Clinical trial NCT04570436
Conditions: Abuse Potential
Keywords: Neurontin Diazepam Abuse Liability Gabapentin
Sponsor: Viatris Specialty LLC
Start date: 2021-03-29; Completion date: 2022-11-10
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This will be a randomized, double-blind, double-dummy, placebo- and active controlled, 5 treatment, 10 sequence, 5 period crossover single dose, Williams square design study in healthy adult, non drug dependent male and female participants with drug abuse experience with sedative drugs.

Detailed description:
The study includes Screening, a Qualification Phase consisting of a Naloxone Challenge and Drug Discrimination crossover study, a Treatment Phase and Follow-up. Following successful completion of the Qualification Phase the participants will be enrolled in the Treatment phase. The Treatment Phase is a randomized, double-blind, double dummy, placebo- and active controlled, 5 treatment, 10-sequence, 5 period crossover, single-dose, Williams square design study in healthy male and/or female adult, non drug-dependent recreational users. On Day 1 of each of the Treatment Phase 5 periods, which will be separated by a washout of at least 14 days, participants will receive an oral dose of either NEURONTIN® 1800 mg, 1200 mg or 600 mg or 20 mg diazepam, or placebo. Study treatments will be administered under fasted conditions (overnight fast and no food until 4 hours after dosing). Water will be allowed without restriction until 1 hour prior to dosing and 1 hour after dosing.

Arms: arm 1: single dose arm 2: single dose arm 3: single dose arm 4: single dose arm 5: single dose
Interventions: intervention 1: gabapentin 600 mg intervention 2: gabapentin 1200 mg intervention 3: gabapentin 1800 mg intervention 4: diazepam 20 mg intervention 5: placebo
Intervention descriptions: intervention 1: participants will receive an oral dose of gabapentin 600 mg intervention 2: participants will receive an oral dose of gabapentin 1200 mg intervention 3: participants will receive an oral dose of gabapentin 1800 mg intervention 4: participants will receive an oral dose of 20 mg dose of diazepam intervention 5: participants will receive an oral dose of placebo

Protocol documents:
Prot_000.pdf: 
PF-00345043 
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Protocol V 5.0, 29 Apr 2022 
Viatris Specialty LLC CONFIDENTIAL 
Page 1 
A 
PHASE 
4, 
RANDOMIZED, 
DOUBLE-BLIND, 
DOUBLE-DUMMY, 
PLACEBO- 
AND 
ACTIVE-CONTROLLED, 
SINGLE-DOSE, 
FIVE-WAY 
CROSSOVER STUDY EVALUATING THE ABUSE POTENTIAL OF THREE DOSES 
OF NEURONTIN® TAKEN ORALLY IN HEALTHY, NON-DRUG DEPENDENT 
PARTICIPANTS WITH SEDATIVE DRUG ABUSE EXPERIENCE 
Investigational Product Number: 
PF-00345043 
Investigational Product Name: 
Neurontin® (gabapentin) 
United States (US) Investigational New Drug 
Application (IND) Number: 
28,454 and 57,813 
European Clinical Trials Database (EudraCT) 
Number: 
Not Applicable (N/A) 
Protocol Number: 
A9451181 
Version Number 
5.0 
Phase: 
4 
Short Title: Evaluating the Abuse Potential of Neurontin® When Taken Orally in Healthy Non-drug 
Dependent Participants with Sedative Drug Abuse Experience 
Sponsor: 
Viatris Specialty LLC 
3711 Collins Ferry Road  
Morgantown, WV 26505 
Sponsor Contacts: 
This document and accompanying materials contain confidential information belonging to  Viatris Specialty 
LLC.  Except as otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold 
this information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Viatris 
Specialty LLC must be promptly notified. 
NCT Number: NCT04570436


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PROTOCOL APPROVAL – SPONSOR SIGNATORY 
Study Title 
A phase 4, randomized, double-blind, double-dummy, placebo- and 
active-controlled, single-dose, five-way crossover study evaluating 
the Abuse Potential of three Doses of Neurontin® taken orally in 
healthy, non-drug dependent participants with sedative drug abuse 
experience 
Protocol Number A9451181 
Version No. 
5.0  
Protocol Date 
29 Apr 2022  
 
Protocol accepted and approved by: 
 
 Global Clinical Operations 
Signature 
 
Date 
 
 
Clinical Development 
 
Global Clinical Development  
Signature 
 
Date 
 


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Protocol Amendment Summary of Changes Table 
Document History 
Document 
Version 
Date 
Summary of Changes and Rationale 
Protocol 
Version 5.0 
29 Apr 2022 
x Change of Sponsor name from Upjohn US 1 LLC to 
Viatris Specialty LLC 
x Increasing the number of subjects enrolled 
x Modifying the definition of the Completer Population 
(upon which other analysis sets are defined) to 
specify the minimum required post-dose responses 
required within the Tmax time periods specific to the 
two study drugs, in line with FDA guidance on 
assessing abuse potential of drugs 
x Addition of the Modified Completer Population as 
the primary analysis population 
x Clarification that the Evaluation Population will be 
the subset of the Modified Completer Population who 
do not have major protocol deviations 
x Redefining the permitted time windows for vital signs 
assessments and PK sampling 
x Reducing the number of residential nights from 4 to 3 
per treatment period, at the investigator’s discretion, 
to facilitate subject enrollment 
x Adding “multi-center” in the study description 
x Clarification that subjects must abstain from using 
THC while resident in the clinic  
x Addition of further forms of acceptable female 
contraception 
x Clarifications and corrections to the statistics sections 
with respect to the null- and alternative-hypothesis 
equations, handling of missing pre-dose VAS values, 
and addition of “site” as a fixed effect 
x Updating the time period for making trial data 
available to reflect the change of Sponsor 
Complete summary of changes is provided in Appendix 
13 (Section 10.13) 


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Protocol 
Version 4.0 
04 Aug 2021 
x Modified three inclusion/exclusion criteria, including 
the definition of an experienced recreational sedative 
user, in order to facilitate subject enrolment. 
x Administrative changes to update Sponsor contact 
details and table numbering change in Appendix 13 
 
Complete summary of changes is provided in Appendix 
13 (Section 10.13) 
 
Protocol 
Version 3.0 
26 Feb 2021 
x Couple of typographic changes for harmonization 
within the protocol were implemented. 
 
Complete summary of changes is provided in 
Appendix 10.13 
Protocol 
Version 2.0 
11 Dec 2020 
x The sponsor for this study is changed from ‘Pfizer’ to 
‘Upjohn US 1 LLC’ 
x The responsibility of an Interactive Response 
Technology (IRT) was transferred to a CRO. 
x Administrative and typographic changes for 
harmonization within the protocol were implemented. 
Complete summary of changes is provided in 
Appendix 10.13 
Original 
Protocol 
14 May 2020 Not applicable (N/A) 


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TABLE OF CONTENTS 
LIST OF TABLES............................................................................................................10 
LIST OF FIGURES ..........................................................................................................10 
1. PROTOCOL SUMMARY.............................................................................................11
1.1. Synopsis (Not Applicable) .................................................................................11 
1.2. Schema .............................................................................................................11 
1.3. Schedule of Activities (SoA) .............................................................................12 
2. INTRODUCTION ........................................................................................................18
2.1. Study Rationale .................................................................................................18 
2.2. Background ......................................................................................................18 
2.2.1. Clinical Overview .................................................................................19 
2.3. Benefit/Risk Assessment ...................................................................................19 
3. OBJECTIVES AND ENDPOINTS................................................................................20
4. STUDY DESIGN .........................................................................................................21
4.1. Overall Design ..................................................................................................21 
4.1.1. Screening ..............................................................................................22 
4.1.2. Qualification Phase (Visit 2; Days -1 to 3)..............................................22 
4.1.2.1. Naloxone Challenge (Day -1) ................................................22 
4.1.2.2. Instrument Training...............................................................23 
4.1.2.3. Drug Discrimination (Days 1 to 3) .........................................23 
4.1.3. Treatment Phase (Visits 3 to 7) ..............................................................24 
4.2. Scientific Rationale for Study Design.................................................................24 
4.3. Justification for Dose.........................................................................................25 
4.4. End of Study Definition.....................................................................................25 
5. STUDY POPULATION................................................................................................25
5.1. Inclusion Criteria ..............................................................................................26 
5.2. Exclusion Criteria .............................................................................................27 
5.3. Lifestyle Considerations ....................................................................................29 
5.3.1. Meals and Dietary Restrictions ..............................................................29 
5.3.2. Caffeine, Alcohol, and Tobacco .............................................................30 
5.3.3. Activity.................................................................................................30 
5.3.4. Contraception ........................................................................................30 


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5.4. Screen Failures..................................................................................................31 
6. STUDY INTERVENTION ...........................................................................................31
6.1. Study Interventions Administered ......................................................................31 
6.1.1. Administration ......................................................................................31 
6.2. Preparation/Handling/Storage/Accountability.....................................................31 
6.2.1. Preparation and Dispensing....................................................................32 
6.3. Measures to Minimize Bias: Randomization and Blinding ..................................33 
6.3.1. Allocation to Investigational Product .....................................................33 
6.3.2. Breaking the Blind ................................................................................33 
6.4. Study Intervention Compliance..........................................................................34 
6.5. Concomitant Therapy ........................................................................................34 
6.6. Dose Modification.............................................................................................34 
6.7. Emergency Intervention ....................................................................................34 
6.8. Intervention After the End of the Study ..............................................................35 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ......................................................................35 
7.1. Discontinuation of Study Intervention ................................................................35 
7.2. Participant Discontinuation/Withdrawal from the Study .....................................36 
7.3. Lost to Follow up ..............................................................................................37 
8. STUDY ASSESSMENTS AND PROCEDURES ...........................................................38
8.1. Efficacy Assessments (Not applicable)...............................................................39 
8.2. Safety Assessments ...........................................................................................39 
8.2.1. Physical Examinations...........................................................................39 
8.2.2. Vital Signs ............................................................................................39 
8.2.2.1. Respiratory Monitoring .........................................................40 
8.2.2.2. Temperature..........................................................................40 
8.2.3. Electrocardiograms................................................................................40 
8.2.3.1. Continuous Cardiac Monitoring by Telemetry........................41 
8.2.4. Clinical Safety Laboratory Assessments .................................................41 
8.2.5. Suicidal Ideation and Behavior Risk Monitoring.....................................42 
8.2.5.1. Columbia Suicidality Severity Rating Scale (C-SSRS) ...........42 
8.2.5.2. Risk Assessment During Screening........................................42 


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8.2.5.3. Risk Assessment During the Study ........................................43 
8.2.6. Pregnancy Testing .................................................................................43 
8.3. Adverse Events and Serious Adverse Events ......................................................43 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ......44 
8.3.1.1. Reporting SAEs to Pfizer Safety ............................................44 
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF ................45 
8.3.2. Method of Detecting AEs and SAEs.......................................................45 
8.3.3. Follow-up of AEs and SAEs ..................................................................45 
8.3.4. Regulatory Reporting Requirements for SAEs ........................................45 
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure....................................................................................................46 
8.3.5.1. Exposure During Pregnancy ..................................................46 
8.3.5.2. Exposure During Breastfeeding .............................................48 
8.3.5.3. Occupational Exposure..........................................................48 
8.3.6. Cardiovascular and Death Events ...........................................................49 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs.........................................................................49 
8.3.8. Adverse Events of Special Interest .........................................................49 
8.3.8.1. Lack of Efficacy ...................................................................49 
8.3.9. Medical Device Deficiencies .................................................................49 
8.3.10. Medication Errors................................................................................49 
8.4. Treatment of Overdose ......................................................................................50 
8.5. Pharmacokinetics ..............................................................................................50 
8.6. Pharmacodynamics ...........................................................................................51 
8.6.1. Subjective Effects..................................................................................51 
8.6.2. Visual Analog Scale (VAS) ....................................................................51 
8.7. Genetics............................................................................................................52 
8.7.1. Specified Genetics .................................................................................52 
8.7.2. Banked Biospecimens for Genetics ........................................................52 
8.8. Biomarkers .......................................................................................................52 
8.9. Health Economics .............................................................................................53 
9. STATISTICAL CONSIDERATIONS ...........................................................................53 
9.1. Statistical Hypotheses........................................................................................53 


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9.2. Sample Size Determination................................................................................54 
9.3. Populations for Analysis....................................................................................54 
9.4. Statistical Analyses ...........................................................................................55 
9.5. Interim Analyses ...............................................................................................55 
9.6. Endpoint Analysis .............................................................................................55 
9.7. Study Validity Analysis of Endpoints.................................................................56 
9.8. Analysis of Primary and Secondary Endpoints ...................................................56 
9.8.1. Pharmacodynamic Analysis ...................................................................57 
9.8.2. Derivation of Pharmacodynamic Parameters ..........................................58 
9.8.3. Pharmacokinetic Analysis......................................................................58 
9.8.3.1. Pharmacokinetic Parameters ..................................................59 
9.8.3.2. Derivation of Pharmacokinetic Parameters .............................59 
9.9. Efficacy Analyses .............................................................................................60 
9.10. Safety Analyses...............................................................................................60 
9.10.1. Electrocardiogram Analyses.................................................................60 
9.11. Exploratory Analyses ......................................................................................60 
9.12. Data Monitoring Committee ............................................................................61 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...................................................................................................62 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..............62 
10.1.1. Regulatory and Ethical Considerations .................................................62 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ....................................................................62 
10.1.2. Financial Disclosure ............................................................................63 
10.1.3. Informed Consent Process....................................................................63 
10.1.4. Data Protection....................................................................................64 
10.1.5. Dissemination of Clinical Study Data ...................................................64 
10.1.6. Data Quality Assurance .......................................................................66 
10.1.7. Source Documents...............................................................................67 
10.1.8. Study and Site Closure.........................................................................67 
10.1.9. Publication Policy................................................................................67 
10.1.10. Sponsor’s Qualified Medical Personnel ..............................................68 
10.2. Appendix 2: Clinical Laboratory Tests .............................................................69 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..................................................................71 
10.3.1. Definition of AE..................................................................................71 
10.3.2. Definition of SAE................................................................................72 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs .....................73 
10.3.4. Reporting of SAEs...............................................................................76 
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .........................................................................................................78 
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................78 
10.4.2. Female Participant Reproductive Inclusion Criteria ..............................78 
10.4.3. Woman of Childbearing Potential (WOCBP)........................................79 
10.4.4. Contraception Methods ........................................................................79 
10.5. Appendix 5: Genetics ......................................................................................82 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments........83 
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................85 
10.8. Appendix 8: Clinical Opioid Withdraw Scale ...................................................87 
10.9. Appendix 9: Abbreviations ..............................................................................88 
10.10. Appendix 10: VAS Assessment Methods .......................................................91 
10.11. Alertness/Sedation Assessment ......................................................................94 
10.12. Appendix 12: Alternative Measures During Public Emergencies .....................95 
10.12.1. Eligibility ..........................................................................................95 
10.12.2. Telehealth Visits................................................................................95 
10.12.3. Alternative Facilities for Safety Assessments ......................................95 
10.12.4. Study Intervention .............................................................................95 
10.12.5. Home Health Visits ...........................................................................95 
10.12.6. Adverse Events and Serious Adverse Events ......................................95 
10.12.7. Efficacy Assessments ........................................................................95 
10.12.8. Independent Oversight Committees ....................................................95 
10.13. Appendix 13: Summary of Changes ...............................................................96 
11. REFERENCES .........................................................................................................119 
 


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LIST OF TABLES 
Table 1. 
Schedule of Activities for Screening, Naloxone Challenge and 
Qualification Phase..............................................................................12 
Table 2. 
Schedule of Activities for Treatment Phase ..........................................15 
Table 3. 
Schema for Qualification Phase............................................................23 
Table 4. 
Derivation of Pharmacodynamic Parameters.........................................58 
Table 5. 
Derivation of Pharmacokinetic Parameters ...........................................59 
Table 6. 
Protocol-Required Safety Laboratory Tests ..........................................69 
Table 7. 
Other Subjective Effects Visual Analog Scales .....................................93 
Table 8. 
Modified Observer’s Assessment of Alertness/Sedation Scale...............94 
Table 9. 
Summary of changes from Protocol dated 14 May 2020 to Protocol 
2.0 dated 11 Dec 2020 .........................................................................97 
Table 10. 
Summary of changes from Protocol version 2.0 dated 11 Dec 2020 
to Protocol version 3.0 dated 26 Feb 2021 ..........................................106 
Table 11. 
Summary of changes from Protocol version 3.0 dated 26 Feb 2021 
to Protocol version 4.0 dated 04 Aug 2021 .........................................107 
Table 12. 
Summary of changes from Protocol version 4.0 dated 04 Aug 2021 
to Protocol version 5.0 dated 29 Apr 2022 ..........................................109 
 
LIST OF FIGURES 
Figure 1. 
Schematic of Study Visits ....................................................................11 
 


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1. PROTOCOL SUMMARY 
1.1. Synopsis (Not Applicable) 
1.2. Schema 
The participants will be screened, undergo a naloxone challenge to ensure that they are not 
drug dependent and a drug discrimination test to demonstrate that they can differentiate 
between a positive control and placebo.  Once the participant has passed these tests, they may 
be enrolled into the Treatment Phase of the study.  The Treatment Phase of the study will use 
a Williams square study design involving approximately 50 participants (5 participants in 
each sequence) to ensure at least 32 participants meeting the definition of the Modified 
Completer Population complete the treatment phase of the study as shown in Figure 1.  Drop-
out participants in the treatment phase for non-safety reasons may be replaced at the 
discretion of investigator in consultation with the sponsor. 
Figure 1. Schematic of Study Visits 
 


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1.3. Schedule of Activities (SoA) 
The SoA tables (Table 1 and Table 2) provide an overview of the protocol visits and procedures.  Refer to the STUDY 
ASSESSMENTS AND PROCEDURES section of the protocol for detailed information on each procedure and assessment required 
for compliance with the protocol.  The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, 
to conduct evaluations or assessments required to protect the well-being of the participant. 
Table 1. 
Schedule of Activities for Screening, Naloxone Challenge and Qualification Phase 
 
Visit 1 
Screening 
 
Visit 2 (Qualification Phase) 
Naloxone 
Challenge 
Drug Discrimination 
Study Day 
Within 28 
Days  
Day -1 
Days 1 and 2 
Day 3p 
Hours Post Dose 
 
 
Pre-dose 
0 
0.25 
0.5 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
24 
Clinical Research Unit (CRU) 
admission 
 
Xa 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
 
Informed consent 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including drug 
abuse) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoing eligibility review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Prior/Concomitant medication 
(including past year recreational 
drug history)  
X 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
Physical examinationc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety laboratory tests 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBsAg, HBcAb, HCVAb, 
HAV IgM, HAV IgG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test (Woman Of 
Childbearing Potential [WOCBP] 
only) 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follicular stimulating hormone 
(FSH) testing 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy test (WOBCP 
only) 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contraception check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breathalyzer 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1. 
Schedule of Activities for Screening, Naloxone Challenge and Qualification Phase 
 
Visit 1 
Screening 
 
Visit 2 (Qualification Phase) 
Naloxone 
Challenge 
Drug Discrimination 
Study Day 
Within 28 
Days  
Day -1 
Days 1 and 2 
Day 3p 
Vital signsg 
X 
Xh 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Pulse oximetry, SpO2 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Respiratory rate 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead Electrocardiogrami 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization for Qualification 
Phase, Day 1 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic (Instrument) 
training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac telemetryj 
 
 
X 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
X 
 
Study treatment administered 
 
Xk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Visual Analogue Scales (VAS)l  
 
 
Xl(a) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Take Drug Again, VAS, Overall 
“Drug 
Liking” 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Opiate Withdrawal Scale 
(COWS) 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious and non-serious adverse 
event monitoringn 
X 
X 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
X 
Columbia Suicide-Severity Rating 
Scale 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Evaluate to proceedo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: COWS = Clinical Opiate Withdrawal Scale; CRU = Clinical Research Unit; FSH = follicle stimulating hormone; HAV IgG = hepatitis A virus 
immunoglobulin G; HAV IgM = hepatitis A virus immunoglobulin M; HBsAg = hepatitis B surface antigen; HCVab  = hepatitis C antibody; HIV = human 
immunodeficiency virus; SpO2 = saturated oxygen; VAS = Visual Analogue Scale; WOCBP = women of childbearing potential. 
a. 
Admission should occur in the morning to ensure adequate time for pre-dose review of clinical laboratory results. 
b. 
Assign a single participant identifier number.  
c. 
Complete physical examination (PE) (including height and weight) only needs to be done once, ie, at Screening or at Day -1 of Visit 2.  However, height and weight 
must be performed at Screening to obtain BMI for determination of eligibility.  A brief symptom-directed physical examination will be conducted as needed on Day -1 
and prior to discharge on Day 3. 
d. 
Review of results are required prior to dosing on Visit 2 (ie, Naloxone Challenge). 
e. 
For confirmation of postmenopausal status only.  
f. 
Must be reviewed and confirmed as negative prior to dosing on Day -1. 


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Table 1. 
Schedule of Activities for Screening, Naloxone Challenge and Qualification Phase 
 
Visit 1 
Screening 
 
Visit 2 (Qualification Phase) 
Naloxone 
Challenge 
Drug Discrimination 
Study Day 
Within 28 
Days  
Day -1 
Days 1 and 2 
Day 3p 
g. 
Includes pulse rate, systolic and diastolic blood pressures.  Temperature (oral or with a temporal infrared scanner) will be measured at Screening and upon admission on 
Day -1 of the Naloxone Challenge Phase.  Vital signs are measured after a resting period of approximately 5 minutes in a sitting p osition. 
h. 
Vital signs will be recorded at pre-dose (first naloxone dose) and at 5 minutes, 0.25, 0.5, 1, 1.5, and 2 hours following the second dose of naloxone. Vital signs will be 
recorded at nominal time points ± 5 minutes. 
i. 
Conducted after a resting period of at least 10 minutes in a supine position. 
j. 
Continuous cardiac telemetry (heart rate, cardiac rhythm, and oxygen saturation) will be monitored for approximately 5 hours post-dose or longer at the discretion of the 
clinical research unit. 
k. 
Naloxone (0.2 mg IV) is administered first.  If there are no signs of withdrawal apparent within 30 seconds after administration, another 0.6 mg naloxone IV is 
administered. 
l. 
Include VASs for Drug Liking, High, Sleepy, Dizzy, Nausea, and Feel Sick. 
l(a); Only for High, Sleepy, Dizzy, Nausea, and Feel Sick are administered at pre-dose. 
m. COWS is collected and recorded at pre-dose, and at 30 seconds following the first naloxone dose and 5 minutes after the second dose is administered. 
n. 
Assessed throughout and collected using open-ended questions.  Symptoms of withdrawal following naloxone administration (Naloxone Challenge Phase) will not be 
collected as adverse events unless they meet the criteria for an SAE.  Adverse events and serious AEs will be collected from the time the informed consent is signed 
through and including 28 calendar days after the last administration of the investigational product.  During the Drug Discrimination Phase, AEs are collected at pre-dose 
and 0.25, 0.5, 1, 1.5, 2,2.5, 3, 3.5, 4, 5 and 24 hours post-dose. 
o. 
Evaluation to proceed must occur prior to next scheduled time and event. 
p. 
If participants fail to qualify, all AEs will be reported with no further SoA testing. 
 
 
 


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Table 2. 
Schedule of Activities for Treatment Phase 
Study Day 
Visits 3 to 7 
Treatment Phase 
Periods 1 to 5a 
Follow-up 
Early 
termination/discontinuation 
(DC) 
Day -1 
Baseline 
Day 1 
Day 
2 
Day 
3 
Day  
4 
28 - 35 Daysn 
 
Hours Post Dose 
 
Pre-dose 0 0.250.5 1 1.5 2 2.5 3 3.5 4 6 8 12 24 36 48 
72 
 
 
CRU admission 
X 
o 
o o o o o o o o o o o o o o o 
o 
o 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Continuing eligibility checkb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
o o o o o o o o o o o o o o o 
o 
o 
X 
X 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Safety laboratory testsd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Urine drug testinge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy test (WOCBP 
only)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test (WOCBP 
only)f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Contraception check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Alcohol breathalyzer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
 
X 
Pulse oximetry, SpO2 
 
X 
o o o o o o o o o o o o X 
X 
 
 
 
 
X 
Respiratory rate 
 
X 
o o o o o o o o o o o o X 
X 
 
 
 
 
 
Tidal volume 
 
X 
o o o o o o o o o o o o X 
X 
 
 
 
 
 
End-tidal carbon dioxide 
 
X 
o o o o o o o o o o o o X 
X 
 
 
 
 
 
Randomization 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic (Instrument) 
training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac telemetryi 
 
X 
o o o o o o o o o o o o 
 
 
 
 
 
 
 
Study treatment administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VASj 
 
Xj (a) 
 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
 
X 
VAS for Overall Drug Liking and 
“Take Drug Again” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
VAS for Good Drug Effect, Bad 
Drug Effect, and Any Drug Effect 
 
 
 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
 
X 
Observer-rated assessment of 
alertness/sedation 
 
X 
 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
 
X 


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Table 2. 
Schedule of Activities for Treatment Phase 
Study Day 
Visits 3 to 7 
Treatment Phase 
Periods 1 to 5a 
Follow-up 
Early 
termination/discontinuation 
(DC) 
Day -1 
Baseline 
Day 1 
Day 
2 
Day 
3 
Day  
4 
28 - 35 Daysn 
 
Hours Post Dose 
 
Pre-dose 0 0.250.5 1 1.5 2 2.5 3 3.5 4 6 8 12 24 36 48 
72 
 
 
Viatris Prep D1 Banked 
biospecimenk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood sampling 
 
X 
  
X X X X X X X X X X X 
X 
X 
X 
X 
X 
 
X 
Serious and non-serious adverse 
event monitoringl 
X 
X 
o o o o o o o o o o o o o o o 
o 
o 
X 
X 
Columbia Suicide-Severity Rating 
Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
ECGo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xp 
X 
 
 
Discharge from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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Table 2. 
Schedule of Activities for Treatment Phase 
Study Day 
Visits 3 to 7 
Treatment Phase 
Periods 1 to 5a 
Follow-up 
Early 
termination/discontinuation 
(DC) 
Day -1 
Baseline 
Day 1 
Day 
2 
Day 
3 
Day  
4 
28 - 35 Daysn 
 
Hours Post Dose 
 
Pre-dose 0 0.250.5 1 1.5 2 2.5 3 3.5 4 6 8 12 24 36 48 
72 
 
 
a. 
Treatment Periods will be separated by at least of 14 days between dosing.   
b. 
Continuing eligibility checks will include checks of UDS, ethanol breath test, pregnancy tests, compliance with Lifestyle guidelines, and any changes to medical conditions 
that may require participant rescheduling or discontinuation.  
c. 
Physical examinations will be brief and symptom-directed (if a change in medical history is reported).  Symptom-directed physical examinations may be performed at 
admission to each visit at the discretion of the Investigator.  A complete physical examination will be conducted at End of Study or early termination (ET). 
d. 
See Appendix 2. 
e. 
Urine drug screens may be repeated for confirmatory purposes at the discretion of the Investigator or designee.  
f. 
For all female participants, urine pregnancy tests will be obtained upon admission to each Treatment Visit and a serum pregnancy test will be obtained at the End of Study 
Visit. 
g. 
Vital signs (including pulse rate, systolic and diastolic blood pressures are measured at the nominal time points after a resting period of at least 5 minutes in a sitting position.  
Temperature (oral or with a temporal infrared scanner) will be measured on Day -1 of each Treatment Visit only. Vital signs will be recorded at nominal time points ±5 min 
for time points up to and including 4 h post-dose, within ±15 minutes for time points from 6-12 h post-dose, and within ±60 minutes for the remaining time points up to and 
including 72 h post-dose. 
h. 
Visit 3 pre-dose only.  
i. 
Continuous cardiac telemetry (heart rate, cardiac rhythm, and oxygen saturation) will be monitored from pre-dose for approximately 8 hours post-dose or longer at the 
discretion of the clinical research unit. 
j. 
Include VASs for Drug Liking, High, Sleepy, Dizzy, Nausea, and Feel Sick. 
J(a); Only VASs for High, Sleepy, Dizzy, Nausea, and Feel Sick are administered at pre-dose.  
k. 
Visit 3 pre-dose only on Day -1.  If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in 
conjunction with a participant visit.  
l. 
Spontaneous AE reporting will occur throughout study; however, AEs will also be elicited using non-leading questions during the Treatment Phase at pre-dose and post-dose 
at the indicated times.  AEs and SAEs will be collected from the time the informed consent is signed through and including 35 calendar days after the last administration of 
the investigational product. 
m. End of study only. 
n. 
Contact may occur via telephone contact and must occur 28 to 35 days from administration of the final dose of investigational product. 
o. 
12-lead Electrocardiogram measurements (conducted after a resting period of at least 10 minutes in a supine position) at Day -1 (baseline) and Day 4 during Treatment Phase 
p. 
Subjects may be discharged after completion of Day 3 assessments and return for Day 4 assessments, at the discretion of the investigator. 


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2. INTRODUCTION 
2.1. Study Rationale 
Neurontin® (gabapentin) is indicated for postherpetic neuralgia in adults, adjunctive therapy 
in the treatment of partial onset seizures, with and without secondary generalization in adults 
and pediatric patients 3 years and older with epilepsy. 
Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta or kappa), or 
cannabinoid 1 receptor sites; however, gabapentin abuse has been reported at increasing 
rates.  Individuals abusing gabapentin describe experiences such as euphoria, improved 
sociability, relaxation and a marijuana-like “high”.1-8  
There are post-marketing reports of abuse and individuals experiencing withdrawal 
symptoms shortly after discontinuing higher than recommended doses of gabapentin used to 
treat illnesses for which the drug is not approved.  Such symptoms included agitation, 
disorientation and confusion after suddenly discontinuing gabapentin that resolved after 
restarting gabapentin.  Most of these individuals were taking higher than recommended doses 
of gabapentin for unapproved uses and had a history of poly-substance abuse or used 
gabapentin to relieve symptoms of withdrawal from other substances.  
Epidemiological studies have shown that gabapentin may have abuse potential, particularly 
among individuals with a history of opioid abuse.  Gabapentin abuse is reported both alone 
(ie, without other drugs), and in conjunction with opioids to enhance the ‘high’ obtained from 
opioids.1,4  Further, published data suggest that gabapentin is recorded on death certificates 
suggesting drug overdose, both as the primary and contributory causes of death, and reported 
with and without other drugs like opioids, benzodiazepines, and alcohol.1,5-7  As a 
consequence, the FDA requires this post-authorization safety study (PASS) to evaluate 
gabapentin in a cross-over design with comparison to placebo and a positive control, 
diazepam, regarding abuse-related subjective responses, physiological responses (including 
an assessment of respiratory depression), and drug pharmacokinetics in a healthy non-drug 
dependent population with drug abuse experience with sedative drugs.  
2.2. Background  
The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions 
are unknown.  Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric 
acid (GABA) but has no effect on GABA binding, uptake, or degradation.  In vitro studies 
have shown that gabapentin binds with high-affinity to the D2G subunit of voltage-activated 
calcium channels; however, the relationship of gabapentin binding to its therapeutic effects 
or potential abuse is unknown.  
Approximately 1.1% of the general population and 22% of those attending addiction 
facilities have a history of abuse of gabapentin8,9 and there have been deaths from gabapentin 
use with benzodiazepines and opioids.1-7  The purpose of the present study is to assess 
prospectively the abuse potential of gabapentin compared to placebo and diazepam. 


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2.2.1. Clinical Overview 
Neurontin® formulations are available in strengths of 100 mg, 300 mg, 400 mg capsules and 
600 mg and 800 mg tablets and in an oral solution containing 250 mg/5 mL of gabapentin.  
Gabapentin is rapidly absorbed following oral administration.  Peak concentrations were 
observed within 2 to 3 hours.  Gabapentin bioavailability is not dose proportional; ie, as dose is 
increased, bioavailability decreases.  Bioavailability of gabapentin is approximately 60%, 47%, 
34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided 
doses, respectively.  Food has only a slight effect on the rate and extent of absorption of 
gabapentin (14% increase in area under the curve [AUC] and maximum observed concentration 
[Cmax]).  Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged 
drug.  Gabapentin is not appreciably metabolized in humans.  Gabapentin elimination half-life is 
5 to 7 hours and is unaltered by dose or following multiple dosing.  Gabapentin elimination rate 
constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.10 
Valium® (diazepam) is indicated for the management of anxiety disorders or for the 
short-term relief of the symptoms of anxiety.  After oral administration >90% of diazepam is 
absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a 
range of 0.25 to 2.5 hours.  Absorption is delayed and decreased when administered with a 
moderate fat meal.  In the presence of food, mean lag times are approximately 45 minutes as 
compared with 15 minutes when fasting.  Diazepam is N-demethylated by Cytochrome 
P450 (CYP)3A4 and 2C19 to the active metabolite N-desmethyldiazepam and is 
hydroxylated by CYP3A4 to the active metabolite temazepam.  N-desmethyldiazepam and 
temazepam are both further metabolized to oxazepam.  Temazepam and oxazepam are 
largely eliminated by glucuronidation.11  Metabolites have 25% to 33% of 
diazepam’s anticonvulsant activity.  As a result of extensive first-pass metabolism, the 
unchanged diazepam in the urine is only 1–3%.12  The initial distribution phase is followed 
by a prolonged terminal elimination phase (half-life up to 48 hours).  The terminal 
elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours.  
Diazepam and its metabolites are excreted mainly in the urine, predominantly as their 
glucuronide conjugates.  The clearance of diazepam is 20 to 30 mL/min in young adults.  
2.3. Benefit/Risk Assessment 
Neurontin® and diazepam are not expected to provide any clinical benefit to healthy 
participants in this study.  This study is designed to assess the effect of Neurontin® compared 
to diazepam when taken orally in healthy non-dependent recreational drug abusers on the 
pharmacokinetics of each drug and the potential for abuse.  
More detailed information about the known and expected benefits and risks and expected 
adverse events (AEs) of gabapentin and diazepam may be found in the single reference safety 
document (SRSD) for this study.  The SRSDs for gabapentin and diazepam are their 
respective United States Package Inserts (USPI).10,11 


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3. OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary:  
Primary:  
x 
To assess the potential abuse liability of orally 
administered Neurontin® taken alone 
compared to placebo in a healthy non-drug 
dependent participants with drug abuse 
experience under fasted condition. 
x 
Bipolar visual analog scale (VAS) for “Drug 
Liking” maximum effect (Emax). 
Secondary:  
Secondary:  
x 
To evaluate additional pharmacodynamic (PD) 
effect, pharmacokinetics (PK), and safety of 
Neurontin® or diazepam taken alone in a 
healthy non-drug dependent participants with 
drug abuse experience under fasted condition. 
PD endpoints: 
x 
Bipolar VAS for “Drug Liking” (Time for Emax 
[TEmax], area under the effect-time profile from 
time 0 to the time of the last quantifiable 
concentration [AUEClast], and partial AUECs 
[AUEC1, AUEC2, AUEC3, AUEC4, AUEC8]). 
x 
Unipolar VAS for “High” (Emax, TEmax, 
AUEClast, and partial AUECs [AUEC1, AUEC2, 
AUEC3, AUEC4, AUEC8]). 
x 
Bipolar VAS for “Take Drug Again” at 24, 36, 
48, and 72 hour post-dose. 
x 
Bipolar VAS for “Overall Drug Liking” at 24, 
36, 48, and 72 hours post-dose. 
x 
Unipolar VAS for “Good Drug Effect”. 
x 
Unipolar VAS for “Bad Drug Effect”.  
x 
Unipolar VAS for “Any Drug Effect”.  
x 
Observer-rated assessment of alertness/sedation. 
PK endpoints: 
x 
Cmax, time for Cmax (Tmax), area under the 
effect-time profile from time 0 to the time of the 
last quantifiable concentration (AUClast) of 
gabapentin and, if deemed necessary for 
diazepam and its active metabolite 
(N-desmethyldiazepam).  
x 
Area under the plasma concentration-time 
profile from time 0 extrapolated to infinity time 
(AUCinf), and terminal half-life (t½), if data 
permits, of gabapentin and, if deemed necessary 


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Objectives 
Endpoints 
for diazepam and its active metabolite 
(N-desmethyldiazepam).  
x 
Partial AUCs (AUC1, AUC2, AUC3, AUC4, and 
AUC8) of gabapentin and, if deemed necessary 
for diazepam and its active metabolite 
(N-desmethyldiazepam).  
Safety endpoints: 
x 
Vital signs (respiratory rate [RR], blood pressure 
[BP], pulse rate [PR]). 
x 
Oxygen saturation of hemoglobin (SpO2). 
x 
Physical examination. 
x 
12-lead electrocardiogram (ECG). 
x 
Clinical lab and AEs. 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
x 
Exposure-response relationship between drug 
(gabapentin or diazepam) concentrations and 
selected PD effect. 
x 
To enable exploratory research through 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision.   
x 
Correlation between drug (gabapentin or 
diazepam) concentrations and selected PD 
endpoints (Bipolar VAS for “Drug Liking”, 
Unipolar VAS for “High”), as data permit.  
x 
Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study). 
4. STUDY DESIGN 
4.1. Overall Design 
This will be a multi-center, randomized, double-blind, double-dummy, placebo- and 
active-controlled, 5-treatment, 10-sequence, 5-period crossover single-dose, Williams square 
design study in healthy adult, non drug-dependent male and female participants with drug 
abuse experience with sedative drugs.  The study includes Screening, a Qualification Phase, a 
Treatment Phase and Follow-up.  This study will randomize approximately 50 participants to 
ensure at least 32 participants meeting the definition of the Modified Completer Population 
complete the Treatment Phase of the study.  Dropouts in the treatment phase for non-safety 
reasons may be replaced at the discretion of investigator in consultation with the sponsor.   
The following study visits are required, see Figure 1 and the SoA (Table 1 and Table 2): 
x Visit 1, Screening will occur within 28 days prior to Visit 2. 


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x Visit 2, Qualification Phase will require inpatient stay at the clinical research unit 
(CRU) for 3 nights: 
x Naloxone Challenge Phase, Day -1. 
x Drug Discrimination, Days 1 and 2 will require inpatient stay at the CRU for 
2 nights. 
x End of Drug Discrimination requires an inpatient stay at the CRU overnight to 
ensure discharge occurs 24 hours after receiving diazepam or placebo.  
x Participant will proceed to Visit 3 after at least 14 and no more than 28-day 
washout.  
x Visits 3 to 7, Treatment Phase: 
x Each visit will require an inpatient stay at the CRU of 3 or 4 nights. Subjects may 
be discharged after completion of 48 h postdose assessments and return for 72 h 
postdose assessments on an ambulatory basis, at the discretion of the investigator. 
x Each visit will be separated by a washout period of at least 14 days. 
x End of Study Assessments will be at the CRU 72 hours after completing the last 
study drug dosing at the end of period 5 or at the time of early withdrawal. 
x For the entire study, 18 - 23 overnight inpatient stays will be required. 
4.1.1. Screening 
As shown in the SoA (Table 1), all participants will complete a Screening Visit with a 
standard medical screening to determine eligibility for this study.  This visit (Visit 1) will 
occur within 28 days of the Qualification Phase of the study (Visit 2).  
4.1.2. Qualification Phase (Visit 2; Days -1 to 3) 
4.1.2.1. Naloxone Challenge (Day -1) 
As shown in the SoA (Table 1), eligible participants who successfully complete the 
Screening Visit will return to the study center to complete the naloxone challenge.  The 
naloxone challenge (Day -1) will be performed to ensure the participant is not physically 
dependent on opioids. 
During the Naloxone Challenge, all participants will receive intravenous (IV) naloxone 
0.2 mg dose as an IV bolus, followed by an assessment for signs of opioid withdrawal.  If 
there are no signs of opioid withdrawal within 30 seconds after administration, a second dose 
of 0.6 mg IV will be administered within 5 minutes of the first dose, followed by another 
assessment for signs of opioid withdrawal 5 minutes after the second naloxone dose.  Only 
participants who do not have signs and symptoms of opioid withdrawal, as assessed by the 


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Clinical Opioid Withdrawal Scale (COWS score <5), [Appendix 8] will be eligible to 
proceed to the Drug Discrimination Phase. 
Any participant demonstrating evidence of withdrawal (COWS score ≥5) on any assessment 
will not be eligible for further participation in the trial.  The participant will be released from 
the study center when medically stable, as determined by the investigator.  Symptoms 
reported in the COWS as a consequence of opioid withdrawal will not be collected as AEs 
unless they meet the criteria for a new AE or serious adverse event (SAE). 
4.1.2.2. Instrument Training 
After successful completion of the Naloxone challenge, all eligible participants will undergo 
training on proper completion of the VAS instrument used to collect the PD endpoints.  This 
will be done to ensure that participants fully understand how to perform the test, that they 
feel comfortable with the testing methods used for PD assessment and have attained a stable 
level of performance on the various performance-based measures.  Detailed instructions for 
participant training will be provided in a separate study specific document. 
4.1.2.3. Drug Discrimination (Days 1 to 3) 
Following completion of the instrument training, the eligible participants will be evaluated for 
drug discrimination.  The purpose of this phase is to select participants who can discriminate 
between the subjective effects of diazepam 20 mg and placebo when administered orally. 
The drug discrimination will be performed over 2 consecutive days.  The treatments will be 
double blind.  The participants will be randomly assigned to receive one of the blinded 
treatments (diazepam 20 mg or placebo) on the first day and then receive the alternate 
treatment the next day according to a Williams square design (Table 3). 
Table 3. 
Schema for Qualification Phase 
Treatment Periods 1 and 2 
Day 1 
Day 2 
A 
B 
B 
A 
Treatment A: diazepam 20 mg. 
Treatment B: placebo. 
Pharmacodynamic (VAS) and safety assessments (vital signs, pulse oximetry and respiratory 
rate) will be conducted at pre-dose and up to 5 hours post dosing.  Continuing eligibility will 
be based on the participant’s ability to: 
x Assess “Drug Liking” using the bipolar VAS of 0-100 such that the administration of 
placebo produces a score between 40-60 points;  
x Have a diazepam VAS score outside of the placebo range of at least 15 points; 
x Tolerate study treatments safely; ie, SpO2 ≥90%, no episodes of vomiting within the 
first 2 hours post-dose; 


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x Demonstrate general behavior suggestive that the participant could successfully 
complete the study, as judged by the study center staff.  
Only those participants who produce these results may be enrolled in the study.  
Participants will be discharged from the clinic on Day 3 of the drug discrimination phase, 
approximately 24 hours after the last dose of either diazepam or placebo. 
Following completion of Day 2 procedures, the study data for each participant will be 
unblinded and a determination will be made by the sponsor and investigator (and/or 
designee) if the participant is eligible to continue in the study. 
4.1.3. Treatment Phase (Visits 3 to 7) 
As shown in the SoA (Table 2), participants who successfully complete the Naloxone 
Challenge and the Drug Discrimination Phase and who meet all the Randomization Criteria 
will be randomized into the Treatment Phase of this randomized, double-blinded, 
placebo- and active-controlled, crossover study. 
On Day 1 of each of the 5 periods, which will be separated by a washout of at least 14 days, 
participants will receive an oral dose of either gabapentin 600 mg, 1200 mg or 1800 mg or 
20 mg dose of diazepam or placebo.  Study treatments will be administered under fasted 
conditions (overnight fast and no food until 4 hours after dosing).  Water will be allowed 
without restriction until 1 hour prior to dosing and 1 hour after dosing. 
Physiological and subjective scales will be used to assess the potential for abuse of 3 doses of 
gabapentin compared to single dose of diazepam monotherapy and placebo.  The blood 
samples for the analysis of gabapentin and diazepam (including its major active metabolite: 
N-desmethyldiazepam) in plasma will be obtained pre-dose (immediately prior to dosing) 
and post-dose as outlined in the SoA (Table 2).  Vital signs including pulse rate (PR), blood 
pressure (BP), respiratory rate (RR), and pulse oximetry will be evaluated, and tolerability 
and safety will be assessed for all treatments by monitoring AEs. 
4.2. Scientific Rationale for Study Design 
There is a need to systematically evaluate the abuse potential of gabapentin with comparison 
to placebo and a positive control (such as diazepam), investigating a range of gabapentin 
dose (the highest therapeutic and supra-therapeutic) in a healthy non-drug dependent 
population with sedative drug abuse experience.  Therefore, the study design will employ a 
10-sequence, 5-period, cross-over design which will include the placebo, positive control, 
and three doses of gabapentin alone to allow for the various comparisons to be systematically 
evaluated.  The washout period will be least 14 days minimizing the carry-over effects of the 
treatments.  PK will be evaluated to allow for an exploratory correlation of 
pharmacodynamic effects.  
Banked biospecimens will be collected for exploratory 
pharmacogenomic/genomic/biomarker analyses and retained in the Biospecimen Banking 
System (BBS), which makes it possible to better understand the investigational product’s 


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mechanism of action and to seek explanations for differences in, for example, exposure, 
tolerability, safety, and/or efficacy not anticipated prior to the beginning of the study. 
4.3. Justification for Dose 
The highest therapeutic single dose of Neurontin® in adults for postherpetic neuralgia is 
600 mg, 3 times a day (TID) (1800 mg/day).  Doses above 1800 mg/day did not demonstrate 
additional clinical benefit.  The recommended maintenance dose of Neurontin® for epilepsy 
is between 300 mg to 600 mg, TID.  Therefore, three doses of Neurontin®, 600 mg (highest 
therapeutic single dose), 1200 mg (2 times of the highest therapeutic single dose), 1800 mg 
(3 times of the highest therapeutic single dose) were selected to adequately explore a range of 
doses to determine the abuse potential of Neurontin® when administered orally alone and 
diazepam monotherapy in this study.   
The prescribing dose of diazepam in the management of anxiety disorders and relief of 
symptoms of anxiety is 2 mg to 10 mg, 2 to 4 times daily upon severity of symptoms.  
According to the literature,13-15 studies using recreational sedative users have obtained 
significant results with doses of diazepam ranging from 10 to 40 mg.  Diazepam showed 
dose-dependent increases in participant- and observer-rated sedation and drug liking within 
the range (eg, 10 mg, 20 mg, and 40 mg).  A single dose of diazepam 20 mg produced 
significant positive subjective effects compared to the placebo group in human abuse 
potential studies.  In the previous Pfizer human abuse potential study (Pregabalin clinical 
study 1008-09816), a single dose of diazepam 15 mg or 30 mg in a cross-over design was 
given in a moderately heavy sedative/alcohol-using population and produced positive 
psychoactive effects indicative of abuse potential.  Thus, a single dose of diazepam 20 mg 
was selected as a positive control for this study. 
Neurontin® formulations are available in capsule, tablet, and oral solution.  The marketed 
Diazepam formulations are also available in tablet and oral solution.    
4.4. End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the study.  
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a participant is suitable for this protocol.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


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5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age and Sex: 
1. Male and female participants must be 18 to 65 years of age, inclusive, at the time of 
screening.  
2. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Type of Participant and Disease Characteristics: 
3. Male and female participants who are overtly healthy.  Healthy is defined as no 
clinically relevant abnormalities identified by a detailed medical history, complete 
physical examination, vital signs, 12-lead electrocardiogram (ECG), and/or clinical 
laboratory tests.  
4. Participants must be recreational sedative users, defined as those reporting using a 
sedative agent (eg, barbiturates, benzodiazepines) for its intoxicating effects on at 
least 10 lifetime occasions and at least once in the 12 weeks before the Screening 
Visit (Visit 1), but who have no signs of dependence and are not seeking treatment for 
their sedative use.  
5. Participants must satisfactorily complete both the Naloxone Challenge and the Drug 
Discrimination phases. 
6. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
Weight: 
7. Body mass index (BMI) of 17.5 to 34 kg/m2, inclusive; and a total body weight 
>50 kg (110 lb).  
Informed Consent: 
8. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol. 


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5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Participants with current or past diagnosis of any type of drug dependence within 
the past year.  Diagnosis of substance and/or alcohol dependence (excluding 
caffeine and nicotine) will be assessed by the Investigator using the Diagnostic 
and Statistical Manual of Mental Disorders IV (DSM-IV) criteria performed at 
Screening.  Current drug use will be allowed if the candidate can produce a 
negative urine sample and are free of any signs/symptoms of withdrawal.  The 
candidate will be informed if they have a positive breathalyzer test. 
2. Participants are heavy smokers or users of other types of nicotine products (>20 
cigarettes equivalents per day) 
3. Participants are unable to abstain from smoking for at least 2 hours before and at 
least 8 hours after study drug administration.   
4. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
5. Participants with any history of sleep apnea, myasthenia or glaucoma. 
6. Any condition possibly affecting drug absorption (eg, gastrectomy) excluding 
cholecystectomy within 1 year prior to study. 
7. Clinical or laboratory evidence of active hepatitis A infection or a history of 
human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C, and/or 
positive testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb), or hepatitis C antibody (HCVAb).  
8. Participants with active suicidal ideation or suicidal behavior within 5 year prior 
to Screening as determined through the use of the Columbia-Suicide Severity 
Rating Scale (C-SSRS) or active ideation identified at Screening or on Day -1.  
9. Other acute or chronic medical or psychiatric condition including recent (within 
the past year) or active suicidal ideation or behavior or laboratory abnormality 
that may increase the risk associated with study participation or investigational 
product administration or may interfere with the interpretation of study results 
and, in the judgment of the investigator, would make the participant inappropriate 
for entry into this study. 
 


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Prior/Concomitant Therapy: 
10. Use of prescription or nonprescription drugs and dietary supplements within 
7 days or 5 half-lives (whichever is longer) prior to the first dose of 
investigational product.  (Refer to Section 6.5 for additional details). 
11. Herbal supplements and herbal medications must be discontinued at least 28 days 
prior to the first dose of study medication. 
Prior/Concurrent Clinical Study Experience: 
12. Previous administration with an investigational drug within 30 days (or as 
determined by the local requirement) or 5 half-lives (whichever is longer) 
preceding the first dose of investigational product used in this study. 
Diagnostic Assessments: 
13. Positive urine drug screen (UDS) for substances of abuse at each admission in 
Qualification and Treatment Phase, excluding tetrahydrocannabinol (THC). If a 
participant presents with a positive UDS excluding THC at any admission or any 
visit, the investigator, at his/her discretion, may reschedule a repeat UDS until the 
UDS is negative, excluding THC, before the participant is permitted to participate 
in any phase of the study.  
14. Participants unable to abstain from using THC during the inpatient stays in the 
Qualification and Treatment Phases of the study. 
15. Has participated in, is currently participating in, or is seeking treatment for 
substance-and/or alcohol-related disorders (excluding nicotine and caffeine). 
16. Has a positive alcohol breathalyzer test at Screening or upon admission to the 
study center at Visits 2-6.  Positive results may be repeated and/or participants 
re-scheduled at the Investigator’s discretions.  
17. Screening sitting BP t140 mm Hg (systolic) or t90 mm Hg (diastolic), following 
at least 5 minutes of rest.  If BP is t140 mm Hg (systolic) or t90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.  Repeated BP tests 
should be spaced at least 5 minutes apart. 
18. Baseline (screening) 12-lead electrocardiogram (ECG) that demonstrates 
clinically relevant abnormalities that may affect participant safety or 
interpretation of study results (eg, baseline corrected QT (QTc) interval >450 
msec, complete left bundle branch block [LBBB], signs of an acute or 
indeterminate-age myocardial infarction, ST-T interval changes suggestive of 
myocardial ischemia, second- or third-degree atrioventricular [AV] block, or 
serious bradyarrhythmias or tachyarrhythmias).  If the baseline uncorrected QT 


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interval is >450 msec, this interval should be rate-corrected using the Fridericia 
method and the resulting QTcF should be used for decision making and reporting.  
If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 
2 more times and the average of the 3 QTc or QRS values should be used to 
determine the participant’s eligibility.  Computer-interpreted ECGs should be 
overread by a physician experienced in reading ECGs before excluding 
participants. 
19. Participants with ANY of the following abnormalities in clinical laboratory tests 
at screening, as assessed by the study-specific laboratory and confirmed by a 
single repeat test, if deemed to be clinically significant in the opinion of the 
investigator: 
x Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
t1.5 × upper limit of normal (ULN); 
x Total bilirubin level t1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this 
study provided the direct bilirubin level is d ULN. 
Other Exclusions: 
20. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) 
or more within 60 days prior to dosing. 
21. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
22. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
23. History of hypersensitivity to gabapentin or diazepam or any of the components in 
the formulation of the study products. 
24. Investigator site staff members directly involved in the conduct of the study and 
their family members, site staff members otherwise supervised by the 
investigator, or Sponsor  employees, including their family members, directly 
involved in the conduct of the study.  
5.3. Lifestyle Considerations 
The following guidelines are provided: 
5.3.1. Meals and Dietary Restrictions 
x Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the 
pre-dose PK sample for fasted treatment. 


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x Water is permitted until 1 hour prior to investigational product administration.  Water 
may be consumed without restriction beginning 1 hour after dosing.  Noncaffeinated 
drinks (except grapefruit or grapefruit-related citrus fruit juices-see below) may be 
consumed with meals and the evening snack. 
x Lunch will be provided approximately 4 hours after dosing. 
x Dinner will be provided approximately 9 to 10 hours after dosing. 
x An evening snack may be permitted. 
x Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of investigational product until collection of the final PK blood sample. 
x While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein.  The daily caloric intake 
per participant should not exceed approximately 3200 kcal. 
5.3.2. Caffeine, Alcohol, and Tobacco 
x Participants will abstain from caffeinecontaining products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 
x Participants will abstain from alcohol for 24 hours prior to admission to the clinical 
research unit (CRU) and continue abstaining from alcohol until collection of the final 
PK sample of each study period.  Participants may undergo an alcohol breath test or 
blood alcohol test at the discretion of the investigator. 
x Participants will not be permitted to smoke from at least 2 hours before until at least 
8 hours after dosing in the Qualification and Treatment Phases. At all other times 
while housed in the study center, smoking may be permitted in short breaks at the 
study center staff’s discretion.  The use of oral or chewed tobacco and/or nicotine-
containing products (including topical patches) is not permitted from at least 2 hours 
before and at least 8 hours after study drug administration. 
5.3.3. Activity 
x Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted. 
5.3.4. Contraception  
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed in its 


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consistent and correct use.  At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use effective contraception 
consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart (participants need to affirm their consistent and correct use of at least 1 
of the selected methods of contraception).  In addition, the investigator or designee will 
instruct the participant to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the participant or partner. 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the Qualification Phase.  Screen failure data are collected and 
remain as source and are not reported to the clinical database. 
6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention. 
6.1. Study Interventions Administered 
For this study, the investigational products are Neurontin® and diazepam.  
Neurontin® and diazepam will be provided by Viatris Specialty LLC. 
6.1.1. Administration 
Following an overnight fast of at least 10 hours, participants will receive investigational 
product at approximately 08:00 hours (±2 hours).  Detailed instructions on preparation of all 
study treatments, including steps to maintain the double blind, will be provided separately in 
Drug Administration Instructions (DAI).  
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for ECG measurements), eating, and 
drinking beverages other than water during the first 4 hours after dosing.  Water may only be 
consumed 1 hour following dosing.   
6.2. Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments.  


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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  All study 
interventions will be accounted for using an investigational product accountability 
form/record. 
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the investigational product (IP) manual. 
5. Any storage conditions stated in the single reference safety document (SRSD) will be 
superseded by the storage conditions stated on the product label.  
6. Study interventions should be stored in their original containers and in accordance 
with the labels.  
7. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Sponsor  upon discovery.  The site should actively 
pursue options for returning the study intervention to the storage conditions described 
in the labeling, as soon as possible.  Once an excursion is identified, the study 
intervention must be quarantined and not used until Sponsor  provides permission to 
use the study intervention.  It will not be considered a protocol deviation if Sponsor  
approves the use of the study intervention after the temperature excursion.  Use of the 
study intervention prior to Sponsor  approval will be considered a protocol deviation.  
Specific details regarding the definition of an excursion and information the site 
should report for each excursion will be provided to the site in the IP manual. 
8. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Sponsor , and all destruction must be adequately 
documented. 
6.2.1. Preparation and Dispensing 
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the participant/caregiver 


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by qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider, participant, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities. 
Investigational products will be prepared at the CRU in the individual dosing containers by 
2 operators, at least 1 of whom is an appropriately qualified and experienced member of the 
study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist).  The investigational products will be provided in 
appropriate containers and labeled in accordance with Sponsor  regulations and the clinical 
site’s labeling requirements.   
6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Allocation to Investigational Product 
At screening, participants will be assigned a subject screening identification number 
(SSID)via an automated Interactive Response Technology (IRT)  or equivalent system. 
Following screening the participants will be randomly assigned a qualification randomization 
number (QRN) via the IRT or equivalent system using a 1:1 randomization.  
The QRN will be retained throughout the study and will correspond to the blinded 
qualification phase. 
 
After satisfactory completion of the qualification phase, participants will randomly be 
assigned a study randomization number (SRN) via the IRT or equivalent system using a 1:1 
randomization for the treatment phase. The SRN will be retained throughout the study and 
will correspond to the blinded treatment sequence. 
. 
6.3.2. Breaking the Blind 
The investigator site, study monitor(s), and Sponsor  personnel will be blinded to study 
treatment.  The site will have an unblinded pharmacist for preparation of the study drugs.  
The unblinded pharmacist or unblinded designee at the study center will be responsible for 
ensuring blinding procedure oversight at the study center, according to the study center 
guidelines.  The unblinded pharmacist will not be able to perform any other duties for this 
study outside of the requirements of ensuring the blind.  
At the completion of the Drug Discrimination Phase, the investigator and/or designee will 
un-blind the subject’s treatment sequence in order for the investigator and Sponsor  personnel 
to assess participant eligibility to continue to the Treatment Phase of the study.  Additional 
information regarding the criteria for Drug Discrimination can be found in Section 4.1.2.3.  
Treatment data during the Treatment Phase of the study will remain blinded throughout the 
course of treatment until the study database has been locked.  Unblinding during the 
Treatment Phase will not occur unless medically necessary for participant safety. 


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The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted.  Participant safety must always be the first consideration 
in making such a determination.  If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor or medical monitor prior to 
unblinding a participant’s treatment assignment unless this could delay further management 
of the participant.  If a participant’s treatment assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and data collection tool (DCT). 
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.  
6.4. Study Intervention Compliance 
Investigational product will be administered under the supervision of investigator site 
personnel.  The oral cavity of each participant will be examined following dosing to ensure 
the investigational product was taken. 
6.5. Concomitant Therapy 
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of 
investigational product.  Limited use of nonprescription medications that are not believed to 
affect participant safety or the overall results of the study may be permitted on a case-by-case 
basis following approval by the sponsor.   
Females using hormonal contraceptives or taking hormone replacement therapy are eligible 
to participate in this study.  
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All participants will be questioned about 
concomitant treatment at each clinic visit. 
Treatments taken within 28 days before the first dose of investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of investigational 
product will be documented as concomitant treatments. 
6.6. Dose Modification 
Dose modification will not be allowed in this single dose study. 
6.7. Emergency Intervention 
x The investigational site shall have a fully equipped “crash cart” and advanced cardiac 
life support (ACLS) certified staff present during the entire study. 
x Acute gabapentin and/or diazepam toxicity can be manifested as drowsiness, 
respiratory depression, and somnolence progressing to stupor, coma or death.  In the 


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event that acute gabapentin and/or diazepam toxicity occurs, primary attention shall 
be given to re-establishment and/or maintenance of an open airway including assisted 
or controlled ventilation.   
x Other supportive measures including the use of oxygen and vasopressors should be 
employed in the standard management of circulatory shock if it occurs in the event of 
gabapentin and/or diazepam toxicity, or other/further treatments as appropriate. 
6.8. Intervention After the End of the Study 
No intervention will be provided to study participants at the end of the study. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue 
investigational product.  If investigational product is permanently discontinued, the 
participant will not remain in the study.  See the SoA for data to be collected at the time of 
discontinuation of investigational product. 
ECG Changes  
If the ECG of a participant meets the bulleted criteria below, then 2 more ECGs will be 
performed.  If the average of the three ECGs meets the bulleted criteria below, the participant 
is to be withdrawn from the study.  
x QTc, corrected QT using Bazett’s method (QTcB), corrected QT using Fridericia’s 
method (QTcF) >500 msec. 
x Change from baseline: QTc >60 msec. 
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed.  This review of the ECG printed at the time of collection must be documented.  Any 
new clinically relevant finding should be reported as an AE. 
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed. 
Potential Cases of Acute Kidney Injury 
Abnormal values in serum creatinine (SCr) concurrent with presence or absence of increase 
in blood urea nitrogen (BUN) that meet the criteria below, in the absence of other causes of 
kidney injury, are considered potential cases of acute kidney injury and should be considered 
important medical events.  


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An increase of ≥0.3 mg/dL (or ≥26.5 Pmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness. 
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 Pmol/L] in SCr 
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 Pmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury. 
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result.  This evaluation should include laboratory tests, detailed history, and physical 
assessment.  In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices.  All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr.  If ≥2 healthy participants in a given period are noted to have 2 consecutive 
SCr results of ≥0.3 mg/dL (or ≥26.5 Pmol/L), an assessment of whether the finding may be 
considered an adverse drug reaction should be undertaken. 
Pregnancy 
In the case of a positive confirmed pregnancy, the participant will be withdrawn from the 
study. 
7.2. Participant Discontinuation/Withdrawal from the Study  
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.  
The early discontinuation visit applies only to participants who are randomized and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  The participant will be permanently discontinued both from the study 
intervention and from the study at that time. 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already generated from the samples will continue to be available and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records. 


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If the participant withdraws from the study and withdraws consent (see below) for disclosure 
of future information, no further evaluations should be performed, and no additional data 
should be collected.  The sponsor may retain and continue to use any data collected before 
such withdrawal of consent. 
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial (CT) SAE Report. 
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved. 
Withdrawal of Consent:  
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page.  
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law. 
7.3. Lost to Follow up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study; 
x Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record; 
x Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1. 
8. STUDY ASSESSMENTS AND PROCEDURES 
Participants will be screened within 28 days prior of the Qualification Phase to confirm that 
they meet the study population criteria for the study.  The investigator (or an appropriate 
delegate at the investigator site) must obtain a signed and dated ICD before performing any 
study-specific procedures.  If the time between screening and dosing exceeds 28 days as a 
result of unexpected delays (eg, delayed drug shipment), then participants do not require 
rescreening if the laboratory results obtained prior to first dose administration meet eligibility 
criteria. 
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study.  In 
addition, other clinical assessments or specimen collections, eg, banked biospecimens, may 
be used without repeat collection, as appropriate.  
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner. 
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter. 


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For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
The total blood sampling volume for individual participants in this study is approximately 
479 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Sponsor, provided the 
total volume taken during the study does not exceed 550 mL during any period of 
60 consecutive days. 
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol. 
8.1. Efficacy Assessments (Not applicable) 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns. 
8.2.1. Physical Examinations 
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems.  
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.  
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  
Height and weight will also be measured and recorded as per the SoA.  For measuring 
weight, a scale with appropriate range and resolution is used and must be placed on a stable, 
flat surface.  Participants must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains.  They must also remove the contents of their pockets and remain 
still during measurement of weight.  
8.2.2. Vital Signs 
Sitting BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) should be used throughout the study.  Participants should be 
instructed not to speak during measurements. 
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP is acceptable.  Pulse rate and oxygen saturation 
will be measured with a pulse oximeter.  When the timing of these measurements coincides 


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with a blood collection, BP, pulse oximetry and respiratory rate should be obtained prior to 
the nominal time of the blood collection.  
Pulse and respiratory rates, oxygen saturation, diastolic and systolic blood pressure will be 
monitored post-drug (See SoA).  These measures are done in abuse liability testing to ensure 
safety. 
Additional collection times, or changes to collection times, of BP, pulse oximetry and 
respiratory rates will be permitted, as necessary, to ensure appropriate collection of safety 
data. 
If the participant develops orthostatic hypotension, the procedure for collecting postural or 
orthostatic data will be: 
x Assess BP after the participant is in the supine position for a minimum of 5 minutes; 
x Have the participant stand up for 2 minutes; 
x Assess BP after the participant is in the standing position for approximately 
2 minutes. 
Orthostatic hypotension is defined as a decrease of ≥20 mm Hg for systolic BP or 
≥10 mm Hg for diastolic BP 2 minutes after standing from a supine position.  Orthostatic 
hypotension may be symptomatic or asymptomatic.  Symptoms of orthostatic hypotension 
are those that develop upon assuming the erect posture from a supine position and may 
include: lightheadedness, dizziness, blurred vision, weakness, fatigue, cognitive impairment, 
nausea, palpitations, tremulousness, headache, and/or neck ache. 
If a participant has symptoms suggestive of orthostasis, but not documented orthostatic 
hypotension, repeated measurements of supine/standing BP should be obtained.  Lesser 
degrees of BP reduction may still be considered clinically significant if the participant 
becomes symptomatic upon standing, especially in the presence of a significant increase in 
pulse rate (≥30 beats per minute [bpm]). 
8.2.2.1. Respiratory Monitoring 
Respiratory rate (RR, breaths/min), pulse oximetry, tidal volume (VT, mL) and end-tidal 
carbon dioxide (ETCO2, mmHg) will be measured continuously, pre-dose to 8 hours and 
then for 5 minutes at 12 hours and 24 hours post-dose during the Treatment Phase (see SoA). 
8.2.2.2. Temperature  
Temperature will be measured orally or with a temporal infrared scanner.  No eating, 
drinking, or smoking is allowed for 15 minutes prior to the oral measurement. 
8.2.3. Electrocardiograms 
Twelve (12)-lead ECGs should be collected at times specified in the SoA section of this 
protocol using an ECG machine that automatically calculates the heart rate and measures 


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pulse rate (PR), QT, and QTc intervals and QRS complex.  All scheduled ECGs should be 
performed after the participant has rested quietly for at least 10 minutes in a supine position.  
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  Additional ECG monitoring will occur if a) a 
post-dose QTc interval is increased by ≥30 msec from the baseline and is >450 msec; or 
b) an absolute QTc value is ≥500 msec for any scheduled ECG.  If either of these conditions 
occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to 
confirm the original measurement.  If the QTc values from these repeated ECGs remain 
above the threshold value, then a single ECG must be repeated at least hourly until QTc 
values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement. 
If a post-dose QTc interval remains t30 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, 
at the discretion of the investigator), or QTc intervals get progressively longer, the participant 
should undergo continuous ECG monitoring.  A cardiologist should be consulted if QTc 
intervals do not return to less than the criterion listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator).  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range. 
ECG values of potential clinical concern are listed in Appendix 7. 
8.2.3.1. Continuous Cardiac Monitoring by Telemetry 
Continuous cardiac monitoring will be performed as noted in the SoA. The time, duration, 
and description of any clinically significant abnormal rhythm will be reported as an adverse 
event. 
8.2.4. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 to 35 days after the last dose of study intervention 


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should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA. 
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF. 
Participants may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for participants to receive 
investigational product.  
8.2.5. Suicidal Ideation and Behavior Risk Monitoring  
8.2.5.1. Columbia Suicidality Severity Rating Scale (C-SSRS) 
The Columbia Suicide-Severity Rating Scale (C-SSRS) will be collected at timepoints on the 
SoA.  The C-SSRS is being used in the current study to provide a summary measure of 
suicidal ideation and behavior risks.  This scale is to be completed by trained staff.  Training 
materials on the scale will be provided to investigator sites by Sponsor . 
8.2.5.2. Risk Assessment During Screening 
The Investigator will review the results of the C-SSRS (baseline), and medical history.  The 
following criteria would indicate a potential suicide risk: 
x Suicidal ideation associated with actual intent and/or method and/or plan and/or 
action (eg, selfharming behaviors) in the past year based on CSSRS assessment 
(“yes” answers on items 4 or 5 of the CSSRS).  
x Any previous history of suicide behaviors reported or documented within the past 
10 years. 
x For events that occurred within the past 5 years, an answer of “yes” to any of the 
suicidal behavior items of the CSSRS). 
x Investigator’s judgment. 
If any of these criteria are met and the participant is being considered for study participation, 
a risk assessment must be completed to determine whether it is appropriate for the participant 
to be enrolled. 


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Risk assessments should be done by a qualified mental health professional (MHP).  In the 
United States, a qualified MHP is a psychiatrist or a licensed PhD level clinical psychologist.  
In other countries a qualified MHP is a clinically-qualified professional with appropriate 
training in the assessment of suicide risk (according to the local clinical practice standards 
and regulations) and who would normally evaluate the risk for suicide for a participant. 
The MHP may be a member of the study site team.  If an MHP is not available within the 
study team, the Investigator should make the necessary referral. 
The Investigator must obtain and review the risk assessment prior to the participant being 
randomized.  A written copy of the risk assessment should be included in the participant’s 
clinical record (source documentation). 
8.2.5.3. Risk Assessment During the Study 
Beginning with Period 1, if there are any “yes” responses on items 4, 5 or on any behavioral 
question of the C-SSRS (since last visit), a risk assessment should be done by a qualified 
MHP to determine whether it is safe for the participant to continue to participate in the trial.  
Suicidal risk should be managed appropriately by the Investigator together with a qualified 
MHP (or the Investigator alone if the Investigator is a qualified MHP).  In addition, the 
Investigator should consult with the Sponsor  medical monitor to determine whether the 
participant can continue in the trial. 
A narrative should be prepared for participants who have undergone any post-baseline risk 
assessment, using information from the C-SSRS. 
8.2.6. Pregnancy Testing  
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in woman of childbearing potential 
(WOCBP) at the times listed in the SoA.  Following a negative pregnancy test result at 
screening, appropriate contraception must be commenced and a second negative pregnancy 
test result will be required at the baseline visit prior the participant’s receiving the study 
treatment.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during 
the active treatment period (or when potential pregnancy is otherwise suspected) and at the 
end of the study.  Pregnancy tests may also be repeated if requested by institutional review 
boards (IRBs)/ethics committees (ECs) or if required by local regulations.  If a urine test 
cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required.  In such cases, the participant must be excluded if the serum pregnancy result is 
positive. 
8.3. Adverse Events and Serious Adverse Events 
The definitions of an AE and an SAE can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 


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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7).  
Each participant will be questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days, except as indicated below, after the last administration of the 
investigational product. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form. 
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 


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SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety. 
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.  
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
8.3.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.  
Further information on follow-up procedures is given in Appendix 3. 
8.3.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 


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Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure 
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness. 
8.3.5.1. Exposure During Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 28 calendar days 
after the last administration of the investigational product. 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
An Exposure During Pregnancy (EDP) occurs if:  
x A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.  
x A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.  
x A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy:   
x A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention or by other possible routes of 
exposure, eg, ingestion or skin contact. 
x A male family member or healthcare provider who has been exposed to the study 
intervention or by other possible routes of exposure, eg, ingestion or skin contact 
then exposes his female partner prior to or around the time of conception.  
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred.  The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).  


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x If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred.  Details of the 
pregnancy will be collected after the start of study intervention and until 28 calendar 
days after the last administration of the investigational product. 
x If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form.  Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly [in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death]), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows:  
x Spontaneous abortion including miscarriage and missed abortion; 
x Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention.  
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 


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8.3.5.2. Exposure During Breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding. 
An exposure during breastfeeding occurs if: 
x A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
x A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure).  An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion or skin contact.   
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF.  However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file. 
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding. 
8.3.5.3. Occupational Exposure 
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care. 
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file. 


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8.3.6. Cardiovascular and Death Events 
Not applicable 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable 
8.3.8. Adverse Events of Special Interest 
Not applicable 
8.3.8.1. Lack of Efficacy 
Not applicable since this is an abuse liability study in healthy participants. 
8.3.9. Medical Device Deficiencies 
Not applicable 
8.3.10. Medication Errors 
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.   
Exposures to the investigational product under study may occur in clinical trial settings, such 
as medication errors. 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness 
Medication errors  All (regardless of whether 
associated with an AE) 
Only if associated with an SAE 
Medication errors include: 
x Medication errors involving participant exposure to the investigational product; 
x Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
In the event of a medication dosing error, the sponsor should be notified immediately. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 


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applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.4. Treatment of Overdose 
For this study, any dose of Neurontin® >1800 mg or diazepam >20 mg within a 24-hour time 
period will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
gabapentin and diazepam can no longer be detected systemically (at least 3 days). 
3. Obtain a blood sample for PK analysis within 3 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
5. Overdose is reportable to Safety only when associated with an SAE. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.5. Pharmacokinetics  
Blood samples of approximately 5 mL, to provide a total of approximately 2 mL of plasma 
volume, will be collected for measurement of plasma concentrations of gabapentin and 
diazepam as specified in the SoA.  Instructions for the collection and handling of biological 
samples will be provided in the laboratory manual or by the sponsor.  The actual date and 
time (24-hour clock time) of each sample will be recorded. 
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 5 
minutes or 10% of the nominal time (eg, within 6 minutes of a 60-minute sample), whichever 
is greater, relative to dosing will not be captured as a protocol deviation, as long as the exact 
time of the collection is noted on the source document and data collection tool (eg, CRF).  
Collection of samples more than 10 hours after dose administration that are obtained ≤1 hour 
away from the nominal time relative to dosing will not be captured as a protocol deviation, as 


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long as the exact time of the collection is noted on the source document and data collection 
tool (eg, CRF).  
Samples will be used to evaluate the PK of gabapentin and diazepam (including its major 
active metabolite, N-desmethyldiazepam).  Samples collected for analyses of gabapentin and 
diazepam plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, or for other internal exploratory purposes. 
Genetic analyses will not be performed on these plasma samples.  Participant confidentiality 
will be maintained. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment.  The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
8.6. Pharmacodynamics 
8.6.1. Subjective Effects 
The questionnaire described below is used in drug abuse as well as clinical efficacy and 
toxicity evaluation of pharmacologic agents, and its usefulness is widely accepted.  
Furthermore, previous results indicate that the instrument is sensitive, reliable, and valid. 
8.6.2. Visual Analog Scale (VAS)  
The VAS consists of horizontal 100-mm lines, each labeled with an adjective such as “Drug 
Liking” or “High”, etc.  Participants will be instructed to place a mark on each line indicating 
how they feel at the moment.  For example, measuring “Drug Liking” on the bipolar VAS, 
the participant will be asked: Do you like the drug effect you are feeling now?  The 
participant will then rate on the 0 to 100 scale, where: Strong disliking = 0; Neither like or 
Dislike = 50; and Strong Liking = 100.  Further information on follow-up procedures is given 
in Appendices 10 and 11. All VAS testing will be administered at the nominal time points 
±5 minutes for time points up to and including 4 h post-dose, within ±15 minutes for time 
points from 6-12 h post-dose, and within ±60 minutes for the remaining time points up to and 
including 72 h post-dose.  


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Primary Endpoints: 
x VAS for Drug Liking presented on a bipolar 0 to 100 scale. 
Secondary Endpoints: 
x VAS for High presented on a unipolar 0 to 100 scale. 
x VAS for Take Drug Again presented on a bipolar 0 to 100 scale. 
x VAS for Overall Drug Liking presented on a bipolar 0 to 100 scale. 
x VAS for Any Drug Effects, Good Effects, and Bad Effects presented on unipolar 0 to 
100 scales. 
Additional Secondary Endpoint: 
x Modified Observer's Assessment of Alertness/Sedation scale or comparable scale. 
8.7. Genetics 
8.7.1. Specified Genetics 
Specified genetics are not evaluated in this study. 
8.7.2. Banked Biospecimens for Genetics 
A 4-mL blood sample optimized for deoxyribonucleic acid (DNA) isolation Prep D1 will be 
collected as local regulations and IRBs/ECs allow.  
Banked biospecimens may be used for research related to drug response.  Genes and other 
analytes (eg, proteins, ribonucleic acid (RNA), nondrug metabolites) may be studied using 
the banked samples.  
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked biospecimens to also 
be used to design and conduct research in order to gain a further understanding of other 
diseases and to advance science, including development of other medicines for patients.  This 
component of the sampling banking is optional for participants; they may still participate in 
the study even if they do not agree to the additional research on their banked biospecimens.  
The optional additional research does not require the collection of any further samples.  
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in the Lab Manual. 
8.8. Biomarkers 
Biomarkers are not evaluated in this study. 


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8.9. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. STATISTICAL CONSIDERATIONS  
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment. 
Statistically, the study will be evaluated as a safety study.  Consequently, the null hypothesis 
for gabapentin will be constructed on the presumption that these treatments produce abuse 
potential similar to placebo.  To demonstrate that these treatments have no abuse potential 
the null hypothesis will be statistically rejected. 
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.   
9.1. Statistical Hypotheses 
To assess the abuse potential of gabapentin the following tests will be performed in the order 
they are given: 
Study Validation: 
The sensitivity and integrity of the study will be validated by comparing the mean responses 
of diazepam, the positive control (C), to the placebo (P):  
H0: μC - μP ≤ δ1 versus Ha: μC - μP > δ1 where δ1 =15. 
Gabapentin versus diazepam: 
1. Does gabapentin (T) produce mean responses that show less abuse potential than 
diazepam? 
H0: μC - μT ≤ δ2 versus Ha: μC - μT > δ2 where δ2 =0. 
Gabapentin versus placebo (Primary): 
2. Does gabapentin (T) produce mean responses that show abuse potential similar to 
placebo? 
H0: μT - μP ≥ δ3 versus Ha: μT - μP < δ3 where δ3 =11. 


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For each of the gabapentin hypotheses, the statistical significance of the test will be assessed 
for all doses of gabapentin. 
9.2. Sample Size Determination 
An 11-point VAS Emax “Drug Liking” difference between the treatment and the placebo is 
being selected as the cutoff for demonstrating abuse.  This criterion is clinically meaningful 
for oral drug discrimination and is within the range used by previous studies to assess 
potential abuse liability.17-20  This assumes no difference in Bipolar VAS for “Drug Liking” 
Emax for the comparison of gabapentin to placebo and a standard deviation of 18 points.  
Under these assumptions, 32 completed participants will provide at least 90% power for the 
comparison of gabapentin to placebo at the 1-sided significance level of 0.05.  This study 
will randomize approximately 50 participants to ensure at least 32 participants who meet the 
definition of the Modified Completer Population complete the Treatment Phase of the study. 
Among the 50 participants, at least 20% will be females to ensure that the findings are valid 
across different populations. 
9.3. Populations for Analysis  
The following populations are planned for this study: 
x The Safety Population will include all participants who receive at least one dose of 
study drug, beginning with the Naloxone Challenge.  This population will be 
analyzed as treated. 
x The PK population will include all enrolled participants treated who have at least 
1 concentration in the Treatment Phase.  The PK parameter analysis population will 
include all enrolled participants treated who have at least 1 of the PK parameters of 
interest. 
x The Completer Population will include all randomized participants who complete all 
5 periods of the Treatment Phase and who contribute post-dose PD data from each 
period.  These participants must have at least one post-dose response on the VAS for 
Drug Liking within 2 hours of Tmax for each treatment group: ie, at least one VAS 
response within the interval 0-3h postdose (assuming the Tmax of 20 mg diazepam is 
1h) and at least one VAS response within the interval 1-5h postdose (assuming the 
Tmax of 600/1200/1800 mg gabapentin is 3h).  This population will be analyzed as 
randomized. 
x The Modified Completer Population will include all randomized participants in the 
Completer Population, but will exclude any participant who meet either or both of the 
following criteria for Drug Liking VAS: 
1. Emax scores are within a 5 point difference across all five treatments (ie, 
Maximum Emax score – Minimum Emax score ≤5); 
2. Emax(P) > 60 AND Emax(P) - Emax(Dia) ≥5; 


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where Emax(P) and Emax(Dia) are the VAS Emax scores for placebo and diazepam 
20 mg, respectively. 
 This population will be analyzed as randomized. 
x The Evaluable Population will include all randomized participants in the Modified 
Completer Population who do not have major protocol violations or adverse events 
that would interfere with drug absorption such as vomiting within 4 hours of study 
drug administration.  Major protocol violations, including deviations related to study 
drug intake are defined as those that could potentially affect the PD conclusions of the 
study.  Prior to unblinding the Treatment Phase data, the sponsor (or designee) will 
identify protocol violations or adverse events that would disqualify a participant from 
the evaluable population and determine which participants or participant visits will be 
excluded.  This population will be analyzed as randomized. 
All PD analyses will be performed using the Modified Completer Population and all 
available post-dose data; these will be the primary PD analyses.  Key PD analyses may be 
repeated on the Evaluable Population using all available post-dose data. 
9.4. Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 
9.5. Interim Analyses 
No formal interim analysis will be conducted for this study. 
9.6. Endpoint Analysis 
The following parameters will be calculated for VAS for “Drug Liking” (primary endpoint)  
and VAS for “High” (secondary endpoint) during the Treatment Period: 
x Maximum (peak) effect (Emax); calculated as maximum change from pre-dose 
response if pre-dose assessment is performed; the neutral VAS point (50 for Drug 
liking, 0 for High) will be used as pre-dose response when VAS not performed or 
missing. 
x Time of maximum (peak) effect (TEmax); 
x Area under the effect curve to the last measurement (AUEClast); 
x Area under the effect curve to 1 hour (AUEC1); 
x Area under the effect curve to 2 hours (AUEC2); 


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x Area under the effect curve to 3 hours (AUEC3); 
x Area under the effect curve to 4 hours (AUEC4); 
x Area under the effect curve to 8 hours (AUEC8). 
The additional endpoints of VAS for “Overall Drug Liking”, “Take Drug Again”, “Good 
Drug Effect”, “Bad Drug Effect”, and “Any Drug Effect” and the observer-rated assessment 
of alertness/sedation will be summarized by timepoints. 
9.7. Study Validity Analysis of Endpoints 
Study validity will first be confirmed through the comparison of mean Emax for Drug Liking 
between diazepam 20 mg and placebo administered during the Treatment Phase.  This 
comparison will be made using a mixed-effect model with treatment, period, and sequence as 
fixed effects, and participant nested within the sequence as a random effect.  If the treatment 
comparison of diazepam 20 mg vs. placebo is statistically significant by a margin of 
15 (ie, one-sided p ≤0.05) in the appropriate direction, it will confirm the sensitivity of the 
study.  If study validity is not confirmed, comparisons between gabapentin and diazepam will 
not be performed. 
9.8. Analysis of Primary and Secondary Endpoints 
A linear mixed-effects model that includes site, period, sequence, and treatment as fixed 
effects, and the participant as a random effect will be used.  The primary analyses of abuse 
potential will be based on testing the differences between the means from the primary 
measure(s) at the peak of drug response effects (VAS Emax) produced by gabapentin, 
diazepam and placebo at a significance level of 0.05 (1-sided). 
The primary PD endpoint is the Emax of bipolar VAS for “Drug Liking”.  
The principal parameters for the primary and secondary endpoints will be summarized by 
treatment using descriptive statistics (mean, standard deviation [SD], median, first and third 
quartiles, minimum and maximum).  These parameters will be analyzed using a mixed-effect 
model with treatment, period, and sequence as fixed effects, and participant nested within the 
sequence as a random effect.  Analyses of endpoints with baseline (pre-dose) measurements 
will include the baseline measurement as a covariate in the model.  Least squares means, 
standard errors, and 90% confidence intervals will be provided for each treatment and for the 
difference between treatments.  Data will be summarized graphically, where appropriate. 
The treatment comparison to test for study validity will be: 
x diazepam 20 mg vs. placebo; (This comparison is used for validation of the study and 
adjustments for multiple comparisons will not be applied for this treatment 
comparison).  
Comparisons of gabapentin versus diazepam will be: 


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x gabapentin 600 mg vs. diazepam 20 mg;  
x gabapentin 1200 mg vs. diazepam 20 mg; 
x gabapentin 1800 mg vs. diazepam 20 mg.  
Comparisons of gabapentin versus placebo will be (Primary): 
x gabapentin 600 mg vs. placebo;  
x gabapentin 1200 mg vs. placebo;  
x gabapentin 1800 mg vs. placebo. 
Statistical significance of all treatment differences will be reported.  All statistical tests will 
be conducted using one tailed significance criteria.  These comparisons will be used to assess 
the primary study objective.  
Regression diagnostics will be performed to verify model assumptions and adequacy of the 
fitted linear models for the primary endpoints.  Levene’s test will be used to diagnose 
potential heterogeneity of variance and the Shapiro–Wilk test will be used to diagnose 
potential non-normality of the model residuals. 
If the resulting p-value from Levene’s test is ≤0.05, the null hypothesis of equal variances is 
rejected and it will be concluded that there is a difference between the treatment group 
variances.  An unequal variance model will then be applied using the Satterthwaite method in 
order to produce an accurate F-approximation. 
If the resulting p-value from the Shapiro-Wilk test is ≤0.05, symmetry of the distribution of 
paired differences will be tested using the Triples Test and either the t-test (symmetry) or 
sign test (asymmetry) will be performed. 
9.8.1. Pharmacodynamic Analysis 
PD parameter values that will be evaluated are listed in Table 4.  The pre-dose psychometric 
measurements of each period will be the baseline for calculating the changes in these 
parameters post dose.  Descriptive statistics for the changes from baseline will be reported by 
treatment and by hours postdose.  The changes from baseline will be analyzed with an 
analysis of variance (ANOVA) model consisting of: Site, Sequence, Site*Sequence, Period, 
Treatment, Time, Period*Time, Site*Treatment and Treatment*Time terms as fixed effects, 
and a participant (Site*Sequence) term as a random effect for testing Site, Sequence, and 
Site*sequence effect. Site*Treatment interaction will be evaluated and this interaction term 
will be dropped from the final model if it is not significant. To accommodate the repeated 
measures aspect of the design, a compound symmetric covariance matrix will be employed, 
with the participant set to Period*Participant (Sequence).  The Treatment*Time least-squares 
means and differences among them will be assessed for trends likely to be of clinical 
relevance. 


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Descriptive statistics of the mean, standard error, and other summary statistics such as 
minimum, first quartile (Q1), median, third quartile (Q3) and maximum for each subjective 
measure, each treatment and each paired difference among treatments will be calculated and 
used to create tables and graphs. 
As an exploratory analysis, the time course of the different subjective measures in relation to 
each other (and to abuse-related AEs) will evaluate the outcome of positive or negative 
assessments of the drug before, during and after the peak of drug effects.  The physiological 
effects such as pulse rate, blood pressure and respiratory rate will be monitored over the 
course of the study session and correlated to both the drug dose administered and the PK of 
the drug. 
9.8.2. Derivation of Pharmacodynamic Parameters  
PD parameters for VAS “Drug Liking” and “High” will be derived from the concentration-
time profiles as shown in Table 4. 
Table 4. 
Derivation of Pharmacodynamic Parameters 
Paramete
r 
Definition 
Method of Determination 
Emax 
Maximum effect 
Observed directly from data 
TEmax 
Time for Emax 
Observed directly from data 
as time of first occurrence 
AUEClast 
Area under the effect-time profile from time 0 to the time of 
the last quantifiable effect (Elast) 
Linear trapezoidal method 
AUEC1 
Area under the effect-time profile from time 0 to 1 hour 
postdose 
Linear trapezoidal method 
AUEC2 
Area under the effect-time profile from time 0 to 2 hour 
postdose 
Linear trapezoidal method 
AUEC3 
Area under the effect-time profile from time 0 to 3 hour 
postdose 
Linear trapezoidal method 
AUEC4 
Area under the effect-time profile from time 0 to 4 hour 
postdose 
Linear trapezoidal method 
AUEC8 
Area under the effect-time profile from time 0 to 8 hour 
postdose 
Linear trapezoidal method 
9.8.3. Pharmacokinetic Analysis 
Blood samples will be collected throughout a study session in order to assess drug PK.  
Samples from gabapentin treatment will be analyzed using a validated analytical method in 
compliance with Viatris standard operating procedures.  If deemed necessary, samples of 
placebo and diazepam (including its major active metabolite; N-desmethyldiazepam) will be 
analyzed.  This will be done to primarily confirm that plasma levels of the drug are 
equivalent between participants and to evaluate whether subjective measures and AEs can be 
correlated with drug levels over time.  Typically, blood will be drawn immediately after the 
collection of subjective measures are completed at each time point.  If an analysis shows that 
a participant had low plasma levels of a drug, it may account for a lack of subjective 
responses in a drug session.  


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9.8.3.1. Pharmacokinetic Parameters 
The PK parameter values for gabapentin and, if deemed necessary, for diazepam (including 
its major active metabolite as data permit: N-desmethyldiazepam) will be calculated for each 
non-placebo treatment and each participant using noncompartmental analysis of 
concentration-time data.  PK parameter values that will be evaluated are listed in Table 5. 
The PK parameters (AUCinf, AUClast, Cmax, tmax, t½, partial AUCs [AUC1, AUC2, AUC3, 
AUC4, AUC8]) will be derived for each participant/period/analyte and will be summarized by 
treatment and analyte.  Individual participant PK parameters, as well as summary statistics 
(eg, group averages, SD, geometric means, coefficient of variation [CV], and geometric 
CV%) by treatment will be reported for PK parameters, as appropriate.  Plasma 
concentration-time profiles of gabapentin, diazepam and its metabolite 
(N-desmethyldiazepam) will be presented.  Concentrations will be listed and summarized by 
PK sampling time and treatment for each analyte. 
9.8.3.2. Derivation of Pharmacokinetic Parameters  
PK parameters will be derived from the concentration-time profiles as shown in Table 5. 
Table 5. 
Derivation of Pharmacokinetic Parameters 
Parameter 
Definition 
Method of Determination 
Cmax 
Maximum plasma concentration 
Observed directly from data 
Tmax 
Time for Cmax 
Observed directly from data as 
time of first occurrence 
AUClast 
Area under the plasma concentration-time profile from 
time 0 to the time of the last quantifiable concentration 
(Clast) 
Linear/Log trapezoidal method 
AUCinfa 
Area under the plasma concentration-time profile from 
time 0 extrapolated to infinity time 
AUClast + (Clast*/kel), 
where Clast* is the predicted 
plasma concentration at the last 
quantifiable time point 
estimated from the log-linear 
regression analysis 
AUC1 
Area under the plasma concentration-time profile from 
time 0 to 1 hour postdose 
Linear/Log trapezoidal method 
AUC2 
Area under the plasma concentration-time profile from 
time 0 to 2 hour postdose 
Linear/Log trapezoidal method 
AUC3 
Area under the plasma concentration-time profile from 
time 0 to 3 hour postdose 
Linear/Log trapezoidal method 
AUC4 
Area under the plasma concentration-time profile from 
time 0 to 4 hour postdose 
Linear/Log trapezoidal method 
AUC8 
Area under the plasma concentration-time profile from 
time 0 to 8 hour postdose 
Linear/Log trapezoidal method 


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Table 5. 
Derivation of Pharmacokinetic Parameters 
Parameter 
Definition 
Method of Determination 
t½a  
Terminal elimination half-life  
Loge(2)/kel, 
where kel is the terminal phase 
rate constant calculated by a 
linear regression of the log-
linear concentration-time curve.  
Only those data points judged 
to describe the terminal log-
linear decline will be used in the 
regression 
a. 
If data permit. 
9.9. Efficacy Analyses 
An efficacy analysis is not applicable to this study.  
9.10. Safety Analyses 
All safety analyses will be performed on the safety population. 
The safety data will be described and summarized in accordance with the sponsor’s Data 
Standards. 
AEs, ECGs, BP, RR, PR, SpO2, continuous cardiac monitoring, and safety laboratory data 
will be reviewed and summarized on an ongoing basis during the study to evaluate the safety 
of participants.  Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential 
clinical concern will be described.  Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate. 
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported. 
9.10.1. Electrocardiogram Analyses 
Electrocardiogram results collected at Screening will be listed. 
9.11. Exploratory Analyses 
Exploratory analysis will be conducted to evaluate the correlation between drug (gabapentin 
or diazepam) concentrations and selected PD endpoints (Bipolar VAS for “Drug Liking” and 
Unipolar VAS for “High”), as data permit. 


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9.12. Data Monitoring Committee  
This study will not use a data monitoring committee (DMC). 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
x Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines; 
x Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines; 
x Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, USPIs, and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
x Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
x Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Sponsor  should be informed immediately.  


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In addition, the investigator will inform Sponsor  immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of. 
10.1.2. Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.3. Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study. 
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC 
or study center. 
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data.  
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD. 
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study. 


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A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative. 
A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 28 days from the previous ICD signature date. 
10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password protected to ensure that only authorized study staff have access.  The study 
site will implement appropriate technical and organizational measures to ensure that the 
personal data can be recovered in the event of disaster.  In the event of a potential personal 
data breach, the study site shall be responsible for determining whether a personal data 
breach has in fact occurred and, if so, providing breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.  
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred.  All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code.  The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity.  In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws. 
10.1.5. Dissemination of Clinical Study Data 
Viatris fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and other public registries in accordance with applicable local 
laws/regulations.  In addition, Viatris reports study results outside of the requirements of 
local laws/regulations pursuant to its standard operating procedures (SOPs). 
In all cases, study results are reported by Viatris in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
 


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www.clinicaltrials.gov 
Viatris posts clinical trial US Basic Results on www.clinicaltrials.gov for Viatris-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations. 
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated. 
EudraCT 
Viatris posts European Union (EU) Basic Results on EudraCT for all Viatris-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations. 
Documents within marketing authorization packages/submissions 
Viatris complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.  
Data Sharing 
Viatris provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Viatris will make available data from these trials 
12 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 


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10.1.6. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 


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with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
10.1.7. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available. 
Definition of what constitutes source data can be found in the Clinical Monitoring Plan. 
10.1.8. Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants. 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
x Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines; 
x Inadequate recruitment of participants by the investigator; 
x Discontinuation of further study intervention development. 
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.9. Publication Policy 
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first.  


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The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Viatris-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results. 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by 
agreement. 
Authorship of publications for the overall study results will be determined by agreement and 
in line with International Committee of Medical Journal Editors authorship requirements.  
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply. 
10.1.10. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the team SharePoint site.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.   


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests (Table 6) will be performed at times defined in the SoA 
section of this protocol.  Additional laboratory results may be reported on these samples as a 
result of the method of analysis or the type of analyzer used by the clinical laboratory; or as 
derived from calculated values.  These additional tests would not require additional 
collection of blood.  Unscheduled clinical laboratory measurements may be obtained at any 
time during the study to assess any perceived safety concerns. 
Table 6. 
Protocol-Required Safety Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN/urea and 
creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
FSHb 
Urine drug screeningc 
Alcohol breathalyzer 
β-hCGd 
Hepatitis B surface 
Antigen 
Hepatitis B core 
Antibody  
Hepatitis C core 
Antibody 
Human 
Immunodeficiency 
Virus 
 
Additional Tests 
(Needed for Hy’s Law) 
 
HAV IgM 
HAV IgG 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
CK 
GGT 
PT/INR 
Total bile acids 
Acetaminophen drug 
and/or protein adduct 
levels 
 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = beta human 
chorionic gonadotropin; BUN = blood urea nitrogen; FSH = follicle stimulating hormone; GGT = gamma 
glutamyl transferase; HAV IgG = hepatitis A virus immunoglobulin G; HAV IgM = hepatitis A virus 
immunoglobulin M; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCHC 
= mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin 
time; RBC = red blod cell; WBC = white blood cell.  
 


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Table 6. 
Protocol-Required Safety Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
a. 
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
b. 
For confirmation of postmenopausal status only. 
c. 
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol (THC), opiates/opioids, 
benzodiazepines, and amphetamines (others are site and study specific). 
d. 
Serum or urine E-hCG for female participants of childbearing potential. 
 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigator 
sites or other blinded personnel until the study has been unblinded. 
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings.  These data will not be included in the CSR.  Samples to be used for this 
purpose will be shipped to either a Viatris-approved Biospecimen Banking System (BBS) 
facility or other designated laboratory and retained for up to 1 year following the completion 
of the study. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1. Definition of AE 
AE Definition 
x An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention. 
x NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the AE Definition 
x Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator.  Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE: 
x Is associated with accompanying symptoms; 
x Requires additional diagnostic testing or medical/surgical intervention; 
x Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
x Exacerbation of a chronic or intermittent preexisting condition including either 
an increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae. 
 


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Events NOT Meeting the AE Definition 
x Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 
x The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
x Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
10.3.2. Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 


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d. Results in persistent disability/incapacity 
x The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
x This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
x Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should usually be considered serious. 
x 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs 
AE and SAE Recording/Reporting 
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse 
Event (SAE) Report Form to Pfizer Safety.  These requirements are delineated for 
3 types of events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to 
the investigational product under study during pregnancy or breastfeeding, and 
occupational exposure.  
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must 
be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information. 


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Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure 
None 
All (and exposure during 
pregnancy [EDP] 
supplemental form for 
EDP)   
x When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
x The investigator will then record all relevant AE/SAE information in the CRF. 
x It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page. 
x There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
x The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
x Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
x Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
x Severe: An event that prevents normal everyday activities.  An AE that is 
assessed as severe should not be confused with an SAE.  Severe is a category 


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utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
x An event is defined as “serious” when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe. 
 
Assessment of Causality 
x The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
x A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out. 
x The investigator will use clinical judgment to determine the relationship. 
x Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
x The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment. 
x For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
x There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor. 
x The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
x The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
x If the investigator does not know whether or not the investigational product 
caused the event, then the event will be handled as “related to investigational 
product” for reporting purposes, as defined by the sponsor.  In addition, if the 
investigator determines that an SAE is associated with study procedures, the 


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investigator must record this causal relationship in the source documents and 
CRF, and report such an assessment in the dedicated section of the CT SAE 
Report Form and in accordance with the SAE reporting requirements. 
 
Follow-up of AEs and SAEs 
x The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers. 
x If a participant dies during participation in the study or during a recognized 
followup period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.   
x New or updated information will be recorded in the originally completed CRF. 
x The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information. 
10.3.4. Reporting of SAEs 
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool 
x The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool. 
x If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
x The site will enter the SAE data into the electronic system as soon as the data 
become available. 
x After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data. 
x If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to Pfizer Safety by telephone. 
 


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SAE Reporting to Pfizer Safety via CT SAE Report Form 
x Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
x In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service. 
x Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames. 


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 93 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate study intervention(s) plus an additional 90 days 
(a spermatogenesis cycle):  
x Refrain from donating sperm. 
PLUS either: 
x Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent;  
OR 
x Must agree to use contraception/barrier as detailed below:  
x Agree to use a male condom when engaging in any activity that allows for passage of 
ejaculate to another person. 
x Male participants should be advised of the benefit for a female partner to use a highly 
effective method of contraception, as a condom may break or leak when having 
sexual intercourse with a WOCBP who is not currently pregnant. 
10.4.2. Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
x Is not a WOCBP (see definitions below in Section 10.4.3); 
OR 
x Is a WOCBP and using a contraceptive method, as described below, during the 
intervention period and for at least 42 days after the last dose of study intervention, 
which corresponds to the time needed to eliminate any study intervention(s).   
x A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.  


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10.4.3. Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
x Documented hysterectomy; 
x Documented bilateral salpingectomy; 
x Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (eg, mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in 
the participant’s medical record for the study. 
2. Postmenopausal female. 
x A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause.  
x A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT).  
x Females on HRT and whose menopausal status is in doubt will be required to use 
at least one of the contraception methods below. 
10.4.4. Contraception Methods 
Female subjects of child-bearing potential must use at least one form of the following 
contraception methods. 
1. Intrauterine device (IUD).  
2. Bilateral tubal occlusion. 


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3. Hormonal contraception. 
4. Contraceptive implants. 
5. Double-barrier method (any combination of physical and chemical methods). 
6. Confirmed infertility of sexual partner. 
7. Engaged exclusively in a same-sex relationship. 
8. Total abstinence (periodic abstinence is not acceptable). 
9. Vasectomized partner. 
x Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional method of 
contraception should be used.  The spermatogenesis cycle is approximately 
90 days. 
 
Collection of Pregnancy Information 
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if: 
x A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
x An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products); 
x A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 


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irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows:  
x Spontaneous abortion includes miscarriage and missed abortion; 
x Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.  
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 


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10.5. Appendix 5: Genetics 
Use/Analysis of DNA 
x Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease.  Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis. 
x Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome (as appropriate). 
x The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to gabapentin and diazepam or study interventions of this 
class to understand treatments for the disease(s) under study or the disease(s) 
themselves. 
x The results of genetic analyses may be reported in the clinical study report (CSR) or 
in a separate study summary, or may be used for internal decision making without 
being included in a study report. 
x The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
x The samples will be retained as indicated: 
x Samples for banking (see Section 8.7.2) will be stored indefinitely or other period as 
per local requirements.   
x Participants may withdraw their consent for the storage and/or use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.   
x Banked biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank. 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.” 
Liver function tests (LFTs) results should be managed and followed as described below. 
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin (TBili) 
elevations (>2 × ULN) by several days or weeks.  The increase in TBili typically occurs 
while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample).  In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
x Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
x For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
x Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller). 
x Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller). 


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern 
ECG Findings That May Qualify as Adverse Events (AEs) 
x Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
x New PR interval prolongation >280 msec. 
x New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from 
baseline. 
x New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm. 
x New-onset type I second-degree (Wenckebach) atrioventricular (AV) block of 
>30 seconds’ duration. 
x Frequent premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes. 
ECG Findings That May Qualify as Serious Adverse Events (SAEs) 
x QTcF prolongation >500 msec. 
x New ST-T changes suggestive of myocardial ischemia. 
x New-onset left bundle branch block (QRS >120 msec). 
x New-onset right bundle branch block (QRS >120 msec). 
x Symptomatic bradycardia.  
x Asystole: 
x In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node.  
x In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer.  
x Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
x Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 


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x Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades 
de pointes). 
x Type II second-degree (Mobitz II) AV block. 
x Complete (third-degree) heart block. 
ECG Findings That Qualify as Serious Adverse Events 
x Change in pattern suggestive of new myocardial infarction.  
x Sustained ventricular tachyarrhythmias (>30 seconds’ duration). 
x Second- or third-degree AV block requiring pacemaker placement. 
x Asystolic pauses requiring pacemaker placement. 
x Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion. 
x Ventricular fibrillation/flutter. 
x At the discretion of the investigator, any arrhythmia classified as an adverse 
experience. 
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Viatris study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs. 


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10.8. Appendix 8: Clinical Opioid Withdraw Scale 
For each item, circle the number that best describes the patient' s signs or symptom.  Rate on 
just the apparent relationship to opiate withdrawal.  For example, if pulse rate is increased 
because the patient was jogging just prior to assessment, the increase pulse rate would not 
add to the score. 
Patient' s Name: 
Date and Time:  
Reason for this assessment: 
Resting Pulse Rate:                   beats/minute                  
Measured after patient is sitting or lying for one minute  
0 pulse rate 80 or below  
1 pulse rate 81-100  
2 pulse rate 101-120  
4 pulse rate greater than 1 20 
GI Upset: over last 1/2 hour  
0 no GI symptoms  
1 stomach cramps  
2 nausea or loose stool  
3 vomiting or diarrhea  
5 multiple episodes of diarrhea or vomiting 
Sweating: over past 1/2 hour not accounted for by room 
temperature or patient activity.  
0 no report of chills or flushing  
1 participant report of chills or flushing  
2 flushed or observable moistness on face  
3 beads of sweat on brow or face  
4 sweat streaming off face 
Tremor observation of outstretched hands  
0 no tremor  
1 tremor can be felt, but not observed  
2 slight tremor observable  
4 gross tremor or muscle twitching 
Restlessness Observation during assessment  
0 able to sit still  
1 reports difficulty sitting still, but is able to do so  
3 frequent shifting or extraneous movements of legs/arms  
5 unable to sit still for more than a few seconds 
Yawning Observation during assessment  
0 no yawning  
1 yawning once or twice during assessment  
2 yawning three or more times during 
assessment  
4 yawning several times/minute 
Pupil size  
0 pupils pinned or normal size for room light  
1 pupils possibly larger than normal for room light  
2 pupils moderately dilated  
5 pupils so dilated that only the rim of the iris is visible 
Anxiety or Irritability  
0 none  
1 patient reports increasing irritability or 
anxiousness  
2 patient obviously irritable or anxious  
4 patient so irritable or anxious that 
participation in the assessment is difficult 
Bone or Joint aches if patient was having pain 
previously, only the additional component attributed to 
opiates withdrawal is scored  
0 not present  
1 mild diffuse discomfort  
2 patient reports severe diffuse aching of joints/muscles  
4 patient is rubbing joints or muscles and is unable to sit 
still because of discomfort 
Gooseflesh skin  
0 skin is smooth  
3 piloerection of skin can be felt or hairs 
standing up on arms  
5 prominent piloerection 
Runny nose or tearing Not accounted for by cold -
symptoms or allergies  
0 not present  
1 nasal stuffiness or unusually moist eyes  
2 nose running or tearing  
4 nose constantly running or tears streaming down cheeks 
Total Score __________ 
 
The total score is the sum of all 11 items  
 
Initials of person completing 
assessment:______ 
Score: 5- 12 = mild; 1 3-24 = moderate; 25-36 = moderately severe; more than 36 = severe withdrawal 


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10.9. Appendix 9: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation 
Term 
Abs 
absolute 
ACLS 
advanced cardiac life support 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUCinf 
area under the plasma concentration-time 
profile from time 0 extrapolated to infinity time 
AUClast 
area under the plasma concentration-time profile from time 0 to the 
time of the last quantifiable concentration  
AUEC 
area under the effect curve 
AUEClast 
area under the effect-time profile from time 0 to the time of the last 
quantifiable effect 
AV 
atrioventricular 
E-hCG 
beta-human chorionic gonadotropin 
BBS 
biospecimen banking system 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CANTAB 
cambridge neuropsychological test automated battery  
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
Cmax 
maximum observed concentration 
CO2 
carbon dioxide (bicarbonate) 
COWS 
clinical opiate withdrawal scale 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSR 
clinical study report 
CT 
clinical trial 
CTMS 
clinical trial management system 
CV 
coefficient of variation 
CYP 
Cytochrome P450 
DAI 
Drug Administration Instructions 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 


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Abbreviation 
Term 
DNA 
deoxyribonucleic acid 
DSM- IV 
Diagnostic and Statistical Manual of Mental Disorders IV 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
Electronic case report form 
EDP 
exposure during pregnancy 
EMA 
European Medicines Agency 
Emax 
maximum effect 
ETCO 
end-tidal carbon dioxide 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HAV IgM/G 
Hepatitis A virus immunoglobulin M/G 
HBcAb 
hepatitis B core antibody 
HBsAg  
hepatitis B surface antigen 
HCVAb 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
IND 
investigational new drug application 
INR 
international normalized ratio 
IP  
investigational product  
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IVRS 
Interactive Voice Response System  
LFT 
liver function test 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MHP 
mental health professional 
msec 
millisecond 
N/A 
not applicable 
PCD 
primary completion date 


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Abbreviation 
Term 
CRU 
Clinical Research Unit 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
PT 
prothrombin time 
PVC 
premature ventricular complex 
Q1 
first quartile 
Q3 
third quartile 
QTc 
corrected QT 
QTcB 
corrected QT using Bazett’s method 
QTcF 
corrected QT using Fridericia’s method 
qual 
qualitative 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCr 
serum creatinine 
SD 
standard deviation 
SE 
standard error 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SpO2 
peripheral oxygen saturation 
SRSD 
single reference safety document 
SToD 
study team on demand 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
Terminal elimination half-life 
TBili 
total bilirubin 
TEmax 
time for Emax 
Tmax 
time for Cmax 
THC 
tetrahydrocannabinol  
TID 
3 times a day 
UDS 
urine drug screen 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Package Insert 
VAS 
visual analog scale 
VT 
tidal volume 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 


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10.10. Appendix 10: VAS Assessment Methods 
The overall appearance of all VAS items utilizing the Cambridge Neuropsychological Test 
Automated Battery (CANTAB) or using comparable software will be similar to screen 
images shown below.  The participants will be trained to use the software at the site. 
Image A: screen display of Drug Liking VAS 
 
The questions and anchors on VAS items will be modified appropriately to reflect study 
specific questions as shown in Images B-D (see Table 7). 
 


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Image B: screen display of High VAS 
 
Image C: screen display of Overall Drug Liking VAS 
 


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Image D: screen display of Take Drug Again VAS 
 
 
Table 7. 
Other Subjective Effects Visual Analog Scales 
SCALE DESCRIPTION 
STATEMENT TEXT 
RESPONSE ANCHORS 
Good Drug Effects 
I can feel good drug 
effects 
0: Not at all 
100: Extremely 
Bad Drug Effects 
I can feel bad drug effects 
Feeling Sick 
I am feeling sick 
Nausea 
I am feeling nausea 
Any Drug Effects 
I can feel any drug effect 
Sleepy 
I am feeling sleepy 
Dizzy 
I am feeling dizzy 
 


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10.11. Alertness/Sedation Assessment 
The Modified Observer’s Assessment of Alertness/Sedation scale or comparable scale will 
be used for the assessment of alertness/sedation (see Table 8).  
 
Table 8. 
Modified Observer’s Assessment of Alertness/Sedation Scale 
Responsiveness 
Numerical score 
Responds readily to name spoken in normal tone 
5 
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 
Responds only after painful trapezius squeeze* 
1 
No response after painful trapezius squeeze 
0 
*Purposeful response, not withdrawal. 
 


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10.12. Appendix 12: Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Viatris.  
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories).  
10.12.1. Eligibility 
Not applicable 
10.12.2. Telehealth Visits  
Not applicable  
10.12.3. Alternative Facilities for Safety Assessments   
Not applicable  
10.12.4. Study Intervention  
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered. For participant discontinuation reporting in the CRF: select 
the most appropriate status for discontinuation; if the discontinuation is associated with the 
current COVID-19 pandemic, enter “COVID-19” in the “Specify Status” field. 
10.12.5. Home Health Visits  
Not applicable 
10.12.6. Adverse Events and Serious Adverse Events 
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided.  
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor.  
10.12.7. Efficacy Assessments 
Not applicable 
10.12.8. Independent Oversight Committees 
Not applicable 


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10.13. Appendix 13: Summary of Changes 
Protocol Title 
A phase 4, randomized, double-blind, double-dummy, placebo- and 
active-controlled, single-dose, five-way crossover study evaluating the 
Abuse Potential of three Doses of Neurontin® taken orally in healthy, 
non-drug dependent participants with sedative drug abuse experience 
Product 
Neurontin® (gabapentin) 
Protocol 
Number 
A9451181 
Study Type 
Phase 4 
Version 
5.0 
Protocol Date 
29 Apr 2022 
Legal/Filing 
Sponsor 
Viatris Specialty LLC 
3711 Collins Ferry Road 
Morgantown, WV 26505 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 9. 
Summary of changes from Protocol dated 14 May 2020 to Protocol 2.0 dated 11 Dec 2020 
Section  
Old Text  
(Protocol dated 14 May 2020 
New Text  
(Protocol Version 2.0 dated 11 Dec 2020) 
Rationale for 
amendment 
Administrative 
Changes  
Sponsor and 
Sponsor contacts 
details updated 
Missing 
Sponsor name ‘Pfizer’ 
Added 
Upjohn US 1 LLC 
235 East 42nd Street 
New York, NY 10017-5703 
Dr. Sandeep Jagtap 
Clinical Strategy Lead – CNS 
Global Clinical Strategy & Innovation 
David Gillogly 
Head, Global Clinical Operations 
The sponsor name changed from ‘Pfizer’ to 
‘Upjohn’ wherever applicable throughout the 
protocol 
The sponsor for this 
study is changed from 
‘Pfizer’ to ‘Upjohn 
US 1 LLC’ 
Administrative 
changes are made to 
include updated 
Sponsor details and 
authorized sponsor 
protocol approvers 
Section 1.3 
Schedule of 
Activities 
(Table:1 footer) 
Missing text for bullet h. vital signs 
will be recorded at pre-do
rst 
naloxone dose) and at 5 m
s, 0.25, 
0.5, 1, 1.5, and 2 hours follo
ng the 
second dose of naloxone.  
Added “vital signs will be recorded at pre-
ose (first naloxone dose) and at 5 minutes, 
.25, 0.5, 1, 1.5, and 2 hours following the 
econd dose of naloxone. Vital signs will be 
ecorded at nominal time points ± 5 minutes” 
The changes are 
made to provide 
clarification 
 
Section 1.3 
Schedule of 
Activities  
(Table:2-footer) 
Missing “12-lead Electrocar
gram” 
measurements at Day -1 (baseline) and 
Day 4 during Treatment Phase. 
 
dded “12-lead Electrocardiogram” 
easurements (Conducted after a resting 
eriod of at least 10 minutes in a supine 
position) at Day -1 (baseline) and Day 4 
during Treatment Phase. 
The changes are 
made to add missing 
and typographical 
error 
 


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Missing text for bullet g. Vital signs 
(including pulse rate, systolic and 
diastolic blood pressures are measured 
at the nominal time points after a 
resting period of at least 5 minutes in a 
sitting position. Temperature (oral or 
with a temporal infrared scanner) will 
be measured on Day -1 of each 
Treatment Visit only. 
Added “Vital signs (including pulse rate, 
systolic and diastolic blood pressures are 
measured at the nominal time points after a 
resting period of at least 5 minutes in a sitting 
position. Temperature (oral or with a 
temporal infrared scanner) will be measured 
on Day -1 of each Treatment Visit only. Vital 
signs will be recorded at nominal time points 
± 5 minutes” 
The changes are 
made to add missing 
and typographical 
error 
Section 2.1 Study 
Rationale From 
(4th paragraph): 
Epidemiological studies have shown 
that gabapentin may have abuse 
potential, particularly among 
individuals with a history of opioid 
abuse. Gabapentin abuse is reported 
both alone (ie, without other drugs), 
and in conjunction with opioids to 
enhance the ‘high’ obtained from 
opioids.1,4 Further, published data 
suggest that gabapentin is recorded on 
death certificates suggesting drug 
overdose, both as the primary and 
contributory causes of death, and 
reported with and without other drugs 
like opioids, benzodiazepines, and 
alcohol.1,5-7 This clinical trial will 
evaluate gabapentin in a cross-over 
design with comparison to placebo and 
a positive control, diazepam, regarding 
abuse-related subjective responses, 
physiological responses (including an 
assessment of respiratory depression), 
and drug pharmacokinetics in a 
Epidemiological studies have shown that 
gabapentin may have abuse potential, 
particularly among individuals with a history 
of opioid abuse. Gabapentin abuse is reported 
both alone (ie, without other drugs), and in 
conjunction with opioids to enhance the 
‘high’ obtained from opioids.1,4 Further, 
published data suggest that gabapentin is 
recorded on death certificates suggesting drug 
overdose, both as the primary and 
contributory causes of death, and reported 
with and without other drugs like opioids, 
benzodiazepines, and alcohol.1,5-7  As a 
consequence, the FDA has required this post-
authorization safety study (PASS) to evaluate 
gabapentin in a cross-over design with 
comparison to placebo and a positive control, 
diazepam, regarding abuse-related subjective 
responses, physiological responses (including 
an assessment of respiratory depression), and 
drug pharmacokinetics in a healthy non-drug 
The changes were 
made for clarification 
(modifying the last 
sentence from “This 
clinical trial will 
evaluate gabapentin 
in a cross-over 
design-----” to “As a 
consequence, the 
FDA has required this 
post-authorization 
safety study (PASS) 
to evaluate 
gabapentin in a cross-
over design 


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healthy non-drug dependent 
population with drug abuse experience 
with sedative drugs. 
dependent population with drug abuse 
experience with sedative drugs. 
Section 5.2 
Exclusion 
Criteria 
Participants are heavy smokers (>20 
cigarettes per day) and/or use e-
cigarettes, pipes, cigars, chewing 
tobacco, nicotine topical patches, 
nicotine gum, or nicotine lozenges. 
Participants are heavy smokers or users of 
other types of nicotine products (>20 
cigarettes equivalents per day) 
Changes are made to 
provide clarification 
 
Section 5.2 
Exclusion 
Criteria and  
Section 5.3 
Lifestyle 
Considerations 
Section 5.2: Participants are unable to 
abstain from smoking for at least 1 
hour before and at least 8 hours after 
study drug administration. 
Section 5.3: Participants will not be 
permitted to smoke from at least 1 
hour before until at least 8 hours after 
dosing in the Qualification and 
Treatment Phases. 
Section 5.2: Participants are unable to abstain 
from smoking for at least 2 hours before and 
at least 8 hours after study drug 
administration.  
Section 5.3: Participants will not be permitted 
to smoke from at least 2 hours before until at 
least 8 hours after dosing in the Qualification 
and Treatment Phases. 
The changes are 
made due to a 
typographical error 
(e.g. From “at least 1 
hour before” To “at 
least 2 hours before”).  
 
Section 5.3.2 
Caffeine, 
Alcohol, and 
Tobacco 
The use of oral or chewed tobacco 
and/or nicotine-containing products 
(including topical patches) is not 
permitted for the entire study  
The use of oral or chewed tobacco and/or 
nicotine-containing products (including 
topical patches) is not permitted from at least 
2 hours before and at least 8 hours after study 
drug administration 
The changes are 
made to correct the 
typographical error 
Section 6.3.1 
Allocation to 
Investigational 
Product 
At screening, participants will be 
assigned a Single Participant Identifier 
number via an automated Interactive 
Voice Response System (IVRS) or 
equivalent system provided by Pfizer. 
Following screening the participants 
will be randomized. The 
randomization number for the 
At screening, participants will be assigned a 
subject screening identification number 
(SSID) via an automated Interactive 
Response Technology (IRT) or equivalent 
system. 
Following screening the participants will be 
randomly assigned a qualification 
randomization number (QRN)via the IRT or 
Changes are made to 
provide clarity for 
changes in study 
conduct 


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participant will be allocated via the 
IVRS or equivalent system using a 1:1 
randomization within each of the 
randomization strata. This number will 
be retained throughout the study and 
will correspond to a blinded treatment 
schedule determined by a Pfizer 
generated randomization code. 
 
equivalent system using a 1:1 randomization. 
The QRN will be retained throughout the 
study and will correspond to the blinded 
qualification phase. 
After satisfactory completion of the 
qualification phase, participants will 
randomly be assigned a study randomization 
number (SRN) via the IRT or equivalent 
system using a 1:1 randomization for the 
treatment phase. The SRN will be retained 
throughout the study and will correspond to 
the blinded treatment sequence. 
Section 6.3.2 
Breaking the 
Blind 
From (the 3rd and 
4th paragraphs): 
 
The method for breaking the blind in 
this study will be manual.  A sealed 
envelope that contains the study 
intervention assignment(s) for each 
participant will be provided to the 
investigator.  The sealed envelope will 
be retained by the investigator (or 
representative) in a secured area.  In 
case of an emergency, the investigator 
has the sole responsibility for 
determining if unblinding of a 
participant’s treatment assignment is 
warranted.  Participant safety must 
always be the first consideration in 
making such a determination.  If the 
investigator decides that unblinding is 
warranted, the investigator should 
make every effort to contact the 
sponsor prior to unblinding a 
The IRT will be programmed with 
blind-breaking instructions.  In case of an 
emergency, the investigator has the sole 
responsibility for determining if unblinding of 
a participant’s treatment assignment is 
warranted.  Participant safety must always be 
the first consideration in making such a 
determination.  If the investigator decides that 
unblinding is warranted, the investigator 
should make every effort to contact the 
sponsor or medical monitor prior to 
unblinding a participant’s treatment 
assignment unless this could delay further 
management of the participant.  If a 
participant’s treatment assignment is 
unblinded, the sponsor must be notified 
within 24 hours after breaking the blind.  The 
date and reason that the blind was broken 
The changes are 
made to transfer 
responsibility of an 
IRT to a CRO and 
provide a flexibility 
of randomization to 
the CRO. 
 


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participant’s treatment assignment 
unless this could delay further 
management of the participant.  If a 
participant’s treatment assignment is 
unblinded, the sponsor must be 
notified within 24 hours after breaking 
the blind.  When the blinding code is 
broken, the reason must be fully 
documented and entered on the CRF. 
Once the study is complete, all 
envelopes (sealed and opened) must be 
inventoried and retained until 
authorization for destruction has been 
provided.  
must be recorded in the source documentation 
and data collection tool (DCT). 
The study-specific IRT reference manual and 
IP manual will provide the contact 
information and further details on the use of 
the IRT system. 
 
Section 8.2.2 
Vital Signs  
From (3rd 
paragraphs):  
 
Pulse and respiratory rates, oxygen 
saturation, diastolic and systolic blood 
pressure will be monitored 
continuously post-drug. These 
measures are done in abuse liability 
testing to ensure safety. 
Pulse and respiratory rates, oxygen saturation, 
diastolic and systolic blood pressure will be 
monitored post-drug (see SoA). These 
measures are done in abuse liability testing to 
ensure safety. 
The changes are 
made due to a 
typographical error. 
 
Section 8.2.3.1 
Continuous 
Cardiac 
Monitoring by 
Telemetry  
 
All abnormal rhythms will be recorded 
and reviewed by the study physician 
for the presence of rhythms of 
potential clinical concern.  The time, 
duration, and description of the 
clinically significant event will be 
recorded in the CRF.  In addition, a 
printed record of the tracing(s) of the 
clinically significant rhythm(s) will be 
Continuous cardiac monitoring will be 
performed as noted in the SoA. The time, 
duration, and description of any clinically 
significant abnormal rhythm will be reported 
as an adverse event. 
 
The change are made 
because, as part of 
standard of care, an 
ECG will be 
performed for any 
clinically significant 
abnormal rhythm 
making telemetry 
record storage and 
data transfer 


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made and retained with other source 
documents. 
Telemetry should be collected using a 
centralized system that also allows for 
the storage and advanced analysis of 
all recorded data in order to preserve 
important events for future 
evaluations.  Holter monitoring should 
not be used in parallel with continuous 
telemetry, unless it is the only means 
of data storage available at the 
investigator site, or verifiable 
arrhythmia quantification is required.  
To establish a baseline, telemetry 
should be recorded for at least 2 hours 
before dosing in Period 1 of the 
Treatment Phase.  This may be done 
immediately prior to dosing or at some 
2-hour continuous interval in the 
24 hours prior to dosing, as long as the 
recording is performed when the 
participant is awake.  Telemetry may 
be stopped within a reasonably short 
period of time prior to dosing, in order 
to avoid interference with study 
operations conducted immediately 
before dosing.  However, it is expected 
that the telemetry leads will be in place 
and the system connected prior to 
dosing. 
capability 
unnecessary.  
 


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Section 8.6.2 
Visual Analog 
Scale (VAS)  
 
Missing a text at the end of 1st 
paragraph for the VAS testing time 
window as “All VAS testing will be 
administered at the nominal time 
points ±5 minutes.” 
Add a text at the end of 1st paragraph for the 
VAS testing time window as “All VAS 
testing will be administered at the nominal 
time points ±5 minutes.” 
The change are made 
to provide 
clarification. 
 
Section 10.1.5 
Dissemination of 
Clinical Study 
data 
Removed www.pfizer.com 
Pfizer posts public disclosure synopsis, 
a clinical study report (CSR) in which 
any data that could be used to identify 
individual participants have been 
removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies 
at the same time the US Basic Results 
document is posted to 
www.clinicaltrials.gov. 
No information added 
This information is 
removed due to 
change of study 
sponsor from Pfizer 
to Upjohn.  
Section 10.1.10 
Sponsor’s 
Qualified 
Medical 
Personnel 
Removed  
For sites other than a Pfizer CRU, the 
contact number is not intended for use 
by the participant directly and if a 
participant calls that number, he or she 
will be directed back to the 
investigator site. 
No information added 
This statement is 
removed due to 
change of study 
sponsor from Pfizer 
to Upjohn.  


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Section 
10.13. Appendix 
13: Alternative 
Measures 
During Public 
Emergencies 
None (No appendix information 
available in the protocol regarding 
COVID-19) 
 
10.13. Appendix 13: Alternative Measures 
During Public Emergencies 
The alternative study measures described in 
this section are to be followed during public 
emergencies, including the COVID-19 
pandemic. This appendix applies 
for the duration of the COVID-19 pandemic 
globally and will become effective for other 
Public emergencies only upon written 
notification from Upjohn.  
Use of these alternative study measures are 
expected to cease upon the return of business 
as usual circumstances (including the lifting 
of any quarantines and travel 
bans/advisories).  
10.12.1 Eligibility 
Not applicable 
10.12.2 Telehealth Visits  
Not applicable  
10.12.3 Alternative Facilities for Safety 
Assessments   
Not applicable  
10.12.4 Study Intervention  
If the safety of a trial participant is at risk 
because they cannot complete required 
evaluations or adhere to critical mitigation 
steps, then discontinuing that participant from 
study intervention must be considered. For 
The changes were 
made to provide 
sufficient details 
about the protocol 
changes and enable 
an impact assessment 
of alternative 
measures due to 
COVID-19. 
 
 


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participant discontinuation reporting in the 
CRF: select the most appropriate status for 
discontinuation; if the discontinuation is 
associated with the current COVID-19 
pandemic, enter “COVID-19” in the “Specify 
Status” field.  
10.12.5 Home Health Visits  
Not applicable 
10.12.6 Adverse Events and Serious Adverse 
Events 
If a participant has COVID-19 during the 
study, this should be reported as an adverse 
event (AE) or serious adverse events (SAE) 
and appropriate medical intervention 
provided.  
It is recommended that the investigator 
discuss temporary or permanent 
discontinuation of study intervention with the 
study medical monitor.  
10.12.7 Efficacy Assessments 
Not applicable 
10.12.8 Independent Oversight Committees 
Not applicable 
 


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Table 10. Summary of changes from Protocol version 2.0 dated 11 Dec 2020 to Protocol version 3.0 dated 26 Feb 2021 
Section  
Old Text  
(Protocol Version 2.0 dated 11 Dec 
2020) 
New Text  
(Protocol Version 3.0 dated 26 Feb 2021) 
Rationale for 
amendment 
Section 1.3,  
Table 2 schedule 
of activities for 
treatment phase 
There is ‘X’ denoting VAS pre-dose 
assessment for good drug effects, bad 
drug effects & any drug effects in the 
treatment phase.  
 
‘X’ denoting VAS pre-dose assessment for 
good drug effects, bad drug effects & any 
drug effects in the treatment phase is deleted. 
Correction of 
inadvertent error  
Section 5.2 
Exclusion 
Criteria # 11: 
Herbal supplements, herbal 
medications and hormone replacement 
therapy must be discontinued at least 
28 days prior to the first dose of study 
medication. 
Herbal supplements and herbal medications 
must be discontinued at least 28 days prior to 
the first dose of study medication. 
(hormone replacement therapy is deleted) 
Correction of 
typographical error 
 
 


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Table 11. Summary of changes from Protocol version 3.0 dated 26 Feb 2021 to Protocol version 4.0 dated 04 Aug 2021 
Section  
Old Text  
(Protocol Version 3.0 dated 26 Feb 2021) 
New Text  
(Protocol Version 4.0 dated 04 Aug 
2021) 
Rationale for 
amendment 
Administrative 
change 
Upjohn US 1 LLC 
Upjohn US 1 LLC, a Viatris Company 
Sponsor name change 
Administrative 
change 
Sponsor contact 
details updated 
Sandeep Jagtap, MD 
Clinical Strategy Lead – CNS
Viatris, Bangalore 
Prestige Platina, Block 3, Ka
nah
Village,  
Outer Ring Road, Bangalore 
60
7, 
Karnataka, INDIA 
Sandeep.Jagtap@viatris.com
g, PhD 
al Development Lead 
s 
very Park 
gate Road 
wich, Kent, CT13 9ND 
ited Kingdom 
.ng@viatris.com 
Change to Sponsor 
personnel 
Section 5.1 
Inclusion 
criterion #1 
Male and female participants must 
 18
 
55 years of age, inclusive, at the ti
 of 
screening 
Male and female participants must be 18 
to 65 years of age, inclusive, at the time of 
screening 
Increase in age range 
to facilitate subject 
enrolment 
Section 5.1 
Inclusion 
criterion #4 
Participants must be recreational sedativ
users, defined as those report
 
sedative agent (eg, barbiturat
benzodiazepines) for its intox
on at least 10 occasions with
 
 
and at least once in the 8 wee
Screening Visit (Visit 1), but 
signs of dependence and are 
ing 
treatment for their sedative u
Participants must be recreational sedative 
, defined as those reporting using a 
ive agent (eg, barbiturates, 
diazepines) for its intoxicating 
ts on at least 10 lifetime occasions 
t least once in the 12 weeks before 
 Screening Visit (Visit 1), but who have 
 signs of dependence and are not 
king treatment for their sedative use 
Aligning the 
definition of an 
experienced 
recreational sedative 
user to other similar 
Human Abuse 
Potential studies in 
recreational sedative 
users to facilitate 
subject enrolment 


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Section 5.2 
Exclusion 
criterion #19 
Participants with ANY of the following 
abnormalities in clinical laboratory tests at 
screening, as assessed by the study specific 
laboratory and confirmed by a single repeat 
test, if deemed necessary: 
x Aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) level Ŏ
1.5 灤 upper limit of normal (ULN) 
Total bilirubin level Ŏ 1.5 灤 ULN; 
participants with a history of Gilbert瀠s 
syndrome may have direct bilirubin 
measured and would be eligible for this 
study provided the direct bilirubin level is 
ō ULN 
Participants with ANY of the following 
abnormalities in clinical laboratory tests at 
screening, as assessed by the study 
specific laboratory and confirmed by a 
single repeat test, if deemed to be 
clinically significant in the opinion of the 
investigator: 
x Aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) level 
Ŏ1.5 灤 upper limit of normal (ULN) 
Total bilirubin level Ŏ 1.5 灤 ULN; 
participants with a history of Gilbert瀠s 
syndrome may have direct bilirubin 
measured and would be eligible for this 
study provided the direct bilirubin level is 
ō ULN 
Clarification to allow 
the investigator to 
apply clinical 
judgement 
Administrative 
change 
Appendix 13 
Table 
numbering re-
ordered 
Table 9. Summary of changes from 
Protocol version 2.0 dated 11 Dec 2020 to 
Protocol version 3.0 dated 26 Feb 2021 
Table 10. Summary of changes from 
Protocol dated 14 May 2020  to Protocol 
2.0 dated 11 Dec 2020 
 
Table 9. Summary of changes from 
Protocol dated 14 May 2020  to Protocol 
2.0 dated 11 Dec 2020 
Table 10. Summary of changes from 
Protocol version 2.0 dated 11 Dec 2020 to 
Protocol version 3.0 dated 26 Feb 2021 
To enable new 
amendments to be 
assigned successively 
higher table numbers 
in date order 
 
 


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Table 12. Summary of changes from Protocol version 4.0 dated 04 Aug 2021 to Protocol version 5.0 dated 29 Apr 2022 
Section  
Old Text  
(Protocol Version 4.0 dated 04 Aug 2021) 
New Text  
(Protocol Version 5.0 dated 29 Apr 
2022) 
Rationale for 
amendment 
Administrative 
change 
Sponsor details 
throughout the 
document 
Upjohn US 1 LLC 
Viatris Specialty LLC 
3711 Collins Ferry Road 
Morgantown, WV 26505 
Sponsor name change 
Section 1.2  
The Treatment Phase of the study will use a 
Williams square study design involving 
approximately 40 participants (4 
participates in each sequence) to ensure at 
least 32 participants complete the treatment 
phase of the study as shown in Figure 1 
The Treatment Phase of the study will use 
a Williams square study design involving 
approximately 50 participants (5 
participants in each sequence) to ensure at 
least 32 participants meeting the definition 
of the Modified Completer Population 
complete the treatment phase of the study 
as shown in Figure 1 
Increasing the 
number of subjects 
enrolled to ensure 
sufficient subjects 
meeting the newly-
defined Modified 
Completer Population 
Table 2, 
footnote g 
Vital signs (including pulse rate, systolic 
and diastolic blood pressures are measured 
at the nominal time points after a resting 
period of at least 5 minutes in a sitting 
position.  Temperature (oral or with a 
temporal infrared scanner) will be 
measured on Day -1 of each Treatment 
Visit only. Vital signs will be recorded at 
nominal time points ±5 min 
Vital signs (including pulse rate, systolic 
and diastolic blood pressures are measured 
at the nominal time points after a resting 
period of at least 5 minutes in a sitting 
position.  Temperature (oral or with a 
temporal infrared scanner) will be 
measured on Day -1 of each Treatment 
Visit only. Vital signs will be recorded at 
nominal time points ±5 min for time points 
up to and including 4 h post-dose, within 
±15 minutes for time points from 6-12 h 
post-dose, and within ±60 minutes for the 
Increasing the 
permitted time 
windows for vital 
signs assessments 


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remaining time points up to and including 
72 h post-dose 
Table 2, 
footnote p 
None (new text added) 
Subjects may be discharged after 
completion of Day 3 assessments and 
return for Day 4 assessments, at the 
discretion of the investigator. 
Reducing the number 
of residential nights 
from 4 to 3 to 
facilitate subject 
enrollment 
Section 4.1 
This will be a randomized, double-blind, 
double-dummy, placebo- and active 
controlled, 5 treatment, 10 sequence, 5 
period crossover single dose, Williams 
square design study in healthy adult, non 
drug dependent male and female 
participants with drug abuse experience 
with sedative drugs…This study will 
randomize approximately 40 participants to 
ensure at least 32 participants complete  the 
Treatment Phase of the study. 
This will be a multi-center, randomized, 
double-blind, double-dummy, placebo- 
and active controlled, 5 treatment, 10 
sequence, 5 period crossover single dose, 
Williams square design study in healthy 
adult, non drug dependent male and 
female participants with drug abuse 
experience with sedative drugs…This 
study will randomize approximately 50 
participants to ensure at least 32 
participants meeting the definition of the 
Modified Completer Population complete  
the Treatment Phase of the study. 
Adding “multi-
center” in the study 
description and 
increasing the number 
of subjects enrolled to 
ensure sufficient 
subjects meeting the 
newly-defined 
Modified Completer 
Population 
Section 4.1 
x Visits 3 to 7, Treatment Phase: 
x Each visit will require an inpatient 
stay at the CRU of 4 nights. 
x For the entire study, 23 overnight 
inpatient stays will be required 
x Visits 3 to 7, Treatment Phase: 
x Each visit will require an inpatient 
stay at the CRU of 3 or 4 nights. 
Subjects may be discharged after 
completion of 48 h postdose 
assessments and return for 72 h 
postdose assessments on an 
ambulatory basis, at the discretion of 
the investigator. 
Reducing the number 
of residential nights 
from 4 to 3, at the 
investigator’s 
discretion, to 
facilitate subject 
enrollment 


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x For the entire study, 18 - 23 overnight 
inpatient stays will be required 
Section 5.2 
14. Participants unable to abstain from 
using THC during the Qualification and 
Treatment Phases of the study 
14. Participants unable to abstain from 
using THC during the inpatient stays 
in the Qualification and Treatment 
Phases of the study 
Clarification that 
subjects must abstain 
from using THC 
while resident in the 
clinic 
Section 5.3.4 
At time points indicated in the schedule of 
activities (SoA), the investigator or 
designee will inform the participant of the 
need to use highly effective contraception 
consistently and correctly and document 
the conversation and the participant’s 
affirmation in the participant’s chart 
(participants need to affirm their consistent 
and correct use of at least 1 of the selected 
methods of contraception) 
At time points indicated in the schedule of 
activities (SoA), the investigator or 
designee will inform the participant of the 
need to use effective contraception 
consistently and correctly and document 
the conversation and the participant’s 
affirmation in the participant’s chart 
(participants need to affirm their 
consistent and correct use of at least 1 of 
the selected methods of contraception) 
Change to reflect the 
addition of further  
forms of acceptable 
female contraception, 
in order to facilitate 
subject enrollment 
Section 8.2.2 
The same arm (preferably the dominant 
arm) will be used throughout the study.   
The same arm (preferably the dominant 
arm) should be used throughout the study.   
Change from the 
mandatory 
requirement to a 
recommendation 
Section 8.5 
Collection of samples up to and including 
10 hours after dose administration that are 
obtained within 10% of the nominal time 
(eg, within 6 minutes of a 60 minute 
sample) relative to dosing will not be 
captured as a protocol deviation, as long as 
the exact time of the collection is noted on 
Collection of samples up to and including 
10 hours after dose administration that are 
obtained within 5 minutes or 10% of the 
nominal time (eg, within 6 minutes of a 60 
minute sample), whichever is greater, 
relative to dosing will not be captured as a 
protocol deviation, as long as the exact 
time of the collection is noted on the 
Redefining the 
permitted time 
windows for PK 
sampling 


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the source document and data collection 
tool (eg, CRF).   
source document and data collection tool 
(eg, CRF).   
Section 8.6.2 
All VAS testing will be administered at the 
nominal time points ±5 minutes. 
All VAS testing will be administered at 
the nominal time points ±5 minutes for 
time points up to and including 4 h post-
dose, within ±15 minutes for time points 
from 6-12 h post-dose, and within ±60 
minutes for the remaining time points up 
to and including 72 h post-dose. 
Increasing the 
permitted time 
windows for vital 
signs assessments 
Section 9.1 
Study Validation: 
The sensitivity and integrity of the study 
will be validated by comparing the mean 
responses of diazepam, the positive control 
(C), to the placebo:  
H0: μC - μP ō 煩1 versus Ha: μC - μP > 煩
1 where 煩1 >15. 
Gabapentin versus diazepam: 
1. Does gabapentin (T) produce mean 
responses that show less abuse potential 
than diazepam? 
H0: μC - μT ō 煩2 versus Ha: μC - μT > 煩
2 where 煩2 Ŏ0. 
Gabapentin versus placebo (Primary): 
Study Validation: 
The sensitivity and integrity of the study 
will be validated by comparing the mean 
responses of diazepam, the positive 
control (C), to the placebo (P):  
H0: μC - μP ō 煩1 versus Ha: μC - μP > 
煩1 where 煩1 =15. 
Gabapentin versus diazepam: 
1. Does gabapentin (T) produce mean 
responses that show less abuse potential 
than diazepam? 
H0: μC - μT ō 煩2 versus Ha: μC - μT > 
煩2 where 煩2 =0. 
Gabapentin versus placebo (Primary): 
Corrections to the 
three equations 


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2. Does gabapentin (T) produce mean 
responses that show abuse potential similar 
to placebo? 
H0: μT - μP Ŏ 煩3 versus Ha: μp - μT < 煩
3 where 煩3 >11. 
2. Does gabapentin (T) produce mean 
responses that show abuse potential 
similar to placebo? 
H0: μT - μP Ŏ 煩3 versus Ha: μT - μP < 
煩3 where 煩3 =11. 
Section 9.2 
This study will randomize 40 participants 
to ensure at least 32 participants complete 
the Treatment Phase of the study. 
This study will randomize approximately 
50 participants to ensure at least 32 
participants who meet the definition of the 
Modified Completer Population complete 
the Treatment Phase of the study. Among 
the 50 participants, at least 20% will be 
females to ensure that the findings are 
valid across different populations. 
Increasing the 
number of subjects 
enrolled to ensure 
sufficient subjects 
meeting the newly-
defined Modified 
Completer Population 
and to specify the 
proportion of females 
Section 9.3 
x The Completer Population will include 
all randomized participants who 
complete all 5 periods of the Treatment 
Phase and who contribute post dose PD 
data from each period.  These 
participants must have all post dose 
responses for each treatment group 
present until median Tmax sampling 
time after dosing. This population will be 
analyzed as randomized. 
x The Evaluable Population will include all 
randomized participants in the Completer 
Population who do not have major 
protocol violations or adverse events that 
would interfere with drug absorption 
x The Completer Population will include 
all randomized participants who 
complete all 5 periods of the Treatment 
Phase and who contribute post dose PD 
data from each period.  These 
participants must have at least one post 
dose response on the VAS for Drug 
Liking within 2 hours of Tmax for each 
treatment group: ie, at least one VAS 
response within the interval 0-3h 
postdose (assuming the Tmax of 20 mg 
diazepam is 1h) and at least one VAS 
response within the interval 1-5h 
postdose (assuming the Tmax of 
600/1200/1800 mg gabapentin is 3h).  
Modifying the 
definition of the 
Completer Population 
(upon which other 
analysis sets are 
defined) to specify 
the minimum 
required post-dose 
responses required 
within the Tmax time 
periods specific to the 
two study drugs, in 
line with FDA 
guidance on assessing 


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such as vomiting within 4 hours of study 
drug administration.  Major protocol 
violations, including deviations related to 
study drug intake are defined as those 
that could potentially affect the PD 
conclusions of the study.  Prior to 
unblinding the Treatment Phase data, the 
sponsor (or designee) will identify 
protocol violations or adverse events that 
would disqualify a participant from the 
evaluable population and determine 
which participants or participant visits 
will be excluded.  This population will be 
analyzed as randomized. 
All PD analyses will be performed using 
the Modified Completer Population and all 
available post dose data; these will be the 
primary PD analyses.  Key PD analyses 
may be repeated on the Evaluable 
Population using all available post-dose 
data. 
This population will be analyzed as 
randomized. 
x The Modified Completer Population 
will include all randomized participants 
in the Completer Population, but will 
exclude any participant who meet either 
or both of the following criteria for 
Drug Liking VAS: 
1. Emax scores are within a 5 point 
difference across all five treatments 
(ie, Maximum Emax score 瀤 
Minimum Emax score ō5); 
2. Emax(P) > 60 AND Emax(P) - 
Emax(Dia) Ŏ5; 
where Emax(P) and Emax(Dia) are the 
VAS Emax scores for placebo and 
diazepam 20 mg, respectively. 
This population will be analyzed as 
randomized. 
x The Evaluable Population will include 
all randomized participants in the 
Modified Completer Population who do 
not have major protocol violations or 
adverse events that would interfere with 
drug absorption such as vomiting within 
4 hours of study drug administration.  
Major protocol violations, including 
abuse potential of 
drugs 
Also, addition of the 
Modified Completer 
Population as the 
primary analysis 
population, and 
clarification that the 
Evaluation 
Population will be the 
subset of the 
Modified Completer 
Population who do 
not have major 
protocol deviations 


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deviations related to study drug intake 
are defined as those that could 
potentially affect the PD conclusions of 
the study.  Prior to unblinding the 
Treatment Phase data, the sponsor (or 
designee) will identify protocol 
violations or adverse events that would 
disqualify a participant from the 
evaluable population and determine 
which participants or participant visits 
will be excluded.  This population will 
be analyzed as randomized. 
All PD analyses will be performed using 
the Modified Completer Population and all 
available post dose data; these will be the 
primary PD analyses.  Key PD analyses 
may be repeated on the Evaluable 
Population using all available post-dose 
data. 
Section 9.6 
Maximum (peak) effect (Emax); calculated 
as maximum change from pre-dose 
response if pre-dose assessment is 
performed; 
Maximum (peak) effect (Emax); 
calculated as maximum change from pre-
dose response if pre-dose assessment is 
performed; the neutral VAS point (50 for 
Drug liking, 0 for High) will be used as 
pre-dose response when VAS not 
performed or missing. 
Clarification of how 
missing pre-dose 
VAS values will be 
handled 
Section 9.8 
x A linear mixed-effects model that 
includes period, sequence, and treatment 
x A linear mixed-effects model that 
includes site, period, sequence, and 
treatment as fixed effects, and the 
Addition of “site” as 
a fixed effect in 
response to the 


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as fixed effects, and the participant as a 
random effect will be used 
participant as a random effect will be 
used 
addition of a new 
investigator site 
Section 9.8.1 
The changes from baseline will be analyzed 
with an analysis of variance (ANOVA) 
model consisting of: Sequence, Period, 
Treatment, Time, Period*Time and 
Treatment*Time terms as fixed effects, and 
a participant (Sequence) term as a random 
effect for. To accommodate the repeated 
measures aspect of the design, a compound 
symmetric covariance matrix will be 
employed, with the participant set to 
Period*Participant (Sequence). 
The changes from baseline will be 
analyzed with an analysis of variance 
(ANOVA) model consisting of: Site, 
Sequence, Site*Sequence, Period, 
Treatment, Time, Period*Time, 
Site*Treatment and Treatment*Time 
terms as fixed effects, and a participant 
(Site*Sequence) term as a random effect 
for testing Site, Sequence, and 
Site*sequence effect. Site*Treatment 
interaction will be evaluated and this 
interaction term will be dropped from the 
final model if it is not significant. To 
accommodate the repeated measures 
aspect of the design, a compound 
symmetric covariance matrix will be 
employed, with the participant set to 
Period*Participant (Sequence). 
Addition of “site” as 
a fixed effect in 
response to the 
addition of a new 
investigator site 
Section 9.8.3 
Samples from gabapentin treatment will be 
analyzed using a validated analytical 
method in compliance with Pfizer standard 
operating procedures 
Samples from gabapentin treatment will 
be analyzed using a validated analytical 
method in compliance with Viatris 
standard operating procedures 
Updating the 
applicable standard 
operating procedures 
of the new Sponsor 
Section 10.1.5 
Data Sharing 
Upjohn will make available data from these 
trials 24 months after study completion.   
Data Sharing 
Viatris will make available data from 
these trials 12 months after study 
completion.   
Updating the time 
period for making 
trial data available to 
reflect the change of 
Sponsor 


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Section 10.4.2 
Is a WOCBP and using a contraceptive 
method that is highly effective (with a 
failure rate of <1% per year), with low user 
dependency, as described below, during the 
intervention period and for at least 42 days 
after the last dose of study intervention, 
which corresponds to the time needed to 
eliminate any study intervention(s). 
Is a WOCBP and using a contraceptive 
method, as described below, during the 
intervention period and for at least 42 days 
after the last dose of study intervention, 
which corresponds to the time needed to 
eliminate any study intervention(s). 
Change to reflect the 
addition of further  
forms of acceptable 
female contraception, 
in order to facilitate 
subject enrollment 
Section 10.4.3 
2. Postmenopausal female. 
x Females on HRT and whose menopausal 
status is in doubt will be required to use 
one of the non-hormonal highly effective 
contraception methods. 
2. Postmenopausal female. 
x Females on HRT and whose 
menopausal status is in doubt will be 
required to use at least one of the 
contraception methods below. 
Change to reflect the 
addition of further  
forms of acceptable 
female contraception, 
in order to facilitate 
subject enrollment 
Section 10.4.4 
Highly Effective Methods That Have Low 
User Dependency. 
1. Intrauterine device (IUD).  
2. Bilateral tubal occlusion. 
3. Vasectomized partner. 
x Vasectomized partner is a highly 
effective contraceptive method 
provided that the partner is the sole 
sexual partner of the woman of 
childbearing potential and the absence 
of sperm has been confirmed.  If not, 
an additional highly effective method 
of contraception should be used.  The 
Female subjects of child-bearing potential 
must use at least one form of the following 
contraception methods. 
1. Intrauterine device (IUD).  
2. Bilateral tubal occlusion. 
3. Hormonal contraception. 
4. Contraceptive implants. 
5. Double-barrier method (any 
combination of physical and chemical 
methods). 
6. Confirmed infertility of sexual 
partner. 
Change to add further  
forms of acceptable 
female contraception, 
in order to facilitate 
subject enrollment 


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spermatogenesis cycle is 
approximately 90 days. 
7. Engaged exclusively in a same-sex 
relationship. 
8. Total abstinence (periodic abstinence 
is not acceptable). 
9. Vasectomized partner. 
x Vasectomized partner is a highly 
effective contraceptive method 
provided that the partner is the sole 
sexual partner of the woman of 
childbearing potential and the absence 
of sperm has been confirmed.  If not, 
an additional method of contraception 
should be used.  The spermatogenesis 
cycle is approximately 90 days. 
 


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11. REFERENCES  
1 
Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. 
Drugs 2017; 77(4):403-26. 
2 
Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among 
nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry 2015; 
172(5):487-8. 
3 
Wilens T, Zulauf C, Ryland D, et al. Prescription medication misuse among opioid 
dependent patients seeking inpatient detoxification. Am J Addict 2015; 24(2):173-7. 
4 
Hedegaard H, Bastian BA, Trinidad JP, et al. Drugs most frequently involved in drug 
overdose deaths: United States, 2011-2016. Natl Vital Stat Rep 2018; 67(9):1-14. 
5 
Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-
related death: a population-based nested case-control study. PLoS Med 2017; 
14(10):e1002396. 
6 
Hakkinen M, Vuori E, Kalso E, et al. Profiles of pregabalin and gabapentin abuse by 
postmortem toxicology. Forensic Sci Int 2014; 241:1-6. 
7 
Slavova S, Miller A, Bunn TL, et al. Prevalence of gabapentin in drug overdose 
postmortem toxicology testing results. Drug Alcohol Depend 2018; 186(5):80-5. 
8 
Mersfelder TL, Nichols WH. Gabapentin: abuse, dependence, and withdrawal. Ann 
Pharmacother 2016; 50(3):229-33. 
9 
Bonnet U, Scherbaum N. [On the risk of dependence on gabapentinoids]. Fortschr 
Neurol Psychiatr 2018; 86(2):82-105. 
10 Neurotin®. Package Insert. Parke-Davis, Division of Pfizer Inc. New York, NY. 2020. 
11 Diazepam. Package Insert. Genentech USA, Inc. South San Francisco, CA. 2016. 
12 Vernau KM, LeCouteur RA. Anticonvulsant drugs. In: Maddison JE, Page SW, Church 
DB, editors. Small animal clinical pharmacology. 2nd ed. Edinburgh: W.B. Saunders; 
2008: p. 367-9. 
13 Busto U, Kaplan HL, Zawertailo L, et al. Pharmacologic effects and abuse liability of 
bretazenil, diazepam, and alprazolam in humans. Clin Pharmacol Ther 1994; 55:451-63.  
14 Orzack MH, Friedman L, Dessain E, et al. Comparative study of the abuse liability of 
alprazolam, lorazepam, diazepam, methaqualone, and placebo. Int J Addict 
1988;23(5)(May ):449-67. 


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15 Funderburk FR, Griffiths RR, McLeod DR, et al. Relative abuse liability of lorazepam 
and diazepam: an evaluation in 'recreational' drug users. Drug Alcohol Depend 1988; 
22:215-22. 
16 RR-MEMO 720-30015. Abuse Liability of Pregabalin (CI-1008) in Recreational 
Sedative/Alcohol Users. 09 May 2001. 
17 US Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Assessment of abuse potential of drugs. In: 
Guidance for industry. Silver Spring, MD: Food and Drug Administration; 2017: 34 
pages. 
18 Schoedel KA, Szeto I, Setnik B, et al. Abuse potential assessment of cannabidiol (CBD) 
in recreational polydrug users: a randomized, double-blind, controlled trial. Epilepsy 
Behav 2018; 88(11):162-71. 
19 Eaton TA, Comer SD, Revicki DA, et al. Determining the clinically important 
difference in visual analog scale scores in abuse liability studies evaluating novel opioid 
formulations. Qual Life Res 2012; 21(6):975-81. 
20 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)(Mar):294-306. 

SAP_001.pdf: 
Protocol A9451181 
A PHASE 4, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO- AND 
ACTIVE-CONTROLLED, SINGLE-DOSE, FIVE-WAY CROSSOVER STUDY 
EVALUATING THE ABUSE POTENTIAL OF THREE DOSES OF NEURONTIN® 
TAKEN ORALLY IN HEALTHY, NON-DRUG DEPENDENT PARTICIPANTS WITH 
SEDATIVE DRUG ABUSE EXPERIENCE 
Statistical Analysis Plan  
(SAP) 
Version: 
4.0  
SAP Author:  
Date:  
27 January 2023 
NCT Number: NCT04570436


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Protocol A9451181                                                                                                             
27 January 2023
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Page 1
 
SIGNATURE PAGE
Prepared by:
Reviewed and Approved at Viatris, Inc. by:
 of Clinical Pharmacology Statistics & Data 
Manegement
Global Clinical Pharmacology
Viatris, Inc.


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TABLE OF CONTENTS 
SIGNATURE PAGE .................................................................................................................1 
LIST OF TABLES .....................................................................................................................3 
APPENDICES ...........................................................................................................................3 
1. VERSION HISTORY ............................................................................................................4 
2. INTRODUCTION .................................................................................................................5 
2.1. Study Objectives and Endpoints ...............................................................................6 
2.2. Study Design .............................................................................................................8 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9 
3.1. Primary Endpoint(s) ..................................................................................................9 
3.2. Secondary Endpoint(s) ..............................................................................................9 
3.3. Other Endpoint(s) ......................................................................................................9 
3.4. Baseline Variables ...................................................................................................10 
3.5. Safety Endpoints .....................................................................................................11 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................11 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................13 
5.1. Hypotheses and Decision Rules ..............................................................................13 
5.2. General Methods .....................................................................................................13 
5.3. Potential Additional Analysis ..................................................................................13 
6. ANALYSES AND SUMMARIES ......................................................................................14 
6.1. Study Validity Analysis of Endpoints .....................................................................14 
6.2. Analysis of Primary and Secondary Endpoints .......................................................14 
6.2.1. Sensitivity/Supplementary Analyses ..........................................................15 
6.2.2. Pharmacodynamic Analysis ........................................................................16 
6.2.3. Pharmacokinetic Analysis ..........................................................................17 
6.2.4. Electrocardiogram Analyses .......................................................................18 
6.2.5. Exploratory Analysis ..................................................................................18 
6.2.6. Safety Summaries and Analyses .................................................................18 
7. INTERIM ANALYSES .......................................................................................................18 
8. REFERENCES ....................................................................................................................18 
9. APPENDICES .....................................................................................................................20 
 


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LIST OF TABLES 
Table 1. 
Summary of Changes ..................................................................................4 
Table 2. 
Derivation of Pharmacodynamic Parameters ............................................9 
Table 3. 
Derivation of Pharmacokinetic Parameters .............................................10 
Table 4. 
Analysis Sets .............................................................................................11 
 
APPENDICES 
Appendix 1. SAS Code ............................................................................................................20 
Appendix 2. List of Abbreviations...........................................................................................25 
 
 
 


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1. VERSION HISTORY 
Table 1. 
Summary of Changes  
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1/ 
16 Nov 
2020 
Original 
20 May 
2020 
N/A 
N/A 
1.1/21 Oct 
2021 
V2.0, 11 
Dec 2020 
To add the definition 
of the Modified 
Completer 
Population 
 
To incorporate other 
clarifications and 
typographical edits 
x Section 4 Table 4: added definition of 
the Modified Completer Population  
x Section 4 Table 4: Evaluable 
Population will based on the Modified 
Completer Population, instead of 
Completer population 
x Section 5.2: specified that all PD 
analyses will be performed using the 
Modified Completer Population 
x Section 5.3: changed the heading to 
Potential Additional Analysis to 
match the contents better 
x Section 6.2: added description on how 
primary and secondary PD data will 
be summarized and presented 
x Other minor clarifications and 
typographical edits have been made in 
various sections 
1.2/25 Oct 
2021 
N/A 
To reflect scope of 
PK sample analysis 
and ensure the 
consistency within 
the section 
x Section 6.2.3: removed ‘if deemed 
necessary’ for the Placebo and 
Diazepam PK sample analysis. 
3.0 / 4 Jan 
2023 
V5.0 29 
Apr 2022 
Addional site added 
to the study 
 
Modify Evaluable 
Population 
 
 
Defining PK based 
Protocol Deviation 
 
 
Missing pre-dose 
VAS score 
 
x Update the model due to additional 
site added. 
 
x Change the Evaluable Population to 
be based on Modified Completer 
Population 
 
x PK deviations are pre-defined based 
on PK results according to PK 
expection. 
 
x The neutral VAS score will be used as 
the baseline value for High Emax and 


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Clarify the statistical 
model will be used in 
6.2.2 
 
Outline how to 
handle repeated 
VAS values.  
 
Update the 
statistical models 
to be used in 6.2 
and 6.2.2 
 
all AUEC calculation when the pre-
dose VAS is missing.  
 
x ANOVA was changed to linear 
mixed-effects model per FDA 
guidance and comment. 
 
x 
Repeated VAS values will be 
averaged for statistical analysis.  
 
 
x 
Updated the dependent and 
independent variable of the models 
 
4.0 / 27 Jan 
2023 
V5.0 29 
Apr 2022 
Defining the 
calculatable PK 
parameter 
 
 
Defining 
nordiazepam based 
major protocol 
devistion 
x A subject/period must have at least 3 
consecutive samples above LLOQ to 
be included in the PK parameter 
calculation. 
x A subject/period with significant 
measurable concentrations of the 
active metabolite of diazepam, N-
desmethyldiazepam, that is not 
consistent with diazepam dosing in 
that period or the following period 
(carryover due to long half-life of the 
metabolite or possible poor 
metabolizers) will be defined as a 
major protocol deviation.   
 
2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study A9451181. This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment. 
Neurontin® (gabapentin) is indicated for postherpetic neuralgia in adults, adjunctive therapy 
in the treatment of partial onset seizures, with and without secondary generalization in adults 
and pediatric patients 3 years and older with epilepsy. 
Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta or kappa), or 
cannabinoid 1 receptor sites; however, gabapentin abuse has been reported at increasing 


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rates. Individuals abusing gabapentin describe experiences such as euphoria, improved 
sociability, relaxation and a marijuana-like “high”.1-8  
There are post-marketing reports of abuse and individuals experiencing withdrawal 
symptoms shortly after discontinuing higher than recommended doses of gabapentin used to 
treat illnesses for which the drug is not approved. Such symptoms included agitation, 
disorientation and confusion after suddenly discontinuing gabapentin that resolved after 
restarting gabapentin. Most of these individuals were taking higher than recommended doses 
of gabapentin for unapproved uses and had a history of poly-substance abuse or used 
gabapentin to relieve symptoms of withdrawal from other substances.  
Epidemiological studies have shown that gabapentin may have abuse potential, particularly 
among individuals with a history of opioid abuse. Gabapentin abuse is reported both alone 
(i.e., without other drugs), and in conjunction with opioids to enhance the ‘high’ obtained 
from opioids. 1,4 Further, published data suggest that gabapentin is recorded on death 
certificates suggesting drug overdose, both as the primary and contributory causes of death, 
and reported with and without other drugs like opioids, benzodiazepines, and alcohol.1,5-7  
This clinical trial will evaluate gabapentin in a cross-over design with comparison to placebo 
and a positive control, diazepam, regarding abuse-related subjective responses, physiological 
responses (including an assessment of respiratory depression), and drug pharmacokinetics in 
a healthy non-drug dependent population with drug abuse experience with sedative drugs.  
2.1. Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary:  
Primary:  
x 
To assess the potential abuse liability of orally 
administered Neurontin® taken alone 
compared to placebo in a healthy non-drug 
dependent participants with drug abuse 
experience under fasted condition. 
x 
Bipolar visual analog scale (VAS) for “Drug 
Liking” maximum effect (Emax) as obervered 
directly from the data without baseline 
correction 
Secondary:  
Secondary:  
x 
To evaluate additional pharmacodynamic 
(PD) effect, pharmacokinetics (PK), and safety 
of Neurontin® or diazepam taken alone in a 
healthy non-drug dependent participants with 
drug abuse experience under fasted condition. 
PD endpoints: 
x 
Bipolar VAS for “Drug Liking” (Time for Emax 
[TEmax], area under the effect-time profile from 
time 0 to the time of the last quantifiable 
concentration [AUEClast], and partial AUECs 
[AUEC1, AUEC2, AUEC3, AUEC4, AUEC8]). 
x 
Unipolar VAS for “High” (Emax, TEmax, 
AUEClast, and partial AUECs [AUEC1, AUEC2, 
AUEC3, AUEC4, AUEC8]). 
x 
Bipolar VAS for “Take Drug Again” at 24, 36, 
48, and 72 hour post-dose. 


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Objectives 
Endpoints 
x 
Bipolar VAS for “Overall Drug Liking” at 24, 
36, 48, and 72 hours post-dose. 
x 
Unipolar VAS for “Good Drug Effect”. 
x 
Unipolar VAS for “Bad Drug Effect”.  
x 
Unipolar VAS for “Any Drug Effect”.  
x 
Observer-rated assessment of alertness/sedation. 
PK endpoints: 
x 
Cmax, time for Cmax (Tmax), area under the 
effect-time profile from time 0 to the time of the 
last quantifiable concentration (AUClast) of 
gabapentin and, if deemed necessary for 
diazepam and its active metabolite 
(N-desmethyldiazepam).  
x 
Area under the plasma concentration-time 
profile from time 0 extrapolated to infinity time 
(AUCinf), and terminal half-life (t½), if data 
permits, of gabapentin and, if deemed necessary 
for diazepam and its active metabolite 
(N-desmethyldiazepam).  
x 
Partial AUCs (AUC1, AUC2, AUC3, AUC4, and 
AUC8) of gabapentin and, if deemed necessary 
for diazepam and its active metabolite 
(N-desmethyldiazepam).  
Safety endpoints: 
x 
Vital signs (respiratory rate [RR], blood 
pressure [BP], pulse rate [PR]). 
x 
Oxygen saturation of hemoglobin (SpO2). 
x 
Physical examination. 
x 
12-lead electrocardiogram (ECG). 
x 
Clinical lab and AEs. 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
x 
Exposure-response relationship between drug 
(gabapentin or diazepam) concentrations and 
selected PD effect. 
x 
To enable exploratory research through 
collection of banked biospecimens, unless 
x 
Correlation between drug (gabapentin or 
diazepam) concentrations and selected PD 
endpoints (Bipolar VAS for “Drug Liking”, 
Unipolar VAS for “High”), as data permit.  


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Objectives 
Endpoints 
prohibited by local regulations or ethics 
committee decision.   
x 
Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study). 
2.2. Study Design 
This will be a multi-center, randomized, double-blind, double-dummy, placebo- and 
active-controlled, 5-treatment, 10-sequence, 5-period crossover single-dose, Williams square 
design study in healthy adult, non drug-dependent male and female participants with drug 
abuse experience with sedative drugs. The study includes Screening, a Qualification Phase, a 
Treatment Phase and Follow-up. This study will randomize approximately 50 participants to 
ensure at least 32 participants complete the Treatment Phase of the study. Dropouts in the 
treatment phase for non-safety reasons may be replaced at the discretion of investigator in 
consultation with the sponsor.   
The following study visits are required, see Figure 1 and the SoA (Table 1 and Table 2) of 
the protocol: 
x Visit 1, Screening will occur within 28 days prior to Visit 2. 
x Visit 2, Qualification Phase will require inpatient stay at the clinical research unit 
(CRU) for 3 nights: 
x Naloxone Challenge Phase, Day -1. 
x Drug Discrimination, Days 1 and 2 will require inpatient stay at the CRU for 
2 nights. 
x End of Drug Discrimination requires an inpatient stay at the CRU overnight to 
ensure discharge occurs 24 hours after receiving diazepam or placebo.  
x Participant will proceed to Visit 3 after at least 14 and no more than 28-day 
washout.  
x Visits 3 to 7, Treatment Phase: 
x Each visit will require an inpatient stay at the CRU of 3 or 4 nights.  
x Each visit will be separated by a washout period of at least 14 days. 
x End of Study Assessments will be at the CRU 72 hours after completing the last study 
drug dosing at the end of period 5 or at the time of early withdrawal. 
x For the entire study, 18 - 23 overnight inpatient stays will be required. 


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3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
The following parameter will be calculated for VAS for “Drug Liking” during each 
Treatment Period: 
x Maximum (peak) effect (Emax) as observed directly from the data.  
3.2. Secondary Endpoint(s) 
The following parameters will be calculated for VAS for “Drug Liking” and VAS for “High” 
during each Treatment Period: 
Table 2. 
Derivation of Pharmacodynamic Parameters 
Parameter 
Definition 
Method of Determination 
Emax (High only) 
Maximum change from pre-dose 
response 
Observed directly from data. If 
Emax is less than 0 then 0 will 
be used as the Emax values. 
TEmax 
Time for Emax 
Observed directly from data as 
time of first occurrence 
AUEClast 
Area under the effect-time profile from 
time zero to the time of  the last 
quantifiable effect (Elast) 
Linear trapezoidal method 
AUEC1 
Area under the effect-time profile from 
time zero to 1 hour postdose 
Linear trapezoidal method 
AUEC2 
Area under the effect-time profile from 
time zero to 2 hours postdose 
Linear trapezoidal method 
AUEC3 
Area under the effect-time profile from 
time zero to 3 hours postdose 
Linear trapezoidal method 
AUEC4 
Area under the effect-time profile from 
time zero to 4 hours postdose 
Linear trapezoidal method 
AUEC8 
Area under the effect-time profile from 
time zero to 8 hours postdose 
Linear trapezoidal method 
 
The additional endpoints of VAS for “Overall Drug Liking”, “Take Drug Again”, “Good 
Drug Effect”, “Bad Drug Effect”, and “Any Drug Effect” and the observer-rated assessment 
of alertness/sedation will be summarized by timepoints. 
3.3. Other Endpoint(s) 
PK parameters will be derived from the concentration-time profiles as shown in Table 3. 
A subject/period must have at least 3 consecutive samples above LLOQ to be included in the 
PK parameter calculation. 


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Table 3. 
Derivation of Pharmacokinetic Parameters 
Parameter 
Definition 
Method of Determination 
Cmax 
Maximum plasma concentration 
Observed directly from data 
Tmax 
Time for Cmax 
Observed directly from data as 
time of first occurrence 
AUClast 
Area under the plasma concentration-
time profile from time zero to the time 
of the last quantifiable concentration 
(Clast) 
Linear up/Log linear down 
trapezoidal method 
AUCinfa 
Area under the plasma concentration-
time profile from time zero extrapolated 
to infinity time 
AUClast + (Clast*/kel), 
where Clast* is the predicted 
plasma concentration at the 
last quantifiable time point 
estimated from the log-linear 
regression analysis. 
AUC1 
Area under the plasma concentration-
time profile from time zero to 1 hour 
postdose 
Linear up/Log linear down 
trapezoidal method 
AUC2 
Area under the plasma concentration-
time profile from time zero to 2 hours 
postdose 
Linear up/Log linear down 
trapezoidal method 
AUC3 
Area under the plasma concentration-
time profile from time zero to 3 hours 
postdose 
Linear up/Log linear down 
trapezoidal method 
AUC4 
Area under the plasma concentration-
time profile from time zero to 4 hours 
postdose 
Linear up/Log linear down 
trapezoidal method 
AUC8 
Area under the plasma concentration-
time profile from time zero to 8 hours 
postdose 
Linear up/Log linear down 
trapezoidal method 
t1/2a 
 
 
 
Terminal elimination half-life 
 
Loge(2)/kel, 
where kel is the terminal phase 
rate constant calculated by a 
linear regression of the 
log-linear concentration-time 
curve. Only those data points 
judged to describe the terminal 
log-linear decline will be used 
in the regression. 
a. If data permit.  
3.4. Baseline Variables 
The pre-dose psychometric measurements of each period will be the baseline for calculating 
the changes in these parameters post dose. 


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When the pre-dose psychometric measures were not collected or missing, the neutral VAS 
point (50 for Drug liking, 0 for High) will be used as baseline for Emax (High only) and 
AUEC calculation purpose. 
3.5. Repeated VAS values 
For post-dose VAS data collection, when VAS evaluations were taken within a 10-minute 
window, the values will be treated as repeated measures. In this case, the mean value will be 
used for the VAS score; the median time will be used as the data collection time. 
For pre-dose VAS data collection, when there were multiple VAS values collected, the 
values will be averaged to be the baseline values.  
 
3.6. Safety Endpoints 
Any adverse events (AEs) occurring following start of treatment or increasing in severity will 
be counted as treatment emergent.  
Adverse events that occur in a non-treatment period (for example, Washout or Follow-up) 
will be counted as treatment emergent and attributed to the previous treatment. 
Adverse events will be summarized by treatment and Phase of the study (i.e., Naloxone 
Challenge Phase, Drug Discrimination Phase, and Treatment Phase).   
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters): 
x adverse events, 
x laboratory data, 
x vital signs data (respiratory rate [RR], blood pressure [BP], pulse rate [PR]).  
x 
12-lead electrocardiogram (ECG).  
 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding, other than the Modified Completer 
Population and Evaluable Population which will be done after unblinding, and releasing the 
database and classifications will be documented per standard operating procedures. 
Table 4. 
Analysis Sets 
Population 
Description 
Safety 
The Safety Population will include all participants who receive 
at least one dose of study drug, beginning with the Naloxone 
Challenge. This population will be analyzed as treated. 
PK 
The PK population will include all enrolled participants treated 
who have at least 1 concentration in the Treatment Phase. The 
PK parameter analysis population will include all enrolled 


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Table 4. 
Analysis Sets 
Population 
Description 
participants treated who have at least 1 of the PK parameters 
of interest. 
Completer 
The Completer Population will include all randomized 
participants who complete all 5 periods of the 
Treatment Phase and who contribute post-dose PD data 
during each period. These participants must have at 
least one post-dose response on the VAS for Drug Liking 
within 2 hours of Tmax for each treatment group: ie, at 
least one VAS response within the interval 0-3h postdose 
(assuming the Tmax of 20 mg diazepam is 1h) and at 
least one VAS response within the interval 1-5h postdose 
(assuming the Tmax of 600/1200/1800 mg gabapentin is 
3h).  This population will be analyzed as randomized. 
Modified Completer 
The Modified Completer Population will include all 
randomized participants in the Completer Population, 
excluding any participants who meet either or both of the 
following criteria for Drug Liking VAS:  
1. Emax scores are within a 5 point difference across all five 
treatments (ie, Maximum Emax score – Minimum Emax score ≤5);  
2. Emax(P) > 60 AND Emax(P) - Emax(Dia20) ≥5;  
where Emax(P) and Emax(Dia20) are the VAS Emax scores for 
placebo and diazepam 20 mg, respectively.  
 
This population will be analyzed as randomized. 
Evaluable 
The Evaluable Population will include all randomized 
participants in the Modified Completer Population who do not 
have major protocol violations or adverse events that would 
interfere with drug absorption, such as vomiting within 4 hours 
of study drug administration. Major protocol violations, 
including deviations related to study drug intake, are defined as 
those that could potentially affect the PD conclusions of the 
study.  Prior to unblinding the Treatment Phase data, the 
Sponsor (or designee) will identify protocol violations or 
adverse events that would disqualify a participatnt from the 
evaluable population and determine which participants or 
participant visits will be excluded. This population will be 
analyzed as randomized. 
   


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5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
To assess the abuse potential of gabapentin, the following tests will be performed in the order 
they are given: 
Study Validation: 
The sensitivity and integrity of the study will be validated by comparing the mean responses 
of diazepam, the positive control (C), to the placebo (P):  
H0: μC - μP İ ¥1 versus Ha: μC - μP > δ1 where δ1 = 15. 
Gabapentin versus diazepam: 
1. Does gabapentin (T) produce mean responses that show less abuse potential than 
diazepam (C)? 
H0: μC - μT İ ¥2 versus Ha: μC - μT > δ2 where δ2 = 0. 
Gabapentin versus placebo (Primary): 
2. Does gabapentin (T) produce mean responses that show abuse potential similar to 
placebo (P)? 
H0: μT - μP ı ¥3 versus Ha: μT - μP < δ3 where δ3 = 11. 
For each of the gabapentin hypotheses, the statistical significance of the test will be assessed 
for all doses of gabapentin. 
The study will be considered validated if the one-sided p-value for the validation hypothesis 
test is less than 0.05. 
5.2. General Methods 
Statistically, the study will be evaluated as a safety study. Consequently, the null hypothesis 
for gabapentin will be constructed on the presumption that these treatments produce abuse 
potential similar to placebo. To demonstrate that these treatments have no abuse potential the 
null hypothesis will be statistically rejected.   
All PD analyses will be performed using the Modified Completer Population and all 
available post-dose data; these will be the primary PD analyses. 
5.3. Potential Additional Analysis 
Key PD analyses may be repeated on the Evaluable Population using all available post-dose 
data.  


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6. ANALYSES AND SUMMARIES 
6.1. Study Validity Analysis of Endpoints 
Study validity will first be confirmed through the comparison of mean Emax for Drug Liking 
between diazepam 20 mg and placebo administered during the Treatment Phase. This 
comparison will be made using a mixed-effect model with site, sequence, site by sequence 
interaction, period, treatment and site by treatment interaction as fixed effects, and 
participant nested within site by sequence as a random effect. If site by treatment interaction 
is not signfiant by p level of 0.1 then the term will be dropped form the final model. If the 
treatment comparison of diazepam 20 mg vs. placebo is statistically significant by a margin 
of 15 (ie, one-sided p İ0.05) in the appropriate direction, it will confirm the sensitivity of 
the study. If study validity is not confirmed, comparisons between gabapentin and diazepam 
will not be performed. 
6.2. Analysis of Primary and Secondary Endpoints 
A linear mixed-effects model that includes site, sequence, site by sequence, period, treatment 
and site by treatment as fixed effects, and the participant nested within site by sequence as a 
random effect will be used, baseline will be used as covriate for High Emax calcualtion. If 
site by treatment interaction is not signfiant by p level of 0.1 then the term will be dropped 
form the final model. The primary analyses of abuse potential will be based on testing the 
differences between the means from the primary measure(s) at the peak of drug response 
effects (VAS Drug Liking Emax) produced by gabapentin, diazepam and placebo at a 
significance level of 0.05 (1-sided). 
The primary PD endpoint is the Emax of bipolar VAS for “Drug Liking”.  
The principal parameters for the primary and secondary endpoints will be summarized by 
treatment using descriptive statistics (mean, standard deviation [SD], median, first and third 
quartiles, minimum and maximum). These parameters will be analyzed using a mixed-effect 
model with site,  sequence, site by sequence, period, treatment and sitey by treatment as fixed 
effects, and participant nested within the site by sequence as a random effect; site by 
treatment interaction will be tested first, the interaction term will be removed from the final 
model when the interaction test p value is less than 0.1. Analyses of endpoints (VAS Feel 
High Emax) with baseline (pre-dose) measurements will include the baseline measurement as 
a covariate in the model. Least squares means, standard errors, and 90% confidence intervals 
will be provided for each treatment and for the difference between treatments. Data will be 
summarized graphically, where appropriate. 
The treatment comparison to test for study validity will be: 
x diazepam 20 mg vs. placebo; (This comparison is used for validation of the study and 
adjustments for multiple comparisons will not be applied for this treatment 
comparison).  
Comparisons of gabapentin versus diazepam will be: 
x gabapentin 600 mg vs. diazepam 20 mg;  


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x gabapentin 1200 mg vs. diazepam 20 mg; 
x gabapentin 1800 mg vs. diazepam 20 mg.  
Comparisons of gabapentin versus placebo will be (Primary): 
x gabapentin 600 mg vs. placebo;  
x gabapentin 1200 mg vs. placebo;  
x gabapentin 1800 mg vs. placebo. 
Statistical significance of all treatment differences will be reported.  All statistical tests will 
be conducted using one tailed significance criteria.  These comparisons will be used to assess 
the primary study objective.  
The additional endpoints of VAS for “Overall Drug Liking”, “Take Drug Again”, “Good 
Drug Effect”, “Bad Drug Effect”, and “Any Drug Effect” and the observer-rated assessment 
of alertness/sedation will be summarized by timepoints. 
Mean time plots (linear scale) against nominal time postdose by treatment (all treatments on 
the same plot) of VAS for“Drug Liking”, “High”, “Overall Drug Liking”, “Take Drug 
Again”, “Good Drug Effect”, “Bad Drug Effect”, and “Any Drug Effect” will be presented. 
6.2.1. Sensitivity/Supplementary Analyses 
Regression diagnostics will be performed to verify model assumptions and adequacy of the 
fitted linear models for the primary endpoints. Levene’s test will be used to diagnose 
potential heterogeneity of variance and the Shapiro–Wilk test will be used to diagnose 
potential non-normality of the model residuals. 
If the resulting p-value from Levene’s test is İ0.05, the null hypothesis of equal variances is 
rejected and it will be concluded that there is a difference between the treatment group 
variances. An unequal variance model will then be applied using the Satterthwaite method in 
order to produce an accurate F-approximation. 
If the resulting p-value from the Shapiro-Wilk test is İ0.05, symmetry of the distribution of 
paired differences will be tested using the Triples Test and either the t-test (symmetry) or 
sign test (asymmetry) will be performed. 
If needed (Shapiro-Wilk test has a p-value İ0.05), symmetry will be tested for each of the 
primary comparisons using the Triples Test in the following manner: 
1. Calculate the paired differences of the treatments being compared 
2. Calculate T as follows: 


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4. Calculate the test statistic  
 
5. If 
 then the distribution of the differences in responses will be considered 
asymmetric, otherwise they will be considered symmetric. 
The test for median of differences for each treatment comparison and endpoint (Emax) will 
be determined by the t test if the paired differences are symmetric, or by the Sign Test if the 
paired differences are asymmetric.  
6.2.2. Pharmacodynamic Analysis 
For PD parameter values are not analyzed in primary and secondary endpoints., Descriptive 
statistics will be reported by treatment and by hours . The values will be analyzed with linear 
mixed-effect model consisting of: Site, Sequence, Site*Sequence, Period, Treatment, Time, 
Period*Time, Treatment*Time, and site by treatment terms as fixed effects, and a participant 
(site*Sequence) term as a random effect; site by treatment interaction will be tested first, the 
interaction term will be removed from the final model when the interaction test p value is less 
than 0.1. To accommodate the repeated measures aspect of the design, a compound 
symmetric covariance matrix will be employed, with the participant set to Participant 
(Site*Sequence). The Treatment*Time least-squares means and differences among them will 
be assessed for trends likely to be of clinical relevance. 
Descriptive statistics of the mean, standard error, and other summary statistics such as 
minimum, first quartile (Q1), median, third quartile (Q3) and maximum for each subjective 
measure, each treatment and each paired difference among treatments will be calculated and 
used to create tables and graphs. 
As an exploratory analysis, the time course of the different subjective measures in relation to 
each other (and to abuse-related AEs) will evaluate the outcome of positive or negative 
assessments of the drug before, during and after the peak of drug effects. The physiological 
effects such as pulse rate, blood pressure and respiratory rate will be monitored over the 


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course of the study session and correlated to both the drug dose administered and the PK of 
the drug. 
6.2.3. Pharmacokinetic Analysis 
Blood samples will be collected throughout a study session in order to assess drug PK.  
Samples from gabapentin treatment will be analyzed using a validated analytical method in 
compliance with Viatris standard operating procedures. The samples of placebo and 
diazepam (including its major active metabolite: N-desmethyldiazepam) will be analyzed. 
This will be done to primarily confirm that plasma levels of the drug are equivalent between 
participants and to evaluate whether subjective measures and AEs can be correlated with 
drug levels over time. Typically, blood will be drawn immediately after the collection of 
subjective measures are completed at each time point. If an analysis shows that a participant 
had low plasma levels of a drug, it may account for a lack of subjective responses in a drug 
session.  
The PK parameter values for gabapentin and if deemed necessary, for diazepam (including 
its major active metabolite as data permit: N-desmethyldiazepam) will be calculated for each 
non-placebo treatment and each participant using noncompartmental analysis of 
concentration-time data. PK parameter values that will be evaluated are listed in Table 3. 
PK parameters (Table 3) will be calculated for each participant/period/analyte using 
noncompartmental analysis of concentration-time data. Concentration values below the 
LLOQ were set to 0 before any summary, analyses and date presentations. Actual sample 
collection times will be  used for the PK analysis. 
A subject/period which lacks of any measurable concentrations or only has very low plasma 
concentrations on a supposed non-placebo period(s) will be defined as a major protocol 
deviation. A subject/period is considered to have very low plasma concentrations if its AUC 
is less than 5% of the corresponding analyte/treatment geometric mean AUC (which should 
be calculated without inclusion of data from the outlying subject). 
A subject/period, with significant measurable concentrations on the placebo period or a 
specific treatment period in which the drug was not administered, will be defined as a major 
protocol deviation. A subject/period is considered to have significant plasma concentrations 
if its AUC is more than 5% of corresponding analyte and treatment geometric mean AUC. In 
the case of Gabapentin concentration, the 600 mg dose period will be used as the reference 
geometric mean.  
A subject/period with significant measurable concentrations of the active metabolite of 
diazepam, N-desmethyldiazepam, that is not consistent with diazepam dosing in that period 
or the following period (carryover due to long half-life of the metabolite or possible poor 
metabolizers) will be defined as a major protocol deviation.  A subject/period is considered 
to have significant plasma concentrations if its AUC is more than 5% of corresponding 
analyte and treatment geometric mean AUC. 
Any period with the pre-dose concentration over 5% of the Cmax of the same period will be 
defined as major protocol deviation for that period.  


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A subject at any period classified as a major protocol deviation will be further excluded from 
the Evaluable Population for that period.The PK parameters (AUCinf, AUClast, Cmax, tmax, t½, 
partial AUCs [AUC1, AUC2, AUC3, AUC4, AUC8]) will be derived for each 
participant/period/analyte and will be summarized by treatment and analyte. PK parameters 
for individual participant, as well as summary statistics (eg, group averages, SD, geometric 
means, coefficient of variation [CV], and geometric CV%) by treatment will be reported for 
PK parameters, as appropriate. Plasma concentration-time profiles of gabapentin, diazepam 
and its metabolite (N-desmethyldiazepam) will be presented. Concentrations will be listed 
and summarized by PK sampling time and treatment for each analyte. 
6.2.4. Electrocardiogram Analyses 
Electrocardiogram results collected at Screening will be listed. 
6.2.5. Exploratory Analysis 
Exploratory analysis may be conducted to evaluate the correlation between drug (gabapentin 
or diazepam) concentrations and selected PD endpoints (Bipolar VAS for “Drug Liking” and 
Unipolar VAS for “High”), as data permit. 
6.2.6. Safety Summaries and Analyses 
All safety analyses will be performed on the safety population. 
The safety data will be described and summarized in accordance with the sponsor’s Data 
Standards. 
AEs, ECGs, BP, RR, PR, SpO2, continuous cardiac monitoring, and safety laboratory data 
will be reviewed and summarized on an ongoing basis during the study to evaluate the safety 
of participants. Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential 
clinical concern will be described. Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate. 
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported. 
7. INTERIM ANALYSES 
No formal interim analysis will be conducted for this study. 
8. REFERENCES 
1. 
Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. 
Drugs 2017; 77(4):403-26. 


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2. 
Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among 
nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry 2015; 
172(5):487-8. 
3. 
Wilens T, Zulauf C, Ryland D, et al. Prescription medication misuse among opioid 
dependent patients seeking inpatient detoxification. Am J Addict 2015; 24(2):173-7. 
4. 
Hedegaard H, Bastian BA, Trinidad JP, et al. Drugs most frequently involved in drug 
overdose deaths: United States, 2011-2016. Natl Vital Stat Rep 2018; 67(9):1-14. 
5. 
Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-
related death: a population-based nested case-control study. PLoS Med 2017; 
14(10):e1002396. 
6. 
Hakkinen M, Vuori E, Kalso E, et al. Profiles of pregabalin and gabapentin abuse by 
postmortem toxicology. Forensic Sci Int 2014; 241:1-6. 
7. 
Slavova S, Miller A, Bunn TL, et al. Prevalence of gabapentin in drug overdose 
postmortem toxicology testing results. Drug Alcohol Depend 2018; 186(5):80-5. 
8. 
Mersfelder TL, Nichols WH. Gabapentin: abuse, dependence, and withdrawal. Ann 
Pharmacother 2016; 50(3):229-33. 
9. 
Randles RH, Fligner MA, Policello GE II, Wolfe DA. “An Asymptotically Distribution-
Free Test for Symmetry Versus Asymmetry,” Journal of the American Statistical 
Association, 1980; 369 (75): 168-172. 
 


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9. APPENDICES 
Appendix 1. SAS Code 


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  run; 
 
 


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%TRIPLETEST(TEST,DIFF,TRIPLES TEST ON DIFFERENCES); 
Appendix 2. List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the curve 
AUEC 
area under the effect-time profile from time zero to the last 
quantifiable effect 
BP 
blood pressure 
Cmax 
maximum observed concentration 
CRU 
Clinical Research Unit 


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Abbreviation 
Term 
CV 
coefficient of variation 
ECG 
electrocardiogram 
Emax 
maximum effect 
GABA 
gamma-amino butyric acid 
HCl 
hydrochloride 
IR 
immediate release 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
Q1 
first quartile (25th percentile) 
Q3 
third quartile (75th percentile) 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
Schedule of Activities 
Tmax 
time of maximum concentration 
VAS 
visual analog scale