Clinical trial NCT06247488
Conditions: Abuse Potential
Sponsor: Arbor Pharmaceuticals, Inc.
Start date: 2022-01-31; Completion date: 2023-04-25
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the abuse potential of gabapentin enacarbil immediate release capsules taken alone and in combination with oxycodone in healthy adult, non-dependent, recreational opioid 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, taken alone and taken in combination with oxycodone, compared to that of oxycodone alone.

This study is a randomized, double-blind, active- and placebo-controlled, 6-way crossover design, aimed to assess the abuse potential, safety, and pharmacokinetics (PK) of GE-IR doses when administered alone or in combination with an opioid active control (oxycodone), and compared to placebo and oxycodone intake alone, in healthy, nondependent, recreational opioid users.

Arms: arm 1: oral masked Placebo arm 2: oral active control arm 3: single oral dose arm 4: single oral dose arm 5: oral doses given together arm 6: oral doses given together
Interventions: intervention 1: Placebo intervention 2: Oxycodone 20 mg intervention 3: GE-IR 200 mg intervention 4: GE-IR 450 mg
Intervention descriptions: intervention 1: Participant will receive oral dose of placebo. intervention 2: Participant will receive oral dose of oxycodone 20 mg. intervention 3: Participant will receive oral dose of GE-IR 200 mg and oxycodone 20 mg. intervention 4: Participant will receive oral dose of GE-IR 450 mg and oxycodone 20 mg.

Protocol documents:
Prot_000.pdf: 
 
A RANDOMIZED, DOUBLE-BLIND, ACTIVE- AND PLACEBO-CONTROLLED, 
6-WAY CROSSOVER STUDY TO EVALUATE THE ABUSE POTENTIAL OF 
ORALLY ADMINISTERED GABAPENTIN ENACARBIL IMMEDIATE RELEASE 
CAPSULES TAKEN ALONE AND IN COMBINATION WITH OXYCODONE IN 
HEALTHY, NONDEPENDENT, RECREATIONAL OPIOID USERS 
Protocol Number: 
AR26.3031.2 
Altasciences Project Number: 
ABO-P4-292 
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 
NCT 
06247488 
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 
2.0 
(Amendment 01) 
August 13, 2021 
 
 
 
 
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. 


Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
Version 2.0, 13AUG2021 
Page 2 of 84 
PROTOCOL AMENDMENT 01 – SUMMARY OF CHANGES 
Description of Change Made 
Section/Location 
Rationale 
Modified the primary objectives 
to remove the evaluation of 
abuse potential for single oral 
doses of GE-IR taken alone. 
• Synopsis (Primary 
Objectives) 
• Section 2 (Study 
Objectives and Endpoints) 
Added as per FDA 
recommendation. 
Added appropriateness of 
including High VAS as a key 
secondary endpoint 
Section 8.2 (Appropriateness 
of Measures) 
Added High VAS for 
completeness. 
Added “in addition to the option 
“RANDOM SUBJECT;” 
Section 8.5.2.1 (Primary 
Analysis) 
Added clarification, as per 
FDA recommendation. 
Added sentences clarifying that 
Hypotheses 3 and 4 will be 
removed. Removed Hypotheses 
3 and 4, and any references to 
them for the primary endpoint. 
Section 8.5.2.1 (Primary 
Analysis), Test Hypotheses 
for Primary Endpoint, Drug 
Liking VAS Emax) 
Added as per FDA 
recommendation: the 
primary objective is 
pertaining to the combination 
drug of GE-IR and OXY20 
rather than GE-IR alone. 
Removed Hypotheses 3 and 4, 
and any references to them for 
key secondary endpoints 
Section 8.5.2.1 (Primary 
Analysis), Test Hypotheses 
for Key Secondary 
Endpoints 
Added as per FDA 
recommendation: the 
primary objective is 
pertaining to the combination 
drug of GE-IR and OXY20 
rather than GE-IR alone. 
Removed Hypotheses 3 and 4, 
and any references to them for 
non-key secondary endpoints 
Section 8.5.2.1 (Primary 
Analysis), Test Hypotheses 
for Non-Key Secondary 
Endpoints 
Added as per FDA 
recommendation: the 
primary objective is 
pertaining to the combination 
drug of GE-IR and OXY20 
rather than GE-IR alone. 
Removed reference for “Chen 
L. Statistical Considerations on 
Pharmacodynamic Assessment 
of Human Abuse Potential 
Studies. CCALC/CSS, October 
11, 2018”, as it contains 
information regarding the alpha 
level for 2 sided-tests which 
will no longer be done as 
Hypotheses 3 and 4 have been 
removed. 
Section 9 (References) 
Reference no longer needed. 
 


Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
Version 2.0, 13AUG2021 
Page 3 of 84 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT 01 – SUMMARY OF CHANGES ........................................................................... 2 
TABLE OF CONTENTS ............................................................................................................................................ 3 
LIST OF IN-TEXT TABLES ..................................................................................................................................... 7 
STUDY SYNOPSIS ..................................................................................................................................................... 8 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE ................................................................ 15 
1. INTRODUCTION .............................................................................................................................................. 17 
1.1. Background ................................................................................................................................................... 17 
1.2. Study Rationale ............................................................................................................................................. 17 
1.3. Rationale for Dose Selection ......................................................................................................................... 20 
1.4. Risk/Benefit Assessment ............................................................................................................................... 20 
1.4.1. Known Potential Risks ........................................................................................................................... 20 
1.4.2. Known Potential Benefits....................................................................................................................... 21 
2. STUDY OBJECTIVES AND ENDPOINTS .................................................................................................... 22 
3. STUDY DESIGN ................................................................................................................................................ 23 
3.1. Overall Study Design .................................................................................................................................... 23 
3.1.1. Screening and Qualification Phase ......................................................................................................... 23 
3.1.2. Treatment Phase and Follow-Up ............................................................................................................ 24 
3.2. Study Treatments ........................................................................................................................................... 27 
4. SUBJECT POPULATION ................................................................................................................................ 27 
4.1. Inclusion Criteria ........................................................................................................................................... 28 
4.2. Exclusion Criteria .......................................................................................................................................... 29 
4.3. Inclusion Criteria into Qualification Phase ................................................................................................... 31 
4.4. Qualification Criteria for Treatment Phase ................................................................................................... 31 
4.5. Withdrawal Criteria ....................................................................................................................................... 32 
4.5.1. Before First Treatment Administration .................................................................................................. 32 
4.5.2. After First Treatment Administration..................................................................................................... 32 
4.6. Lifestyle and/or Dietary Requirements ......................................................................................................... 32 
4.7. Concomitant Treatment ................................................................................................................................. 33 
5. STUDY TREATMENTS .................................................................................................................................... 34 
5.1. Investigational Products ................................................................................................................................ 34 
5.1.1. Gabapentin Enacarbil ............................................................................................................................. 34 
5.1.2. Oxycodone ............................................................................................................................................. 34 
5.2. Investigational Product Management ............................................................................................................ 34 
5.2.1. Packaging, Labeling and Dispensing ..................................................................................................... 34 
5.2.2. Storage and Handling ............................................................................................................................. 34 


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5.2.3. Method of Assigning Subjects to Treatment Groups ............................................................................. 35 
5.2.4. Blinding .................................................................................................................................................. 36 
5.2.5. Study Drug Accountability..................................................................................................................... 36 
5.3. Study Treatment Administration, Meals and Fluids ...................................................................................... 37 
5.3.1. Treatment Compliance ........................................................................................................................... 37 
5.4. Other Protocol Restrictions ........................................................................................................................... 37 
6. STUDY PROCEDURES .................................................................................................................................... 37 
6.1. Safety Assessments ....................................................................................................................................... 38 
6.1.1. Medical History ...................................................................................................................................... 38 
6.1.2. Recreational Alcohol/Drug Use ............................................................................................................. 38 
6.1.3. Physical Examination ............................................................................................................................. 38 
6.1.4. Vital Signs .............................................................................................................................................. 39 
6.1.5. 12-Lead Electrocardiogram .................................................................................................................... 40 
6.1.6. Laboratory Evaluations .......................................................................................................................... 40 
6.1.7. Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................................... 40 
6.1.8. Assessment of Respiratory Depression .................................................................................................. 40 
6.1.9. Rescue Therapy ...................................................................................................................................... 41 
6.2. Blood Volume Collected ............................................................................................................................... 41 
6.3. Pharmacokinetic Assessments ....................................................................................................................... 41 
6.3.1. Pharmacokinetic Sample Processing, Storage and Shipping .................................................................. 42 
6.4. Pharmacodynamic Assessments .................................................................................................................... 43 
6.4.1. Subjective Effects................................................................................................................................... 43 
6.4.2. Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) .................................................... 45 
7. ADVERSE EVENTS DOCUMENTATION .................................................................................................... 45 
7.1. Definitions ..................................................................................................................................................... 45 
7.2. Severity Assessment ...................................................................................................................................... 46 
7.3. Causality Assessment .................................................................................................................................... 47 
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 
8.2. Appropriateness of Measures ........................................................................................................................ 50 
8.3. Missing Values .............................................................................................................................................. 50 
8.4. Demographic Data and Other Baseline Characteristics ................................................................................. 51 
8.5. Pharmacodynamics ........................................................................................................................................ 52 


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8.5.1. Pharmacodynamic Endpoints ................................................................................................................. 52 
8.5.2. Pharmacodynamic Statistical Methodology ........................................................................................... 52 
8.6. Pharmacokinetics .......................................................................................................................................... 58 
8.6.1. Measurements Below the Lower Limit of Quantitation ......................................................................... 58 
8.6.2. Actual Time ............................................................................................................................................ 58 
8.6.3. Noncompartmental Analysis (NCA) ...................................................................................................... 58 
8.6.4. Pharmacokinetic Statistical Methodology .............................................................................................. 59 
8.7. Safety............................................................................................................................................................. 60 
8.7.1. Safety Endpoints .................................................................................................................................... 60 
8.7.2. Safety Analysis....................................................................................................................................... 60 
8.8. Planned Interim Analyses .............................................................................................................................. 61 
8.9. Determination of Sample Size ....................................................................................................................... 61 
9. REFERENCES ................................................................................................................................................... 63 
10. APPENDIX 1: ETHICS ..................................................................................................................................... 66 
10.1. Institutional Review Board ............................................................................................................................ 66 
10.2. Ethical Conduct of the Study ......................................................................................................................... 66 
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 


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18. APPENDIX 9: ADDICTION RESEARCH CENTER INVENTORY (ARCI) MORPHINE-
BENZEDRINE GROUP (MBG) SCALE ................................................................................................................ 82 
19. APPENDIX 10: ADDICTION RESEARCH CENTER INVENTORY (ARCI) PENTOBARBITAL-
CHLORPROMAZINE-ALCOHOL GROUP (PCAG) SCALE ............................................................................ 83 
20. APPENDIX 11: CLINICAL OPIATE WITHDRAWAL SCALE (COWS) .................................................. 84 
 


Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
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LIST OF IN-TEXT TABLES 
Table 1. Schedule of Activities ..................................................................................................... 11 
Table 2 Sample Qualification Phase Sequences .......................................................................... 35 
Table 3 Sample Treatment Phase Sequences .............................................................................. 36 
Table 4. Pharmacokinetic Blood Sampling Schedule (Gabapentin and Oxycodone) .................. 42 
Table 5. Visual Analog Scale (VAS) Descriptions ....................................................................... 44 
Table 6. Adverse Event Relationship to Study Drug .................................................................... 47 
Table 7. Pharmacodynamic Endpoints ......................................................................................... 52 
Table 8. Pharmacokinetic Parameters ........................................................................................... 59 


Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
Version 2.0, 13AUG2021 
Page 8 of 84 
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, 6-Way 
Crossover Study to Evaluate the Abuse Potential of Orally Administered 
Gabapentin Enacarbil Immediate Release Capsules Taken Alone and in 
Combination with Oxycodone in Healthy, Nondependent, Recreational Opioid 
Users 
Study Development 
Phase: 
Not applicable 
Objectives: 
Primary Objectives: 
To evaluate the abuse potential of single oral doses of GE-IR taken in 
combination with an opioid active control (oxycodone) in healthy, 
nondependent, recreational opioid users 
Secondary Objectives: 
To evaluate the pharmacokinetics (PK) of gabapentin from GE-IR when 
administered alone or in combination with oxycodone in healthy nondependent, 
recreational opioid users 
To evaluate the effects on safety and tolerability of single oral doses of GE-IR 
taken alone or in combination with oxycodone, compared to placebo and 
oxycodone alone, in healthy nondependent, recreational opioid users 
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 (minimum effect [Emin], time of maximum effect 
[TEmax], time of minimum effect [TEmin], and time-averaged area under 
the effect-time curve [TA_AUE]) 
Positive Effects 
• 
Good Effects VAS (Emax, TEmax, and TA_AUE) 
• 
High VAS (Emax, TEmax, and TA_AUE) 
Negative Effects 
• 
Bad Effects VAS (Emax, TEmax, and TA_AUE) 


Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
Version 2.0, 13AUG2021 
Page 9 of 84 
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 area over the effect-time 
curve [TA_AUE]) 
• 
Relaxation/Agitation (Emin, TEmin, and TA_AUE) 
• 
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_AUE) 
Pharmacokinetic Endpoints: 
Pharmacokinetic parameters of gabapentin include maximum observed 
concentration (Cmax), time of occurrence of Cmax (Tmax), area under the curve 
from time 0 to the last measureable observed concentration (AUC0-t), and area 
under the curve from time 0 to infinity (AUC0-inf). 
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, electrocardiograms (ECGs), Columbia Suicide 
Severity Rating Scale (C-SSRS), and physical examination findings. 
Study Product, 
Doses, and Mode of 
Administration 
(proposed): 
Gabapentin Enacarbil Immediate Release (GE-IR) Capsules 
Manufacturer: Arbor Pharmaceuticals, LLC 
Mode of administration: Doses of GE-IR 200 mg and 450 mg will be 
administered orally according to the randomization schedule during the 
treatment phase. 
GE-IR 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 will be 
administered orally according to the randomization schedule during the 
treatment phase. 
Active Control, Dose, 
and Mode of 
Administration: 
Oxycodone 10 mg immediate-release (IR) tablets 
Dose: Over-encapsulated oxycodone 20 mg; administered as 2 × 10 mg tablets 
Mode of administration: Single doses of oxycodone 20 mg will be administered 
orally alone or in combination with GE-IR, according to the randomization 


Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
Version 2.0, 13AUG2021 
Page 10 of 84
schedule, during the qualification and treatment phases, respectively. 
Oxycodone Placebo, 
Dose, and Mode of 
Administration: 
Placebo-to-match oxycodone 
Over-encapsulated placebo tablets to match oxycodone IR tablets 
Mode of administration: Single doses of placebo-to-match oxycodone tablets 
will be administered orally alone or in combination with GE-IR, according to 
the randomization schedule, during the qualification and treatment phases, 
respectively. 
Naloxone, Dose and 
Mode of 
Administration: 
Naloxone HCl solution for intravenous (i.v.) injection, 0.4 mg/mL 
Mode of administration: Naloxone HCl will be administered as i.v. bolus 
injections in single ascending doses of 0.2 mg (Step 1) and 0.6 mg (Step 2) 
during the qualification phase. 
Study Design: 
This study will be a randomized, double-blind, active- and placebo-controlled, 
6-way crossover study to evaluate the abuse potential, PK, safety and 
tolerability of GE-IR co-administered with oxycodone relative to GE-IR alone, 
oxycodone, and placebo, in nondependent, recreational opioid users. 
This study will consist of 4 phases: screening, qualification, treatment, and 
follow-up. 
Duration of 
Treatment and 
Subject 
Confinement: 
Duration of clinical trial (per subject): 
Screening: Day -30 to Day -2 (up to 28 days) 
Treatment period (qualification, treatment, and follow-up phases): Subjects will 
be confined to the clinical site from Day -1 of the qualification phase until 
Day 17of the treatment phase and will return to the clinical site for a follow-up 
visit 7 days after the last dose of study drug (Day 23 ±2 days). 
Total study duration: up to 59 days (including screening) 
Study Population: 
Healthy, male and female nondependent, recreational opioid users, aged 18 to 
55 years. 
Planned Number of 
Subjects: 
Approximately 66 subjects will be randomized into the treatment phase, such 
that at least 54 subjects complete the treatment phase of the study. 
Bioanalysis: 
Gabapentin and oxycodone plasma concentrations will be measured by 
validated bioanalytical methods. 
Pharmacokinetic 
Analysis: 
Pharmacokinetic analyses will be performed by non-compartmental analysis 
(NCA) and Cmax, Tmax, AUC0-t, and AUC0-inf will be estimated for gabapentin 
and oxycodone. 
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 8.6, 
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. 
 


Protocol No: Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
Version 2.0, 13AUG2021 
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Table 1. Schedule of Activities 
 
Screening 
Qualification 
Phasea 
Treatment Phase 
Early 
Termination 
(ET)/ 
Follow-Up 
Visit b 
Day 
-30 to -2 
-1 
1 
2 
3 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
23±2 
Subject Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review  
X 
X 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication & 
recreational drug 
use history 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSe 
X 
X 
 
 
X
f 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Study restrictions 
review 
 
X 
 
 
X
f 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
Xg 
 
 
Xf, g Xf,g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Xg 
Height, weight & 
body mass index 
(BMI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
X 
X 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine drug and 
alcohol screen 
X 
X 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 testv 
 
X 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
evaluations 
X 
X 
 
 
X
f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Follicle stimulating 
hormone (FSH)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening 
Qualification 
Phasea 
Treatment Phase 
Early 
Termination 
(ET)/ 
Follow-Up 
Visit b 
Day 
-30 to -2 
-1 
1 
2 
3 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
23±2 
Vital signsk 
X 
X 
X 
X 
X 
Xf 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Continuous 
respiratory ratel 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Continuous pulse 
oximetryl 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Continuous and 
Spot End Tidal 
CO2l 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Concomitant 
medicationsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
(AEs)n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmaco-
dynamics (PD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training/practiceo 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjective 
measuresp 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
MOAA/Sq 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pharmacokinetics 
(PK) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samplesr 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Study 
Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admissionf 
 
X 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Naloxone 
challenge 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COWS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizations 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No: Protocol No: AR26.3031.2 
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Version 2.0, 13AUG2021 
Page 13 of 84
 
Screening 
Qualification 
Phasea 
Treatment Phase 
Early 
Termination 
(ET)/ 
Follow-Up 
Visit b 
Day 
-30 to -2 
-1 
1 
2 
3 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
23±2 
Study treatment 
administration  
 
 
X
t 
X
t 
 
 
Xu 
 
 
Xu 
 
 
X
u 
 
 
Xu 
 
 
Xu 
 
 
Xu 
 
 
Discharge 
 
 
 
 
X
f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
C-SSRS= Columbia Suicide Severity Rating Scale, ECG= electrocardiogram, GE-IR = Gabapentin Enacarbil Immediate Release, MOAA/S= Modified Observer’s Assessment of 
Alertness/Sedation, COWS= Clinical Opiate Withdrawal Scale 
When timepoints coincide, procedures should be carried out in the following order, with the following windows: (1) vital signs, ECG and spot EtCO2 (±15 minutes), (2) VAS/PD 
(±15 minutes), (3) PK blood sampling (±5 minutes), (5) MOAA/S to be done at any time around the other procedures (±30 minutes). 
 
a Includes naloxone challenge and qualification (oxycodone versus placebo). 
b Early termination/follow-up visit can be performed in a window of ±2 days. 
c The latest version must be signed prior to subject’s inclusion (prior to naloxone challenge on Day -1) 
d Review of qualification criteria (section 4.3). 
e Baseline/screening version of C-SSRS evaluation at screening visit. Since last visit version of C-SSRS evaluation at all other visits. 
f Subjects should remain housed at the clinical research unit (CRU) from Day -1 of the qualification phase through Day 17 of the treatment phase. Only if subjects are discharged 
between the qualification and treatment phases, the noted discharge procedures will be performed on Day 3 of the qualification phase and noted admission procedures will be 
performed again on Day -1 (treatment phase). If subjects remain housed at the CRU the noted procedures are NOT required. Time between discharge from the qualification phase 
and admission for the treatment phase cannot exceed 14 days. 
g Symptom-directed physical examination. 
h Serum pregnancy test at Screening. Urine pregnancy test at all other visits. 
i Postmenopausal women only. 
j Serology screening as described in APPENDIX 6APPENDIX 6. 
k Blood pressure, pulse rate, oxygen saturation (SpO2) and respiratory rate. Measured at screening; each admission to the qualification phase and treatment phase; 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) 
for the qualification and treatment phases 
l Oxygen saturation (SpO2) 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 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 recorded 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. Predose measurements for EtCO2, SpO2 and respiratory rate will be collected to establish an 
average baseline value prior to each dose. 
m Medications taken within 30 days prior to screening and throughout the duration of study participation will be recorded. 
n Adverse events will be collected on an ongoing basis from the time of first study treatment 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 treatment administration in the qualification phase will be recorded as medical history. 


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o Additional training sessions may be conducted as needed. 
p 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-Bezedrine 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 
*24 hour postdose timepoint relative to the first dose of the qualification phase is to be performed prior to the second dose of the qualification phase. 
q Conducted during the qualification and treatment phases within 1 hour prior to dosing and approximately 0.5, 1, 1.5, 2, 3, 4, and 6 hours postdose. 
r Blood samples will be collected as indicated in Table 4Table 4. When clinical activities are scheduled to occur at the same time, pharmacodynamic data collection (vital signs, 
including spot EtCO2, then subjective measures) is to be prioritized, followed by PK blood sampling. 
s Randomization will be performed for qualification phase only on Day -1. Subjects who meet qualification criteria will be randomized for the treatment phase on Day -1 
(treatment phase). 
t Subjects administered 20 mg oxycodone or placebo according to randomization with a minimum of 24 hours between doses during the qualification phase. 
u Subjects administered placebo, GE-IR 200 mg + oxycodone 20 mg, GE-IR 450 mg + oxycodone 20 mg, GE-IR 200 mg, GE-IR 450 mg, or oxycodone 20 mg (minimum washout 
period of at least 3 days between doses). 
v Covid-19 test will be performed before each admission. 
 


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INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE 
SPONSOR’S CONTACT: 
 
Tania D. Johnson, RN, BSN 
Director, Clinical Development 
Arbor Pharmaceuticals, LLC 
6 Concourse Parkway, Suite 1800 
Atlanta, GA 30328 USA 
Office: 404-496-5903; Cell 770-314-3006 
E-mail: tania.johnson@arborpharma.com 
PRINCIPAL INVESTIGATOR: 
Debra Kelsh, MD 
Altasciences 
10103 Metcalf Avenue 
Overland Park, KS 66212 USA 
CLINICAL RESEARCH UNIT: 
Altasciences 
10103 Metcalf Avenue 
Overland Park, KS 66212 USA 
 
10203 Metcalf Avenue 
Overland Park, KS 66212 
 
10183 Metcalf Avenue 
Overland Park, KS 66212 USA 
CLINICAL LABORATORY  
FACILITY: 
 
 
 
Quest Diagnostics 
10101 Renner Boulevard 
Lenexa, KS 66219 USA 
BIOANALYTICAL FACILITY: 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
MEDICAL WRITING &  
SCIENTIFIC AFFAIRS: 
 
Altasciences 
575 Armand-Frappier Boulevard 
Laval, Quebec, Canada 
H7V 4B3 
STATISTICAL FACILITY: 
Altasciences 
1200 Beaumont Avenue 
Mount-Royal, Quebec, Canada 
H3P 3P1 
DATA MANAGEMENT FACILITY: Altasciences 
10103 Metcalf Ave. 
Overland Park, KS 66212 USA 


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PROJECT MANAGEMENT: 
 
Altasciences 
575 Armand-Frappier Boulevard 
Laval, Quebec, Canada 
H7V 4B3 
 
COGNITIVE TESTS: 
Cambridge Cognition 
2750 Rasmussen Road 
Park City, UT 84098, USA 
 
MONITORING: 
Randstad Life Sciences 
4 Parkway North; Suite 120 
Deerfield, IL 60480 


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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. 
The mechanism of action by which gabapentin is efficacious in PHN is unknown but in animal 
models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a 
normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). 
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 
The primary purpose of this study is to evaluate the abuse potential of gabapentin enacarbil 
immediate-release (GE-IR), the active moiety in Horizant, taken alone and taken in combination 
with oxycodone, compared to that of oxycodone alone. 
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 June 2019 contained 606 reports categorized under drug 
abuse. Of these, 13 (2.1%) were attributed to Horizant, 344 to gabapentin, and 249 to Regnite 
(gabapentin enacarbil reports in Japan). Of the 13 Horizant cases, the most frequently reported 
were intentional product misuse and use issue cases (n=6, 46%). These cases involved 
consumers who reported adjusting their own dose to manage their own symptoms/tolerability. 
This was followed in frequency by overdose (n=4, 31%). The overdose cases involved reports of 


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being jittery 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. The remaining 3 cases of Horizant-related abuse involved accidental 
overdose (n=2) and dependence (n=1) and contained limited information in each case. The 
Regnite cases involved similar events, with intentional product misuse and use issue cases 
accounting a larger majority of cases (6%). 
Gabapentin abuse cases were different, however. The most common event was toxicity to 
various agents with (97.7%). Of the 336 cases that involved toxicity to various agents more 
specificity was provided in 86 of the cases. These 86 cases also included accidental overdose 
(n=51), drug abuse (n=21), overdose (n=8), and intentional product misuse (n=4), intentional 
overdose (n=1), and cardiorespiratory arrest (n=1). With the exception of toxicity to various 
agents, no term was reported more than 3 times. There have been no Horizant reports from the 
American Association Poison Control Centers National Poison Data System Annual Report. 
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 
Further, per FAERS update (cumulative to June 30 2019), the proportional reporting ratio (PRR) 
of gabapentin versus gabapentin enacarbil abuse related events was 2.22 [calculated as 
(Ga/Gt)/(GEa/GEt) = (576/10038)/(55/2128)]. This indicates that the number of abuse-related 
events in relation to the number of reported ADEs is greater for gabapentin compared to 
gabapentin enacarbil. 
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, 6-way crossover 
design, aimed to assess the abuse potential, safety, and PK of GE-IR doses when administered 
alone or in combination with an opioid active control (oxycodone), and compared to placebo and 
oxycodone intake alone, in healthy, nondependent, recreational opioid users. The overall design 
is consistent with United States (US) Food and Drug Administration (FDA) guidelines for 
human abuse potential (HAP) assessment.4, 5 
Further, gabapentin abuse is reported both alone (i.e., without other drugs), and in conjunction 
with opioids to enhance the ‘high’ obtained from opioids.22, 23,24  This study is thus designed with 
the goal of characterizing any additive or synergistic effects on the abuse potential and 
physiologic effects of co-administered GE-IR and opioid. 


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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. In this study, immediate-release (IR) oxycodone 20 mg (oral) will be 
administered during the qualification and treatment phases, given that this dose is used by 
recreational drug users, is within the range of recommended label doses, and is supported by 
published abuse potential studies.27, 28 A placebo control will be used to establish the frequency 
and magnitude of changes in clinical endpoints that may occur in the absence of active treatment 
as well as to minimize subject and investigator bias. Blinded treatment, including the use of 
double-blind and double-dummy procedures, will be used to reduce potential bias during data 
collection and evaluation of clinical endpoints. 
The subjects in this study will be healthy individuals with previous nontherapeutic (recreational) 
experience with opioids. These subjects represent the population at greater 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 opioid use), subjects 
will also be required to pass a pharmacologic qualification. 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 
A double-blind qualification phase has been included in the study design as an enrichment 
procedure to ensure that study subjects are not opioid dependent (through a naloxone challenge) 
and that subjects who meet the drug use history criteria can also distinguish the subjective effects 
of the active control (i.e., oxycodone) 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. 
The 3-day washout interval between the qualification phase and treatment phase is considered 
sufficient to ensure complete washout of oxycodone. Given the T½ of gabapentin when receiving 
GE-IR (4.38 - 5.47 hours) and oxycodone (approximately 3-5 hours)27 following oral 
administration, the 3-day interval between study treatment administrations will ensure sufficient 
washout of GE-IR and oxycodone. 
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. 


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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, 13 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 and 450 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 and1200 mg Horizant in healthy individuals. 
Oxycodone is the selected positive control for this study. The dose of oxycodone selected 
(20 mg) will be used per the recommendations of the Food and Drug Administration (FDA) and 
has been well tolerated in the study population.26, 30, 31 
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 SpO2 are the standard in monitoring respiratory function, 
change in oxygenation, and change in ventilation.38,39,40,41 Monitoring ETCO2 has been shown to 


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be more sensitive in detection of respiratory depression than monitoring respiratory rate and 
pulse oximetry alone.42 
In the clinical setting, respiratory depression is usually described in terms of decreased 
respiratory rates, decreased SpO2 levels, or elevated ETCO2 levels 42 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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2. STUDY OBJECTIVES AND ENDPOINTS 
The primary and secondary objectives of the study and corresponding endpoints are: 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To evaluate the abuse potential of single oral 
doses of GE-IR taken in combination with an 
opioid active control (oxycodone) in healthy, 
nondependent, recreational opioid users. 
The primary endpoint of this study will be Emax over 
24 hours for Drug Liking (“at this moment”), assessed 
on a bipolar (0 to 100 points) 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 (minimum effect [Emin], 
time of maximum effect [TEmax], time of 
minimum effect [TEmin] and area under the 
effect-time curve [AUE])  
Positive Effects 
• 
Good Effects VAS (Emax, TEmax, and 
TA_AUE) 
• 
High VAS (TEmax, and TA_AUE) 
Negative Effects 
• 
Bad Effects VAS (Emax, TEmax, and TA_AUE) 
Other Subjective Effects 
• 
Any Effects VAS (Emax, TEmax, and 
TA_AUE) 
• 
Feeling Drunk (Emax, TEmax, and TA_AUE) 
• 
Drowsiness/Alertness VAS (Emin, TEmin, and 
area over the effect-time curve [TA_AUE]) 
• 
Relaxation/Agitation VAS (Emin, TEmin, and 
area over the effect-time curve [TA_AUE]) 
• 
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, change 
from baseline to minimum effect [CFBmin], 
and TA_AUE) 
 
 


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OBJECTIVES 
ENDPOINTS 
Secondary 
 
To evaluate the PK of gabapentin from GE-IR 
when administered alone or in combination 
with oxycodone in healthy nondependent, 
recreational opioid users. 
Pharmacokinetic parameters of gabapentin include 
Cmax, Tmax, area under the curve from time 0 to the 
time of last measurable observed concentration 
(AUC0-t), and area under the curve from time 0 to 
infinity (AUC0-inf) 
To evaluate the effects on safety and 
tolerability of single oral doses of GE-IR 
taken alone or in combination with 
oxycodone, compared to placebo and 
oxycodone alone, in healthy nondependent, 
recreational opioid users. 
Secondary endpoints will include a summary of the 
incidence of AEs, serious adverse events (SAEs), as 
well as descriptive summary and statistics of the 
safety parameters, which 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, 
electrocardiograms (ECGs), Columbia Suicide 
Severity Rating Scale (C-SSRS), and physical 
examination findings. 
3. STUDY DESIGN 
3.1. Overall Study Design 
This study will be a randomized, double-blind, active- and placebo-controlled, 6-way crossover 
study to evaluate the abuse potential, PK, safety and tolerability of GE-IR co-administered with 
oxycodone relative to GE-IR alone, oxycodone, and placebo, in nondependent, recreational 
opioid users 
This study will consist of 4 phases: screening, qualification, treatment, and follow-up. The study 
schema is presented in Figure 1Figure 1. 
3.1.1. Screening and Qualification Phase 
After a screening period of up to 30 days, eligible subjects will be admitted to the clinical 
research unit (CRU) on Day -1 of the qualification phase. 
A sufficient number of subjects will be screened and entered into the qualification phase to 
ensure that approximately 66 subjects will be randomized in the treatment phase, so that at least 
54 subjects complete the study. Females will be recruited on a best-effort basis to ensure an 
appropriate representation of females in the study. 
All subjects will complete a naloxone challenge at least 24 hours prior to the first drug 
administration in the qualification phase, to confirm that they are not opioid-dependent. The test 
will be administered in the following 2 steps: 
1. Naloxone 0.2 mg will be given via intravenous (i.v.) bolus followed by a 2 to 3 mL saline 
flush. The subject will be observed for 1 minute after bolus administration for signs or 
symptoms of withdrawal. 


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2. If there is no evidence of withdrawal after 1 minute, naloxone 0.6 mg will be given via 
i.v. bolus within 5 minutes of the first administration followed by a 2 to 3 mL saline 
flush. The subject will be observed for an additional 5 minutes. 
The naloxone doses selected for the challenge are consistent with doses commonly administered 
to confirm opioid nondependence. The Clinical Opiate Withdrawal Scale (COWS)28 will be used 
to record any signs or symptoms of opioid withdrawal observed in step 1 (predose and 1 minute 
after administration) and step 2 (5 minutes after administration) of the naloxone challenge test. 
Subjects who present symptoms of withdrawal during predose assessment or following 
administration of the naloxone challenge (i.e., COWS score ≥5, unless in the opinion of an 
investigator the symptoms present are not related to opioid withdrawal) will be excluded from 
the study and will not be eligible to enter the qualification phase. 
The qualification phase will further determine whether subjects like and tolerate the effects of 
oxycodone, and can discriminate these from placebo; this visit will also determine if each subject 
is suitable for entry into and is likely to complete the treatment phase (i.e. likely to comply with 
the study protocol). 
On Days 1 and 2 of the qualification phase, subjects will receive the following treatments in a 
randomized, double-dummy, crossover manner as further detailed in section 3.2: 
 
Day 1 
Day 2 
Sequence 1 
Treatment X: 
Placebo 
Treatment Y: 
Oxycodone 20 mg 
Sequence 2 
Treatment Y: 
Oxycodone 20 mg 
Treatment X: 
Placebo 
Each dose will be separated by approximately 24 hours. 
Each subject must meet all of the qualification criteria (see section 4.3) to be randomized for 
participation in the treatment phase. 
It is preferred that subjects remain confined at the CRU from the start of the qualification phase 
through completion of the treatment phase; however, subjects may be discharged between these 
phases if required. Appropriate discharge and re-admission procedures are noted in Table 1Table 
1. 
3.1.2. Treatment Phase and Follow-Up 
The treatment phase is a randomized, double-blind, active- and placebo-controlled, 6-way 
crossover design in which subjects will receive the following 6 treatments in a crossover manner 
and blinded fashion, as further detailed in section 3.2: 
• Treatment A: Placebo 
• Treatment B: Oxycodone 20 mg 
• Treatment C: GE-IR 200 mg + oxycodone 20 mg 
• Treatment D: GE-IR 450 mg + oxycodone 20 mg 


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• Treatment E: GE-IR 200 mg 
• Treatment F: GE-IR 450 mg 
Each study treatment administration will be separated by 3 days. Drug administrations will be 
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 of the 
treatment phase, if deemed medically stable for discharge by an investigator. A follow-up visit 
will occur 7 days (±2 days) following the final dose. 
Study assessments will be performed at the timepoints outlined in the Schedule of Activities 
(Table 1Table 1). 
The maximum duration of subject participation, including screening, will be approximately 
59 days. 
Subjects who terminate the study early will perform follow-up procedures at the time of early 
termination (ET). 


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Figure 1. Study Schema 
 
Screening 
 
 
 
 
Admission within 30 days of screening 
 
 
 
Qualification Phase - Naloxone Challenge 
(Day -1) 
 
 
 
 
↕ 24 hours 
 
 
 
Qualification Phase - Randomized Double-Blind 
Discrimination 
(crossover treatments on Day 1 and Day 2) 
 
 
 
 
Treatment X 
Placebo 
↔ 
24 hours 
Treatment Y 
Oxycodone 20 mg 
 
 
 
 
≥3 days between last qualification phase treatment and first 
treatment phase treatment 
 
 
Randomized Double-Blind Treatment Phase 
(6 crossover treatment periods) 
 
 
Treatment 
A 
Placebo 
≥3 
days 
Treatment B 
Oxycodone 
20 mg 
≥3 
days 
Treatment C 
GE-IR 
200 mg 
+ 
Oxycodone 
20 mg 
 
≥3 
days 
Treatment D 
GE-IR 
450 mg 
+ 
Oxycodone 
20 mg g 
≥3 
days 
Treatment E 
GE-IR  
200 mg 
 
≥3 
days  
Treatment F 
GE-IR  
450 mg 
 
 
 
 
Follow-Up Visit 
(7 ±2 days after last study drug administration) 
 
 
Note: the sequence of treatments shown is for illustration of the overall design and does not necessarily represent an 
actual treatment sequence. 


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3.2. Study Treatments 
During the qualification phase each dose will consist of 1 capsule containing oxycodone or 
placebo. The following treatments will be administered orally with approximately 240 mL of 
room temperature water in the morning under fasted conditions: 
• Treatment X (Placebo): 2 × placebo tablets over-encapsulated to match oxycodone 
• Treatment Y (Active Control): 2 × 10 mg oxycodone tablets over-encapsulated 
During the treatment phase, each dose will consist of 2 capsules of GE-IR and/or placebo to 
match GE-IR to achieve assigned dose plus 2 capsules containing oxycodone or placebo. The 
following treatments will be administered orally with approximately 240 mL of room 
temperature water in the morning under fasted conditions: 
• Treatment A (Placebo): 
2 × placebo capsules to match GE-IR and 2 × placebo tablets over-encapsulated to match 
oxycodone 
• Treatment B (Active Control): 
2 × placebo capsules to match GE-IR and 2 × 10 mg oxycodone tablets over-
encapsulated 
• Treatment C (GE-IR 200 mg + Oxycodone): 
1 × 200 mg GE-IR capsules, 1 × placebo capsules to match GE-IR, and 2 × 10 mg 
oxycodone tablets over-encapsulated 
• Treatment D (GE-IR 450 mg + Oxycodone): 
2 × 225 mg GE-IR capsules and 2 × 10 mg oxycodone tablets over-encapsulated 
• Treatment E (GE-IR 200 mg): 
1 × 200 mg GE-IR capsules, 1 × placebo capsules to match GE-IR, and 2 × placebo 
tablets over-encapsulated to match oxycodone 
• Treatment F (GE-IR 450 mg): 
2 × 225 mg GE-IR capsules and 2 × placebo tablets over-encapsulated to match 
oxycodone 
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 treatment 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 opioid user who has used opioid drugs for 
recreational (nontherapeutic) purposes (i.e., for psychoactive effects) at least 5 times in 
the subject’s lifetime and at least once in the last 12 weeks, 
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 treatment administration, during the study, and 
for at least 30 days after the last dose of the study treatment. 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), or 
• 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 
treatment. 
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 treatment 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 study treatment, 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, in the opinion of an investigator. 
9. Negative Covid-19 test prior to each admission. 
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 naloxone, opioids (e.g., oxycodone), or related 
drugs 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, naloxone, or oxycodone, 
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 treatment administration or planning to become pregnant within 30 days following 
the last study treatment 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 ever been in a drug or alcohol rehabilitation 
program within the last 2 years, 
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 


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admission to the qualification phase and treatment phase, 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 treatment administration 
(including e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine 
gum, or nicotine lozenges), 
11. Is a heavy opioid user and not likely to be sensitive to a 20 mg dose of oxycodone, in the 
opinion of an investigator or designee, 
12. 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, 
13. History of suicidal ideation 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 7APPENDIX 7), or is currently at risk of suicide 
in the opinion of an investigator, 
14. 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, 
15. Has creatinine clearance ≤60ml/min as calculated by the Cockcroft-Gault equation, 
16. Any history of tuberculosis, 
17. Positive screening results to human immunodeficiency virus (HIV) 1 and 2 antibodies, 
hepatitis B virus surface antigen (HBsAg) or hepatitis C virus antibody (HCVAb) tests, 
18. Intake of an investigational product (IP) within 30 days or 5 times the half-life 
(whichever is longer) prior to screening, 
19. Use of any prescription drugs (with the exception of hormonal contraceptives or hormone 
replacement therapy) in the 30 days prior to the first study treatment administration, that 
in the opinion of an investigator would put into question the status of the subject as 
healthy, 


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20. Use of over-the-counter (OTC) products (including herbal preparations and supplements) 
within 7 days prior to the first study treatment administration, with the exception of 
ibuprofen or acetaminophen, 
21. Use of a prohibited medication as specified in section 4.7, 
22. Donation of plasma in the 7 days prior to screening, 
23. Blood donation (excluding plasma) of approximately 500 mL of blood in the 56 days 
prior to screening, 
24. Is, in the opinion of an investigator or designee, considered unsuitable or unlikely to 
comply with the study protocol for any reason. 
25. Poor venous access at screening, as judged by an investigator. 
4.3. Inclusion Criteria into Qualification Phase 
Subjects must not present symptoms of withdrawal during predose assessment or following 
administration of the naloxone challenge (i.e., COWS score <5). 
4.4. 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 of at least 65 points in response to oxycodone 20 mg and greater than that of 
placebo on the Drug Liking VAS (difference of at least 15 points), with a peak score of at 
least 65 points for oxycodone. 
2. Acceptable placebo response based on Drug Liking VAS (scores between 40 and 
60 points, inclusive). 
3. Acceptable overall responses to oxycodone and placebo on the subjective measures, as 
judged by an investigator or designee. 
4. Able to tolerate the 20 mg dose of oxycodone, as judged by an investigator, including no 
episodes of vomiting during the first 3 hours postdose.  
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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4.5. Withdrawal Criteria 
4.5.1. Before First Treatment Administration 
Before the first treatment administration of the qualification phase (oxycodone or placebo), 
inclusion/exclusion criteria will govern the subjects to be dosed. Subjects withdrawn before first 
treatment administration of the qualification phase 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. 
4.5.2. 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 and documented to have such subjects complete the ET assessments. 
Early termination 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). 
4.6. 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 administration 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 until the follow-up visit. 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 


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investigator. If THC is positive at check-in, a cannabis intoxication evaluation will be 
done by an investigator, and inclusion will be at his or her discretion. 
• Subjects will be prohibited from consuming food or beverages containing xanthines 
(i.e., tea, coffee, cola drinks, energy drinks or chocolate) for 48 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 asked to abstain from strenuous physical activity for 48 hours prior to 
screening and prior to each admission to the CRU and during inpatient stays. 
• During the study, smokers will abstain from smoking for at least 1 hour prior to and until 
at least 6 hours after each drug administration. Subjects will not be permitted to use other 
nicotine-containing products (including nicotine topical patches, nicotine gum, or 
nicotine lozenges). 
• Subjects will be asked 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 engage in sexual activity that has a risk of pregnancy will be expected to use 
an acceptable contraceptive regimen and not to donate sperm from the first study 
treatment administration, during the study, and until at least 90 days after the last drug 
administration, as described in section 4.1. 
4.7. Concomitant Treatment 
Except for medication 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 
and treatment phase if a subject is discharged during this interim period. Information on any 
concomitant medications administered will be collected daily while subjects are in the clinic. 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. 


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5. STUDY TREATMENTS 
5.1. Investigational Products 
The lot number and the measured content of each dosage formulation will be included in the 
final report. 
5.1.1. Gabapentin Enacarbil 
Gabapentin enacarbil immediate release capsules (GE-IR) 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 225 mg capsule and the composition is the same. Placebo will be filled with 
225 mg of calcium phosphate dibasic dihydrate in the capsules. Patheon will take into 
consideration the client’s request for the same opaque and simple in color capsule to encapsulate 
both the active and placebo strengths. 
5.1.2. Oxycodone 
Oxycodone IR will be supplied as 10 mg tablets, and over-encapsulated. 
Placebo to match oxycodone tablets will be over-encapsulated 100 mg lactose tablets. 
Both products may be obtained by the CRU and will be over-encapsulated with the same 
capsules (Swedish Orange Opaque AAE-DB capsules [Capsugel] or similar) to maintain study 
blinding. 
5.2. Investigational Product Management 
5.2.1. Packaging, Labeling and Dispensing 
The sponsor will be responsible for ensuring that the study drug 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 contract research unit’s (CRU’s) pharmacy, unless the sponsor 
supplies the pharmacy with pre-labeled individual dosing samples. 
5.2.2. Storage and Handling 
Once received, all study drugs will be stored in the CRU’s pharmacy. 
Gabapentin enacarbil immediate release (GE-IR) capsules and placebo should be stored at 25°C 
with excursions between 15°C and 30°C allowed. Both placebo to match oxycodone and 
oxycodone 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. 


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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, 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. Replacement subjects will be assigned a new randomization number 
equivalent to the Treatment randomization + 1000 (e.g., 3000 series). 
Subjects who enter the treatment phase will be assigned a unique treatment randomization 
number. Subjects will be randomized to 1 of 6 treatment sequences, according to one 6 x 6 
Williams Squares. The range of qualification and treatment randomization numbers may be 
distinct to avoid confusion (e.g., 1000 series and 2000 series). 
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 2Table 2). 
Table 2 
Sample Qualification Phase Sequences 
Treatment Sequence 
Day 1 
Day 2 
XY 
X 
Y 
YX 
Y 
X 
Treatment X: Placebo 
Treatment Y: Oxycodone 20 mg 
5.2.3.2. Treatment Phase 
For the treatment phase, qualified subjects will be randomized to 1 of 6 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 6 treatments in the order specified by the 
treatment sequence according to one 6 x 6 Williams Square (Table 3Table 3). 


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Table 3 
Sample Treatment Phase Sequences 
Treatment 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
Period 5 
Period 6 
ABFCED 
A 
B 
F 
C 
E 
D 
BCADFE 
B 
C 
A 
D 
F 
E 
CDBEAF 
C 
D 
B 
E 
A 
F 
DECFBA 
D 
E 
C 
F 
B 
A 
EFDACB 
E 
F 
D 
A 
C 
B 
FAEBDC 
F 
A 
E 
B 
D 
C 
Treatment A: Placebo 
Treatment B: Oxycodone 20 mg 
Treatment C: GE-IR 200 mg + Oxycodone 20 mg 
Treatment D: GE-IR 450 mg + Oxycodone 20 mg 
Treatment E: GE-IR 200 mg 
Treatment F: GE-IR 450 mg 
5.2.4. Blinding 
The treatment assignment will not be known by the study subjects or by the sponsor. 
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, 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 administration 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 to 
the subject or to complete a SAE report. Code break envelopes containing 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 at the completion of the trial. 


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5.3. Study Treatment Administration, Meals and Fluids 
Study treatments will be administered in the morning as described in section 3.2. The date and 
time of each dose will be recorded. For each subject, all scheduled postdose activities and 
assessments will be performed relative to the time of study treatment administration. 
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. If needed, subjects may be provided 
additional water, in 50-mL increments, to ensure complete dose is swallowed. Any additional 
water given will be recorded. 
Food and fluid intake other than water will be controlled for each confinement period and for all 
subjects. 
Subjects will fast for at least 4 hours following each drug administration. Water will be provided 
as needed until at least 1 hour prior to dosing and will be allowed beginning at least 1 hour after 
each drug administration. 
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). 
5.4. Other Protocol Restrictions 
Subjects will remain seated or kept in minimal ambulatory movement for at least 6 hours 
following each drug administration, avoiding both vigorous exertion and complete rest. 
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. 
An overview of the study activities for each subject is detailed in Table 1Table 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 3 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 2. Subjects not qualifying for the treatment 
phase may be discharged on Qualification Day 3 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. 


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Subjects will be discharged on Day 17 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), continuous SpO2 
monitoring, continuous End Tidal CO2, 12-lead ECG, clinical laboratory tests, and AE 
monitoring. 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 
The medical history will be reviewed as scheduled in Table 1Table 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. 
Any medical conditions occurring from the time of signing the ICF 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 worsening and judged to be clinically significant will be recorded as AEs. 
6.1.2. Recreational Alcohol/Drug Use 
A lifetime history of all drug use will be collected as scheduled in Table 1Table 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 by drug class (e.g., cannabinoids, depressants, dissociative 
anesthetics, hallucinogens, opioids and morphine derivatives, and stimulants). A history of 
alcohol use will also be collected. 
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 1Table 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 1Table 1, at the 
discretion of an investigator. 


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6.1.4. Vital Signs 
Vital signs will be measured as scheduled in Table 1Table 1 and will include spot blood 
pressure, pulse rate, respiratory rate and oxygen saturation (SpO2) measures. 
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 1Table 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 continuous pulse oximeter during the Qualification phase and through a capnography 
monitor during the Treatment phase. 
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. 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. 
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 1Table 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 1Table 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 1Table 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 1Table 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. 


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6.1.5. 12-Lead Electrocardiogram 
A 12-lead ECG will be performed as scheduled in Table 1Table 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 1Table 1. 
The laboratory evaluations to be conducted for this study are presented in APPENDIX 
6APPENDIX 6. Additional clinical laboratory tests may be performed by the medical laboratory 
as part of larger standard test panels (not required for subject safety). 
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. 
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 unique, simple, and short method of assessing 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. 
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 1Table 1. 
A trained rater will record the clinical observations on the scale, which will be used as the source 
document. See APPENDIX 7APPENDIX 7 for a sample C-SSRS –Baseline/Screening version 
assessment and APPENDIX 8APPENDIX 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. 
6.1.8. Assessment of Respiratory Depression 
Predose measurements for EtCO2, SpO2, and respiratory rate will be collected prior to each dose 
in order to establish an average baseline value and calculate the threshold of absolute change for 
each safety assessment, as defined below: 
Capnography alarms will be set to evaluate for respiratory depression, for whichever threshold is 
reached first for a given endpoint, and will include: 


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• An increase in EtCO2 to >50 mmHg, or an absolute increase in EtCO2 of 10 mmHg 
compared to baseline 
• A reduction in SpO2 to <90%, or an absolute decrease in SpO2 of 4% compared to 
baseline 
• A reduction in respiratory rate to <8 breaths per minute, or an absolute decrease in 
respiratory rate of 50% compared to baseline 
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 treatment administration until at least 6 hours postdose. 
ACLS-certified staff will be present on site and an investigator will be readily available by 
telephone. 
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. Blood Volume Collected 
The total blood volume for screening and safety assessments will be approximately 15 mL. 
Blood volume required for pharmacokinetic assessments will be included in the informed 
consent. 
6.3. Pharmacokinetic Assessments 
Blood samples will be collected for each dose in the treatment phase for PK assessments of 
gabapentin and oxycodone. The complete blood sampling schedule is presented in Table 4Table 
4. 


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Table 4. Pharmacokinetic Blood Sampling Schedule (Gabapentin and Oxycodone) 
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 that 
will be placed in the vein of the subject. 
The time of PK blood sample collection will be calculated relative to the time of treatment 
administration. The actual time of all PK blood draws will be recorded and reported for all 
subjects. Each subject will be dosed at approximately the same time in each period and all 
activities (e.g., PK sampling, scales, meals) will be based on that dosing time. 
Urine samples to be collected during the course of this study include pregnancy tests and drug 
screens as outlined in Table 1Table 1. 
Gabapentin and oxycodone concentrations for PK assessments will be obtained through 
bioanalysis of the plasma derived from the blood samples drawn during this study, using 
validated bioanalytical methods. 
6.3.1. 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 (e.g., analyte, sample collection time, subject identifier). 


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6.4. Pharmacodynamic Assessments 
Pharmacodynamic assessments will be performed throughout the study as outlined in Table 
1Table 1. 
Prior to completing the computerized PD measures, all subjects will undergo a scripted training 
and practice session. Eligible subjects experiencing 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 practice 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 the study 
(i.e., qualification and treatment phases). 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 may be aborted and the reason for discontinuation of a PD assessment will be provided. 
6.4.1. Subjective Effects 
6.4.1.1. Visual Analogue Scales 
All VAS will be scored on a 100-point scale, as shown in Table 5Table 5. The VAS 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 
No 
Unipolar 
Good Effects 
At this moment, I feel good 
drug effects 
0: Not at all 
100: Extremely 
Positive 
Yes 
Unipolar 
High 
At this moment, I am feeling 
high 
Negative 
No 
Unipolar 
Bad Effects 
At this moment, I feel bad 
drug effects 
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 relaxed 
50: Neither relaxed 
nor agitated 
100: Very agitated 
 


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6.4.1.2. Addiction Research Center Inventory (ARCI) 
Martin et al. 35 have compiled a shortened version (49 true-false items) from the 550-item 
Addiction Research Center Inventory (ARCI) originally developed by Haertzen.36,37 This version 
of the shortened ARCI contains 5 scales, which measure the following effects: 
• 
Euphoria: Morphine-Benzedrine Group (MBG) scale 
• 
Stimulant effects: Amphetamine (A) scale, Benzedrine Group (BG) scale 
• 
Dysphoria: Lysergic Acid Diethylamide (LSD) scale 
• 
Sedation: Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) scale 
The ARCI MBG and PCAG scales will be administered as scheduled in Table 1Table 1. The 
ARCI MBG and PCAG scales are presented in APPENDIX 9APPENDIX 9 and APPENDIX 
10APPENDIX 10, respectively. 
6.4.2. 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.34 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) 
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. 


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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, or 
• 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. 
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, or 
• 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. 


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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 6Table 6. 
Table 6. Adverse Event Relationship to Study Drug 
Relationship to Drug 
Comment 
Reasonable Possibility 
A temporal relationship exists between the adverse event (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 serious adverse events (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 the follow-up visit. If AEs are ongoing 
after the follow-up visit, attempts will be made to follow the AEs to resolution. Any medical 
conditions occurring from the time of signing the ICF 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. 
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 
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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 is found, 
or it 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 23.0 or higher. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary-
Enhanced (WHO-DDE March 2019 or later). 
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 at (470) 235-2400 or scanned and 
emailed to AEreports@arborpharma.com. The SAE may also be reported by telephone to 
Arbor Drug Safety at (866) 516-4950. 
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 


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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. 
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 or designee 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 placebo or oxycodone. 
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 in the Randomized population who receive at 
least 1 dose of study drug (e.g. placebo, oxycodone or GE-IR). 
8.1.2.3. Completer Population 
All subjects in the Safety population who complete all 6 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. 


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8.1.2.4. Modified Completer Population 
All subjects in the Completer population excluding problematic subjects with unreliable 
responses which can alter study results. 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 
If such subjects do not exist in the study, then the Modified Completer population is the same as 
the Completer population. 
8.1.2.5. Pharmacokinetic (PK) Population 
The PK population will include all subjects in the Safety population who receive at least 1 dose 
of GE-IR during the treatment phase, have evaluable PK data, and have no protocol deviations or 
other circumstances that would exclude them from analysis. 
8.2. Appropriateness of Measures 
The selected PD measures will assess positive and negative subjective drug effects associated 
with the abuse potential of a 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 nondependent, recreational drug users. 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 data, 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/Completer population, as 


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appropriate). 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/Completer population (as appropriate) 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 
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 phase, and for 
qualification failures. Tables for demographic and baseline characteristics (sex, age, race, 
ethnicity, body weight, height, BMI) will be presented by population, and by qualification 
failures. Demographics and baseline characteristics for subjects who pass and who fail the 
qualification phase will be listed. 
8.4.2. Treatment Phase 
A disposition table will be presented for 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 23.0 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. 


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8.5. Pharmacodynamics 
8.5.1. Pharmacodynamic Endpoints 
Pharmacodynamic endpoints will be evaluated as described in Table 7Table 7 and PD data will 
be analyzed for the Modified Completer population. 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 using descriptive statistics. 
Table 7. Pharmacodynamic Endpoints 
Description 
Type 
Endpoints 
Drug Liking 
Balance of effects, Bipolar VAS 
Emax, Emin, TEmax, TEmin, and 
TA_AUE 
Overall Drug Liking 
Global effects, Bipolar VAS 
Emax 
Take Drug Again 
Global effects, Bipolar VAS 
Emax 
Good Effects 
Positive effects, Unipolar VAS 
Emax, TEmax, and TA_AUE 
High 
Positive effects, Unipolar VAS 
Emax, TEmax, and TA_AUE 
Bad Effects 
Negative effects, Unipolar VAS 
Emax, TEmax, and TA_AUE 
Any Effects 
Other effects, Unipolar VAS 
Emax, TEmax, and TA_AUE 
Feeling Drunk 
Other effects, Unipolar VAS 
Emax, TEmax, and TA_AUE 
Drowsiness/Alertness 
Other effects, Bipolar VAS 
Emin, TEmin, and TA_AUE 
Relaxation/Agitation 
Other effects, Bipolar VAS 
Emin, TEmin, and TA_AUE 
Addiction Research Center Inventory 
(ARCI) Morphine-Benzedrine Group 
(MBG) Scale 
Positive, euphoric effects, 
Questionnaire score 
Emax, TEmax, and TA_AUE 
ARCI Pentobarbital–
Chlorpromazine–Alcohol Group 
(PCAG) Scale 
Other, sedative effects, 
Questionnaire score 
Emax, TEmax, and TA_AUE 
Modified Observer’s Assessment of 
Alertness/Sedation (MOAA/S) 
Other, sedative effects, Observer’s 
score 
Emin, CFBmin, and TA_AUE 
TA_AUE=time-averaged area under the effect-time curve, CFBmin= change from baseline to minimum effect, Emax= 
maximum (peak) effect, Emin=minimum effect, TEmax=time of maximum (peak) effect, TEmin=time of minimum 
effect 
8.5.2. Pharmacodynamic Statistical Methodology 
Drug Liking 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. 


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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 
each subject. Treatments for each PD endpoint will be tested for homogeneity of variance using 
the SAS procedure PROC GLIMMIX COVTEST. If treatments for a given PD endpoint are 
homogeneous, the option “RANDOM SUBJECT;” will be used in the PROC MIXED model. If 
treatments for a give PD endpoint are heterogeneous, the option 
“REPEATED/SUBJECT=SUBJECT GROUP=TREATMENT;” will be used in addition to the 
option “RANDOM SUBJECT;” in the PROC MIXED model. 
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 Tsong 16 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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If the paired difference is not normally distributed, that is, p-value < 0.05, the following steps 
will be taken to test skewness: 
a) If the alternative hypothesis is upper-tailed, and skewness is [0, 0.5] then mean 
difference, SE, 1-sided 95% CI, and p-value from the t-test will be output. 
b) If the alternative hypothesis is upper-tailed, and skewness < 0 or skewness > 0.5 then 
median of the paired difference (Q1-Q3), 1-sided 95% CI, and p-value from the sign 
test will be output. 
c) If the alternative hypothesis is lower-tailed, and skewness is [-0.5, 0] then mean 
difference, SE, 1-sided 95% CI, and p-value from the t-test will be output. 
d) If the alternative hypothesis is lower-tailed, and skewness < -0.5 or skewness > 0 then 
median of the paired difference (Q1-Q3), 1-sided 95% CI, and p-value from the sign 
test will be output. 
e) If the alternative hypothesis is two-tailed, and skewness is [-0.5, 0.5] then mean 
difference, SE, 2-sided 95% (Hypotheses 1, 2 and 3) or 2-sided 90% CI (Hypothesis 
4), and p-value from the t-test will be output. 
f) If the alternative hypothesis is two-tailed, and skewness < -0.5 or skewness > 0.5 then 
median of the paired difference (Q1-Q3), 2-sided 95% (Hypotheses 1, 2 and 3) or 2-
sided 90% CI (Hypothesis 4), and p-value from the sign test will be output. 
The calculation of the sign test, and the confidence interval for the median based on the sign test 
will exclude subjects who have zero difference in scores between the 2 treatments.32 
Test Hypotheses for Primary Endpoint, Drug Liking VAS Emax 
The primary objective of a HAP study is to provide information on the relative abuse potential of 
a test drug in humans.4 The statistical analysis of a HAP study should address the following 
questions: 
1. Does the known drug of abuse (positive control) produce reliable abuse-related responses 
compared to placebo (study validity)? 
2. Does the combination of the test drug and the positive comparator produce abuse-related 
responses that are larger than those of the positive control? 
3. Does the test drug produce abuse-related responses that are smaller than those of the 
positive control? 
4. Does the test drug produce abuse-related responses that are similar to placebo? 
The objective of this study to assess the relationship between oxycodone and the combination of 
GE-IR and oxycodone therefore Questions 3 and 4 will not be addressed in this study. 


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To address Questions 1 and 2, the following hypotheses will be tested. 
1. Validation test of the sensitivity and integrity of the study: Does the positive control (C) 
produce mean responses that show greater abuse potential compared to placebo (P)? This 
question may be expressed using the following hypothesis: 
Ho: μC - μP ≤ δ1 vs. Ha: μC - μP > δ1 where δ1 > 0 
(Hypothesis 1) 
2. Does the combination drug (COMBO) produce mean responses that show more abuse 
potential compared to the positive control (C)? 
Ho: μCOMBO – μC ≥ δ2 vs. Ha: μCOMBO – μC < δ2 where δ2 = 0.xx(μC ― μP  
(Hypothesis 2) 
These hypotheses will be applied to the primary endpoint, Drug Liking VAS Emax. For Drug 
Liking VAS Emax at a significance level of 0.05; 1-sided 95% confidence intervals will be 
presented for both hypotheses. For Hypothesis 2, a 2-sided 95% confidence interval will also be 
provided; it will provide information about the absolute difference between the combination and 
20 mg dose of oxycodone. 
For study validity purposes, the primary endpoint, Emax for Drug Liking VAS, will be compared 
between the positive control (oxycodone 20 mg) and placebo. The comparison will assess the 
null hypothesis that the mean difference in Drug Liking Emax between oxycodone and placebo is 
less than or equal to 15 against the alternative hypothesis that the mean difference in Drug Liking 
Emax between oxycodone and placebo is greater than 15. 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: 
Ho: μC - μP ≤ 15 vs. Ha: μC - μP > 15 
(Hypothesis 1) 
where μC is the mean for the positive control, oxycodone, and μP is the mean for placebo. This 
hypothesis will be applied to the following contrast: 
• Treatment B: Oxycodone 20 mg vs. Treatment A: Placebo 
Although a margin of 15 has been selected for Hypothesis 1 for consistency with the 
qualification phase criteria, subjects may have lower responses in the treatment phase as 
compared to the qualification phase.21,33 Therefore, in the case that the difference between the 
positive control and placebo does not meet the pre-specified criteria for validity of more than 
15 points, a post-hoc analysis will be performed (refer to Section 8.5.2.2). Hypothesis 2 with 
0.xx= 0.2 has been suggested by an FDA reviewer. A margin of 11 points for Hypothesis 4 is 
considered appropriate based on an analysis of Drug Liking VAS Emax data.1717 These will be 
included in the post-hoc analysis. Further details will be described in the SAP. 
To assess whether the combination drug has more abuse potential than the positive control, the 
null hypothesis will be that the mean difference in Drug Liking Emax between GE-IR + 
oxycodone and oxycodone is greater than or equal to 0.xx(mean difference of positive control vs. 
placebo) against the alternative hypothesis that the mean difference in Drug Liking Emax between 


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GE-IR + oxycodone and oxycodone is less than or equal to 0.xx(mean difference of positive 
control vs. placebo). 
Comparison between the combination and the positive control, will be: 
Ho: μCOMBO – μC ≥ δ2 vs. Ha: μCOMBO – μC < δ2 where δ2 = 0.xx(μC ― μP) 
The value of 0.xx is defined as 0.2. The 1-sided test will be performed using 
an alpha level of 0.05. If the test result is significant for 0.xx = 0.2 then 
testing of the null hypothesis will continue with 0.xx values decreasing by 
increments of 0.05 until a non-significant result is obtained. 
(Hypothesis 2) 
where μCOMBO is the mean for the combination of GE-IR + the positive control, μC is the mean 
for the positive control, oxycodone, and μP is the mean for placebo. This hypothesis will be 
applied to the following contrasts: 
• Treatment C: GE-IR 200 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg 
• Treatment D: GE-IR 450 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg 
Test Hypotheses for Key Secondary Endpoints 
The key secondary endpoints in this study will be Emax of Overall Drug Liking, Take Drug Again 
and High. For the comparisons of key secondary PD endpoints, the following hypotheses will be 
used: 
Hypothesis 1: Ho: μC − μP ≤ 0 vs. Ha: μC − μP > 0 
Hypothesis 2: Ho: μCOMBO – μC ≥ δ2 vs. Ha: μCOMBO – μC < δ2 where δ2 = 0.xx(μC ― μP) 
The hypothesis for comparison between the positive control, oxycodone and placebo will be: 
Ho: μC − μP ≤ 0 vs. Ha: μC − μP > 0 
(Hypothesis 1) 
where μC is the mean for the positive control, oxycodone, and μP is the mean for placebo. This 
hypothesis will be applied to the following contrast: 
• Treatment B: Oxycodone 20 mg vs. Treatment A: Placebo 
The hypothesis for comparison between the combination and the positive control, will be: 
Ho: μCOMBO – μC ≥ δ2 vs. Ha: μCOMBO – μC < δ2 where δ2 = 0.xx(μC ― μP) 
The value of 0.xx is defined as 0.2. The 1-sided test will be performed using 
an alpha level of 0.05. If the test result is significant for 0.xx = 0.2 then 
testing of the null hypothesis will continue with 0.xx values decreasing by 
increments of 0.05 until a non-significant result is obtained. 
(Hypothesis 2) 


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where μCOMBO is the mean for the combination of GE-IR + the positive control, μC is the mean 
for the positive control, oxycodone, and μP is the mean for placebo. This hypothesis will be 
applied to the following contrasts: 
• Treatment C: GE-IR 200 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg 
• Treatment D: GE-IR 450 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg 
A significance level of 0.05 will be used for all 1-sided tests; 1-sided 95% confidence intervals 
will be presented. For Hypothesis 2, a 2-sided 95% confidence interval will also be provided; it 
will provide information about the absolute difference between the combination and 20 mg dose 
of oxycodone. 
No adjustments for p-values will be made to account for multiple comparisons. 
Test Hypotheses for Non-Key Secondary Endpoints 
For the comparisons of all other non-key secondary PD endpoints, the following hypotheses will 
be used: 
Hypothesis 1: Ho: μC − μP = 0 vs. Ha: μC − μP ≠ 0 
Hypothesis 2: Ho: μCOMBO – μC = δ2 vs. Ha: μCOMBO – μC ≠ δ2 where δ2 = 0.xx(μC ― μP) 
The hypothesis for comparison between the positive control, oxycodone and placebo will be: 
Ho: μC − μP = 0 vs. Ha: μC − μP ≠ 0 
(Hypothesis 1) 
where μC is the mean for the positive control, oxycodone, and μP is the mean for placebo. This 
hypothesis will be applied to the following contrast: 
• Treatment B: Oxycodone 20 mg vs. Treatment A: Placebo 
The hypothesis for comparison between the combination and the positive control, will be: 
Ho: μCOMBO – μC = δ2 vs. Ha: μCOMBO – μC ≠ δ2 where δ2 = 0.xx(μC ― μP) 
The value of 0.xx is defined as 0.2. The 1-sided test will be performed using 
an alpha level of 0.05. If the test result is significant for 0.xx = 0.2 then 
testing of the null hypothesis will continue with 0.xx values decreasing by 
increments of 0.05 until a non-significant result is obtained. 
(Hypothesis 2) 
where μCOMBO is the mean for the combination of GE-IR + the positive control, μC is the mean 
for the positive control, oxycodone, and μP is the mean for placebo. This hypothesis will be 
applied to the following contrasts: 


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• Treatment C: GE-IR 200 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg 
• Treatment D: GE-IR 450 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg 
A significance level of 0.05 will be used for Hypotheses 1 and 2. For Hypotheses 1 and 2, 
2-sided 95% confidence intervals will be presented. No adjustments for p-values will be made to 
account for multiple comparisons. 
8.5.2.2. Post-Hoc 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 oxycodone and higher 
responses with placebo in the treatment phase as compared to the qualification phase,21,33 
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 do not meet the 
pre-specified criteria for validity of at least 15, exploratory analysis will be performed. Details of 
the post-hoc 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. Pharmacokinetic analyses will be 
performed using the PK population. 
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: 


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• Data: Serial sampled data 
• Model/Dose options Type:  Plasma (200 -202) / Extravascular 
• AUC Calculation Method: 
Linear Trapezoidal with Linear Interpolation 
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 8Table 8. 
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 time 0 to the last 
measurable observed concentration 
AUC0-inf 
Area under the concentration time curve from time 0 to infinity 
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, actual sampling times, 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. 


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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. 
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 Treatment 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. Adverse events will 
be presented by body system and preferred term (MedDRA, version 23.0 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. 


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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. 
8.9. Determination of Sample Size 
The sample sizes are based on data from Setnik et al.3030 which evaluated doses of 20 mg 
oxycodone and placebo; approximate means for oxycodone 15 mg and 30 mg were provided by 
the FDA. 
Validation Test 
For Drug Liking VAS Emax VAS, the mean (SD) was 54.7 (3.9) for placebo, and 68 (15.6) for 
oxycodone 20 mg.30 Using the FDA recommendation of approximate means of 78 for oxycodone 
15 mg, and 84 for oxycodone 30 mg, standard deviation (SD) of 15.6 for both oxycodone 15 mg 
and 30 mg, a margin of 15, correlation of 0, and an upper-tailed test with a significance level of 
0.05, 34 completers would be needed for the comparison of oxycodone 15 mg vs. placebo, and 
13 completers would be needed for the comparison of oxycodone 30 mg vs. placebo. 
Primary Comparison 
The primary comparison, 
Ho: μCOMBO – μC ≥ δ2 vs. Ha: μCOMBO – μC < δ2 where δ2 = 0.xx(μC ― μP), 
is written as a linear combination of three means as follows: 
Ho: 1.2μC -0.2 μP –μCOMBO ≤ 0 versus Ha: 1.2μC -0.2 μP –μCOMBO > 0 
Using the information for oxycodone 15 mg for the estimate of 1.2μC -0.2 μP, the mean (SD) is 
82.66 (18.74). The mean for oxycodone 15 mg was increased by 10% to approximate the mean 
for the combination drug. The mean (SD) for the combination drug is estimated to be 86 (15.6). 
Using a with a margin of 0, correlation of 0.9 and a upper-tailed test with a significance level of 
0.05, 54 completers would be needed for the primary comparison. 
Inflating the most conservative estimate of 54 completers for balanced sequences, drop-outs, and 
problematic subjects, approximately 66 subjects will be randomized into the treatment phase in 
order to ensure 54 completers. 
The SAS code for the sample size calculations are shown below. 
*Validation Test: Oxycodone 15 mg; 
proc power; 
 
pairedmeans test=diff 
 
sides=u 
 
nulldiff=15 
 
pairedmeans=54.7|78 


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pairedstddevs=(3.9 15.6) 
 
corr=0 
 
alpha=0.05 
 
power=0.9 
 
npairs=.; 
run; 
*Validation Test: Oxycodone 30 mg; 
proc power; 
 
pairedmeans test=diff 
 
sides=u 
 
nulldiff=15 
 
pairedmeans=54.7|84 
 
pairedstddevs=(3.9 15.6) 
 
corr=0 
 
alpha=0.05 
 
power=0.9 
 
npairs=.; 
run; 
*Primary Comparison 
proc power; 
 
pairedmeans test=diff 
 
sides=u 
 
alpha=0.05 
 
nulldiff=0 
 
pairedmeans=82.66|86 
 
pairedstddevs=(18.74 15.6) 
 
corr=0.9 
 
power=0.9 
 
npairs=.; 
run; 


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9. REFERENCES 
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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. 
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3. Draft Guidance for Industry: Assessment of Abuse Potential of Drugs. U.S. Department 
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4. Assessment of Abuse Potential of Drugs. U.S. Department of Health and Human 
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5. US Food and Drug Administration. Guidance for Industry: Abuse-Deterrent Opioids 
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6. Balster RL, Bigelow GE. Guidelines and methodological reviews concerning drug abuse 
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7. Griffiths RR, Bigelow GE, Ator NA. Principles of initial experimental drug abuse 
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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 
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Psychopharmacol. 2017; 37(6):675-683. 
10. Schoedel KA, Stockis A, Sellers EM. Human abuse potential of brivaracetam in healthy 
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11. Schoedel KA, Szeto I, Setnik B, et al. Abuse potential assessment of cannabidiol (CBD) 
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Behav. 2018b; 88:162-171. 
12. Horizant [Product Monograph] (October 2016).  
13. 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. 


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14. 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. 
15. Cashman, JN, Dolin SJ. Respiratory and haemodynamic effects of acute postoperative 
pain management: evidence from published data. British Journal of Anaesthesia. 2004; 
93 (2): 212–23. 
16. 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. 
17. 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. 
18. 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. 
19. 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. 
20. Chen L. Principles and methods of statistical assessment of abuse-deterrent opioids. Ther 
Innov Regul Sci. 2018; 52(1):7-13. 
21. Mills C. Statistical Issues in Abuse-Deterrent Formulation (ADF) and Human Abuse 
Potential (HAP) Studies. CCALC, Abuse Potential Dialogue Session, 12-Oct-2018. 
22. Evoy K, et al. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017; 77: 
403-426. 
23. Smith R, et al. Abuse and Diversion of Gabapentin Among Nonmedical Prescription 
Opioid Users in Appalachian Kentucky. American Journal of Psychiatry. 2015; 172(5): 
487-488. 
24. Willens T, et al. Prescription Medication Misuse Among Opioid Dependent Patients 
Seeking Inpatient Detoxification. The American Journal on Addictions. 2015; 24 :173-
177. 
25. Webster LR, et al. Randomized double-blind, placebo-controlled study of the abuse 
potential of different formulations of oral oxycodone. Pain Med. 2012, 13(6) :790-801. 
26. Levy-Cooperman N, et al. Abuse Potential and Pharmacodynamic Characteristics of Oral 
and Intranasal Eluxadoline, a Mixed mu- and kappa- Opioid Receptor Agonist and delta-
Opioid Antagonist. The Journal of Pharmacology and Experimental Therapeutics. 
27. Ordóñez Gallego A, González Barón M, Espinosa Arranz E. Oxycodone: a 
pharmacological and clinical review. Clin Transl Oncol. 2007 May;9(5):298-307. 
28. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs. 2003, 35 (2) :253-9. 


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29. Pathak S, Vince B, Kelsh D, Setnik B, Nangia N, et al.  Abuse potential of samidorphan : 
a phase 1 oxycodone-, pentazocine-, naltrexone-, and placebo-controlled study. J Clin 
Pharmacol. 2019; 59(2) : 218-228. 
30. Setnik B, Roland CL, Pixton G, Webster L. Measurement of Drug Liking in Abuse 
Potential Studies: A Comparison of Unipolar and Bipolar Visual Analog Scales. The 
Journal of Clinical Pharmacology. 2017; 57(2) 266–274. 
31. Zacny JP, Gutierrez S. Characterizing the subjective, psychomotor, and physiological 
effects of oral oxycodone in non-drug-abusing volunteers. Psychopharmacology. (2003); 
170:242-254. 
32. Daniel, W. W. (1990). Applied Nonparametric Statistics, Second Edition, PWS-KENT 
Publishing Company. 
33. 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) 81st Annual Scientific Meeting, June 15-19, 2019. 
34. 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. 
35. 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. 
36. 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. 
37. 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. 
38. Linko K, Paloheimoi M. Inspiratory end-tidal oxygen content difference: a sensitive 
indicator of hypoventilation. Crit Care Med. 1989;17(4):345-348. 
39. 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. 
40. 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. 
41. 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 
42. 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. 


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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 is transcribed from source into an 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). Pharmacodynamic/VAS data is 
electronic.  
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 encrypted (or posted to a secure File Transfer Protocol) and is 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 are 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 (e.g., 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. 
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, 


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documented and reported in compliance with the protocol and applicable requirements as 
outlined in the Food and Drug Administration (FDA) and Organisation for Economic 
Co-operation 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 access to source data/documents 
and read-only access to the EDC. 


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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 Principal Investigator (PI), 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) when 
required. 


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13. APPENDIX 4: PROTOCOL REVIEW AND APPROVALS 
 
TITLE: A Randomized, Double-Blind, Active- and Placebo-Controlled, 6-Way Crossover Study 
to Evaluate the Abuse Potential of Orally Administered Gabapentin Enacarbil Immediate 
Release Capsules Taken Alone and in Combination with Oxycodone in Healthy, Nondependent, 
Recreational Opioid Users 
 
I have carefully read this study protocol and agree it contains all necessary information required 
to conduct this study. I agree to conduct the study according to this protocol and in accordance 
with Good Clinical Practice (GCP) and the applicable regulatory requirements. 
___________________________ 
____________________ 
Debra Kelsh, MD 
Date (yyyy/mm/dd) 
Principal Investigator 
Altasciences Clinical Kansas Inc. 
 


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TITLE: A Randomized, Double-Blind, Active- and Placebo-Controlled, 6-Way Crossover Study 
to Evaluate the Abuse Potential of Orally Administered Gabapentin Enacarbil Immediate 
Release Capsules Taken Alone and in Combination with Oxycodone in Healthy, Nondependent, 
Recreational Opioid Users 
On behalf of the sponsor, I am aware of, and agree to comply with, all of the procedures 
contained within this protocol. 
_____________________________ 
____________________ 
Steven D. Caras, MD, PhD 
 
Date (yyyy/mm/dd) 
Vice President Clinical Development 
Arbor Pharmaceuticals, LLC 


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14. APPENDIX 5: LIST OF ABBREVIATIONS 
ACLS 
Advanced cardiac life support 
ADE 
Adverse drug event 
AE 
Adverse event 
Ab 
Antigen/antibody 
ALT 
Alanine aminotransferase 
ARCI 
Addiction Research Center Inventory 
AST 
Aspartate aminotransferase 
AUC0-T 
Area under the concentration-time curve from 0 to the last measured 
observable concentration 
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 
COWS 
Clinical Opiate Withdrawal Scale 
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 
ET 
Early termination 


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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 
GLP 
Good Laboratory Practice 
HAP 
Human Abuse Potential 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HEENT 
Head, eyes, ears, nose, and throat 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IP 
Investigational product 
IR 
Immediate release 
IRB 
Institutional review board 
IU 
International unit 
IUD 
Intrauterine device 
i.v. 
Intravenous 
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 


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PCAG 
Pentobarbital–Chlorpromazine–Alcohol Group 
PD 
Pharmacodynamic 
pH 
The logarithm, on the base 10, of the reciprocal of the hydrogen ion 
concentration 
PHN 
Postherpetic neuralgia 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PRR 
Proportional Reporting Ratio 
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  
TA_AUE 
Time-averaged area under the effect-time curve 
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 
TQTc 
Thorough corrected QT 
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 postmenopausal 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) and 
hepatitis C (HCV)  
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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18. APPENDIX 9: ADDICTION RESEARCH CENTER INVENTORY (ARCI) MORPHINE-
BENZEDRINE GROUP (MBG) SCALE 
Instructions:  Answer each question as to how you are feeling at this moment. 
One point is given for every “true” answer to the following: 
1. 
I would be happy all the time if I felt as I feel now  - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
2. 
I am in the mood to talk about the feeling I have - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
3. 
I am full of energy - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
4. 
I would be happy all the time if I felt as I do now - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
5. 
Things around me seem more pleasing than usual - - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
6. 
I feel less discouraged than usual - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
7. 
I fear that I will lose the contentment that I have now - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
8. 
I feel as if something pleasant just happened to me - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
9. 
Today I say things in the easiest possible way - - - - - - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
10. I feel so good that I know other people can tell it - - - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
11. I feel more clear-headed than dreamy - - - - - - - - - - - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
12. I can completely appreciate what others are saying when I am in this mood- -  
True □ 
 
False □ 
13. I feel as if I would be more popular with people today - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
14. I feel a very pleasant emptiness - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
15. I feel in complete harmony with the world and those about me - - - - - - - - - - -  
True □ 
 
False □ 
16. I have a pleasant feeling in my stomach - - - - - - - - - - - - - - - - - - - - - - - - - - - -   
True □ 
 
False □ 
17. I feel high - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
 


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19. APPENDIX 10: ADDICTION RESEARCH CENTER INVENTORY (ARCI) 
PENTOBARBITAL-CHLORPROMAZINE-ALCOHOL GROUP (PCAG) SCALE 
1. 
I feel dizzy  - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - -  
True □ 
 
False □ 
2. 
I feel like avoiding people, although I usually do not feel this way - - - - - - - - -  
True □ 
 
False □ 
3. 
My speech is slurred - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
4. 
I have a feeling of just dragging along rather than coasting - - - - - - - - - - - - - -  
True □ 
 
False □ 
5. 
People might say that I am a little dull today - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
6. 
My head feels heavy - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
7. 
I am not as active as usual- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
8. 
It seems harder than usual to move around- - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
9. 
I feel drowsy - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- -  
True □ 
 
False □ 
10. I am moody - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - -  
True □ 
 
False □ 
11. I feel sluggish- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
12. I am full of energy- - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
13. A thrill has gone through me one or more times since I started the test - - - - - -  
True □ 
 
False □ 
14. I feel more excited than dreamy- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
15. I feel more clear-headed than dreamy - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
True □ 
 
False □ 
 


Protocol No: AR26.3031.2 
Altasciences Project Number: ABO-P4-292 
 
Version 2.0, 13AUG2021 
Page 84 of 84
20. APPENDIX 11: CLINICAL OPIATE WITHDRAWAL SCALE (COWS) 
 

SAP_001.pdf: 
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Page 1 of 56  
  
  
STATISTICAL ANALYSIS PLAN  
  
  
For:  
Arbor Pharmaceuticals, LLC  
  
  
PROTOCOL No. AR26.3031.2  
PROTOCOL VERSION: Final v2.0 (Amendment 01), 13-Aug-2021  
  
A Randomized, Double-Blind, Active- and Placebo-Controlled, 6-Way Crossover Study to  
Evaluate the Abuse Potential Of Orally Administered Gabapentin Enacarbil Immediate Release  
Capsules Taken Alone And In Combination With Oxycodone in Healthy, Nondependent,  
Recreational Opioid Users  
  
NCT 06247488  
Altasciences Project No. ABO-P4-292  
  
Prepared by:  
Altasciences Company Inc.  
575 Armand-Flappier Boulevard Laval, 
Quebec  
Canada, H7V 4B3  
  
  
Version: Final 1.0  
Date: 05-Dec-2022  
STATISTICAL ANALYSIS PLAN APPROVAL  
 
We have carefully read this statistical analysis plan and agree it contains the necessary information 
required to handle the statistical analysis of study data.  


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Page 2 of 56  
  
  
  
 
Catherine Mills  
Director, Pharmacodynamic Analysis, Data Services  
Altasciences  
 
  
Date  
 
  
 
Ramadevi Vemuri  
Senior Biostatistician, Data Services  
Altasciences  
 
  
Date  
 
  
  
Denise Milovan  
Senior Neuroscientist, Neuropsychologist, Data  
Services  
Altasciences  
 
  
Date  
 
  
  
Rabiya Chandani  
Manager, Pharmacology, Medical Writing  
Altasciences  
 
 
On behalf of the Sponsor:  
 
 
  
Date  
 
 
 
Tania D. Johnson, RN, BSN  
Director, Clinical Development  
Arbor Pharmaceuticals, LLC  
 
Date  


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Page 3 of 56  
VERSION CONTROL  
 
Version  
Date  
Author  
Description of Changes  
Final 1.0  
05-Dec-2022  
Catherine Mills  
Not applicable  
  
 
 
 
  
 
 
 
  
 
 
 
  
 


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TABLE OF CONTENTS  
 
STATISTICAL ANALYSIS PLAN APPROVAL ............................................................................ 1 
VERSION CONTROL .................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................. 4 
TABLE OF TABLES ....................................................................................................................... 7 
TABLE OF FIGURES ..................................................................................................................... 8 
ABBREVIATIONS ......................................................................................................................... 9 
1  INTRODUCTION ..................................................................................................................... 11 
2  STUDY OBJECTIVES .............................................................................................................. 13 
3  STUDY DESIGN ....................................................................................................................... 15 
3.1  Overall Study Design ......................................................................................................... 15 
3.2  Determination of Sample Size ........................................................................................... 18 
3.3  Treatments .......................................................................................................................... 18 
3.4  Study Procedures .............................................................................................................. 19 
3.5  Randomization and Unblinding Procedures .................................................................. 19 
3.5.1 Method of Assigning Subjects to Treatment Groups .................................................. 19 
3.5.1.1  Qualification Phase ............................................................................................. 19 
3.5.1.2  Treatment Phase.................................................................................................. 20 
3.5.2 Blinding ........................................................................................................................... 20 
4  Analysis Populations .................................................................................................................. 21 
4.1  Qualification Phase ............................................................................................................ 21 
4.1.1  Qualification Randomized Population ..................................................................... 21 
4.1.2  Qualification Safety Population ............................................................................... 21 
4.2  Treatment Phase ................................................................................................................. 21 
4.2.1  Randomized Population ........................................................................................... 21 
4.2.2 Safety Population ...................................................................................................... 21 
4.2.3 Completer Population ............................................................................................... 21 
4.2.4  Modified Completer Population .............................................................................. 21 
4.2.5  Pharmacokinetic (PK) Population ........................................................................... 22 
5  STUDY SUBJECTS .................................................................................................................. 22 
5.1  Disposition ......................................................................................................................... 22 
5.1.1  Qualification Phase ..................................................................................................... 22 


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5.1.2  Treatment Phase .......................................................................................................... 22 
5.2  Protocol Deviations ............................................................................................................ 22 
6  DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................................... 22 
6.1  Qualification Phase........................................................................................................ 22 
6.2  Treatment Phase ............................................................................................................ 23 
7  PHARMACODYNAMICS ANALYSIS ................................................................................... 23 
7.1  Pharmacodynamics Assessments ....................................................................................... 23 
7.1.1  Subjective Effects Visual Analogue Scales (VASs) .................................................... 23 
7.1.2  Addiction Research Center Inventory (ARCI) Scales ................................................ 24 
7.1.3  Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ......................... 24 
7.2  Appropriateness of Measures ............................................................................................. 25 
7.3  Pharmacodynamics Assessment Visit Windows ................................................................ 25 
7.4  Analysis of Pharmacodynamics Measures ......................................................................... 25 
7.4.1  Test Hypotheses for Primary Endpoint, Drug Liking VAS Emax ................................ 28 
7.4.2  Test Hypotheses for Key Secondary Endpoints ......................................................... 30 
7.4.3  Secondary Analysis ..................................................................................................... 30 
7.4.4  Adjustment for Covariates .......................................................................................... 31 
7.4.5  Adjustment for Multiple Comparison/Multiplicity .................................................... 31 
8  PHARMACOKINETICS ANALYSIS....................................................................................... 31 
8.1  Pharmacokinetic Analysis .................................................................................................. 31 
8.1.1  Concentration Data ..................................................................................................... 31 
8.1.2  Missing Values ............................................................................................................ 31 
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 .................................................................................................................................... 33 
9.1  Adverse Events ................................................................................................................... 33 
9.1.1  Qualification Phase ..................................................................................................... 34 
9.1.2  Treatment Phase .......................................................................................................... 34 
9.1.2.1 Severity Categorization ....................................................................................... 34 


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9.1.2.2 Relationship Categorization ................................................................................ 34 
9.1.2.3  General Summary of Treatment-Emergent Adverse Events ............................... 35 
9.1.2.4  Summaries of Treatment-Emergent Adverse Events .......................................... 35 
9.2  Clinical Laboratory Evaluations ........................................................................................ 36 
9.2.1  Viral Screen ................................................................................................................ 37 
9.2.2  Urine Drug Screen and Urine Alcohol Testing ........................................................... 37 
9.2.3  Pregnancy and Follicle Stimulating Hormone (FSH) Tests ....................................... 37 
9.3  Vital Signs .......................................................................................................................... 37 
9.4  12-Lead Electrocardiograms .............................................................................................. 37 
9.5  Physical Examination Findings .......................................................................................... 37 
9.6  Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................................... 38 
10  DATA HANDLING AND PRESENTATION .......................................................................... 38 
10.1 Safety Analysis Presentation .......................................................................................... 38 
10.2 Pharmacokinetic Analysis .............................................................................................. 39 
10.3 Analysis Time Points ....................................................................................................... 40 
10.4 Methods for Handling Missing Data ............................................................................. 40 
11  INTERIM ANALYSES AND DATA SAFETY MONITORING ............................................. 41 
12  CHANGES TO PROTOCOL-SPECIFIED ANALYSES ........................................................ 42 
13  GENERAL INFORMATION RELATED TO DATA PRESENTATIONS .............................. 45 
13.1 INDEX OF TABLES ........................................................................................................ 46 
13.2 INDEX OF FIGURES ...................................................................................................... 49 
13.3 INDEX OF LISTINGS ..................................................................................................... 50 
14  REFERENCES ........................................................................................................................ 52 
APPENDIX A: STUDY SCHEDULE ........................................................................................... 53 
 


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TABLE OF TABLES  
Table 1: Objectives and Related Endpoints ..............................................................................12  
Table 2: Sample Qualification Phase Sequences ......................................................................18  
Table 3: Sample Treatment Phase Sequences ...........................................................................19  
Table 4: Visual Analog Scale (VAS) Descriptions ...................................................................24  
Table 5: Pharmacokinetic Parameters in Plasma ......................................................................33  
Table 6: Clinical Laboratory Assessments ...............................................................................37  


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TABLE OF FIGURES  
Figure 1: Study Schema ..........................................................................................................16  


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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  
GE-IR  
Gabapentin Enacarbil Immediate Release  
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  
LLOQ  
Lower Limit of Quantitation  
ln  
Natural Log  


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λZ  
Individual estimate of the terminal elimination rate constant, calculated using 
loglinear regression of the terminal portions of the plasma concentration-versus-
time curves  
Max  
Maximum  
MBG  
Morphine-Benzedrine Group  
MCV  
Mean Corpuscular Volume  
MedDRA  
Medical Dictionary For Regulatory Activities  
Min  
Minimum  


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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  
World Health Organization  
1 INTRODUCTION  
 
This study will be a randomized, double-blind, active- and placebo-controlled, 6-way crossover 
study to evaluate the abuse potential, pharmacokinetics (PK), safety, and tolerability of 
Gabapentin Enacarbil Immediate Release (GE-IR) co-administered with oxycodone relative to 
GE-IR alone, oxycodone, and placebo, in nondependent, recreational opioid users. This study 
will consist of 4 phases: screening, qualification, treatment, and follow-up.  


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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 AR26.3031.2. 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 secondary 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 2.0 (Amendment 01), 
dated 13-Aug-2021.  
 


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2 STUDY OBJECTIVES  
 
The primary objective of this study is to evaluate the abuse potential of single oral doses of GEIR 
taken in combination with an opioid active control (oxycodone) in healthy, nondependent, 
recreational opioid users  
The objectives of the study and corresponding study endpoints are detailed in Table 1.  
Table 1: Objectives and Related Endpoints  
Objective(s)  
Endpoint  
Analysis  
Pharmacodynamic (PD)  
  
  
To evaluate the abuse potential of 
single oral doses of GE-IR taken in 
combination with an opioid active 
control (oxycodone) in healthy, 
nondependent, recreational opioid 
users.  
The primary endpoint will be the 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).  
Refer to Section  
7.4.1  


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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 (minimum effect [Emin], 
time of maximum effect [TEmax], 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)  
Other Subjective Effects  
• 
Any Effects VAS (Emax, TEmax, and 
TA_AUE)  
• 
Feeling Drunk (Emax, TEmax, and TA_AUE)  
• 
Drowsiness/Alertness VAS (Emin, TEmin, and 
area over the effect-time curve  
[TA_AOE])  
• 
Relaxation/Agitation VAS (Emin, TEmin, and 
TA_AOE)  
• 
Addiction Research Center Inventory  
(ARCI) Morphine-Benzedrine Group  
(MBG) Scale (Emax, TEmax, and TA_AUE)  
• 
ARCI Pentobarbital-Chlorpromazine-  
Refer to Section  
7.4.2 and  
Section 7.4.3  
Objective(s)  
Endpoint  
Analysis  
 
• 
Alcohol Group (PCAG) Scale (Emax, TEmax, 
and TA_AUE)  
Observer Assessments  
• 
Modified 
Observer’s 
Assessment 
of 
Alertness/Sedation (MOAA/S; Emin, change  
from baseline to minimum effect [CFBmin], 
and TA_AOE)  
 
Pharmacokinetic (PK)  
  
  


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To evaluate the PK of gabapentin 
from GE-IR when administered 
alone or in combination with 
oxycodone in healthy  
nondependent, recreational opioid 
users.  
Secondary Endpoint:  
Pharmacokinetic parameters of gabapentin 
include Cmax, Tmax, area under the curve from 
time 0 to the time of last measurable observed 
concentration (AUC0-t), and area under the 
curve from time 0 to infinity (AUC0-inf).  
Refer to Section 
8  
Safety  
  
  
To evaluate the effects on safety 
and tolerability of single oral doses 
of GE-IR taken alone or in 
combination 
with 
oxycodone, 
compared 
to 
placebo 
and 
oxycodone 
alone, 
in 
healthy 
nondependent, recreational opioid 
users.  
Secondary endpoints will include the incidence 
of AEs, serious adverse events (SAEs), as well as 
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, electrocardiograms  
(ECGs), Columbia Suicide Severity Rating 
Scale (C-SSRS), and physical examination 
findings.  
Refer to Section 
9  
3 STUDY DESIGN  
 
3.1  Overall Study Design  
This study will be a randomized, double-blind, active- and placebo-controlled, 6-way crossover 
study to assess the abuse potential, PK, safety and tolerability of GE-IR co-administered with 
oxycodone relative to GE-IR alone, oxycodone, and placebo, in healthy, nondependent, 
recreational opioid users.  
This study will consist of 4 phases: screening, qualification, treatment, and follow-up. The study 
schema is presented in Figure 1. Screening and Qualification Phase  
After a screening period of up to 30 days, eligible subjects will be admitted to the clinical research 
unit (CRU) on Day -1 of the qualification phase.  
A sufficient number of subjects will be screened and entered into the qualification phase to ensure 
that approximately 66 subjects will be randomized in the treatment phase, so that at least 54 
subjects will complete the study. Females will be recruited on a best-effort basis to ensure an 
appropriate representation of females in the study.  
All subjects will complete a naloxone challenge at least 24 hours prior to the first drug 
administration in the qualification phase, to confirm that they are not opioid-dependent. The test 
will be administered in the following 2 steps:  
1. Naloxone 0.2 mg will be given via intravenous (i.v.) bolus followed by a 2 to 3 mL saline 
flush. The subject will be observed for 1 minute after bolus administration for signs or 
symptoms of withdrawal.  
2. If there is no evidence of withdrawal after 1 minute, naloxone 0.6 mg will be given via  
i.v. bolus within 5 minutes of the first administration followed by a 2 to 3 mL saline flush. 
The subject will be observed for an additional 5 minutes.  


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The naloxone doses selected for the challenge are consistent with doses commonly administered 
to confirm opioid nondependence. The Clinical Opiate Withdrawal Scale (COWS) will be used 
to record any signs or symptoms of opioid withdrawal observed in step 1 (predose and 1 minute 
after administration) and step 2 (5 minutes after administration) of the naloxone challenge test.  
Subjects who present symptoms of withdrawal during predose assessment or following 
administration of the naloxone challenge (i.e., COWS score ≥5, unless in the opinion of an 
investigator the symptoms present are not related to opioid withdrawal) will be excluded from 
the study and will not be eligible to enter the qualification phase.  
The qualification phase will further determine whether subjects like and tolerate the effects of 
oxycodone, and can discriminate these from placebo; this visit will also determine if each subject 
is suitable for entry into and is likely to complete the treatment phase (i.e., likely to comply with 
the study protocol).  
  
  
On Days 1 and 2 of the qualification phase, subjects will receive the following treatments in a 
randomized, double-dummy, crossover manner:  
  
Day 1  
Day 2  
Sequence 1  
Treatment X: 
Placebo  
Treatment 
Y: 
Oxycodone 20 mg  
Sequence 2  
Treatment 
Y: 
Oxycodone 20 mg  
Treatment X: 
Placebo  
Each dose will be separated by approximately 24 hours.  
Each subject must meet all of the qualification criteria to be randomized for participation in the 
treatment phase.  
It is preferred that subjects remain confined at the CRU from the start of the qualification phase 
through completion of the treatment phase; however, subjects may be discharged between these 
phases if required. Appropriate discharge and re-admission procedures are noted in APPENDIX 
A.  
Treatment and Follow-up  
The treatment phase is a randomized, double-blind, active- and placebo-controlled, 6-way 
crossover design in which subjects will receive the following 6 treatments in a crossover manner 
in blinded fashion:  
• 
Treatment A: Placebo  
• 
Treatment B: Oxycodone 20 mg  
• 
Treatment C: GE-IR 200 mg + oxycodone 20 mg  
• 
Treatment D: GE-IR 450 mg + oxycodone 20 mg  
• 
Treatment E: GE-IR 200 mg  
• 
Treatment F: GE-IR 450 mg  
Each study drug administration will be separated by at least 3 days. Drug administrations will be 
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 of the 


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treatment phase, if deemed medically stable for discharge by an investigator. A follow-up visit 
will occur 7 days (±2 days) following the final dose.  
Study assessments will be performed at the time points outlined in the Study Schedule 
(APPENDIX A).  
The maximum duration of subject participation, including screening, will be approximately 59 
days.  
Subjects who terminate the study early will perform follow-up procedures at the time of early 
termination (ET).  
  
  
Figure 1: Study Schema  
  
Note: the sequence of treatments shown is for illustration of the overall design and does not necessarily 
represent an actual treatment sequence.  


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3.2  Determination of Sample Size  
The sample sizes are based on data from Setnik et al.1 which evaluated doses of 20 mg 
oxycodone and placebo; approximate means for oxycodone 15 mg and 30 mg were provided by 
the FDA.  
Validation Test  
For Drug Liking VAS Emax VAS, the mean (SD) was 54.7 (3.9) for placebo, and 68 (15.6) for 
oxycodone 20 mg. Using the FDA recommendation of approximate means of 78 for oxycodone 
15 mg, and 84 for oxycodone 30 mg, standard deviation (SD) of 15.6 for both oxycodone 15 mg 
and 30 mg, a margin of 15, correlation of 0, and an upper-tailed test with a significance level of  
0.05, 34 completers would be needed for the comparison of oxycodone 15 mg vs. placebo, and 13 
completers would be needed for the comparison of oxycodone 30 mg vs. placebo.  
Primary Comparison  
The primary comparison,  
Ho: μCOMBO - μC ≥ δ2 vs. Ha: μCOMBO - μC < δ2 where δ2 = 0.xx(μC ― μP),  
is written as a linear combination of three means as follows:  
Ho: 1.2μC -0.2 μP -μCOMBO ≤ 0 versus Ha: 1.2μC -0.2 μP -μCOMBO > 0  
Using the information for oxycodone 15 mg for the estimate of 1.2μC -0.2 μP, the mean (SD) is 
82.66 (18.74). The mean for oxycodone 15 mg was increased by 10% to approximate the mean 
for the combination drug. The mean (SD) for the combination drug is estimated to be 86 (15.6). 
With a margin of 0, correlation of 0.9 and a upper-tailed test with a significance level of 0.05, 54 
completers would be needed for the primary comparison.  
Inflating the most conservative estimate of 54 completers for balanced sequences, drop-outs, and 
problematic subjects, approximately 66 subjects will be randomized into the treatment phase in 
order to ensure 54 completers.  
3.3  Treatments  
During the qualification phase, each dose will consist of 1 capsule containing oxycodone or 
placebo. The following treatments will be administered orally with approximately 240 mL of 
room temperature water in the morning under fasted conditions:  
• Treatment X (Placebo): 20 mg placebo tablet over-encapsulated to match oxycodone  
• Treatment Y (Active Control): 20 mg oxycodone tablet over-encapsulated  
During the treatment phase, each dose will consist of 2 capsules of GE-IR and/or placebo to 
match GE-IR to achieve assigned dose plus 2 capsules containing oxycodone or placebo. The 
following treatments will be administered orally with approximately 240 mL of room 
temperature water in the morning under fasted conditions:  
• Treatment A (Placebo): 2 × placebo capsules to match GE-IR and 2 × placebo tablets 
overencapsulated to match oxycodone  
• Treatment B (Active Control): 2 × placebo capsules to match GE-IR and 2 × 10 mg oxycodone 
tablets over-encapsulated  


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• Treatment C (GE-IR 200 mg + Oxycodone): 1 × 200 mg GE-IR capsules, 1 × placebo capsules 
to match GE-IR, and 2 × 10 mg oxycodone tablets over-encapsulated  
• Treatment D (GE-IR 450 mg + Oxycodone): 2 × 225 mg GE-IR capsules and 2 × 10 mg 
oxycodone tablets over-encapsulated  
• Treatment E (GE-IR 200 mg): 1 × 200 mg GE-IR capsules, 1 × placebo capsules to match GE-
IR, and 2 × placebo tablets over-encapsulated to match oxycodone  
• Treatment F (GE-IR 450 mg): 2 × 225 mg GE-IR capsules and 2 × placebo tablets 
overencapsulated to match oxycodone  
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.  
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. Replacement subjects will be assigned a new 
randomization number equivalent to the Treatment randomization + 1000 (e.g., 3000 series).  
Subjects who enter the treatment phase will be assigned a unique treatment randomization 
number. The range of qualification and treatment randomization numbers may be distinct to 
avoid confusion (e.g., 1000 series and 2000 series).  
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 2  
XY  
X  
Y  
YX  
Y  
X  
Treatment X: Placebo  
Treatment Y: Oxycodone 20 mg  


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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 6 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 6 treatments in the order specified by the 
treatment sequence according to one 6 × 6 Williams square design (Table 3).  
Table 3: Sample Treatment Phase Sequences  
Treatment Sequence  
Period 1  
Period 2  
Period 3  
Period 4  
Period 5  
Period 6  
ABFCED  
A  
B  
F  
C  
E  
D  
BCADFE  
B  
C  
A  
D  
F  
E  
CDBEAF  
C  
D  
B  
E  
A  
F  
DECFBA  
D  
E  
C  
F  
B  
A  
EFDACB  
E  
F  
D  
A  
C  
B  
FAEBDC  
F  
A  
E  
B  
A  
C  
Treatment A: Placebo  
Treatment B: Oxycodone 20 mg  
Treatment C: GE-IR 200 mg + Oxycodone 20 mg  
Treatment D: GE-IR 450 mg + Oxycodone 20 mg  
Treatment E: GE-IR 200 mg  
Treatment F: GE-IR 450 mg  
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 


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(SUSAR) report. Randomization information will be held by designated individual(s). The date 
and reason for breaking the blind must be recorded.  
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 placebo or oxycodone.  
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 in the Randomization population who receive at 
least 1 dose of study drug (e.g., placebo, oxycodone, or GE-IR).  
4.2.3  
Completer Population  
All subjects in the Safety population who complete all 6 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  
If such do not exist in the study, then the Modified Completer population will be the same as the 
Completer population.  


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4.2.5  
Pharmacokinetic (PK) Population  
The PK population will include all subjects in the Safety population who receive at least 1 dose of 
GE-IR during the treatment phase, have evaluable PK data, and have no protocol deviations or 
other circumstances that would exclude them from analysis.  
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 (and the basis for such exclusions) will be summarized 
and listed for each phase of the study. The 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 will be listed for the qualification and treatment 
phases using the Qualification Randomized and Randomized populations, respectively. 
Information for PD and PK sampling time deviations during the treatment phase will be derived 
programmatically and presented in listings.  
Protocol deviations will be collected in the clinic deviation tracking system (DTS) and presented 
as entered in a general protocol deviation listing.  
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, and body mass index [BMI]) will be summarized separately for the 
Qualification Randomized and Qualification Safety populations. Subjects who did not complete 
the qualification phase or were not randomized into the treatment phase will also be summarized.  


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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 listed by subject for the 
Qualification Randomized population.  
6.2  
Treatment Phase  
Demographics, baseline characteristics and informed consent information will be listed for the 
Randomized population. Demographics and baseline characteristics (sex, age, race, ethnicity, 
body weight, height, and 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).  
Histories of recreational drug use, alcohol use and smoking history will be summarized for the 
Randomized population using descriptive statistics.  
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.  
 


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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  
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):  


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The Observer’s Assessment of Alertness/Sedation Scale (OAA/S) was developed to measure the 
level of alertness in subjects who are sedated. 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)  
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 studies 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. 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 


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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 key 
secondary PD endpoints between treatments (e.g., Emax, Emin, CFBmin, and 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.  
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 each subject. Treatments for each PD endpoint will be tested for 
homogeneity of variance using the SAS procedure GLIMMIX with COVTEST statement. If 
treatments for a given PD endpoint are homogeneous, only the RANDOM statement will be 
added to the PROC MIXED (“RANDOM SUBJECT;”). If the variance among treatments for a 
given PD endpoint are heterogeneous, the option “REPEATED/SUBJECT=SUBJECT  
GROUP=TREATMENT;” will be used in addition to the option “RANDOM SUBJECT;’ in the 
PROC MIXED model.  
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.  
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 analysis model. If the carryover effect is found to be significant at the alpha < 0.25, it will be 
included in the model.  
The conditional residuals from the mixed-effects model will be investigated for normality using 
the Shapiro-Wilk W-test. The following provides an example of the SAS code that will be used 
if the variance is homogeneous:  


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PROC MIXED DATA=ADPD;  
CLASS SUBJECT TRTPCD APERIOD SEQCODE;  
MODEL ENDPOINT = TRTPCD APERIOD SEQCODE BASELINE/OUTP=RESIDUALS DDFM = KR; RANDOM 
SUBJECT;  
RUN;  
  
ODS OUTPUT TESTSFORNORMALITY = NORMTEST;  
PROC UNIVARIATE DATA= RESIDUALS NORMAL;  
VAR RESID; RUN;  
If the normality assumption of the model is satisfied, least squares means, SE, and 1-sided 95% 
or 2-sided 90% or 95% 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 for a PD endpoint, 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, i.e., p-value ≥ 0.05, a paired t-test 
will be used.  
If the paired difference is not normally distributed, that is, p-value < 0.05, the following steps will 
be taken to test skewness:  
a) If the alternative hypothesis is upper-tailed, and skewness is [0, 0.5] then mean difference, SE, 
1-sided 95% or 2-sided 90% CI, and p-value from the t-test will be output.  
b) If the alternative hypothesis is upper-tailed, and skewness < 0 or skewness > 0.5 then median 
of the paired difference (Q1-Q3), 1-sided 95% or 2-sided 90% CI, and p-value from the sign 
test will be output.  
c) If the alternative hypothesis is lower-tailed, and skewness is [-0.5, 0] then mean difference, 
SE, 1-sided 95% or 2-sided 90% CI, and p-value from the t-test will be output.  
d) If the alternative hypothesis is lower-tailed, and skewness < -0.5 or skewness > 0 then median 
of the paired difference (Q1-Q3), 1-sided 95% or 2-sided 90% CI, and p-value from the sign 
test will be output.  
e) If the alternative hypothesis is two-tailed, and skewness is [-0.5, 0.5] then mean difference, 
SE, 2-sided 95% (Hypotheses 1 and 2) or 2-sided 90% CI (Hypothesis 3), and p-value from 
the t-test will be output.  
f) If the alternative hypothesis is two-tailed, and skewness < -0.5 or skewness > 0.5 then median 
of the paired difference (Q1-Q3), 2-sided 95% (Hypotheses 1 and 2) or 2-sided 90% CI 
(Hypothesis 3), and p-value from the sign test will be output.  
The following provides an example of the SAS code that will be used for a t-test and a sign test 
respectively:  
PROC TTEST DATA=ADPD_PARM SIDES=U H0=Mu ALPHA=0.05;  
     VAR DIFF_TRT;  
RUN;  
  
ODS SELECT BASICMEASURES TESTSFORLOCATION;  
PROC UNIVARIATE DATA=ADPD_PAR;  
   VAR DIFF_TRT;  
RUN;  


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where:  
Mu= margin of interest in the hypothesis and DIFF_TRT= difference in the PD parameters 
between the two treatments (paired of interest).  
The calculation of the sign test, and the CI for the median of the paired difference based on the 
sign test, will exclude subjects who have zero difference in scores between the 2 treatments.2  
7.4.1 Test Hypotheses for Primary Endpoint, Drug Liking VAS Emax  
The primary objective of a HAP study is to provide information on the relative abuse potential of 
a test drug in humans. The statistical analysis of a HAP study should address the following 
questions:  
1. Does the known drug of abuse (positive control) produce reliable abuse-related responses 
compared to placebo (study validity)?  
2. Does the combination of the test drug and the positive control produce abuse-related 
responses that are larger than those of the positive control?  
3. Does the test drug produce abuse-related responses that are smaller than those of the positive 
control?  
4. Does the test drug produce abuse-related responses that are similar to placebo?  
The objective of this study is to assess the relationship between oxycodone and the combination 
of GE-IR and oxycodone. Questions 3 and 4 will therefore not be addressed.  
To address Questions 1 and 2, the following hypotheses will be tested.  
1. Validation test of the sensitivity and integrity of the study: Does the positive control (C) 
produce mean responses that show greater abuse potential compared to placebo (P)? This 
question may be expressed using the following hypothesis:  
Ho: μC - μP ≤ δ1 vs. Ha: μC - μP > δ1 where δ1 > 0  
(Hypothesis 1)  
2. Does the combination drug (COMBO) produce mean responses that show more abuse 
potential compared to the positive control (C)?  
Ho: μCOMBO - μC ≥ δ2 vs. Ha: μCOMBO - μC < δ2 where 
δ2 = 0.xx(μC - μP)  
(Hypothesis 2)  
These hypotheses will be applied to the primary endpoint, Drug Liking VAS Emax.   
For Drug Liking VAS Emax at a significance level of 0.05; 1-sided 95% confidence intervals will 
be presented for both hypotheses.  
For Hypothesis 2, a 2-sided 95% confidence interval will also be applied; it will provide 
information about the absolute difference between the combination drug and the positive control.  
For study validity purposes, the primary endpoint, Emax for Drug Liking VAS, will be compared 
between the positive control (oxycodone 20 mg) and placebo. The comparison will assess the 
null hypothesis that the mean difference in Drug Liking Emax between oxycodone and placebo is 


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less than or equal to 15 against the alternative hypothesis that the mean difference in Drug 
Liking Emax between oxycodone and placebo is greater than 15. If statistically significant, it will 
confirm the sensitivity of the study and allow for the comparison of the other pairwise 
comparisons shown below. The hypothesis can be expressed as follows:  
Ho: μC - μP ≤ 15 vs. Ha: μC - μP > 15  
(Hypothesis 1)  
where μC is the mean for the positive control, oxycodone, and μP is the mean for placebo. This 
hypothesis will be applied to the following contrast:  
• 
Treatment B: Oxycodone 20 mg vs. Treatment A: Placebo  
For Hypothesis 1, although a margin of 15 was selected for consistency with the qualification 
phase criteria, subjects may have lower responses in the treatment phase as compared to the 
qualification phase.3 Therefore, in the event that the difference between the positive control and 
placebo does not meet the pre-specified validity criterion of more than 15 points, a secondary 
analysis will be performed (refer to Section 7.4.3 for additional details). For Hypothesis 2, a 
margin of 0.xx = 0.2 was suggested by an FDA reviewer.  
To assess whether the combination drug has greater abuse potential than the positive control, the 
null hypothesis will be that the mean difference in Drug Liking Emax between GE-IR + 
oxycodone and oxycodone is greater than or equal to 0.xx (mean difference of positive control 
vs. placebo) against the alternative hypothesis that the mean difference in Drug Liking Emax 
between GE-IR + oxycodone and oxycodone is less than or equal to 0.xx (mean difference of 
positive control vs. placebo). The hypothesis can be expressed as follows:  
Ho: μCOMBO - μC ≥ δ2 vs. Ha: μCOMBO - μC < δ2 where δ2 = 0.xx(μC 
- μP)  
The value of 0.xx is defined as 0.2. A 1-sided test will be 
performed using an alpha level of 0.05. If the test result is 
significant for 0.xx = 0.2, then testing of the null hypothesis will 
continue with 0.xx values decreasing by increments of 0.05 until 
a non-significant result is obtained.  
(Hypothesis 2)  
where μCOMBO is the mean for the combination of GE-IR + positive control, μC is the mean for 
the positive control, oxycodone, and μP is the mean for placebo. This hypothesis will be applied 
to the following contrasts:  
• 
Treatment C: GE-IR 200 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg  
• 
Treatment D: GE-IR 450 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg  
The following SAS code is an example of the PROC MIXED model that might be used for Drug 
Liking VAS Emax if the treatment variance is heterogeneous.  
PROC MIXED DATA=ADPD;  
CLASS SUBJECT TRTPCD PERIOD SEQCODE;  
MODEL VALUE=TRTPCD PERIOD SEQCODE CARRYCD [if applicable]/ DDFM=KR;  
RANDOM SUBJECT;  
REPEATED/SUBJECT=SUBJECT GROUP=TREATMENT;  
LSMEANS TRTPCD/CL;  
LSMESTIMATE TRTPCD “B: Oxycodone 20 mg vs. A: Placebo” -1 1 0 0 0 0/UPPER CL TESTVALUE=15 
ALPHA=0.05;  
LSMESTIMATE TRTPCD "positional 1.2B - 0.2A - C" -0.2 + 1.2 -1 0 0 0, "nonpositional 1.2B - 0.2A -  


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C" [-0.2, 1] [1.2,2] [-1,3] /UPPER CL TESTVALUE=0 ALPHA=0.05;  
LSMESTIMATE TRTPCD "positional 1.2B - 0.2A - D" -0.2 + 1.2 0 -1 0 0, "nonpositional 1.2B - 0.2A - 
D" [-0.2, 1] [1.2,2] [-1,4] /UPPER CL TESTVALUE=0 ALPHA=0.05; RUN;  
7.4.2 Test Hypotheses for Key Secondary Endpoints  
The key secondary endpoints in this study will be Emax of Overall Drug Liking, Take Drug Again 
and High. For the comparisons of key secondary PD endpoints, the following hypotheses will be 
used:  
Hypothesis 1: Ho: μC − μP ≤ 0 vs. Ha: μC − μP > 0  
Hypothesis 2: Ho: μCOMBO - μC ≥ δ2 vs. Ha: μCOMBO - μC < δ2 where δ2 = 
0.xx(μC - μP)  
The hypothesis for comparison between the positive control, oxycodone, and placebo will be:  
Ho: μC − μP ≤ 0 vs. Ha: μC − μP > 0  
(Hypothesis 1)  
where μC is the mean for the positive control, oxycodone, and μP is the mean for placebo. This 
hypothesis will be applied to the following contrast:  
• 
Treatment B: Oxycodone 20 mg vs. Treatment A: Placebo  
The hypothesis for comparison between the combination drug and the positive control, will be:  
Ho: μCOMBO - μC ≥ δ2 vs. Ha: μCOMBO - μC < δ2 where δ2 = 0.xx(μC 
- μP)  
The value of 0.xx is defined as 0.2. A 1-sided test will be 
performed using an alpha level of 0.05. If the test result is 
significant for 0.xx = 0.2, then testing of the null hypothesis will 
continue with 0.xx values decreasing by increments of 0.05 until 
a non-significant result is obtained.  
(Hypothesis 2)  
where μCOMBO is the mean for the combination of GE-IR + the positive control, μC is the mean 
for the positive control, oxycodone, and μP is the mean for placebo. This hypothesis will be 
applied to the following contrasts:  
• 
Treatment C: GE-IR 200 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg  
• 
Treatment D: GE-IR 450 mg + Oxycodone 20 mg vs. Treatment B: Oxycodone 20 mg  
A significance level of 0.05 will be used for all 1-sided tests; 1-sided 95% confidence intervals 
will be presented. For Hypothesis 2, a 2-sided 95% confidence interval will also be applied; it 
will provide information about the absolute difference between the combination drug and the 
positive control.  
No adjustments for p-values will be made to account for multiple comparisons.  
7.4.3 Secondary Analysis  
Although a margin of 15 was selected for Hypothesis 1 for consistency with the qualification phase 
criteria, subjects may have lower responses with oxycodone and higher responses with placebo in 
the treatment phase as compared to the qualification phase,3 particularly for a study that does not 


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follow the traditional abuse potential evaluation described in the guidelines for HAP studies4 (e.g., 
Does the test drug produce abuse-related responses that are smaller than those of the positive 
control?), but is rather designed to evaluate whether the co-administration of GE-IR with an opioid 
may be associated with additive or synergistic abuse potential effects (ie, Does the combination of 
the test drug and the positive control produce abuse-related responses that are larger than those of 
the positive control?). Therefore, if the difference between the active control and placebo does not 
meet the pre-specified criterion for validity of at least 15, secondary analysis will be performed.  
Drug Liking VAS Emax will be explored in terms of the following criteria using descending point 
differences starting at 4.  
a) Similar Emax scores (within a 4-point difference) for a subject across all study treatments 
(including placebo)  
OR  
b) Emax for placebo > 60 AND the Emax(placebo) - Emax(positive control) ≥ 4  
7.4.4 Adjustment for Covariates  
Baseline (pre-dose) measurement will be included as a covariate, where applicable, in the mixed 
effects models.  
7.4.5 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.  
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 and 450 mg dose 
administration of the investigational product (GE-IR) from the treatment phase will be 
determined to establish the PK profile of gabapentin when administered alone or in combination 
with oxycodone 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.  


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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 
concentrationtime 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:  
  Data:  
  
  
Serial sampled data  
  Model/Dose options Type:   
Plasma (200 - 202) / Extravascular  
  AUC Calculation Method:  
Linear Trapezoidal with Linear Interpolation 
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 to be determined are defined in Table 5.  
Table 5: Pharmacokinetic Parameters in Plasma  
PK Parameter  
Definition  
Cmax (ng/mL)  
Maximum observed concentration occurring at time Tmax  
Tmax (h)  
Time of maximum observed concentration. If the maximum observed 
concentration is not unique, then the first maximum is used.  
AUC0-1 (h*ng/mL),  
Area under the concentration-time curve from the time 0 to 1 h  
AUC0-2 (h*ng/mL),  
Area under the concentration-time curve from the time 0 to 2 h  
AUC0-12 (h*ng/mL),  
Area under the concentration-time curve from the time 0 to 12 h  
AUC0-24 (h*ng/mL),  
Area under the concentration-time curve from the time 0 to 24 h  
AUC0-T (h*ng/mL),  
Area under the concentration-time curve from the time 0 to Tlast  
AUC0-inf (h*ng/mL),  
Area under the concentration-time curve from the time 0 extrapolated to 
infinity  


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T1/2 (h)  
Terminal elimination half-life  
Tlast (h)  
Time of last measurable (positive) observed concentration  
λZ (1/h)  
Individual estimate of the terminal elimination rate constant, calculated 
using log-linear regression of the terminal portions of the plasma 
concentration-versus-time curves  
8.1.6 Summary Statistics  
Summary statistics of the individual concentration data and derived parameters will be calculated 
with Phoenix® WinNonlin® for the PK population. Summary statistics will be calculated for 
concentrations at each individual time point and for all PK parameters.  
Concentration data will be summarized by group using the following statistics: number of 
observations (N), mean, SD, minimum (min), median, maximum (max), and coefficient of 
variation percentage (CV%). Pharmacokinetic parameters will be summarized using these same 
statistics, as well as geometric mean and geometric mean CV%.  
Summary statistics will be displayed with the same precision as the individual values (Section 
10.2) with the exception of N and CV% which will be presented with 0 and 1 decimal place, 
respectively; SD and CV% will not be calculated when N<3, and only min and max will be 
reported if N=1.  
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 
ColumbiaSuicide Severity Rating Scale (C-SSRS). All safety analyses will be conducted on the 
Safety population. All other listings for safety endpoints will be based on the Qualification 
Randomized population.  
9.1 Adverse Events  
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 TEAEs 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. 


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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.  
• 
In the instance where the time of onset or time of resolution is unknown, worst-case 
scenario will be considered, i.e., 00h01 will be considered the onset time; 23h59 will be 
considered the resolution time.  
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.  
9.1.2 Treatment Phase  
The Safety population will include all subjects in the Randomization population who receive at 
least 1 dose of study drug (e.g., placebo, oxycodone, or GE-IR).  
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  


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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).  
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, as well as 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.  


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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.  
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, the treatment phase, and at Day 17/Early Termination (ET)/Follow-up visit. 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.  


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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.  
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 
CSSRS will be administered at the Screening visit. 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.  
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’ 
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 (WHO) 
Drug Global dictionary, 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:  


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• 
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:  
• 
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 1 additional 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.  


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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 
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 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 
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  
2. STUDY  
OBJECTIVES AND  
ENDPOINTS   
Drug Liking VAS  
(minimum effect  
[Emin], 
time 
of 
maximum effect  
[TEmax], 
time 
of 
minimum 
effect 
[TEmin] and area under  
the effect-time curve  
[AUE])  
Table 1: Objectives and 
Related Endpoints  
AUE changed to  
TA_AUE for Drug  
Liking VAS  
Study Synopsis  
Pharmacodynamic  
(PD) Endpoints and 2.  
STUDY  
OBJECTIVES AND  
ENDPOINTS, and  
Table 7.  
Pharmacodynamic  
Endpoints  
Drowsiness/Alertness  
VAS (Emin, TEmin, and 
area 
over 
the 
effecttime curve  
[TA_AUE])  
Relaxation/Agitation  
(Emin, TEmin, and  
TA_AUE)  
Modified 
Observer’s 
Assessment of  
Alertness/Sedation  
(MOAA/S; Emin,  
CFBmin, and  
TA_AUE)  
Table 1: Objectives and 
Related Endpoints  
TA_AUE changed to 
TA_AOE 
for 
the 
following 
3 
PD 
measures:  
Drowsiness/Alertness  
VAS,  
Relaxation/Agitation  
VAS, and Modified  
Observer’s  
Assessment of  
Alertness/Sedation  
(MOAA/S)  
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  


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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  
Protocol Section  
Original Text  
SAP Section  
Change  
 
 
 
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 
maximum for  
continuous 
variables, 
and the proportion of  
subjects 
for 
categorical 
variables) 
for 
the 
Safety population.  
6.1.2 Treatment Phase  Demographics 
and 
baseline 
characteristics will be 
summarized for all 
populations in the 
treatment 
phase. 
Recreational drug use 
history, alcohol use 
history, and smoking 
history 
will 
be 
summarized for the 
Randomized 
population rather than 
the Safety population.  


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Page 44 of 56  
8.5.2  
Pharmacodynamic  
Statistical  
Methodology  
Drug Liking 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, Take Drug  
Again, and High 
VAS have been 
added.  
8.5.2  
Pharmacodynamic  
Statistical  
Methodology: Test  
Hypotheses 
for 
NonKey Secondary  
Endpoints  
For the comparisons  
of all other non-key 
secondary 
PD 
endpoints, 
the 
following 
hypotheses will be 
used:  
Hypothesis 1: Ho: μC  
  
Removed 
hypothesis 
testing 
for 
non-key 
secondary 
endpoints.  
Protocol Section  
Original Text  
SAP Section  
Change  
 
− μP = 0 vs. Ha: μC − 
μP ≠ 0  
Hypothesis 2: Ho:  
μCOMBO - μC = δ2 
vs. Ha: μCOMBO - 
μC ≠ δ2 where δ2 = 
0.xx(μC ― μP)  
 
 
8.5.2.2 Post-Hoc  
Analysis  
Details of the post-hoc 
analysis 
will 
be 
described in the SAP.  
7.4.3 Secondary  
Analysis  
Post-Hoc 
Analysis 
changed to  
Secondary Analysis 
as Post-Hoc Analysis 
may be interpreted as 
representing 
an 
unplanned analysis. 
Therefore, post-hoc 
has been changed to 
secondary to clarify 
that this is a planned 
secondary analysis.  


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Page 45 of 56  
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.  
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, but, rather they may be documented 
in a Note to SAP.  
  
  
 


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Page 46 of 56  
13.1 INDEX OF TABLES  
The following tables will be produced (table numbers and titles may be different in the final 
versions):  
Header  
Table Number  
Table Title  
Analysis Population  Template  
14  
  
Tables, Figures, and Graphs Referred to but not Included in the Text  
  
  
14.1  
  
Demographic Data Summary Tables  
  
  
14.1.1  
  
Subject Disposition  
  
  
  
14.1.1.1.1  
Disposition of Subjects - Qualification Phase  
Qualification  
Randomized  
T1.1a  
  
14.1.1.1.2  
Disposition of Subjects - Treatment Phase  
Randomized  
T1.1b  
  
14.1.1.2  
Subject Discontinuations by Last Treatment Prior to Discontinuation 
During the Treatment Phase  
Safety  
T1.2  
  
14.1.1.3.1  
Subject Populations - Qualification Phase  
Qualification  
Randomized  
T1.3a  
  
14.1.1.3.2  
Subject Populations  - Treatment Phase  
Randomized  
T1.3b  
  
14.1.1.4  
Demographic and Baseline Characteristics by Population - Qualification 
and Treatment Phases  
  
T1.4  
  
14.1.1.5  
Recreational Drug Use History - Treatment Phase  
Randomized  
T1.5  
  
14.1.1.6  
Alcohol Use History - Treatment Phase  
Randomized  
T1.6  
  
14.1.1.7  
Smoking History - Treatment Phase  
Randomized  
T1.7  
  
14.1.1.8  
Protocol Deviations During the Treatment Phase  
Randomized  
T1.8  
14.2  
  
Pharmacodynamic and Pharmacokinetic Data Summary Tables and 
Figures  
  
  
14.2.1.1  
  
Pharmacodynamic Evaluations - Balance of Effects  
  
  
  
14.2.1.1.1.1  
Drug Liking VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.1.1.2.1  
Drug Liking VAS - Pharmacodynamic Parameters and Paired Difference 
- Qualification Phase  
Modified Completer  
T2.2a  
  
14.2.1.1.1.2.2  
Drug Liking VAS - Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.1.1.2.3  
Drug Liking VAS - Pharmacodynamic Parameters Paired Differences - 
Treatment Phase  
Modified Completer  
T2.2c  
  
14.2.1.1.1.3  
Drug Liking VAS - Treatment Comparison of Emax  
Modified Completer  
T2.3  
  
14.2.1.1.1.4  
Drug Liking VAS - Treatment Comparison of Emin  
Modified Completer  
T2.3  
  
14.2.1.1.1.5  
Drug Liking VAS - Treatment Comparison of TA_AUE  
Modified Completer  
T2.3  
  
14.2.1.1.2.1  
Overall Drug Liking VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.1.2.2.1  
Overall Drug Liking VAS - Pharmacodynamic Parameters and Paired 
Difference - Qualification Phase  
Modified Completer  
T2.2a  
  
14.2.1.1.2.2.2  
Overall Drug Liking VAS - Pharmacodynamic Parameters - Treatment 
Phase  
Modified Completer  
T2.2b  
  
14.2.1.1.2.3  
Overall Drug Liking VAS - Pharmacodynamic Parameters Paired 
Differences - Treatment Phase  
Modified Completer  
T2.2c  
  
14.2.1.1.2.4  
Overall Drug Liking VAS - Treatment Comparison of Emax  
Modified Completer  
T2.3  
  
14.2.1.1.3.1  
Take Drug Again VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.1.3.2.1  
Take Drug Again VAS - Pharmacodynamic Parameters and Paired 
Difference - Qualification Phase  
Modified Completer  
T2.2a  
  
14.2.1.1.3.2.2  
Take Drug Again VAS - Pharmacodynamic Parameters - Treatment Phase  Modified Completer  
T2.2b  
  
14.2.1.1.3.3  
Take Drug Again VAS - Pharmacodynamic Parameters Paired Differences 
- Treatment Phase  
Modified Completer  
T2.2c  


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14.2.1.1.3.4  
Take Drug Again VAS - Treatment Comparison of Emax  
Modified Completer  
T2.3  
14.2.1.2  
  
Pharmacodynamic Evaluations - Positive Effects  
  
  
  
14.2.1.2.1.1  
High VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.2.1. 2.1  
High VAS - Pharmacodynamic Parameters and Paired Difference - 
Qualification Phase  
Modified Completer  
T2.2a  
  
14.2.1.2.1.2.2  
High VAS - Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.2.1.3  
High VAS - Pharmacodynamic Parameters Paired Differences - Treatment 
Phase  
Modified Completer  
T2.2c  
Header  
Table Number  
Table Title  
Analysis Population  Template  
  
14.2.1.2.1.4  
High VAS - Treatment Comparison of Emax  
Modified Completer  
T2.3  
  
14.2.1.2.1.5  
High VAS - Treatment Comparison of TA_AUE  
Modified Completer  
T2.3  
  
14.2.1.2.2.1  
Good Effects VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.2.2.2  
Good Effects VAS - Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.2.2.3  
Good Effects VAS - Pharmacodynamic Parameters Paired Differences - 
Treatment Phase  
Modified Completer  
T2.2c  
14.2.1.3  
  
Pharmacodynamic Evaluations - Negative Effects  
  
  
  
14.2.1.3.1  
Bad Effects VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.3.2  
Bad Effects VAS - Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.3.3  
Bad Effects VAS - Pharmacodynamic Parameters Paired Differences - 
Treatment Phase  
Modified Completer  
T2.2c  
14.2.1.4  
  
Pharmacodynamic Evaluations - Other Subjective Effects  
  
  
  
14.2.1.4.1.1  
Any Effects VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.4.1.2  
Any Effects VAS - Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.4.1.3  
Any Effects VAS - Pharmacodynamic Parameters Paired Differences - 
Treatment Phase  
Modified Completer  
T2.2c  
  
14.2.1.4.2.1  
Feeling Drunk VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.4.2.2  
Feeling Drunk VAS - Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.4.2.3  
Feeling Drunk VAS - Pharmacodynamic Parameters Paired Differences - 
Treatment Phase  
Modified Completer  
T2.2c  
  
14.2.1.4.3.1  
Drowsiness/Alertness VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.4.3.2  
Drowsiness/Alertness VAS - Pharmacodynamic Parameters - Treatment 
Phase  
Modified Completer  
T2.2b  
  
14.2.1.4.3.3  
Drowsiness/Alertness VAS - Pharmacodynamic Parameters Paired 
Differences - Treatment Phase  
Modified Completer  
T2.2c  
  
14.2.1.4.4.1  
Relaxation/Agitation VAS by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.4.4.2  
Relaxation/Agitation VAS - Pharmacodynamic Parameters - Treatment 
Phase  
Modified Completer  
T2.2b  
  
14.2.1.4.4.3  
Relaxation/Agitation VAS - Pharmacodynamic Parameters Paired 
Differences - Treatment Phase  
Modified Completer  
T2.2c  
  
14.2.1.4.5.1  
Addiction Research Center Inventory (ARCI) Morphine-Benzedrine 
Group (MBG) Scale by Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.4.5.2  
Addiction Research Center Inventory (ARCI) Morphine-Benzedrine  
Group (MBG) Scale - Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.4.5.3  
Addiction Research Center Inventory (ARCI) Morphine-Benzedrine Group 
(MBG) Scale - Pharmacodynamic Parameters Paired Differences -  
Treatment Phase  
Modified Completer  
T2.2c  
  
14.2.1.4.6.1  
ARCI Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) Scale by 
Treatment and Time Point  
Modified Completer  
T2.1  


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14.2.1.4.6.2  
ARCI Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) Scale - 
Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.4.6.3  
ARCI Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) Scale - 
Pharmacodynamic Parameters Paired Differences - Treatment Phase  
Modified Completer  
T2.2c  
14.2.1.5  
  
Pharmacodynamic Evaluations - Observer Assessments  
  
  
  
14.2.1.5.1  
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S)  by 
Treatment and Time Point  
Modified Completer  
T2.1  
  
14.2.1.5.2  
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S)  - 
Pharmacodynamic Parameters - Treatment Phase  
Modified Completer  
T2.2b  
  
14.2.1.5.3  
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S)  - 
Pharmacodynamic Parameters Paired Differences - Treatment Phase  
Modified Completer  
T2.2c  
14.2.2  
  
Pharmacokinetic Evaluations  
  
  
  
14.2.2.1  
Summary Statistics of Plasma Gabapentin Concentrations Following 
Single Dose Administration of GE-IR  
Pharmacokinetic  
T2.4  
  
14.2.2.2  
Summary Statistics of Plasma Gabapentin Pharmacokinetic Parameters 
Following Single Dose Administration of GE-IR  
Pharmacokinetic  
T2.5  
14.3  
  
Safety Data Summary Tables  
  
  
14.3.1  
  
Display of Adverse Events  
  
  
  
14.3.1.1  
Treatment-Emergent Adverse Events (TEAEs) - Overall Summary  
Safety  
T3.1  
Header  
Table Number  
Table Title  
Analysis Population  Template  
  
14.3.1.2  
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term  
Safety  
T3.2  
  
14.3.1.3  
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class, 
Preferred Term, and Maximum Severity  
Safety  
T3.3  
  
14.3.1.4  
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class, 
Preferred Term, and Maximum Relationship  
Safety  
T3.4  
  
14.3.1.5  
Listings of Deaths, Other Serious and Significant Adverse Events  
Safety  
L8  
14.3.2  
  
Other Safety Data  
  
  
14.3.2.1  
  
Clinical Laboratory Data  
  
  
14.3.2.1.1  
  
Hematology Data  
  
  
  
14.3.2.1.1.1  
Hematology: Summary of Continuous Tests  
Safety  
T4.1  
  
14.3.2.1.1.2  
Hematology: Abnormal Results - Listing  
Safety  
T4.3  
14.3.2.1.2  
  
Biochemistry Data  
  
  
  
14.3.2.1.2.1  
Biochemistry: Summary of Continuous Tests  
Safety  
T4.1  
  
14.3.2.1.2.2  
Biochemistry: Abnormal Results - Listing  
Safety  
T4.3  
14.3.2.1.3  
  
Urinalysis Data  
  
  
  
14.3.2.1.3.1  
Urinalysis: Summary of Continuous Tests  
Safety  
T4.1  
  
14.3.2.1.3.2  
Urinalysis: Summary of Categorical Tests  
Safety  
T4.2  
  
14.3.2.1.3.3  
Urinalysis: Abnormal Results - Listing  
Safety  
T4.3  
  
14.3.2.2.1  
Summary of Vital Signs  
Safety  
T5.1  
  
14.3.2.2.2  
Vital Signs: Abnormal Results - Listing  
Safety  
T5.2  
14.3.2.3  
  
Electrocardiogram (ECG) Data  
  
  
  
14.3.2.3.1  
Summary of Overall ECG Interpretation  
Safety  
T5.3  
  
14.3.2.3.2  
Summary of ECG Data  
Safety  
T5.4  
  
14.3.2.3.3  
ECG: Abnormal Results - Listing  
Safety  
T5.5  


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Page 49 of 56  
13.2  
INDEX OF FIGURES  
The following figures will be produced (figure numbers and titles may be different in the final 
versions):  
Header  
Figure Number  
Figure Title  
Analysis Population  Template  
14.2.1  
  
Pharmacodynamic Summary Figures  
  
  
14.2.1.1  
  
Pharmacodynamic Evaluations - Balance of Effects  
  
  
  
14.2.1.1.1.1  
Mean (± SE) of Drug Liking VAS vs. Treatment and Time Point - Treatment 
Phase  
Modified Completer  
F1  
  
14.2.1.1.1.2  
Box Plot of Drug Liking VAS Emax vs. Treatment - Treatment Phase  
Modified Completer  
F2  
  
14.2.1.1.1.3  
Box Plot of Drug Liking VAS Emin vs. Treatment - Treatment Phase  
Modified Completer  
F2  
  
14.2.1.1.1.4  
Box Plot of Drug Liking VAS TA_AUE vs. Treatment - Treatment Phase  Modified Completer  
F2  
  
14.2.1.1.2  
Mean (± SE) of Overall Drug Liking VAS vs. Treatment and Time Point - 
Treatment Phase  
Modified Completer  
F3  
  
14.2.1.1.3  
Mean (± SE) of Take Drug Again VAS vs. Treatment and Time Point - 
Treatment Phase  
Modified Completer  
F3  
14.2.1.2  
  
Pharmacodynamic Evaluations - Positive Effects  
  
  
  
14.2.1.2.1  
Mean (± SE) of High VAS vs. Treatment and Time Point - Treatment 
Phase  
Modified Completer  
F1  
  
14.2.1.2.2  
Mean (± SE) of Good Effects VAS vs. Treatment and Time Point - 
Treatment Phase  
Modified Completer  
F1  
14.2.1.3  
  
Pharmacodynamic Evaluations - Negative Effects  
  
  
  
14.2.1.3.1  
Mean (± SE) of Bad Effects VAS vs. Treatment and Time Point - Treatment 
Phase  
Modified Completer  
F1  
14.2.1.4  
  
Pharmacodynamic Evaluations - Other Subjective Effects  
  
  
  
14.2.1.4.1  
Mean (± SE) of Any Effects VAS vs. Treatment and Time Point - Treatment 
Phase  
Modified Completer  
F1  
  
14.2.1.4.2  
Mean (± SE) of Feeling Drunk VAS vs. Treatment and Time Point - 
Treatment Phase  
Modified Completer  
F1  
Header  
Figure Number  
Figure Title  
Analysis Population  Template  
  
14.2.1.4.3  
Mean (± SE) of Drowsiness/Alertness VAS vs. Treatment and Time Point - 
Treatment Phase  
Modified Completer  
F1  
  
14.2.1.4.4  
Mean (± SE) of Relaxation/Agitation VAS vs. Treatment and Time Point - 
Treatment Phase  
Modified Completer  
F1  
  
14.2.1.4.5  
Mean (± SE) of Addiction Research Center Inventory (ARCI) Morphine- 
Benzedrine Group (MBG) Scale vs. Treatment and Time Point -  
Treatment Phase  
Modified Completer  
F1  
  
14.2.1.4.6  
Mean (± SE) of Modified Observer’s Assessment of Alertness/Sedation 
(MOAA/S)  vs. Treatment and Time Point - Treatment Phase  
Modified Completer  
F1  
14.2.1.5  
  
Pharmacodynamic Evaluations - Observer Assessments  
  
  
  
14.2.1.5.1  
Mean (± SE) of Modified Observer’s Assessment of Alertness/Sedation 
(MOAA/S) vs. Treatment and Time Point - Treatment Phase  
Modified Completer  
F1  
14.2.2  
  
Pharmacokinetic Summary Figures  
  
  
  
14.2.2.1.1  
Mean Plasma Concentration-Time Profiles of Gabapentin - Linear Scale  Pharmacokinetic  
F4  
  
14.2.2.1.2  
Mean 
Plasma 
Concentration-Time 
Profiles 
of 
Gabapentin 
- 
SemiLogarithmic Scale  
Pharmacokinetic  
F5  
16.2.6.2  
16.2.6.2.4  
Individual Profiles of Plasma Gabapentin - Linear Scale  
Pharmacokinetic  
F6  
  
16.2.6.2.5  
Individual Profiles of Plasma Gabapentin - Semi-Logarithmic Scale  
Pharmacokinetic  
F7  
  
  
 


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Page 50 of 56  
13.3  
INDEX OF LISTINGS  
The following listings will be produced (listing numbers and titles may be different in the final 
versions):  
Note that if the Qualification Randomized population is the same as the Qualification Safety 
population, the Qualification Randomized population will be changed to the Qualification Safety 
population. Likewise, if the Randomized population is the same as the Safety population, the 
Randomized population will be changed to the Safety population.  
Header  
Listing Number  Listing Title  
Analysis Population  
Template  
16.1.7  
  
  
  
  
  
16.1.7.1  
Randomization Scheme and Code, Qualification and Treatment 
Phases  
  
L1  
16.2  
  
Subject Data Listings  
  
  
  
16.2.1.1  
Subject Disposition & Completion /Discontinuation - Treatmemt 
Phase  
Randomized  
L2  
  
16.2.2.1.1  
Protocol Deviations  
Qualification Randomized  
L3.1  
  
16.2.2.1.2  
Protocol Deviations  
Randomized  
L3.1  
  
16.2.2.3  
Pharmacodynamic Measurement Times - Treatment Phase  
Randomized  
L3.2  
  
16.2.2.4  
Pharmacokinetic Measurement Times - Treatment Phase  
Randomized  
L3.3  
16.2.3  
  
Subjects Excluded from Analysis  
  
  
  
16.2.3.1  
Subject Exclusions from Analysis Populations - Qualification 
Phase  
Qualification Randomized  
L4.1  
  
16.2.3.2  
Subject Exclusions from Analysis Populations - Treatment Phase  Randomized  
L4.2  
16.2.4  
  
Demographic Data  
  
  
  
16.2.4.1  
Demographics and Informed Consent  
Qualification Randomized  
L5.1  
  
16.2.4.2  
Medical History  
Qualification Randomized  
L5.2  
16.2.4.3  
  
Baseline Characteristics  
  
  
  
16.2.4.3.1  
Recreational Drug Use History  
Qualification Randomized  
L5.3  
  
16.2.4.3.2  
Alcohol Use History  
Qualification Randomized  
L5.4  
  
16.2.4.3.3  
Smoking History  
Qualification Randomized  
L5.5  
  
16.2.4.4  
Prior and Concomitant Medications  
Qualification Randomized  
L5.6  
16.2.5  
  
Study Drug Administration and Compliance  
  
  
  
16.2.5.1  
Study Drug Administration and Compliance  
Qualification 
Randomized 
and Treatment Randomized  
L6  
16.2.6  
  
Pharmacodynamic and Pharmacokinetic Data  
  
  
16.2.6.1  
  
Pharmacodynamic Data  
  
  
  
16.2.6.1.1  
Pharmacodynamic 
(PD) 
Assessment 
Missing 
Values 
- 
Qualification Phase  
Qualification Randomized  
L7.1a  
  
16.2.6.1.2  
Pharmacodynamic (PD) Assessment Missing Values - Treatment 
Phase  
Randomized  
L7.1b  
16.2.6.2  
  
Pharmacokinetic Data  
  
  
  
16.2.6.2.1  
Listing of Individual Gabapentin Concentration Data Following 
Single Dose Administration of GE-IR  
Pharmacokinetic  
L7.2  
  
16.2.6.2.2  
Listing of Individual Plasma Pharmacokinetic Parameters of 
Gabapentin Following Single Dose Administration of GE-IR   
Pharmacokinetic  
L7.3  
16.2.7  
  
Adverse Event Listings  
  
  


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Page 51 of 56  
  
16.2.7.1  
Adverse Events - Qualification Phase  
Qualification Safety  
L8  
  
16.2.7.2  
Adverse Events - Treatment Phase  
Safety  
L8  
16.2.8  
  
Listing of Individual Laboratory Measurements by Patient  
  
  
16.2.8.1  
  
Clinical Laboratory Data  
  
  
  
16.2.8.1.1  
Hematology  
Qualification Randomized  
L9.1  
  
16.2.8.1.2  
Biochemistry  
Qualification Randomized  
L9.1  
  
16.2.8.1.3  
Urinalysis  
Qualification Randomized  
L9.1  
  
16.2.8.1.4  
Pregnancy and Follicle Stimulating Hormone (FSH) Tests  
Qualification Randomized  
L9.2  
Header  
Listing Number  Listing Title  
Analysis Population  
Template  
  
16.2.8.1.5  
Viral Screen  
Qualification Randomized  
L9.3  
  
16.2.8.1.6  
Urine Drugs of Abuse Screen and Alcohol  
Qualification Randomized  
L9.4  
16.2.8.2  
  
Other Safety Data  
  
  
  
16.2.8.2.1  
Vital Signs  
Qualification Randomized  
L10.1  
  
16.2.8.2.2  
ECG Data  
Qualification Randomized  
L10.2  
  
16.2.8.2.3  
Physical Examination Abnormalities  
Qualification Randomized  
L10.3  
  
16.2.8.2.4  
Columbia-Suicide Severity Rating Scale (C-SSRS)  
Qualification Randomized  
L10.4  
  
  
 


Protocol No. AR26.3031.2 | Altasciences Project No. ABO-P2-292 Final Version 1.0 | 05-Dec-2022  
Page 52 of 56  
14  
REFERENCES  
 
1. Setnik B, Roland CL, Pixton G, Webster L.   Measurement of Drug Liking in Abuse 
Potential Studies:A Comparison of Unipolar and Bipolar Visual Analog Scales. The 
Journal of Clinical Pharmacology 2017, 57(2) 266-274.  
2. Daniel, W. W. (1990). Applied Nonparametric Statistics, Second Edition, PWS-KENT 
Publishing Company.  
3. Mills C. Statistical Issues in Abuse-Deterrent Formulation (ADF) and Human Abuse 
Potential (HAP) Studies. CCALC, Abuse Potential Dialogue Session, 12-Oct-2018.  
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.  
  


  
 
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Page 53 of 56  
APPENDIX A: STUDY SCHEDULE  
 
  
Screening 
Qualification 
Phasea  
Treatment Phase  
Early  
Termination  
(ET)/  
Follow-Up  
Visit b  
Day  
-30 to -2  
-1  
1  
2  
3  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14  
15  
16  
17  
23±2  
Subject Review  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consentc  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion 
criteria review   
X  
X  
  
  
  
Xd  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medication 
& 
recreational 
drug use history  
X  
X  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C-SSRSe  
X  
X  
  
  
X 
f  
Xf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
Study restrictions 
review  
  
X  
  
  
X 
f  
Xf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
Safety  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical 
examination  
X  
Xg  
  
  Xf, g Xf,g  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xg  
Xg  
Height, weight & 
body mass index 
(BMI)  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy testh  
X  
X  
  
  
  
Xf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
Urine 
drug 
and 
alcohol screen  
X  
X  
  
  
  
Xf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
COVID-19 testv  
  
X  
  
  
  
Xf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical laboratory 
evaluations  
X  
X  
  
  
X 
f  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  


  
 
Protocol No. AR26.3031.2 | Altasciences Project No. ABO-P2-292 Final Version 1.0 | 05-Dec-2022  
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Follicle stimulating 
hormone (FSH)i  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serologyj  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Screening 
Qualification 
Phasea  
Treatment Phase  
Early  
Termination  
(ET)/  
Follow-Up  
Visit b  
Day  
-30 to -2  
-1  
1  
2  
3  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14  
15  
16  
17  
23±2  
Vital signsk  
X  
X  
X  X  X  
Xf  
X  
X  
  
X  
X  
  
X  X  
  
X  
X  
  
X  
X  
  
X  
X  
X  
12-lead ECG  
X  
X  
  
  
  
Xf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
Continuous 
respiratory ratel  
  
  
X  X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
Continuous pulse 
oximetryl  
  
  
X  X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
Continuous and  
Spot End Tidal 
CO2l  
  
  
X  X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
Concomitant 
medicationsm  
X  
X  
X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Adverse events 
(AEs)n  
X  
X  
X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Pharmacodynamics 
(PD)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Training/practiceo  
  
X  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Subjective 
measuresp  
  
  
X  X  X  
  
X  
X  
  
X  
X  
  
X  X  
  
X  
X  
  
X  
X  
  
X  
X  
  
MOAA/Sq  
  
  
X  X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
X  
  
  
Pharmacokinetics 
(PK)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PK blood samplesr  
  
  
  
  
  
  
X  
X  
  
X  
X  
  
X  X  
  
X  
X  
  
X  
X  
  
X  
X  
  
Study  
Administration  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Admissionf  
  
X  
  
  
  
Xf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


  
 
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Naloxone challenge  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
COWS  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomizations  
  
X  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Study treatment 
administration   
  
  
X 
t  
X 
t  
  
  
Xu  
  
  
Xu  
  
  
X 
u  
  
  
Xu  
  
  
Xu  
  
  
Xu  
  
  
  
Screening 
Qualification 
Phasea  
Treatment Phase  
Early  
Termination  
(ET)/  
Follow-Up  
Visit b  
Day  
-30 to -2  
-1  
1  
2  
3  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14  
15  
16  
17  
23±2  
Discharge  
  
  
  
  
X 
f  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
  
C-SSRS= Columbia Suicide Severity Rating Scale, ECG= electrocardiogram, GE-IR = Gabapentin Enacarbil Immediate Release, MOAA/S= Modified Observer’s Assessment of  
Alertness/Sedation, COWS= Clinical Opiate Withdrawal Scale  
When time points coincide, procedures should be carried out in the following order, with the following windows: (1) vital signs, ECG and spot EtCO2 (±15 minutes), (2) VAS/PD 
(±15 minutes), (3) PK blood sampling (±5 minutes), (5) MOAA/S to be done at any time around the other procedures (±30 minutes).  
  
a Includes naloxone challenge and qualification (oxycodone versus placebo). b 
Early termination/follow-up visit can be performed in a window of ±2 days.  
c The latest version must be signed prior to subject’s inclusion (prior to naloxone challenge on Day -1) d Review of qualification criteria (Section 4.3 of the protocol). e 
Baseline/screening version of C-SSRS evaluation at screening visit. Since last visit version of C-SSRS evaluation at all other visits. f Subjects should remain housed at the clinical 
research unit (CRU) from Day -1 of the qualification phase through Day 17 of the treatment phase. Only if subjects are discharged between the qualification and treatment phases, 
the noted discharge procedures will be performed on Day 3 of the qualification phase and noted admission procedures will be performed again on Day -1 (treatment phase). If subjects 
remain housed at the CRU the noted procedures are NOT required. Time between discharge from the qualification phase and admission for the treatment phase cannot exceed 14 
days. g Symptom-directed physical examination. h Serum pregnancy test at Screening. Urine pregnancy test at all other visits.  
i Postmenopausal women only. j Serology screening as described 
in Appendix 6 of the protocol.  
k Blood pressure, pulse rate, oxygen saturation (SpO2) and respiratory rate. Measured at screening; each admission to the qualification phase and treatment phase; 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) 
for the qualification and treatment phases  
l Oxygen saturation (SpO2) 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 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 recorded 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. Predose measurements for EtCO2, SpO2 and respiratory rate will be collected to establish an average baseline value prior 
to each dose. m Medications taken within 30 days prior to screening and throughout the duration of study participation will be recorded.  


  
 
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n Adverse events will be collected on an ongoing basis from the time of first study treatment 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 treatment administration in the qualification phase will be recorded as medical history.  
o Additional training sessions may be conducted as needed. p Subjective measures will be evaluated as follows: q Conducted during the qualification and treatment phases within 1 
hour prior to dosing and approximately 0.5, 1, 1.5, 2, 3, 4, and 6 hours postdose. r 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, including spot EtCO2, then subjective measures) is to be prioritized, followed by PK blood 
sampling. s Randomization will be performed for qualification phase only on Day -1. Subjects who meet qualification criteria will be randomized for the treatment phase on Day -1 
(treatment phase). t Subjects administered 20 mg oxycodone or placebo according to randomization with a minimum of 24 hours between doses during t he qualification phase. u 
Subjects administered placebo, GE-IR 200 mg + oxycodone 20 mg, GE-IR 450 mg + oxycodone 20 mg, GE-IR 200 mg, GE-IR 450 mg, or oxycodone 20 mg (minimum washout 
period of at least 3 days between doses). v Covid-19 test will be performed before each admission.  
Category  
Evaluations  
Phase  
Time Points  
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-Bezedrine Group (MBG) 
and 
Pentobarbital-
ChlorpromazineAlcohol 
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  
*24 hour postdose time point relative to the first dose of the qualification phase is to be performed prior to the second dose of the qualification phase.