16 
17-
19 
20 
21-
23 
24 
25 
26 
EOSa
/27 
28-
29 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Drinking Goal 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
14 
 X 
18 
X 
22 
X 
 
X 
X 
 
RANDOMIZATION 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Telephone 
Interviewi 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Take Control 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Treatment Referral 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Follow-Up Telephone 
Interview 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Final Subject Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Subject Reported 
Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family History of 
Alcohol Problems 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ImBIBe 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
TLFB 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Drinking questionj 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
ACQ-SR-R 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Fagerström Test for 
Nicotine Dependence 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking 
quantity/frequency 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
PSQI 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
BAI 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 

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Screen 
Ti-
trate 
Maintenance 
Taper 
 
Safety 
Follow-
up 
Clinic Visit # 
0 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
12 
 
Study Week 
-2 to -1 
Day 
-1 
1 
2 
Mid 
week 2 
& 3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 -
15 
16 
17-
19 
20 
21-
23 
24 
25 
26 
EOSa
/27 
28-
29 
BDI-II 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
POMS 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Other Services Used for 
Alcohol Use Problems 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
a EOS=end of study. These assessments are to be done at Week 27 or if the subject discontinues early and agrees to a final clinic visit. 
b Test for opioids, cocaine, amphetamines, methamphetamine, tetrahydrocannabinol (THC), buprenorphine, methadone or benzodiazepines. 
c Only the AUD module is performed at Week 26. 
d AST, ALT, total bilirubin, creatinine, GGT. 
e Sitting blood pressure and heart rate. 
f Only for subjects who consent to provide this sample. 
g For each subject, blood collections should be scheduled at different times relative to the morning dose at these 3 clinic visits. 
h Only SAEs will be reported from the time of signing informed consent until the first dose of investigational product administration. Thereafter, AEs and SAEs 
will be reported for the duration of the study. 
i AEs, concomitant medications, CIWA-AR, and drug compliance reminder. 
j Only asked to subjects who are no longer participating in clinic visits and not willing to providing TLFB drinking data. 
 

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7. 
Study Interventions 
7.1. 
Investigational Products: HORIZANT Extended-Release Tablets and Placebo 
HORIZANT Extended-Release Tablets, 600 mg, are white to off-white, oval-shaped tablets 
debossed with “GS LFG”. HORIZANT Extended-Release Tablets may contain occasional 
black/grey spots. 
Placebo tablets debossed with “GS LFG” that are identical in appearance to HORIZANT 
Extended-Release Tablets will also be used in this study. 
Both the HORIZANT Extended-Release Tablets and placebo tablets will be provided by 
XenoPort Inc., Santa Clara, CA. 
7.2. 
Investigational Product Packaging, Labeling, and Distribution of Drug Kits to 
Sites 
Investigational products will be provided in drug kits containing 14 bottles of either HORIZANT 
Extended-Release Tablets or placebo in each kit. Each bottle contains 30 tablets and each kit 
contains a total of 420 tablets. Each subject is scheduled to receive a total of 354 tablets, thus 
providing a sufficient supply of tablets for the entire study for a single subject in one kit. Kits 
will be shipped periodically to sites during the study depending on enrollment. 
The study number and a brief protocol title that does not link the subject with an alcohol research 
study will be preprinted on each bottle label. The label will also have a kit number, the number 
of tablets contained in the bottle, storage conditions, and the words “Caution: New Drug – 
Limited by Federal law to investigational use” and “Keep Out of Reach of Children”. A separate 
label will be supplied to affix to the bottle each time a bottle is dispensed. This label will contain 
the clinical site name, clinical site phone number and 24/7 emergency phone number, and places 
to record the subject number and the date dispensed. 
7.3. 
Investigational Product Storage 
Kits should be stored at room temperature (within the range of 59°F to 86°F) in a secured area at 
the clinical site. 
7.4. 
Investigational Product Dispensing 
The dispensing plan is provided in Table 6. At each visit when bottles are dispensed the 
appropriate number of drug diary cards will be given to the subject as well. An example of the 
drug card is provided in Appendix 19.1. As shown in Table 6, an extra bottle (#14) will be 
dispensed at Week 2 to the subject to hold at home until the end of the study in case of shortage 
due to scheduling conflicts or other unanticipated circumstances. Drug accountability and 
compliance will be performed by the clinical site at each clinic visit. The subject will be 
instructed to return all study bottles, including bottle #14 at the last clinic visit. 
The subject will be asked to bring all bottles and the drug cards at each subsequent visit for 
accountability. Bottle #14 will be re-dispensed after performing accountability. The first time 
that investigational products are dispensed, the subject will also be given a copy of the 
Medication Guide for HORIZANT Extended-Release Tablets (Appendix 19.2). 

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Table 6: 
Schedule for Dispensing Study Drug Bottles 
Study 
Visit 
Study 
Week 
Bottle #s 
Dispensed 
# 
Tabletsa 
Anticipated 
Usage 
Anticipated 
Return  
Return for 
Accountability 
1 
Day -1b 
Dispense #1 
30 
12 
18 
 
2 
2 
Dispense #2 & #14 
30 
28 
2 
Bottle #1  
3 
4 
Dispense #3 & #14 
30 
28 
2 
Bottle #2 & #14 
4 
6 
Dispense #4 & #14 
30 
28 
2 
Bottle #3 & #14 
5 
8 
Dispense #5 & #14 
30 
28 
2 
Bottle #4 & #14 
6 
10 
Dispense #6 & #14 
30 
28 
2 
Bottle #5 & #14 
7 
12 
Dispense #7, #8, & #14 
60 
56 
4 
Bottle #6 & #14 
8 
16 
Dispense #9, #10 & #14 
60 
56 
4 
Bottle #7, #8, & #14 
9 
20 
Dispense #11, #12 & #14 
60 
56 
4 
Bottle #9, #10 & #14 
10 
24 
Dispense #13 & #14 
30 
28 
2 
Bottle  #11, #12 & #14 
11 
26 
Dispense #14 
30 
6 
24 
Bottle #13 & #14 
12 
27 
none 
 
 
 
Bottle #14 
Total: 
 
420 
354 
66 
 
a Does not include Bottle #14 tablets until Week 26. 
b Study drug will be dispensed on the day of randomization. Subjects are expected to take the first dose of drug the 
following morning, Week 1, Day 1 of the study. 
7.5. 
Investigational Product Accountability 
The site principal investigator (PI) or designated study personnel will maintain a log of the 
receipt of all investigational products and record of dispensing of all investigational products to 
the subject. Investigational product for each subject will be inventoried and accounted for 
throughout the trial. The site PI or his/her staff will count the tablets remaining at the end of the 
study and record the tablet count on the appropriate drug accountability form. Subject 
compliance with investigational product will be assessed by comparing unused tablet count to 
dispensing logs and dosing records (number of tablets dispensed, number of tablets prescribed, 
versus the number returned). Subjects will also be asked to account for any missing tablets. If the 
bottle is not returned, the subject will be asked to report daily drug self-administration. 
7.6. 
Used/Unused Investigational Product Supplies 
Unused investigational products will be retained at the clinical sites pending instructions for 
return by the Study Coordinating Center to XenoPort.  
7.7. 
Investigational Product Administration 
Dose titration, maintenance and taper will occur as shown in Table 7. The target maintenance 
dose of HORIZANT Extended-Release Tablets is 600 mg BID. Subjects receiving placebo will 
take the same number of tablets as those prescribed for HORIZANT Extended-Release Tablets 
to preserve the study blind. 

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Table 7: 
Schedule of Administration of Investigational Products 
Study 
Period 
Time Period 
AM Dose 
(# of tablets) 
PM Dose 
(# of tablets) 
Titration 
Week 1, Days 1- 3 
600 mg (1) 
 None 
Titration 
Week 1, Days 4-7 
600 mg (1) 
600 mg (1) 
Maintenance 
Weeks 2-25 
600 mg (1) 
600 mg (1) 
Taper 
Week 26 
600 mg (1) 
 None 
Tablets should be swallowed whole and should not be cut, crushed, or chewed. Tablets should be 
taken with food.  
Missed Doses: Subjects will be instructed, if the dose is not taken at the recommended time, to 
skip this dose, and the next dose should be taken at the time of next scheduled dose; doses should 
never be doubled up. Subjects will be instructed to record the dose that was missed. 
Dose Reduction and Discontinuation. If the subject is not tolerating the investigational product 
or has a medical condition requiring dose reduction or discontinuation of the investigational 
product, a reduction to one tablet in the evening is permitted. If discontinuation of the 
investigational product altogether is necessary, then if the subject was taking the investigational 
product twice daily, he/she should taper to one tablet per day for one week before stopping. If the 
subject was already taking just one tablet per day, he/she can simply discontinue unless clinically 
inappropriate to do so. In the event that a female subject becomes pregnant, she will be instructed 
to undergo the same dose reduction of investigational product as is recommended for all subjects 
as sudden discontinuation from 600 mg BID to zero could potentially increase the risk for 
withdrawal seizures.  
7.8. 
Take Control Behavioral Platform 
The behavioral platform “Take Control” will consist of a series of 11 computerized modules. 
Subjects will view a single module of “Take Control” at each clinic visits from Visit 1 to 11. If a 
visit is missed, missed modules will be reviewed at the next visit. The paper versions of the 
modules are not to be given to the subject to take home and must remain at the clinic. The 
intervention is derived from a self-help approach developed by NIAAA that provides evidence-
based, field tested information for individuals with alcohol problems, and suggestions for making 
changes in their drinking. The NIAAA material is publically available in a NIAAA booklet 
entitled “Rethinking Drinking” and on a NIAAA website http://rethinkingdrinking.niaaa.nih.gov. 
Delivering these materials in a computerized method in this trial has the advantage of 
standardizing the amount of educational material received by the subject.  
7.9. 
Concomitant Medications 
Although there are no specific contraindicated medications, due to the somnolence effects of 
HORIZANT Extended-Release Tablets, drugs with sedative properties should be used with 
caution as it is assumed that sedative properties could be additive. While taking study drug, 
subjects may not take HORIZANT Extended-Release Tablets, gabapentin or other 
gabapentinoids.  

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For study inclusion, subjects cannot have taken any anti-convulsants, hypnotics, barbiturates, 
antipsychotics, psychomotor stimulants (such as methylphenidate), or benzodiazepines within 
5-half lives prior to the date of randomization. In addition, if a subject is taking a medication for 
depression or anxiety, he or she must have been taking a stable dose in the 2-months prior to 
randomization and plan to continue during the study. This includes drugs such as the following: 
• selective serotonin reuptake inhibitors (SSRIs)  
• dual uptake inhibitors  
• serotonin-norepinephrine reuptake inhibitors (SNRIs)  
• tricyclic antidepressants  
• monoamine oxidase inhibitors (MAOIs) 
• bupropion 
Pharmaceutical treatments approved for treatment of alcoholism or treatments known to be used 
off-label or experimentally for treatment of alcoholism are prohibited during the study. Besides 
HORIZANT Extended-Release Tablets, gabapentin or other gabapentinoids already not allowed 
during the study, the following drugs approved for the treatment of alcoholism are also 
prohibited: 
• Oral naltrexone (Revia, Depade) 
• Depot naltrexone (Vivitrol) 
• Disulfiram (Antabuse) 
• Acamprosate (Campral) 
• Nalmefene (Selincro) 
In addition, a list of prohibited drugs that are prescribed off-label or experimentally for the 
treatment of alcoholism will be included in the Manual of Procedures and updated during the 
study if new drugs are identified. Also, if a subject reports using a drug or having been 
prescribed a drug to treat alcoholism during the trial, they will be asked to discontinue its use. 
Subjects will be instructed to check with study staff before taking any new medications or 
stopping current medications. Subjects will be informed that starting any new medication 
without consulting study staff could pose health risks and/or result in their discontinuation for the 
study drug. 
Management of investigational products and concomitant medications during the study is at the 
discretion of the PI or designated medical doctor. The PI or designee may consult with the 
medical monitor if there are questions. 

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8. 
Study Procedures 
8.1. 
Recruitment of Subjects 
Subject recruitment methods at each site will be based on their local population; however, 
standard tactics will be used (i.e., flyers, newspaper advertisements, radio advertisements, and 
television advertisements). Local institutional review boards (IRBs) and NIAAA will approve all 
advertising materials used for subject recruitment. Interested candidates responding to 
recruitment materials by telephone will be asked to complete a standardized telephone interview 
that includes questions about their drinking behavior, health status, interest in participation, and 
availability for the entire 31 weeks of the trial. Study staff will ask these questions without 
revealing the entry criteria for the study. Candidates who report drinking and other information 
consistent with the entry criteria and appear to be available and interested in the study will meet 
with the investigator or designated investigational staff ideally within 14 days after the initial 
inquiry to start the informed consent and assessment process. 
8.2. 
Informed Consent 
At the first screening visit, candidates will meet with either the PI or his/her designee and receive 
an explanation of the study purpose and requirements. If still interested after receiving an 
explanation of the study, the candidate will be given an opportunity to review, inquire about, and 
sign the study informed consent form approved by the local site’s IRB. Subjects must have blood 
alcohol content (BAC) of 0.000 measured by breathalyzer when signing the informed consent 
document (tested shortly before or just after providing consent). Repeat measurements of BAC 
are permitted at the discretion of the investigator. Subjects will be given a copy of the signed 
informed consent form. 
8.3. 
Selection and Withdrawal of Subjects 
8.3.1. 
Inclusion Criteria 
Subjects must meet each one of the following inclusion criteria in order to be eligible for 
participation in the study: 
1. Be at least 21 years of age. 
2. Have a current (past 12 months) DSM-5 diagnosis of AUD (4 or more symptoms) 
assessed using the MINI neuropsychiatric interview version 7 (moderate severity, ICD-
10-CM Code F10.20 alcohol dependence, uncomplicated). 
3. If male, report drinking an average of at least 28 drinks per week or if female report 
drinking an average of at least 21 drinks per week for the 28-day period prior to consent 
and for both males and females one heavy drinking day per week over the 28-day period. 
4. Have a BAC by breathalyzer equal to 0.000 when s/he signed the informed consent 
document (either just prior to or immediately after signing consent). 
5. Be abstinent (by self report) in the 3-days prior to the day of randomization and have a 
BAC of 0.000 by alcohol breathalyzer on the day of randomization. 

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6. Be seeking treatment for problems with alcohol. 
7. Be able to verbalize an understanding of the consent form, able to provide written 
informed consent, verbalize willingness to complete study procedures, able to understand 
written and oral instructions in English and able to complete the questionnaires required 
by the protocol. 
8. Agree (if the subject is female and of child bearing potential) to use at least one of the 
following methods of birth control, unless she is surgically sterile, partner is surgically 
sterile  or she is postmenopausal: 
a. oral contraceptives, 
b. contraceptive sponge, 
c. patch, 
d. double barrier (diaphragm/spermicidal or condom/spermicidal), 
e. intrauterine contraceptive system, 
f. etonogestrel implant, 
g. medroxyprogesterone acetate contraceptive injection, 
h. complete abstinence from sexual intercourse, and/or 
i. hormonal vaginal contraceptive ring.  
9. Be able to take oral medication and be willing to adhere to the medication regimen.  
10. Complete all assessments required at screening and baseline.  
11. Have a place to live in the 2 weeks prior to randomization and not be at risk that s/he will 
lose his/her housing by Study Week 28.   
12. Not anticipate any significant problems with transportation arrangements or available 
time to travel to the study site by Study Week 28. 
13. Not have any plans to move within Study Week 28 to a location which would make 
continued participation in the study impractical. 
14. Not have any unresolved legal problems that could jeopardize continuation or completion 
of the study. 
15. Provide contact information of someone, such as a family member, spouse, or significant 
other, who may be able to contact the subject in case of a missed clinic appointment. 
16. Be someone who in the opinion of the investigator would be expected to complete the 
study protocol. 
17. Agree to the schedule of visits, verbally acknowledge that s/he will be able to attend each 
scheduled visit, participate in phone visits and that s/he does not have any already 
scheduled events or a job that may substantially interfere with study participation. 
18. If taking a medication for depression or anxiety, must have been taking a stable dose in 
the 2-months prior to randomization and plan to continue during the study. This includes 
drugs such as the following: 
• SSRIs 
• dual uptake inhibitors  

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• SNRIs 
• tricyclic antidepressants  
• MAOIs 
• bupropion 
8.3.2. 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if any one of the following exclusion 
criteria is met: 
1. Have current substance use disorder for any psychoactive substance (including sedatives 
and hypnotics) other than alcohol and nicotine as defined by DSM-5 criteria. 
2. Have a urine toxicology screen positive during screening or baseline for any of the 
following substances:  
a. benzodiazepines,  
b. cocaine, 
c. opioids,  
d. amphetamines,  
e. buprenorphine, 
f. methadone, and/or 
g. methamphetamines. 
Note: Testing for tetrahydrocannabinol (THC) will be included in the urine drug test; 
however, subjects who test positive for THC are still eligible to participate in the study 
unless they endorse moderate or severe substance use disorder for marijuana as indicated 
by DSM-5 criteria. The results for THC will be recorded for information only. If positive 
for opioids but recent opiate use for acute pain is reported by the subject, then the subject 
can be re-screened. 
3. Have been hospitalized for alcohol intoxication delirium, alcohol withdrawal delirium, 
alcohol-induced persisting dementia or amnestic disorder, or have had an alcohol 
withdrawal seizure, alcohol-induced psychotic disorder with a primary diagnosis of 
alcohol use disorder or a history of any seizure disorder. 
4. Have participated (received treatment) in any behavioral and/or pharmacological 
intervention research study for the treatment of alcohol problems in the past 7 years. 
5. Be mandated by the court to obtain treatment for problems with alcohol. 
6. Be anyone who in the opinion of the investigator could not be safely withdrawn from 
alcohol without medical detoxification. 
7. Be currently undergoing psychotherapy by a licensed therapist or psychiatrist for alcohol 
problems  
NOTE: Current psychotherapy should be considered on a case-by-case basis. Psychotherapy 
for a disorder that may be related to the subject’s use of alcohol should be exclusionary. 
However, shorter term focused behavioral therapy for defined problems for non-alcohol 
related problems may be acceptable. 

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8. Have undergone medical detoxification (e.g., reports using a benzodiazepine) during the 
screening phase (prior to randomization). 
9. Have been treated with a pharmacotherapy for alcohol problems within 6 months prior to 
randomization. 
10. Have taken any anti-convulsants, hypnotics, barbiturates, antipsychotics, psychomotor 
stimulants (such as methylphenidate), or benzodiazepines within 5-half lives days prior to 
the date of randomization. 
11. Have any of the following, based on DSM-5 criteria as assessed using the MINI: 
a. Current or lifetime diagnosis of psychotic disorders 
b. Current bipolar disorder, 
c. Current major depressive episode, or 
d. Current (past 3 months) eating disorder (anorexia or bulimia). 
Note: Subjects diagnosed with psychiatric disorders not specifically excluded above may 
be included at the discretion of the PI as long as the concurrent treatment for the 
comorbid psychiatric condition does not compromise the study integrity by virtue of its 
type, duration, or intensity. 
12. Have any of the following: 
a. attempted suicide past year,  
b. current (past year) suicide behavior disorder in accordance with DSM-5 criteria as 
assessed using the MINI (see note below about assessment of subjects diagnosed at 
low risk), or 
c. current (since screening MINI) suicidality risk as indicated during the conduct of the 
C-SSRS with concurrence after a study physician’s evaluation if the response to 
C-SSRS questions 1 or 2 is “yes”). 
Note: The MINI suicidality module rates scores of 1 to 8 as a diagnosis of low risk of 
suicidality. As the MINI questions that could result in a low risk score are considered 
inadequate to fully determine the potential suicidal risk of an individual (e.g., “Feel 
hopeless” and “Think that you would be better off dead or wish you were dead?” 
responses of “yes” dictates a score of 1 for each question), any subject who scores in the 
low risk category should be evaluated further by a study physician who should document 
whether the subject is appropriate for study inclusion based on his/her clinical judgment 
of the potential suicide risk of the subject. Likewise, if the subject responds “yes” to 
either the first two questions on the screening C-SSRS performed on the day of 
randomization as a final eligibility check, the subject should also evaluated by a study 
physician for current suicidality risk, who should document the subject’s suitability for 
study inclusion. 
13. Have moderate or serious dementia as assessed by clinical exam. 
14. Be pregnant or breast-feeding or have plans to become pregnant at any time during the 
study. 

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15. Have clinically significant abnormal laboratory values, including elevation of liver 
enzymes (AST, ALT) 5-fold above the upper limit of normal (ULN), or bilirubin greater 
than 2 times the ULN. 
Note: If the subject has values of liver enzyme that are 3.0-to-4.9 fold above the ULN and 
bilirubin that is 1.5-to-1.9 fold above the ULN of normal, these assessments should be 
repeated at least a week apart and if still in this range or higher, the subject should be 
excluded from the study and referred to their physician for further follow-up.  
16. Have abnormal calculated creatinine clearance (<60 mL/min), as calculated by Cockcroft 
and Gault formula (section 11.8). 
17. Have a serious or unstable medical illness or any potentially life-threatening or 
progressive medical condition other than addiction that may compromise subject safety 
or study conduct. 
18. Have data suggesting cirrhosis of the liver. 
19. Have taken HORIZANT Extended-Release Tablets, gabapentin or other gabapentinoids 
during the 6 month period prior to randomization for treatment of any disorder or if ever 
treated with these drugs for AUD.  
8.4. 
Eligibility Screening 
After the subject signs informed consent, screening may begin. During the first screening visit 
(additional visits are permitted if needed), subjects will undergo the following assessments: 
• Demographics and locator form 
• Urine drug screen 
• Medical history 
• Physical examination (weight may be recorded at this visit or the randomization visit) 
• MINI Version 7.0 
• Clinical chemistry 
• Pregnancy test for females of child bearing potential and birth control methods, if 
female 
• Vital signs 
• ECG 
• TLFB for the previous 28 days 
• Prior medication use 
• CIWA-AR 
Eligible subjects will be instructed that they must be abstinent (no alcoholic beverage 
consumption) for 3 days prior to the date of randomization. Subjects will be instructed that if 
they are taking a medication for depression or anxiety that they should continue to do so 
throughout the study. They will also be instructed not to take HORIZANT Extended-Release 

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Tablets, gabapentin or other gabapentinoids from the start of the study or during the study and 
that they should report any new medications they are taking at each visit or telephone contract.  
The above assessments can be performed in any order except that it is recommended to perform 
physical examinations including vital signs prior to blood draws. If any of these assessments 
reveal that the subject is not eligible for the study, screening can be immediately terminated. 
Clinical chemistry tests may be repeated at the discretion of the investigator if the first 
assessment yields values outside normal laboratory limits. The eligibility checklist will be 
reviewed, and if the subject is still eligible after the assessments are completed at the first 
screening visit (or additional screening visits), the subject will be scheduled for the final 
eligibility baseline visit. It is recommended that hypertensive subjects be referred to their 
primary care physician for additional assessment and possible treatment, and then be further 
evaluated for study inclusion.  
8.5. 
Baseline and Final Eligibility Assessments 
If the subject is eligible after performing all the initial screening assessments, s/he will be 
scheduled to start the study and will come to the clinic for a final eligibility check including the 
following assessments: 
• Alcohol breathalyzer (must have a reading of 0.0 to support abstinence) 
• Urine drug screen 
• Update medical history 
• Update physical exam – new symptoms directed exam 
• Vital signs 
• Weight (if not recorded at the initial screening visit) 
• CIWA-AR 
• C-SSRS* 
• Pregnancy test for females of child bearing potential (must be completed within 2 
days of the subject being randomized and dispensed investigational product) 
• Birth control methods, if female 
• Prior medications update 
• TLFB (must report 3 days of abstinence prior to randomization) 
*Note that the MINI will be used to rule out subjects who attempted suicide in the past year and 
current (past year) suicidal ideation at initial screening, with the C-SSRS providing an update on 
current suicidal ideation since screening. 
An eligibility checklist will be completed and reviewed by a study investigator and, if the subject 
is still eligible, he/she will complete the following baseline assessments: 
• Blood for DNA genomics and RNA expression testing 
• Blood spot collection for phosphatidylethanol (PEth) level determination 

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The subject will complete the following questionnaires electronically:  
• ACQ-SR-R 
• Drinking Goal  
• Modified Fagerström Test for Nicotine Dependence 
• Smoking Quantity Frequency Questionnaire 
• PSQI 
• BAI 
• BDI-II 
• ImBIBe 
• Family History of Alcohol Problems 
• Barratt Impulsiveness Scale (BIS) 
• POMS 
• Other Services for Alcohol Use Problems 
If the subject reported drinking in the three days prior to randomization, they can be rescheduled 
for another randomization visit if they agree to try to stop drinking for the required period of 3 
consecutive days prior to randomization. The screening period will not be extended. If the 
investigator determines that the subject could be a viable participant who could not for 
extenuating circumstances complete the screening period in 14-days, the subject can be re-
screened by completing all of the screening assessments again. In this case, the subject will be 
assigned a new subject number. 
8.6. 
Measures Taken to Minimize/Avoid Bias 
8.6.1. 
Randomization (Day -1) 
If eligible for the study, subjects will be randomized in an approximate 1:1 ratio to receive either 
HORIZANT Extended-Release Tablets or placebo using a stratified permuted block 
randomization procedure with “clinical site” as the stratification variable. Clinical site was 
chosen because both local study populations, and the investigative staff influence on the 
subject’s drinking behaviors may differentially influence endpoints.  
Centralized randomization will be performed using an interactive web response system (IWRS). 
The IWRS is available for randomization of subjects 24 hours/day, 7 days/week from any 
computer using a web browser. 
If the subject is determined to be eligible, site personnel who are authorized to randomize 
subjects and who have completed training for the IWRS, will log onto the system and provide 
the pre-assigned unique subject number and the subject’s date of birth. The IWRS provides the 
randomized group kit number and assigns the subject to one of the two interventions. If the 
subject is randomized and is never dispensed study drug, then the subject will be considered a 
randomization failure and an additional subject will be randomized with the next randomization 
sequence at the time he/she is randomized at that site. Likewise, if the subject was randomized 

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and then is determined to not be eligible for the study, and never received study drug, then 
another subject will be randomized such that the total numbers of subjects who were eligible, 
randomized, and dispensed study drug meet the enrollment goals. In the case of a subject who 
was eligible, randomized, and dispensed study drug but did not return for follow-up visits, this 
subject will not be replaced. Any subject who received study drug but was later determined to be 
ineligible will likewise not be replaced. The reason(s) that a subject was considered a 
randomization failure or screen failure will be documented in source documents and eCRFs. 
8.6.2. 
Blinding 
HORIZANT Extended-Release Tablets and placebo tablets will be identically matched in 
appearance and the bottle labels will not reveal the drug identity. The site investigator or 
designated approved study physician will make the decision to un-blind the identity of the 
investigational product in the event that the study blind needs to be broken to make medical 
decisions regarding subject treatment. If it is determined that unblinding is necessary to assess 
AEs or SAEs for expedited reporting, NIAAA may decide to request unblinding of a subject. 
Site staff or Sponsor’s designee approved to un-blind the study drug will log into the IWRS to 
obtain the name of the investigational product to which the subject was randomized. The IWRS 
will automatically notify the un-blinded staff member at the Data Coordinating Center who will 
notify the Medical Monitor. NIAAA will be notified that an unblinding has occurred if 
unblinding has been performed by the investigator or medical monitor. 
8.7. 
Interventions on Day -1 and Day 1 
At study Day -1, after the subject is randomized, he/she will receive the first bottle of study drug 
and the instructional drug card to take home (Appendix 19.1). Site staff will explain the dosing 
plan to the subject (one tablet in the morning for the first 3 days, then one tablet in the morning 
and one in the evening for the next 4 days) and how to complete the drug card to track when 
tablets are taken. The subject will be instructed to take the first dose in the morning of Day 1 
(expected to occur the day after the date of randomization). Subjects will be instructed to take 
tablets with meals and will be advised to avoid driving and operating heavy machinery, until they 
are aware of how the study drug affects them. The subject will watch the first module of Take 
Control (Day -1), will be given the schedule of visits, and the Week 2 visit will be scheduled.  
Every study subject will be provided with a wallet card and instructed to carry this card that 
identifies the potential investigational products that s/he could be taking during the study. The 
card will provide the name and 24-hour phone number of the investigator (physician) at the site 
who can be contacted in the event of an emergency. The card will also instruct the non-study 
physician rendering emergency care to contact the study physician and inform him/her about the 
care. 
If possible, clinic visits should be scheduled on the same day of the week that the subject 
received the first dose of study drug, but a 3-day window is allowed for conducting visits within 
the scheduled study week. Visits may be scheduled and conducted on any day of the week. Visits 
can be conducted outside of the scheduled study week, but only based upon subject request (e.g., 
for reasons related to patient non-compliance with the study schedule). Each subject will receive 
a visit schedule to take home for future reference. 

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8.8. 
Weeks 1 and 2 Safety Telephone Contact 
Midway through Weeks 1 and 2 subjects will be called for a safety assessment. The call during 
Week 1 should ideally be the day before the subject escalates their dose to 2 pills per day. 
Assessments will be the same as all other telephone contacts (see section 8.10). 
8.9. 
Maintenance Phase 
During Study Weeks 2 through 25 of the maintenance phase of the study, subjects will be seen in 
person at the clinical site 9 times and assessed by telephone 16 times. Week 26 is dose taper and 
there is a final clinic visit at Week 27 at the end of dose taper.  
An alcohol breathalyzer will be administered at each visit, prior to any study assessments, to 
determine if the subject meets the BAC requirement of a BAC ≤ 0.020 before proceeding with 
assessments. A urine drug test will be performed at each visit. At each of the clinic visits, 
subjects will meet with one or more study staff members who will systematically assess AEs 
since the last visit, take vital signs, administer questionnaires (CIWA-AR and C-SSRS), inquire 
about other medication use and assess drinking by TLFB. Clinical chemistry, pregnancy test for 
women of child-bearing potential and birth control methods (if female), blood for study drug 
compliance, and subject’s weights will be collected in accordance with the schedule in Table 5. 
In addition, subjects will complete the battery of questionnaires in accordance with the schedule 
in Table 5. 
Brief telephone assessments will occur weekly between in-clinic visits. The final in-clinic 
assessment will occur during Week 27. This visit should be scheduled after the subject takes the 
last dose of study drug.  
Subjects will view a single module of Take Control that is expected to have a run-time of 10-15 
minutes during each clinic visit. After completion of the Take Control module, a new supply of 
investigational product will be given and the bottle(s) from the previous period will be collected 
and a tablet count will be performed for accountability. Bottles with unused tablets will be 
returned to the subject. The dosing schedule will be reviewed and the subject will be provided 
instructions on how to complete the drug card to track tablet consumption. The subject will be 
instructed to bring the bottle(s) and drug cards with them to the next visit so the site staff can 
perform drug accountability (tablet counts). The subject will also be instructed to contact site 
staff if they are experiencing any intolerable AEs and are contemplating drug discontinuation. 
Additional in-clinic visits are permitted under the protocol, if needed, due to the following 
circumstances: (1) the subject has concerns either about the medication or their drinking and 
wishes to be seen at a time other than their next scheduled in-clinic visit, or, (2) the subject has 
missed a visit and wishes to resume regular participation before their next scheduled visit, (3) the 
subject has reported some change in health, functioning, or circumstances which necessitate a 
visit to conduct safety assessments and evaluate the risk of continued participation in the trial, or 
(4) clinical laboratory measurements need to be repeated.   
Subjects desiring additional counseling or professional therapy for non-crisis psychiatric matters 
(e.g., marital problems, work issues) should be encouraged to postpone such activity until their 
study participation is concluded. Attendance at self-help support groups (i.e., alcoholics 
anonymous) will neither be encouraged or discouraged. Any attendance at self-help support 

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groups will be recorded at the randomization visit and monthly in the Other Services Used for 
Alcohol Use Problems electronic case report form (eCRF). 
8.10. 
Telephone Assessments 
The brief telephone interview (approximately 10 minutes) will occur in accordance with the 
schedule in Table 5 to assess AEs, concomitant medication use and the emergence of withdrawal 
symptoms, to encourage the subject to continue taking investigational products, to verify that the 
subject is taking the prescribed dose, and to remind the subject of the next scheduled visit. A 
summary of the telephone script follows: 
1. AEs: An open-ended question will be asked as follows: “How have you been feeling since 
your last clinic visit or phone contact?” If the subject reports a new AE, the resolution of an 
AE, or a change in the severity of an AE, ask additional questions to determine the severity 
and dates of occurrence or resolution.  
2. CIWA-AR: Subjects will be assessed for the emergence of withdrawal symptoms using the 
CIWA-AR. The subject may be asked about changes in drinking status after responses to the 
CIWA-AR interview indicate significant withdrawal. 
3. Concomitant Medications: Ask the following question: “Have you taken any new 
medications since you were last seen in the clinic or since our last call? If the subject 
responds affirmatively, record the name of the medication, the daily dose, route of 
administration, and reason used. If the medication is contraindicated for the study 
(HORIZANT Extended-Release Tablets, gabapentin or gabapentinoids), then notify a study 
physician, nurse practitioner, or physician assistant for follow-up with the subject. 
4. Drug Compliance: Verification that the subject is taking the prescribed dose and a reminder 
to take investigational product and to return the bottle(s) with untaken tablets at the next visit 
will be made. During the Week 1 call, the subject will be reminded of the drug escalation 
schedule. 
5. Reminders: Remind the subject of their next scheduled clinic visit, and adjust the date within 
the visit week if they have a conflict.  
8.11. 
Final Clinic Visit 
The final clinic visit occurs during Week 27; at which time the subject has completed taking 
investigational product. In addition to the assessments previously stated, subjects will have an 
Exit Interview assessment. The subject will be asked about their drinking for his/her impression 
of whether he/she was receiving active drug or placebo, if they felt that the medication helped 
drinking, how they would describe their experience taking the medication, if they would 
recommend it to a friend, if they would take it again if they needed further treatment in the 
future, and a question about desire to please people. The subject will be provided with a referral 
to a treatment program for their alcohol dependence. If a subject withdraws from the study early 
for any reason, the subject should be asked to return to the clinic for the conduct of all of the 
final clinic visit assessments. 

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8.12. 
Telephone Follow-up  
Subjects will be contacted by telephone for a follow-up interview 1-to-2 weeks after the final in-
clinic visit. During the telephone follow-up interview, the subject will be asked about any 
ongoing AEs that they may have been experiencing at the last clinic visit and any newly emerged 
medical conditions/AEs since that visit. To prompt reporting of new AEs, the subject will also be 
asked about any ongoing or new medication use. 
8.13. 
Duration of Subject Participation 
The total time period that each individual subject will participate is 31 weeks including up to 2 
weeks for screening, 26 weeks of study interventions, and final safety and efficacy follow-up the 
week after completing treatment (Week 27), and a final safety follow-up telephone contact from 
1-to-2 weeks after completion of study drug dosing. 
8.14. 
Dose-adjustment Criteria 
8.14.1. 
Safety Criteria for Dose Adjustment or Stopping Doses 
The PI or sub-investigator will follow the protocol to identify and intervene with subjects 
experiencing clinical deterioration during study participation. Criteria to determine when a 
subject requires a higher level of care and discontinuation from the trial intervention are detailed 
below.  
8.14.1.1. Investigational Product Dose Reduction 
The daily dosage of investigational product may be reduced by the study physician for any AE 
determined, by the study physician, to compromise the subject’s ability to maintain activities of 
daily living or if the subject reports undue discomfort. As the investigational products are taken 
twice per day, only one dose reduction can occur. If dose reduction is warranted, the subject 
should continue to only take the evening dose.  
8.14.1.2. Investigational Product Discontinuation 
Subject who will discontinue investigational products will have the dose reduced to once daily 
for 1 week prior to discontinuation to minimize the potential of withdrawal seizure. Subjects 
should continue in the study, even if withdrawn from investigational products and complete all 
assessments. 
Pregnancy. Females who become pregnant during the course of the study will be instructed to 
reduce the dose to once daily for 1 week prior to discontinuation to minimize the potential of 
withdrawal seizure. If already on once daily dosing, females should immediately discontinue use 
of the investigational product. The investigator must report a pregnancy within 1 working day of 
the site being aware to the NIAAA Study Manager and the Medical Monitor.  
Physical Illness. Subjects will need to be removed from investigational products if they have a 
serious illness or a disabling condition that precludes them from taking the investigational 
product. 
Adverse Events. If the subject experiences any AEs that are considered study drug related and 
for which the investigator has determined that continuation of the study drug could be 

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detrimental to the health of the subject, then drug will be reduced for 1 week, then discontinued, 
or immediately discontinued as described above. 
8.15. 
Subject Withdrawal or Discontinuation Procedures 
Each subject has the right to withdraw consent and withdraw from the study at any time. In 
addition, the investigator may find it necessary to discontinue a subject for any reason, including 
the occurrence of an AE or noncompliance with the protocol.  
In the event that a subject withdraws or is discontinued from the study, the reason(s) for the 
discontinuation from the study will be recorded and a pregnancy test (females only), body 
weight, vital signs measurement, ECG, clinical chemistry, C-SSRS, TLFB and an assessment of 
AEs will be performed as soon as possible after discontinuation from the study. Other 
assessments scheduled for the end of study visit will be collected if possible (Table 5). 
Additional blood samples for study drug measurement may be collected at the time of 
discontinuation from subjects who are discontinued due to AEs. 
8.16. 
Situations Requiring Discontinuation from the Study as well as from 
Investigational Product 
It is possible that there will be some subjects who cannot be safely managed in the clinical study 
even though investigational products have been discontinued. Examples are given below. 
1. Increased Drinking. Subjects whose alcohol problem worsens, and, in the opinion of the site 
medical staff, require a more intense level of care than provided in the study may have 
investigational product suspended, and referred to more appropriate care.  
2. Psychiatric Crises. Examples of psychiatric crises include but are not limited to the 
following: 
a. Acute psychosis (hallucinations, impaired reality testing, paranoid ideation, etc.) 
requiring medication and/or hospitalization or intensive outpatient intervention;  
b. Suicidal or homicidal ideation that results in a credible threat of violence directed at 
oneself or others; 
c. Hospitalization for psychiatric symptoms  
Subjects requiring more intensive treatment resulting from acute psychosis or 
suicidal/homicidal behavior will be referred to local treatment centers, emergency 
departments, or hospitalization as appropriate, but will not be provided with medication or 
psychotherapy by study staff.  
3. Absence from the Protocol due to Confinement in a Controlled Environment. If a 
subject is confined to a controlled environment (such a hospital or jail where access to 
alcohol is presumably restricted) for less than 2 weeks, they can resume full participation in 
the trial if in the judgment of the investigator, the subject is still a good candidate for the 
study and continues to meet eligibility requirements. Before resuming investigational 
products the subject should be assessed by the study physician for appropriateness to resume 
the trial (e.g. any new medications or symptoms, pregnancy test, etc.). The decision to restart 
study drug at the full dose or titrate to the full dose will be made in the judgment of the 
investigator based on the subject’s time off study drug and past experience with side effects 
with the study drug. 

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If a subject is in a controlled environment (such a hospital or jail where access to alcohol is 
presumably restricted) for 2 weeks or more, the subject will be discontinued from the study. 
8.17. 
Study Termination Criteria 
NIAAA may terminate this study prematurely, either in its entirety or at any sites, for reasonable 
cause provided that written notice is submitted in advance of the intended termination. The 
investigator may also terminate the study at his/her site for reasonable cause, after providing 
written notice to NIAAA in advance of the intended termination. Advance notice is not required 
by either party if the study is stopped due to safety concerns. If NIAAA terminates the study for 
safety reasons, NIAAA will immediately notify the investigators by telephone and subsequently 
provide written instructions for study termination. The FDA may stop the study at any time as 
well. If the FDA notifies NIAAA to stop the study, then NIAAA will notify the sites of this 
action. 

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9. 
Study Endpoints 
9.1. 
Efficacy Endpoints 
9.1.1. 
Primary Efficacy Endpoint 
Self-reported daily alcohol consumption will be assessed using the TLFB method from 28 days 
before signing informed consent until the last study visit or contact. The primary efficacy 
endpoint examines the hypothesis that HORIZANT Extended-Release Tablets will increase the 
PSNHDD compared to placebo during the last 4 weeks of maintenance period of treatment 
(Study Weeks 22-25). A “heavy drinking day” is 4 or more drinks per drinking day for women 
and 5 or more drinks per drinking day for men. PSNHDD will also be analyzed during other time 
periods (i.e., the last 8, 12, 16, 20, and 24 weeks of the maintenance period) in exploratory 
analyses. 
9.1.2. 
Secondary Efficacy Endpoints 
Secondary endpoints will be analyzed over the last 4 weeks of the maintenance phase of 
treatment.  
1. Percentage of subjects abstinent from alcohol (key secondary endpoint) 
2. Percentage of subjects with a WHO drinking risk category decrease of: 
a.  1-level  
b.  2-levels  
3. Percentage of days abstinent per week 
4. Percentage of heavy drinking days per week  
5. Weekly mean number of drinks per week 
6. Weekly mean drinks per drinking day 
7. Cigarettes smoked per week among smokers 
8. Alcohol craving score (ACQ-SR-R) 
9. Alcohol related consequences (ImBIBe) score 
10. PSQI score 
11. BAI score 
12. BDI-II score 
9.2. 
Safety Endpoints 
Safety endpoints will be analyzed over the entire treatment and follow-up period. 
1. Vital signs 
2. Blood chemistries 
3. BAC by breathalyzer  

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4. Urine drug tests 
5. AEs 
6. ECG results 
7. CIWA-AR scores 
8. POMS scores 
9. Frequency of subjects with suicidal ideation at any time during the treatment period 
(C-SSRS) 
9.3. 
Compliance 
Compliance will be assessed by self report of compliance with investigational products and 
gabapentin plasma levels. Compliance will be calculated as the percentage of investigational 
products taken as prescribed. 
9.4. 
Pharmacokinetics 
A population PK/PD analysis will be performed using gabapentin plasma levels determined from 
blood samples collected at Weeks 12, 20, and 24 from subjects in the HORIZANT Extended-
Release Tablets group. Blood will be collected from each subject at a different time at each PK 
visit (pre-dose and up to 12 hours post-dose). A total of three samples per subject will be taken 
over 3 sampling visits. Times to target post-dose collections include 8 hours post-dose (expected 
Cmax,ss) and 12 hours post-dose (Cmin,ss). It is preferable not to take samples before 4 hours post-
dose. 

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10. 
Safety Monitoring Plan 
Safety monitoring will be conducted throughout the study; therefore safety concerns will be 
identified by continuous review of the data by the PI, clinic staff, clinical monitor, medical 
monitor, and NIAAA.  
Study Safety Management: The IRB, Medical Monitor, PI, clinical monitors, NIAAA and 
XenoPort (or its affiliates) will review any safety concerns throughout the trial. In addition, a 
data and safety monitoring board (DSMB) will participate in this study. The roles of these 
individuals/committee are described below. 
Medical Monitor: A Medical Monitor and Alternate Medical Monitor have been appointed by 
NIAAA for the study. The Medical Monitor will be available for making recommendations to 
the investigator and NIAAA on the severity of any SAEs, and the relatedness to the study 
interventions. The Medical Monitor will also be responsible for tracking and assessing trends in 
the AEs reported.  
Clinical Monitors: All investigators will allow representatives of the Data Coordinating Center 
(Fast-Track Drugs and Biologics, LLC) staff to periodically monitor, at mutually convenient 
times during and after the study, all study data. These monitoring visits provide the Data 
Coordinating Center, NIAAA, and XenoPort with the opportunity to evaluate the progress of the 
study and to obtain information about potential problems. The monitors will assure that 
submitted data are accurate and in agreement with any paper source documentation used; verify 
that investigational products are properly stored and accounted for, verify that subjects’ consent 
for study participation has been properly obtained and documented, confirm that research 
subjects entered into the study meet inclusion and exclusion criteria, and assure that all essential 
documentation required by Good Clinical Practices (GCP) guidelines are appropriately filed. 
Monitors will conduct a site initiation visit prior to the start of the study. At this visit, they will 
assure that proper study-related documentation exists, assist in training investigators and other 
site personnel in study procedures and GCP guidelines, confirm receipt of study supplies, and 
assure that acceptable facilities are available to conduct the study. 
Routine monitoring visits by the Data Coordinating Center and NIAAA’s representatives will be 
scheduled at appropriate intervals but more frequently at the beginning of the study. A 
monitoring visit soon after the first two subjects have been randomized is planned. At these 
visits, the monitors will verify that study procedures are being conducted according to the 
protocol guidelines, monitor eCRFs against source documents, review AEs and SAEs, and 
perform drug accountability. At the end of the study, they will confirm that the site has the 
appropriate essential documents on file, advise on storage of study records, and inspect the return 
and destruction records for unused investigational products.  
Sponsor and XenoPort Site Visits: All investigators will allow NIAAA and XenoPort full 
access to study records during periodic site visits by NIAAA and XenoPort. Visits by NIAAA 
and XenoPort will be made for a mutually convenient time and will be scheduled in advance. 
DSMB: An independent DSMB of external advisors will meet prior to the start of the study, 
quarterly during enrollment and follow-up and at trial end to review safety data. The Board will 
be blinded to subjects’ actual randomized group assignments but may request at any time that the 

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blind be broken by the data center, if concerns arise from the blinded data. In addition to 
quarterly meetings, the DSMB will meet after half of the subjects (173) have been randomized to 
review safety data and the integrity of the study (i.e., an evaluation of the dropout rate and 
impact on the planned statistical analysis of the data) and make a formal recommendation to the 
sponsor on the continuation or early stopping of the study due to safety concerns. Ad hoc 
meetings will be convened if SAEs occur that are considered at least possibly related to the 
investigational product. 
 

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11. 
Assessment Methods 
All study assessments will be performed at the visits and time points outlined in the Schedule of 
Assessments (Table 5); the following sections outline the details and procedures associated with 
the assessments. All assessments will be recorded on a source document with the exception of 
staff or subject completed questionnaires. 
11.1. 
Alcohol Breathalyzer 
An alcohol breathalyzer will be administered at consent, at screening, and at every in-clinic visit 
as a safety measure. Acceptable BAC level at consent and screening visit 2 (Day -1, the day of 
randomization) is equal to 0.000 and less than or equal to 0.020 for all other in-clinic visits prior 
to performing other assessments. 
11.2. 
Adverse Events and Serious Adverse Events 
The investigator and study site staff are responsible for the detection, documentation, 
classification, reporting, and follow up of events meeting the definition of an AE or SAE.  
11.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and may not necessarily have a causal relationship with 
the administered treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant laboratory abnormality), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational 
product. Pre-existing conditions, diseases, or disorders are not considered AEs unless there is a 
change in severity or frequency. 
11.2.2. 
Serious Adverse Events and Serious Unexpected Adverse Events Definition 
An SAE is any untoward medical occurrence that meets one of the following: 
• Results in death 
• Is life-threatening (at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in 
the risk information included in the Product Label for the drug. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the study subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition.  

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11.2.3. 
Methods/Timing for Assessing, Recording, and Analyzing Safety Endpoints 
AEs will be assessed at study visits starting after the first administration of investigational 
product until the final follow-up visit. However, SAEs will be collected from the time of 
informed consent onward. General symptoms will be collected via an open ended question: 
“How have you been feeling since your last visit or the last time we spoke?”  
AEs will be documented in the source records, and recorded on the eCRFs using accepted 
medical terms and/or the diagnoses that accurately characterize the event. When a diagnosis is 
known, the AE term recorded on the eCRF will be the diagnosis rather than a constellation of 
symptoms. The investigator will assess all AEs for seriousness, relationship to investigational 
product, and severity. When an event has not resolved by study closure, it will be documented on 
the AE eCRF as “ongoing”. 
If a woman has a positive or borderline pregnancy test after enrollment, the NIAAA Medical 
Monitor will be contacted and the pregnancy will be recorded as an AE. The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
terminated or completed. The outcome of the pregnancy will be reported to the NIAAA Medical 
Monitor without delay within 24 hours of knowledge of the event if the outcome is a SAE (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed by study physicians until satisfactory resolution (the event either 
resolved or stabilized and is not expected to resolve in the near term). AEs must be reported up 
to 2 weeks following completion of, or termination from investigational product administration. 
At the follow-up telephone contact, AEs will be recorded and followed to resolution only if they 
are serious, or if the study physician assesses them to be clinically significant. 
11.2.4. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Abnormal clinical laboratory findings (e.g., clinical chemistry) or other abnormal assessments 
(e.g., from vital signs or ECG), judged as clinically significant by the investigator will be 
recorded as AEs or SAEs, if they meet the definitions provided in Section 11.2.2. Abnormal 
laboratory or other findings present at baseline that significantly worsen following start of the 
study will be reported as AEs or SAEs. Abnormal findings present at the start of the study that 
do not worsen will not be reported as AEs or SAEs, unless the investigator or designee judges 
them as more severe than expected for the subject’s condition.  
11.2.5. 
Classification of Adverse Event Intensity and Relationship to Investigational 
Product 
For each recorded AE or SAE, a physician- investigator must make an assessment of severity. 
For those AEs included in the National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE version 4.03), these severity criteria will apply. For those not listed in 
the CTCAE, the following criteria will be used: 

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Mild: 
An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention.  
Severe: 
 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
Life-threatening 
An event that puts the subject into imminent risk of death without 
intervention. 
In particular, clinical chemistry severity and blood pressure increases will be graded in 
accordance with the CTCAE version 4.03. The severity grades for the chemistry tests used in this 
study and for systolic and diastolic blood pressure are provided in Appendix 19.3. 
The investigator must make an assessment of relationship to the investigational product based on 
the following criteria: 
Unrelated: 
The subject did not receive the investigational product, the temporal sequence 
of the AE/SAE onset relative to administration of the investigational product 
is not reasonable, or there is another obvious cause of the AE/SAE. 
Unlikely: 
There is evidence of exposure to the investigational product but there is 
another more likely cause of the AE/SAE. 
Possible: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, but the AE/SAE could have been due to another equally 
likely cause. 
Probable: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, and the AE/SAE is more likely explained by the 
investigational product than by any other cause. 
Definite 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, the AE/SAE is more likely explained by the 
investigational product than by any other cause, and the AE/SAE shows a 
pattern consistent with previous knowledge of the investigational product or 
investigational product class. 
11.2.6. 
Outcomes and Actions Taken 
All unresolved AEs will be followed for a minimum of 14 days (unless the AE is an ongoing 
pregnancy which must be followed to conclusion) after the subject’s final study visit, unless the 
investigator’s judgment dictates otherwise, the event has resolved or stabilized prior to the 14-
day period, or the subject is lost to follow-up.  

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Investigators are not obligated to actively seek AEs or SAEs in former study subjects that occur 
following the follow-up period.  
For each recorded AE or SAE, the investigator must make an assessment of outcome at the time 
of last observation, as follows: 
Fatal: 
The subject died. 
Resolved without Sequelae: 
The AE or SAE has ended. 
Resolved with Sequelae: 
The AE or SAE has ended but changes are noted from 
baseline. 
Unresolved – Ongoing: 
The AE has not ended and is ongoing at the end of the 
reporting period (i.e., 14 days after the final Follow-up visit) 
and the investigator deems that further follow up is not 
medically required 
Unknown – Lost to Follow-up: 
Lost to follow-up after repeated unsuccessful attempts to 
contact the subject. 
Actions taken with respect to investigational agents (discontinuation or not) will also be 
recorded. In addition, if the AE was treated (medications or other physical measures), this will 
also be recorded. 
11.2.7. 
Reporting Serious Adverse Events 
11.2.7.1. 24 hour Reporting Requirements (Initial Report) 
Any SAE, including death due to any cause, which occurs to any subject from the time of 
signing consent through the final follow-up visit whether or not related to the investigational 
product, must be reported within 24 hours of knowledge of the event by completing the SAE 
eCRF. This will trigger an automatic notification of the SAE via an email communication to 
NIAAA and Fast-Track. Fast-Track will notify the Medical Monitors upon receipt of the 
notification and coordinate communications with the Medical Monitors.  
11.2.7.2. 3-Day Supporting Documentation Requirements (Follow-up Report) 
Written documentation for all SAEs must be received by the NIAAA Medical Monitor/Alternate 
within 3 days of reporting the event. Required eCRF that must be completed include the 
following: 
• SAE eCRF (follow-up) 
• Concomitant Medication eCRF  
• AE eCRF  
In addition, paper copies of the following may be requested 
• Copies of source documents pertinent to the event (laboratory reports, ECG tracings, 
medical chart notes, etc.). These should be identified only by Subject number and not 
include any subject identification information prohibited by Health Insurance Portability 
Accountability Act (HIPAA). 

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• Any other relevant information necessary to support the investigator’s judgment 
regarding the SAE’s relatedness severity to the investigational product OR by request of 
the Medical Monitor/Alternate. 
These paper documents may be submitted by facsimile, as email attachments, or by attaching 
them to the subject’s eCRF casebook. 
11.2.7.3. Reporting to the IRB 
Unanticipated problems involving risk to subjects or others, SAEs related to participation in the 
study and all subject deaths should be promptly reported by phone, email, or fax to the local IRB. 
Investigators are required to forward safety information provided by the sponsor’s representative 
to the IRB. 
11.3. 
Alcohol Craving Scale 
The ACQ-SR-R contains 12-items adapted from the 47-item ACQ-NOW developed by Singleton 
et al (1994) to assess craving for alcohol among alcohol users in the current context (right now). 
There are 4 subscale scores for compulsivity, expectancy, purposefulness and emotionality and a 
total score. Each item has a 1 to 7 raw score (from strongly disagree to strongly agree). The sum 
of the raw scores for each factor are divided by 3 to yield a factor based score. Items 3, 8, and 11 
are reverse keyed. A general craving index is derived by summing all items and dividing by 12. 
This form takes ~5 minutes to complete. This questionnaire will be completed by the subject 
electronically and will be both the source and eCRF. 
11.4. 
Barratt Impulsiveness Scale 
The BIS is a widely used measure of impulsiveness that includes 30 self-reported items that are 
scored to yield six first-order factors (attention, motor, self-control, cognitive complexity, 
perseverance, and cognitive instability impulsiveness) and three second-order factors 
(attentional, motor, and non-planning impulsiveness) (Patton et al-1995). This questionnaire will 
be completed by the subject electronically and will be both the source and eCRF. 
11.5. 
Beck Anxiety Inventory 
The BAI consists of 21 questions about how the subject has been feeling in the last week, 
expressed as common symptoms of anxiety (such as numbness and tingling, sweating not due to 
heat, and fear of the worst happening). This inventory was designed to minimize the overlap with 
depression scales (Beck et al-1988). Each question has the same set of four possible answer 
choices, which are arranged in columns and are answered by marking the appropriate one with a 
cross. These are: 
Not at all. (0 points) 
Mildly: It did not bother me much. (1 point) 
Moderately: It was very unpleasant, but I could stand it. (2 points) 
Severely: I could barely stand it. (3 points) 
The BAI has a maximum score of 63. The standardized cutoffs for anxiety severity are: 

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0-7: minimal level of anxiety 
8-15: mild anxiety 
16-25: moderate anxiety 
26-63: severe anxiety 
This questionnaire will be completed by the subject electronically and will be both the source 
and eCRF. 
11.6. 
Beck Depression Inventory – II 
The BDI-II is a 21-item multiple choice questionnaire that is used for measuring the severity of 
depression (Beck et al-1966). Each item is scored on a scale value of 0 to 3. The standardized 
cutoffs for depression severity are: 
0–13: minimal depression 
14–19: mild depression 
20–28: moderate depression 
29–63: severe depression 
This questionnaire will be completed by the subject electronically and will be both the source 
and eCRF. 
11.7. 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) 
The CIWA-AR modified telephone version is an adaptation for telephone administration of the 
CIWA-AR a brief 10-item measure used to provide a quantitative index of the severity of the 
alcohol withdrawal syndrome (Sullivan et al-1989). The CIWA-AR has been used both in 
clinical and research applications and has demonstrated both reliability and validity (Sellers et al-
1992, Stuppaeck et al-1994). This questionnaire will be administered by a clinical staff member 
and subject responses will be recorded electronically and will be both the source and eCRF. 
11.8. 
Clinical Chemistry 
Clinical laboratory tests will be performed at the clinical site’s local clinical laboratory. 
Laboratories performing these assessments should be directly regulated by the College of 
American Pathologists (CAP) or Clinical Laboratory Improvement Act (CLIA) guidelines. The 
laboratory will need to provide a copy of current certification. All clinical laboratory data will be 
reviewed by the investigator for clinical significance. The total blood volume is approximately 
72 mL. Additional laboratory samples may be taken at the discretion of the investigator if the 
results of any tests fall outside reference ranges or clinical symptoms necessitate testing to ensure 
safety. Clinical chemistry tests are listed below. 
• Creatinine 
• Total bilirubin 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 

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• Gamma glutamyl transferase (GGT) 
Serum creatinine levels will be used to calculate creatinine clearance (CrCl) according to the 
Cockroft-Gault (1976) formula as follows:  
 
Males 
CrCl (mL/min) = 
(140 – age in years) x body weight in kg 
72 x serum creatinine mg/dL 
 
Females 
CrCl (mL/min) = 
0.85 x (140 – age in years) x body weight in kg 
72 x serum creatinine mg/dL 
For any laboratory test value outside the reference range that the investigator considers clinically 
significant: 
• The investigator will repeat the test to verify the out-of-range value 
• The investigator will follow the out-of-range value to a satisfactory clinical resolution 
• A laboratory test value that requires a subject to be discontinued from the study or 
requires a subject to receive treatment will be recorded as an AE 
11.9. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a 4-page form asking questions about suicidal ideation, intensity of ideation, and 
suicidal behavior developed by Posner and collaborators at the New York State Psychiatric 
Institute (Oquendo et al-2003). This scale is intended for use by trained administrators. The 
questions contained in the C-SSRS are suggested probes. Ultimately, the determination of the 
presence of suicidality depends on clinical judgment. Training is required before administering 
the C-SSRS through a 30-minute interactive slide presentation followed by a question-answer 
session through the Columbia University Medical Center. Those completing the training are 
certified to administer the C-SSRS, and will receive a training certificate. As the MINI will be 
used to establish subject initial eligibility with respect to suicidality, the “Since Last Visit” 
version of the C-SSRS will be used at each clinic visit starting with Visit 1 at Week 1. At Visit 1, 
Week 1, this scale will be used to assess current suicidal ideation since the MINI interview. This 
questionnaire will be administered by a clinical staff member and subject responses will be 
recorded electronically and will be both the source and eCRF. 
11.10. 
Demographics 
Demographics data include the subject’s age, gender, race/ethnicity, marital status, education, 
employment pattern, occupation, and income level. These data will be collected by site staff on a 
source document and entered into an eCRF. 
11.11. 
Drinking Question 
If a subject is withdrawn from the study early and is no longer participating in clinic visits or 
providing TLFB drinking data but is willing to be contacted by phone at the week most proximal 
to dropout, then they will be asked about any drinking and heavy drinking during the time since 
last contact. Phone calls will continue until the end of the treatment period, as deemed acceptable 
by the patient, to obtain data on the primary efficacy endpoint (any heavy drinking days defined 
as 5 drinks per day for males and 4 drinks per day for females) and on the secondary efficacy 

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endpoint of abstinence. The rules regarding standard drinking units (SDU) applies. This data will 
be recorded on a source document and eCRF. This does not apply to subjects who are willing to 
supply daily drinking data by the TLFB method. 
11.12. 
ECG 
A 12-lead resting ECG will be obtained. Any abnormalities will be noted and an assessment of 
clinical significance will be done by a study physician.  
11.13. 
Exit Interview 
At the final in-clinic visit (or by phone if the subject withdraws early), the subject will complete 
a questionnaire for his/her impression of whether he/she was receiving active drug or placebo, if 
they felt that the medication helped drinking, how they would describe their experience taking 
the medication, if they would recommend it to a friend, if they would take it again if they needed 
further treatment in the future, and a question about desire to please people. This questionnaire 
will be completed by the subject electronically and will be both the source and eCRF. 
11.14. 
Fagerström Test for Nicotine Dependence 
The Fagerström Test for Nicotine Dependence will be used to assess smoking status and 
motivation to change smoking behavior at baseline (Heatherton et al-1991). This questionnaire 
will be completed by the subject electronically and will be both the source and eCRF. 
11.15. 
Cigarette Smoking Quantity-Frequency  
A quantity frequency interview at baseline will include three questions to assess cigarette 
smoking behavior and other tobacco/nicotine containing products use during the study: 1) “Over 
the past week, on how many days did you smoke cigarettes?”, 2) “On the days you smoked 
during the past week, how many cigarettes did you smoke on average?”, and 3) “Have you used 
any other tobacco or nicotine containing products besides cigarettes in the past week (e.g., cigars, 
cigarellos, pipes, bidis, or smokeless tobacco such as pan, chewing tobacco, or snuff, or nicotine 
replacement therapies such as patch or gum)?”. This questionnaire will be completed by the 
subject electronically and will be both the source and eCRF. 
11.16. 
Family History of Alcohol Problems 
Information on family history of alcohol problems will also be collected using the Family 
History of Alcohol Problems. The questionnaire provides subjects with a consistent set of cues 
for identifying blood relatives with alcohol problems by using a family tree listing for relatives 
(Mann et al-1985). This questionnaire will be completed by the subject electronically and will be 
both the source and eCRF. 
11.17. 
Genetic Analysis  
Blood samples for genotyping and expression analysis will be collected using standard 
phlebotomy techniques into PAXgene tubes containing special preservatives for subsequent 
isolation of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Tubes will be stored 
frozen at < -20°C and will be shipped to a central storage facility at the end of the study for 

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storage prior to analysis. Details of sample collection, storage and shipping are provided in the 
study Manual of Operations. 
One or two 4 mL tubes of whole blood sample for DNA isolation will be collected from each 
subject who consents to provide samples for pharmacogenetic analysis. One tube will be 
collected from all subjects. The second tube is optional and will only be collected from subjects 
who agree to have their sample analyzed for a broader range of research.  
One 2.5 mL tube of blood for RNA analysis will be collected at baseline and at Week 24 at 
approximately the same time of day to control for circadian rhythm. 
The samples will be retained while research on HORIZANT Extended-Release Tablets (or drugs 
of this class) continues but no longer than 20 years in cases where the subject agrees to provide 
the second optional sample. If the subject withdraws consent for testing or storage before the 
sample is shipped to the central laboratory, the site will destroy the sample. If the subject 
withdraws consent for testing or storage after the sample is shipped to the central laboratory, any 
results already obtained will be kept. 
11.18. 
ImBIBe 
ImBIBe is a 15-item questionnaire in which the subject responds on a 5-point scale responses to 
questions on the consequences of alcohol use. This scale was adapted from the Drinker Inventory 
of Consequences questionnaire based on FDA recommendations on patient reported outcomes 
(Miller & Tonigen-1995). This questionnaire will be completed by the subject electronically and 
will be both the source and eCRF. 
11.19. 
Locator Form/Mobile Phone Contact 
After signing informed consent, subjects will be asked to provide names, addresses, and phone 
numbers of several friends and/or family members who can be contacted if the subject cannot be 
located (Locator Form). This locator form will be used to assist in contacting subjects between 
visits and at follow-up. This form asks subjects his/her name, address, and phone number and to 
provide names, addresses, and phone numbers of several friends and family members who can be 
contacted if the subject cannot be located. This information is essential and will be collected 
during screening, and will be updated throughout the study as necessary. This information will 
remain exclusively at the site. In addition, a mobile phone provided by the clinical site will be 
offered to subjects who do not have a mobile phone or who do not wish to use their personal 
mobile phone for study related contacts. The mobile phone will only be given to subjects who 
are determined to be eligible and who are dispensed study drug. 
11.20. 
Medical History 
A medical history will be taken for all potential study subjects to assure medical fitness during 
screening. The age at which the subject started drinking alcohol regularly at least 3 times per 
month (age of onset) will also be collected as part of the medical history. Prior (lifetime) 
treatment for alcohol problems and drinking will also be collected. The answers to the following 
questions will be collected: 
1. Number of lifetime inpatient hospitalizations (i.e. at least one overnight stay) to get help 
with reducing or quitting drinking. 

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2. Number of lifetime inpatient hospitalizations (i.e. at least one overnight stay) for 
illnesses, injuries, or accidents due to drinking. 
3. Number of times in lifetime underwent alcohol detoxification using medication.  
4. Number of lifetime outpatient visits (i.e. no overnight stay) with a health professional to 
get help with reducing or quitting drinking. 
5. In the past year, how many alcoholics anonymous (AA), 12 Step, Save Ourselves, or 
similar group meetings attended for alcohol problems or drinking. 
The medical history will be updated on the day planned for randomization by asking the subject 
if anything has changed since the initial screening interview.  
11.21. 
MINI 
The MINI (paper version 7.0) is a short structured diagnostic interview, developed jointly by 
psychiatrists and clinicians in the United States and Europe, for DSM-5 and ICD-10 psychiatric 
disorders (Sheehan et al-1998). With an administration time of approximately 15 minutes, it was 
designed to meet the need for a short but accurate structured psychiatric interview for multicenter 
clinical trials and epidemiology studies and to be used as a first step in outcome tracking in non-
research clinical settings. Diagnoses recorded on the MINI will be recorded on the interview 
form and entered into an eCRF. The individual items of the Alcohol Use Disorders Module will 
be also collected on an eCRF in addition to all other diagnoses. At the last study visit, the 
Alcohol Use Disorders Module will be assessed again, but the initial drinking question will not 
be asked and the time period for which the questions apply has been revised to “the past month” 
instead of the past 12 months. 
11.22. 
Other Services Used for Alcohol Use Problems 
At randomization (past 4 weeks) and monthly during the study, the subject will be interviewed 
about attendance at group meetings [AA, 12-step programs, secular organizations for sobriety 
(SOS), or similar group meetings] and visits with health professionals for assistance in reducing 
or stopping drinking. Use of additional counseling or professional therapy for non-crisis 
psychiatric matters or any additional pharmacologic or non-pharmacologic treatments received 
will be documented. This questionnaire will be administered by a clinical staff member and 
subject’s responses will be recorded electronically and will be both the source and eCRF. 
11.23. 
Phosphatidylethanol Determination 
Phosphatidylethanol (PEth) as a biomarker for chronic alcohol use has been reviewed recently by 
Viel et al-2012). PEth is formed in the blood by hydrolysis of phosphatidylcholine catalyzed by 
phospholipase D to phosphatidic acid that when in the presence of blood alcohol results in the 
production of PEth (Mueller et al-1988). In clinical studies conducted on chronic heavy drinkers, 
PEth was found to be detectable in blood up to 28 days after sobriety (Aradottir et al-2006; 
Hansson et al-1997; Hartmann et al-2007; Varga et al-1998; Wurst et al-2010; Wurst et al-2012). 
In 15 alcoholics following a detoxification program, the mean half-life of blood PEth was 4.0 ± 
0.7 days with a range of 3.0-5.3 days (Varga et al-2000). It has been demonstrated that sex, 

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gender, age and body mass index do not influence the normalization rate of PEth (Wurst et al-
2010). In a recent experiment during which, after three weeks of abstinence, 11 social drinkers 
were exposed to an amount of ethanol of 1 g/Kg for five consecutive days (daily alcohol intake 
ranging between 67 and 109 g/day), and then remained abstinent for 16 days, undergoing regular 
and scheduled blood sampling, the mean half-life of PEth ranged from 4.5 to 10.1 days in the 
first week and from 5.0 to 12.0 days in the second week (Gnann et al-2012). 
A dried blood spot method will be used by pricking the subject’s finger (after wiping with an 
alcohol swab) with the lancet provided in the collection kit and allowing blood to wick onto the 
collection card (5 total spots will be collected on the card). The card may be stored at room 
temperature for up to one year before assay. Cards will be sent periodically during the study to 
the central laboratory (United States Drug Testing Laboratories, Des Plaines, IL) for analysis.  
11.24. 
Pittsburg Sleep Quality Index (PSQI) 
The PSQI is a 19-item questionnaire with 6 subscales (subjective sleep quality, sleep latency, 
sleep duration, habitual sleep disturbances, use of sleep medication and day time dysfunction) 
(Buysse et al-1989). Each subscale is rated from 0 to 3 with the higher scores reflecting more 
severe sleep complaints. The addition of all the scores permits an analysis of the subject’s overall 
sleep experience in the past 30 days. The lower the overall score, the better the person sleeps. 
The tool has an adequate internal reliability, validity and consistency for clinical and community 
samples of the various populations. This questionnaire will be completed by the subject 
electronically and will be both the source and eCRF. 
11.25. 
Procedures for Monitoring Subject Compliance 
11.25.1. 
Drug Accountability/Compliance 
Drug accountability will be performed by recording the number of tablets dispensed and the 
number of tablets returned at clinic visits. The amount dispensed, daily dose prescribed, and 
amount returned will be reconciled and recorded at each visit. The drug card will be reviewed for 
subject reported consumption of investigational product. If the subject reports missing tablets 
that were not taken, these data will also be recorded and used to calculate total drug exposure. If 
the investigational product bottle was not returned, then the subject’s self-report of drug taken 
will be reported. If the study drug was discontinued, the reason for discontinuation will also be 
recorded. 
11.25.2. 
Gabapentin Plasma Levels 
Blood samples for determining plasma levels of gabapentin to assess for drug compliance and to 
perform population PK/PD analysis will be collected according to the schedule in Table 5. Blood 
will be collected in one 8 mL K3EDTA tube and placed on ice. The tube will be centrifuged and 
plasma collected, aliquoted, and frozen at ≤ - 20°C until shipment to PPD laboratories for 
analysis. Gabapentin levels will be determined using a validated liquid chromatography–mass 
spectrometry/mass spectrometry (LC–MS/MS) method. The LC–MS/MS method was validated 
for gabapentin in plasma over the range 80-10,000 ng/mL. The lower limit of quantitation is 80 
ng/mL. The details for collection, centrifugation, aliquoting, storage and shipment of samples to 
the central laboratory are provided in the Manual of Procedures. If a subject has discontinued 

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investigational product for at least two days, then blood for PK determination does not need to be 
collected. 
11.26. 
Profile of Mood State (POMS) 
The POMS measures dimensions of affect or mood (McNair and Heuchert-2005). It consists of 
65 adjectives to which the subject responds according to a 5-point scale ranging from “not at all” 
to “extremely.” Six subscale scores will be computed for items grouped as follows: Tension-
Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and 
Confusion=Bewilderment. A total mood disturbance score will also be computed which consists 
of the sum of the 5 of the six subscale scores (the Vigor-Activity score is not included). This 
questionnaire will be completed by the subject electronically and will be both the source and 
eCRF. 
11.27. 
Pregnancy Test and Birth Control Record 
An FDA approved rapid result urine pregnancy test will be used (i.e., dipstick test), unless the 
site IRB requires a blood-based assay. If applicable, subjects will be asked to sign a release of 
information form for study personnel to access medical records to obtain information regarding 
the outcome of a pregnancy that occurred during the study. 
The Birth Control Assessment is designed to determine a female subject’s compliance with the 
birth control specifications detailed in the inclusion criteria.  
11.28. 
Prior and Concomitant Medications 
All medications taken by the subject 2-months prior to the start of screening, during the 
screening period, and through the final follow-up contact will be recorded. All medications 
reported by the subject will be recorded on a source document and eCRF.  
11.29. 
Physical Examination 
A physical examination of the oral cavity, head, eyes, ears, nose, and throat, cardiovascular 
system, lungs, abdomen, extremities, skin, neuropsychiatric mental status and sensory/motor 
status, musculoskeletal system and general appearance will be performed during screening. The 
physical exam will be updated on the day planned for randomization by querying the subject 
about any physical changes since the screening examination. Weight (kg) will be collected per 
the schedule in Table 5. A symptom directed physical examination will be performed, as 
applicable, at other visits if the subject reports any problems. Abnormal findings will be reported 
as AEs, if appropriate. 
11.30. 
Screen Failures Documentation 
To document the reason that a subject who consented to the study was not randomized, the 
Enrollment and Eligibility Checklist eCRFs will be completed for these subjects.  
11.31. 
Subject Disposition 
A subject disposition eCRF will be completed for all subjects who are randomized to the study 
and who are dispensed investigational product. This eCRF will be used to record the following 

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data as applicable: 1) completion status of the subject at the end of their participation and if they 
were discontinued early, and reason for early discontinuation. 
Completion status is as follows: 
1. Subject completed full study (i.e., telephone contact was made at the Weeks 28 to 29 
follow-up). 
2. Subject completed the full intervention phase of the study (i.e., subject came to Week 27 
clinic visit). 
3. Subject was withdrawn prior to the Week 27 visit (reasons for early withdrawal are to be 
specified). 
4. If the subject discontinued study medications. 
Even if the subject had investigational product suspended for any reason but attended clinic 
visits, the above definitions still apply. 
In addition, if the subject was confined and/or incarcerated at any time during the study, the dates 
of confinement and/or incarceration will be collected. 
11.32. 
Drinking Goal  
The Thoughts About Abstinence Scale developed by Marlatt et al (1988) for smoking was 
adapted for drinking and items for a drinking goal, and confidence and motivation to meet the 
selected goal have been included. The resultant assessment, named Drinking Goal, is a 3-item 
questionnaire completed by the subject and will be both the source and eCRF.  
11.33. 
TLFB Interview 
Drinking behavior will be assessed using the TLFB methodology (Sobell & Sobell-1992). The 
TLFB is a semi-structured interview that provides estimates of the daily quantity of alcohol 
consumption during specified time periods. It uses a calendar prompt and a number of other 
memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate 
recall of drinking or other drug use during the target period. The procedure has been widely used 
in clinical and research contexts. It has demonstrated adequate levels of reliability and validity 
when administered as an in-person interview, over the telephone, and when administered via 
computer (Carey-1997, Sobell et al-1988, Sobell et al-1996). After consent is signed, the TLFB 
interview will be performed for the 28-day period prior to signing consent. Thereafter, the 
interview will be for the previous days between the last assessment and the day prior to the day 
of the assessment. It is estimated that a 28-day TLFB assessment will take 20 minutes to 
complete. In the event of missed visits, collection of missed drinking data at the following visit is 
required. 
If a subject requests to withdraw from the study but agrees to continued telephone contact to 
assess drinking, the TLFB will be performed over the phone for the duration of the study at a 
frequency acceptable to the study subject and site staff.  
An Excel spreadsheet customized for use in this study will be used for double data entry by 
clinical site staff to collect the TLFB drinking data. This spreadsheet contains a calculator to 

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determine standard drink units (SDUs). This spreadsheet will be reviewed, compared with source 
documents and collected by study monitors for upload into the main study database. 
Drinking days are defined as the number of days in which the subject reported any alcohol 
consumption (i.e., > 0 standard drinking units [SDUs]). A standard drink contains approximately 
0.6 fluid ounces (oz) of pure alcohol. The data given by the subjects on amount and type of 
alcoholic beverage(s) consumed will be converted to SDUs. Standard drink unit definitions are 
provided in Table 8. 
Table 8: Standard Drink Unit Definitions 
For Beer (~ 5% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.0  
• 16 oz = 1.3 
• 22 oz = 2.0 
• 40 oz = 3.3 
For malt liquor (~ 7% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.4 
• 16 oz = 1.9 
• 22 oz = 2.6 
• 40 oz = 4.7 
For table wine (~ 12% alcohol), the approximate number of SDUs in: 
• 750 mL bottle = 25oz = 5.0 
• 5 oz glass = 1.0 
• 10 oz glass = 2.0 
For 80 proof spirits (~ 40% alcohol), or hard liquor, the approximate number of 
SDUs in: 
• 1.5 oz (mixed drink) = 1.0 
• 16 oz (pint) = 11.0 
• 25 oz ( a fifth) = 17.0 
• 1.75 L (59 oz) = 39.0 
11.34. 
World Health Organization Drinking Risk Categorical Scale 
The WHO has developed a drinking risk categorical scale that can be used in a responder 
analysis approach to assess clinically relevant decreases in alcohol consumption (Aubin et 
al-2015). Two dichotomous endpoints will be analyzed: WHO 1-level and WHO 2-level 
decrease in alcohol consumption. The WHO 1- and 2-level decrease endpoints are the percentage 
of subjects experiencing at least 1- and 2-level decrease in WHO levels of alcohol consumption, 
respectively, from the level at baseline (the period including the 28 days before screening) to the 
level during the last 4 weeks of the maintenance phase (Study Weeks 22-25).  
 
 

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The WHO levels of average alcohol consumption per day are as follows: 
             
 
 
Males              Females 
Low Risk        
1 to 40g            1 to 20g 
Medium Risk    
41 to 60g          21 to 40g 
High Risk       
61 to 100g        41 to 60g 
Very High Risk  101+g               61+g 
where 14g = 1 SDU (WHO-2000). In computing the WHO alcohol consumption level, average 
drinks per day will be used, computed as the sum of all drinks in the 28 day period divided by 
the number of days with non-missing drinking data in that period. Abstinent subjects will be 
included in a separate “Abstinent” category. A subject must have at least 1 week of data during 
the last 4 weeks of the maintenance phase to be considered non-missing. 
11.35. 
Urine Drug Screen 
An FDA cleared, CLIA waived urine drug test card will be used to assess candidates for recent 
use of opioids, cocaine, amphetamines, methamphetamine, THC, buprenorphine, methadone or 
benzodiazepines. During screening subjects must be negative for all substances except THC and 
in special cases opioids. If positive for opioids but recent opiate use for acute pain is reported by 
the subject, then the subject can be re-screened. If positive for these drugs at other times during 
the study, the subject will not be removed from the study but should be asked about medication 
use and possibly re-evaluate their medical history for substance abuse. 
11.36. 
Vital Signs  
Vital signs to be assessed include sitting blood pressure and pulse rate (after sitting for at least 3 
minutes).  

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12. 
Statistical Methods and Determination of Sample Size 
12.1. 
Statistical and Analytical Plans 
Complete details of the statistical analyses to be performed will be documented in a SAP, which 
will be completed prior to locking and unblinding the study data. This document will include 
more detail of analysis populations, summary strategies, and any amendments to the proposed 
analyses listed here, if necessary. Any changes to the SAP will be outlined in the final study 
report. 
12.2. 
Statistical Hypotheses 
Primary Efficacy Endpoint: It is hypothesized that HORIZANT Extended-Release Tablets, as 
compared to placebo will increase the PSNHDD during Study Weeks 22 to 25 (last 4 weeks of 
the maintenance period (where a heavy drinking day is defined as 5 or more drinks per drinking 
day for men, 4 or more drinks per drinking day for women). This hypothesis will be explored 
using other time periods in exploratory analyses. 
Secondary Efficacy Endpoints: 
Over the last 4 weeks of the maintenance period, it is hypothesized that the HORIZANT 
Extended-Release Tablets group, as compared to the placebo group, will: 
1. Increase the percentage of subjects abstinent from alcohol (key secondary endpoint) 
2. Increase the percentage of subjects with a WHO drinking risk category decrease of: 
a.  1-level 
b.  2-levels  
3. Increase the percentage of days abstinent per week 
4. Decrease the percentage of heavy drinking days per week 
5. Decease the weekly mean number of drinks per week  
6. Decrease the weekly mean drinks per drinking day 
7. Decrease the cigarettes smoked per week among smokers 
8. Decrease the alcohol craving score (ACQ-SR-R) per visit 
9. Decrease the alcohol related consequences (ImBIBe) score per visit 
10. Decrease PSQI score 
11. Decrease the BAI score 
12. Decrease the BDI-II score 
12.3. 
Analysis Populations 
The study analysis populations will consist of the following: 
Modified Intention-to-Treat (mITT) Analysis Set: The mITT set is defined as subjects 
randomized to participate in the study who took at least one dose of investigational product. 

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Evaluable Analysis Set: The evaluable analysis set is defined as those subjects randomized to 
the study who took at least 80% of the prescribed dose of tablets during the maintenance period 
(Weeks 2 - 25) and did not have a major protocol violation.  
The primary and secondary efficacy endpoints will be analyzed on both the mITT and evaluable 
analysis sets. Exploratory analyses will be performed on the mITT analysis set, unless otherwise 
specified. Safety analyses will be conducted on the mITT analysis set. 
12.4. 
Description of Statistical Methods 
12.4.1. 
General Approach 
For descriptive purposes, dichotomous and categorical variables will be presented as number of 
observations and percentages; continuous variables will be given as means, standard deviations 
(SD), median, minimum (min) and maximum (max). Statistical tests will be two-tailed at a 0.05 
Type I error rate. P-values for the primary and secondary endpoints of < 0.05 will be considered 
statistically significant. Covariates will be pre-specified in the SAP. Endpoint data will also be 
screened for outliers and skewness. Appropriate non-parametric tests will be used to compare 
treatment groups on continuous baseline characteristics that are not normally distributed. 
Continuous endpoint data that are not normally distributed will be transformed. Cohen’s d will 
be used to calculate the effect size for means and Cohen’s h will be used to calculate the effect 
size for proportions. Odds ratios will be provided for all dichotomous outcomes and converted to 
Cohen’s d where appropriate. Descriptive statistics – mean, SD, median, min and max – of all 
endpoint data will be provided for each assessment point or summarized at each week for 
drinking endpoints. All data will be presented in listings. 
12.4.2. 
Analysis Addressing the Primary Efficacy Endpoint 
The primary analysis will be conducted via a fully covaried logistic regression analysis of the 
PSNHDD during Study Weeks 22 to 25 (last 4 weeks of the maintenance period on the mITT 
population). The model includes treatment group, clinical site, pre-randomization drinking goal 
(abstinence versus not abstinent), and baseline percent heavy drinking days (in the 28-day period 
prior to the date that the subject signed the informed consent form). Exploratory analyses will 
examine other timeframes beyond the last 4 weeks. A two-tailed p-value < 0.05 will be 
considered statistically significant. The primary analysis will use all mITT subjects and will 
employ imputation for missing drinking data such that any subject with any missing drinking 
data during the evaluation period for this endpoint will be imputed as a subject with a heavy 
drinking day.  
Prior to the subject dropping out of the study, every attempt will be made to continue to collect 
TLFB data; however, if the subject does not want to participate in the collection of the TLFB 
they will be asked to participate in a periodic follow-up phone call to collect a summary of 
drinking information. If the subject agrees to be contacted then they will be asked about any 
drinking and heavy drinking during the time since last contact. Phone calls will continue until the 
end of the treatment period, as deemed acceptable by the patient. The two questions cover 
whether the subject had any heavy drinking days or drinking days during the period covered. 
This summary drinking data will be used for the primary endpoint when TLFB data are not 
available. If the subject does not agree to participate with phone contact, thus no summary 
drinking data nor TLFB data is available, then imputation as indicated above will be used. An 

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analysis of PSNHDD without imputation for missing data will be performed as an exploratory 
analysis.  
12.4.3. 
Secondary Efficacy Endpoints Analysis 
12.4.3.1. Key Secondary Endpoint: Percentage of Subjects Abstinent from Alcohol 
Percentage of subjects abstinent during Weeks 22 to 25 is the key secondary endpoint. 
Covariates for percentage of subjects abstinent will be the same as those for the primary endpoint 
PSNHDD as described in Section 9.4.2. Fewer covariates for the logistic regression may be used 
depending upon the number of events. If the number of events permits the inclusion of a baseline 
drinking covariate, the percentage of days abstinent will be used as the covariate for the percent 
subjects abstinent endpoint. The testing procedure utilizes the serial gate keeping methodology 
(Dmitrienko and Tamhane-2009). The key secondary endpoint can only be evaluated for 
statistical significance after the primary endpoint has been identified as statistically significant. 
In this situation, percentage of subjects abstinent will be evaluated using the Wald statistic from 
the logistic regression model at p<0.05 after PSNHDD is found to have p<0.05. If PSNHDD is 
not statistically significant at the 0.05 level then no significance testing of percentage of subjects 
abstinent will be performed. This analysis will be performed on mITT subjects with no 
imputation for missing data. However, if drinking data are missing by TLFB, but the subject 
reports any drinking during Weeks 22 to 25 using the Drinking Question eCRF, then the subject 
will be considered not abstinent. An analysis of percent subjects abstinent without imputation for 
missing data will be performed as an exploratory analysis.  
12.4.3.2. Supportive Secondary Efficacy Endpoints  
Supportive secondary efficacy endpoints will also be analyzed based on data during the last 4 
weeks of the maintenance period (Weeks 22 through 25), including TLFB and other 
questionnaire data assessed at Week 26 that reflect data collected during this period. No 
imputation will be done on any supportive secondary efficacy endpoint. 
In general, every continuous secondary efficacy endpoint is analyzed using a repeated measures 
mixed effects model where subjects are random effects; factors and covariates are fixed effects.  
 
The primary analysis model for all continuous endpoint is: 
• Appropriately transformed endpoint = treatment + week + treatment*week + clinical 
site + baseline equivalent of endpoint + covariates  
Covariates for continuous secondary efficacy endpoints include the baseline equivalent of the 
endpoint, clinical site, treatment, time and the treatment by time interaction. Additional 
covariates for the secondary efficacy endpoints may include baseline characteristics with a 
theoretical and/or empirical basis for a relationship with a particular secondary endpoint. 
Such characteristics may include, but are not limited to, drinking goal (total abstinence versus 
less than total abstinence), age, years of regular drinking (age minus age first started drinking 
alcohol regularly), baseline alcohol craving scale total score. Prior to the unblinding of the data, 
matrices of correlations between these baseline characteristics and each of the secondary efficacy 
endpoints, pooled across blinded treatment assignment, will be produced (using Pearson for 
continuous variables, Spearman for categorical outcomes). Selection of baseline variables to 

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include as covariates in the models will be based on consideration of the following criteria: at 
least modest correlation with outcome (i.e., r>0.20), and clinical expertise. Each endpoint may 
have a unique set of covariates. Care is taken to only select a limited number of covariates such 
that the models are not over fitted. 
This primary model will also be applied to the untransformed endpoint. 
Results based on the primary analysis model and the model of the untransformed endpoint will 
be presented in tabular form. The overall least squares means and least square means for each 
time point along with the 95% confidence intervals will be presented for the untransformed 
endpoint only, while two-tailed p-values and Cohen’s d will be presented for both the 
untransformed and transformed data. Inference and Cohen’s d will be based upon the results 
using appropriately transformed data.  
Analysis of the dichotomous secondary drinking endpoints, percent subjects with a WHO 1- and 
2-level decrease in alcohol consumption (Aubin et al-2015), will be conducted via a fully 
covaried logistic regression model and contingency table. Covariates for the logistic regression 
model will be selected using a similar approach as that used for the primary endpoint PSNHDD 
as described in Section 9.4.2. Fewer covariates for the logistic regression may be used depending 
upon the number of observed events. No baseline drinking covariate will be employed for the 
endpoints, as these endpoints already adjust for baseline drinking in their calculation. 
Covariates for both of these endpoints will be pre-specified in the SAP. 
Analyses of supportive secondary endpoints with imputation for missing data will be performed 
as exploratory analyses.  
12.4.4. 
Safety Analyses 
AEs will be coded using the most recent version of the MedDRA and will be grouped by SOC 
and PT designation. The severity, frequency, and relationship of AEs to investigational product 
will be presented by SOC and PT groupings. Listings of each individual AE including start date, 
stop date, severity, relationship, outcome, and duration will be provided. Each AE (based on PT) 
will be counted once only for a given study subject. If the same AE occurred on multiple 
occasions, the highest severity will be assumed. Thus, study subjects are not counted multiple 
times in a given numerator in the calculation of frequencies for a specific AE. C-SSRS reports of 
suicidality or suicidal ideation will be reported as AEs and analyzed as AEs if the investigator 
determines after an interview with the subject that the responses are consistent with suicidal 
ideation or attempt.  
Chemistry data, urine drug screen results, pregnancy test results, and alcohol breathalyzer results, 
will be reported as summary statistics. Vital signs will be presented as summary statistics and 
change from baseline. The proportions of ECG results considered abnormal and clinically 
significant will also be provided. CIWA-AR scores will be analyzed similar to the efficacy 
endpoints: mixed effects models with and without baseline characteristics. In addition, change 
from baseline (shift tables) will also be presented for clinical laboratory data. The numbers and 
proportion of subjects who reported CIWA-AR scores ≥ 10 at any time after the start of dosing 
will be presented.  

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12.4.5. 
Compliance and Retention Analyses 
Medication compliance, defined as the amount of investigational product taken as a proportion of 
the total amount prescribed per protocol, will be evaluated for the HORIZANT Extended-
Release Tablets and placebo groups. Self-reported compliance with HORIZANT Extended-
Release Tablets will be compared against plasma samples having detectable levels of gabapentin. 
Average amounts of investigational product taken will be reported for the HORIZANT 
Extended-Release Tablets and placebo groups. The research participation rate, defined as 
percentage of subjects with complete drinking data, will be compared between treatment groups. 
Average amounts of investigational product taken will be reported on a weekly basis and across 
the entire trial duration. In addition, the percentage of subjects discontinuing medication and a 
listing of the reasons for discontinuation will be provided. Weekly days of attendance at self-help 
meetings or other professional service providers to help reduce/quit drinking will be presented as 
summary statistics by treatment group. 
12.4.6. 
PK Analysis 
Plasma levels of gabapentin will be presented as descriptive statistics including mean, SD, 
coefficient of variation, geometric mean, minimum and maximum levels and mean ± SD will be 
presented graphically over time. Population PK analyses will be conducted in accordance with a 
separate PK/PD SAP. 
12.4.7. 
Baseline Descriptive Statistics 
Summaries of the characteristics of the subjects in each of the study groups at baseline will be 
prepared for the mITT, safety, and evaluable analysis sets. Baseline characteristics will be 
compared between the HORIZANT Extended-Release Tablets and placebo groups using 
appropriate statistical methods. A summary will be prepared to show dropouts/retention over 
time in each group, along with the reason for early termination. The number of missing 
observations will be presented between groups. 
12.4.8. 
Exploratory Analyses 
Exploratory analyses of the continuous secondary drinking endpoints, and the WHO 1- and 
2-risk level decrease in alcohol consumption endpoints, will employ a multiple imputation 
method for handling missing weekly drinking data for the mITT population (Hopke et al-2001, 
Rubin-1976, Rubin-1996, Schafer-1997). Multiple imputation replaces each missing value with a 
set of “m” plausible values that represent the uncertainty about the right value to impute. The 
imputation model will include a limited set of variables likely to be associated with missingness 
on the primary endpoint, excluding treatment assignment. The variables may include but are not 
limited to site, time and baseline alcohol use. Specification of the variables used in the multiple 
imputation models will be provided in the SAP. 
Analysis of abstinence from alcohol will not employ imputation for missing drinking data.  
The percentage of subjects abstinent from smoking will be analyzed only among subjects who 
smoked at baseline. Analysis will include two treatment time periods of interest: during the last 
4 weeks of the maintenance period and over the entire maintenance period. All analyses of this 
endpoint will be conducted on both a nonimputed and imputed endpoint using the same 
modeling methods as other dichotomous secondary endpoints. Imputation will proceed such that 

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any subject with any missing cigarettes per week data during the evaluation periods for this 
endpoint will be imputed as a smoker. 
Blood PEth levels at Week 26 will be compared between treatment groups using analysis of 
covariance with treatment group, clinical site, and baseline blood PEth level. The proportion of 
positive samples [a test result > 8 ng/mL - the lower limit of quantitation (LLOQ) of the test] at 
Week 26 data will be modeled using logistic regression with treatment group, clinical site, and 
baseline level as covariates provided there are sufficient observed events.  
The MINI AUD number of symptoms (identifiers) at Week 26 (covering the last 4 weeks of the 
maintenance period) will be compared between the treatment groups using analysis of 
covariance. 
Primary and secondary efficacy endpoints will be compared between treatment groups over the 
entire maintenance period using the same analytic methods described above for these endpoints; 
in addition, these endpoints will be analyzed with and without imputation. The PSNHDD, 
percent subjects abstinent from alcohol, and the WHO 1- and 2- risk level decrease endpoints 
will be analyzed on a weekly and monthly basis; and cumulatively over Weeks 18-25 (last 8 
weeks), Weeks 14-25 (last 12 weeks), and over Weeks 10-25 (last 16 weeks).   
A number of variables will be tested as potential moderators of the medication treatment effect 
on the imputed PSNHDD endpoint over the last 4 weeks of the maintenance period (primary 
endpoint). The potential moderator variables that will be examined include measures suggestive 
of alcohol withdrawal (i.e., withdrawal question on the MINI for alcohol use disorder, BAI, BDI-
II, PSQI total score, POMS total and subscales, ACQ-SR-R total score, and number of days 
abstinent prior to randomization), severity of alcohol use disorder (i.e., drinks per week [28 days 
prescreen], years of regular drinking), reducer status (change in baseline drinks per day), alcohol-
related treatment goal (total abstinence vs. less than total abstinence), BIS score, and baseline 
smoking status. 
12.4.9. 
Adjustment for Covariates 
Covariates used in logistic regression and mixed effects models are described in section 12.4.2 
and 12.4.3. 
12.4.10. 
Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. 
12.4.11. 
Multiple Comparison/Multiplicity 
The primary endpoint and key secondary endpoint use the serial gate keeping methodology 
(Dmitrienko and Tamhane 2009) to maintain a family-wise Type I error of 0.05. This process 
requires an ordering of the hypotheses; namely, that the primary hypothesis for PSNHDD is 
evaluated first, followed conditionally by the key secondary hypothesis for percentage of 
subjects abstinent. This procedure requires that the primary hypothesis be rejected at p<0.05 then 
the hypothesis for the key secondary endpoint may be evaluated. If the primary hypothesis is not 
rejected then there is no test for the key secondary hypothesis. The serial gate keeping 
methodology indicates that if the primary hypothesis is rejected then the entire alpha (0.05, two-

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sided) is available for the key secondary hypothesis. As such, the key secondary endpoint of 
percentage of subjects abstinent is evaluated at p<0.05 (two-sided) for statistical significance. 
12.4.12. 
Tabulation of Individual Response Data 
Individual subject data will be listed by measure and time point. 
12.5. 
Determination of Sample Size 
The sample size was based on a conservative approach to the results of the randomized, placebo-
controlled trial reported by Mason et al (2014). Mason et al (2014) found an effect size for 
PSNHDD of odds ratio = 2.8 (Cohen’s h = 0.48). However, this study was a single site trial and 
single site trials are known to have greater effect sizes than multi-site trials (Feinn and 
Kranzler-2005). Taking a conservative approach, we assumed a smaller effect size for the current 
multi-site trial, an odds ratio = 2.5; (Cohen’s h=.34, that occurs given a placebo PSNHDD during 
Study Weeks 22-25 of 13% and an active study drug PSNHDD of 27%). To achieve 91% power 
for this trial, given a two-tailed alpha of 0.05, then a sample size of 173 per group (346 total) is 
needed (Fleiss et al-2003). The estimates of 13% and 27% for placebo and gabapentin, 
respectively, assumes 15% of the randomized subjects in each treatment group will dropout prior 
to or during the last 4 weeks of the Maintenance Period, and consequently, these dropouts will be 
imputed as subjects with heavy drinking days (i.e., treatment failures). 
 

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13. 
Quality Control and Quality Assurance 
This study will be conducted under International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines and all applicable regulatory requirements.  
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers; the review of protocol procedures with the 
investigator and study personnel prior to study start; the design of suitable source documents 
with appropriate instructions for use; the internal audit of source data according to GCP and 
internal procedures to ensure their accuracy, completeness, and verifiability; as well as the 
periodic site monitoring by the Sponsor’s representatives (clinical monitors of Fast-Track Drugs 
& Biologics, LLC). Written instructions will be provided for collection, preparation, and 
shipment of blood and plasma samples. Clinical monitors will review source documents and 
eCRFs for accuracy and completeness during on-site monitoring visits; any discrepancies will be 
resolved with the investigator, as appropriate.  
Significant and/or repeated noncompliance will be investigated and remedial action instituted 
when appropriate. Failure to comply with remedial actions may result in study site termination 
and regulatory authority notification. 
13.1. 
 Study Monitoring 
Study monitoring will be the responsibility of designated clinical monitors of Fast-Track. 
Monitors will assure compliance with the clinical protocol and ICH GCPs, human subject’s 
protection, drug accountability, maintenance of the site regulatory file, and conformance of 
eCRF data with source documents. Monitoring visits by clinical monitors will be scheduled to 
take place at the initiation of the study, during the study at appropriate intervals, and after the last 
subject has completed the study. A report of monitoring observations will be provided to the PI 
(for corrective actions) and the Sponsor. 
13.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, the FDA, and the IRB may visit the site to perform 
audits or inspections, including source data verification. The purpose of the audit or inspection is 
to systematically and independently examine all study related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines, and any applicable regulatory 
requirements. 
The PI should contact the Sponsor’s representative and Fast-Track if contacted by a regulatory 
agency about an inspection. 
 
 

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14. 
Ethics 
14.1. 
Ethics Review 
The study will be conducted under a protocol reviewed by the local site’s IRB; the study is to be 
conducted by scientifically and medically qualified persons; the benefits of the study are in 
proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study will ensure that the hazards do not outweigh the potential benefits; the 
results to be reported will be accurate; subjects will give their informed consent and will be 
competent to do so and not under duress; and all study staff will comply with the ethical 
principles in 21 Code of Federal Regulations (CFR) Part 50 and the Belmont Principles. 
14.1.1. 
Review/Approval of Study Protocol 
The study may not begin until the IND has been submitted to the FDA and the 30-day waiting 
period has expired without notification by FDA to the Sponsor of any clinical hold issues. 
NIAAA will be the study Sponsor. The site must obtain written approval from the appropriate 
IRB to conduct the study before study initiation. NIAAA will issue a formal authorization letter 
for the study to be initiated at the site. Progress reports will be submitted to the IRB by the 
Investigator at the frequency requested by the site’s IRB. 
14.1.2. 
Protocol Modifications 
All necessary protocol changes will be submitted in writing as protocol amendments to the IRB 
by the site PI for approval prior to implementation. NIAAA will submit all protocol amendments 
to the FDA. 
14.1.3. 
Protocol Deviation Reporting Procedures 
All subject-specific deviations from the protocol are to be documented. The PI or designee will 
be responsible for identifying and reporting all deviations, which are occurrences involving a 
procedure that did not follow the study protocol. Any protocol deviation that adversely affects 
the safety or rights of a subject or scientific integrity of the study is considered a major deviation 
and will be reported immediately to the NIAAA Project Manager and the local site’s IRB. 
14.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with all applicable Federal human research 
protections requirements and the Belmont Principles of respect for persons, beneficence, and 
justice.  
The procedures set out in this study are designed to ensure that the sponsor’s representative and 
all study personnel abide by the principles of the ICH GCP Guideline and the Code of Federal 
Regulations (CFR). The PI confirms this by signing this study protocol and Form FDA 1572. 

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14.2.1. 
Confidentiality 
14.2.1.1. Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom of 
Information Act providing, in part, that proprietary information furnished to clinical investigators 
and IRBs will be kept confidential by the FDA only if maintained in confidence by the clinical 
investigator and IRB. 
By signing this protocol the investigator affirms to NIAAA that information furnished to the 
investigator by NIAAA will be maintained in confidence and such information will be divulged 
to the IRB or similar or expert committee; affiliated institution; and employees only under an 
appropriate understanding of confidentiality with such board or committee, affiliated institution 
and employees. 
14.2.1.2. Confidentiality of Subject Records 
To maintain subject confidentiality, all laboratory specimens, eCRFs, reports and other records 
will be identified by a subject number only. Research and clinical records will be stored in a 
locked cabinet. Only research staff, NIAAA program officials, Fast-Track Drugs & Biologics 
clinical monitors, and XenoPort representatives will have access to the records. Subject 
information will not be released without written permission, except as necessary for monitoring 
by representatives of NIAAA. Upon approval of the study by an IRB, an application will be filed 
with NIAAA for a Certificate of Confidentiality. The use and procedure for applying for a 
Certificate of Confidentiality are provided in Appendix 19.4. 
By signing the protocol the investigator agrees that within local regulatory restrictions and 
ethical considerations, NIAAA or any regulatory agency may consult and/or copy study 
documents in order to verify eCRF data. 
14.2.2. 
Compensation for Participation 
Subjects will be compensated for travel expenses and for time contributed to this research study 
in the form of cash or vouchers. Compensation will be provided in increasing amounts with each 
subject visit and is detailed in the informed consent form.  
14.2.3. 
Written Informed Consent 
The informed consent process and document will be reviewed and approved by the IRB and 
sponsor’s representative prior to initiation of the study. The consent document contains a full 
explanation of the possible risks, advantages, and alternate treatment options, and availability of 
treatment in the case of injury, in accordance with 21 CFR Part 50. The consent document 
indicates that by signature, the subject, permits access to relevant medical records by the 
sponsor’s representative and by representatives of the FDA. The sponsor’s representative will 
submit a copy of the initial IRB- and sponsor’s representative-approved consent form to the FDA 
and will maintain copies of revised consent documents that have been reviewed and approved by 
the site’s IRB. 

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A written informed consent document, in compliance with 21 CFR Part 50, 32 CFR Part 219, 
and the Belmont Principles, and HIPAA Authorization will be signed by the subject before any 
study-related procedures are initiated for each subject.  
All potential subjects for the study will be given a current copy of the Informed Consent Form to 
read. All aspects of the study and informed consent will be explained in lay language to the 
subject by either the investigator, or a medically trained designee. Any subject who is unable to 
demonstrate understanding of the information contained in the informed consent will be 
excluded from study participation. 
All study subjects will be given a copy of the signed informed consent. 
14.2.4. 
 Delegation of Responsibilities and Adequate Resources 
The PI should have adequate time to conduct the study properly and should have an adequate 
number of qualified staff to assist with the conduct of the study.  
The term “investigator” used throughout this protocol refers to the PI and/or qualified 
subinvestigators. The PI may delegate responsibilities to other study site personnel. The PI shall 
delegate tasks only to individuals qualified by education, training, and experience to perform the 
delegated tasks. The PI shall have direct oversight of all delegated activities and shall document 
delegation of responsibilities. The PI is responsible for ensuring all delegated staff has been 
properly trained on the protocol and their assigned study responsibilities. A delegation log 
identifying all delegated duties and the individual to whom they have been delegated will be 
maintained at the study site.  
14.2.5. 
Financial Disclosure 
Clinical investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 
54.2, a clinical investigator is a listed or identified investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research subjects. The term also includes the spouse 
and each dependent child of the investigator. In addition, investigators must promptly update 
financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 
 

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15. 
Data Handling and Record Keeping 
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, laboratory results, 
data recorded in automated instruments, and pharmacy records, etc. This study will use an 
electronic data management system (EDMS) (Merge eClinicalOS) and eCRFs. Data will be 
transcribed from source documentation into web-based eCRFs. Only questionnaire data will be 
entered directly into eCRF (i.e., without prior written or electronic record of data). Paper copies 
of the eCRFs will be provided in the event that the site cannot access the EDMS at the time the 
questionnaire is being completed. The transcribed data will be consistent with the source 
documents or the discrepancies will be explained.  
Clinical monitors will review all source records and compare them to the data entered into the 
eCRF. All entries, corrections, and alterations will be made by the investigator or other 
authorized study personnel. Any errors identified during monitoring will have a query posted by 
monitor for site staff to address. The EDMS system maintains a full audit trail of data entry, data 
corrections, and data queries. 
15.1. 
Subject Identification and Confidentiality 
Subjects will be identified on eCRFs by a unique subject number. No personal identifier will be 
used in any publication or communication used to support this research study. The subject 
number will be used if it becomes necessary to identify data specific to a single subject. The 
Sponsor’s representative and designated clinical monitors of Fast-Track, the IRB, and the FDA 
are eligible to review medical and research records related to this study as a part of their 
responsibility to protect human subjects in clinical research. Personal identifiers will be removed 
from photocopied or electronic medical and research records. 
15.2. 
Inspection of Records 
The sponsor’s representative or designee will be allowed to visit the investigation facilities for 
the purpose of monitoring any aspect of the study. The investigator agrees to allow the monitor 
to inspect the drug storage area, investigational product stocks, drug accountability records, 
subject charts, study source documents, and other records relative to study conduct. 
Subjects’ health information is used to report results of research to the sponsor’s representative 
and Federal regulators and may be reviewed during study audits for compliance with study plans, 
regulations, and research policies. The consent document indicates that by signature, the subject 
permits access to relevant medical records by the sponsor’s representative, XenoPort 
representatives, and by representatives of the FDA. 
Upon a subject’s termination from the trial, completed eCRFs will be ready and available for on-
site review by the sponsor’s representative at scheduled monitoring visits. 
15.3. 
Retention of Records 
The investigator is responsible for creating and/or maintaining all study documentation required 
by Title 21 Code of Federal Regulations (21CFR) Parts 50, 54, 56, and 312, ICH E6 section 8, as 
well as any other documentation defined in the protocol. The investigator must provide key 

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documents to the Sponsor prior to start of the study. A complete list of required regulatory 
documents will be provided in the study Manual of Procedures. 
Federal and local regulations require that the investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
• A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
• A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study drug for the purposes that 
were the subject of the investigation. 
The Sponsor will notify investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 
of the Investigational New Drug application/Clinical Trial Authorization or request for 
marketing approval (New Drug Application/Marketing Authorization Application).  
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
15.4. 
Trial Registration 
As the IND holder and Sponsor, NIAAA will register the trial on the National Library of 
Medicine’s Clinical Trials Registry on the world wide web at http://www.clinicaltrials.gov.  

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16. 
Publication Policy 
Review of manuscripts resulting from this study or from data generated during this study must 
occur according to the NIAAA Publications Policy prior to submission for publication. 
Authorship shall be consistent with NIAAA policies. 

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17. 
Protocol Signature Page  
 
NIAAA REPRESENTATIVES 
Typed Name  
 
 
 
Signature  
 
 
 
 
 
Date 
 
Raye Z. Litten, Ph.D.  
 
______________________  
_________________ 
NIAAA PI 
 
Joanne Fertig, Ph.D.  
 
______________________  
_________________ 
NIAAA Investigator  
 
 
Daniel E. Falk, Ph.D.  
 
 ______________________  
_________________ 
NIAAA Investigator 
 
Megan Ryan, MBA, CCRP ______________________  
_________________ 
NIAAA Project Manager 
 
MEDICAL MONITOR 
 
Roberta Kahn, M.D.  
 
______________________  
_________________ 
 
INVESTIGATORS 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment with the IRB approval. I also agree to report all information or data in accordance 
with the protocol, and in particular I agree to report any serious adverse experiences as defined in 
section 11.2.7 of this protocol. 
 
Typed Name  
 
    Signature  
 
 
 
 
 
Date 
 
________________  
_________________________     __________________ 
 
 
________________  
_________________________     __________________ 
 

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18. 
References 
Anton RF, Myrick H, Baros AM, et al. Efficacy of a combination of flumazenil and gabapentin 
in the treatment of alcohol dependence. J Clin Psychopharmacol. 2009:29:334-342. 
Anton RF, Myrick H, Wright TM, et al. Gabapentin combined with naltrexone for the treatment 
of alcohol dependence. Am J Psychiatry. 2011;168:709-717. 
Aradottir S, Asanovska G, Gjerss S, Hansson P, Alling C. Phosphatidylethanol (PEth) 
concentrations in blood are correlated to reported alcohol intake in alcohol-dependent patients. 
Alcohol Alcohol. 2006;41:431–437. 
Aubin HJ, Reimer J, Nutt DJ, Bladstrom A, Torup L, Francois C, Chick J. Clinical relevance of 
as-needed treatment with nalmefene in alcohol dependent patients. Eur Addict Res. 
2015;21:160–68. 
Backonia MM, Canfax DM, Cundy KC. Efficacy of gabapentin enacarbil vs placebo in patients 
with postherpetic neuralgia and a pharmacokinetic comparison with oral gabapentin. Pain Med. 
2011;12:1098-108. 
Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II 
in psychiatric outpatients. J Personality Assess. 1966;67: 588-97. 
Beck AT, Epstein N, Brown G, Steer RA. "An inventory for measuring clinical anxiety: 
Psychometric properties. J Consult Clinical Psych. 1988;56:893-897. 
Brower KJ, Kim HM, Strobbe S, et al. A randomized double-blind pilot trial of gabapentin 
versus placebo to treat alcohol dependence and comorbid insomnia. Alcohol Clin Exp Res. 
2008;32:1-10. 
Buysse, D. J., Reynolds, C. F., 3rd, Monk, T. H., et al. The Pittsburgh Sleep Quality Index: a 
new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193-213. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41. 
Carey KB. Reliability and validity of the time-line follow-back interview among psychiatric 
outpatients: a preliminary report. Psych Addic Behav. 1997;11, 26-33. 
Dmitrienko A, Tamhane AC.  Gatekeeping procedures in clinical trials. Multiple Testing 
Problems in Pharmaceutical Statistics. Dmitrienko A, Tamhane, A.C., Bretz, F. (editors). 
Chapman and Hall/CRC Press, New York. 2009. 
Feinn R, Kranzler HR. Does effect size in naltrexone trials for alcohol dependence differ for 
single-site vs. multi-center studies? Alcohol Clin Exp Res. 2005;29:963-988.  
Fleiss JL, Levin B., Paik MC. Statistical Methods for Rates and Proportions. Third Edition. John 
Wiley & Sons. New York. 2003. 
Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and of patients 
with heart disease. Acta Medica Scandinavica. 1920;53:469-486. 
Furieri FA, Nakamura-Palacios EM. Gabapentin reduces alcohol consumption and craving: A 
randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007:68:1691-1700. 

HORIZANT for Alcohol Use Disorder 
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Garbutt JC, Kranzler HR, O'Malley SS, et al. Efficacy and tolerability of long-acting injectable 
naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005;293:1617. 
Gnann H, Weinmann W, Thierauf A. Formation of phosphatidylethanol and its subsequent 
elimination during an extensive drinking experiment over 5 days. Alcohol. Clin. Exp. Res. 2012, 
doi:10.1111/j.1530-0277.2012.01768.x. 
Hansson P, Caron M, Johnson G, Gustavsson L, Alling C. Blood phosphatidylethanol as a 
marker of alcohol abuse: Levels in alcoholic males during withdrawal. Alcohol Clin. Exp. Res. 
1997;21:108–110. 
Hartmann S, Aradottir S, Graf M, Wiesbeck G, Lesch O, Ramskogler K, Wolfersdorf M, Alling, 
C, Wurst FM. Phosphatidylethanol as a sensitive and specific biomarker: Comparison with 
gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient 
transferrin. Addict. Biol. 2007;12:81–84. 
Heilig M, Egli M. Pharmacological treatment of alcohol dependence: target symptoms and target 
mechanisms. Pharmacol Ther. 2006;111:855-76. 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for Nicotine 
Dependence: A revision of the Fagerstrom Tolerance Questionnaire. British J Addictions. 
1991;86:1119-27. 
Hopke PK, Liu C, Rubin DB. Multiple imputation for multivariate data with missing and below-
threshold measurements: time-series concentrations of pollutants in the Arctic. Biometrics. 
2001;57:22-33. 
Jonas D E, Amick HR, Feltner C, Bobashev G, et al. Pharmacotherapy for adults with alcohol 
use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 
2014:311:1889-1900. 
Kline-Simon AH, Falk DE, Litten RZ, Mertens JR, Fertig J, Ryan M, Weisner CM. 
Posttreatment low-risk drinking as a predictor of future drinking and problem outcomes among 
individuals with alcohol use disorders. Alcoholism: Clinical and Experimental Research. 
2013;37:E373-E380. 
Kline-Simon AH, Weisner CM, Parthasarathy S, Falk DE, Litten RZ, Mertens JR. Five-year 
healthcare utilization and costs among lower-risk drinkers following alcohol treatment. 
Alcoholism: Clinical and Experimental Research. 2014; 38:579-586. 
Laaksonen E, Koski-Jiinnes A, Salaspuro M, et al. A randomized, multicentre, open-label, 
comparatiw trial of disulfiram, naltrexone and acamprosate in the treatment of alcohol 
dependence. Alcohol. 2008;43:53. 
Litten RZ, Egli M, Heilig M, et al. Medications development to treat alcohol dependence: A 
vision for the next decade. Add Biol. 2012;17:513-527. 
Mann RE, Sobell LC, Sobell MB, Pavan D. Reliability of a family tree questionnaire for 
assessing family history of alcohol problems. Drug Alcohol Depend. 1985;15:61-7. 
Marlatt GA, Curry S, Gordon JR. A longitudinal analysis of unaided smoking cessation. J 
Consult Clin Psychol. 1988;56:715-20. 

HORIZANT for Alcohol Use Disorder 
NCIG, NIAAA, NIH 
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Mason BJ, Light JM, Williams LD, Drobes DJ. Proof-of-concept human laboratory study for 
protracted abstinence in alcohol dependence: Effects of gabapentin. Addict Biol. 2009;14:73-83. 
Mason BJ, Quello S, Goodell V, Shadan F. Gabapentin treatment for alcohol dependence. 
JAMA. 2014;174:70-77. 
McNair DM, Heuchert JWP. Profile of Mood States (POMS) Multi-Health Systems, Tonawanda, 
NY. 2005. 
Miller WR, Tonigan JS. The Drinker Inventory of Consequences (DrInC): an instrument for 
assessing adverse consequences of alcohol abuse. In Mattson, M. E., and Marshall, L. A. (Eds.) 
NIAAA Project MATCH Monograph Series, Vol. 4. Rockville, MD: National Institute on 
Alcohol Abuse and Alcoholism. 1995. 
Mueller GC, Fleming MF, LeMahieu, MA, Lybrand GS, Barry KJ. Synthesis of 
phosphatidylethanol—A potential marker for adult males at risk for alcoholism. Proc. Natl. 
Acad. Sci. USA 1988;85:9778–82. 
Myrick H, Malcolm R, Randall PK, et al. A double-blind trial of gabapentin versus lorazepam in 
the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33:1582-1588. 
NIAAA. Alcohol Facts and Statistics, 2014. Available at http://www.niaaa.nih.gov/alcohol-
health/overview-alcohol-consumption/alcohol-facts-and-statistics.  
Oquendo M. A. HB, Mann J. J. Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -
130. 2003. 
Patton JH, Stanford MS, Barratt ES. Factor structure of the Barratt Impulsiveness Scale. J Clin 
Psych.1995;51:768-74. 
Rasner S, Leucht S, Lehert P, Soyka M. Acamprosate supports abstinence, naltrexone prevents 
excessive drinking: Evidence from a meta-analysis with unreported outcomes. J 
Psychopharmacol. 2008; 22:11. 
Rasner S, Hacki-Herrwerth A, Leucht S, et al. Opioid antagonists for alcohol dependence. 
Cochrane Database Syst Rev. 2010;CD001867. 
Rubin DB. Inference and Missing Data. Biometrika. 1976;63:581–592. 
Rubin DB. Multiple Imputation After 18+ Years. J Amer Statistical Assoc. 1996;91:473–489. 
Schafer JL. Analysis of Incomplete Multivariate Data, New York: Chapman and Hall. 1997. 
Sellers EM, Sullivan JT, Somer G, Sykora K. Characterization of DSM-III-R criteria for 
uncomplicated alcohol withdrawal: proposal for a diagnostic inventory and revised withdrawal 
scale. In Naranjo, C. A. and Sellers, E. M. (Eds.) Novel pharmacological interventions for 
alcoholism. New York (pp. 369-71). 1992. 
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, 
Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin 
Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57. 

HORIZANT for Alcohol Use Disorder 
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Singleton EG, Tiffany, ST, Henningfield JE. Development and validation of a new questionnaire 
to assess craving for alcohol. In: Harris LS (ed) Problems of Drug Dependence, 1994; 
Proceedings of the 56th Annual Scientific Meeting, The College on Problems of Drug 
Dependence, Inc. National Institute of Drug Abuse Research Monograph Series. Vol. 153. 
Rockville, MD 1995. p. 289. 
Sobell LC, Sobell MB. Timeline followback: a technique for assessing self reported alcohol 
consumption. In Litten, R. Z. and Allen, J.P. (Eds.) Measuring alcohol consumption: 
psychosocial and biochemical methods. Totowa, NJ: Humana Press (pp. 41-72) 1992. 
Sobell LC, Brown J, Leo GI, Sobell MB. The reliability of the Alcohol Timeline Followback 
when administered by telephone and by computer. Drug Alcohol Depend 1996;42:49-54. 
Sobell LC, Sobell MB, Leo GI, Cancilla A. Reliability of a timeline method: assessing normal 
drinkers' reports of recent drinking and a comparative evaluation across several populations. Br J 
Addict. 1988;83:393-402. 
Srisurapanont M, Jarusuraisin  N. Opioid antagonists for alcohol dependence. Cochrane 
Database Syst Rev. 2005;CD001867. 
Stuppaeck CH, Barnas C, Falk M, Guenther V, Hummer M, Oberbauer H, Pycha R, Whitworth 
AB, Fleischhacker WW. Assessment of the alcohol withdrawal syndrome--validity and 
reliability of the translated and modified Clinical Institute Withdrawal Assessment for Alcohol 
scale (CIWA-A). Addiction. 1994;89:1287-92. 
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol 
withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-AR). 
Br J Addict. 1989;84:1353-7. 
Varga A, Hansson P, Lundqvis, C, Alling C. Phosphatidylethanol in blood as a marker of  
ethanol consumption in healthy volunteers: comparison with other markers. Alcohol. Clin. Exp. 
Res. 1998;22:1832–1837.  
Varga A, Hansson P, Johnson G, Alling C. Normalization rate and cellular localization of 
phosphatidylethanol in whole blood from chronic alcoholics. Clin. Chim. Acta 2000;299:141–
150.   
Viel G, Boscolo-Berto R, Cecchetto G, Pais P, Nalesso A, Ferrara SD. Phosphatidylethanol in 
blood as a marker of chronic alcohol use: A systematic review and meta-analysis. Int J Mol Sci. 
2012;13:14788-14812. doi:10.3390/ijms131114788. 
Weisner C, McLellan AT, Hunkeler EM. Addiction severity index data from general 
membership and treatment samples of HMO members. One case of norming the ASI. J Subst 
Abuse Treat. 2000;19:103-109. 
World Health Organization (WHO): International Guide for Monitoring Alcohol Consumption 
and Related Harm. Geneva, WHO, 2000. Available at: 
http://whqlibdoc.who.int/hq/2000/who_msd_msb_00.4.pdf. 
Wurst FM, Alexson S, Wolfersdorf M, Bechtel G, Forster S, Alling C, Aradottir S, Jachau K, 
Huber P, Allen JP, et al. Concentration of fatty acid ethyl esters in hair of alcoholics: 
Comparison to other biological state markers and self reported-ethanol intake. Alcohol Alcohol. 
2004;39:33–38.  

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Wurst FM, Thon N, Aradottir S, Hartmann S, Wiesbeck GA, Lesch O, Skala K, Wolfersdorf M, 
Weinmann W, Alling C. Phosphatidylethanol: Normalization during detoxification, gender 
aspects and correlation with other biomarkers and self-reports. Addict. Biol. 2010;15:88–95.  
Wurst FM, Thon N, Weinmann W, Tippetts S, Marques P, Hahn JA, Alling C, Aradottir S, 
Hartmann S, Lakshman R. Characterization of sialic acid index of plasma apolipoprotein J and 
phosphatidylethanol during alcohol detoxification—A pilot study. Alcohol. Clin. Exp. Res. 
2012;36:251–257.  
Zweben A, Cisler RA. Clinical and methodological utility of a composite outcome measure for 
alcohol treatment research. Alcohol Clin Exp Res. 2003;27:1680-1685. 
 

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19. 
Appendices 
19.1. 
Example Drug Card 
 
ID Number:______________________________  
Study Week (circle one):  1, 2, 3, 4, 5, 6, 7, 8, 9,  
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24,  
25, 26 
  
First day tablets were taken:________________ 
 mm/dd/yy 
# of morning tablets to take:________________ 
# of evening tablets to take:_________________ 
Record tablet/time taken each day below: 
Day 
# Tabs 
taken in 
morning 
Time 
# Tabs taken 
in evening 
Time 
1 
  
  
  
  
2 
  
  
  
3 
  
  
  
  
4 
  
  
  
5 
  
  
  
  
6 
  
  
  
7 
  
  
  
  
 

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19.2. 
Medication Guide to Be Given to Subjects 

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19.3. 
Common Terminology Criteria for Adverse Events for Clinical Laboratory and 
Blood Pressure Elevation Adverse Events 
The following are the toxicity grades for which grading criteria are provided by the CTCAE 
(Version 4.03) for chemistry tests performed in this study and for elevated blood pressure 
measurements. 
Table 9: 
CTCAE Criteria for Clinical Laboratory and Blood Pressure Elevation 
Adverse Events 
Analyte 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Blood Chemistries 
 
 
 
 
ALT elevated 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
AST elevated 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Total bilirubin elevated 
(bilirubinemia) 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
Gamma glutamyl 
transferase  
(GGT) elevated 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Creatinine elevated 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
Hypertension 
Pre-hypertension 
(systolic BP 120 - 139 
mmHg or diastolic BP 80 
- 89 mmHg) 
Stage 1 hypertension 
(systolic BP 140 - 
159 mmHg or 
diastolic BP 90 - 99 
mmHg); medical 
intervention 
indicated; recurrent 
or persistent (24 hrs); 
symptomatic increase 
by >20 mmHg 
(diastolic) or to 
>140/90 mmHg if 
previously WNL; 
monotherapy 
indicated  
Stage 2 hypertension 
(systolic BP≥160 
mmHg or diastolic BP 
≥100 mmHg); medical 
intervention indicated; 
more than one drug or 
more intensive therapy 
than previously used 
indicated  
Life-threatening 
consequences (e.g., 
malignant 
hypertension, 
transient or 
permanent neurologic 
deficit, hypertensive 
crisis); urgent 
intervention indicated  
 

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19.4. 
Certificate of Confidentiality 
The only people who will know the identity of the subjects are members of the research team 
including authorized staff responsible for oversight of the study at the local IRB, authorized 
representatives of the FDA, and representatives of NIAAA including Fast-Track Drugs & 
Biologics, LLC, and NIAAA’s collaborator, XenoPort Inc. No information about the subjects, or 
provided by the subjects during the research, will be disclosed to others without the subjects’ 
written permission, except if necessary to protect subjects’ rights or welfare. 
When the results of the research are published or discussed in conferences, no information will 
be included that would reveal subjects’ identity. Authorized representatives of the FDA, NIAAA, 
and XenoPort Inc. may need to review records of individual subjects periodically. As a result, 
they may know subjects’ names, but they are bound by rules of confidentiality not to reveal their 
identity to others. The results of this study including laboratory results and clinical information 
collected during this study will be submitted to the FDA and may be used for research purposes. 
The results of this study may be published but will not personally identify any subjects. All 
records will be kept in locked storage locations that will be accessible only to authorized study 
personnel.  
The clinical sites, XenoPort Inc., and Fast-Track Drugs & Biologics, LLC will apply for a 
Certificate of Confidentiality electronically through the following website: 
https://www.nichd.nih.gov/health/clinicalresearch/cccert/default.aspx?ic=NIAAA 
This Certificate of Confidentiality helps researchers protect the privacy of subjects in health 
research projects against compulsory legal demands (e.g., court orders and subpoenas) that seek 
the names or other identifying characteristics of research subjects. The certificate was developed 
to protect against the involuntary release of personally identified research information of a 
sensitive nature sought through any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. This authority was granted under the Comprehensive Drug 
Abuse Prevention and Control Act of 1970, Public Law No. 91-513, Section 3(a).  
This certificate is necessary for investigators to avoid being required to involuntarily disclose 
personally identifiable research information about individual study subjects. Under this statute: 
"The Secretary [of the Department of Health and Human Services] may authorize persons 
engaged in biomedical, behavioral, clinical, or other research (including research on mental 
health, and on the use and effect of alcohol and other psychoactive drugs) to protect the privacy 
of individuals who are the subject of such research by withholding from all persons not 
connected with the conduct of such research the names or other identifying characteristics of 
such individuals. Persons so authorized to protect the privacy of such individuals may not be 
compelled in any Federal, State, or local civil, criminal, administrative, legislative, or other 
proceedings to identify such individuals" (Public Health Service Act 301 (d), 42 U. S. C. 241 (d), 
as amended by Public Law No. 100-607, Section 163 (November 4, 1988)).” 
Accordingly, this special privacy protection can be granted only to research (i.e., a systematic 
investigation, designed to develop or contribute to generalizable knowledge). It is granted only 
when the research is of a sensitive nature where the protection is judged necessary to achieve the 
research objectives. 

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The study subjects should be informed that a Certificate is in effect, and be given a fair and clear 
explanation of the protection it affords, including the limitations and exceptions. This 
information will be included in the informed consent. Please see below some suggested wording: 
“If you decide to take part in this research study, you will be required to give us information 
about substance use. A Certificate of Confidentiality (CoC) issued by the National Institute on 
Alcohol Abuse and Alcoholism (NIAAA) which is part of the National Institutes of Health 
(NIH). NIH is governed by a part of the federal government called the Department of Health and 
Human Services (DHHS) has been granted for this study. This Certificate, however, does not 
imply that the Secretary, DHHS, approves or disapproves of the project. 
The CoC is issued to protect the investigators on this study from being forced to tell people that 
are not connected with this study about your participation in this study, even under a subpoena. 
This protection, however, is not absolute. The protection offered by the CoC does not stop us 
from voluntarily reporting information about suspected or known sexual, physical, or other abuse 
of a child or older person, or a subject's threats of violence to self or others. 
If any member of the research team is given such information, he or she will make a report to the 
appropriate authorities. Individuals who participate as research subjects in the specified research 
project are protected permanently during any time the Certificate is in effect - even if the subject 
gave the researcher data before the Certificate is issued. Also, because this research is sponsored 
by NIAAA, staff from NIAAA and other DHHS agencies may review records that identify you 
but only for the purposes of audit for quality and accuracy or program evaluation.  
Even when a CoC is in place, you must still continue to actively protect your own privacy. If you 
voluntarily give your written consent to anyone to receive information about your participation 
in the research or freely volunteer information to anyone other than the study staff that you are a 
research subject in this study, then we may not use the CoC to withhold this information.” 
Study subjects will be notified that a Certificate has expired if they are recruited to the study 
after the expiration date of the Certificate and an extension of the Certificate's coverage has not 
been granted. 
If the research scope of a project covered by a Certificate should change substantially, the PI will 
request an amendment to the Certificate; however, the NIAAA Certificate Coordinator may 
require a new Certificate depending on the extent of the change in scope. An extension of 
coverage must be requested if the research extends beyond the expiration date of the original 
Certificate, as research information collected after the expiration of a Certificate is not protected 
from compelled release. 
A Certificate of Confidentiality is a legal defense against a subpoena or court order, and is to be 
used by the researcher to resist disclosure. The researcher should seek legal counsel from his or 
her institution if legal action is brought to release personally identifying information protected by 
a certificate. The Office of General Counsel for DHHS is willing to discuss the regulations with 
the researcher's attorney.