Clinical trial NCT06097676
Conditions: Abuse Potential
Sponsor: Arbor Pharmaceuticals, Inc.
Start date: 2021-09-28; Completion date: 2022-06-30
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the abuse potential of gabapentin enacarbil in healthy adult, non-dependent, recreational drug users.

Detailed description:
The primary purpose of this study is to evaluate the abuse potential of gabapentin enacarbil immediate-release (GE-IR), the active moiety in Horizant in comparison to placebo and an active control with known abuse potential (i.e., alprazolam).

This study will be a randomized, double-blind, active- and placebo-controlled, 5-way crossover study to determine the abuse potential of gabapentin enacarbil immediate release (GE-IR) relative to alprazolam (active control) and placebo, in nondependent, recreational drug users with sedative drug use experience.

This study will consist of 3 phases: screening, qualification, and treatment.

Arms: arm 1: \- Single oral dose arm 2: * Single oral dose
* Drug: Alprazolam 2 mg capsule arm 3: * Single oral dose
* Drug: GE-IR 200 mg capsule arm 4: * Single oral dose
* Drug: GE-IR 450 mg capsule arm 5: * Single oral dose
* Drug: GE-IR 700 mg capsule
Interventions: intervention 1: Placebo intervention 2: Alprazolam 2 mg intervention 3: Gabapentin Enacarbil Immediate Release (GE-IR) 200 mg intervention 4: Gabapentin Enacarbil Immediate Release (GE-IR) 450 mg intervention 5: Gabapentin Enacarbil Immediate Release (GE-IR) 700 mg
Intervention descriptions: intervention 1: Placebo intervention 2: Oral dose of alprazolam 2 mg intervention 3: Oral dose of GE-IR 200 mg intervention 4: Oral dose of GE-IR 450 mg intervention 5: Oral dose of GE-IR 700 mg

Protocol documents:
Prot_000.pdf: 
A RANDOMIZED, DOUBLE-BLIND, ACTIVE- AND PLACEBO-CONTROLLED, 
5-WAY CROSSOVER STUDY TO DETERMINE THE ABUSE POTENTIAL OF
ORALLY ADMINISTERED GABAPENTIN ENACARBIL IMMEDIATE RELEASE 
CAPSULES IN HEALTHY, NONDEPENDENT, RECREATIONAL DRUG USERS 
WITH SEDATIVE EXPERIENCE 
Protocol Number: 
AR26.3031.1 
Altasciences Project Number: 
ABO-P1-904 
Investigational Product: 
Gabapentin Enacarbil Immediate Release 
Capsules 
Phase of Development: 
Not applicable 
Sponsor: 
Arbor Pharmaceuticals, LLC 
6 Concourse Parkway, Suite 1800 
Atlanta, GA 30328 USA 
COMPLIANCE 
The study will be conducted in accordance with standards of Good Clinical Practice, as defined by the 
International Council for Harmonisation and all applicable federal and local regulations. 
Protocol Version 
Date 
3.0 
(Amendment 02) 
09AUG2021 
 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to investigator(s) 
and to the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It may not be 
used, divulged, published or otherwise disclosed without the written authorization from Altasciences or the 
sponsor. 
ClinicalTrials.gov: NCT06097676


Protocol No: AR26.3031.1 
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PROTOCOL AMENDMENT 02 – SUMMARY OF CHANGES 
Description of Change Made 
Section/Location 
Rationale 
Added continuous monitoring of 
oxygen saturation from 1 hour 
before up to 6 hours after drug 
administration in the 
Qualification Phase. 
Table 1 (Schedule of 
Activities) 
Requested by the 
Institutional Review Board 
(IRB). 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT 02 – SUMMARY OF CHANGES ........................................................................... 2 
TABLE OF CONTENTS ............................................................................................................................................ 3 
STUDY SYNOPSIS ..................................................................................................................................................... 7 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE ................................................................ 14 
1 
INTRODUCTION .............................................................................................................................................. 16 
1.1 
Background ................................................................................................................................................... 16 
1.2 
Study Rationale ............................................................................................................................................. 16 
1.3 
Rationale for Dose Selection ......................................................................................................................... 19 
1.4 
Risk/Benefit Assessment ............................................................................................................................... 20 
1.4.1 Known Potential Risks ........................................................................................................................... 20 
1.4.2 Known Potential Benefits....................................................................................................................... 20 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................................... 21 
3 
STUDY DESIGN ................................................................................................................................................ 22 
3.1 
Overall Study Design .................................................................................................................................... 22 
3.2 
Study Treatments ........................................................................................................................................... 25 
4 
SUBJECT POPULATION ................................................................................................................................ 25 
4.1 
Inclusion Criteria ........................................................................................................................................... 26 
4.2 
Exclusion Criteria .......................................................................................................................................... 27 
4.3 
Qualification Criteria for Treatment Phase ................................................................................................... 29 
4.4 
Withdrawal Criteria ....................................................................................................................................... 30 
4.4.1 Before First Treatment Administration .................................................................................................. 30 
4.4.2 After First Treatment Administration..................................................................................................... 30 
4.5 
Lifestyle and/or Dietary Requirements ......................................................................................................... 31 
4.6 
Concomitant Treatment ................................................................................................................................. 31 
5 
STUDY TREATMENTS .................................................................................................................................... 32 
5.1 
Investigational Products ................................................................................................................................ 32 
5.1.1 Gabapentin Enacarbil ............................................................................................................................. 32 
5.1.2 Alprazolam ............................................................................................................................................. 32 
5.2 
Investigational Product Management ............................................................................................................ 32 
5.2.1 Packaging, Labeling and Dispensing ..................................................................................................... 32 
5.2.2 Storage and Handling ............................................................................................................................. 33 
5.2.3 Method of Assigning Subjects to Treatment Groups ............................................................................. 33 
5.2.3.1 Qualification Phase ......................................................................................................................... 33 
5.2.3.2 Treatment Phase .............................................................................................................................. 33 
5.2.4 Blinding .................................................................................................................................................. 35 


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5.2.5 Study Drug Accountability..................................................................................................................... 35 
5.3 
Administration of Study Drug, Meals and Fluids .......................................................................................... 35 
5.3.1 Treatment Compliance ........................................................................................................................... 35 
5.4 
Other Protocol Restrictions ........................................................................................................................... 36 
6 
STUDY PROCEDURES .................................................................................................................................... 36 
6.1 
Safety Assessments ....................................................................................................................................... 36 
6.1.1 Medical History ...................................................................................................................................... 36 
6.1.2 Recreational Alcohol/Drug Use ............................................................................................................. 37 
6.1.3 Physical Examination ............................................................................................................................. 37 
6.1.4 Vital Signs .............................................................................................................................................. 37 
6.1.4.1 Continuous and Spot Oxygen Saturation ........................................................................................ 37 
6.1.4.2 Continuous and Spot End-Tidal CO2 .............................................................................................. 38 
6.1.4.3 Continuous and Spot Respiratory Rate ........................................................................................... 38 
6.1.5 12-Lead Electrocardiogram .................................................................................................................... 38 
6.1.6 Laboratory Evaluations .......................................................................................................................... 38 
6.1.7 Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................................... 39 
6.1.8 Assessment of Respiratory Depression .................................................................................................. 39 
6.1.9 Rescue Therapy ...................................................................................................................................... 39 
6.2 
Pharmacokinetic Assessments ....................................................................................................................... 40 
6.2.1 Pharmacokinetic Sample Processing, Storage and Shipping .................................................................. 41 
6.3 
Pharmacodynamic Assessments .................................................................................................................... 41 
6.3.1 Subjective Effects................................................................................................................................... 41 
6.3.1.1 Visual Analogue Scales .................................................................................................................. 41 
6.3.1.2 Questionnaires ................................................................................................................................. 43 
6.3.2 Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) .................................................... 44 
7 
ADVERSE EVENTS DOCUMENTATION .................................................................................................... 45 
7.1 
Definitions ..................................................................................................................................................... 45 
7.2 
Severity Assessment ...................................................................................................................................... 46 
7.3 
Causality Assessment .................................................................................................................................... 46 
7.4 
Adverse Event Monitoring ............................................................................................................................ 47 
7.5 
Reporting of Pregnancy ................................................................................................................................. 48 
7.6 
Serious Adverse Event Reporting ................................................................................................................. 48 
8 
DATA ANALYSIS AND STATISTICAL METHODS ................................................................................... 49 
8.1 
Analysis Populations ..................................................................................................................................... 49 
8.1.1 Qualification Phase ................................................................................................................................ 49 
8.1.1.1 Qualification Randomized Population ............................................................................................ 49 


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8.1.1.2 Qualification Safety Population ...................................................................................................... 49 
8.1.2 Treatment Phase ..................................................................................................................................... 49 
8.1.2.1 Randomized Population .................................................................................................................. 49 
8.1.2.2 Safety Population ............................................................................................................................ 49 
8.1.2.3 Completer Population ..................................................................................................................... 49 
8.1.2.4 Modified Completer Population ...................................................................................................... 49 
8.1.2.5 Pharmacokinetic (PK) Population ................................................................................................... 50 
8.2 
Appropriateness of Measures ........................................................................................................................ 50 
8.3 
Missing Values .............................................................................................................................................. 50 
8.4 
Demographic Data and Other Baseline Characteristics ................................................................................. 51 
8.4.1 Qualification Phase ................................................................................................................................ 51 
8.4.2 Treatment Phase ..................................................................................................................................... 51 
8.5 
Pharmacodynamics ........................................................................................................................................ 51 
8.5.1 Pharmacodynamic Endpoints ................................................................................................................. 51 
8.5.2 Pharmacodynamic Statistical Methodology ........................................................................................... 52 
8.5.2.1 Primary Analysis ............................................................................................................................. 52 
8.5.2.2 Secondary Analysis ......................................................................................................................... 58 
8.6 
Pharmacokinetics .......................................................................................................................................... 59 
8.6.1 Measurements Below the Lower Limit of Quantitation ......................................................................... 59 
8.6.2 Actual Time ............................................................................................................................................ 59 
8.6.3 Noncompartmental Analysis (NCA) ...................................................................................................... 59 
8.6.4 Pharmacokinetic Statistical Methodology .............................................................................................. 60 
8.6.4.1 Descriptive Statistics ....................................................................................................................... 60 
8.6.4.2 Statistical Analysis .......................................................................................................................... 60 
8.7 
Safety............................................................................................................................................................. 60 
8.7.1 Safety Endpoints .................................................................................................................................... 60 
8.7.2 Safety Analysis....................................................................................................................................... 61 
8.7.3 Safety Statistical Methodology .............................................................................................................. 61 
8.7.3.1 Qualification Phase ......................................................................................................................... 61 
8.7.3.2 Treatment Phase .............................................................................................................................. 61 
8.8 
Planned Interim Analyses .............................................................................................................................. 61 
8.9 
Determination of Sample Size ....................................................................................................................... 62 
9 
REFERENCES ................................................................................................................................................... 63 
10 APPENDIX 1: ETHICS ..................................................................................................................................... 66 
10.1 Institutional Review Board ............................................................................................................................ 66 
10.2 Ethical Conduct of the Study ......................................................................................................................... 66 


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10.3 Subject Information and Consent .................................................................................................................. 66 
10.4 Subject Confidentiality .................................................................................................................................. 66 
11 APPENDIX 2: DATA COLLECTION, RETENTION, AND MONITORING ............................................ 67 
11.1 Case Report Forms ........................................................................................................................................ 67 
11.2 Data Management and Processing ................................................................................................................. 67 
11.3 Quality Control and Quality Assurance......................................................................................................... 67 
11.4 Record Retention ........................................................................................................................................... 68 
11.5 Monitoring of the Study ................................................................................................................................ 68 
12 APPENDIX 3: ADMINISTRATIVE PROCEDURES .................................................................................... 69 
12.1 Liabilities ....................................................................................................................................................... 69 
12.2 Adherence to Protocol ................................................................................................................................... 69 
12.3 Statement of Investigator ............................................................................................................................... 69 
12.4 Delegation of Investigator Duties .................................................................................................................. 69 
12.5 Premature Termination or Suspension of a Study ......................................................................................... 69 
13 APPENDIX 4: PROTOCOL REVIEW AND APPROVALS ......................................................................... 70 
14 APPENDIX 5: LIST OF ABBREVIATIONS .................................................................................................. 72 
15 APPENDIX 6: CLINICAL LABORATORY EVALUATIONS ..................................................................... 75 
16 APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) –
BASELINE/SCREENING VERSION ..................................................................................................................... 76 
17 APPENDIX 8: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) –SINCE LAST VISIT 
VERSION ................................................................................................................................................................... 79 
 
LIST OF IN-TEXT TABLES 
Table 1. Schedule of Activities ..................................................................................................... 10 
Table 2. Sample Qualification Phase Sequences .......................................................................... 33 
Table 3. Sample Treatment Phase Sequences ............................................................................... 34 
Table 4. Pharmacokinetic Blood Sampling Schedule ................................................................... 40 
Table 5. Visual Analog Scale (VAS) Descriptions ....................................................................... 42 
Table 6. Adverse Event Relationship to Study Drug .................................................................... 47 
Table 7. Pharmacodynamic Endpoints ......................................................................................... 52 
Table 8. Pharmacokinetic Parameters ........................................................................................... 60 


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STUDY SYNOPSIS 
Name of 
Sponsor/Company: 
Arbor Pharmaceuticals, LLC 
Name of Product: 
Gabapentin enacarbil immediate release capsules (GE-IR) 
Title of Study: 
A Randomized, Double-Blind, Active- and Placebo-Controlled, 5-Way Crossover 
Study to Determine the Abuse Potential of Orally Administered Gabapentin 
Enacarbil Immediate Release Capsules in Healthy, Nondependent, Recreational 
Drug Users with Sedative Experience 
Study Development 
Phase: 
Not applicable 
Objectives: 
Primary Objective: 
To evaluate the abuse potential of single oral doses of GE-IR relative to 
alprazolam and placebo, when administered to nondependent recreational drug 
users with sedative drug use experience. 
Secondary Objectives: 
To evaluate the pharmacokinetics (PK) of gabapentin from GE-IR when 
administered to nondependent, recreational drug users with sedative drug use 
experience. 
To evaluate the effects on safety and tolerability of single oral doses of GE-IR 
relative to alprazolam and placebo, when administered to nondependent, 
recreational drug users with sedative drug use experience. 
Endpoints: 
Pharmacodynamic (PD) Endpoints: 
The primary endpoint of this study will be maximum (peak) effect (Emax) over 
24 hours for Drug Liking (“at this moment”), assessed on a bipolar (0 to 
100 points) visual analog scale (VAS). 
Key Secondary PD endpoints will be: 
 
Overall Drug Liking VAS (Emax) 
 
Take Drug Again VAS (Emax) 
 
High VAS (Emax) 
Non-Key Secondary PD endpoints will be: 
Balance of Effects 
 
Drug Liking VAS (time of maximum effect [TEmax], minimum effect 
[Emin], time of minimum effect [TEmin], and time-averaged area under the 
effect-time curve [TA_AUE]) 
Positive Effects 
 
High VAS (TEmax, and TA_AUE) 
 
Good Effects VAS (Emax, TEmax, and TA_AUE) 
Negative Effects 
 
Bad Effects VAS (Emax, TEmax, and TA_AUE) 


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Other Subjective Effects 
 
Any Effects VAS (Emax, TEmax, and TA_AUE) 
 
Feeling Drunk VAS (Emax, TEmax, and TA_AUE) 
 
Drowsiness/Alertness VAS (Emin, TEmin, and time-averaged area over the 
effect-time curve [TA_AOE]) 
 
Relaxation/Agitation (Emin, TEmin, and TA_AOE) 
 
Addiction Research Center Inventory (ARCI) Morphine-Benzedrine 
Group (MBG) Scale (Emax, TEmax, and TA_AUE) 
 
ARCI Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) Scale 
(Emax, TEmax, and TA_AUE) 
Observer Assessments 
 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) (Emin, 
CFBmin, and TA_AOE) 
Pharmacokinetic Endpoints: 
Pharmacokinetic parameters of GE-IR include maximum observed concentration 
(Cmax), time of maximum observed concentration (Tmax), time of last measurable 
observed concentration (Tlast), and area under the curve from time 0 to the last 
measurable observed concentration (AUC0-T). 
Safety Endpoints: 
Endpoints will include a summary of the incidence of adverse events (AEs), 
serious adverse events (SAEs), as well as descriptive summary and statistics of 
the safety parameters. 
Safety parameters will include clinical laboratory values, vital signs (i.e., systolic 
and diastolic blood pressure, pulse rate, respiratory rate, oral temperature, oxygen 
saturation [SpO2]), continuous SpO2 monitoring, continuous End Tidal CO2 
monitoring, electrocardiograms (ECGs), Columbia Suicide Severity Rating Scale 
(C-SSRS), and physical examination findings. 
Study Product, 
Dose, and Mode of 
Administration 
(proposed): 
Gabapentin Enacarbil Immediate Release (GE-IR) Capsules 
Manufacturer: Arbor Pharmaceuticals, LLC 
Mode of administration: Doses of GE-IR capsules including 200 mg (1 × 200 mg 
capsule), 450 mg (2 × 225 mg capsules) and 700 mg (3 × 233.3 mg capsules) will 
be administered orally according to the randomization schedule during the 
Treatment phase. 
Active Control, 
Dose, and Mode of 
Administration: 
Over-encapsulated Xanax (alprazolam) 1 mg tablets 
Manufacturer: Pfizer, Inc. 
Mode of administration: Single doses of 2 mg alprazolam (2 × 1 mg tablets 
over-encapsulated in one Swedish Orange Opaque AAEL-DB capsule) will be 
administered orally according to the randomization schedule during the 
Qualification and Treatment phases. 
Placebo, Dose, and 
Mode of 
Administration: 
Placebo-to-match GE-IR capsules 
Manufacturer: Arbor Pharmaceuticals, LLC 
Mode of administration: Single doses of placebo-to-match GE-IR (233.3 mg 


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over-encapsulated placebo) capsule in one Swedish Orange Opaque AAEL-DB 
capsule) capsule(s) will be administered orally according to the randomization 
schedule during the Treatment phase. 
Over-encapsulated placebo-to-match alprazolam 
Mode of administration: Single doses of placebo-to-match alprazolam (2 × over-
encapsulated placebo tablets in one Swedish Orange Opaque AAEL-DB capsule) 
will be administered orally according to the randomization schedule during the 
Qualification and Treatment phases. 
Study Design: 
This study will be a randomized, double-blind, active- and placebo-controlled, 
5-way crossover study to determine the abuse potential of GE-IR relative to 
alprazolam and placebo, in nondependent, recreational drug users with sedative 
drug use experience. 
This study will consist of 3 phases: screening, qualification and treatment. 
Duration of 
Treatment and 
Subject 
Confinement: 
Duration of clinical trial (per subject): 
Screening: Day -30 to Day -2 
Qualification phase: Subjects will be confined to the clinical site from Day -1 
until Day 4. A minimum 3-day washout will be required between the last dose in 
the Qualification phase and the first dose of the Treatment phase. 
Treatment phase: Subjects will be confined to the clinical site from Treatment 
phase Day -1 until Day 14. 
Total study duration: up to approximately 49 days (including screening) 
Study Population: 
Healthy, male and female nondependent, recreational drug users with sedative 
drug experience, aged 18 to 55 years. 
Planned Number 
of Subjects: 
Approximately 60 subjects will be randomized into the Treatment phase, such 
that approximately 48 subjects complete the Treatment phase of the study. 
Bioanalysis: 
Gabapentin plasma concentrations will be measured by a validated bioanalytical 
method. 
Pharmacodynamic 
Analysis: 
For each PD endpoint, descriptive statistics by treatment and paired difference, 
and inferential analysis using a mixed-effects model, a paired t-test or the sign 
test, as appropriate, will be performed. 
Pharmacokinetic 
Analysis: 
PK analyses will be performed by non-compartmental analysis (NCA) and Cmax, 
Tmax, Tlast, and AUC0-T will be estimated for gabapentin. 
The PK analysis will be further detailed in the statistical analysis plan (SAP). 
Statistical 
Analysis: 
The PD and PK statistical analyses are discussed in sections 8.5 and 8.5.2.2, 
respectively, and will be fully detailed in the SAP. 
Safety Analysis: 
The safety analysis is discussed in section 8.7 and will be fully detailed in the 
SAP. 
 
 








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l Additional training sessions may be conducted as needed. Training will be conducted on Day -1 of the Qualification Phase and, if applicable, upon re-admission to the Treatment 
Phase. 
m Subjective measures will be evaluated as follows: 
Category 
Evaluations 
Phase 
Timepoints 
Drug-specific 
VAS 
Drug Liking, Good Drug Effects, 
Bad Drug Effects, and Any Drug 
Effects 
Qualification phase 
approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
Treatment phase 
approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 24 hours postdose 
Overall Drug Liking and Take Drug 
Again 
Qualification 
and 
treatment phases 
approximately 12 and 24 hours postdose 
Other VAS 
High, Feeling Drunk, 
Relaxation/Agitation, and 
Drowsiness/Alertness 
Qualification phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
Treatment phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 24 hours 
postdose 
ARCI Scales 
Morphine-Benzedrine Group 
(MBG) and Pentobarbital–
Chlorpromazine–Alcohol Group 
(PCAG) 
Qualification phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
Treatment phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 24 hours 
postdose 
n Conducted during the Qualification and Treatment phases within 1 hour prior to dosing and approximately (±15 minutes) at 0.5, 1, 1.5, 2 hours postdose and approximately 
(±30 minutes) at 3, 4, and 6 hours postdose. 
o Blood samples will be collected as indicated in Table 4. When clinical activities are scheduled to occur at the same time, pharmacodynamic data collection (vital signs then 
subjective measures) is to be prioritized, followed by PK blood sampling. 
p If subjects are discharged between the Qualification and Treatment phases, noted discharge procedures will be performed on Day 4 of the Qualification phase and noted 
re-admission procedures will be performed again on Day -1 of the Treatment phase. A minimum 3-day washout will be required between the last dose in the Qualification phase 
and the first dose of the Treatment phase. 
q Randomization will be performed for Qualification phase only on Day -1 of the Qualification phase then, subjects who meet qualification criteria will be randomized for the 
Treatment phase on Day -1 of the Treatment phase. 
r Subjects administered 2 mg alprazolam or placebo according to randomization with a minimum of 48 hours between doses during the Qualification phase. 
s Subjects administered 200 mg GE-IR, 450 mg GE-IR, 700 mg GE-IR, or GE-IR placebo, and 2 mg alprazolam or alprazolam placebo (section 3.2) according to randomization 
with a minimum washout period of 3 days between doses. 
t Covid-19 testing will be performed prior to admission for the Qualification Phase and, if applicable, upon re-admission for the Treatment Phase. 
u Oxygen saturation (SpO2) will be monitored continuously from 1 hour prior to each drug administration (alprazolam or placebo) and will continue for up to 6 hours following 
each drug administration, or longer if deemed medically necessary. 
 


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INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE 
SPONSOR’S CONTACT: 
 
 
 
Arbor Pharmaceuticals, LLC 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
Altasciences Clinical Kansas, Inc. 
 
 
CLINICAL RESEARCH UNIT: 
Altasciences Clinical Kansas, Inc 
 
 
 
 
 
 
 
 
CLINICAL LABORATORY  
FACILITY: 
 
 
 
Quest Diagnostics 
 
 
BIOANALYTICAL FACILITY: 
Altasciences 
 
 
 
MEDICAL WRITING &  
SCIENTIFIC AFFAIRS: 
 
Altasciences 
 
 
 
STATISTICAL FACILITY: 
Altasciences 
 
 
 
DATA MANAGEMENT FACILITY: Altasciences 
 
 


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PROJECT MANAGEMENT: 
 
Altasciences 
 
 
 
 
COGNITIVE TESTS: 
Cambridge Cognition 
 
 
 
MONITORING: 
Randstad Life Sciences 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Gabapentin enacarbil is a transported prodrug of gabapentin designed and engineered to be stable 
in gastrointestinal contents and to be actively absorbed after oral dosing. It converts to 
gabapentin rapidly by non-specific carboxylesterase primarily in enterocytes and to a lesser 
extent in the liver upon absorption. The concentration of intact prodrug in blood is transient and 
≤2% of the corresponding gabapentin level. As a prodrug of gabapentin, its therapeutic effects in 
restless legs syndrome (RLS) and postherpetic neuralgia (PHN) are attributable to gabapentin. 
Gabapentin prevents pain-related responses in several models of neuropathic pain in rats and 
mice (e.g., spinal nerve ligation models, spinal cord injury model, and acute herpes zoster 
infection model). Gabapentin also decreases pain-related responses after peripheral inflammation 
(carrageenan footpad test, late phase of formalin test), but does not alter immediate pain-related 
behaviors (rat tail flick test, formalin footpad acute phase). The relevance of these models to 
human pain is not known. 
Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but 
has no effect on GABA binding, uptake, or degradation. Gabapentin enacarbil 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 gabapentin enacarbil in RLS and PHN is unknown. 
1.2 
Study Rationale 
Horizant is formulated as an extended-release (ER) formulation of gabapentin enacarbil. The 
primary purpose of this study is to evaluate the abuse potential of gabapentin enacarbil 
immediate-release (GE-IR), the active moiety in Horizant in comparison to placebo and an active 
control with known abuse potential (i.e., alprazolam). 
Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta, or kappa), or 
cannabinoid 1 receptor sites, however, a small number of post-marketing cases report gabapentin 
misuse and abuse.1 These individuals were taking higher-than-recommended doses of gabapentin 
for unapproved uses. Most of the individuals described in these reports had a history of 
poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other 
substances. 
The Arbor drug safety database through November 2020 contained 728 reports categorized under 
drug abuse. Of these, 16 (2.2%) were attributed to Horizant, 452 (62%) to gabapentin, 242 
(33.2%) to Regnite (gabapentin enacarbil reports in Japan), and 20 (2.7%) to gabapentin 
enacarbil (6 of these are specified as ER in the narrative). Of the 16 Horizant cases, the most 
frequently reported were intentional product misuse and use issue cases (n=9, 56%). These cases 
involved consumers who reported independently adjusting their dose to manage their 
symptoms/tolerability. This includes 6 who decreased the dose, 1 who increased the dose, and 2 
with unspecified changes. This was followed in frequency by overdose (n=4, 25%). The 


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overdose cases involved reports of feeling "out of sorts", jittery, dizzy, and sleepy after taking 
1200 mg; short-term memory loss after increasing the dose from 1200 mg to 1800 mg; and 
sedation after taking 600 mg instead of 300 mg. The fourth overdose case involved a male who 
took several pills to treat pain while golfing and was hospitalized after being found unconscious. 
Two cases of Horizant-related abuse involved accidental overdose (n=2). One was associated 
with a suspected drug interaction that increased the side effects of her seizure medication. The 
second accidental overdose resulted in death. An autopsy and investigation deemed the cause to 
be combined toxicity of multiple drugs (including Percocet, Xanax, alcohol and medical 
marijuana). Dependence (n=1) was reported by a male with a history of addiction to narcotics. 
After an unknown duration of taking Horizant for an unreported indication, he reported addiction 
issues. No further information was received. Horizant reports from the American Association 
Poison Control Centers National Poison Data System Annual Report are included. 
The Regnite cases involved similar events, with intentional product misuse and use issue cases 
accounting for a larger majority of cases (95%). 
Gabapentin abuse cases were different, however. The most common event was toxicity to 
various agents with (93.8%, 424/452). Of the 424 cases that involved toxicity to various agents, 
more specificity was provided in 173 of the cases. These 173 cases included cardiorespiratory 
arrest (n=73), accidental overdose (n=51), drug abuse (n=37), overdose (n=5), intentional 
product misuse (n=6), and intentional overdose (n=1). Gabapentin enacarbil was reported in 
19 cases related to abuse. Aside from toxicity to various agents, the most frequently reported 
term was intentional product misuse (n=21; including the 6 report also involving toxicity to 
various agents). The remaining reports involved the same terms previously listed and were 
reported no more than 5 times each. Of the gabapentin reports, 65% involved intentional product 
misuse or use issues. The remaining terms, consistent with other products, were reported no 
more than 4 times each. 
In addition, the Food and Drug Administration’s Adverse Event Reporting System (FAERS) 
from October 2012 to December 2016 reportedly contained 634 gabapentinoid abuse-related 
reports (10.2% of all adverse drug event [ADE] reports). Of these, abuse was associated with 
5.7% of total reports for gabapentin ADEs (576 of 10,038) compared to 10.2% of total reports 
for pregabalin ADEs (58 of 571). The abuse-related proportional reporting rate of pregabalin to 
gabapentin is 1.77. Abuse was more common relative to the total ADEs reported with pregabalin 
than gabapentin.2 
Regardless of reported abuse, drugs that affect the central nervous system (CNS), are chemically 
or pharmacologically similar to other drugs with known abuse potential, or produce psychoactive 
effects are required to undergo assessments related to their abuse potential.3, 4 Horizant, a 
CNS -active drug, is currently approved for use in humans as a treatment for moderate to severe 
primary RLS and PHN; however, its abuse potential has not been formally evaluated. 
This study is a randomized, double-blind, active- and placebo-controlled, 5-way crossover 
design, aimed to assess the abuse potential, safety, and PK of Horizant compared with an active 
control and placebo in healthy, nondependent, recreational sedative drug users. The overall 
design is consistent with United States (US) Food and Drug Administration (FDA) guidelines for 
human abuse potential (HAP) assessment.4, 5 


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Because of inter-individual variability in subjective responses, HAP studies are typically 
conducted as double-blind crossover studies including the investigational drug and active 
control, as well as placebo. The active control should be a controlled drug, ideally from the same 
pharmacological class as the study drug, which has measurable abuse liability established 
through experimental studies and epidemiological data, such that it will produce a significant, 
dose-dependent increase on measures of subjective effects. The active control provides evidence 
of the sensitivity of the methodology and the validity of the study.6, 7 Therefore, based on the 
observed clinical effects to date, the sedative (benzodiazepine) class was considered the most 
appropriate pharmacologic class for an active control in this study. A placebo- control is also 
included to control and account for expectancy effects. 
Alprazolam, the active control selected for this study, is a benzodiazepine that is widely known 
to be abused and has been repeatedly demonstrated to show positive effects on common 
measures of abuse potential in clinical investigations. Historically, alprazolam has been 1 of the 
most frequently used positive controls in human abuse potential studies evaluating sedative 
effects and has previously been found to have higher reinforcing effects compared to diazepam 
in a drug choice test.33 Alprazolam has been used as an active control in several recent studies at 
doses ranging between 1.5 and 3.0 mg.8, 9, 10, 11 An intermediate dose of 2.0 mg was selected as 
this is the common dose that is used for qualification phases in human abuse potential studies 
and reliably produces significant increases on subjective measures of drug effects (including 
Drug Liking), can be safely administered, and does not impose significant sedation that would 
limit the collection of study measures. In recent studies, alprazolam has been shown to maintain 
study validity on the measure of Drug Liking under the new statistical testing requirements 
outlined in the 2017 FDA guidance for industry.4 Therefore, alprazolam was chosen as a positive 
control that can also reliably maintain study validity. 
A double-blind Qualification phase has been included in this study design as an enrichment 
procedure to ensure that subjects who meet the drug use history criteria can also distinguish the 
subjective effects of the active control (i.e., alprazolam) from placebo. The pharmacologic 
qualification procedure provides more objective confirmation of drug use history, ensures that 
subjects can respond appropriately in a clinical setting, and reduces the chance of a false positive 
response to placebo. The washout between treatments in the Qualification phase is consistent 
with previous studies of this type, and the duration of pharmacodynamic (PD) effects associated 
with alprazolam has been shown to have returned to baseline by 24 hours postdose.8, 9, 10, 11 
In clinical studies conducted to date, adverse events (AEs) of sedation, somnolence, and 
dizziness have been the most commonly reported in both healthy subject and patient studies of 
Horizant. Thus, subjects will be healthy individuals with previous nontherapeutic (recreational) 
experience with sedative drugs. These subjects represent the population at greatest risk for abuse 
of the drug and can provide meaningful ratings of the drug experiences with a lower risk of false 
negative results; therefore, they are the population with the most face validity. 
In addition to the requirement that subjects are “history qualified” (i.e., history of recreational 
sedative drug use), subjects will also be required to pass a pharmacologic qualification (see 
above). In an abuse potential study, a negative result with a non-drug-using population can be 
considered inconclusive, since these subjects often do not like the effects of drugs that are readily 
abused by substance users.4, 7 


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The mean T½ of alprazolam is 11.2 hours. The minimum 3-day washout interval between the 
Qualification phase and Treatment phase is considered sufficient given the PD effects associated 
with alprazolam return to baseline by 24 hours postdose, as stated above. . 23 Given the T½ of 
gabapentin when receiving GE-IR (4.38 - 5.47 hours) by oral administration, the minimum 3-day 
interval between dosing during the treatment periods will ensure sufficient washout of GE-IR 
and alprazolam. 
Based on the pharmacokinetic (PK) profile of gabapentin, the 24-hour assessment period 
following administration of study drug during the Treatment phase is sufficient to evaluate the 
safety and tolerability and to capture the profile of pharmacodynamic (PD) effects. 
The selection of subjective abuse potential measures in this study, including the use of maximum 
(peak) effect (Emax) of the “at this moment” Drug Liking visual analog scale (VAS; administered 
as a bipolar scale) as a primary endpoint, is consistent with regulatory guidelines.4 Additional 
VAS items will measure positive, negative, and other subjective effects to assess the 
pharmacologic response to the study treatments. The Overall Drug Liking and Take Drug Again 
VAS will provide a measure of the balance of drug effects and will indicate the subject’s 
willingness to take the drug again.  
Pharmacokinetic and safety assessments suitable for evaluating risks associated with 
administration of doses of GE-IR will also be included. 
1.3 
Rationale for Dose Selection 
Standard guidelines for HAP studies indicate that doses above the anticipated therapeutic dose 
should be tested.4, 7, 12 The current US FDA Guidance for Industry on the assessment of abuse 
potential of drugs recommends including multiple doses of the study treatment in the HAP study, 
ranging from therapeutic to supratherapeutic.4 
The GE-IR doses in this study will include 200 mg, 450 mg and 750 mg doses, in order to 
evaluate the dose response of the drug. These doses of GE-IR correspond to the Cmax values 
produced by single oral doses of 600 mg, 1200 mg, and 1800 mg gabapentinin healthy 
individuals. 
The dose of alprazolam selected (2 mg) is consistent with doses previously evaluated in human 
abuse potential studies.8, 9, 10, 11 and are expected to show significant abuse-related subjective 
effects. Alprazolam doses up to 3 mg have been administered in human abuse potential studies, 
and this dose has relatively strong sedative effects; therefore, subjects who experience 
unarousable sedation during the Qualification phase at a dose of 2 mg will not be enrolled. The 
2 mg dose is expected to demonstrate separation from placebo based on previous data with 
alprazolam and will ensure that subjects are able to tolerate (with respect to sedation) and 
respond appropriately in the Treatment phase. 
All doses of study drug will be administered in the fasted state. A previous study of alprazolam 
demonstrated the rate of alprazolam absorption was slower after administration during fed 
relative to fasted conditions. In this study, the mean maximum observed plasma concentration 
(Cmax) decreased approximately 25%, and time to Cmax (Tmax) was delayed approximately 
1.5 hours when food was administered before dosing (4.0 hours [range=2.53-6.03 hours] versus 
2.5 hours [range=0.75-4.01 hours]).34 


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1.4 
Risk/Benefit Assessment 
1.4.1 Known Potential Risks 
The safety of GE-IR in doses ranging from 350 mg to 2800 mg has been evaluated in 88 healthy 
subjects in 2 clinical trials (single ascending dose trial [XP 006] and multiple ascending dose 
trial [XP 018]). 
In study XP 006, dizziness was the most common AE experienced and appeared to be dose-
dependent; occurring mostly at doses from 1400 to 2800 mg. Headache was also reported and 
did not appear related to dose level. Fatigue, nausea and vomiting tended to be reported with 
higher doses or higher gabapentin concentrations. 
Similarly, in study XP 018, dizziness was the most common AE experienced, followed by 
headache, somnolence and nausea. Adverse events were mild with frequencies that were possibly 
dose-related. 
The doses of GE-IR administered in this study are not anticipated to induce any potential risk to 
the subjects. Single dose studies using up to 2800 mg of GE-IR (XP 006) as mentioned above did 
not result in any respiratory depression or serious adverse events. The safety monitoring 
practices employed by this protocol are adequate to protect the subjects’ safety and to detect any 
treatment-emergent AEs (TEAEs). 
The following safety measures will be monitored continuously for signs of respiratory depression 
from up to 1 hour prior to dosing up to approximately 6 hours following dosing in the Treatment 
phase: 
 end-tidal CO2 (EtCO2) monitoring 
 blood oxygen saturation (SpO2) monitoring 
 respiratory rate monitoring 
Safety measurements of EtCO2 and O2 saturation are the standard in monitoring respiratory 
function, change in oxygenation, and change in ventilation.21, 22, 23, 24 Monitoring EtCO2 has been 
shown to be more sensitive in detection of respiratory depression than monitoring respiratory 
rate and pulse oximetry alone.25 
In the clinical setting, respiratory depression is usually described in terms of decreased 
respiratory rates, decreased SpO2 levels, or elevated EtCO2 levels26 and, therefore, these 
measures are appropriate to monitor respiratory depression. 
Additional safety measures implemented at predose and specified timepoints postdose will 
include the collection and documentation of AEs and vital signs (i.e., systolic and diastolic blood 
pressure, pulse rate, respiratory rate, oral temperature, SpO2), and EtCO2. Subjects will be 
determined as healthy for inclusion into the study based on measures of clinical laboratory 
testing, vital signs, medical history, C-SSRS, physical examination, and ECG. 
1.4.2 Known Potential Benefits 
As the study treatments are not being given to subjects to treat any symptoms or illness, there 
will be no direct medical benefit from participation in this trial. 






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The Treatment phase is a randomized, double-blind, active- and placebo-controlled 5-way 
crossover design. Subjects will be randomized to 1 of the 10 pre-specified treatment sequences in 
which they will receive the following 5 treatments in a crossover manner (1 per treatment period) 
and blinded fashion: 
 Placebo 
 Alprazolam 2 mg (active control) 
 GE-IR 200 mg 
 GE-IR 450 mg 
 GE-IR 700 mg 
Each study drug administration will be separated by at least 3 days. Drug administration will 
occur on the first day of each treatment period followed by PD, PK, and safety assessments for 
up to 24 hours postdose. Subjects will be discharged from the investigational site approximately 
24 hours after the final dose if deemed medically stable for discharge by an investigator. 
Study assessments will be performed at the timepoints outlined in the Schedule of Activities 
(Table 1). 
The maximum duration of subject participation will be approximately 49 days, including 
screening. 


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Figure 1. Study Schema 
 
Screening 
 
 
 
 
Admission within 30 days of screening 
 
 
 
Randomized Double-Blind Qualification Phase  
(Crossover treatments on Day 1 and Day 3) 
 
 
 
 
Alprazolam 2 mg 
↔ 
48 hours 
Placebo 
 
 
 
 
≥3 days between last Qualification phase treatment 
and first Treatment phase treatment 
 
 
Randomized Double-Blind Treatment Phase 
(5 crossover treatment periods) 
 
 
GE-IR 
200 mg 
↔ 
≥3 days 
GE-IR 
450 mg 
↔ 
≥3 
days 
GE-IR 
700 mg 
↔ 
≥3 days 
Placebo 
Control 
↔ 
≥3 days
Alprazolam Active 
Control 
2 mg 
 
 
 
Note: the sequence of treatments shown is for illustration of the overall design and does not necessarily represent an 
actual treatment sequence. Refer to Table 3 for all treatment sequences. A minimum 3-day washout will be required 
between the last dose in the Qualification phase and the first dose of the Treatment phase. 


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3.2 
Study Treatments 
The following treatments will be administered with approximately 240 mL of room temperature 
water in the morning under fasted conditions during the Qualification phase: 
 Placebo: A single dose of placebo to match alprazolam (2 lactose 100 mg tablets over-
encapsulated in one Swedish Orange Opaque AAEL-DB capsule) will be administered 
orally. 
 Active Control: A single 2 mg dose of alprazolam (2 × 1 mg tablets over-encapsulated in 
one Swedish Orange Opaque AAEL-DB capsule) will be administered orally. 
The following treatments will be administered with approximately 240 mL of room temperature 
water in the morning under fasted conditions during the Treatment phase: 
 Placebo: Three placebo capsules to match GE-IR + 1 placebo capsule to match 
alprazolam [2 × over-encapsulated placebo tablets in one Swedish Orange Opaque 
AAEL-DB capsule] will be administered orally. 
 Active Control: A single 2 mg dose of over-encapsulated alprazolam (2 × 1 mg tablets 
over-encapsulated in one Swedish Orange Opaque AAEL-DB capsule) + 3 placebo 
capsules to match GE-IR will be administered orally. 
 A single 200 mg dose of GE-IR (1 × 200 mg immediate-release [IR] capsule + 2 placebo 
capsules to match GE-IR capsule + 1 placebo capsule to match alprazolam [2 × 1 mg 
placebo tablets over-encapsulated in one Swedish Orange Opaque AAEL-DB capsule]) 
will be administered orally. 
 A single 450 mg dose of GE-IR (2 × 225 mg immediate-release [IR] capsule + 1 placebo 
capsule to match GE-IR capsule + 1 placebo capsule to match alprazolam [2 × over-
encapsulated placebo tablets in one Swedish Orange Opaque AAEL-DB capsule]) will be 
administered orally. 
 A single 700 mg dose of GE-IR (3 × 233.3 mg immediate-release [IR] capsules + 
1 placebo capsule to match to alprazolam [2 × over-encapsulated placebo tablets in one 
Swedish Orange Opaque AAEL-DB capsule]) will be administered orally. 
4 
SUBJECT POPULATION 
Subjects who meet all the inclusion criteria and none of the exclusion criteria at the screening 
visit may be eligible for participation in this study. Continued eligibility will be assessed upon 
admission to the clinical site, prior to the first study drug administration. 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
subsequently randomly assigned to treatment in the Qualification phase. Subjects who enter the 
Qualification phase and fail to qualify for the Treatment phase will be considered qualification 
failures. 


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4.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be enrolled: 
1. Provision of signed and dated informed consent form (ICF), 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study, 
3. Male or female, between 18 and 55 years of age, inclusive, 
4. Current nondependent, recreational drug user who has used sedative drugs for 
recreational (nontherapeutic) purposes (i.e., for psychoactive effects) at least 10 times in 
the subject’s lifetime and at least once in the 12 weeks before screening, 
5. Body mass index (BMI) within 18.0 kg/m2 to 36.0 kg/m2, inclusive, 
6. If female, meets 1 of the following criteria: 
a) If of childbearing potential agrees to use 1 of the accepted contraceptive regimens from 
at least 30 days prior to the first study drug administration, during the study, and for at 
least 30 days after the last dose of the study drug. An acceptable method of 
contraception includes 1 of the following: 
 Abstinence from heterosexual intercourse, 
 Hormonal contraceptives (birth control pills, injectable/implantable/insertable 
hormonal birth control products, transdermal patch), 
 Intrauterine device (IUD; with or without hormones), 
 
Or 
 
b) If of childbearing potential agrees to use a double barrier method (e.g., condom and 
spermicide) during the study and for at least 30 days after the last dose of study drug. 
 
Or 
c) If of non-childbearing potential, defined as surgically sterile (i.e., has undergone 
complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a 
postmenopausal state (i.e., at least 1 year without menses without an alternative 
medical condition and confirmed follicle stimulating hormone (FSH) ≥ 40 mIU/mL 
prior to the first study drug administration), 
7. If male and engaging in sexual activity that has the risk of pregnancy must agree to use a 
double barrier method (e.g., condom and spermicide) and agree to not donate sperm 
during the study and for at least 90 days after the last dose of the study medication, a 
male who has a pregnant partner shall be excluded, 


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8. Healthy, as determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs or clinical laboratory (including 
hematology, clinical chemistry, urinalysis, and serology [screening visit only]) at 
screening visit and admission, as applicable, in the opinion of an investigator, 
9. Negative Covid-19 test prior to each admission, as applicable. 
4.2 
Exclusion Criteria 
Subjects meeting the following criteria will be excluded from participation: 
1. History of significant hepatic, renal, cardiovascular, pulmonary, hematologic, 
neurological, psychiatric, gastrointestinal, endocrine, immunologic, ophthalmologic, or 
dermatologic disease of any etiology (including infections), 
2. Presence or history of significant gastrointestinal, liver or kidney disease, or surgery that 
may affect drug bioavailability with the exception that cholecystectomy is permitted at 
the discretion of an investigator, 
3. Presence of any significant respiratory illness or presence or history of chronic 
respiratory disease (e.g., upper respiratory illness, sleep apnea, emphysema, asthma) at 
screening (subjects with acute respiratory illness may be rescheduled upon resolution at 
the discretion of an investigator), 
4. Personal or family history (first degree relatives) of allergy, hypersensitivity, or drug rash 
with eosinophilia and systemic symptoms (DRESS) syndrome to gabapentin enacarbil, 
gabapentin or any drug product including anti-convulsants (e.g., alprazolam, 
carbamazepine) or related drugs (e.g., other benzodiazepines) or known excipients of any 
of the drug products in this study (e.g., lactose),  
5. History of sensitivity to or poor tolerance of gabapentin enacarbil, gabapentin, 
pregabalin, or alprazolam, 
6. Female who is lactating at screening, 
7. Female who is pregnant according to the pregnancy test at screening or prior to the first 
study drug administration or planning to become pregnant within 30 days following the 
last study drug administration, 
8. History of substance or alcohol dependence (excluding nicotine and caffeine) within the 
past 2 years, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV), and/or subject has been in a drug or alcohol rehabilitation program 
within the last 2 years, 


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9. Subjects with positive UDS results at screening and admission will be assessed for 
inclusion at the discretion of an Investigator. If tetrahydrocannabinol (THC) is positive at 
admission to the Qualification phase and Treatment phase, as applicable, a cannabis 
intoxication evaluation will be done by an investigator and subjects may be permitted to 
continue in the study, rescheduled, or discontinued at the discretion of an investigator. 
Other positive test results should be reviewed to determine if the subject may be 
rescheduled, in the opinion of the investigator, 
10. Is a heavy smoker (>20 cigarettes per day or nicotine-equivalent) and/or is unable to 
abstain from smoking or unable to abstain from the use of prohibited nicotine-containing 
products for at least 1 hour before and 6 hours after study drug administration (including 
e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine gum, or 
nicotine lozenges), 
11. Regularly consumes excessive amounts of caffeine or xanthines within 30 days prior to 
screening, defined as greater than 6 servings (1 serving is approximately equivalent to 
120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day, 
12. History of suicidal ideation within 24 months or suicidal behaviour within 2 years of 
screening, showing suicidal tendency as per the Columbia Suicide Severity Rating Scale 
(C-SSRS) administered at screening (APPENDIX 7), or is currently at risk of suicide in 
the opinion of an investigator, 
13. Presence of clinically significant ECG abnormalities at the screening visit, as defined by 
medical judgment, NOTE: QT corrected according to Fridericia's formula (QTcF) 
interval of >450 msec in male subjects or >470 msec in female subjects will be 
exclusionary. The ECG may be repeated once for confirmatory purposes if the initial 
value obtained exceeds the limits specified, 
14. Has creatinine clearance ≤60 ml/min as calculated by the Cockcroft-Gault equation, 
15. Any history of tuberculosis, 
16. Positive screening results to human immunodeficiency virus (HIV) 1 and 2 antibodies, 
hepatitis B virus surface antigen (HBsAg) or hepatitis C virus antibody (HCV Ab) tests, 
17. Intake of an investigational product (IP) within 30 days or 5 times the half-life 
(whichever is longer) prior to screening, 
18. Use of any prescription drugs (with the exception of hormonal contraceptives or hormone 
replacement therapy) in the 30 days prior to the first study drug administration, that in the 
opinion of an investigator would put into question the status of the subject as healthy, 


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19. Use of over-the-counter (OTC) products (including herbal preparations and supplements) 
within 7 days prior to the first study drug administration, with the exception of ibuprofen 
or acetaminophen, 
20. Donation of plasma in the 7 days prior to screening, 
21. Blood donation (excluding plasma) of approximately 500 mL of blood in the 56 days 
prior to screening, 
22. Is, in the opinion of an investigator or designee, considered unsuitable or unlikely to 
comply with the study protocol for any reason, 
23. Poor venous access at screening, as judged by an investigator. 
4.3 
Qualification Criteria for Treatment Phase 
Subjects must meet the following criteria to be considered eligible for enrollment in the 
Treatment phase of the study: 
1. Peak score in response to alprazolam 2 mg greater than that of placebo on Drug Liking 
VAS (difference of at least 15 points), with a peak score of at least 65 points for 
alprazolam. 
2. Acceptable placebo response based on Drug Liking VAS (peak score between 40 and 
60 points, inclusive). 
3. Acceptable overall responses to alprazolam and placebo on the subjective measures, as 
judged by an investigator or designee. 
4. Able to tolerate the 2 mg dose of alprazolam, as judged by an investigator, including no 
episodes of vomiting during the first 3 hours postdose. Subjects with unarousable 
sedation within the first 4 hours postdose will not be eligible for the Treatment phase. 
5. General behavior suggests that the subject could successfully complete the study, as 
judged by the investigational site staff. On a case-by-case basis, otherwise eligible 
subjects who appear to have difficulty differentiating between bipolar and unipolar VAS 
(e.g., making errors such as selecting 50 as neutral for a unipolar scale) or difficulty 
distinguishing between "at this moment" and "next-day" measures during the 
Qualification phase may be permitted into the Treatment phase, and will undergo 
additional training on the difference between the scale types. Additional training sessions 
will be documented in source files. 


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4.4 
Withdrawal Criteria 
4.4.1 Before First Treatment Administration 
Before the first treatment administration, inclusion/exclusion criteria will govern the subjects to 
be dosed. Subjects withdrawn before first treatment administration will not be followed up and 
will not undergo ET assessments. Other safety assessments may be performed if required. 
Subjects are free to withdraw their consent to participate in the study at any time, without 
prejudice. The reason for their withdrawal or for deciding to end their participation will be 
documented. 
4.4.2 After First Treatment Administration 
Subjects may, at any time, voluntarily withdraw from the study or be removed from the study at 
the discretion of an investigator or sponsor. An investigator may withdraw a subject at any time 
if it is determined that continuing the study would result in a significant safety risk to the subject 
or if their behavior is deleterious to the study environment. 
If such withdrawal occurs, or if the subject fails to return for visits, an investigator should 
determine the primary reason for a subject’s premature withdrawal from the study and record the 
reason in the subject’s study documents. 
Attempts should be made to have such subjects complete the ET assessments. ET assessments 
should be performed as soon as possible after the last study treatment administration. 
The blind may be broken only in emergency situations, where knowledge of the treatment that 
the subject received is necessary for safety management (section 5.2.4) 
Details of reasons for removal of subjects will be recorded, reported to the sponsor and 
documented in the clinical study report (CSR). 
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), an investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the subject 
(e.g., dates of telephone calls, registered letters). 


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4.5 
Lifestyle and/or Dietary Requirements 
 Subjects will be prohibited from consuming food or beverages containing grapefruit, 
pomelo, pomegranate, star fruit, Seville orange, poppy seeds, and quinine (i.e., tonic 
water) for 7 days prior to the first study treatment and throughout the study. 
 Subjects will be prohibited from consuming alcohol for 48 hours prior to each study visit 
and from recreational drug use from screening and throughout the study. In case of any 
doubt, a test for alcohol and/or a drug screen may be performed if requested by an 
investigator. If a subject presents with a positive alcohol test or drug screen at any visit 
after the screening visit, the subject may be rescheduled at the discretion of an 
investigator. If THC is positive at check-in, a cannabis intoxication evaluation will be 
done by an investigator, and inclusion will be at the investigator’s discretion. 
 Subjects will be prohibited from consuming food or beverages containing xanthines 
(i.e., tea, coffee, cola drinks, energy drinks or chocolate) for 24 hours prior to the first 
study treatment through clinic discharge. 
 Subjects will eat only the food provided by the study site during confinement at the CRU. 
 Subjects will be instructed to abstain from strenuous physical activity for 48 hours prior 
to screening, each study treatment, and during inpatient stays at the investigational site. 
 During the study, smokers will abstain from smoking for at least 1 hour prior to and until 
at least 6 hours after drug administration at each study period. Subjects will not be 
permitted to use other nicotine-containing products (including nicotine topical patches, 
nicotine gum, or nicotine lozenges). 
 Subjects will be instructed to refrain from driving, operating machinery, or engaging in 
hazardous activities until they and an investigator are convinced the study drug is not 
impairing their judgment and/or ability to perform skilled tasks. 
 Female subjects of childbearing potential will have to take appropriate measures to 
prevent pregnancy as described in section 4.1. It is the subject’s responsibility to notify 
the CRU if a pregnancy occurs from the end of their study participation until 30 days 
after the last dose of the study drug. 
 Males who are sexually active will be expected to use an acceptable contraceptive 
regimen and not to donate sperm from the first administration of the study drug, during 
the study, and until at least 90 days after the last drug administration, as described in 
section 4.1. 
4.6 
Concomitant Treatment 
Except for medication or treatments specifically allowed per protocol and those which may be 
required to treat AEs, no other treatment or medication other than the study drugs will be 
allowed from screening until all study activities and evaluations have been completed. 
Systemic contraceptives and hormone replacement therapy are permitted for female subjects. 
Subjects will be asked about any new medications (including herbal preparations and 
supplements) taken between screening and admission to the clinic, and between the Qualification 


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and Treatment phase, if a subject is discharged during this interim period. Information on any 
concomitant medications administered after consent will be collected throughout the study. All 
medications and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the subject has received the study treatment must be listed in the 
subject case report form (CRF) and related conditions (e.g., AEs) documented. The drug name 
and dose taken will be noted. An investigator and/or the sponsor will decide whether the subject 
will be permitted to remain in the study, depending on the drug used, the time of drug intake, etc. 
5 
STUDY TREATMENTS 
5.1 
Investigational Products 
GE-IR capsules will be provided by the sponsor. The lot number and the measured content of the 
dosage form, when available, of each formulation will be included in the final report. 
5.1.1 Gabapentin Enacarbil 
GE-IR capsules will be provided by Arbor Pharmaceuticals, LLC for oral administration, and 
will be provided in opaque capsules of a suitable size to contain all study doses in order to 
maintain the blind during dosing. 
Placebo capsules matched to GE-IR will be supplied by the sponsor. The weight is matched to 
the sponsor’s GE-IR capsule and the composition is the same, including excipients. 
5.1.2 Alprazolam 
Xanax (alprazolam) is manufactured by Pfizer, Inc. and will be supplied as 1 mg tablets. To 
maintain the study blind alprazolam tablets will be over-encapsulated. A single dose of 
alprazolam 2 mg will consist of 2 × 1 mg tablets over-encapsulated. 
Placebo to match alprazolam tablets will be over-encapsulated 2 × 100 mg lactose tablets. 
Over-encapsulated doses may be prepared up to 72 hours prior to dosing. Both the placebo to 
match alprazolam and alprazolam treatment assignments will utilize the Swedish Orange Opaque 
AAE-DB capsules by Capsugel for over-encapsulation, to ensure the study blind is maintained. 
5.2 
Investigational Product Management 
5.2.1 Packaging, Labeling and Dispensing 
The sponsor will be responsible for ensuring that GE-IR is manufactured in accordance with 
applicable current Good Manufacturing Practice (cGMP) regulations and requirements. 
The study drug will be labeled according to the requirements of local law and legislation. The 
study drug will be dispensed according to International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) by the CRU’s pharmacy, unless the sponsor supplies the pharmacy with 
pre-labeled individual dosing samples. 


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5.2.2 Storage and Handling 
Once received, all study drugs will be stored in the CRU’s pharmacy. 
GE-IR capsules and placebo should be stored at 25°C with excursions between 15°C and 30°C 
allowed. Both placebo to match alprazolam and alprazolam should be stored between 15°C and 
30°C. All study drugs should be kept in a tightly closed container, with provided desiccants, to 
protect from moisture. The products should not be used if expired and should not be frozen. 
The CRU’s pharmacy will maintain an inventory record of the study drugs received, stored (in a 
secure restricted area), and dispensed. Study drugs will be provided to study subjects only. 
5.2.3 Method of Assigning Subjects to Treatment Groups 
The designated, unblinded biostatistician will generate the separate randomization codes for the 
Qualification and Treatment phases with a computer program according to the study design, the 
number of subjects and the sequence of treatment administration. For the Qualification and 
Treatment phases, the random allocation of each sequence of treatment administration to each 
subject will be done in such a way that the study is balanced. Once generated, the randomization 
codes will be final and will not be modified. 
Subjects who sign the ICF and are randomized but do not receive a study treatment in the 
Treatment phase may be replaced. Subjects who sign the ICF, are randomized and receive a 
study treatment in the Treatment phase, and subsequently withdraw, or are withdrawn or 
discontinued from the study, may be replaced. 
5.2.3.1 Qualification Phase 
Subjects who enter the Qualification phase will be assigned, in ascending order, a qualification 
randomization number to identify the sequence of their treatments (Table 2). 
Table 2. Sample Qualification Phase Sequences 
Treatment Sequence 
Day 1 
Day 3 
XY 
X 
Y 
YX 
Y 
X 
Treatment X: Placebo 
Treatment Y: Alprazolam 2 mg (active control) 
A minimum 3-day washout will be required between the last dose in the Qualification phase and 
the first dose of the Treatment phase. 
5.2.3.2 Treatment Phase 
For the Treatment phase, qualified subjects will be randomized to 1 of 10 treatment sequences 
based on a computer-generated randomization schedule. The first dose will be administered 
at least 3 days after the Qualification phase. The study drug will be prepared for each subject 
based on their randomization code. Subjects will receive all 5 treatments in the order specified by 
the treatment sequence according to two 5 × 5 Williams square design (Table 3). 


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Table 3. Sample Treatment Phase Sequences 
Treatment 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
Period 5 
ABECD 
A 
B 
E 
C 
D 
BCADE 
B 
C 
A 
D 
E 
CDBEA 
C 
D 
B 
E 
A 
DECAB 
D 
E 
C 
A 
B 
EADBC 
E 
A 
D 
B 
C 
DCEBA 
D 
C 
E 
B 
A 
EDACB 
E 
D 
A 
C 
B 
AEBDC 
A 
E 
B 
D 
C 
BACED 
B 
A 
C 
E 
D 
CBDAE 
C 
B 
D 
A 
E 
Treatment A: Placebo 
Treatment B: Alprazolam 2 mg (active control) 
Treatment C: GE-IR 200 mg 
Treatment D: GE-IR 450 mg 
Treatment E: GE-IR 700 mg 


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5.2.4 Blinding 
The treatment assignment will not be known by the study subjects. 
Furthermore, the randomization code will not be available to investigators and clinical staff 
involved in the collection, monitoring, revision, or evaluation of AEs, as well as clinical staff 
that could have an impact on the outcome of the study, including the biostatistician and 
pharmacokineticist (or delegate). When all PD assessments during the Qualification phase have 
been completed for each cohort, the randomization will be released to allow for the evaluation of 
qualification criteria. For the Treatment phase, the randomization will remain blinded until all 
the CRFs have been approved and signed. 
The preparation and/or dispensing of the products will be performed by designated personnel 
that are not directly involved in the clinical aspects of the trial. 
The randomization code must not be broken except in emergency situations where the 
identification of a subject’s study treatment is required by an investigator for further treatment of 
the subject or by the designated unblinding person(s) in the case of a suspected, unexpected SAE 
(SUSAR) report. Randomization information will be held by designated individual(s). The date 
and reason for breaking the blind must be recorded. 
5.2.5 Study Drug Accountability 
Complete and accurate inventory records of all study drugs will be kept. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. 
Drug accountability will be performed throughout the trial and at the completion of the trial. 
5.3 
Administration of Study Drug, Meals and Fluids 
Study treatments, as described in section 3.2, will be administered in the morning. Each subject 
will be dosed at approximately the same time in each period, and all scheduled postdose 
activities and assessments will be performed relative to the time of study drug administration. 
The date and time of each dose will be recorded. 
An oral dose of the assigned treatment will be administered to subjects with approximately 
240 mL of water at ambient temperature following at least a 10-hour fast. The dose must be 
swallowed whole and must not be chewed or broken. After the subject indicates that the study 
drug has been swallowed, study personnel will inspect the oral/buccal cavity to ensure that the 
study drug was swallowed. 
Food and fluid intake other than water will be controlled for each confinement period and for all 
subjects. Water will be provided as desired until at least 1-hour predose. Water will be allowed 
beginning at least 1 hour after the administration of the drug. No food will be allowed until at 
least 4 hours after each dose. 
5.3.1 Treatment Compliance 
The study drug(s) will be dispensed only to eligible subjects and administered under the 
supervision of study personnel. Treatment compliance will be verified according to the site’s 
standard operating procedures (SOPs). 


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5.4 
Other Protocol Restrictions 
Subjects will remain seated or kept in minimal ambulatory movement in the immediate study 
area for at least 6 hours following drug administration, avoiding vigorous exertion. However, 
should AEs occur at any time, subjects may be placed in an appropriate position. During this 
interval subjects will be permitted, under supervision, to get up (e.g., to use the washroom 
facilities). Subjects will not engage in strenuous activity at any time during the confinement 
periods. 
6 
STUDY PROCEDURES 
Unless otherwise stated in this protocol, the SOPs of the study facilities, which are available for 
all activities relevant to the quality of the study, will be followed during this study. Procedure 
windows, including PK/PD sample collection windows, will be documented in a separate clinical 
document. 
An overview of the study activities for each subject is detailed in Table 1. 
Pharmacodynamic data collection (vital signs then subjective measures) is to be prioritized, 
followed by PK blood sampling, when clinical activities are scheduled to occur at the same time. 
Subjects will be confined to the clinical site from Day -1 of the Qualification phase through 
Day 4 of the Qualification phase. Subjects will be admitted to the clinical site on Day -1 of the 
Qualification phase and be dosed on Days 1 and 3. Subjects not qualifying for the Treatment 
phase may be discharged on Qualification Day 4 after final assessments are completed. Those 
subjects qualifying for the study will continue to the Treatment phase. These subjects will be 
encouraged to remain in the clinic, but may be discharged, if necessary, and return to the clinical 
site on Day -1 of the Treatment phase. A minimum 3-day washout will be required between the 
last dose in the Qualification phase and the first dose of the Treatment phase. 
Subjects will be discharged on Day 14 of the Treatment phase. 
Any deviation from protocol procedures shall be noted in the source documentation and 
compiled for reporting in the clinical study report. 
6.1 
Safety Assessments 
Safety assessments will include physical examination, C-SSRS, vital signs (i.e., systolic and 
diastolic blood pressure, pulse rate, respiratory rate, oral temperature, SpO2), 12-lead ECG, 
clinical laboratory tests, and AE monitoring. Continuous SpO2 monitoring and continuous EtCO2 
will be conducted for approximately 6 hours postdose. Additional safety measurements may be 
performed at the discretion of an investigator for reasons related to subject safety. 
An investigator will be present at the clinical site for at least the first 6 hours following each drug 
administration and will remain available at all times throughout the study. 
6.1.1 Medical History 
Medical history will be reviewed as scheduled in Table 1 and will include all queries by the 
medical and clinical staff related to the subject’s well-being and history of relevant past medical 
events/experiences. Medical history will include all demographic data (age, gender, race, body 
weight, height, and BMI) and baseline characteristics. Smoking habits will also be recorded. 


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Any medical conditions occurring from the time of signing informed consent through the first 
dose of study treatment in the Qualification phase will be recorded as medical history. If the 
condition meets the criteria for an SAE it will be reported as described in section 7.6. Medical 
history conditions that worsen and are judged to be clinically significant will be recorded as AEs. 
6.1.2 Recreational Alcohol/Drug Use 
A lifetime history of all drug use, including alcohol, will be collected as scheduled in Table 1. 
History, including drug preference (i.e., drug of choice), frequency of use, and date of last use 
will be collected using reported drug names and drug class (e.g., cannabinoids, depressants, 
dissociative anesthetics, hallucinogens, opioids and morphine derivatives, and stimulants). 
DSM-IV modules will be included as a part of the recreational drug/alcohol use history and used 
to screen for alcohol and substance dependence. 
6.1.3 Physical Examination 
A physical examination will be performed by a medically qualified and licensed individual as 
scheduled in Table 1. 
The physical examination will include a general review of the following body systems (at 
minimum): general appearance, head, eyes, ears, nose and throat (HEENT), neck/thyroid, 
cardiovascular, respiratory, gastrointestinal, neurological, musculoskeletal/extremities, and skin. 
A symptom-oriented physical exam may be conducted as indicated in Table 1, at the discretion 
of an investigator. 
6.1.4 Vital Signs 
Vital signs will be measured as scheduled in Table 1 and will include blood pressure, pulse rate, 
respiratory rate and SpO2 measures at designated times. 
All vital signs will be interpreted by an investigator as normal, abnormal not clinically 
significant (NCS), or abnormal clinically significant (CS). New or worsening abnormalities that 
are judged to be clinically significant will be recorded as AEs. 
Vital signs will be measured after being in supine or semi-supine position for at least 5 minutes. 
6.1.4.1 Continuous and Spot Oxygen Saturation 
Assessments of respiratory depression will include continuous and spot SpO2 monitoring, as 
scheduled in Table 1. Spot oxygen saturation will be measured using a portable pulse oximeter 
placed on the subject’s fingertip. Continuous oxygen saturation will be monitored through a 
capnography monitor. 
SpO2 will be monitored for alarms continuously up to 1 hour prior to each study drug 
administration and will continue for up to 6 hours following each drug administration, or longer 
if deemed medically necessary. In addition, respiratory rate will be recorded at nominal 
timepoints post dosing, as scheduled in Table 1. Any SpO2 event that is deemed clinically 
significant will be reported as an AE if it meets the criteria of significance defined in 
section 6.1.8. 


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6.1.4.2 Continuous and Spot End-Tidal CO2 
Assessments of respiratory depression will include continuous and spot EtCO2 through a 
capnography monitor, as scheduled in Table 1. 
EtCO2 will be monitored continuously for alarms up to 1 hour prior to each study drug 
administration and will continue for up to 6 hours following each drug administration, or longer 
if deemed medically necessary. Baseline EtCO2 will be recorded within 1 hour prior to each dose 
administration. In addition, EtCO2 will be recorded at nominal timepoints post dosing, as 
scheduled in Table 1. Any EtCO2 event that is deemed clinically significant will be reported as 
an AE if it meets the criteria of significance defined in section 6.1.8. 
6.1.4.3 Continuous and Spot Respiratory Rate 
Assessments for respiratory depression will be monitored for alarms by continuous and spot 
respiratory rate as scheduled in Table 1. Spot respiratory rate will be measured by counting 
breaths for 1 minute. Continuous respiratory rate will be monitored through a capnography 
monitor. 
Respiratory rate will be monitored continuously up to 1 hour prior to each study drug 
administration and will continue for up to 6 hours following each drug administration, or longer 
if deemed medically necessary. Baseline respiratory rate will be recorded within 1 hour prior to 
each dose administration. In addition, respiratory rate will be recorded at nominal timepoints 
post dosing, as scheduled in Table 1. Any respiratory rate event that is deemed clinically 
significant will be reported as an AE if it meets the criteria of significance defined in 
section 6.1.8. 
6.1.5 12-Lead Electrocardiogram 
A 12-lead ECG will be performed as scheduled in Table 1. 
Electrocardiograms will be performed after the subject has been resting in a supine position for 
at least 5 minutes. 
All abnormal ECGs will be interpreted by an investigator as abnormal NCS, or abnormal CS in 
source documents. New or worsening abnormalities that are judged to be clinically significant 
will be recorded as AEs. 
6.1.6 Laboratory Evaluations 
Laboratory evaluations will be performed as scheduled in Table 1. 
The laboratory evaluations to be conducted for this study are presented in APPENDIX 6. The 
total blood volume for screening and safety assessments will be approximately 15 mL. 
Each abnormal value will be interpreted by an investigator as abnormal NCS, or abnormal CS. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs. 
Urine samples to be collected during the course of this study include pregnancy tests and drug 
screens as outlined in Table 1. 


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Additional clinical laboratory tests may be performed by the medical laboratory as part of larger 
standard test panels (not required for subject safety). Only test results required by the protocol 
and/or abnormal results will be entered in the clinical database and reported in the CSR, based on 
report requirements. 
6.1.7 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire designed for the assessment of suicidal ideation and behavior in 
adolescents and adults. 
To monitor for a history of (the past 2 years/24 months to present) or the emergence during study 
participation of suicidal ideation and behavior, subjects will undergo C-SSRS evaluations at the 
timepoints indicated in Table 1. 
The questionnaire must be administered by an investigator or other individual that is suitably 
qualified by education or training and designated. See APPENDIX 7 for a sample C-SSRS –
Baseline/Screening version assessment and APPENDIX 8 for a sample C-SSRS-Since Last Visit 
version assessment. 
If a subject becomes suicidal during the study, an investigator or medically qualified 
sub-investigator should provide the appropriate treatment and/or referral to the subject, and 
record as an AE. 
6.1.8 Assessment of Respiratory Depression 
Capnography alarms will be set to evaluate for respiratory depression and will include: 
 An increase in EtCO2 to >50 mmHg 
 A reduction in O2 saturation to <90% 
 A reduction in respiratory rate to <6 breaths per minute 
All alarms will be assessed for clinical significance and reported as AEs, as applicable. 
Supplemental oxygen will be given as medically necessary. 
6.1.9 Rescue Therapy 
The clinical study site is equipped with emergency equipment and supplies that correspond with 
the level of risk associated with this study. In case of a medical emergency or an SAE requiring 
medical intervention, emergency equipment and supplies will be available and will include, but 
may not be limited to, stocked crash carts, oxygen source, suction pump, and defibrillator. 
Emergency medication (e.g., flumazenil, diphenhydramine, epinephrine, methylprednisolone, 
ranitidine, rescue medication required for advanced cardiac life support [ACLS]) may be 
administered if deemed necessary by an investigator or designee. If required, subjects will be 
transported to a hospital. 
During the Qualification and Treatment phases, the principal investigator (PI) or designee will be 
on-site at the time of study drug administration until at least 6 hours postdose. ACLS-certified 
staff will be present on site and an investigator will be readily available by telephone. 


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When not available on-site, the PI or designee will be on-call until the end of the study. While 
confined in the CRU, subjects will be supervised by staff nurses and/or paramedics. Dedicated 
nurses and/or paramedics will be available to monitor AEs and perform safety measures. 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication will be recorded. 
6.2 
Pharmacokinetic Assessments 
A total of 14 blood samples will be collected following each dose in the Treatment phase for PK 
assessments. The complete blood sampling schedule is presented in Table 4. 
Table 4. Pharmacokinetic Blood Sampling Schedule 
Sample No 
Nominal Time* 
(hours) 
01 
0.0 
02 
0.5 
03 
1 
04 
1.5 
05 
2 
06 
2.5 
07 
3 
08 
4 
09 
5 
10 
6 
11 
7 
12 
8 
13 
10 
14 
24 
* 
Nominal times listed are relative to the time of study treatment administration. 
Blood samples will be collected by direct venipuncture into a labeled tube containing the 
appropriate anticoagulant as specified by the bioanalytical facility. As an option to the subject, or 
if judged necessary by the clinical staff, blood samples may be collected using a catheter, which 
will be placed in the vein of the subject. 
The time of PK blood sample collection will be calculated relative to the time of dose 
administration. The actual time of all PK blood draws will be recorded and reported for all 
subjects. Each subject will be dosed at the same time in each period and all activities 
(e.g., scales, meals) will be based on that dosing time. Blood volume required for PK 
assessments will be included in the total blood volume reported in the informed consent. 


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Gabapentin concentrations for PK assessments will be obtained through bioanalysis of the 
plasma derived from the blood samples drawn during this study, using a validated bioanalytical 
method. 
6.2.1 Pharmacokinetic Sample Processing, Storage and Shipping 
Blood samples for PK determination will be processed, stored, and shipped according to the 
sample processing instructions supplied by the bioanalytical facility. Each tube will be 
appropriately labeled. 
6.3 
Pharmacodynamic Assessments 
Pharmacodynamic assessments will be performed throughout the study as outlined in Table 1. 
Prior to completing the computerized PD measures, all subjects will undergo a scripted training 
and practice regimen. Eligible subjects who appear to have difficulty differentiating between 
bipolar and unipolar VAS (e.g., making errors such as selecting 50 as neutral for a unipolar 
scale) or difficulty distinguishing between "at this moment" and "next-day" measures during the 
Qualification phase will undergo additional training on the difference between the scale types. 
Additional training sessions will be documented in source files. 
Testing conditions for PD assessments should remain as consistent as possible across treatment 
periods. Subjects will be monitored carefully to ensure that they are completing the PD 
assessments appropriately; all reasonable attempts should be made to rouse subjects who fall 
asleep during testing cycles. If subjects cannot complete the PD assessments in a timely manner 
prior to the next required procedure or timepoint due to an AE, testing will be aborted. 
6.3.1 Subjective Effects 
6.3.1.1 Visual Analogue Scales 
All VASs will be scored on a 100-point scale, as shown in Table 5. The VASs may be 
administered as bipolar or unipolar scales, as appropriate, and the choice is determined by the 
nature of the subjective effect being measured. Bipolar scales ask about the neutrality, the 
direction and the intensity of a subjective opinion, whereas unipolar scales only ask about the 
extremity or intensity of a subjective opinion. When VASs are administered as bipolar scales, a 
neutral point equal to 50 is embedded within the scale (e.g., Drug Liking, Overall Drug Liking, 
Take Drug Again, Drowsiness/Alertness VAS). The neutral point reflects a state whereby a 
subject is experiencing neither negative nor positive effects (e.g., neither dislike nor like the 
effects of the drug) and is labeled with an anchor, such as “neither like nor dislike.” When VASs 
are administered as unipolar scales, anchors will be presented using text such as “Not at all” 
(score = 0) to “Extremely” (score = 100; e.g., Good, Bad, High, and Any Effects VASs). 
Unipolar scales do not include a neutral point but rather, a rating of “0” reflects the complete 
absence of a subjective effect while a rating of “100” reflects the maximum presence of a 
subjective effect (e.g., No Good Effects = 0, Extremely Good Effects = 100). Scales that refer 
specifically to drug (e.g., Drug Liking, Good Effects VAS, Bad Effects VAS, and Any Effects 
VAS) are not administered at predose. 


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Table 5. Visual Analog Scale (VAS) Descriptions 
Scale 
Interpretation 
Include 
Predose
Type of 
Scale 
Description 
Question Text 
Response 
Anchors 
Balance 
No 
Bipolar 
Drug Liking 
At this moment, my 
liking for this drug is 
0: Strong 
disliking 
50: Neither like 
nor dislike 
100: Strong 
liking 
Balance 
No 
Bipolar 
Overall Drug Liking 
Overall, my liking for 
this drug is 
Balance 
No 
Bipolar 
Take Drug Again 
I would take this drug 
again 
0: Definitely 
would not 
50: Neither 
would nor would 
not 
100: Definitely 
would 
Positive 
Yes 
Unipolar 
High 
At this moment, I am 
feeling high 
0: Not at all 
100: Extremely 
Positive 
No 
Unipolar 
Good Effects 
At this moment, I feel 
good drug effects 
Negative 
No 
Unipolar 
Bad Effects 
At this moment, I feel 
bad drug effects 
Other 
No 
Unipolar 
Any Effects 
At this moment, I feel 
any drug effect 
Other 
Yes 
Unipolar 
Feeling Drunk 
At this moment, I am 
feeling drunk 
Other  
Yes 
Bipolar 
Drowsiness/Alertness 
At this moment, my 
mental state is 
0: Very drowsy 
50: Neither 
drowsy nor alert 
100: Very alert 
Other 
Yes 
Bipolar 
Relaxation/Agitation 
At this moment, my 
mental state is 
0: Very relaxed 
50: Neither 
relaxed nor 
agitated 
100: Very 
agitated 


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6.3.1.2 Questionnaires 
The ARCI MBG and PCAG scales will be administered as scheduled in Table 1. 
The 49-item ARCI is a shortened version (49 true-false items) compiled by Martin et al.37 from 
the 550-item Addiction Research Center Inventory (ARCI) originally developed by Haertzen.38,39 
This version contains 5 scales, which measure the following effects: Euphoria -- Morphine-
Benzedrine Group (MBG) scale; Stimulant effects -- Amphetamine (A) scale and Benzedrine 
Group (BG) scale; Dysphoria -- Lysergic Acid Diethylamide (LSD) scale; and Sedation --
Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) scale. Subjects indicate their responses 
by selecting “False” or “True.” One point is given for each response that agrees with the scoring 
direction on the scale (i.e., True items receive a score of 1 if the answer is “True;” no points are 
given when the answer is opposite to the scoring direction). 
The following 2 scales will be administered: 
 Pentobarbital Chlorpromazine Alcohol Group – PCAG 
 Morphine Benzedrine Group – MBG 
The items pertaining to the ARCI MBG and ARCI PCAG scales are presented below: 
Questions Contributing to ARCI MBG & PCAG Scales  
Scale 
PCAG MBG
1. My speech is slurred. 
T 
 
2. I am not as active as usual. 
T 
 
3. I have a feeling of just dragging along rather than coasting. 
T 
 
4. I feel sluggish. 
T 
 
5. My head feels heavy. 
T 
 
6. I feel like avoiding people, although I usually do not feel this way.
T 
 
7. I feel dizzy. 
T 
 
8. It seems harder than usual to move around. 
T 
 
9. I am moody. 
T 
 
10. People might say that I am a little dull today. 
T 
 
11. I feel drowsy. 
T 
 
12. I am full of energy. 
F 
 
13. Today I say things in the easiest possible way. 
 
T 
14. Things around me seem more pleasing than usual. 
 
T 
15. I have a pleasant feeling in my stomach. 
 
T 
16. I feel I will lose the contentment that I have now. 
 
T 


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17. I feel in complete harmony with the world and those about me. 
 
T 
18. I can completely appreciate what others are saying when 
I am in this mood. 
 
T 
19. I would be happy all the time if I felt as I feel now. 
 
T 
20. I feel so good that I know other people can tell it. 
 
T 
21. I feel as if something pleasant had just happened to me. 
 
T 
22. I would be happy all the time if I felt as I do now. 
 
T 
23. I feel more clear-headed than dreamy. 
F 
T 
24. I feel as if I would be more popular with people today. 
 
T 
25. I feel a very pleasant emptiness. 
 
T 
26. My thoughts come more easily than usual. 
 
T 
27. I feel less discouraged than usual. 
 
T 
28. I am in the mood to talk about the feelings I have. 
 
T 
29. I feel more excited than dreamy. 
F 
 
30. A thrill has gone through me one or more times since 
I started this test. 
F 
 
T = True item 
F = False item 
Responses to individual items will be included. If one of the individual items is missing, the 
associated scale(s) score will not be calculated. 
6.3.2 Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
The MOAA/S is an observer-rated measure of alertness/sedation that is used widely in clinical 
research. It is based on the following 6 items, rated on a scale from 5 (not sedated) to 
0 (unarousable): 
The Observer’s Assessment of Alertness/Sedation Scale (OAA/S) was developed to measure the 
level of alertness in subjects who are sedated.36 The OAA/S is a reliable validated measure and 
was shown to be sensitive to different levels of sedation and is composed of 4 assessment 
categories that include responsiveness, speech, facial expression, and eyes. The Modified 
Observer's Assessment of Alertness/Sedation Scale (MOAA/S) includes only the Responsiveness 
assessment category. It is easy and quick to administer (less than 1 minute). The subjects’ level 
of responsiveness is measured in a 5-point Likert scale: 


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Responsiveness 
Score 
Responds readily to name spoken in normal tone 
5 (Alert) 
Lethargic response to name spoken in normal tone 
4 
Responds only after name is called loudly and/or repeatedly 
3 
Responds only after mild prodding or shaking 
2 
Does not respond to mild prodding or shaking 
1 (Deep Sleep) 
7 
ADVERSE EVENTS DOCUMENTATION 
7.1 
Definitions 
An AE is defined as any untoward medical occurrence in a subject administered an 
investigational product and which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal clinical laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational 
product. 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility the 
drug caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the AE. A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any AE caused by a drug. 
Regarding marketed medicinal products, an adverse drug reaction is defined as a response to a 
drug which is noxious and unintended and which occurs at doses normally used in man for 
prophylaxis, diagnosis, or therapy of disease or for modification of physiological function. 
An AE may be: 
 A new illness, 
 Worsening of a concomitant illness, 
 An effect of the study drug including comparator; it could be an abnormal clinical 
laboratory value as well as a significant shift from baseline within normal range which an 
investigator considers to be clinically important. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 


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An SAE or reaction is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions), 
 Is a congenital anomaly or birth defect, 
 Is an important medical event (including development of drug dependence or drug abuse) 
that may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above (according to medical judgment of an investigator). 
7.2 
Severity Assessment 
All AEs will be graded as mild, moderate, or severe according to the following definitions: 
Mild: 
Causing no limitation of usual activities; the subject may experience transient slight 
discomfort. 
Moderate: Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
Severe: 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
Every effort will be made to obtain an adequate evaluation of the severity. 
7.3 
Causality Assessment 
An investigator will determine the relationship of any AE to the study drug using the guidelines 
presented in Table 6. 


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Table 6. Adverse Event Relationship to Study Drug 
Relationship to Drug 
Comment 
Reasonable Possibility 
A temporal relationship exists between the AE onset and 
administration of the investigational product that cannot be readily 
explained by the subject’s clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be 
related, based on the known therapeutic and pharmacologic actions or 
AE profile of the investigational product. 
In case of cessation or reduction of the dose the AE may abate or 
resolve and it may reappear upon rechallenge. 
No Reasonable Possibility 
Evidence exists that the AE has an etiology other than the 
investigational product. 
For SAEs, an alternative causality must be provided (e.g., preexisting 
condition, underlying disease, intercurrent illness, or concomitant 
medication). 
 
7.4 
Adverse Event Monitoring 
For the purposes of this study, the monitoring period for AEs extends from the time of first study 
treatment administration in the Qualification phase until Day 14 of the Treatment phase. Any 
medical conditions occurring from the time of signing informed consent until the first dose of 
study treatment in the Qualification phase will be recorded as medical history. If the condition 
meets the criteria for an SAE it will be reported as described in section 7.6. 
Subjects will be questioned on their health status prior to each study treatment and periodically 
thereafter, including prior to PD measurements. Open-ended questions will be asked. 
During the study, all AEs spontaneously reported by the subject, observed by the clinical staff or 
elicited by general questioning will be recorded for all subjects and reported in the CRF. 
Every effort will be made to obtain an adequate follow-up of the subjects and the final outcome. 
Should any subject choose to withdraw from the study, they will be advised of the safety 
precautions to be taken. 
Any AE which remains unresolved as of the last visit will require an appropriate evaluation and 
follow-up until the AE has been resolved or a reasonable explanation for its persistence found, or 
is deemed mild and safely resolving. 
It is an investigator’s responsibility to ensure subjects experiencing adverse events receive 
appropriate follow-up, treatment where required, and that every action is well-documented. 
Classification of AEs will be performed by system organ class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA), version 22.0 or higher. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary-
Enhanced (WHO-DDE March 2019 or later). 


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7.5 
Reporting of Pregnancy 
Pregnancy in a female study subject shall be reported to the sponsor within 24 hours of the 
knowledge of its occurrence by an investigator or delegate (for pregnancies occurring during the 
course of the study or up to 30 days following the end of the study). Because of the possibility 
the fetus/embryo could have been exposed to the study drug through the parent and for the 
subject’s safety, the pregnancy will be followed up to determine its outcome, including 
spontaneous or voluntary termination, details of birth, presence or absence of any birth defects, 
congenital anomalies, or maternal and/or newborn complications. 
The pregnancy will be recorded and reported by the clinical site to the sponsor. Pregnancy 
follow-up will also be properly recorded to ensure quality and completeness of the data 
belonging to the study drug and will include an assessment of the possible causal relation 
between the study drug and any pregnancy outcome. Any SAE experienced during pregnancy 
will be reported on an SAE Report Form. 
7.6 
Serious Adverse Event Reporting 
The CRU will notify any SAE to the sponsor or designee, without regard to causality, within 
24 hours after becoming aware of its occurrence. 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, 
that AE should be recorded as a new SAE. 
The initial SAE report must be as complete as possible, including details of any current illness 
and SAE, and an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (e.g., an end date for the AE, 
laboratory values received after the report, or hospital discharge summary) must be documented. 
All follow-up information must be reported as soon as the relevant info is available, in the same 
manner as the initial report. 
If an SAE occurs to a subject during this study, the SAE report and relevant medical records 
should be faxed at the time of the report to Arbor Safety Inbox 
 or scanned and 
emailed 
. The SAE may also be reported by telephone to 
Arbor Drug Safety
. 
An SAE will be considered “unexpected” if the AE is not listed in the US product inserts 
(USPIs) or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application. "Unexpected," as used in this 
definition, also refers to AEs that are mentioned in the USPIs as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
The CRU will determine whether any serious, unexpected, related AE must be reported to the 
institutional review board (IRB). If so, the event will be reported via fax or email within 
15 calendar days of an investigator or staff becoming aware of the event. 


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The sponsor will determine whether the SAE must be reported in an expedited manner to the 
applicable regulatory agencies. If so, the sponsor will report the event to those agencies and to all 
participating investigators. 
If reports of any new and unexpected AEs become available to the sponsor during the clinical 
portion of this study, the sponsor will advise the CRU, through its clinical investigator, of those 
events. If required, the sponsor will report to the applicable regulatory authorities. 
8 
DATA ANALYSIS AND STATISTICAL METHODS 
8.1 
Analysis Populations 
8.1.1 Qualification Phase 
8.1.1.1 Qualification Randomized Population 
The Qualification Randomized population will include all subjects who are assigned a 
randomization number in the Qualification phase. 
8.1.1.2 Qualification Safety Population 
The Qualification Safety population will include all subjects who are randomized into the 
Qualification phase and receive at least 1 dose of either the study drug or placebo. 
8.1.2 Treatment Phase 
8.1.2.1 Randomized Population 
The Randomized population will include all subjects who are assigned a randomization number 
in the Treatment phase. 
8.1.2.2 Safety Population 
The Safety population will include all subjects who are randomized into the Treatment phase and 
receive at least 1 dose of 1 of the study drugs or placebo. 
8.1.2.3 Completer Population 
All subjects in the Safety population who complete all 5 crossover periods in the Treatment 
phase of the study, and have sufficient data for evaluation of the primary endpoint (based on a 
blinded review of data prior to database lock) will be included in the Completer population. 
Subjects who do not have at least 1 observation within 2 hours of Tmax for each treatment for 
Drug Liking VAS will be excluded from the Completer population. 
8.1.2.4 Modified Completer Population 
All subjects in the Completer population, excluding problematic subjects with unreliable 
responses which can alter study results, will be included in the Modified Completer population. 
For the Drug Liking VAS scale, the following elimination criteria will be used to define the 
Modified Completer population. 
a) Similar Emax scores (within a 5-point difference) for a subject across all study treatments 
(including placebo) 
OR 


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b) Emax for placebo > 60 AND the Emax(placebo) – Emax(positive control) ≥ 5 
Criterion a) and b) will be applied to the Drug Liking VAS data on the Completer population. If 
no subjects are excluded when these criteria are applied, then the Modified Completer population 
is the same as the Completer population. 
8.1.2.5 Pharmacokinetic (PK) Population 
All subjects in the Safety population who receive at least 1 dose of GE-IR, and have at least 1 PK 
concentration after dosing will be included in the PK population. 
8.2 
Appropriateness of Measures 
The selected PD measures will assess positive and negative subjective drug effects associated 
with the abuse potential of this drug. These subjective measures are consistent with guidelines 
for HAP studies4 and are similar to those used in previous studies. Although data from all 
measures will be considered in the assessment of abuse potential, the Drug Liking VAS has been 
selected as the primary endpoint for practical purposes (such as calculating power and assessing 
qualification eligibility), as it is considered 1 of the most sensitive and face-valid measures of 
abuse potential.6, 7 Overall Drug Liking VAS and Take Drug Again VAS have been selected as 
key secondary endpoints as they represent the subject’s global assessment of the drug and have 
face validity for predicting continued use of a drug. High VAS has also been selected as a key 
secondary endpoint because it has been shown to be sensitive in capturing the positive subjective 
effects of test drugs. Additional secondary endpoints assess other subjective effects of the drug 
that may help with interpretation of the data. 
Standard PK parameters will be evaluated to confirm plasma concentrations and the PK profile 
of GE-IR in the PK population. Standard measures of safety will be included to monitor the 
safety and tolerability of the GE-IR doses used in the study. 
8.3 
Missing Values 
No imputation of missing PD or PK data will be performed. 
The occurrence of missing PD data will be minimized by only including subjects who are 
rousable and complete PD assessments in the Qualification phase. In addition, all reasonable 
attempts will be made to rouse subjects for completion of the PD assessments in both the 
Qualification and Treatment phases. Missing PD assessments, including reasons for the missing 
data, will be listed by subject, and examined on a case-by-case basis to determine if these affect 
subject allocation (i.e., inclusion in the Modified Completer population). If for a given PD 
measure, the predose value is missing, calculation of CFBmin and TA_AOE will not be possible, 
and the subject will not be included in the Modified Completer population for that PD endpoint. 
If the actual date and/or time of a postdose PD assessment is unknown, but there is a result at that 
timepoint, the value will be used in descriptive statistics of treatment by timepoint summaries, 
and PD endpoint by treatment summaries but will be excluded from calculation of TA_AUE and 
TA_AOE which need actual time from dose in order to be calculated. 
If the actual collection time of a postdose PK sample is unknown, but a valid concentration value 
has been measured, the sample will be set to missing in the PK analysis and will be presented in 


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listing but excluded from descriptive statistics. Unknown baseline collection times will be 
handled on a case-by-case basis. 
Further details on handling of missing values will be provided in the Subject Allocation and 
Request to Break the Blind Form, and in the Statistical Analysis Plan (SAP). 
8.4 
Demographic Data and Other Baseline Characteristics 
8.4.1 Qualification Phase 
All subjects who are randomized into the qualification phase will be entered into the database. 
Disposition tables and listings will be presented for all subjects in the Qualification Randomized 
population. Demographics and baseline characteristics (sex, age, race, ethnicity, body weight, 
height, BMI) will be summarized for the Qualification Safety population. Qualification passes 
and failures will be listed separately. 
8.4.2 Treatment Phase 
A disposition table will be presented for all subjects randomized to the Treatment phase. 
Demographics and baseline characteristics (sex, age, race, ethnicity, body weight, height, BMI), 
recreational drug use history, alcohol use history, and smoking history will be summarized using 
descriptive statistics (n, mean, SD, minimum, median, and maximum for continuous variables, 
and the proportion of subjects for categorical variables) for the Safety population. No formal 
statistical comparison between the groups will be performed. 
Medical history will be listed by subject. Medical history will be coded into the most recent 
version of MedDRA available (version 22.0 or later). 
Prior and concomitant medications will be assigned a 12-digit code using the most recent version 
of the World Health Organization drug codes available. Prior and concomitant medications will 
be listed by subject. 
The number of subjects in each treatment group will be presented, in addition to the number of 
subjects who complete each treatment period. The reasons for all post-randomization 
discontinuations will be tabulated and grouped by treatment and major reason. All deviations 
related to study inclusion or exclusion criteria, conduct of the trial, subject management, or 
subject assessment will be listed. 
8.5 
Pharmacodynamics 
8.5.1 Pharmacodynamic Endpoints 
Pharmacodynamic endpoints will be evaluated as described in Table 7 and all PD data will be 
analyzed using the Modified Completer population. 


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Table 7. Pharmacodynamic Endpoints 
Description 
Type 
Endpoints 
Drug Liking 
Bipolar VAS 
Emax, Emin, TEmax, TEmin, and 
TA_AUE 
Overall Drug Liking 
Bipolar VAS 
Emax 
Take Drug Again 
Bipolar VAS 
Emax 
High 
Unipolar VAS 
Emax, TEmax, and TA_AUE 
Good Effects 
Unipolar VAS 
Emax, TEmax, and TA_AUE 
Bad Effects 
Unipolar VAS 
Emax, TEmax, and TA_AUE 
Any Effects 
Unipolar VAS 
Emax, TEmax, and TA_AUE 
Feeling Drunk 
Unipolar VAS 
Emax, TEmax, and TA_AUE 
Drowsiness/Alertness 
Bipolar VAS 
Emin, TEmin, and TA_AOE 
Relaxation/Agitation 
Bipolar VAS 
Emin, TEmin, and TA_AOE 
Addiction Research Center 
Inventory (ARCI) Morphine-
Benzedrine Group (MBG) Scale 
Questionnaire score 
Emax, TEmax, and TA_AUE 
ACRI Pentobarbital–
Chlorpromazine–Alcohol Group 
(PCAG) Scale 
Questionnaire score 
Emax, TEmax, and TA_AUE 
Modified Observer’s Assessment 
of Alertness/Sedation (MOAA/S) 
Observer’s score 
Emin, CFBmin, and TA_AOE 
CFBmin= change from baseline to minimum effect, Emax= maximum (peak) effect, Emin=minimum effect, 
TA_AOE= time-averaged area over the effect-time curve, TA_AUE=time-averaged area under the effect-time 
curve, TEmax=time of maximum (peak) effect, TEmin=time of minimum effect, VAS=Visual Analog Scale 
8.5.2 Pharmacodynamic Statistical Methodology 
Drug Liking and Take Drug Again VAS Emax from the Qualification phase will be summarized 
by treatment and paired difference for the Modified Completer population. The data will be 
evaluated to confirm that an appropriate population was selected for the Treatment phase. 
During the Treatment phase, PD values at each timepoint will be summarized by treatment using 
descriptive statistics and presented graphically. Derived endpoints will be summarized by 
treatment and paired difference using descriptive statistics. 
8.5.2.1 Primary Analysis 
Pharmacodynamic endpoints for the Treatment phase (Emax, Emin, CFBmin, TA_AUE and 
TA_AOE, as appropriate) will be analyzed using a mixed-effect model if the residuals are 
normally distributed. The model will include treatment, period, treatment sequence, and 
first-order carryover effect (where applicable) as fixed effects, and the baseline (predose) 
measurement as a covariate (where applicable). If the variance among treatments is 
homogeneous, subject will be considered a random effect; if the variance among treatments is 
heterogeneous, the default variance components (VC) variance structure block will be used for 


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each subject. Treatments for each PD endpoint will be tested for homogeneity of variance using 
 
 
 
 
 
After it is determined if the treatment variance is homogeneous or heterogeneous, the residuals 
from each mixed-effect model will be investigated for normality using the Shapiro-Wilk W test. 
The null and alternative hypotheses for this analysis are shown below: 
H0: distribution of residuals is normal vs. Ha: distribution of residuals is not normal 
If the residuals from the mixed-effect model are normally distributed, e.g., p-value ≥ 0.05, it will 
be determined if carryover effects should be included. 
When conducting drug abuse potential studies, Chen and Tsong14 have recommended the 
inclusion of first-order carryover as a fixed effect in the mixed-effect model. The adoption of this 
conservative approach would address possible effects associated with the subjective nature of 
these studies. Carryover effects are defined as the treatment administered in the previous 
treatment period. As there are no carryover effects in treatment period 1, placebo will be used in 
this period. If the carryover effect is found to be non-significant at alpha ≥ 0.25, then the term 
will be dropped from the mixed-effects model. If the carryover effect is found to be significant at 
alpha < 0.25, it will be included in the model. 
If the normality assumption of the model is satisfied, least-square means, standard errors (SEs), 
and 1-sided 95% or 2-sided 95% or 90% confidence intervals (CIs) for treatments and treatment 
differences will be derived from the mixed-effect model. P-values will be provided for the effects 
and the contrasts. 
If the normality assumption of the model is not satisfied, the distribution of the paired difference 
for each contrast will be examined in terms of normality and skewness. Each paired difference 
will be investigated for normality using the Shapiro-Wilk W-test. If the p-value for the 
distribution of the paired difference is normal, that is, p-value ≥ 0.05, a paired t-test will be used. 




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These hypotheses will be applied to the primary endpoint, Drug Liking VAS Emax. 
Although a margin of 15 has been selected for Hypothesis 1 to ensure consistency with the 
Qualification phase criteria, subjects are expected to provide lower responses in the Treatment 
phase as compared to the Qualification phase.19, 31 Therefore, if the difference between the 
positive control and placebo does not meet the recommended criterion for validity (i.e., δ1= 15), 
a secondary planned analysis will be performed (refer to section 8.5.2.2) A margin of 11 points is 
considered appropriate for Hypothesis 3 based on an analysis of Drug Liking VAS Emax data.15 
Further details will be described in the SAP.. 
For study validity purposes, the primary endpoint, Emax for Drug Liking VAS, will be compared 
between the positive control (alprazolam 2 mg) and placebo. 
 
 
 
 
 
 
If statistically significant, it will confirm 
the sensitivity of the study and allow for the comparison of the other pairwise comparisons 
shown below. The hypotheses can be expressed as follows: 
  
 
 
  
 
 
 
where μC is the mean for the positive control, alprazolam, and μP is the mean for placebo, and 
will be applied to the following contrast: 
 
 
To assess whether the test drug has less abuse potential than the positive control, the null 
hypothesis will be that the mean difference in Drug Liking Emax between alprazolam and GE-IR 
is less than or equal to 0 against the alternative hypothesis that the mean difference in Drug 
Liking Emax between alprazolam and GE-IR is greater than 0. 




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The hypothesis for comparison between the positive comparator, alprazolam, and the test drug, 
GE-IR, will be: 
  
 
 
  
 
 
 
where μC is the mean for the positive control, alprazolam, and μT is the mean for the test drug, 
GE-IR, and will be applied to the following contrasts: 
The hypothesis for comparison between the test drug, GE-IR, and placebo will be: 
  
 
 
  
 
 
 
where μT is the mean for the test drug, GE-IR, and μP is the mean for placebo, and will be 
applied to the following contrasts: 
 
 
 
 
 
 
A significance level of 0.05 will be used for all 1-sided tests; 1-sided 95% confidence intervals 
will be presented. For 2-sided tests, a significance level of 0.1 will be used 32 with 2-sided 90% 
confidence intervals. No adjustments for p-values will be made to account for multiple 
comparisons. 
8.5.2.1.3 Test Hypotheses for Non-Key Secondary Endpoints 
For the comparisons of all other non-key secondary PD endpoints, the following hypothesis will 
be used to provide information on the relative abuse potential of the test drug in humans: 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 


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The hypothesis for comparison between the positive control, alprazolam and placebo will be: 
  
 
 
  
 
 
 
where μC is the mean for the positive control, alprazolam, and μP is the mean for placebo, and 
will be applied to the following contrast: 
 
 
The hypothesis for comparison between the positive comparator, alprazolam, and the test drug, 
GE-IR, will be: 
  
 
 
  
 
 
 
where μC is the mean for the positive control, alprazolam, and μT is the mean for the test drug, 
GE-IR, and will be applied to the following contrasts: 
 
 
 
 
 
 
The hypothesis for comparison between the test drug, GE-IR, and placebo will be: 
  
 
 
  
 
 
 
where μT is the mean for the test drug, GE-IR, and μP is the mean for placebo, and will be 
applied to the following contrasts: 
 
 
 
 
 
 
A significance level of 0.05 will be used for Hypotheses 1 and 2, and a significance level of 0.1 
will be used for Hypothesis 3.32 For Hypotheses 1 and 2, 2-sided 95% confidence intervals will 
be presented while 2-sided 90% confidence intervals will be presented for Hypothesis 3. No 
adjustments for p-values will be made to account for multiple comparisons. 
8.5.2.2 Secondary Analysis 
Although a margin of 15 has been selected for Hypothesis 1 for consistency with the 
Qualification phase criteria, subjects may have lower responses with alprazolam and higher 
responses with placebo in the Treatment phase as compared to the Qualification phase, 19,31 
particularly for lower abuse potential drugs such as benzodiazepines (i.e., Schedule IV drugs). 
Therefore, in the case that the difference between the active control and placebo does not meet 


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the pre-specified criteria for validity of at least 15 points, secondary analysis will be performed. 
Details of the secondary analysis will be described in the SAP. 
8.6 
Pharmacokinetics 
The PK analysis will be carried out according to Altasciences SOPs. Pharmacokinetic data 
handling and analysis will be further detailed in the SAP. 
8.6.1 Measurements Below the Lower Limit of Quantitation 
Concentration values below the lower limit of quantitation (LLOQ) associated with predose and 
postdose collection times will be replaced with zero for the non-compartmental analyses (NCA). 
Concentration values below the LLOQ will be replaced with 0 for mean PK profile 
representations as well as for descriptive statistic calculations. 
8.6.2 Actual Time 
Analysis will be based on the actual sampling times, except for predose samples, which will 
always be reported as 0, regardless of time deviations. 
The individual concentration/time profiles will be presented using actual sampling times whereas 
the mean concentration/time profiles and tables presenting summary statistics of 
concentration-time series will be presented using nominal sampling times. 
Actual times will be listed in the report. 
8.6.3 Noncompartmental Analysis (NCA) 
The following configuration for the NCA analysis (with Phoenix® WinNonlin® version 8, or 
higher) will be used: 
 
 
 
 
  
 
 
 
 
Reason for exclusion of AUC: In the case where less than 3 consecutive measurable 
concentrations are observed, the AUC parameters will not be estimated. 
The PK parameters for gabapentin are presented in Table 8. 


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Table 8. Pharmacokinetic Parameters 
Parameter 
Definition 
Cmax 
Maximum observed concentration occurring at time Tmax 
Tmax 
Time of maximum observed concentration. If the maximum observed 
concentration is not unique, then the first maximum is used. 
AUC0-T 
Area under the concentration time curve from the time 0 to Tlast.  
Tlast  
Time of last measurable (positive) observed concentration 
8.6.4 Pharmacokinetic Statistical Methodology 
8.6.4.1 Descriptive Statistics 
Descriptive statistics of the individual concentration data and derived parameters will be 
calculated with the build-in Phoenix® WinNonlin® platform and displayed with the same 
precision as received from the bioanalytical laboratory. 
Precision for individual values will be display as follows: 
 Cmax and AUC will be displayed with the same precision as the raw PK concentration 
data 
 Parameters associated with time will be displayed with 2 decimal places 
Summary statistics will be displayed with the same precision as the individual values, with the 
exception of number of observations (N) and coefficient of variation (CV%) which will be 
presented with 0 and 1 decimal place, respectively. 
Descriptive statistics will be calculated for concentrations at each individual timepoint and for all 
PK parameters. Individual concentrations, and PK parameters obtained from the NCA will be 
summarized per treatment group using the following descriptive statistics: N, minimum, 
arithmetic mean, geometric mean, median, maximum, standard deviation (SD), CV%. 
8.6.4.2 Statistical Analysis 
No formal statistical analysis of PK data will be performed. 
8.7 
Safety 
8.7.1 Safety Endpoints 
For the Treatment phase, safety endpoints will include a summary of the incidence of AEs, 
SAEs, as well as descriptive summary and statistics of the safety parameters (clinical laboratory 
values, vital signs [i.e., systolic and diastolic blood pressure, pulse rate, respiratory rate, oral 
temperature, SpO2], continuous SpO2 monitoring, continuous EtCO2 monitoring, ECGs, C-SSRS, 
and physical examination findings. 


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8.7.2 Safety Analysis 
The clinical laboratory tests and the measurements of vital signs, continuous SpO2 and EtCO2 
monitoring, ECGs, C-SSRS and physical examination parameters will be used to perform the 
safety statistical analysis. 
8.7.3 Safety Statistical Methodology 
8.7.3.1 Qualification Phase 
The Qualification Randomized population will be used to list all AEs occurring in the 
Qualification phase. Qualification passes and failures will be listed separately. 
8.7.3.2 Treatment Phase 
Analysis of safety assessments will be performed using the Safety population. Assessment of 
safety will be based on the incidence of AEs, AEs resulting in discontinuation, and SAEs by 
treatment. AE summaries will be provided showing the number and percentage of subjects who 
experienced at least 1 TEAE during the Treatment phase. TEAEs will also be tabulated by 
maximum severity and by maximum relationship to study drug. These summaries will be 
presented by body system and preferred term (Medical Dictionary for Regulatory Activities 
[MedDRA], version 22.0 or higher). SAEs and AEs resulting in discontinuation will be 
summarized separately. All AEs will be listed by subject for the Safety population. 
Laboratory data collected during the Treatment phase will be summarized by the type of 
laboratory test and visit. Descriptive statistics (n, mean, SD, minimum, median, and maximum) 
and the number of subjects with laboratory test results below, within, and above normal ranges 
will be tabulated by visit. Abnormal findings in laboratory data will be listed. 
Treatment phase vital signs (blood pressure, heart rate, respiratory rate, SpO2) and EtCO2 will be 
analyzed as minimum, maximum, and final postdose values since the analyses of these extremes 
are more meaningful than analyses of individual timepoints. Vital signs will be summarized 
using descriptive statistics (n, mean, SD, minimum, median, and maximum). Abnormal findings 
in vital signs data will be listed.  
12-Lead ECG data during the Treatment phase (absolute values in heart rate and PR, QRS, QT, 
and QTcF intervals) will be summarized by parameter and visit using descriptive statistics (n, 
mean, SD, minimum, median, and maximum). Overall ECG interpretation will be summarized 
(normal; abnormal, non-clinically significant; and abnormal, clinically significant). Abnormal 
findings in ECG data will be listed. 
Physical examination abnormal results will be listed by subject and visit. Baseline and since last 
visit scores from the C-SSRS questionnaire will be listed. No summaries will be provided. 
8.8 
Planned Interim Analyses 
No formal interim analyses will be performed. 


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8.9 
Determination of Sample Size 
As reported in an unpublished HAP study evaluating doses of 1.5 mg and 3.0 mg of alprazolam, 
the mean paired difference (SD) for Drug Liking VAS Emax VAS between alprazolam 1.5 mg 
and placebo was 26.3 (18.62). For alprazolam 3.0 mg vs. placebo, the mean difference (SD) was 
26.6 (17.83). A margin of 15, with a correlation of 0, and an upper-tailed test with a significance 
level of 0.05 results in 48 completers for the comparison of alprazolam 1.5 mg vs. placebo, and 
42 completers for the comparison alprazolam 3.0 mg vs. placebo. The more conservative sample 
size estimate of 48 subjects will be used. 
Assuming a drop-out rate of approximately 25%, and allowing for missed data and problematic 
subjects as defined for the Modified Completer population, approximately 60 subjects are 
planned for randomization into the Treatment phase in order to achieve a minimum of 
48 completers (at least 4 subjects per 10 treatment sequences). 
Due to potential sedative effects that may prevent subjects from completing measures and 
expected natural attrition, replacement subjects may be considered in order to meet the minimum 
number of completers, in the event that the preplanned attrition rate of 25% is surpassed. 
Subjects will be consecutively randomized into the Qualification phase until the target number of 
60 subjects eligible for participation in the Treatment phase is reached. 


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9 
REFERENCES 
1. Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic 
review. Eur Neuropsychopharmacol. 2017 Dec;27(12):1185-1215. doi: 
10.1016/j.euroneuro.2017.08.430. Epub 2017 Oct 5. 
2. Evoy KE, Covvey JR, Peckham AM, Ochs L, Hultgren KE. Reports of gabapentin and 
pregabalin abuse, misuse, dependence, or overdose: an analysis of the Food and Drug 
Administration Adverse Events Reporting System (FAERS). Res Social Adm Pharm. 
2019; 953-958. 
3. Draft Guidance for Industry: Assessment of Abuse Potential of Drugs. U.S. Department 
of Health and Human Services. Food and Drug Administration. Center for Drug 
Evaluation and Research. January 2010. 
4. Assessment of Abuse Potential of Drugs. U.S. Department of Health and Human 
Services. Food and Drug Administration. Center for Drug Evaluation and Research. 
January 2017. 
5. US Food and Drug Administration. Guidance for Industry: Abuse-Deterrent Opioids 
Evaluation and Labeling. Guidance for Industry; April 2015. 
6. Balster RL, Bigelow GE. Guidelines and methodological reviews concerning drug abuse 
liability assessment. Drug Alcohol Depend. 2003; 70(3 Suppl):S13-40. 
7. Griffiths RR, Bigelow GE, Ator NA. Principles of initial experimental drug abuse 
liability assessment in humans. Drug and Alcohol Depend. 2003; 70(3) Suppl: S41-54.  
8. Levy-Cooperman N, Schoedel KA, Chakraborty B, Blum D, Cheng H. Abuse liability 
assessment of eslicarbazepine acetate in healthy male and female recreational sedative 
users: a phase I randomized controlled trial. Epilepsy Behav. 2016; 61:63-71.  
9. Schoedel KA, Andreas JO, Doty P, Eckhardt K, Sellers EM. Randomized, double-blind, 
placebo- and active comparator-controlled crossover study evaluating the abuse potential 
of the antiepileptic drug lacosamide in healthy recreational drug users. J Clin 
Psychopharmacol. 2017; 37(6):675-683. 
10. Schoedel KA, Stockis A, Sellers EM. Human abuse potential of brivaracetam in healthy 
recreational central nervous system depressant users. Epilepsy Behav. 2018a; 78:194-
201. 
11. Schoedel KA, Szeto I, Setnik B, et al. Abuse potential assessment of cannabidiol (CBD) 
in recreational polydrug users: A randomized, double-blind, controlled trial. Epilepsy 
Behav. 2018b; 88:162-171. 
12. Schoedel KA, Sellers EM. Assessing abuse liability during drug development: changing 
standards and expectations. Clin Pharmaco Ther. 2008; 83(4):622–626. 
doi:10.1038/sj.clpt.6100492. 
13. Comer SD, Collins ED, MacArthur RB, Fischman MW. Comparison of intravenous and 
intranasal heroin self-administration by morphine-maintained humans. 
Psychopharmacology. 1999; 143: 327.338. 


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14. Chen L, Tsong Y. Design and analysis for drug abuse potential studies: issues and 
strategies for implementing a crossover design. Drug Information J. 2007; 41:481-489. 
15. Chen L, Bonson KR. An equivalence test for the comparison between a test drug and 
placebo in human abuse potential studies. J Biopharm Stat. 2013; 23(2):294-306. 
16. Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG. CONSORT (Consolidated 
Standards of Reporting Trials) Statement. Reporting of Noninferiority and Equivalence 
Randomized Trials-Extension of the CONSORT 2010 Statement. JAMA. 2012; 308(24): 
2594-2604. 
17. Curran, P.J., S.G. West, and J.F. Finch, The robustness of test statistics to non-normality 
and specification error in confirmatory factor analysis. Psychological Methods. 1996; 
1(1): p. 16-29. 
18. Chen L. Principles and methods of statistical assessment of abuse-deterrent opioids. Ther 
Innov Regul Sci. 2018; 52(1):7-13. 
19. Mills C. Statistical Issues in Abuse-Deterrent Formulation (ADF) and Human Abuse 
Potential (HAP) Studies. CCALC, Abuse Potential Dialogue Session, 12-Oct-2018. 
20. Valium® [Label] (12/16/2016). NDA 013263, Drugs@FDA, FDA Web site. 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed January 19, 2020. 
21. Linko K, Paloheimoi M. Inspiratory end-tidal oxygen content difference: a sensitive 
indicator of hypoventilation. Crit Care Med 1989;17(4):345-348. 
22. Jabre P, Jacob L, Auger H, et al. Capnography monitoring in nonintubated patients with 
respiratory distress. Am J Emerg Med 2009;27(9):1056-1059. 
23. Manifold CA, David N, Villers LC, Wampler DA. Capnography for the non-intubated 
patient in the emergency setting. J Emerg Med 2013;45(4):626-632. 
24. Waugh JB, Epps CA, Khodneva YA. Capnography enhances surveillance of respiratory 
events during procedural sedation: a meta-analysis. J Clin Anesth 2011;23(3):189-196. 
25. Goli V, Webster LR, Lamson MJ, et al. Effects of concurrent intravenous morphine 
sulfate and naltrexone hydrochloride on end-tidal carbon dioxide. Harm Reduct J 
2012;9:13. 
26. Cashman JN, Dolin S J. Respiratory and haemodynamic effects of acute postoperative 
pain management: evidence from published data. Br J Anaesth 2004;93(2):212-223. 
27. Overdyk FJ, Carter R, Maddox RR, et al. Continuous oximetry/capnometry monitoring 
reveals frequent desaturation and bradypnea during patient-controlled analgesia. Anesth 
Analg 2007;105(2):412-418. 
28. Sivilotti M, Messenger DW, van Vlymen J, et al. A comparative evaluation of 
capnometry versus pulse oximetry during procedural sedation and analgesia on room air. 
CJEM 2010;12(5):397-404. 


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29. Busto U, Kaplan HL, Zawertailo L, Sellers EM. Pharmacologic effects and abuse liability 
of bretazenil, diazepam and alprazolam in humans. Clin Pharmacol Ther 1994; Apr 55 
(4) : 451-63. 
30. Griffiths RR, McLeod DR, Begelow GE, Liebson IA, Roache JD. Relative abuse liability 
of diazepam and oxazepam: behavioral and subjective dose effects. Psychopharmacology 
(Berl) 1984; 84(2) : 147-54. 
31. Chen L, Tolliver J, Calderon S., Chiapperino D. Improving the Design of Qualification 
Phase in Human Abuse Potential Studies. The College on Problems of Drug Dependence 
(CPDD) 81th Annual Scientific Meeting, June 15-19, 2019. 
32. Chen L. Statistical Considerations on Pharmacodynamic Assessment of Human Abuse 
Potential Studies. CCALC, Abuse Potential Dialogue Session, 12-Oct-2018. 
33. Apelt S, Schmauss C, Emrich HM. Preference for alprazolam as opposed to diazepam in 
benzodiazepine-dependent psychiatric inpatients.Pharmacopsychiatry. 1990 
Mar;23(2):70-5. 
34. Erdman K, Stypinski D, Combs M, Witt P, Stiles M, Pollock S. Absence of food effect 
on the extent of alprazolam absorption from an orally disintegrating tablet. 
Pharmacotherapy. 2012; 27(8): 1120-1124. 
35. Daniel, W. W. (1990). Applied Nonparametric Statistics, Second Edition, PWS-KENT 
Publishing Company. 
36. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, 
Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation 
Scale: study with intravenous midazolam. J Clin Psychopharmacol. 
1990 Aug;10(4):244-51. 
37. Martin WR, Sloan JW, Sapira JD, Jasinski DR. Physiologic, subjective, and behavioral 
effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and 
methylphenidate in man. Clin Pharmacol Ther 1971;12(2):245–258. 
38. Haertzen CA, Hill HE, Belleville RE. Development of the Addiction Research Center 
Inventory (ARCI): selection of items that are sensitive to the effects of various drugs. 
Psychopharmacologia 1963;70:155–166. 
39. Haertzen CA. An Overview of the Addiction Research Center Inventory (ARCI): An 
Appendix and Manual of Scales. Rockville, MD: National Institute on Drug Abuse; 1974. 


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10 APPENDIX 1: ETHICS 
10.1 Institutional Review Board 
This protocol and the informed consent form (ICF) will be submitted to an institutional review 
board (IRB) prior to initiation of the study and the study will not start until the board has 
approved the documents. Notification of the board’s approval will be appended to the final 
report. 
10.2 Ethical Conduct of the Study 
This study will be conducted in compliance with the study protocol, the ethical principles that 
have their origins in the Declaration of Helsinki, the International Council for Harmonisation 
(ICH) Guideline E6 for Good Clinical Practice (GCP), the Food and Drug Administration (FDA) 
GCP Code of Federal Regulations (CFR) Title 21 (part 56), the European regulation EU 
536/2014, and the Tri-Council Policy Statement (Canada). 
10.3 Subject Information and Consent 
Before screening activities commence, each subject will be given a copy of the ICF to read, as 
well as a full explanation of the purpose of the study, the procedures to be carried out, and the 
potential adverse events (AEs). Once this essential information is provided to the subject and an 
investigator or delegate has the conviction the subject understands the implications of 
participating in the study, and if the subject chooses to continue the screening process, they will 
be requested to sign and date a properly executed ICF prior to enrollment. Subjects will be 
assured they may withdraw from the study at any time without jeopardizing their medical care or 
future study participation (for which they may qualify). 
Subjects will be given a signed copy of the ICF. If an amended or revised ICF is introduced 
during the study, each subject’s further consent must be obtained. 
10.4 Subject Confidentiality 
Investigators and the sponsor will preserve the confidentiality of all subjects taking part in the 
study, in accordance with GCP and local regulations. Subjects shall be identified by a unique 
subject identifier on all study documents provided to the sponsor. In compliance with federal 
regulations/ICH GCP Guidelines, it is required an investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and IRB access to review the 
subject’s original medical records for verification of study-related procedures and data. An 
investigator is obligated to inform the subject that his/her study-related records will be reviewed 
by the above-named representatives without violating the subject’s confidentiality. 


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11 APPENDIX 2: DATA COLLECTION, RETENTION, AND MONITORING 
11.1 Case Report Forms 
The data required by the protocol is obtained in 2 ways. Source Documents are used in the clinic 
as recording devices during procedures. The data will be transcribed from source into electronic 
data capture software (Medrio) and stored in the secure database for each subject included in a 
clinical trial (i.e., subjects randomized to the Qualification phase which includes qualification 
failures, and subjects randomized to the Treatment phase). 
Data assembled outside the clinic source (i.e., clinical laboratory data, pharmacokinetic [PK] 
concentration data, and pharmacodynamics [PD] measures [e.g., visual analog scale (VAS) 
scores]), will be received from a specified external vendor via an electronic data file. The file 
received will be encrypted (or posted to a secure File Transfer Protocol) and will be stored in a 
secure folder on a server. The electronic data file(s) are independent of the Medrio electronic 
data capture (EDC) data during the conduct of the study. 
The Medrio EDC cleaned data will be reviewed, approved and electronically signed by the 
principal investigator or delegate. The Medrio EDC data will be output in a case report form 
(CRF) format. The external data files will be output in SAS® datasets. At review cycles, tables, 
figures and listings will be provided in rtf format. All data will be included with the final report 
provided to the sponsor. 
11.2 Data Management and Processing 
Data Management develops documentation to define activities performed during the data 
management conduct of the study trial. Medrio EDC system is the tool used to conduct all data 
cleaning activities, monitoring activities and review/approval activities for clinic collected data 
and procedure data. The external data files will be reconciled (to compare the external vendor 
data and Medrio EDC sample collection data). Data Management activities are performed in 
accordance with the Data Management standard operating procedures (SOPs). 
In addition to the cleaning activities, data entered in Medrio EDC will be checked for accuracy 
through quality control (QC) assessments. When the database data is declared to be complete and 
accurate; the database will be locked, and user access removed. 
11.3 Quality Control and Quality Assurance 
Designated personnel from the quality assurance unit(s) of the clinical, PK, PD, and statistical 
facilities will be responsible for maintaining quality assurance (QA) systems to ensure that the 
trial is conducted, and that clinical/PK/PD/statistical data is generated, documented and reported, 
in compliance with the protocol and the integrated addendum to International Conference on 
Harmonisation (ICH) E6: Guideline for Good Clinical Practice E6 (R2). 
Designated personnel from each corresponding operation unit (i.e., clinical, PK, PD, and 
statistical facilities) will be responsible to maintain and assure the QC of all data generated and 
documented in compliance with the protocol and SOPs. 
All parts of the bioanalytical phase of the study and all its documentation will be subject to 
inspection by the QA unit of the bioanalytical facility to ensure that the data are generated, 
documented and reported in compliance with the protocol and applicable requirements as 


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outlined in the Food and Drug Administration (FDA) and Organization for Economic 
Cooperation and Development (OECD) Principles of Good Laboratory Practice (GLP). 
11.4 Record Retention 
All essential documents and records will be maintained by the clinical site in accordance with, 
and for the period specified in the applicable regulatory requirement(s) (FDA Code of Federal 
Regulations [CFR] 312.57 (C)). 
11.5 Monitoring of the Study 
The sponsor or its representative may monitor the study in order to maintain current and personal 
knowledge of the study through review of the records, comparison with source documents, 
observation and discussion of the conduct and progress of the study. The clinical site will permit 
trial-related monitoring, audits, institutional review board (IRB)/independent ethics committee 
(IEC) review, and regulatory inspection(s) by providing direct and/or virtual, where possible, 
access to source data/documents. 


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12 APPENDIX 3: ADMINISTRATIVE PROCEDURES 
12.1 Liabilities 
It is the sponsor’s responsibility to guarantee sufficient insurance coverage should any serious 
events or deaths result, either directly or indirectly, from the execution of the present protocol. 
12.2 Adherence to Protocol 
Excluding an emergency situation in which proper treatment is required for the protection, safety 
and well-being of the study subjects, the study will be conducted as described in the approved 
protocol and performed according to International Conference on Harmonisation (ICH)/Good 
Clinical Practice (GCP) and the applicable regulatory requirements. Any deviation from the 
protocol will be recorded and explained. 
If amendments to the protocol and/or amendments or revisions to the informed consent form 
(ICF) are required, the modifications will be documented and submitted to an institutional review 
board (IRB) for approval. 
12.3 Statement of Investigator 
The Food and Drug Administration (FDA) Form 1572, Statement of Investigator [Title 21, CFR 
Part 312], will be signed by the investigator, and will be kept on file. 
12.4 Delegation of Investigator Duties 
In the context of this protocol, the term ‘an investigator’ includes the Principal Investigator and 
any sub-investigator. 
An investigator will ensure all personnel involved in the trial are adequately qualified and 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
An investigator will maintain a list of sub-investigator(s) and other appropriately qualified 
persons to whom he/she delegates significant trial-related duties. 
Should an investigator delegate the supervision of the study drug administration to a designated 
person, this individual must have the appropriate professional-legal qualifications and 
certifications. An investigator should also ensure key staff personnel have the appropriate 
medical qualifications to effectively conduct or supervise any potential resuscitation procedures. 
12.5 Premature Termination or Suspension of a Study 
The sponsor or its representative may terminate the study at any time for scientific or corporate 
reasons. 
If the trial is prematurely terminated or suspended for any reason, the clinical site or an 
investigator (or delegate) should promptly inform the trial subjects, should assure appropriate 
therapy and follow-up for the subjects, and should inform the regulatory authority(ies) and IRB, 
when required. 






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14 APPENDIX 5: LIST OF ABBREVIATIONS 
Ab 
Antigen/antibody 
 
ACLS 
Advanced cardiac life support 
 
ADE 
Adverse drug event 
 
AE 
Adverse event 
 
ALT 
Alanine aminotransferase 
 
AOE 
Area under the effect-time curve 
 
ARCI 
Addiction Research Center Inventory 
 
AST 
Aspartate aminotransferase 
 
AUC0-T 
Area under the concentration-time curve from 0 to the last measured observable 
concentration 
 
AUE 
Area under the effect-time curve 
 
BMI 
Body mass index 
 
BUN 
Blood urea nitrogen 
 
CFBmin 
Change from baseline to minimum effect 
 
CFR 
Code of Federal Regulations 
 
cGMP 
Current Good Manufacturing Practice 
 
CI 
Confidence interval 
 
Cmax 
Maximum concentration 
 
CNS 
Central nervous system 
 
CRF 
Case report form 
 
CRU 
Clinical research unit 
 
CS 
Clinically significant 
 
CSR 
Clinical study report 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
 
CV 
Coefficient of variation 
 
DRESS 
Drug rash with eosinophilia and systemic symptoms 
 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
 
ECG 
Electrocardiogram 
 
EDC 
Electronic data capture 
 
Emax 
Maximum (peak) effect 
 
Emin 
Minimum effect 
 
ER 
Extended-release 
 


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ET 
Early termination 
 
EtCO2 
End Tidal CO2 
 
FAERS 
Food and Drug Administration Adverse Event Reporting System 
 
FDA 
Food and Drug Administration 
 
FSH 
Follicle-stimulating hormone 
 
GABA 
Gamma-aminobutyric acid 
 
GCP 
Good Clinical Practice 
 
GE-IR 
Gabapentin Enacarbil Immediate Release 
 
GLP 
Good Laboratory Practice 
 
HBsAg 
Hepatitis B Virus Surface Antigen 
 
HCV 
Hepatitis C virus 
 
HIV 
Human immunodeficiency virus 
 
ICF 
Informed consent form 
 
ICH 
International Council for Harmonisation 
 
IEC 
Independent ethics committee 
 
IP 
Investigational product 
 
IRB 
Institutional review board 
 
IU 
International unit 
 
IUD 
Intrauterine device 
 
kg 
Kilogram 
 
LLOQ 
Lower Limit of Quantitation 
 
MBG 
Morphine-Benzedrine Group 
 
MCV 
Mean corpuscular volume 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
mg 
Milligram 
 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
 
N 
Number of observations 
 
NCA 
Noncompartmental analysis 
 
NCS 
Not clinically significant 
 
OECD 
Organization for Economic Co-operation and Development 
 
OTC 
Over-the-counter 
 
PCAG 
Pentobarbital–Chlorpromazine–Alcohol Group 
 
PD 
Pharmacodynamic 
 


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pH 
The logarithm, on the base 10, of the reciprocal of the hydrogen ion concentration 
 
PHN 
Postherpetic neuralgia 
 
PI 
Principal investigator 
 
PK 
Pharmacokinetic 
 
PT 
Preferred term 
 
QA 
Quality assurance 
 
QC 
Quality control 
 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
 
RLS 
Restless legs syndrome 
 
SAE 
Serious adverse event 
 
SAP 
Statistical analysis plan 
 
SAR 
Suspected adverse reaction 
 
SD 
Standard deviation 
 
SOC 
System organ class 
 
SOP 
Standard operating procedure 
 
SpO2 
Oxygen saturation  
 
SUSAR 
Suspected, unexpected SAE 
 
T½ 
Elimination half-life 
 
TEAE 
Treatment-emergent adverse event 
 
TEmax 
Time of maximum (peak) effect 
 
TEmin 
Time of minimum effect 
 
THC 
Tetrahydrocannabinol 
 
Tlast 
Last measured observable concentration 
 
Tmax 
Time of maximum concentration 
 
US 
United States 
 
USPI 
United States Product Insert 
 
VAS 
Visual analog scale 
 
WHO-DDE 
World Health Organization Drug Dictionary-Enhanced  
 


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15 APPENDIX 6: CLINICAL LABORATORY EVALUATIONS 
Clinical Laboratory Test Panel 
Description 
General biochemistry: 
Sodium, potassium, chloride, glucose, blood urea nitrogen (BUN), 
creatinine, bilirubin total, alkaline phosphatase, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), and 
albumin  
Endocrinology: 
Follicle stimulating hormone (FSH; for female subjects) 
Hematology: 
White cell count with differential (absolute values of neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil), red cell count, 
hemoglobin, hematocrit, mean corpuscular volume (MCV), and 
platelet count 
Serology1: 
Human immunodeficiency virus (HIV) antigen/antibody (Ag/Ab) 
Combo, Hepatitis B (HBsAg (B)) and Hepatitis C (HCV (C))  
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, glucose, 
ketones, bilirubin, blood, nitrite, urobilinogen. Microscopic 
examination will only be performed if the dipstick test is outside of 
the reference range for leukocyte, blood, nitrite or protein 
Urine drug screen: 
Alcohol, amphetamines, barbiturates, cannabinoids, cocaine, 
opiates, benzodiazepines, and phencyclidine 
Urine OR serum pregnancy test: 
To be performed for all female subjects 
                                                 
1 Screening visit only. 


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16 APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) –
BASELINE/SCREENING VERSION 


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17 APPENDIX 8: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) –SINCE 
LAST VISIT VERSION 


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SAP_001.pdf: 
ClinicalTrials.gov: NCT06097676




 
 
 
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VERSION CONTROL 
Version 
Date 
Author 
Description of Changes 
Final 1.0 
16-Jan-2022 
 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
VERSION CONTROL ....................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
TABLE OF TABLES ......................................................................................................................7 
TABLE OF FIGURES .....................................................................................................................8 
ABBREVIATIONS .........................................................................................................................9 
1. 
INTRODUCTION ................................................................................................................11 
2. 
STUDY OBJECTIVES ........................................................................................................12 
3. 
STUDY DESIGN .................................................................................................................14 
3.1 
Overall Study Design ......................................................................................................14 
3.3 
Determination of Sample Size .........................................................................................15 
3.4 
Treatments .......................................................................................................................16 
3.4 
Study Procedures .............................................................................................................16 
3.5 
Randomization and Unblinding Procedures ....................................................................16 
3.5.1 
Method of Assigning Subjects to Treatment Groups .............................................16 
3.5.1.1 
Qualification Phase ......................................................................................17 
3.5.1.2 
Treatment Phase ...........................................................................................17 
3.5.2 
Blinding..................................................................................................................18 
4. 
Analysis Populations ............................................................................................................19 
4.1 
Qualification Phase ................................................................................................19 
4.1.1 
Qualification Randomized Population .........................................................19 
4.1.2 
Qualification Safety Population ...................................................................19 
4.2 
Treatment Phase .....................................................................................................19 
4.2.1 
Randomized Population ...............................................................................19 
4.2.2 
Safety Population .........................................................................................19 
4.2.3 
Completer Population ...................................................................................19 
4.2.4 
Modified Completer Population ...................................................................19 
4.2.5 
Pharmacokinetic (PK) Population ................................................................19 
5. 
STUDY SUBJECTS ............................................................................................................20 
5.1 
Disposition .......................................................................................................................20 
5.1.1 
Qualification Phase ................................................................................................20 
5.1.2 
Treatment Phase .....................................................................................................20 
5.2 
Protocol Deviations .........................................................................................................20 


 
 
 
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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...............................21 
6.1 
Qualification Phase ................................................................................................21 
6.2 
Treatment Phase .....................................................................................................21 
7. 
PHARMACODYNAMICS ANALYSIS .............................................................................22 
7.1 
Pharmacodynamics Assessments ....................................................................................22 
7.1.1 
Subjective Effects Visual Analogue Scales (VASs) ..............................................22 
7.1.2 
Addiction Research Center Inventory (ARCI) Scales ...........................................23 
7.1.3 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ...................23 
7.2 
Appropriateness of Measures ..........................................................................................24 
7.3 
Pharmacodynamics Assessment Visit Windows .............................................................24 
7.4 
Analysis of Pharmacodynamics Measures ......................................................................24 
7.4.1 
Test Hypotheses for Primary Endpoint, Drug Liking VAS Emax ...........................26 
7.4.2 
Test Hypotheses for Key Secondary Endpoints.....................................................29 
7.4.3 
Test Hypotheses for Non-Key Secondary Endpoints ............................................30 
7.4.4 
Secondary Analysis ................................................................................................31 
7.4.5 
Adjustment for Covariates .....................................................................................31 
7.4.6 
Adjustment for Multiple Comparison/Multiplicity ................................................31 
8. 
PHARMACOKINETICS ANALYSIS ................................................................................32 
8.1 
Pharmacokinetic Analysis ...............................................................................................32 
8.1.1 
Concentration Data ................................................................................................32 
8.1.2 
Missing Values.......................................................................................................32 
8.1.3 
Measurements Below the Lower Limit of Quantitation ........................................32 
8.1.4 
Actual Times ..........................................................................................................32 
8.1.5 
Non-Compartmental Analysis ...............................................................................32 
8.1.6 
Summary Statistics.................................................................................................33 
9. 
SAFETY ...............................................................................................................................34 
9.1 
Adverse Events ................................................................................................................34 
9.1.1 
Qualification Phase ................................................................................................34 
9.1.2 
Treatment Phase .....................................................................................................35 
9.1.2.1 
Severity Categorization ................................................................................35 
9.1.2.2 
Relationship Categorization .........................................................................35 
9.1.2.3 
General Summary of Treatment-Emergent Adverse Events ........................36 
9.1.2.4 
Summaries of Treatment-Emergent Adverse Events ...................................36 


 
 
 
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9.2 
Clinical Laboratory Evaluations ......................................................................................37 
9.2.1 
Viral Screen ...........................................................................................................37 
9.2.2 
Urine Drug Screen and Urine Alcohol Testing......................................................38 
9.2.3 
Pregnancy and Follicle Stimulating Hormone (FSH) Tests ..................................38 
9.3 
Vital Signs .......................................................................................................................38 
9.4 
12-Lead Electrocardiograms ...........................................................................................38 
9.5 
Physical Examination Findings .......................................................................................38 
9.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................................38 
10. 
DATA HANDLING AND PRESENTATION ....................................................................40 
10.1 Safety Analysis Presentation ...........................................................................................40 
10.2 Pharmacokinetic Analysis ...............................................................................................41 
10.3 Analysis Time Points .......................................................................................................41 
10.4 Methods for Handling Missing Data ...............................................................................41 
11. 
INTERIM ANALYSES AND DATA SAFETY MONITORING .......................................43 
12. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ....................................................44 
13. 
GENERAL INFORMATION RELATED TO DATA PRESENTATIONS ........................46 
13.1 INDEX OF TABLES ......................................................................................................47 
13.2 INDEX OF FIGURES .....................................................................................................50 
13.3 INDEX OF LISTINGS ....................................................................................................51 
14. 
REFERENCES .....................................................................................................................53 
APPENDIX A: STUDY SCHEDULE...........................................................................................54 


 
 
 
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TABLE OF TABLES 
Table 1: Objectives and Related Endpoints .................................................................................. 12 
Table 2: Sample Qualification Phase Sequences .......................................................................... 17 
Table 3: Sample Treatment Phase Sequences ............................................................................... 17 
Table 4: Visual Analog Scale (VAS) Descriptions....................................................................... 22 
Table 5: Pharmacokinetic Parameters in Plasma .......................................................................... 33 
Table 6: Clinical Laboratory Assessments ................................................................................... 37 


 
 
 
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TABLE OF FIGURES 
Figure 1: Study Schema ................................................................................................................ 15 


 
 
 
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ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARCI 
Addiction Research Center Inventory 
AST 
Aspartate Aminotransferase 
AUC0-inf 
Area under the concentration-time curve from the time 0 extrapolated to 
infinity 
AUC0-t 
Area under the concentration-time curve from time 0 to t h 
AUC0-T 
Area under the concentration-time curve from time 0 to the last measurable 
observed concentration 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
C 
Positive Control 
CFBmin 
Change from baseline to minimum effect (predose - postdose) 
CI 
Confidence Interval 
Cmax 
Maximum observed concentration 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV% 
Coefficient Of Variation Percentage 
DMP 
Data Management Plan 
DTS 
Deviation Tracking System 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
Emax 
Maximum effect 
Emin 
Minimum effect 
ER 
Extended Release 
EtCO2 
End Tidal CO2 
FSH 
Follicle Stimulating Hormone 
HAP 
Human Abuse Potential 
HBsAg (B) 
Hepatitis B Virus Surface Antigen 
HCV (C) 
Hepatitis C Virus Antibody 
HEENT 
Head, Eyes, Ears, Nose, Throat 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
λZ 
Individual estimate of the terminal elimination rate constant, calculated using 
log-linear regression of the terminal portions of the plasma concentration-
versus-time curves 


 
 
 
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LLOQ 
Lower Limit of Quantitation 
ln 
Natural Log 
Max 
Maximum 
MBG 
Morphine-Benzedrine Group 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary For Regulatory Activities 
Min 
Minimum 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
n 
Number of Subjects 
N 
Number of Observations 
NCA 
Non-Compartmental Analyses 
P 
Placebo 
PCAG 
Pentobarbital-Chlorpromazine-Alcohol Group 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Oxygen Saturation 
SUSAR 
Suspected Unexpected Serious Adverse Event 
T 
Test Drug 
T1/2 
Terminal elimination half-life 
Tlast 
Time of the last measurable observed concentration 
Tmax 
Time of maximum observed concentration 
TA_AOE 
Time-averaged area over the effect-time curve 
TA_AUE 
Time-averaged area under the effect-time curve 
TEAE 
Treatment-Emergent Adverse Event 
TEmax 
Time of maximum effect 
TEmin 
Time of minimum effect 
TFLs 
Tables, Figures, and Listings 
UDS 
Urine Drug Screen 
VAS 
Visual Analog Scale 
VC 
Variance Components 
WHO-DDE 
World Health Organization Drug Dictionary - Enhanced 


 
 
 
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1. 
INTRODUCTION 
This study will be a randomized, double-blind, active- and placebo-controlled, 5-way crossover 
study to determine the abuse potential of GE-IR relative to alprazolam and placebo, in heatlhy, 
nondependent, recreational drug users with sedative drug use experience. This study will consist 
of 3 phases: screening, qualification and treatment. 
This statistical analysis plan (SAP) provides a detailed description of the statistical methods and 
procedures to be implemented for the analyses of data from protocol AR26.3031.1. Pre-planning 
of analyses reduces the potential for bias and often reduces disputes between sponsor and the 
regulatory authority regarding the validity of the results. The same principles apply to supportive 
and/or post-hoc analyses. These analyses must be prospectively specified. (Good Review 
Practice: Clinical Review of Investigational New Drug Applications, December 2013). 
The analyses described in the SAP are based upon the final protocol version 3.0 (Amendment 
02), dated 09-Aug-2021. 






 
 
 
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3. 
STUDY DESIGN 
3.1 
Overall Study Design 
This study will be a randomized, double-blind, active- and placebo-controlled, 5-way crossover 
study to assess the abuse potential, safety, and PK of GE-IR relative to alprazolam and placebo, 
in healthy, nondependent, recreational drug users with sedative drug use experience. 
This study will consist of 3 phases: screening, qualification and treatment. The study schema is 
presented in Figure 1. 
After a screening period of up to 30 days, eligible subjects will be admitted to the clinical 
research unit (CRU) and randomized (1:1) into the double-blind qualification phase. During the 
qualification phase, subjects will receive oral doses of alprazolam 2 mg (active control) and 
matching placebo in a randomized, double-blind, crossover manner to ensure they are able to 
discriminate and show positive effects of the active control in a clinical setting and to 
demonstrate that they are able to tolerate the administered dose. Two doses in the qualification 
phase will be separated by 48 hours. 
Subjects will be encouraged to remain in the CRU but may be discharged between the 
qualification phase and treatment phase, if necessary. A minimum 3-day washout will be 
required between the last dose in the qualification phase and the first dose of the treatment phase. 
Appropriate discharge and re-admission procedures are noted in Appendix A. 
The treatment phase is a randomized, double-blind, active- and placebo-controlled 5-way 
crossover design. Subjects will be randomized to 1 of the 10 pre-specified treatment sequences in 
which they will receive the following 5 treatments in a crossover manner (1 per treatment period) 
in blinded fashion: 
• Placebo 
• Alprazolam 2 mg (active control) 
• GE-IR 200 mg 
• GE-IR 450 mg 
• GE-IR 700 mg 
Each study drug administration will be separated by at least 3 days. Drug administration will 
occur on the first day of each treatment period followed by PD, PK, and safety assessments for 
up to 24 hours postdose. Subjects will be discharged from the investigational site approximately 
24 hours after the final dose if deemed medically stable for discharge by an investigator. 
The maximum duration of subject participation will be approximately 49 days, including 
screening. 


 
 
 
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Figure 1: Study Schema 
 
Screening 
 
 
 
 
Admission within 30 days of screening 
 
 
 
Randomized Double-Blind Qualification Phase  
(Crossover treatments on Day 1 and Day 3) 
 
 
 
 
Alprazolam 2 mg 
↔ 
48 hours 
Placebo 
 
 
 
 
≥3 days between last qualification phase treatment 
and first treatment phase treatment 
 
 
Randomized Double-Blind Treatment Phase 
(5 crossover treatment periods) 
 
 
GE-IR 
200 mg 
↔ 
≥3 days 
GE-IR 
450 mg 
↔ 
≥3 
days 
GE-IR 
700 mg 
↔ 
≥3 days 
Placebo 
Control 
↔ 
≥3 days 
Alprazolam Active 
Control 
2 mg 
Note: the sequence of treatments shown is for illustration of the overall design and does not necessarily represent an 
actual treatment sequence. Refer to Table 2 and Table 3 for all treatment sequences. A minimum 3 day washout will 
be required between the last dose in the qualification phase and the first dose of the treatment phase. 
3.3 
Determination of Sample Size 
As reported in an unpublished human abuse potential (HAP) study evaluating doses of 1.5 mg 
and 3.0 mg of alprazolam, the mean paired difference (SD) for Drug Liking VAS Emax VAS 
between alprazolam 1.5 mg and placebo was 26.3 (18.62). For alprazolam 3.0 mg vs. placebo, 
the mean difference (SD) was 26.6 (17.83). A margin of 15, with a correlation of 0, and an 
upper-tailed test with a significance level of 0.05 results in 48 completers for the comparison of 
alprazolam 1.5 mg vs. placebo, and 42 completers for the comparison alprazolam 3.0 mg vs. 
placebo. The more conservative sample size estimate of 48 subjects will be used. 
Assuming a drop-out rate of approximately 25%, and allowing for missed data and problematic 
subjects as defined for the Modified Completer population, approximately 60 subjects are 
planned for randomization into the treatment phase in order to achieve a minimum of 
48 completers (at least 4 subjects per 10 treatment sequences). 
Due to potential sedative effects that may prevent subjects from completing measures and 
expected natural attrition, replacement subjects may be considered in order to meet the minimum 
number of completers, in the event that the preplanned attrition rate of 25% is surpassed. 
Subjects will be consecutively randomized into the qualification phase until the target number of 
60 subjects eligible for participation in the treatment phase is reached. 


 
 
 
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3.4 
Treatments 
The following treatments will be administered with approximately 240 mL of room temperature 
water in the morning under fasted conditions during the qualification phase: 
• Placebo: A single dose of placebo to match alprazolam (2 lactose 100 mg tablets over-
encapsulated in one Swedish Orange Opaque AAEL-DB capsule) will be administered 
orally. 
• Active Control: A single 2 mg dose of alprazolam (2 × 1 mg tablets over-encapsulated in 
one Swedish Orange Opaque AAEL-DB capsule) will be administered orally. 
The following treatments will be administered with approximately 240 mL of room temperature 
water in the morning under fasted conditions during the treatment phase: 
• Placebo: Three placebo capsules to match GE-IR + 1 placebo capsule to match 
alprazolam [2 × over-encapsulated placebo tablets in one size 0 opaque white capsules 
with no markings] will be administered orally. 
• Active Control: A single 2 mg dose of over-encapsulated alprazolam (2 × 1 mg tablets 
over-encapsulated in one size 0 opaque white capsules with no markings) + 3 placebo 
capsules to match GE-IR will be administered orally. 
• A single 200 mg dose of GE-IR (1 × 200 mg immediate-release [IR] capsule + 2 placebo 
capsules to match GE-IR capsule + 1 placebo capsule to match alprazolam [2 × 1 mg 
placebo tablets over-encapsulated in one size 0 opaque white capsules with no markings]) 
will be administered orally. 
• A single 450 mg dose of GE-IR (2 × 225 mg immediate-release [IR] capsule + 1 placebo 
capsule to match GE-IR capsule + 1 placebo capsule to match alprazolam [2 × over-
encapsulated placebo tablets in one size 0 opaque white capsules with no markings]) will 
be administered orally. 
• A single 700 mg dose of GE-IR (3 × 233.3 mg immediate-release [IR] capsules + 
1 placebo capsule to match to alprazolam [2 × over-encapsulated placebo tablets in one 
size 0 opaque white capsules with no markings]) will be administered orally. 
3.4 
Study Procedures 
For complete details on the study assessments to be performed for each study period, refer to 
Appendix A. 
3.5 
Randomization and Unblinding Procedures 
3.5.1 
Method of Assigning Subjects to Treatment Groups 
The designated, unblinded biostatistician will generate the separate randomization codes for the 
qualification and treatment phases with a computer program according to the study design, the 
number of subjects and the sequence of treatment administration. For the qualification and 
treatment phases, the random allocation of each sequence of treatment administration to each 
subject will be done in such a way that the study is balanced. Once generated, the randomization 
codes will be final and will not be modified. 


 
 
 
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Subjects who sign the informed consent form (ICF) and are randomized but do not receive a 
study treatment in the treatment phase may be replaced. Subjects who sign the ICF, are 
randomized and receive a study treatment in the treatment phase, and subsequently withdraw, or 
are withdrawn or discontinued from the study, may be replaced. 
3.5.1.1 
Qualification Phase 
Subjects who enter the qualification phase will be assigned, in ascending order, a qualification 
randomization number to identify the sequence of their treatments Table 2. 
Table 2: Sample Qualification Phase Sequences 
Treatment Sequence 
Day 1 
Day 3 
XY 
X 
Y 
YX 
Y 
X 
Treatment X: Placebo 
Treatment Y: Alprazolam 2 mg 
A minimum 3 day washout will be required between the last dose in the qualification phase and 
the first dose of the treatment phase. 
3.5.1.2 
Treatment Phase 
For the treatment phase, qualified subjects will be randomized to 1 of 10 treatment sequences 
based on a computer-generated randomization schedule. The first dose will be administered at 
least 3 days after the qualification phase. The study drug will be prepared for each subject based 
on their randomization code. Subjects will receive all 5 treatments in the order specified by the 
treatment sequence according to two 5 × 5 Williams square design (Table 3). 
Table 3: Sample Treatment Phase Sequences 
Treatment 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
Period 5 
ABECD 
A 
B 
E 
C 
D 
BCADE 
B 
C 
A 
D 
E 
CDBEA 
C 
D 
B 
E 
A 
DECAB 
D 
E 
C 
A 
B 
EADBC 
E 
A 
D 
B 
C 
DCEBA 
D 
C 
E 
B 
A 
EDACB 
E 
D 
A 
C 
B 
AEBDC 
A 
E 
B 
D 
C 
BACED 
B 
A 
C 
E 
D 
CBDAE 
C 
B 
D 
A 
E 
Treatment A: Placebo 
Treatment B: Alprazolam 2 mg 
Treatment C: GE-IR 200 mg 
Treatment D: GE-IR 450 mg 
Treatment E: GE-IR 700 mg 


 
 
 
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3.5.2 
Blinding 
The treatment assignment will not be known by the study subjects. 
Furthermore, the randomization code will not be available to investigators and clinical staff 
involved in the collection, monitoring, revision, or evaluation of AEs, as well as clinical staff 
that could have an impact on the outcome of the study, including the biostatistician and 
pharmacokineticist (or delegate). When all PD assessments during the qualification phase have 
been completed for each cohort, the randomization will be released to allow for the evaluation of 
qualification criteria. For the treatment phase, the randomization will remain blinded until all the 
CRFs have been approved and signed. 
The preparation and/or dispensing of the products will be performed by designated personnel 
that are not directly involved in the clinical aspects of the trial. 
The randomization code must not be broken except in emergency situations where the 
identification of a subject’s study treatment is required by an investigator for further treatment of 
the subject or by the designated unblinding person(s) in the case of a suspected, unexpected SAE 
(SUSAR) report. Randomization information will be held by designated individual(s). The date 
and reason for breaking the blind must be recorded. 


 
 
 
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4. 
ANALYSIS POPULATIONS 
4.1 
Qualification Phase 
4.1.1 
Qualification Randomized Population 
The Qualification Randomized population will include all subjects who are assigned a 
randomization number in the qualification phase. 
4.1.2 
Qualification Safety Population 
The Qualification Safety population will include all subjects who are randomized into the 
Qualification phase and receive at least 1 dose of either the study drug or placebo. 
4.2 
Treatment Phase 
4.2.1 
Randomized Population 
The Randomized population will include all subjects who are assigned a randomization number 
in the treatment phase. 
4.2.2 
Safety Population 
The Safety population will include all subjects who are randomized into the treatment phase and 
receive at least 1 dose of 1 of the study drugs or placebo. 
4.2.3 
Completer Population 
All subjects in the Safety population who complete all 5 crossover periods in the treatment phase 
of the study, and have sufficient data for evaluation of the primary endpoint (based on a blinded 
review of data prior to database lock) will be included in the Completer population. Subjects who 
do not have at least 1 observation within 2 hours of Tmax for each treatment for Drug Liking VAS 
will be excluded from the Completer population. 
4.2.4 
Modified Completer Population 
All subjects in the Completer population, excluding problematic subjects with unreliable 
responses which can alter study results, will be included in the Modified Completer population. 
For the Drug Liking VAS scale, the following elimination criteria will be used to define the 
Modified Completer population. 
a) Similar Emax scores (within a 5-point difference) for a subject across all study treatments 
(including placebo) 
OR 
b) Emax for placebo > 60 AND the Emax(placebo) - Emax(positive control) ≥ 5 
Criterion a) and b) will be applied to the Drug Liking VAS data on the Completer population. If 
no subjects are excluded when these criteria are applied, then the Modified Completer population 
is the same as the Completer population. 
4.2.5 
Pharmacokinetic (PK) Population 
All subjects in the Safety population who receive at least 1 dose of GE-IR, and have at least 1 PK 
concentration after dosing will be included in the PK population. 


 
 
 
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5. 
STUDY SUBJECTS 
5.1 
Disposition 
5.1.1 
Qualification Phase 
All subjects who are randomized into the qualification phase will be entered into the database. 
Disposition tables and listings will be presented for all subjects in the qualification phase, and for 
qualification failures using the Qualification Randomized population. 
5.1.2 
Treatment Phase 
Subject disposition will be summarized and listed for subjects randomized to the treatment phase 
using the Randomized population. Percentages will be calculated using the number of 
randomized subjects. Completion by population, by period, by study, and reasons for 
discontinuation will be included in this table. 
Subject discontinuations will be summarized by last treatment prior to discontinuation during the 
treatment phase. Listings of subject disposition by completion/discontinuation will also be 
provided. 
Subject exclusions from each population will be summarized and listed for each phase of the 
study. Randomization scheme and code will be listed for the each phase of the study. 
5.2 
Protocol Deviations 
All protocol deviations related to study inclusion or exclusion criteria, conduct of the study, 
subject management, or subject assessment (including PD and PK sample processing deviations) 
will be listed for the qualification and randomized phases using the Qualification and 
Randomized populations, respectively. Information for PD and PK sampling time deviations 
during the treatment phase will be derived programmatically, and presented in listings. 
Deviations will be collected in the clinic deviation tracking system (DTS) and presented as 
entered in a general protocol deviation listing. 


 
 
 
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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Qualification Phase 
Demographics, baseline characteristics and informed consent information will be listed for the 
Qualification Randomized population. Demographics and baseline characteristics (sex, age, race, 
ethnicity, body weight, height, BMI) will be summarized separately for the Qualification 
Randomized and Safety populations. Subjects who did not complete the qualification phase or 
were not randomized into the treatment phase will also be summarized. 
6.2 
Treatment Phase 
Demographics, baseline characteristics and informed consent information will be listed for the 
Qualification Randomized population. Demographics and baseline characteristics (sex, age, race, 
ethnicity, body weight, height, and body mass index (BMI)) will be summarized by each 
population in the treatment phase using descriptive statistics (number of subjects (n), mean, 
standard deviation (SD), minimum, median, and maximum for continuous variables, and number 
of subjects and the proportion of subjects for categorical variables). 
Prior and concomitant medications will be assigned a 12-digit code using the most recent version 
of the World Health Organization drug code available. Prior and concomitant medications will be 
listed by subject for the Qualification Randomized population. 
Histories of recreational drug use, alcohol use and smoking history will be summarized for the 
Randomized population using descriptive statistics and listed by subject for the Qualification 
Randomized population. 


 
 
 
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7. 
PHARMACODYNAMICS ANALYSIS 
Unless otherwise specified, all available PD data and analysis results will be presented for the 
Modified Completer population. 
7.1 
Pharmacodynamics Assessments 
Prior to completing the computerized pharmacodynamics measures, all subjects will undergo a 
scripted training and practice regimen with additional training sessions as necessary. 
7.1.1 
Subjective Effects Visual Analogue Scales (VASs) 
All VASs will be scored on a 100-point scale, as shown in Table 4. The VASs may be 
administered as bipolar or unipolar scales, as appropriate, and the choice is determined by the 
nature of the subjective effect being measured. When VASs are administered as bipolar scales, 
the neutral point equals 50 (e.g., Drug Liking, Overall Drug Liking, Take Drug Again, 
Drowsiness/Alertness and Relaxation/Agitation VAS). The neutral point will also be labeled 
with an anchor, such as “neither like or dislike.” When VASs are administered as unipolar scales, 
the anchors will be presented using text such as “Not at all” (score = 0) to “Extremely” (score = 
100; e.g., Good, Bad, High, and Any Effects VASs). Scales that refer specifically to drug (e.g., 
Drug Liking, Good Effects VAS, Bad Effects VAS, and Any Effects VAS) are not administered 
at predose. 
Table 4: Visual Analog Scale (VAS) Descriptions 
Scale 
Interpretation 
Include 
Predose 
Type of 
Scale 
Description 
Question Text 
Response 
Anchors 
Balance 
No 
Bipolar 
Drug Liking 
At this moment, my liking 
for this drug is 
0: Strong disliking 
50: Neither like or 
dislike 
100: Strong liking 
Balance 
No 
Bipolar 
Overall Drug Liking 
Overall, my liking for this 
drug is 
Balance 
No 
Bipolar 
Take Drug Again 
I would take this drug 
again 
0: Definitely 
would not 
50: Neither would 
or would not 
100: Definitely 
would 
Positive 
Yes 
Unipolar 
High 
At this moment, I am 
feeling high 
0: Not at all 
100: Extremely 
Positive 
No 
Unipolar 
Good Effects 
At this moment, I feel 
good drug effects 
Negative 
No 
Unipolar 
Bad Effects 
At this moment, I feel bad 
drug effects 


 
 
 
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Scale 
Interpretation 
Include 
Predose 
Type of 
Scale 
Description 
Question Text 
Response 
Anchors 
Other 
No 
Unipolar 
Any Effects 
At this moment, I can feel 
any drug effect 
Other 
Yes 
Unipolar 
Feeling Drunk 
At this moment, I am 
feeling drunk 
Other  
Yes 
Bipolar 
Drowsiness/Alertness 
At this moment, my 
mental state is 
0: Very drowsy 
50: Neither 
drowsy nor alert 
100: Very alert 
Other 
Yes 
Bipolar 
Relaxation/Agitation 
At this moment, my 
mental state is 
0: Very agitated 
50: Neither 
agitated or relaxed 
100: Very relaxed 
7.1.2 
Addiction Research Center Inventory (ARCI) Scales 
The ARCI Morphine-Benzedrine Group (MBG) consists of a series of 17 true/false statements, 
and Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) scales consist of a series of 15 
true/false statements. The respective questionnaires are presented in Appendix 9 and 10 of the 
protocol. 
7.1.3 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
The MOAA/S is an observer-rated measure of alertness/sedation that is used widely in clinical 
research. It is based on the following 6 items, rated on a scale from 5 (not sedated) to 
0 (unarousable): 
The Observer’s Assessment of Alertness/Sedation Scale (OAA/S) was developed to measure the 
level of alertness in subjects who are sedated.1 The OAA/S is a reliable validated measure and 
was shown to be sensitive to different levels of sedation and is composed of 4 assessment 
categories that include responsiveness, speech, facial expression, and eyes. The Modified 
Observer's Assessment of Alertness/Sedation Scale (MOAA/S) includes only the Responsiveness 
assessment category. It is easy and quick to administer (less than 1 minute). The subjects’ level 
of responsiveness is measured in a 5-point Likert scale: 
Responsiveness 
Score 
Responds readily to name spoken in normal tone 
5 (Alert) 
Lethargic response to name spoken in normal tone 
4 
Responds only after name is called loudly and/or repeatedly 
3 
Responds only after mild prodding or shaking 
2 
Does not respond to mild prodding or shaking 
1 (Deep Sleep) 


 
 
 
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7.2 
Appropriateness of Measures 
The selected PD measures will assess positive and negative subjective drug effects associated 
with the abuse potential of this drug. These subjective measures are consistent with guidelines 
for HAP studies2 and are similar to those used in previous studies. Although data from all 
measures will be considered in the assessment of abuse potential, the Drug Liking VAS has been 
selected as the primary endpoint for practical purposes (such as calculating power and assessing 
qualification eligibility), as it is considered one of the most sensitive and face-valid measures of 
abuse potential.3,4 Overall Drug Liking VAS and Take Drug Again have been selected as key 
secondary endpoints as they represent the subject’s global assessment of the drug, and have face 
validity for predicting continued use of a drug. High VAS has also been selected as a key 
secondary endpoint because it has been shown to be sensitive in capturing the positive subjective 
effects of test drugs. Additional secondary endpoints assess other subjective effects of the drug 
that may help with interpretation of the data. 
Standard PK parameters will be evaluated to confirm plasma concentrations and the PK profile 
of GE-IR in the PK population. Standard measures of safety will be included to monitor the 
safety and tolerability of the GE-IR doses used in the study. 
7.3 
Pharmacodynamics Assessment Visit Windows 
Predose measures should be no more than 1 hour prior to dosing. Visit windows for VAS and 
ARCI should be ±15 minutes from each postdose time point. MOAA/S will be conducted during 
the qualification and treatment phases within 1 hour prior to dosing and approximately (±15 
minutes) at 0.5, 1, 1.5, 2 hours postdose, and approximately (±30 minutes) at 3, 4, and 6 hours 
postdose (refer to Appendix A for more details regarding the order of administration). 
7.4 
Analysis of Pharmacodynamics Measures 
The primary analysis of PD data will be analyzed for the Modified Completer population. 
Emax of Drug Liking, Overall Drug Liking, Take Drug Again and High VAS from the 
qualification phase will be summarized by treatment and paired difference for the Modified 
Completer population using standard descriptive statistics. The data will be evaluated to confirm 
that an appropriate population was selected for the treatment phase. 
During the treatment phase, PD measures at each time point will be summarized by treatment 
using descriptive statistics and presented graphically. Derived endpoints will be summarized by 
treatment and paired difference using descriptive statistics. Only descriptive statistics will be 
output for TEmax and TEmin. Descriptive statistics will include n, mean, standard error (SE), 
minimum, first quartile (Ql), median, third quartile (Q3) and maximum for all PD values and 
endpoints other than TEmax and TEmin. For TEmax and TEmin, minimum, Q1, median, Q3 and 
maximum will be output. 
A mixed-effects model for a crossover study design will be used to compare the primary and 
secondary PD endpoints between treatments (e.g., Emax, Emin, CFBmin, TA_AUE and TA_AOE) 
with appropriate covariance-variance structure, if the residuals are normally distributed. 
Necessary adjustment in the model will be made for possible heteroscedasticity of variances 
through Kenward Roger approximation of degrees of freedom. 












 
 
 
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A significance level of 0.05 will be used for Hypotheses 1 and 2, and a significance level of 0.1 
will be used for Hypothesis 3.9 For Hypotheses 1 and 2, 1-sided 95% confidence intervals will be 
presented while 2-sided 90% confidence intervals will be presented for Hypothesis 3. 
7.4.3 
Test Hypotheses for Non-Key Secondary Endpoints 
For the comparisons of all other non-key secondary PD endpoints, the following hypothesis will 
be used to provide information on the relative abuse potential of the test drug in humans: 
 
 
 
The hypothesis for comparison between the positive control, alprazolam and placebo will be: 
 
 
where μC is the mean for the positive control, alprazolam, and μP is the mean for placebo, and 
will be applied to the following contrast: 
• Treatment B: Alprazolam 2 mg vs. Treatment A: Placebo 
The hypothesis for comparison between the positive comparator, alprazolam, and the test drug, 
GE-IR, will be: 
 
 
where μC is the mean for the positive control, alprazolam, and μT is the mean for the test drug, 
GE-IR, and will be applied to the following contrasts: 
 
 
 
 
 
 
The hypothesis for comparison between the test drug, GE-IR, and placebo will be: 
 
 
where μT is the mean for the test drug, GE-IR, and μP is the mean for placebo, and will be 
applied to the following contrasts: 
 
 
 
 
 
 


 
 
 
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A significance level of 0.05 will be used for Hypotheses 1 and 2, and a significance level of 0.1 
will be used for Hypothesis 3.9 For Hypotheses 1 and 2, 2-sided 95% confidence intervals will be 
presented while 2-sided 90% confidence intervals will be presented for Hypothesis 3. 
7.4.4 
Secondary Analysis 
Although a margin of 15 has been selected for Hypothesis 1 for consistency with the 
qualification phase criteria, subjects may have lower responses with alprazolam and higher 
responses with placebo in the treatment phase as compared to the qualification phase,6,7 
particularly for lower abuse potential drugs such as benzodiazepines (i.e., Schedule IV drugs). 
Therefore, in the case that the difference between the active control and placebo does not meet 
the pre-specified criteria for validity of at least 15 points, Drug Liking VAS Emax will be 
explored in terms of the following criteria using descending point differences starting at 4. 
 
 
 
 
7.4.5 
Adjustment for Covariates 
Baseline (pre-dose) measurement will be included as a covariate, where applicable, in the mixed 
effects models. 
7.4.6 
Adjustment for Multiple Comparison/Multiplicity 
No adjustments will be made for multiple comparisons. The primary hypotheses follow a 
hierarchical (sequential) testing method, and all doses of GE-IR should show statistical 
significance in the hypothesis testing. 


 
 
 
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8. 
PHARMACOKINETICS ANALYSIS 
8.1 
Pharmacokinetic Analysis 
The PK analysis will be carried out according to Altasciences standard operating procedures 
(SOPs). 
8.1.1 
Concentration Data 
Plasma concentrations of gabapentin resulting from the single 200 mg, 450 mg, and 700 mg dose 
administration of the investigational product (GE-IR) from the treatment phase will be 
determined to establish the PK profile of gabapentin in healthy, nondependent, recreational drug 
users with sedative experience. 
8.1.2 
Missing Values 
The lack of concentration values due to failure to collect the sample, a lost or compromised 
sample or due to the subject’s early termination from the study will be termed “missing” in the 
dataset, and no imputation will be done. 
If the actual collection time of a postdose PK sample is unknown, but a valid concentration value 
has been measured, the sample will be set to missing in the PK analysis and descriptive statistics, 
but the concentration value will be presented in the concentration listing. Unknown baseline 
collection times will be handled on a case-by-case basis. 
8.1.3 Measurements Below the Lower Limit of Quantitation 
Concentration values below the lower limit of quantitation (LLOQ) associated with predose and 
postdose collection times will be replaced with zero for the non-compartmental analyses (NCA). 
Concentration values below the LLOQ will be replaced with zero for mean PK profile 
representations as well as for descriptive statistic calculations. 
8.1.4 Actual Times 
The NCA will be based on the actual sampling times, except for predose samples, which will 
always be reported as zero, regardless of time deviations. 
The individual concentration/time profiles will be presented using actual sampling times whereas 
the mean concentration/time profiles and tables presenting summary statistics of concentration-
time series will be presented using nominal sampling times. Concentration profiles will be 
presented on both linear and semi-logarithmic scales. 
Individual actual times will be listed. 
8.1.5 
Non-Compartmental Analysis 
The PK analyses will be based on the PK population. 
The following configuration for the NCA (with Phoenix® WinNonlin® version 8, or higher) will 
be used: 




 
 
 
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9. 
SAFETY 
For the treatment phase, the following safety endpoints will be evaluated: incidence, maximum 
severity and maximum relationship of AEs, AEs leading to discontinuation and SAEs, clinical 
laboratory assessments (hematology, biochemistry, urinalysis), vital signs [e.g. systolic and 
diastolic blood pressure, pulse rate, respiratory rate, oral temperature, SpO2], continuous SpO2 
monitoring, continuous EtCO2 monitoring, ECGs, physical examination findings, and Columbia-
Suicide Severity Rating Scale (C-SSRS). All safety analyses will be conducted on the Safety 
population. By-subject listings of adverse events will be based on the Qualification Safety 
population if occurring in the qualification phase and the Safety population if occurring in the 
treatment phase. All other listings for safety endpoints will be based on the Qualification 
Randomized population. 
9.1 
Adverse Events 
9.1.1 
Qualification Phase 
The Qualification Safety population will be used to list all AEs occurring in the Qualification 
phase. Qualification passes and failures will be listed separately. 


 
 
 
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9.1.2 
Treatment Phase 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered an investigational product and which does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of an investigational product, whether or not related to 
the investigational product. 
Treatment emergent adverse events (TEAEs) are AEs not present prior to the exposure to study 
treatment or AEs already present that worsen in intensity or frequency following exposure to 
study treatment. 
All TEAEs will be assigned to a treatment using the following rules: 
• A TEAE will be assigned to the last treatment taken by the subject where the date and 
time of the last treatment dosing is on or before of the start date and time of the event. 
Such assignment will be performed irrespective of any washout period between the start 
and stop dates of the TEAE. 
• Any TEAE started during the follow-up period will be assigned to the last treatment that 
the subject has taken. 
9.1.2.1 
Severity Categorization 
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of the study drug, must be recorded as 
new AEs on the appropriate electronic case report form (eCRF) page. 
The medical assessment of severity is determined by using the following definitions: 
Term 
Severity Definition 
Mild: 
Causing no limitation of usual activities; the subject may experience 
transient slight discomfort. 
Moderate: 
Causing some limitation of usual activities; the subject may experience 
annoying discomfort. 
Severe: 
Causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
9.1.2.2 
Relationship Categorization 
The causality assessment must be documented in the source document and the AE will should be 
considered as “reasonable possibility” and “not reasonable possibility”. 
The following additional guidance may be helpful: 
Term 
Relationship Definition 
Reasonable 
Possibility 
A temporal relationship exists between the AE onset and administration of the 
investigational product that cannot be readily explained by the subject’s 
clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be related, 


 
 
 
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Term 
Relationship Definition 
based on the known therapeutic and pharmacologic actions or AE profile of 
the investigational product. 
In case of cessation or reduction of the dose the AE may abate or resolve and 
it may reappear upon rechallenge. 
No Reasonable 
Possibility 
Evidence exists that the AE has an etiology other than the investigational 
product. 
For SAEs, an alternative causality must be provided (e.g., preexisting 
condition, underlying disease, intercurrent illness, or concomitant 
medication). 
9.1.2.3 
General Summary of Treatment-Emergent Adverse Events 
An overall summary table of all TEAEs by treatment at onset and overall for the treatment phase 
will be produced to present data below: 
 Number and percentages of subjects (number of events) with any TEAE 
 Number and percentages of subjects (number of events) with study drug discontinued due 
to TEAE 
 Number and percentages of subjects (number of events) with severe TEAE 
 Number and percentages of subjects (number of events) with any related TEAE 
 Number and percentages of subjects (number of events) with any serious TEAE 
 Number and percentages of subjects (number of events) with any serious TEAE leading 
to death 
The denominator for percentages will be the total number of subjects in the Safety population by 
treatment and overall. 
9.1.2.4 
Summaries of Treatment-Emergent Adverse Events 
 Summary of TEAEs by System Organ Class (SOC), Preferred Term (PT), and Treatment 
o A summary of the number and percentages of subjects who experienced at least 
one TEAE, and the number and percentages of subjects who experienced each 
SOC and each PT within each SOC will be presented by treatment and overall. In 
addition, the number of events will be summarized for each of these categories. 
 Summary of TEAEs by SOC, PT, Treatment and Maximum Severity 
o A summary of the number and percentages of subjects who experienced at least 
one TEAE by maximum severity as well as the number and percentages of 
subjects who experienced each SOC and each PT within each SOC by maximum 
severity will be presented by treatment. For this analysis, if a subject has more 
than one occurrence of the same PT, then the PT will be counted only once for 
that subject under the maximum severity at which it was experienced (mild, 
moderate or severe). 


 
 
 
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 Summary of TEAEs by SOC, PT, Treatment and Maximum Relationship 
o A summary of the number and percentages of subjects who experienced at least 
one TEAE by maximum relationship as well as the number and percentages of 
subjects who experienced each SOC and each PT within each SOC by maximum 
relationship will be presented by treatment. For this analysis, if a subject has more 
than one occurrence of the same PT, then the PT will be counted only once for 
that subject under the maximum relationship at which it was experienced 
(reasonable possibility or no reasonable possibility). 
9.2 
Clinical Laboratory Evaluations 
General biochemistry, hematology, and urinalysis assessments, and other laboratory tests are 
listed in Table 6. 
Table 6: Clinical Laboratory Assessments 
Clinical Laboratory Test 
Panel 
Description 
General biochemistry: 
Sodium, potassium, chloride, glucose, blood urea nitrogen (BUN), 
creatinine, bilirubin total, alkaline phosphatase, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), and albumin  
Endocrinology: 
Follicle stimulating hormone (FSH; for female subjects) 
Hematology: 
White cell count with differential (absolute values of neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil), red cell count, 
hemoglobin, hematocrit, mean corpuscular volume (MCV), and platelet 
count 
Serology* 
Human immunodeficiency virus (HIV) antigen/antibody (Ag/Ab) 
Combo, Hepatitis B (HBsAg (B)) and Hepatitis C (HCV (C))  
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, glucose, ketones, 
bilirubin, blood, nitrite, urobilinogen. Microscopic examination will only 
be performed if the dipstick test is outside of the reference range for 
leukocyte, blood, nitrite or protein 
Urine drug screen (UDS) 
Alcohol, amphetamines, barbiturates, cannabinoids, cocaine, opiates, 
benzodiazepines, and phencyclidine 
Urine OR serum pregnancy 
test: 
To be performed for all female subjects 
*Serology will be done at screening only. 
Laboratory data collected during the treatment phase will be summarized by the type of 
laboratory test and visit. Descriptive statistics (n, mean, SD, minimum, median, and maximum), 
and the number of subjects with laboratory test results below, within, and above normal ranges 
will be tabulated by laboratory test and visit. 
All laboratory data will be listed by laboratory panel and test. Laboratory abnormalities and 
clinically significant abnormalities during the treatment phase will also be listed. 
9.2.1 
Viral Screen 
A screening viral screen will be done for HIV 1/2 Antibody, Hepatitis B Virus Surface Antigen, 
and Hepatitis C Virus Antibody. The results of the viral screen will be listed. 


 
 
 
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9.2.2 
Urine Drug Screen and Urine Alcohol Testing 
UDS will test for the following drugs of abuse: amphetamines, barbiturates, cannabinoids, 
cocaine, opiates, benzodiazepines, and phencyclidine. 
Urine alcohol testing may be requested any time during the study. The results of UDS and urine 
alcohol testing will be listed. 
9.2.3 
Pregnancy and Follicle Stimulating Hormone (FSH) Tests 
A listing will be done for pregnancy and FSH tests. Serum pregnancy test will be done at 
screening. Urine pregnancy test will be done at each admission to the qualification phase and, if 
applicable, treatment phase, and at Day 14/early termination. For postmenopausal women, an 
FSH test will be done at screening. 
9.3 
Vital Signs 
Scheduled time points in the treatment phase for blood pressure, pulse rate, oxygen saturation 
(SpO2), and respiratory rate will include predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours 
(±15 minutes) postdose. For EtCO2, scheduled time points in the treatment phase will be recorded 
pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose. 
Treatment phase vital signs (blood pressure, heart rate, respiratory rate, SpO2) and EtCO2 will be 
analyzed as minimum, maximum, and final postdose values since the analyses of these extremes 
are more meaningful than analyses of individual time points. Vital signs will be summarized 
using descriptive statistics (n, mean, SD, minimum, median, and maximum). All vital signs, 
including oral temperature, will be listed. Abnormal and clinically significant abnormal findings 
will be listed. 
9.4 
12-Lead Electrocardiograms 
The ECG variables will include ventricular heart rate and the PR, QRS, QT, and QTcF intervals. 
12-Lead ECG data during the treatment phase (absolute values in heart rate and PR, QRS, QT, 
and QTcF intervals) will be summarized by parameter and visit using descriptive statistics (n, 
mean, SD, minimum, median, and maximum). Overall ECG interpretation will be summarized 
(normal; abnormal, non-clinically significant; and abnormal, clinically significant). Abnormal 
and clinically significant findings in ECG data will be listed. 
9.5 
Physical Examination Findings 
Physical examination includes a review of the following: head, eyes, ears, nose, throat (HEENT), 
neck, chest, back, abdomen, extremities and neurological function. 
Physical examination findings will be presented in a listing by subject and visit. 
9.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be used to assess both behavior and ideation that tracks all suicidal events and 
provides a summary of suicidal ideation and behavior. It assesses the lethality of attempts and 
other features of ideation (frequency, duration, controllability, reasons for ideation, and 
deterrents), all of which are significantly predictive of completed suicide. 


 
 
 
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Two versions of the C-SSRS will be used in this study: the Baseline/Screening version (lifetime 
history and past 12 months) and the Since Last Visit version. The Screening version of the C-
SSRS will be administered at Visit 1 (Screening). The Since Last Visit version of the C-SSRS 
will be administered at all subsequent assessment times. 
The C-SSRS will be listed by subject and visit. 


 
 
 
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10. 
DATA HANDLING AND PRESENTATION 
All safety and statistical outputs will be generated using SAS software, version 9.4. 
Pharmacokinetic outputs will be generated using WinNonlin version 8.0 or higher. 
All programs used to generate statistical analyses will be validated according to Altasciences’s 
SOPs. 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock and prior to breaking the blind. Any analyses performed subsequent to database 
lock and breaking the blind that are not described within the present plan will be considered post 
hoc and secondary. Post hoc analyses will be labeled as such in the corresponding statistical 
output and identified in the clinical study report (CSR). 
10.1 
Safety Analysis Presentation 
Adverse events and medical history will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology as defined in the study data management plan 
(DMP). 
Prior and concomitant medications will be coded with the World Health Organization Drug 
Dictionary- Enhanced (WHO-DDE) as defined in the study DMP. 
In general, all safety summary tables will be presented for the Safety population. Summaries for 
AEs will be presented by treatment. Summaries for other safety endpoints will be presented by 
treatment if the endpoints are measured at the end of each period or by treatment sequence if the 
endpoints are measured not at the end of each period but at the end of study only. 
In general, the data listings will include all randomized subjects up to the point of study 
completion or discontinuation; exceptions will be listings pertaining to a subset of subjects only 
(e.g., subjects with protocol deviations) or a subset of records/events (e.g., abnormal laboratory 
values). 
Categorical variables will be summarized using the PROC FREQ procedure. Continuous 
variables will be summarized using the PROC UNIVARIATE procedure. For natural log (ln)-
transformed endpoints, geometric mean, geometric SD, and CV% will also be presented. 
The following general comments also apply to all statistical analyses and data presentations: 
• Duration variables will be calculated using the general formula: (end date - start date) +1. 
• If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical type), 
a coded value must be appropriately determined and used in the statistical analyses.  In 
general, a value or lower and upper limit of normal range such as ‘<10’ or ‘≤5’ will be 
treated as ‘10’ or ‘5’ respectively, and a value such as ‘>100’ will be treated as ’100’.  
However, the actual values as reported in the database will be presented in data listings. 
• When assessments are repeated for a given time point or performed at unscheduled times, 
only the result which is the closest to the dosing time will be included in summary tables. 
In general, summary statistics for raw variables (i.e., variables measured at the study site or 
central laboratory) will be displayed as follows: 


 
 
 
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• Minima and maxima will be displayed to the same number of decimal places as the raw 
data. 
• Means, medians, and quartiles will be displayed to 1additional decimal place. 
• Standard deviations will be displayed to 2 additional decimal places. 
• Percentages will be displayed to 1 decimal place. Percentages between 0 and 0.1 
(exclusive) will be displayed as ‘<0.1’. 
• P-values will be displayed to 3 decimal places. P-values that are less than 0.001 will be 
displayed as ‘<0.001’. 
The numbers of decimal places for summary statistics of derived variables (i.e., variables that are 
not measured by the study site but are calculated for analysis based on other measured variables) 
will be determined on a case by case basis.  In general: 
• Minima and maxima will be displayed to the commonly used unit of precision for the 
parameter. 
• Means, medians, quartiles, and confidence limits will be displayed to 1 additional 
decimal place. 
• Standard deviations will be displayed to 2 additional decimal places. 
10.2 
Pharmacokinetic Analysis 
In general, all PK summary tables will be presented for the PK population. 
Individual raw PK concentrations will be displayed with the same precision as received from the 
bioanalytical laboratory. 
Precision for individual PK parameters will be displayed as follows: 
• Cmax and AUC0-T will be displayed with the same precision as the raw PK concentration 
data 
• Parameters associated with time (i.e. Tmax and Tlast) will be displayed with 2 decimal 
places 
Summary statistics for concentration and PK parameters will be displayed with the same 
precision as the individual values, with the exception of N and CV% which will be presented 
with 0 and 1 decimal place, respectively. 
10.3 
Analysis Time Points 
Unless otherwise specified, the baseline value will be defined as the last non-missing evaluation 
prior to the first dose of study medication in each treatment period. 
10.4 
Methods for Handling Missing Data 
No imputation of missing PD or PK data will be performed. 
The occurrence of missing PD data will be minimized by only including subjects who are 
rousable, and complete PD assessments in the qualification phase. In addition, all reasonable 
attempts will be made to rouse subjects for completion of the PD assessments in both the 


 
 
 
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qualification and treatment phases. Missing PD assessments, including reasons for the missing 
data, will be listed by subject, and examined on a case-by-case basis to determine if these affect 
subject allocation (i.e., inclusion in the Modified Completer population). If for a given PD 
measure, the predose value is missing, calculation of CFBmin and TA_AOE will not be possible, 
and the subject will not be included in the Modified Completer population for that PD endpoint. 
If the actual date and/or time of a postdose PD assessment is unknown, but there is a result at that 
time point, the value will be used in descriptive statistics of treatment by time point summaries, 
and PD endpoint by treatment summaries but will be excluded from calculation of TA_AUE and 
TA_AOE which need actual time from dose in order to be calculated. 
If the actual collection time of a postdose PK sample is unknown, but a valid concentration value 
has been measured, the sample will be set to missing in the PK analysis and will be presented in 
listing but excluded from descriptive statistics. Unknown baseline collection times will be 
handled on a case-by-case basis. 
Further details on handling of missing values will be provided in the Subject Allocation and 
Request to Break the Blind Form. 


 
 
 
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11. 
INTERIM ANALYSES AND DATA SAFETY MONITORING 
No interim analyses are planned for this study. 


 
 
 
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12. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
Protocol Section 
Original Text 
SAP Section 
Change 
Study Synopsis: 
Pharmacokinetic 
Endpoints; Table 8. 
Pharmacokinetic 
Parameters 
Pharmacokinetic 
Parameters: Cmax, Tmax, 
AUC0-T, Tlast 
Table 1: Objectives and 
Related Endpoints and 
Table 5: 
Pharmacokinetic 
Parameters in Plasma 
Additional PK 
Parameters: AUC0-1 
AUC0-2, AUC0-12, 
AUC0-24, AUC0-inf , 
T1/2, λZ 
Study Synopsis: Active 
Control, Dose, and 
Mode of 
Administration, 
Placebo, Dose, and 
Mode of 
Administration; Section 
3.2 Study Treatments 
one Swedish Orange 
Opaque AAEL-DB 
capsule 
Section 3.3 Treatments 
Replace original text for 
GE-IR and placebo-to-
match with one size 0 
opaque white capsules 
with no markings 
8.4.1 Qualification 
Phase 
Demographics and 
baseline 
characteristics will be 
summarized for the 
Qualification Safety 
populations. 
Qualification passes 
and failures will be 
listed separately. 
6.1.1 Qualification 
Phase 
Demographics and 
baseline 
characteristics will be 
summarized for the 
Qualification 
Randomized and 
Safety populations 
rather than just the 
Qualification Safety 
population. Subjects 
who did not complete 
the qualification phase 
or were not 
randomized into the 
treatment phase will 
also be summarized. 
8.4.2 Treatment Phase 
Demographics and 
baseline 
characteristics (sex, 
age, race, ethnicity, 
body weight, height, 
BMI), recreational 
drug use history, 
alcohol use history, 
and smoking history 
will be summarized 
using descriptive 
statistics (n, mean, 
SD, minimum, 
median, and 
6.1.2 Treatment Phase 
Demographics and 
baseline 
characteristics will be 
summarized for 
treatment phase 
populations Safety 
population. 
Recreational drug use 
history, alcohol use 
history, and smoking 
history will be 
summarized for the 
Randomized 
population rather than 


 
 
 
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Protocol Section 
Original Text 
SAP Section 
Change 
maximum for 
continuous variables, 
and the proportion of 
subjects for 
categorical variables) 
for the Safety 
population. 
the Safety population. 
8.5.2 Pharmacodynamic 
Statistical Methodology 
Drug Liking and Take 
Drug Again VAS Emax 
from the Qualification 
phase will be 
summarized by 
treatment and paired 
difference for the 
Modified Completer 
population. 
7.4 Analysis of 
Pharmacodynamics 
Measures 
Emax of Overall Drug 
Liking and High VAS 
have been added. 
8.7.3.1 Qualification 
Phase 
The Qualification 
Randomized 
population will be 
used to list all AEs 
occurring in the 
Qualification phase. 
9.1.1 Qualification 
Phase 
The Qualification 
Safety population 
rather than the 
Qualification 
Randomized 
population will be 
used to list all AEs 
occurring in the 
Qualification phase. 


 
 
 
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13. 
GENERAL INFORMATION RELATED TO DATA 
PRESENTATIONS 
The formats and layouts of tables, figures and listings (TFLs) will be provided in a separate 
document and are common displays. Their numbering and general content follow the 
International Conference on Harmonisation (ICH) E3 guidelines. Each TFL will have a template 
number which links it to the Indices of TFLs presented below. Actual formats and layouts may 
be altered slightly from those presented as necessary to accommodate actual data or statistics. 
Minor format changes will not require updates to the SAP, rather they may be documented in a 
Note to SAP. 
 
 














 
 
 
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14. 
REFERENCES 
1. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, 
Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation 
Scale: study with intravenous midazolam. J Clin Psychopharmacol. 
1990 Aug;10(4):244-51. 
2. Assessment of Abuse Potential of Drugs. U.S. Department of Health and Human 
Services. Food and Drug Administration. Center for Drug Evaluation and Research. 
January 2017. 
3. Balster RL, Bigelow GE. Guidelines and methodological reviews concerning drug abuse 
liability assessment. Drug Alcohol Depend. 2003; 70(3 Suppl):S13-40. 
4. Griffiths RR, Bigelow GE, Ator NA. Principles of initial experimental drug abuse 
liability assessment in humans. Drug and Alcohol Depend. 2003; 70(3) Suppl: S41-54. 
5. Daniel, W. W. (1990). Applied Nonparametric Statistics, Second Edition, PWS-KENT 
Publishing Company. 
6. Mills C. Statistical Issues in Abuse-Deterrent Formulation (ADF) and Human Abuse 
Potential (HAP) Studies. CCALC, Abuse Potential Dialogue Session, 12-Oct-2018. 
7. Chen L, Tolliver J, Calderon S., Chiapperino D. Improving the Design of Qualification 
Phase in Human Abuse Potential Studies. The College on Problems of Drug Dependence 
(CPDD) 81th Annual Scientific Meeting, June 15-19, 2019. 
8. Chen L, Bonson KR. An equivalence test for the comparison between a test drug and 
placebo in human abuse potential studies. J Biopharm Stat. 2013; 23(2):294-306. 
9. Chen L. Statistical Considerations on Pharmacodynamic Assessment of Human Abuse 
Potential Studies. CCALC, Abuse Potential Dialogue Session, 12-Oct-2018. 
 






 
 
 
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ARCI= Addiction Research Center Inventory, C-SSRS= Columbia Suicide Severity Rating Scale, DSM-IV= Diagnostic and Statistical Manual of Mental Disorders, 4th. Edition, 
ECG= electrocardiogram, EtCO2 = End Tidal CO2, MOAA/S= Modified Observer’s Assessment of Alertness/Sedation, VAS= visual analog scale 
When time points coincide, procedures should be carried out in the following order, with the following windows: (1) vital signs (±15 minutes), (2) VAS/PD (±15 minutes), (3) PK 
blood sampling (±5 minutes), (4) MOAA/S should be administered immediately after the completion of all other PD measures when scheduling occurs at the same time 
(±15 minutes or 30 minutes). 
 
a The latest version must be signed as soon as possible at the subject’s next scheduled visit. 
b Review of qualification criteria (Section 4.3 of the protocol) 
c Use “Baseline/screening version” of C-SSRS evaluation at screening visit. Use “Since last visit version of C-SSRS” evaluation at Day 14/ET, and if discharged between the 
qualification and treatment phases. Additional C-SSRS evaluations may be done at the investigator’s discretion. 
d Symptom directed physical examination. Additional physical examinations may be done at the investigator’s discretion. 
e Serum pregnancy test at Screening. Urine pregnancy test on each admission to the qualification phase and; if applicable, treatment phase; and at Day 14/ET. 
f Women who are reported to be postmenopausal only. 
g Serology screening as described in APPENDIX 6 of the protocol 
h Blood pressure, pulse rate, oxygen saturation (SpO2) and respiratory rate. Measured and documented at screening; each admission to the qualification phase and treatment phase; 
and within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours following each study drug administration. Oral temperature required at screening and at 
check-in (Day -1) of the qualification phase and, if applicable, upon re-admission to the treatment phase. 
i Oxygen saturation (SpO2), EtCO2, and respiratory rate will be monitored continuously up to 1 hour prior to each study drug administration and will continue for up to 6 hours 
following each drug administration, or longer if deemed medically necessary. EtCO2 will be documented within 1 hour prior to each dose administration and approximately 0.5, 
1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours following each study drug administration. 
j Medications taken within 30 days prior to screening and throughout the duration of study participation will be recorded. 
k Adverse events will be collected on an ongoing basis from the time of first study drug administration in qualification phase throughout the duration of study participation. Serious 
adverse events (SAEs) will be reported from the time of signing informed consent through the duration of study participation. Other conditions reported between the time of 
signing informed consent and first study drug administration in the qualification phase will be recorded as medical history. 
l Additional training sessions may be conducted as needed. Training will be conducted on Day -1 of the qualification phase and, if applicable, upon re-admission to the treatment 
phase. 
m Subjective measures will be evaluated as follows: 
Category 
Evaluations 
Phase 
Timepoints 
Drug-specific 
VAS 
Drug Liking, Good Drug Effects, 
Bad Drug Effects, and Any Drug 
Effects 
Qualification phase 
approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
Treatment phase 
approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 24 hours postdose 
Overall Drug Liking and Take Drug 
Again 
Qualification and 
treatment phases 
approximately 12 and 24 hours postdose 
Other VAS 
High, Feeling Drunk, 
Relaxation/Agitation, and 
Drowsiness/Alertness 
Qualification phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
Treatment phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 24 hours 
postdose 
ARCI Scales 
Morphine-Benzedrine Group 
(MBG) and Pentobarbital-
Chlorpromazine-Alcohol Group 
(PCAG) 
Qualification phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose 
Treatment phase 
within 1 hour prior to and approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 24 hours 
postdose 
n Conducted during the qualification and treatment phases within 1 hour prior to dosing and approximately (±15 minutes) at 0.5, 1, 1.5, 2 hours postdose and approximately 
(±30 minutes) at 3, 4, and 6 hours postdose. 
o Blood samples will be collected as indicated in Table 4 of the protocol. When clinical activities are scheduled to occur at the same time, pharmacodynamic data collection (vital 
signs then subjective measures) is to be prioritized, followed by PK blood sampling. 


 
 
 
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p If subjects are discharged between the qualification and treatment phases, noted discharge procedures will be performed on Day 4 of the qualification phase and noted 
re-admission procedures will be performed again on Day -1 of the treatment phase. A minimum 3-day washout will be required between the last dose in the Qualification phase 
and the first dose of the treatment phase. 
q Randomization will be performed for qualification phase only on Day -1 of the qualification phase then, subjects who meet qualification criteria will be randomized for the 
treatment phase on Day -1 of the treatment phase. 
r Subjects administered 2 mg alprazolam or placebo according to randomization with a minimum of 48 hours between doses during the qualification phase. 
s Subjects administered 200 mg GE-IR, 450 mg GE-IR, 700 mg GE-IR, or GE-IR placebo, and 2 mg alprazolam or alprazolam placebo (section 3.2) according to randomization 
with a minimum washout period of 3 days between doses. 
t Covid-19 testing will be performed prior to admission for the qualification phase and, if applicable, upon re-admission for the treatment phase.