Clinical trial NCT05053126
Conditions: Abuse Potential
Keywords: Lyrica Pregabalin Oxycodone Opioid Abuse liability
Sponsor: Viatris Specialty LLC
Start date: 2021-07-27; Completion date: 2022-04-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase 4 clinical study in healthy non-drug dependent recreational opioid users to assess the abuse potential of Lyrica when taken alone or in combination with oxycodone.

Detailed description:
This is a randomized, double-blind, double-dummy, placebo- and active-controlled, 6-treatment, 6-period crossover, single-dose study in healthy male and/or female adult, non drug-dependent recreational opioid users. The study includes Screening, a Qualification Phase, a Treatment Phase and Follow-up. This study will randomize approximately 60 adult male and female (at least 20% female) participants (10 participants in each sequence) in the Treatment Phase to ensure at least 48 participants complete the Treatment Phase of the study. There will be 8 visits to the clinic in total and a follow-up telephone call at the end of the study. The duration of participation will be approximately 16 weeks and 7 of the visits will involve clinic stays of 4 days/3 nights.

Arms: arm 1: Single Dose arm 2: Single Dose arm 3: Single Dose arm 4: Single Dose arm 5: Single Dose arm 6: Single Dose
Interventions: intervention 1: Pregabalin 300mg intervention 2: pregabalin 450 mg intervention 3: Pregabalin 300 mg with oxycodone 20 mg intervention 4: pregabalin 450 mg with oxycodone 20 mg intervention 5: oxycodone 20 mg intervention 6: Placebo
Intervention descriptions: intervention 1: Participant will receive an oral dose of pregabalin 300 mg intervention 2: Participant will receive an oral dose of pregabalin 450 mg intervention 3: Participant will receive an oral dose of pregabalin 300 mg and oxycodone 20 mg intervention 4: Participant will receive an oral dose of pregabalin 450 mg and oxycodone 20 mg intervention 5: Participant will receive an oral dose of oxycodone 20 mg intervention 6: Participant will receive an oral dose of placebo

Protocol documents:
Prot_000.pdf: 
PD-144723 
Protocol A0081365 
Final Protocol Amendment 3, 17 Nov 2021 
 
 
Upjohn US 1 LLC CONFIDENTIAL  
Page 1 
A PHASE 4, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, 
PLACEBO-AND ACTIVE-CONTROLLED, SINGLE-DOSE, SIX-WAY 
CROSSOVER STUDY EVALUATING THE ABUSE POTENTIAL OF LYRICA® 
TAKEN ORALLY CONCOMITANTLY WITH OXYCODONE HYDROCHLORIDE 
IN HEALTHY NON-DRUG DEPENDENT, RECREATIONAL OPIOID USERS  
 
Investigational Product Number: 
PD-144723 
Investigational Product Name: 
Lyrica® (pregabalin) 
United States (US) Investigational New 
Drug (IND) Number:  
053763 
European Clinical Trials Database 
(EudraCT) Number: 
Not Applicable (N/A) 
Protocol Number: 
A0081365 
Phase: 
4 
Short Title: Evaluating the Abuse Potential of Lyrica When Taken Orally Concomitantly 
with Oxycodone Hydrochloride in Healthy Non-drug Dependent, Recreational Opioid 
Users 
Sponsor: 
Upjohn US 1 LLC 
235 East 42nd Street 
New York, NY 10017-5703 
Sponsor Contacts: 
 
Clinical Sciences 
 
 
 
 
 
 
 
 
Global Clinical Operations 
 
  
 
 
 
This document and accompanying materials contain confidential information belonging to Upjohn.  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, Upjohn must be 
promptly notified. 
 
NCT05053126


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Upjohn US 1 LLC CONFIDENTIAL  
Page 2 
PROTOCOL APPROVAL – SPONSOR SIGNATORY 
Study Title 
A phase 4, randomized, double-blind, double-dummy, placebo-and 
active-controlled, singLe-dose, six-way crossover study evaluating the 
abuse potential of Lyrica® taken orally concomitantly with Oxycodone 
hydrochloride In healthy non-drug dependent, recreational opioid users  
 
Protocol Number A0081365 
Amendment No. 
3.0  
Protocol Date 
17 Nov 2021  
 
Protocol accepted and approved by: 
 
Global Clinical Operations 
 
Signature 
 
Date 
 
  
Clinical Sciences
 
Signature 
 
Date 
 
 


PD-144723 
Protocol A0081365 
Final Protocol Amendment 3, 17 Nov 2021 
 
 
Upjohn US 1 LLC CONFIDENTIAL  
Page 3 
Protocol Amendment Summary of Changes Table 
Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Amendment 3 
17 November 2021 
x Administrative changes to update Sponsor 
contact details and authorized sponsor 
protocol approver 
x Changes to allow more forms of female 
contraception 
Complete summary of changes is provided in 
Appendix 10.12 
Amendment 2 
23 December 2020 
x The sponsor for this study is changed from 
‘Pfizer’ to ‘Upjohn US 1 LLC’ 
x Administrative and typographic changes for 
harmonization within the protocol were 
implemented. 
Complete summary of changes is provided in 
Appendix 10.12 
Amendment 1 
12 November 2020  
Updated sample size of Enrolled and Completer 
populations in section 1.2, section 4.1 and 
section 9.2. 
Added The Modified Completer Population 
criteria in Section 9.3. 
The Modified Completer Population will 
include all randomized participants in the 
Completer Population, however will exclude 
any participant who meets either or both of the 
following criteria for Drug Liking VAS: 
1. Emax scores are within a 5 point difference 
across all 6 treatments (ie, Maximum Emax 
score – Minimum Emax score ≤5). 
2. Emax(P) >60 and Emax(P) - Emax(Oxy20) ≥5.  
Where Emax(P) and Emax(Oxy20) are the VAS 
Emax scores for placebo and oxycodone HCl IR 
20 mg, respectively. 
Original 
Protocol  
13 October 2020 
Not applicable (N/A) 
 


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Upjohn US 1 LLC CONFIDENTIAL  
Page 4 
TABLE OF CONTENTS 
LIST OF TABLES..............................................................................................................9 
LIST OF FIGURES ............................................................................................................9 
1. PROTOCOL SUMMARY.............................................................................................10 
1.1. Synopsis (Not Applicable) .................................................................................10 
1.2. Schema .............................................................................................................10 
1.3. Schedule of Activities (SoA) .............................................................................11 
2. INTRODUCTION ........................................................................................................16 
2.1. Study Rationale .................................................................................................16 
2.2. Background ......................................................................................................17 
2.2.1. Clinical Overview .................................................................................17 
2.3. Benefit/Risk Assessment ...................................................................................18 
3. OBJECTIVES AND ENDPOINTS................................................................................19 
4. STUDY DESIGN .........................................................................................................20 
4.1. Overall Design ..................................................................................................20 
4.1.1. Screening ..............................................................................................21 
4.1.2. Qualification Phase (Visit 2; Days 0 to 3) ...............................................21 
4.1.2.1. Naloxone Challenge (Day 0) .................................................21 
4.1.2.2. Instrument Training...............................................................22 
4.1.2.3. Drug Discrimination (Days 1 to 3) .........................................22 
4.1.3. Treatment Phase (Visits 3 to 8) ..............................................................23 
4.2. Scientific Rationale for Study Design.................................................................23 
4.3. Justification for Dose.........................................................................................24 
4.4. End of Study Definition.....................................................................................25 
5. STUDY POPULATION................................................................................................25 
5.1. Inclusion Criteria ..............................................................................................25 
5.2. Exclusion Criteria .............................................................................................26 
5.3. Lifestyle Considerations ....................................................................................29 
5.3.1. Meals and Dietary Restrictions ..............................................................29 
5.3.2. Caffeine, Alcohol, and Tobacco .............................................................29 
5.3.3. Activity.................................................................................................30 
5.3.4. Contraception ........................................................................................30 


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5.4. Screen Failures..................................................................................................30 
6. STUDY INTERVENTION ...........................................................................................30 
6.1. Study Interventions Administered ......................................................................30 
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 ..................................32 
6.3.1. Allocation to Investigational Product .....................................................32 
6.3.2. Breaking the Blind ................................................................................33 
6.4. Study Intervention Compliance..........................................................................33 
6.5. Concomitant Therapy ........................................................................................33 
6.6. Dose Modification.............................................................................................34 
6.7. Emergency Intervention ....................................................................................34 
6.8. Intervention After the End of the Study ..............................................................34 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................34 
7.1. Discontinuation of Study Intervention ................................................................34 
7.2. Participant Discontinuation/Withdrawal from the Study .....................................36 
7.3. Lost to Follow up ..............................................................................................37 
8. STUDY ASSESSMENTS AND PROCEDURES ...........................................................37 
8.1. Efficacy Assessments ........................................................................................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. Pupillometry .........................................................................................40 
8.2.4. Electrocardiograms................................................................................41 
8.2.4.1. Continuous Cardiac Monitoring by Telemetry........................41 
8.2.5. Clinical Safety Laboratory Assessments .................................................42 
8.2.6. Suicidal Ideation and Behavior Risk Monitoring.....................................42 
8.2.6.1. Columbia Suicidality Severity Rating Scale (C-SSRS) ...........42 


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8.2.6.2. Risk Assessment During Screening........................................42 
8.2.6.3. Risk Assessment During the Study ........................................43 
8.2.7. Pregnancy Testing .................................................................................43 
8.3. Adverse Events and Serious Adverse Events ......................................................44 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ......44 
8.3.1.1. Reporting SAEs to Pfizer Safety ............................................45 
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 .............................................46 
8.3.5.3. Occupational Exposure..........................................................46 
8.3.6. Medication Errors..................................................................................47 
8.4. Treatment of Overdose ......................................................................................47 
8.5. Pharmacokinetics ..............................................................................................48 
8.6. Pharmacodynamics ...........................................................................................49 
8.6.1. Subjective Effects..................................................................................49 
8.6.1.1. Visual Analog Scale (VAS) ...................................................49 
8.7. Genetics............................................................................................................50 
8.7.1. Specified Genetics .................................................................................50 
8.7.2. Banked Biospecimens for Genetics ........................................................50 
8.8. Biomarkers .......................................................................................................50 
8.9. Health Economics .............................................................................................50 
9. STATISTICAL CONSIDERATIONS ...........................................................................50 
9.1. Statistical Hypothesis ........................................................................................51 
9.2. Sample Size Determination................................................................................51 
9.3. Populations for Analysis....................................................................................52 
9.4. Statistical Analysis ............................................................................................53 
9.4.1. Endpoint Analysis .................................................................................53 


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9.4.2. Study Validity of Analysis of Endpoints.................................................54 
9.4.3. Analysis of Primary and Secondary Endpoints........................................54 
9.4.3.1. Pharmacodynamic Analysis...................................................55 
9.4.3.2. Pharmacokinetic Analysis .....................................................57 
9.4.4. Efficacy Analyses..................................................................................58 
9.4.5. Safety Analyses.....................................................................................58 
9.4.5.1. Electrocardiogram Analyses ..................................................58 
9.4.6. Exploratory Analyses ............................................................................59 
9.5. Interim Analyses ...............................................................................................59 
9.6. Data Monitoring Committee ..............................................................................59 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...................................................................................................60 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..............60 
10.1.1. Regulatory and Ethical Considerations .................................................60 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ....................................................................60 
10.1.2. Financial Disclosure ............................................................................61 
10.1.3. Informed Consent Process....................................................................61 
10.1.4. Data Protection....................................................................................62 
10.1.5. Dissemination of Clinical Study Data ...................................................62 
10.1.6. Data Quality Assurance .......................................................................63 
10.1.7. Source Documents...............................................................................64 
10.1.8. Study and Site Closure.........................................................................65 
10.1.9. Publication Policy................................................................................65 
10.1.10. Sponsor’s Qualified Medical Personnel ..............................................66 
10.2. Appendix 2: Clinical Laboratory Tests .............................................................67 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..................................................................69 
10.3.1. Definition of AE..................................................................................69 
10.3.2. Definition of SAE................................................................................70 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs .....................71 
10.3.4. Reporting of SAEs...............................................................................74 


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Upjohn US 1 LLC CONFIDENTIAL  
Page 8 
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .........................................................................................................75 
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................75 
10.4.2. Female Participant Reproductive Inclusion Criteria ..............................75 
10.4.3. Woman of Childbearing Potential (WOCBP)........................................76 
10.4.4. Contraception Methods ........................................................................76 
10.5. Appendix 5: Genetics ......................................................................................79 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments........80 
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................82 
10.8. Appendix 8: Clinical Opiate Withdrawal Scale .................................................84 
10.9. Appendix 9: VAS Assessment Methods ...........................................................86 
10.10. Appendix 10: Alternative Measures During Public Emergencies .....................89 
10.10.1. Eligibility ..........................................................................................89 
10.10.2. Telehealth Visits................................................................................89 
10.10.3. Alternative Facilities for Safety Assessments ......................................89 
10.10.4. Study Intervention .............................................................................89 
10.10.5. Home Health Visits ...........................................................................89 
10.10.6. Adverse Events and Serious Adverse Events ......................................89 
10.10.7. Efficacy Assessments ........................................................................89 
10.10.8. Independent Oversight Committees ....................................................89 
10.11. Appendix 11: Abbreviations ..........................................................................90 
10.12. Appendix 12: Summary of Changes ...............................................................94 
11. REFERENCES .........................................................................................................100 
 


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Upjohn US 1 LLC CONFIDENTIAL  
Page 9 
 
LIST OF TABLES 
Table 1. 
Schedule of Activities for Screening, Naloxone Challenge and 
Qualification Phase..............................................................................11 
Table 2. 
Schedule of Activities for the Treatment Phase .....................................14 
Table 3. 
Schema for Qualification Phase............................................................22 
Table 4. 
Derivation of Pharmacodynamic Parameters.........................................56 
Table 5. 
Pharmacokinetic Parameters ................................................................57 
Table 6. 
Laboratory Tests..................................................................................67 
Table 7. 
Other Subjective Effects Visual Analog Scales .....................................88 
Table 8. 
Summary of changes from Amendment 1.0 dated 12 Nov 2020 to 
Amendment 2.0 dated 24 Dec 2020 ......................................................95 
Table 9. 
Summary of changes from Amendment 2.0 dated 24 Dec 2020 to 
Amendment 3.0 dated 17 Nov 2021 .....................................................98 
 
LIST OF FIGURES 
Figure 1. 
Study Schema......................................................................................10 
Figure 2. 
Screen Display of Drug Liking VAS ....................................................86 
Figure 3. 
Screen Display of High VAS ...............................................................87 
Figure 4. 
Screen Display of Overall Drug Liking VAS ........................................87 
Figure 5. 
Screen Display of Take Drug Again VAS.............................................88 
 


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Upjohn US 1 LLC CONFIDENTIAL  
Page 10 
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 60 adult male and female (at least 
20% females) participants (10 participants in each sequence) to ensure 48 participants 
complete the Treatment Phase of the study, as shown in Figure 1.  Drop out participants for 
non-safety reasons in the treatment phase can be replaced at the discretion of the Investigator 
in consultation with the Sponsor. 
Figure 1. Study Schema 
 
 


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Upjohn US 1 LLC CONFIDENTIAL  
Page 11 
1.3. Schedule of Activities (SoA) 
The SoA (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 Identifier 
Visit 1 
Screening 
Visit 2 (Qualification Phase) 
Naloxone 
Challenge 
Drug Discrimination 
Study Day 
Within  
28 Days 
prior to 
Visit 2 
(Day -28 to 
Day -1)  
Day 0 
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 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including drug 
abuse) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoing eligibility review 
 
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 examinationb 
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 (WOCBP 
only) 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follicular stimulating hormone 
(FSH) 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Upjohn US 1 LLC CONFIDENTIAL  
Page 12 
Visit Identifier 
Visit 1 
Screening 
Visit 2 (Qualification Phase) 
Naloxone 
Challenge 
Drug Discrimination 
Study Day 
Within 
28 Days 
prior to 
Visit 2 
(Day -28 to 
Day -1)  
Day 0 
Days 1 and 2 
Day 3p 
Urine Pregnancy test (WOCBP 
only) 
Xe
Contraception check 
X 
Alcohol breathalyzer or urine 
X 
X 
Vital signsf
X 
Xg 
X 
X 
X 
X 
X 
X 
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 Electrocardiogramh 
X 
X 
Randomization for Qualification
Phase, Day 1
Xr 
Pharmacodynamic instrument
trainingq
X 
Cardiac telemetryi 
X 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
Pupillometry
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment administered
Xj 
X 
Visual Analogue Scales (VAS)k
Xk(a)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Take Drug Again VAS, Overall
DrugLiking VAS
X 
Clinical Opiate Withdrawal Scale
(COWS)
Xl 
Adverse and serious adverse
eventsm 
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 proceedn 
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. 


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Upjohn US 1 LLC CONFIDENTIAL  
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a. 
Admission should occur in the morning to ensure adequate time for pre-dose review of clinical laboratory results. 
b. 
Full physical examination (PE) (including height and weight) only needs to be done once, ie, at Screening or at Day 0 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 0 and prior to 
discharge on Day 3. 
c. 
Review of results are required prior to dosing on Visit 2 (ie, Naloxone Challenge). 
d. 
For confirmation of postmenopausal status only.  
e. 
Must be reviewed and confirmed as negative prior to dosing on Day 0. 
f. 
Includes pulse rate, systolic and diastolic blood pressures.  Temperature will be measured at Screening and upon admission on Day 0 of the Naloxone Challenge Phase.  Vital 
signs are measured after a resting period of at least 5 minutes in a sitting position. 
g. 
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.  
h. 
Conducted after a resting period of at least 10 minutes in a supine position. 
i. 
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. 
j. 
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. 
k. 
Include VASs for Drug Liking, High, Sleepy, Dizzy, Nausea, and Feel Sick;  
k(a) Only VASs for High, Sleepy, Dizzy, Nausea, and Feel Sick are administered at pre-dose. 
l. 
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. 
m. 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.  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, 0.5, 1, 1.5, 2, 
2.5, 3, 3.5, 4, 5 and 24 hours post-dose. 
n. 
Evaluation to proceed must occur prior to next scheduled time and event. 
o. 
Assign a single participant identifier number.  
p. 
If participants fail to qualify, all AEs will be reported with no further SoA testing.   
q. 
Retraining is allowed, as needed. 
r. 
Randomization can be done on Day 0, as needed, following completion of naloxone challenge test. 
 


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Table 2. 
Schedule of Activities for the Treatment Phase 
Study Day 
Visits 3 to 8 
Treatment Phase 
Periods 1 to 6a 
Follow-up 
Early 
termination/ 
discontinuation 
(DC) 
Baseline 
Day -1 
Day 1 
Day 2 
Day 3 28-35 Daysn  
 
Hours Post Dose 
 
Pre-
dose 
0 
0.25 0.5 
1 
1.5 
2 
2.5 
3 
3.5 
4 
6 
8 
12 
24 
36 
48 
 
 
CRU admission 
X 
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 
X 
X 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Safety laboratory testsd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Suicidality assessment  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine drug testinge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (WOCBP only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Urine pregnancy test (WOCBP only)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contraception check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Alcohol breathalyzer or urine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsg 
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 X 
X 
X 
 
 
 
X 
Respiratory rate 
 
X 
o 
o 
o 
o 
o o 
o o 
o 
o o X 
X 
X 
 
 
 
 
Tidal volume 
 
X 
o 
o 
o 
o 
o o 
o o 
o 
o o X 
X 
X 
 
 
 
 
End-tidal carbon dioxide 
 
X 
o 
o 
o 
o 
o o 
o o 
o 
o o X 
X 
X 
 
 
 
 
12-lead Electrocardiogramo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Randomization 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic (instrument) 
training/practice session 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac telemetryi 
 
X 
o 
o 
o 
o 
o o 
o o 
o 
o o o 
 
 
 
 
 
 
Pupillometry 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
 
 
Study treatment administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VASj  
 
Xj(a) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
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 
 
 
“Overall Drug Liking” and  
“Take Drug Again” VAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
Upjohn 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 


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Study Day 
Visits 3 to 8 
Treatment Phase 
Periods 1 to 6a 
Follow-up 
Early 
termination/ 
discontinuation 
(DC) 
Baseline 
Day -1 
Day 1 
Day 2 
Day 3 28-35 Daysn  
 
Hours Post Dose 
 
Pre-
dose 
0 
0.25 0.5 
1 
1.5 
2 
2.5 
3 
3.5 
4 
6 
8 
12 
24 
36 
48 
 
 
Adverse and serious event monitoringl 
X 
X 
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 
X 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Discharge from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: CRU = Clinical Research Unit; SpO2 = saturated oxygen; UDS = urine drug screening; VAS = Visual Analogue Scale; WOCBP = women of childbearing 
potential. 
a. 
Treatment Periods will be separated by a minimum of 4 days (not to exceed 28 days) between dosing.   
b. 
Continuing eligibility checks will include checks of urine drug screening (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 (EoS) 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 (±10 minutes) after a resting period of at least 5 minutes in a 
sitting position.  Temperature will be measured on Day -1 of each Treatment Visit only. 
h. 
Pre-dose or Day -1 for Visit 3 only. 
i. 
Continuous cardiac telemetry (heart rate, cardiac rhythm, and oxygen saturation) will be monitored  from predose  to approximately 8 hours post-dose or longer at the 
discretion of the clinical research unit. 
j. 
IncludeVASs for Drug Liking, High, Sleepy, Dizzy, Nausea, and Feel Sick measured at the nominal time points (±5 minutes);  
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 at 
0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36 and 48 hours post dosing.  Serious AEs 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 the 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. 
Conducted after a resting period of at least 10 minutes in a supine position. 


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2. INTRODUCTION 
2.1. Study Rationale 
LYRICA® (pregabalin) immediate release (IR) is indicated for neuropathic pain associated 
with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain 
associated with spinal cord injury and adjunctive therapy for the treatment of partial onset 
seizures in patients 1 month of age and older. 
Pregabalin is an analogue of the neurotransmitter gamma-amino butyric acid (GABA).  Its 
mechanism of action has not been established, but it has a similar pharmacological profile to 
that of gabapentin.  Despite being a derivative of GABA, it is not active at GABA receptors 
and does not appear to mimic GABA physiologically.  Pregabalin is not known to be active 
at receptor sites associated with drugs of abuse; however, several animal models of anxiolytic 
activity have demonstrated that pregabalin may have antianxiety effects similar to classic 
benzodiazepines.  Pregabalin is not known to be active at receptor sites associated with drugs 
of abuse; however, pregabalin is associated with central nervous system (CNS) adverse 
effects such as somnolence and confusion,1 and might cause decreased respiratory rate and 
the combined use of pregabalin and opioids may increase overdose risk.2  The abuse potential 
of pregabalin has been shown to be particularly high among opioid addicts and other 
substance-dependent patients.3,4  
In a study of recreational users (N=15) of sedative/hypnotic drugs (Protocol Clinical Study 
Report [CSR] 720-30015, 1008-098: Abuse Liability of Pregabalin (CI-1008) in Recreational 
Sedative/Alcohol Users), including alcohol, pregabalin (450 mg, single dose) received 
subjective ratings of "good drug effect," "high" and "liking" to a degree that was similar to 
diazepam (30 mg, single dose).5  In controlled clinical studies in over 5500 patients, 4% of 
pregabalin treated patients and 1% of placebo treated patients overall reported euphoria as an 
adverse reaction, though in some patient populations studied, this reporting rate was higher 
and ranged from 1% to 12%.6  
Pregabalin is a Schedule V controlled substance.  Since Lyrica® was approved on 
30 December, 2004, the epidemiological studies showed that pregabalin may be used in 
conjunction with opioids to enhance the ‘high’ obtained from opioids.7-9  In addition, 
observational studies have suggested pregabalin is associated with drug overdose death 
among individuals with concomitant opioid use.3,10  A clinical trial (rather than a nonclinical 
or observational study) is required to evaluate the abuse potential of pregabalin.  As a 
consequence, the FDA requires this post-authorization safety study (PASS) to evaluate 
pregabalin in a cross-over design with comparison to placebo and a positive control, 
oxycodone hydrochloride (HCl), regarding abuse-related subjective responses, physiological 
responses (including an assessment of respiratory depression), and drug pharmacokinetics 
(PK) in a healthy non-drug dependent population with drug abuse experience. 


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2.2. Background  
Pregabalin binds with high affinity to the alpha-delta site (an auxiliary subunit of 
voltage-gated calcium channels) in central nervous system tissues.  Although the mechanism 
of action of pregabalin has not been fully elucidated, results with genetically modified mice 
and with compounds structurally related to pregabalin (such as gabapentin) suggest that 
binding to the alpha-delta subunit may be involved in pregabalin's anti-nociceptive and 
antiseizure effects in animals.  In animal models of nerve damage, pregabalin has been 
shown to reduce calcium dependent release of pro-nociceptive neurotransmitters in the spinal 
cord, possibly by disrupting alpha -delta containing-calcium channel trafficking and/or 
reducing calcium currents.  Evidence from other animal models of nerve damage and 
persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated 
through interactions with descending noradrenergic and serotonergic pathways originating 
from the brainstem that modulate pain transmission in the spinal cord. 
While pregabalin is a structural derivative of the inhibitory neurotransmitter 
gamma-aminobutyric acid (GABA), it does not bind directly to GABA, or benzodiazepine 
receptors, does not augment GABA responses in cultured neurons, does not alter rat brain 
GABA concentration or have acute effects on GABA uptake or degradation.  However, in 
cultured neurons prolonged application of pregabalin increases the density of GABA 
transporter protein and increases the rate of functional GABA transport.  Pregabalin does not 
block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase 
enzyme activity.  It is inactive at serotonin and dopamine receptors and does not inhibit 
dopamine, serotonin, or noradrenaline reuptake. 
2.2.1. Clinical Overview 
Lyrica® formulations are available in capsule strengths of 25 mg, 50 mg, 75 mg, 100 mg, 
200 mg, 225 mg and 300 mg and in a 20 mg/mL solution.  Following oral administration 
under fasting conditions, pregabalin reaches peak plasma concentrations within 1.5 hours.  
Pregabalin oral bioavailability is greater than or equal to 90% and is independent of dose.  
Following single- (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, 
maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve 
(AUC) values increased linearly.  Following repeated administration, steady state was 
achieved within 24 to 48 hours.  Multiple-dose PK can be predicted from single-dose data.6  
The rate of pregabalin absorption is decreased when given with food, resulting in a decrease 
in Cmax of approximately 25% to 30% and an increase in time for peack concentration (Tmax) 
to approximately 3 hours.  However, administration of pregabalin with food has no clinically 
relevant effect on the total absorption of pregabalin.11  
Pregabalin does not bind to plasma proteins.  The apparent volume of distribution of 
pregabalin following oral administration is approximately 0.5 L/kg.  Pregabalin is a substrate 
for system L transporter which is responsible for the transport of large amino acids across the 
blood brain barrier.  Although there are no data in humans, pregabalin has been shown to 
cross the blood brain barrier in mice, rats, and monkeys.  In addition, pregabalin has been 
shown to cross the placenta in rats and is present in the milk of lactating rats. 


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Pregabalin undergoes negligible metabolism in humans.  Following a dose of radiolabeled 
pregabalin, approximately 90% of the administered dose was recovered in the urine as 
unchanged pregabalin.  The N-methylated derivative of pregabalin, the major metabolite of 
pregabalin found in urine, accounted for 0.9% of the dose.  In preclinical studies, pregabalin 
(S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or 
monkeys.  Pregabalin is eliminated from the systemic circulation primarily by renal excretion 
as unchanged drug with a mean elimination half-life of 6.3 hours in participants with normal 
renal function.  Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young 
healthy participants.  Because pregabalin is not bound to plasma proteins this clearance rate 
indicates that renal tubular reabsorption is involved.  Pregabalin elimination is nearly 
proportional to creatinine clearance (CLcr).6 
The immediate-release (IR) oral formulation of oxycodone HCl is indicated for the 
management of moderate to severe pain where the use of an opioid analgesic is appropriate.  
Oxycodone is a μ-agonist opioid of the morphine type and a Schedule II drug.  Like other 
opioids used for analgesia, it can be abused and is subject to criminal diversion.  About 
60% to 87% of an oral dose of oxycodone HCl reaches the systemic circulation.  Oxycodone 
dose proportionality has been established.  A 30 mg oral dose of oxycodone reaches Tmax in 
2.6 ±3 hours and has a half-life (t½) of 3.85 ±1.3 hours.  A single 10 mg dose of oxycodone 
oral solution under fasted condition reaches Tmax in 1.25 ±0.5 hours.12  Oxycodone is 
extensively metabolized in the liver via cytochrome P3A4/5 (CYP3A4/5) to noroxycodone 
(45%) and via CYP2D6 to oxymorphone (19%).  Both noroxycodone and oxymorphone are 
further metabolised to noroxymorphone.  Noroxycodone exhibits only weak antinociceptive 
potency; its affinity for μ-opioid receptors and potency are much lower than that of 
oxycodone.  Although oxymorphone and noroxymorphone have higher affinity for μ-opioid 
receptors and are more potent compared with oxycodone, neither of them can readily cross 
the blood–brain barrier (BBB) and, thus their contributions to analgesia effect following 
oxycodone administration is thought to be clinically insignificant.  The elimination half-life 
of oxycodone has been reported to be approximately 3-5 hours.  Due to CYP-mediated 
metabolism, oxycodone is prone to drug interactions such as concomitant administration with 
either CYP3A inhibitors/inducers or CYP2D6 inhibitors or both.  Oxycodone, as well as 
other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle 
relaxants and produce an increased degree of respiratory depression.  Oxycodone produces 
respiratory depression by direct action on brain stem respiratory centers.  The respiratory 
depression involves both a reduction in the responsiveness of the brain stem respiratory 
centers to increases in carbon dioxide tension and to electrical stimulation.12,13 
Multiple-dose administration of pregabalin (300 mg twice a day) in healthy participants had 
no effect on the rate and extent of oxycodone single-dose PK.  Single-dose administration of 
oxycodone (10 mg) had no effect on the steady-state PK of pregabalin.  However, the 
impairment of cognitive and gross motor function produced by pregabalin alone was 
minimally increased when pregabalin and oxycodone were given in combination.14 
2.3. Benefit/Risk Assessment 
Lyrica® and oxycodone HCl are not expected to provide any clinical benefit to healthy 
participants in this study.  This study is designed to evaluate the abuse potential of Lyrica® 


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when taken orally alone and concomitantly with oxycodone HCl in healthy non-dependent, 
recreational opioid users under a fasted condition. 
More detailed information about the known and expected benefits and risks and expected 
adverse events (AEs) of Lyrica® and oxycodone HCl may be found in the package inserts, 
which are the single reference safety documents (SRSD) for this study.  The SRSD for the 
pregabalin and oxycodone is their respective United States Prescribing Information 
(USPI).6,12 
3. OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary:  
Primary:  
x 
To determine the abuse potential of orally 
administered pregabalin taken concomitantly 
with oxycodone HCl in non-dependent, 
recreational opioid users under a fasted 
condition. 
x 
Bipolar visual analogue scale (VAS) for “Drug 
Liking” [maxium effect (Emax)]. 
Secondary:  
Secondary:  
x 
To evaluate additional pharmacodynamic (PD) 
effect and PK of pregabalin and oxycodone 
HCl taken alone and concomitantly in 
non-dependent, recreational opioid users under 
a fasted condition. 
x 
To evaluate safety of pregabalin and oxycodone 
HCl taken alone and concomitantly in 
non-dependent, recreational opioid users under 
a fasted condition.  
Pharmacodynamic Endpoints: 
x 
Bipolar VAS for “Drug Liking” [time for Emax 
(TEmax), area under the effect-time profile from 
time zero to the last quantifiable effect 
(AUEClast), and partial AUEC (AUEC1, AUEC2, 
AUEC3, AUEC4, AUEC8)]. 
x 
Unipolar VAS for “High” [Emax, TEmax, 
AUEClast , and partial AUEC (AUEC1, AUEC2, 
AUEC3, AUEC4, AUEC8)]. 
x 
Bipolar VAS for “Take Drug Again” at 24, 36, 
48 hour postdose. 
x 
Bipolar VAS for “Overall Drug Liking” at 24, 36 
and 48 hours postdose. 
x 
Unipolar VAS for “Good Drug Effect”.  
x 
Unipolar VAS for “Bad Drug Effect”.  
x 
Unipolar VAS for “Any Drug Effect”.  
x 
Pupil size (diameter). 
Pharmacokinetic Endpoints: 
x 
Cmax, Tmax, and area under the plasma 
concentration-time profile from time zero to the 
time of the last quantifiable concentration 
(AUClast) of pregabalin and oxycodone. 
x 
Area under the plasma concentration-time profile 
from time zero extrapolated to infinity time 
(AUCinf), and half-life (t½), if data permits, of 
pregabalin and oxycodone.  
x 
Partial AUCs (AUC1, AUC2, AUC3, AUC4, 


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Objectives 
Endpoints 
AUC8) of pregabalin and oxycodone.  
Safety Endpoints: 
x 
Vital signs include 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 labs and AEs. 
Tertiary/Exploratory:  
Tertiary/Exploraory:  
x 
Exposure-response relationship between 
pregabalin concentration and selected PD effect 
in the presence and absence of oxycodone. 
x 
To enable exploratory research through 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision.   
x 
Correlation between pregabalin concentrations 
and selected PD endpoints (Biploar VAS for 
“Drug Liking”, Unipolar VAS for “High”, pupil 
diameter) in the presence and absence of 
oxycodone, 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 randomized, double-blind, double-dummy, placebo- and active-controlled, 
6-treatment, 6-period crossover, single-dose, Williams square design study in healthy male 
and/or female adult, non drug-dependent recreational opioid users.  The study includes 
Screening, a Qualification Phase, a Treatment Phase and Follow-up.  This study will 
randomize approximately 60 adult male and female (at least 20% female) participants 
(10 participants in each sequence) in the Treatment Phase to ensure at least 48 participants 
complete the Treatment Phase of the study.  Dropouts for non-safety reasons may be replaced 
at the discretion of the Investigator in consultation with the Sponsor. 


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The following study visits are required, see Figure 1 and the SoA (Table 1 and Table 2): 
1. Visit 1, Screening will occur within 28 days prior to Visit 2. 
2. Visit 2, Qualification Phase will require inpatient stay at the Clinical Research Unit 
(CRU) for 3 nights: 
a. Naloxone Challenge Phase, Day 0; 
b. Drug Discrimination, Days 1 and 2 will require inpatient stay at the CRU for 
2 nights; 
c. End of Drug Discrimination requires an inpatient stay at the CRU overnight to 
ensure discharge occurs 24 hours after receiving oxycodone or placebo;  
d. Participant will proceed to Visit 3 after at least 4-day washout but less than 
28 days after the last dose of study intervention during qualification phase.  
3. Visits 3 to 8, Treatment Phase will require a total of 18 overnight inpatient stays at 
the CRU: 
a. Each visit will require an inpatient stay at the CRU of 3 nights;  
b. Each visit will be separated by a washout period of at least 4 days.  The washout 
period is calculated between two subsequent study drug administraitons.  
4. End of Study Assessments will be at the CRU to occur 48 hours after completing the 
last study drug dosing or time of early withdrawal. 
5. For the entire study, 21 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 first dose in Qualification Phase of the study (Visit 2). 
4.1.2. Qualification Phase (Visit 2; Days 0 to 3) 
4.1.2.1. Naloxone Challenge (Day 0) 
Eligible participants who successfully complete the Screening Visit will return to the study 
center to complete the naloxone challenge.  The Naloxone Challenge (Day 0) 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 


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participants who do not have signs and symptoms of opioid withdrawal, as assessed by the 
Clinical Opiate 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 method being 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.  
Retraining is permitted if required.  
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 report drug 
liking in response to a positive control and demonstrate a meaningfully different response 
from that produced by placebo. 
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 (oxycodone 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: oxycodone 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 A placebo response between 40-60 points on a bipolar Drug Liking Emax VAS 
of 0-100.  


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x The positive control should produce a score outside of the placebo range and should 
be at least 15 points greater than the placebo response. 
x Tolerate study treatments safely; ie, SpO2 ≥90%, no episodes of vomiting within the 
first 2 hours post-dose. 
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 oxycodone or placebo. 
Following completion of the Drug Discrimination phase, 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 participants is eligible to continue in the study.  
If participants fail to qualify, all AEs will be reported with no further study assessments. 
4.1.3. Treatment Phase (Visits 3 to 8) 
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 
Phaseof this randomized, double-blind, placebo- and active-controlled, crossover study.  
Randomization can be done on Day 0, as needed, following completion of the Naloxone 
Challenge test. 
On Day 1 of each of the 6 periods, which will be separated by a washout of at least 4 days, 
participants will receive an oral dose of either pregabalin 300 mg or 450 mg alone or in 
combination with a 20 mg dose of oxycodone IR or 20 mg monotherapy of oxycodone HCl 
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 the 
concomitant use of pregabalin with oxycodone HCl and blood samples for the analysis of 
pregabalin and oxycodone HCl in plasma will be obtained pre-dose (30 minutes prior to 
dosing) and post-dose as outlined in the Schedule of Activities (SoA).  Vital signs including 
respiratory rate, pulse oximetry and pupillometry 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 pregabalin taken 
concomitantly with an opioid, such as oxycodone, investigating a range of pregabalin dose 
(the highest therapeutic and supra-therapeutic) combined with the opioid in healthy non-drug 
dependent population with drug abuse experience.  Therefore, this clinical trial will evaluate 
the pregabalin/opioid combinations in a cross-over design with comparison to placebo, 


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pregabalin alone, and a moderate dose of the opioid taken alone as a positive control.  Hence 
the study design will employ a 6-sequence, 6-period, cross-over design which will include 
the placebo, positive control (20 mg oxycodone IR), two doses of pregabalin alone (300 mg 
and 450 mg) and each pregabalin dose in combination with 20 mg oxycodone IR to allow for 
the various comparisons to be systematically evaluated.  The washout period will be least 
4 days minimizing the carry over effects of the treatments, especially if additive or 
synergistic effects are noted with the combination 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 
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 dose of pregabalin in adults for postherpetic neuralgia and 
neuropathic pain is 300 mg administred 2 times a day (600 mg/day).  This dose of pregabalin 
was well tolerated in healthy adult participants following a single and multiple dosing and 
showed acceptable safety profile.  The most common adverse events for 300 mg dose were 
dizziness and somnolence (>50% of participants).  
Supratherapeutic dose 450 mg of pregabalin was the highest dose of pregabalin evaluated in 
previous abuse liability clinical study.  This dose of pregabalin (450 mg) dose was well 
tolerated in 15 healthy adult recreational drug users.  Only 5 out of 15 participants reported 
adverse events that are mild in nature.  The most common adverse events were headache, 
confusion, and infection.5 
Therefore, the highest therapeutic single dose, 300 mg and a supratherapeutic dose of 450 mg 
(1.5x of the highest therapeutic dose) will be selected to determine the abuse potential of 
pregabalin when administered concomitantly with oxycodone HCl 20 mg in this study. 
A single 20 mg dose of oxycodone HCl is selected based on the request from the United 
States (US) Food and Drug Administration (FDA)  for concomitant administration with 
pregabalin and as positive control.  During concomitant treatment with pregabalin, 20 mg 
oxycodone could allow for assessing potential potentiation effect of pregabalin to oxycodone 
is significantly reduced.  Consequently, 20 mg dose of oxycodone, which is expected to have 
a lower VAS Emax score will be used.  In addition, a 20 mg oxycodone dose has been 
historically used as a positive control in abuse.  Based on published studies, the reported 
mean “Drug Liking” bipolar VAS Emax scores for a 20 mg oxycodone dose were 68.0 and 
76.5.15,16 


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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 scheduled procedure shown in the. 
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. 
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 55 years of age, inclusive, at the time of 
screening.  There must be no less than 20% female participants in the Treatment 
Phase. 
x 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: 
2. Male and female participants who are overtly healthy.  Healthy is defined as no 
clinically relevant abnormalities identified by a detailed medical history, full physical 
examination, vital signs, 12-lead ECG, and/or clinical laboratory tests.  
3. Participants must have drug abuse experience with opioids; ie, must have used 
opioids for non-therapeutic purposes (ie, for psychoactive effects) on at least 
10 occasions within the last year and at least once in the 8 weeks before the Screening 
Visit (Visit 1). 
4. Participants must satisfactorily complete both the Naloxone Challenge and the Drug 
Discrimination. 
5. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 


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Weight: 
6. Body mass index (BMI) of 17.5 to 34 kg/m2, inclusive; and a total body weight 
≥50 kg (110 lb).  
Informed Consent: 
7. 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. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. 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-4 
(DSM-4) 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. 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). 
3. Any condition possibly affecting drug absorption (eg, gastrectomy) excluding 
cholecystectomy within 1 year prior to study. 
4. Abnormal baseline EtCO2 <35mm Hg or >45 mm Hg. 
5. 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).   
6. 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 0. 


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7. 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. 
8. Patients with: sleep apnea, myasthenia gravis and glaucoma. 
Prior/Concomitant Therapy: 
9. 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). 
10. 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: 
11. 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: 
12. Positive urine drug screen (UDS) for substances of abuse at each admission in the 
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 dicretion, may reschedule a repeat of UDS until the 
UDS is negative, excluding THC, before the participant is permitted to participate in 
any phase of the study.  
13. Unable to abstain from using THC during the Qualification and Treatment Phase of 
the study.  
14. Has participated in, is currently participating in, or is seeking treatment for 
substance-and/or alcohol-related disorders (excluding nicotine and caffeine). 
15. Has a positive alcohol breathalyzer or urine test at each admission to the study center 
during qualification and treatment phase.  Positive results may be repeated and/or 
participants re-scheduled at the Investigator’s discretions. 
16. Participants are heavy smokers or users of other types of nicotine products (>20 
cigarettes equivalents per day).  


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17. Participants are unable to abstain from smoking for at least 2 hours before and at least 
8 hours after study drug administration. 
18. Screening sitting blood pressure (BP) ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), following at least 5 minutes rest.  If BP is ≥140 mm Hg (systolic) or 
≥90 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. 
19. 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 as determined by the Fridericia 
method (QTcF) >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 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 QTcF exceeds 
450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and 
the average of the 3 QTcF 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. 
20. 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 
t1.5 × upper limit of normal (ULN); 
x Total bilirubin level ≥1.5 × 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 ≤ ULN. 
Other Exclusions: 
21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
22. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
23. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
24. History of hypersensitivity to pregabalin or oxycodone or any of the components in 
the formulation of the study products. 


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25. 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 at least 10 hours prior to the collection of the 
pre-dose PK sample for fasted treatment. 
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 caffeine-containing 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. 


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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) and will confirm that the participant has been instructed in its 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 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).  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 Lyrica® and oxycodone HCl.  
Lyrica® and oxycodone HCl will be provided by Upjohn US 1 LLC.  


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6.1.1. Administration 
Following an overnight fast of at least 10 hours, participants will receive investigational 
product at approximately 08:00 hours (plus or minus 2 hours).  Investigator site personnel 
will administer investigational product during each period with ambient temperature water to 
a total volume of approximately 240 mL.  Detailed instructions on preparation of all study 
treatments, including steps to maintain the double blind, will be provided separately in Drug 
Administration Instructions (DIA).  
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 at least the first 4 hours after dosing.  Water may 
only be consumed at least 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.  
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 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 


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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 
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. 
Investigaional 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. 


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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 participant’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.  
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.  
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.   
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).  


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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 certified staff present during the entire study. 
x Acute pregabalin and/or oxycodone toxicity can be manifested as drowsiness, 
respiratory depression, and somnolence progressing to stupor, coma or death.  In the 
event that acute pregabalin and/or oxycodone toxicity occurs, primary attention shall 
be given to re-establishment and/or maintenance of a patent airway and sitution of 
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 
pregabalin and/or oxycodone 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 (Table 2) for data to be collected at the 
time of early termination/discontinuation of investigational product. 
SpO2 Changes 
Participants with an absolute change (drop) in SpO2 of 4% should be withdrawn from the 
study and recorded as an AE. 
EtCO2 Changes 
Participants with an absolute change (increase) in EtCO2 of 10 mm Hg should be withdrawn 
from the study and recorded as an AE. 


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ECG Changes  
If the ECG of a participant meets the bulleted criteria below, then two 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 QT, QTcF (corrected QT [Fridericia method]) >500 msec. 
x Change from baseline: QTcF >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 (Table 2) 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.  
An increase of ≥0.3 mg/dL (or ≥26.5 μmol/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 μmol/L] in SCr 
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 μmol/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 


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SCr results of ≥0.3 mg/dL (or ≥26.5 μmol/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 (Table 2) 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. 
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 Case Report Form (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 


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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.  
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 to first dose during Qualification Phase to 
confirm 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.  


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Study procedures and their timing are summarized in the Schedule of Activities (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 Schedule of 
Activities (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. 
Vital signs (HR, BP, RR), SpO2 and EtCO2 and AEs will be determined within 10 minutes 
before the nominal time points. 
PD measures (ie, VAS) will be administered at the nominal time points (±5 minutes), 
followed by pupillometry. 
PK sample collection will occur within approximately 5 minutes of completion of 
pupillometry assessments and the actual sample collection time will be recorded. 
All pre-dose measures will be obtained within 30 minutes before dosing.  
If an intravenous (IV) catheter is utilized for blood sample collections, baseline ECGs and/or 
vital sign assessments (pulse rate and BP) should be collected prior to the insertion of the 
catheter. 
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 
535 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 


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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 Schedule of Activities 
(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 Schedule of Activities 
(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) will 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 
with a blood collection, BP, pulse oximetry and respiratory rate should be obtained prior to 
the nominal time of the blood collection.  


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Heart 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. 
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, mm Hg) 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 
Schedule of Activities (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. Pupillometry 
Both pupils will be measured with a calibrated pupillometer under mesopic lighting during 
the Qualification Phase, predose and postdose, and during the Treatment Phase, predose and 
post dose at time points specified in the Schedule of Activities (SoA).   


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Pupillometry will be monitored before dosing and 0.25, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 
36 and 48 hours post-drug.  These measures are done in abuse liability testing to verify 
dosing. 
8.2.4. Electrocardiograms 
Twelve (12)-Lead ECGs should be collected at times specified in the Schedule of Activities 
(SoA) section of this protocol using an ECG machine that automatically calculates the heart 
rate and measures 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 QTcF interval is increased by ≥30 msec from the baseline and is >450 msec; or 
b) an absolute QT 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 QTcF 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 QTcF interval remains ≥30 msec from the baseline and is >450 msec; or b) an 
absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, 
at the discretion of the investigator), or QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF 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 QTcF values are in the 
acceptable range. 
ECG values of potential clinical concern are listed in Appendix 7. 
8.2.4.1. Continuous Cardiac Monitoring by Telemetry 
Continuous cardiac monitoring will be performed during the Treatment phase as noted in the 
SoA (Table 2).  The time, duration, and description of any clinically significant abnormal 
rhythm will be reported as an adverse event using Appendix 7 as a guide as to what is 
generally considered to be a drug-related adverse event of potential clinical concern. 


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8.2.5. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the 
Schedule of Activities (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 
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 Schedule of Activities (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.  
8.2.6. Suicidal Ideation and Behavior Risk Monitoring  
8.2.6.1. Columbia Suicidality Severity Rating Scale (C-SSRS) 
The Columbia Suicide-Severity Rating Scale (C-SSRS) will be collected at timepoints on the 
Schedule of Activities (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. 
8.2.6.2. 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, self-harming behaviors) in the past year based on C-SSRS assessment 
(“yes” answers on items 4 or 5 of the C-SSRS).  


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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 C-SSRS). 
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. 
Risk assessments should be done by a qualified mental health professional (MHP).  In the US, 
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). 
8.2.6.3. 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. 
8.2.7. 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 women of childbearing potential 
(WOCBP) at the times listed in the Schedule of Activities (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 


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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). 
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).  
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. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF, not the AE section. 
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. 
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 or study participation, the investigator must 
promptly notify the sponsor. 


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8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately 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. 
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 
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF. 
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 


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reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators. 
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 an investigator safety report describing an SAE 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 investigational product 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. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
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. 
8.3.5.3. Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE. 
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 


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information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file. 
8.3.6. 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 
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 Lyrica® >450 mg or oxycodone HCl >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. 


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2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
pregabalin and oxycodone 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 2.1 mL of plasma 
volume, will be collected for measurement of plasma concentrations of pregabalin and 
oxycodone as specified in the Schedule of Activities (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 
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 
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 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 pregabalin and oxycodone.  Samples collected for 
analyses of pregabalin and oxycodone 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. 
Samples collected for measurement of plasma concentrations of pregabalin and oxycodone 
will be analyzed using a validated analytical method in compliance with applicable standard 
operating procedures (SOPs). 


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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. 
8.6.1.1. 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, for “Drug Liking” the participant will be asked: 
At this moment, my liking for this drug is?  The participant will then rate on the 0 to 
100 scale, where: Strong disliking = 0; Neither like nor Dislike = 50; and Strong 
Liking = 100.  
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 Drug Effects, and Bad Drug Effects presented on 
unipolar 0 to 100 scales. 


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8.7. Genetics 
8.7.1. Specified Genetics 
Genetics (specified analysis) 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. 
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. 
The Statistical Analysis Plan 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.   


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9.1. Statistical Hypothesis 
To assess the abuse potential of Lyrica® the following tests will be performed in the order of 
validation test followed by combination vs. oxycodone and then pregabalin alone vs. 
oxycodone: 
Study Validation: 
The sensitivity and integrity of the study will be validated by comparing the mean responses 
of oxycodone HCl, the positive control (C), to the placebo (P):  
H0: μc - μP ≤G1 versus Ha: μc- μP >G1 where G1 =15 
Primary: 
1. Does pregabalin plus oxycodone HCl (T) produce mean responses that show abuse 
potential that is no higher than oxycodone HCl (C)? 
H0: μT - μC ≥0.2(μC - μP) versus Ha: μT - μC <0.2(μC - μP). 
Secondary: 
1. Does pregabalin (L) produce mean responses that show less abuse potential than 
oxycodone HCl (C)?  
H0: μC - μL ≤ 0.2(μC - 50) versus Ha: μC - μL >0.2(μC - 50).17 
2. Does pregabalin (L) produce mean responses that show abuse potential similar to 
placebo (P)? 
H0: μL - μP ≥δ2 versus Ha: μL - μP <δ2 where δ2 =11. 
3. Does pregabalin (L) produce mean responses that show less abuse potential than 
pregabalin plus oxycodone HCl (T)?  
H0: μT - μL ≤ 0.2(μT - 50) versus Ha: μT - μL >0.2(μT - 50).17 
For each of the pregabalin hypothesis, the statistical significance of the test will be assessed 
for all doses of pregabalin. 
9.2. Sample Size Determination 
Forty two (42) participants will provide 90% power to demonstrate the difference between 
pregabalin plus oxycodone HCl and oxycodone HCl alone is no larger than 20% of the 
difference between oxycodone HCl and placebo.  This assumes means (SD) of 75.0 (16), 
75.0 (16), and 51.6 (6.77) for pregabalin plus oxycodone HCl, oxycodone HCl, and placebo, 
respectively.  The correlation between pregabalin plus oxycodone HCl is assumed to be 0.85. 
A 15-point VAS Emax “Drug Liking” difference between the placebo and the positive control 
oxycodone HCl must be demonstrated for validation of the study.  Thirty-six (36) 


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participants will provide at least 90% power to show the positive control (20 mg dose of 
oxycodone IR given alone) is 15 points higher than placebo.  This assumes a difference of 
23 points between placebo and oxycodone HCl given alone, a standard deviation of 16 points 
and a 1-sided significance level of 0.05 and correlation of 0 between oxycodone HCl and 
placebo.   
The maximum number of participants needed for the primary analysis and validation of the 
study will provide at least 90% power for both analyses and to account for participants who 
will be excluded from the Modified Completer Population, 48 participants will be required to 
complete the study.  To account for participants who do not complete all 6 treatments  this 
study will randomize 60 participants to ensure at least 48 participants complete the Treatment 
Phase of the study.  Among the 60 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 
6 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.   
x The Modified Completer Population will include all randomized participants in the 
Completer Population, however will exclude any participant who meets either or both 
of the following criteria for Drug Liking VAS: 
1. Emax scores are within  a 5 point difference across all 6 treatments (ie, Maximum 
Emax score – Minimum Emax score ≤5). 
2. Emax(P) > 60 and Emax(P) - Emax(Oxy20) ≥5.  
where Emax(P) and Emax(Oxy20) are the VAS Emax scores for placebo and oxycodone 
HCl IR 20 mg, respectively. 
 
This population will be analyzed as randomized. 


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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 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 postdose 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 Analysis  
Statistically, the study will be evaluated as a safety study.  Consequently, the null hypothesis 
for pregabalin alone and when used concomitantly with oxycodone HCl will be constructed 
on the presumption that these treatments produce abuse potential similar to oxycodone HCl 
and therefore differentiates from 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.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 
9.4.1. Endpoint Analysis 
The following parameters will be calculated for VAS for “Drug Liking” and VAS for “High”  
during the Treatment Period: 
x Maximum (peak) effect (Emax) for High only; calculated as maximum change from 
pre-dose response if pre-dose assessment is performed;  
x Time of maximum (peak) effect (TEmax); 
x Area under the effect curve to 1 hour (AUEC1); 
x Area under the effect curve to 2 hour (AUEC2); 
x Area under the effect curve to 3 hour (AUEC3); 
x Area under the effect curve to 4 hour (AUEC4); 
x Area under the effect curve to 8 hour (AUEC8); 
x AUEClast. 
The VAS for “Overall Drug Liking”, “Take Drug Again”, “Good Drug Effect”, “Bad Drug 
Effect”, and “Ang Drug Effect” will be summarized by timepoints. 


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9.4.2. Study Validity of Analysis of Endpoints 
Study validity will first be confirmed through the comparison of mean Emax for Drug Liking 
between oxycodone and placebo administered during the Treatment Phase.  This comparison 
will be made using a mixed-effect model with treatment, period, treatment*period 
interaction, a carryover variable and sequence as fixed effects, and participant nested within 
sequence as a random effect.  If the p-value for the carryover variable is >0.25, a reduced 
mixed model will be used with treatment, period and sequence as fixed effects, and 
participant nested within sequence as a random effect.  If the treatment comparison of 
oxycodone vs. placebo is statistically significant (ie, one-sided pd0.05) in the appropriate 
direction and confidence intervals exclude differences of <15 points for Drug Liking, it will 
confirm the sensitivity of the study.  If study validity is not confirmed, comparisons between 
pregabalin and oxycodone will not be performed. 
9.4.3. Analysis of Primary and Secondary Endpoints 
A linear mixed-effects model with treatment, period, treatment*period interaction, a 
carryover variable and sequence as fixed effects, and participant nested within sequence as a 
random effect.  If the p-value for the carryover variable is >0.25, a reduced mixed model will 
be used with treatment, period and sequence as fixed effects, and participant nested within 
sequence as a random effect.  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 pregabalin, oxycodone HCl 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 error [SE], median, first and third 
quartiles, minimum and maximum).  These parameters will be analyzed using a mixed-effect 
model with treatment, period, treatment*period interaction, a carryover variable and 
sequence as fixed effects, and participant nested within sequence as a random effect.  If the 
p-value for the carryover variable is >0.25, a reduced mixed model will be used with 
treatment, period and sequence as fixed effects, and participant nested within 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 one-sided 95% confidence intervals will be provided for each treatment and for the 
difference between treatments.  P-values will be provided for each hypothesis.  A two-sided 
95% confidence interval will be provided for the comparisons of pregabalin (300 mg and 
450 mg) plus oxycodone versus oxycodone IR 20 mg.  Data will be summarized graphically, 
where appropriate. 


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The study validation comparisons will be: 
x Oxycodone HCl IR 20 mg vs. placebo.   
The primary treatment comparisons will be: 
x Pregabalin 300 mg plus oxycodone HCl IR 20 mg vs. oxycodone HCl IR 20 mg; 
x Pregabalin 450 mg plus oxycodone HCl IR 20 mg vs. oxycodone HCl IR 20 mg. 
The secondary treatment comparisons will be: 
x Pregabalin 300 mg vs. placebo; 
x Pregabalin 450 mg vs. placebo; 
x Pregabalin 300 mg plus oxycodone HCl IR 20 mg vs. placebo; 
x Pregabalin 450 mg plus oxycodone HCl IR 20 mg vs. placebo; 
x Pregabalin 300 mg vs. oxycodone HCl IR 20 mg; 
x Pregabalin 450 mg vs. oxycodone HCl IR 20 mg; 
x Pregabalin 300 mg plus oxycodone HCl IR 20 mg vs. pregabalin 300 mg; 
x Pregabalin 450 mg plus oxycodone HCl IR 20 mg vs. pregabalin 450 mg. 
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. 
9.4.3.1. Pharmacodynamic Analysis 
Pharmacodynamic parameter values that will be evaluated are listed in Table 4.  The 
pre-dose measurements of psychometric and pupillomnetry of each period will be the 


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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 covariance (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.  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. 
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. 
Pupil size will be summarized by time points.  
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, respiratory rate and pupil size will be monitored 
over the course of the study session and correlated to both the drug dose administered and the 
PK of the drug. 
9.4.3.1.1. Derivation of Pharmacodynamic Parameters  
PD parameters for VAS “Drug Liking” and “High” will be derived from the effect-time 
profiles as shown in Table 4. 
Table 4. 
Derivation of Pharmacodynamic Parameters 
Parameter 
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 
zero to the time of the last quantifiable effect 
(Clast) 
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 hour postdose 
Linear trapezoidal method 
AUEC3 
Area under the effect-time profile from time 
zero to 3 hour postdose 
Linear trapezoidal method 
AUEC4 
Area under the effect-time profile from time 
zero to 4 hour postdose 
Linear trapezoidal method 
AUEC8 
Area under the effect-time profile from time 
zero to 8 hour postdose 
Linear trapezoidal method 


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9.4.3.2. Pharmacokinetic Analysis 
Blood samples will be collected throughout the study in order to monitor drug PK.  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.  
9.4.3.2.1. Pharmacokinetic Parameters 
The following pregabalin and oxycodone PK parameters (Table 5) will be calculated for each 
participant/period/analyte using noncompartmental analysis of concentration-time data.  
Samples below the LLOQ were set to 0 for analysis.  Actual sample collection times were 
used for the PK analysis. 
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, standard deviation [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 pregabalin and oxycodone will be presented.  
Concentrations will be listed and summarized by PK sampling time and treatment for each 
analyte. 
Table 5. 
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 plasma concentration-time profile 
from time zero to the time for the last 
quantifiable concentration (Clast) 
Linear/Log trapezoidal method 
AUC1  
Area under plasma concentration-time profile 
from time zero to 1 hour postdose  
Linear/Log trapezoidal method 
AUC2  
Area under plasma concentration-time profile 
from time zero to 2 hour postdose  
Linear/Log trapezoidal method 
AUC3 
Area under plasma concentration-time profile 
from time zero to 3 hour postdose  
Linear/Log trapezoidal method 
AUC4 
Area under plasma concentration-time profile 
from time zero to 4 hour postdose  
Linear/Log trapezoidal method 
AUC8 
Area under plasma concentration-time profile 
from time zero to 8 hour postdose  
Linear/Log trapezoidal method 
AUCinfa 
Area under plasma concentration-time profile 
AUClastC0 + (Clast*/kel), where 
Clast* is the predicted plasma 


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Parameter 
Definition 
Method of Determination 
from time zero to infinity postdose 
concentration at the last 
quantifiable time point estimated 
from the log-linear regression 
analysis 
t½a 
Terminal half-life 
Ln(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. 
9.4.4. Efficacy Analyses 
There will not be an efficacy analysis in this study. 
9.4.5. 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. 
9.4.5.1. Electrocardiogram Analyses 
Electrocardiogram results collected at Screening  will be listed. 


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9.4.6. Exploratory Analyses 
Exploratory analysis will be conducted to evaluate the correlation between pregabalin 
concentrations and selected PD endpoints (Biploar VAS for “Drug Liking”, Unipolar VAS 
for “High”, pupil diameter) in the presence and absence of oxycodone, as data permit. 
9.5. Interim Analyses 
No formal interim analysis will be conducted for this study.  
9.6. 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, investigator’s brochure (IB), 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.   
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 


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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 and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary.  Participants 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 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 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. 
A copy of the ICD(s) must be provided to the participant. 


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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/or 
paper and will be password protected or secured in a locked room 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 
Upjohn  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, Upjohn 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 Upjohn 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. 
www.clinicaltrials.gov 
Upjohn  posts clinical trial US Basic Results on www.clinicaltrials.gov for Upjohn-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.   
EudraCT 
Upjohn posts European Union (EU) Basic Results on EudraCT for all Upjohn-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 


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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 
Upjohn 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 
Upjohn 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.  Upjohn will make available data from these trials 
24 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. 
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 and/or paper form and are password protected or secured in a locked room 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. 


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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 
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. 


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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.  
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  Upjohn-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 mutual 
agreement. 


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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 
Schedule of Activities (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. 
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 or 
urine 
E-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 
Creatine kinase 
GGT 
PT/INR 
Total bile acids 
Acetaminophen drug 
and/or protein adduct 
levels 
 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; E-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. 
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. 


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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 Upjohn-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 (ie, not related to progression of 
underlying disease). 
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. 
 
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. 


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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. 
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. 


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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. 
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 


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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 utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
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 


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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 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 professionals. 
x If a participant dies during participation in the study or during a recognized 
follow-up 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. 


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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. 
 
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 that is highly effective (with a failure 
rate of <1% per year), as described below, during the intervention period and for at 
least 28 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 one of the non-hormonal highly effective contraception methods.   
10.4.4. Contraception Methods 
Highly Effective Methods: 
1. Intrauterine device (IUD). 
2. Bilateral tubal occlusion. 


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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 spermatogenesis cycle is 
approximately 90 days. 
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). 
 
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 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 


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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 study intervention 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 aspartate aminotransferase (AST) and/or alanine 
aminotransferase (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). 
x Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 


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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 Upjohn 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 Opiate Withdrawal Scale  
For each item, circle the number that best describes the patient' s signs or symptoms.  Rate on 
just the apparent relationship to opiate withdrawal.  For example, if heart 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 subjective 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 


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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 piloerrection of skin can be felt or hairs 
standing up on arms  
5 prominent piloerrection 
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: 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 the screen 
images (Figure 2 to Figure 5) shown below.  The participants will be trained to use the 
software at the site. 
Figure 2. 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 Figure 3 to Figure 5 (see Table 7). 


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Figure 3. Screen Display of High VAS 
 
Figure 4. Screen Display of Overall Drug Liking VAS 
 
 


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Figure 5. Screen Display of Take Drug Again VAS 
 
Table 7. 
Other Subjective Effects Visual Analog Scales 
SCALE DESCRIPTION 
STATEMENT TEXT 
RESPONSE ANCHORS 
Good Drug Effects 
At this moment I can feel good 
drug effects 
0: Not at all 
100: Extremely 
Bad Drug Effects 
At this moment I can feel bad 
drug effects 
Feeling Sick 
At this moment I am feeling sick 
Nausea 
At this moment I am feeling 
nausea 
Any Drug Effects 
At this moment I can feel any 
drug effect 
Sleepy 
At this moment I am feeling 
sleepy 
Dizzy 
At this moment I am feeling 
dizzy 
 
 


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10.10. Appendix 10: 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). 
10.10.1. Eligibility 
Not applicable. 
10.10.2. Telehealth Visits  
Not applicable. 
10.10.3. Alternative Facilities for Safety Assessments  
Not applicable. 
10.10.4. 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. 
10.10.5. Home Health Visits  
Not applicable. 
10.10.6. 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.  
10.10.7. Efficacy Assessments 
Not applicable. 
10.10.8. Independent Oversight Committees 
Not applicable. 


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10.11. Appendix 11: Abbreviations 
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation 
Term 
Abs 
absolute 
ADA 
antidrug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of covariance 
ARCI 
addiction research center inventory 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AV 
atrioventricular 
BA 
bioavailability 
BBB 
blood–brain barrier 
BBS 
Biospecimen Banking System 
BE 
bioequivalence 
E-hCG 
beta-human chorionic gonadotropin 
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 
CLcr 
creatinine clearance 
Clast 
last quantifiable concentration 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CO2 
carbon dioxide (bicarbonate) 
CONSORT 
Consolidated Standards of Reporting Trials 
COW 
clinical opiate withdrawal scale 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
clinical trial 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
clinical trial management system 
CV 
cardiovascular 
CYP 
cytochrome P450 


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Abbreviation 
Term 
DC 
discontinuation 
DCT 
data collection tool 
DIA 
Drug Administration Instructions  
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DRE 
disease-related event 
DU 
dispensable unit 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
E-DMC 
external data monitoring committee  
EDP 
exposure during pregnancy 
EDR 
extemporaneous dispensing record 
EMA 
European Medicines Agency 
Emax 
maxium effect 
EOS 
end of study 
EU 
European Union 
ET 
early termination 
EtCO2 
end-tidal carbon dioxide 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GABA 
gamma-amino butyric acid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HAV IgG  
hepatitis A virus immunoglobulin G 
HAV IgM 
hepatitis A virus immunoglobulin M 
HBcAb 
hepatitis B core antibody 
HBsAg  
hepatitis B surface antigen 
HCl 
hydrochloride 
HCVAb 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
ID 
identification 
IND 
investigational new drug application 
INR 
international normalized ratio 
IP manual 
investigational product manual 


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Abbreviation 
Term 
IR 
immediate-release 
IRB 
institutional review board 
IRC 
internal review committee 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IVRS 
Interactive Voice Response System 
IWR 
interactive Web-based response 
Kel 
terminal phase rate constant 
LBBB 
left bundle branch block 
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 
NAb 
neutralizing antibodies 
NOAEL 
no-observed-adverse-effect level 
PBMC1 
peripheral blood mononuclear cells 
PCD 
primary completion date 
PD 
pharmacodynamic(s) 
PGx  
pharmacogenomic(s) 
PI 
principal investigator 
PIB 
powder in bottle 
PK 
pharmacokinetic(s) 
POM 
profile of mood states 
PR 
pulse rate 
PT 
prothrombin time 
PVC 
premature ventricular contraction/complex 
Q1 
first quartile 
Q3 
third quartile 
QTc 
corrected QT 
QTcB 
corrected QT (Bazett's method) 
QTcF 
corrected QT (Fridericia method) 
qual 
qualitative 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCr 
serum creatinine 


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Abbreviation 
Term 
SD 
standard deviation 
SE 
standard error 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SpO2 
saturated oxygen 
SRSD 
single reference safety document 
SToD 
study team on demand 
SUSAR 
suspected unexpected serious adverse reaction 
T 
pregabalin 
t½ 
terminal elimination half-life 
TBili 
total bilirubin 
THC 
tetrahydrocannabinol 
UDS 
urine drug screen 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VAS 
visual analog scale 
VT 
tidal volume  
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 


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10.12. Appendix 12: Summary of Changes 
Protocol Title 
A phase 4, randomized, double-blind, double-dummy, placebo-and active-controlled, 
singLe-dose, six-way crossover study evaluating the abuse potential of Lyrica® taken 
orally concomitantly with Oxycodone hydrochloride In healthy non-drug dependent, 
recreational opioid users  
Product 
Lyrica ® (Pregabalin) 
Protocol Number A0081365 
Study Type 
Phase 4 
Amendment 
3.0 
Protocol Date 
17 Nov 2021 
Legal/Filing 
Sponsor 
Upjohn US 1 LLC 
235 East 42nd Street 
New York, NY 10017-5703 
 
 


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Table 8. 
Summary of changes from Amendment 1.0 dated 12 Nov 2020 to Amendment 2.0 dated 24 Dec 2020 
 
Section  
 
Old Text (Protocol Amendment 1 dated 12 
Nov 2020 
New Text (Protocol Amendment 2 dated 24 Dec 
2020) 
Rationale for 
amendment 
Administrative 
Changes  
Sponsor and Sponsor 
contacts details 
updated 
Missing 
 
Sponsor name ‘Pfizer’ 
Added 
Upjohn US 1 LLC 
 
 
 
Global Clinical Strategy 
 
 
  
 
 
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 2.1 Study 
Rationale From (4th 
paragraph): 
Pregabalin is a Schedule V controlled 
substance.  Since Lyrica® was approved on 
30 December, 2004, the epidemiological 
studies showed that pregabalin may be used 
in conjunction with opioids to enhance the 
‘high’ obtained from opioids.7-9  In addition, 
observational studies have suggested 
pregabalin is associated with drug overdose 
death among individuals with concomitant 
opioid use.3,10  A clinical trial (rather than a 
nonclinical or observational study) is 
Pregabalin is a Schedule V controlled substance.  Since 
Lyrica ® was approved on 30 December, 2004, the 
epidemiological studies showed that pregabalin may be 
used in conjunction with opioids to enhance the ‘high’ 
obtained from opioids.7-9  In addition, observational 
studies have suggested pregabalin is associated with 
drug overdose death among individuals with 
concomitant opioid use.3,10  A clinical trial (rather than a 
nonclinical or observational study) is required to 
evaluate the abuse potential of pregabalin.  As a 
consequence, the FDA requires this post-authorization 
The changes were made 
for clarification 
(modifying the last 
sentence from “This 
clinical trial will evaluate 
pregabalin in a cross-over 
design-----” to “As a 
consequence, the FDA has 
required this post-
authorization safety study 
(PASS) to evaluate 


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Section  
 
Old Text (Protocol Amendment 1 dated 12 
Nov 2020 
New Text (Protocol Amendment 2 dated 24 Dec 
2020) 
Rationale for 
amendment 
required to evaluate the abuse potential of 
pregabalin.  This clinical trial will evaluate 
pregabalin in a cross-over design with 
comparison to placebo and a positive control, 
oxycodone hydrochloride (HCl), regarding 
abuse-related subjective responses, 
physiological responses (including an 
assessment of respiratory depression), and 
drug pharmacokinetics (PK) in a healthy non-
drug dependent population with drug abuse 
experience. 
safety study (PASS) to evaluate pregabalin in a cross-
over design with comparison to placebo and a positive 
control, oxycodone hydrochloride (HCl), regarding 
abuse-related subjective responses, physiological 
responses (including an assessment of respiratory 
depression), and drug pharmacokinetics (PK) in a 
healthy non-drug dependent population with drug abuse 
experience. 
pregabalin in a cross-over 
design 
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 5.3.2 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 10.1.5 
Dissemination of 
Clinical Study Data 
 
Pfizer 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/or www.pfizer.com and other 
public registries in accordance with 
applicable local laws/regulations.  In 
addition, Pfizer reports study results outside 
of the requirements of local laws/regulations 
pursuant to its standard operating procedures 
(SOPs). 
 
www.pfizer.com 
 
Pfizer posts public disclosure synopses (CSR 
Upjohn 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, Upjohn reports 
study results outside of the requirements of local 
laws/regulations pursuant to its standard operating 
procedures (SOPs). 
 
 
 
 
No information added 
This is due to change of 
study sponsor from Pfizer 
to Upjohn.  
 
 
 
 
 
 
 
 
 
 
 
 
This information is 


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Section  
 
Old Text (Protocol Amendment 1 dated 12 
Nov 2020 
New Text (Protocol Amendment 2 dated 24 Dec 
2020) 
Rationale for 
amendment 
synopses 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. 
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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Table 9. 
Summary of changes from Amendment 2.0 dated 24 Dec 2020 to Amendment 3.0 dated 17 Nov 2021 
 
Section  
 
Old Text (Protocol Amendment 2 
dated 24 Dec 2020 
New Text (Protocol Amendment 3 
dated 17 Nov 2021) 
Rationale for 
amendment 
Administrative 
Changes  
Sponsor contacts 
details updated 
 
Global Clinical Strategy 
 
e 
 
  
 
 
 
Clinical Sciences 
 
 
 
 
 
 
Administrative changes to 
update Sponsor contact 
details and authorized 
sponsor protocol approver 
Section 10.4.2.  
(Female Participant 
Reproductive Inclusion 
Criteria), bullet #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 28 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 
that is highly effective (with a failure rate of <1% 
per year), as described below, during the 
intervention period and for at least 28 days after 
the last dose of study intervention, which 
corresponds to the time needed to eliminate any 
study intervention(s). 
Change to allow more 
forms of female 
contraception 
Section 10.4.4. 
(Contraception 
Methods) 
Highly Effective Methods That Have Low User 
Dependency: 
1. Intrauterine device (IUD). 
2. Bilateral tubal occlusion. 
3. Vasectomized partner. 
• 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 
spermatogenesis cycle is approximately 90 
days. 
Highly Effective Methods: 
1. Intrauterine device (IUD). 
2. Bilateral tubal occlusion. 
3. Vasectomized partner. 
• 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 
spermatogenesis cycle is approximately 90 
days. 
4. Contraceptive implants. 
Changes to allow more 
forms of female 
contraception 


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Section  
 
Old Text (Protocol Amendment 2 
dated 24 Dec 2020 
New Text (Protocol Amendment 3 
dated 17 Nov 2021) 
Rationale for 
amendment 
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). 


PD-144723 
Protocol A0081365 
Final Protocol Amendment 3, 17 Nov 2021 
 
 
Upjohn US1 LLC CONFIDENTIAL  
Page 100 
11. REFERENCES 
1. 
Zaccara G, Gangemi P, Perucca P, et al. The adverse event profile of pregabalin: a 
systematic review and meta-analysis of randomized controlled trials. Epilepsia 2011; 
52(4):826-36.  
2. 
Garassino MC, Piva S, La Verde N, et al. Randomised phase II trial (NCT00637975) 
evaluating activity and toxicity of two different escalating strategies for pregabalin and 
oxycodone combination therapy for neuropathic pain in cancer patients. PLoS One 
2013; 8(4):e59981.  
3. 
Abrahamsson T, Berge J, Ojehagen A, et al. Benzodiazepine, z-drug and pregabalin 
prescriptions and mortality among patients in opioid maintenance treatment-A 
nation-wide register-based open cohort study. Drug Alcohol Depend 2017; 174:58-64. 
4. 
Hakkinen M, Vuori E, Kalso E, et al. Profiles of pregabalin and gabapentin abuse by 
postmortem toxicology. Forensic Sci Int 2014; 241:1-6. 
5. 
CSR 720-30015. Abuse Liability of Pregabalin (CI-1008) in Recreational 
Sedative/Alcohol Users. 09 May 2001. 
6. 
Lyrica® [package insert]. New York, NY: Parke-Davis, Division of Pfizer Inc; 2019. 
7. 
Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. 
Drugs 2017; 77(4):403-26. 
8. 
Dahlman D, Abrahamsson T, Kral AH, et al. Nonmedical Use of Antihistaminergic 
Anxiolytics and Other Prescription Drugs among Persons with Opioid Dependence. 
J Addict 2016; 2016:9298571. 
9. 
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. 
10. Gomes T, Greaves S, van den Brink W, et al. Pregabalin and the risk for opioid-related 
death: a nested case-control study. Ann Intern Med 2018; 169(10):732-4. 
11. CSR 744-00386. A Single-Dose Food Effect and Relative Bioavailability Study of 
CI-1008 Capsule and Solution Doses in Healthy Volunteers. 2 Aug 2000.  
12. Oxycodone hydrochloride (ROXICODONE®) [Package Insert].  Hazelwood, MO: 
Mallinckrodt Brand Pharmaceuticals, Inc. 
13. Kinnunen M, Piirainen P, Kokki H, et al. Updated clinical pharmacokinetics and 
pharmacodynamics of oxycodone. Clin Pharmacokinet 2019; 58(6):705-25. 
14. CSR 744-00578; Evaluation of the Potential Pharmacodynamic Interaction Between 
Pregabalin and Oxycodone Administered Orally to Healthy Volunteers. 8 Sep 2000. 


PD-144723 
Protocol A0081365 
Final Protocol Amendment 3, 17 Nov 2021 
 
 
Upjohn US1 LLC CONFIDENTIAL  
Page 101 
15. Zacny JP and Gutierrez S. Characterizing the subjective, psychomotor, and 
physiological effects of oral oxycodone in non-drug-abusing volunteers. 
Psychopharmacology 2003; 170:242-54. 
16. Setnik B, Roland CL, Pixton G, et al. Measurement of drug liking in abuse potential 
studies: a comparison of unipolar and bipolar visual analog scales. J Clin Pharmacol 
2017; 57(2):266-74. 
17. Guidance for industry: Abuse-Deterrent Opioids – Evaluation and Labeling. April 2015. 
Available at: https://www.fda.gov/files/drugs/published/Abuse-Deterrent-Opioids-
Evaluation-and-Labeling.pdf.  

SAP_001.pdf: 
Protocol A0081365 (PD-144723) Statistical Analysis Plan
CONFIDENTIAL 
Page 1 
 
  
 
 
 
 
 
 
 
 
 
Protocol A0081365 
 
A PHASE 4, RANDOMIZED, DOUBLE-BLIND, DOUBLE- 
DUMMY, PLACEBO- AND ACTIVE-CONTROLLED, SINGLE- 
DOSE, SIX-WAY CROSSOVER STUDY EVALUATING THE 
ABUSE POTENTIAL OF LYRICA® TAKEN ORALLY 
CONCOMITANTLY WITH OXYCODONE HYDROCHLORIDE 
IN HEALTHY NON-DRUG DEPENDENT, RECREATIONAL 
OPIOID USERS 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
Version: 
3.0 
SAP Author: 
  
Date: 
26-OCT-2022 
 
 
NCT05053126


Protocol A0081365 (PD-144723) Statistical Analysis Plan
CONFIDENTIAL
Page 2
 
Signature Page
Prepared by:
Statistician
EDETEK, Inc.
Date
Reviewed and Approved at Viatris Inc. by:
 Clinical Pharmacology Statistics & Data Management
Global Clinical Pharmacology
Viatris Inc.
Date
10/26/2022


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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TABLE OF CONTENTS 
 
Signature Page .............................................................................................................................. 2 
TABLE OF CONTENTS .............................................................................................................. 3 
1. VERSION HISTORY ............................................................................................................. 5 
2. INTRODUCTION .................................................................................................................. 6 
2.1. 
Study Objectives and Endpoints ................................................................................. 7 
2.2. 
Study Design .............................................................................................................. 9 
2.3. 
Study Treatment ....................................................................................................... 10 
3. ENDPOINTS AND BASELINE VARIABLES DAY -1: DEFINITIONS AND 
CONVENTIONS .................................................................................................................. 10 
3.1. 
Primary Endpoint(s) ................................................................................................. 10 
3.2. 
Secondary Endpoint(s) ............................................................................................. 10 
Table 2. 
Derivation of Pharmacodynamic Parameters ................................................ 10 
3.3. 
PK Endpoint(s) ......................................................................................................... 11 
Table 3. 
Derivation of Pharmacokinetic Parameters ................................................... 11 
3.4. 
Baseline Variables .................................................................................................... 12 
3.5 Repeated VAS values ......................................................................................................... 12 
3.6. 
Safety Endpoints ...................................................................................................... 12 
Table 4. 
Laboratory Test .............................................................................................. 13 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) .................................................... 15 
Table 5. 
Analysis Sets.................................................................................................. 15 
5. GENERAL METHODOLOGY AND CONVENTIONS ..................................................... 16 
5.1. 
Hypotheses and Decision Rules ............................................................................... 16 
5.2. 
General Methods ...................................................................................................... 17 
5.3. 
Potential Additional Analysis ................................................................................... 17 
6. ANALYSES AND SUMMARIES ....................................................................................... 17 
6.1. 
Study Validity of Analysis of Endpoints .................................................................. 17 
6.2. 
Analysis of Primary and Secondary Endpoint ......................................................... 18 
6.3. 
Sensitivity/Supplementary Analyses ........................................................................ 19 
6.4. 
Pharmacodynamic Analysis ..................................................................................... 20 
6.5. 
Exploratory Analysis ................................................................................................ 20 
6.6. 
Pharmacokinetic Analysis ........................................................................................ 21 


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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6.7. 
Safety Summaries and Analyses ............................................................................... 21 
6.8. 
Electrocardiogram Analyses .................................................................................... 22 
7. EXPLORATORY ANALYSES ........................................................................................... 22 
8. INTERIM ANALYSES ........................................................................................................ 22 
8.1. 
Introduction .............................................................................................................. 22 
9. REFERENCES ..................................................................................................................... 23 
Appendix 1. SAS Code ............................................................................................................. 24 
Appendix 2. List of Abbreviations ............................................................................................ 35 
 
 
 
 


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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1. VERSION HISTORY 
 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific 
Changes 
1/ 
12 Nov 2020 
Original 
12 Nov 2020 
N/A 
N/A 
1.1/ 
14 Mar 2022 
2.0/ 
24 Dec 2020 
To update the sample 
size of Enrolled and 
Completer 
populations 
 
To include 
information of safety 
endpoint 
 
To update the 
definition of 
completer population 
and evaluable 
population  
 
To outline how to 
handle repeated VAS 
values 
 
 Section 2.2: updated sample size 
of Enrolled and Completer 
populations 
 Section 3.5: Repeated VAS 
values will be averaged for 
statistical analysis 
 Section 3.6: added definition of 
AE 
 Section 3.6: added listing of 
clinical safety laboratory test 
 Section 3.6: added parameter of 
ECG and physical examination, 
specified the potential clinical 
concern 
 Section 3.6: added ECG as part 
of standard safety summary 
 Section 4: Completer population 
definition updated to be more in
line with FDA guidance for 
abuse liability studies. 
 Section 3.8: added the 
electrocardiogram analyses 
 Section 7: added the exploratory 
analyses 
2.0/ 
 05 Oct 2022 
3.0/ 
17 Nov 2021 
To add Study 
Treatment 
 
To update secondary 
endpoint 
 
To modify Evaluable 
Population and 
Completer for 
Sensitivity Analysis 
 
Defining PK based 
Protocol Deviation 
 
Missing pre-dose VAS 
score 
Format Change 
 
Section 2.3: Study Treatment 
 
Section 3.2: 
part of secondary endpoint 
 
Section 4: Change the Evaluable 
Population to be based on Modified 
Completer Population 
 
Section 4: Remove Completer for 
Sensitivity Analysis 
 
PK deviations are pre-defined based 
on PK results according to PK 
expectation. 
 
The neutral VAS score will be used 
as the baseline value for Emax and 
AUEC calculation when the pre-
dose VAS is missing. 
 
Updated sponsor name, fix typo


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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Clarify the statistical 
model will be used in 
6.4 
 
Treatment by period 
interaction testing  
 
 
ANOVA was changed to linear 
mixed-effects model per FDA 
guidance and comment. 
 
The treatment by period interaction 
testing was removed from the text in 
this plan, as it is not possible to test 
in this study as it is confounded with 
Carryover effect.  
 
Proc mixed model with Kenward-
Roger method will be used, the 
 
3.0/ 26 Oct. 
2022 
3.0/ 
17 Nov 2021 
Clarify major PK 
deviations and 
evaluable population 
 
Adding high pre-dose criteria. 
 
Clarify the Major PK deviation 
introduced Evaluable population.  
 
2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study A0081365. 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. 
 
LYRICA® (pregabalin) immediate release (IR) is indicated for neuropathic pain associated 
with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain 
associated with spinal cord injury and adjunctive therapy for the treatment of partial onset 
seizures in patients 1 month of age and older. 
 
Pregabalin is an analogue of the neurotransmitter gamma-amino butyric acid (GABA). Its 
mechanism of action has not been established, but it has a similar pharmacological profile to 
that of gabapentin. Despite being a derivative of GABA, it is not active at GABA receptors 
and does not appear to mimic GABA physiologically. Pregabalin is not known to be active 
at receptor sites associated with drugs of abuse; however, several animal models of 
anxiolytic activity have demonstrated that pregabalin may have antianxiety effects similar to 
classic benzodiazepines. Pregabalin is not known to be active at receptor sites associated 
with drugs of abuse; however, pregabalin is associated with central nervous system adverse 
effects such as somnolence and confusion,1 and might cause decreased respiratory rate and 
the combined use of pregabalin and opioids may increase overdose risk.2 The abuse 
potential of pregabalin has been shown to be particularly high among opioid addicts and 
other substance-dependent patients.3-4 
In a study of recreational users (N=15) of sedative/hypnotic drugs (Protocol Clinical Study 
Report [CSR] 720-30015, 1008-098: Abuse Liability of Pregabalin (CI-1008) in 
Recreational Sedative/Alcohol Users), including alcohol, pregabalin (450 mg, single dose) 
received subjective ratings of "good drug effect," "high" and "liking" to a degree that was 
similar to diazepam (30 mg, single dose).5 In controlled clinical studies in over 5500 
patients, 4% of pregabalin treated patients and 1% of placebo treated patients overall 
reported euphoria as an adverse reaction, though in some patient populations studied, this 
reporting rate was higher and ranged from 1% to 12%.6 


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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Pregabalin is a Schedule V controlled substance. Since Lyrica® was approved on 30     
December, 2004, the epidemiological studies showed that pregabalin may be used in 
-9 In addition, 
observational studies have suggested pregabalin is associated with drug overdose death 
among individuals with concomitant opioid use.3,10 A clinical trial (rather than a 
nonclinical or observational study) is required to evaluate the abuse potential of pregabalin. 
As a consequence, the FDA requires this post-authorization safety study (PASS) to evaluate 
pregabalin in a cross-over design with comparison to placebo and a positive control, 
oxycodone hydrochloride (HCl), regarding abuse-related subjective responses, physiological 
responses (including an assessment of respiratory depression), and drug pharmacokinetics 
(PK) in a healthy non-drug dependent population with drug abuse experience. 
 
 
 
2.1. Study Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary: 
Primary: 
 
To determine the abuse potential of orally 
administered pregabalin taken concomitantly 
with oxycodone HCl in non-dependent, 
recreational opioid users under a fasted 
condition. 
 
Bipolar visual analogue scale (VAS) for 
 
 [maxium effect (Emax)]. 
Secondary: 
Secondary: 


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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To evaluate additional pharmacodynamic (PD)
effect and PK of pregabalin and oxycodone 
HCl taken alone and concomitantly in 
non-dependent, recreational opioid users 
under a fasted condition. 
 
To evaluate safety of pregabalin and 
oxycodone HCl taken alone and concomitantly 
in non-dependent, recreational opioid users 
under a fasted condition. 
Pharmacodynamic Endpoints: 
 
max 
(TEmax), area under the effect-time profile from 
time zero to the last quantifiable effect 
(AUEClast), and partial AUEC (AUEC1, AUEC2, 
AUEC3, AUEC4, AUEC8)]. 
 
max, TEmax, 
AUEClast , and partial AUEC (AUEC1, AUEC2, 
AUEC3, AUEC4, AUEC8)]. 
 
 
48 hour postdose. 
 
 
36 and 48 hours postdose. 
 
Unipolar VAS for 
 Drug 
 
 
Unipolar VAS for 
 Drug 
 
 
Unipolar VAS for 
 Drug 
 
 
Pupil size (diameter). 
Pharmacokinetic Endpoints: 
 
Cmax, Tmax, and area under the plasma 
concentration-time profile from time zero to the 
time of the last quantifiable concentration 
(AUClast) of pregabalin and oxycodone. 
 
Area under the plasma concentration-time 
profile from time zero extrapolated to infinity 


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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time (AUCinf), )and half-life (t½), if data 
permits, of pregabalin and oxycodone. 
 
Partial AUCs (AUC1, AUC2, AUC3, AUC4, 
AUC8) of pregabalin and oxycodone.
Safety Endpoints: 
 
Vital signs include respiratory rate (RR), blood 
pressure (BP), pulse rate (PR).
 
Oxygen saturation of hemoglobin (SpO2).
 
Physical examination.
 
12-lead electrocardiogram (ECG).
 
Clinical labs and AEs.
Tertiary/Exploratory: 
Tertiary/Exploraory: 
 
Exposure-response relationship between 
pregabalin concentration and selected PD 
effect in the presence and absence of 
oxycodone. 
 
To enable exploratory research through 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision. 
 
Correlation between pregabalin concentrations 
and selected PD endpoints (Biploar VAS for 
 
diameter) in the presence and absence of 
oxycodone, as data permit. 
 
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 randomized, double-blind, double-dummy, placebo- and active-controlled, 
6- treatment, 6-period crossover, single-dose, Williams square design study in healthy male 
and/or female adult, non drug-dependent recreational opioid users. The study includes 
Screening, a Qualification Phase, a Treatment Phase and Follow-up. This study will 
randomize approximately 60 adult male and female (at least 20% female) participants 
(10 participants in each sequence) in the Treatment Phase to ensure at least 48 participants 
complete the Treatment Phase of the study. Dropouts for non-safety reasons may be 
replaced at the discretion of the Investigator in consultation with the Sponsor. 
 
The following study visits are required, see Figure 1 and the SoA from the protocol: 
 
1. Visit 1, Screening will occur within 28 days prior to Visit 2. 
 
2. Visit 2, Qualification Phase will require inpatient stay at the Clinical Research Unit 
(CRU) for 3 nights: 
 
a. Naloxone Challenge Phase, Day -1; 
 
b. Drug Discrimination, Days 1 and 2 will require inpatient stay at the CRU for 
2 nights; 


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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c. End of Drug Discrimination requires an inpatient stay at the CRU overnight to 
ensure discharge occurs 24 hours after receiving oxycodone or placebo; 
 
d. Participant will proceed to Visit 3 after at least 4-day washout but less than 
28 days after the last dose of study intervention during qualification phase. 
 
3. Visits 3 to 8, Treatment Phase will require a total of 18 overnight inpatient stays at 
the CRU: 
 
a. Each visit will require an inpatient stay at the CRU of 3 nights; 
 
b. Each visit will be separated by a washout period of at least 4 days. The washout 
period is calculated between two subsequent study drug administraitons. 
 
4. End of Study Assessments will be at the CRU to occur 48 hours after completing the 
last study drug dosing or time of early withdrawal. 
 
 For the entire study, 21 overnight inpatient stays will be required. 
2.3. Study Treatment 
The study treatment code and label are listed below. 
 
Treatment A: Placebo single.  
 
Treatment B: Oxycodone HCl 20 mg. 
 
Treatment C: Pregabalin 300 mg. 
 
 Treatment D: Pregabalin 450 mg. 
 
Treatment E: Pregabalin 300 mg + oxycodone HCl 20 mg. 
 
Treatment F: Pregabalin 450 mg + oxycodone HCl 20 mg. 
3. ENDPOINTS AND BASELINE VARIABLES DAY -1: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
The following parameter will be calculated for VAS for 
 
 during each 
Treatment Period: 
 
 Maximum (peak) effect (Emax) as observed directly from the data. 
3.2. Secondary Endpoint(s) 
for 
 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 
 


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inf
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 
observed effect (Elast) 
AUEC1 
Area under the effect-time profile from 
time zero to 1hour postdose 
AUEC2 
Area under the effect-time profile from 
time zero to 2 hours postdose 
AUEC3 
Area under the effect-time profile from 
time zero to 3 hours postdose 
AUEC4 
Area under the effect-time profile from 
time zero to 4 hours postdose 
AUEC8 
Area under the effect-time profile from 
time zero to 8 hours postdose 
Linear trapezoidal method 
 
 
Linear trapezoidal method 
Linear trapezoidal method 
Linear trapezoidal method 
Linear trapezoidal method 
Linear trapezoidal method 
 
 
 
 as pupil size (diameter) will be 
collected at the time points shown in the SoA of the protocol. 
 
3.3. PK Endpoint(s) 
 
PK parameters will be derived from the concentration-time profiles as shown in Table 3. 
 
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/Log trapezoidal method 
 
AUC a 
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. 
 
 
 


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1/2
AUC1 
Area under the plasma concentration- 
time profile from time zero to 1 hour 
postdose 
AUC2 
Area under the plasma concentration- 
time profile from time zero to 2 hours 
postdose 
AUC3 
Area under the plasma concentration- 
time profile from time zero to 3 hours 
postdose 
AUC4 
Area under the plasma concentration- 
time profile from time zero to 4 hours 
postdose 
AUC8 
Area under the plasma concentration- 
time profile from time zero to 8 hours 
postdose 
Linear/Log trapezoidal method 
Linear/Log trapezoidal method 
Linear/Log trapezoidal method 
Linear/Log trapezoidal method 
Linear/Log trapezoidal method 
t   a 
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 measurements of psychometric and pupillometry of each period will be the 
baseline for calculating the changes in these parameters post dose. 
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 
AE is defined as 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.  
Any adverse events (AEs) occurring following start of treatment or increasing in severity will 


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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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 taken. 
 
Adverse events will be summarized by treatment and Phase of the study (i.e., Naloxone 
Challenge Phase, Drug Discrimination Phase, and Treatment Phase). 
 
For clinical safety laboratory assessment. Blood and urine samples will be collected at 
the time points specified in the schedule of activities to conduct hematology, 
coagulation, chemistry and urinalysis analyses. See Table 4 for the list of clinical safety 
laboratory tests to be performed: 
 
Table 4. 
Laboratory Test 
 
Abbreviations: ALT = alanine aminotrans
-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 blood cell; WBC = white blood cell.  
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).  
-hCG for female participants of childbearing potential.  


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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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 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
 
For electrocardiograms, twelve (12)-Lead ECGs should be collected at times specified in 
the Schedule of Activities (SoA) section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
complex. ECG values of potential clinical concern are listed in protocol Appendix 7. 
Continuous cardiac monitoring will also be performed during the Treatment phase as noted 
in the SoA. The time, duration, and description of any clinically significant abnormal 
rhythm will be reported as an adverse event using protocol Appendix 7 as a guide as to 
what is generally considered to be a drug-related adverse event of potential clinical 
concern. 
 
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. And a brief physical examination will include, 
at a minimum, assessments of general appearance, the respiratory and cardiovascular 
systems, and participant-reported symptoms. Height and weight will also be measured and 
recorded as per the Schedule of Activities. 
 
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters): 
 
 adverse events, 
 laboratory data, 
 vital signs data, 
 physical examination, 
 12-lead electrocardiogram (ECG), 
 Oxygen Saturation of hemoglobin (SpO2).


Protocol A0081365 (PD-144723) Statistical Analysis Plan
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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 and releasing the database and 
classifications will be documented per standard operating procedures. 
 
Table 5. 
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 
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 6 periods of the Treatment Phase
and who contribute post-dose PD data from each period. 
These participants must have at least one response on the visual 
analog scale (VAS) for Drug Liking within 2 hours of Tmax for each 
treatment in the study; ie, at least one VAS response within the 
interval 0-3h postdose (assuming the Tmax of 20 mg oxycodone is 
1h) and at least one VAS response within the interval 0-3.5h 
postdose (assuming the Tmax of 300/450 mg pregabalin is 1.5h).
Modified Completer 
The Modified Completer Population will include all 
randomized participants in the Completer Population, 
however, will exclude any participant who meet either of the 
following criteria: 
1. VAS Emax scores are within 5 a point difference 
across all six treatments (ie. Maximum Emax score  
Minimum Emax score 
 
 
2. Emax(P) > 60 and Emax(P) - Emax(Oxy20)  5 
 
where Emax(P) and Emax(Oxy20) are the VAS Emax 
scores for placebo and oxycodone HCl IR 20 mg, 
respectively. 
 
This population will be analyzed as randomized.


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Population
Description
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 participant from the 
evaluable population and determine which participants or 
participant visits will be excluded. This population will be 
analyzed as randomized. 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
To assess the abuse potential of pregabalin the following tests will be performed in the order 
of validation test followed by combination vs. oxycodone and then pregabalin alone vs. 
oxycodone: 
 
Study Validation: 
 
The sensitivity and integrity of the study will be validated by comparing the mean 
responses of oxycodone HCl, the positive control (C), to the placebo: 
 
H0: µC - µP < 1 versus Ha: µC - µP > 1 where 1 = 15. 
 
The study will be considered validated if the one-sided p-value for the validation hypothesis test is 
less than 0.05.  
 
Primary: 
 
1. Does pregabalin plus oxycodone HCl (T) produce mean responses that show abuse 
potential that is no higher than oxycodone HCl (C)? 
 
H0: µT - µC > 0.2(µC - µP) versus Ha: µT - µC < 0.2(µC - µP).12 
 
 
The combination of pregabalin plus oxycodone will be considered to not have an additive effect 
for abuse potential compared to oxycodone alone if the one-sided p-value for pregabalin plus 
oxycodone  1.2 * oxycodone alone + 0.2 * placebo to be positive is less than 0.05.  
 
Secondary: 
 
1. Does pregabalin (L) produce mean responses that show less abuse potential than 


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oxycodone HCl (C)? 
 
H0: µC - µL  0.2(µC - 50) versus Ha: µC - µL >0.2(µC - 50).13 
2. Does pregabalin (L) produce mean responses that show abuse potential similar to 
placebo (P)? 
 
H0: µL - µP  2 versus Ha: µL - µP < 2 where 2 =11. 
 
3. Does pregabalin (L) produce mean responses that show less abuse potential than 
pregabalin plus oxycodone HCl (T)? 
 
H0: µT - µL  0.2(µT - 50) versus Ha: µT - µL >0.2(µT - 50).13 
 
 
For each of the pregabalin hypothesis, the statistical significance of the test will be assessed 
for all doses of pregabalin. 
 
 
5.2. General Methods 
Statistically, the study will be evaluated as a safety study. Consequently, the null hypothesis 
for pregabalin alone and when used concomitantly with oxycodone HCl will be constructed 
on the presumption that these treatments produce abuse potential similar to oxycodone HCl 
and therefore differentiates from 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. 
 
6. ANALYSES AND SUMMARIES 
6.1. Study Validity of Analysis of Endpoints 
Study validity will first be confirmed through the comparison of mean Emax 
 
 This 
comparison will be made using a mixed-effect model with treatment, period, a carryover 
variable and sequence as fixed effects, and participant nested within sequence as a random 
effect. If the p-value for the carryover variable is >0.25, a reduced mixed model will be used 
with treatment, period and sequence as fixed effects, and participant nested within sequence 
as a random effect. If the treatment comparison of oxycodone vs. placebo is statistically 
significant (ie, one-sided p 0.05) in the appropriate direction and confidence intervals 
exclude differences of <15 po
max, it will confirm the sensitivity of the 
study. If study validity is not confirmed, comparisons between pregabalin and oxycodone 
will not be performed. 


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6.2. Analysis of Primary and Secondary Endpoint 
 
A linear mixed-effects model with treatment, period,  a carryover variable and sequence as 
fixed effects, and participant nested within sequence as a random effect. If the p-value for the 
carryover variable is >0.25, a reduced mixed model will be used with treatment, period and 
sequence as fixed effects, and participant nested within sequence as a random effect. 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 
pregabalin, oxycodone HCl and placebo at a significance level of 0.05 (1-sided).  
 
 
 
The principal parameters for the primary and secondary endpoints will be summarized by 
treatment using descriptive statistics (mean, standard error [SE], median, first and third 
quartiles, minimum and maximum). These parameters will be analyzed using a mixed-effect 
model with treatment, period, a carryover variable and sequence as fixed effects, and 
participant nested within sequence as a random effect. If the p-value for the carryover variable 
is >0.25, a reduced mixed model will be used with treatment, period and sequence as fixed 
effects, and participant nested within 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 one-sided 95% confidence intervals will be 
provided for each treatment and for the difference between treatments. P-values will be 
provided for each hypothesis. A two-sided 95% confidence interval will be provided for the 
comparisons of pregabalin (300 mg and 450 mg) plus oxycodone versus oxycodone IR 20 mg. 
Data will be summarized graphically, where appropriate. 
The study validation comparisons will be: 
 Oxycodone HCl IR 20 mg vs. placebo. 
The primary treatment comparisons will be: 
 Pregabalin 300 mg plus oxycodone HCl IR 20 mg vs. oxycodone HCl IR 20 mg; 
 Pregabalin 450 mg plus oxycodone HCl IR 20 mg vs. oxycodone HCl IR 20 mg. 
The secondary treatment comparisons will be: 
 Pregabalin 300 mg vs. placebo; 
 Pregabalin 450 mg vs. placebo; 
 Pregabalin 300 mg plus oxycodone HCl IR 20 mg vs. placebo; 
 Pregabalin 450 mg plus oxycodone HCl IR 20 mg vs. placebo; 
 Pregabalin 300 mg vs. oxycodone HCl IR 20 mg; 
 Pregabalin 450 mg vs. oxycodone HCl IR 20 mg; 


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 Pregabalin 300 mg plus oxycodone HCl IR 20 mg vs. pregabalin 300 mg; 
 Pregabalin 450 mg plus oxycodone HCl IR 20 mg vs. pregabalin 450 mg. 
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. 
 
Mean time plots (linear scale) against nominal time postdose by treatment (all treatments on the 
 
 be presented. 
 
6.3. Sensitivity/Supplementary Analyses 
Regression diagnostics will be performed to verify model assumptions and adequacy of 
the  fitted linear models for the primary endpoints. Shapiro Wilk test will be used to 
diagnose potential non-normality of the model residuals. 
If the resulting p-value from the Shapiro-
 
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 
 symmetry will be tested for each of the 
primary comparisons using the Triples Test in the following manner11: 
 
1. Calculate the paired differences of the treatments being compared 
2. Calculate T as follows: 


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3. Calculate s2 as follows: 
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. 
 
6.4. Pharmacodynamic Analysis 
Pharmacodynamic parameter values that will be evaluated are listed in Table 2. The pre- 
dose measurements of psychometric and pupillometry 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 linear mixed-efforts model consisting of: Sequence, Period, 
Treatment, Time, and Treatment*Time terms as fixed effects, and a participant (Sequence) 
term as a random effect. 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. 
 
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. 
 
Pupil size will be summarized by time points. 
 
6.5. Exploratory Analysis 
As an exploratory analysis, the time course of the different subjective measures in relation to 
each other (and to abuse-related AEs) may 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, respiratory rate and pupil size will be monitored 


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over the course of the study session and correlated to both the drug dose administered and 
the PK of the drug. 
 
6.6. Pharmacokinetic Analysis 
Pregabalin and oxycodone PK parameters (Table 3) will be calculated for each 
participant/period/analyte using noncompartmental analysis of concentration-time data. 
Samples below the LLOQ were set to 0 for analysis. Actual sample collection times were 
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 Pregabalin concentration, the 300 mg dose period (either mono- or combo- dose) will 
be used as the reference geometric mean.  
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.  
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. Individual participant PK parameters, as well as summary statistics 
(eg, group averages, standard deviation [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 pregabalin and oxycodone will be presented. 
Concentrations will be listed and summarized by PK sampling time and treatment for each 
analyte. 
 
6.7. Safety Summaries and Analyses 
All safety analyses will be performed on the safety population. 
 
The safety data will be 
 
Standards. 
 
AEs, ECGs, BP, pulse rate, continuous cardiac monitoring, SpO2 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 


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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. 
 
6.8. Electrocardiogram Analyses 
Electrocardiogram results collected at Screening will be listed. 
 
7. EXPLORATORY ANALYSES 
Exploratory analysis will be conducted to evaluate the correlation between pregabalin 
concentrations and selected PD endpoints (Biploar VAS fo
 
8. INTERIM ANALYSES 
8.1. Introduction 
No formal interim analysis will be conducted for this study. 
 
 
 


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9. REFERENCES 
1. 
Zaccara G, Gangemi P, Perucca P, et al. The adverse event profile of pregabalin: a 
systematic review and meta-analysis of randomized controlled trials. Epilepsia 2011; 
52(4):826-36. 
 
2. 
Garassino MC, Piva S, La Verde N, et al. Randomised phase II trial (NCT00637975) 
evaluating activity and toxicity of two different escalating strategies for pregabalin and 
oxycodone combination therapy for neuropathic pain in cancer patients. PLoS One 
2013; 8(4):e59981. 
 
3. 
Abrahamsson T, Berge J, Ojehagen A, et al. Benzodiazepine, z-drug and pregabalin 
prescriptions and mortality among patients in opioid maintenance treatment-A nation- 
wide register-based open cohort study. Drug Alcohol Depend 2017; 174:58-64. 
 
4. 
Hakkinen M, Vuori E, Kalso E, et al. Profiles of pregabalin and gabapentin abuse by 
postmortem toxicology. Forensic Sci Int 2014; 241:1-6. 
 
5. 
CSR 720-30015. Abuse Liability of Pregabalin (CI-1008) in Recreational 
Sedative/Alcohol Users. 09 May 2001. 
 
6. 
Lyrica® [package insert]. New York, NY: Parke-Davis, Division of Pfizer Inc; 2019. 
 
7. 
Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. 
Drugs 2017; 77(4):403-26. 
 
8. 
Dahlman D, Abrahamsson T, Kral AH, et al. Nonmedical Use of Antihistaminergic 
Anxiolytics and Other Prescription Drugs among Persons with Opioid Dependence. J 
Addict 2016; 2016:9298571. 
 
9. 
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. 
 
10. Gomes T, Greaves S, van den Brink W, et al. Pregabalin and the risk for opioid-related 
death: a nested case-control study. Ann Intern Med 2018; 169(10):732-4. 
 
11. Randles RH, Fligner MA, Policello GE II, Wolfe D
- 
Journal of the American Statistical 
Association, 1980; 369 (75): 168-172. 
 
12. Chen, L. Principles and Methods of Statistical Assessment of Abuse-Deterrent Opioids. 
Therapeutic Innovation & Regulatory Science. 2018; 52: 7-13. 
 
13. Guidance for industry: Abuse-Deterrent Opioids  Evaluation and Labeling. April 2015. 
Available at: https://www.fda.gov/files/drugs/published/Abuse-Deterrent-Opioids- 
Evaluation-and-Labeling.pdf 
 


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Appendix 1. SAS Code 
Sample SAS code for PROC MIXED: 
Create a dummy variable, 
 for Periods 2, 3, 4, 5, and 6, carryover is assigned as follows: 
Treatment
carryover
A
1
B
2
C
3
D
4
E
5
F
6
For Period 1, carryover = 1 regardless of the Treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Letter assignments for treatments (trt) within the estimate statement above are as follows: 
Treatment A: Placebo single dose orally while fasting. 
Treatment B: Oxycodone HCl 20 mg single dose orally while fasting. 
Treatment C: Pregabalin 300 mg single dose orally while fasting. 
Treatment D: Pregabalin 450 mg single dose orally while fasting.  
Treatment E: Pregabalin 300 mg + oxycodone HCl 20 mg single dose orally while fasting. 
Treatment F: Pregabalin 450 mg + oxycodone HCl 20 mg single dose orally while fasting. 
 
 
 
 
 


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Appendix 2. List of Abbreviations 
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the curve
AUEC
area under the effect-time profile from time zero to the last quantifiable effect
BP
blood pressure
BUN
blood urea nitrogen
-hCG
beta human chorionic gonadotropin
Cmax
maximum observed concentration
CRU
Clinical Research Unit
CV
coefficient of variation
ECG
electrocardiogram
Emax
maximum effect
Emax(P)
maximum effect for placebo
Emax(Oxy20)
maximum effect for oxycodone HCl IR 20 mg
FSH
follicle stimulating hormone
GABA
gamma-amino butyric acid


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GGT
gamma glutamyl transferase
HAV IgG
hepatitis A virus immunoglobulin G
HAV IgM
hepatitis A virus immunoglobulin M
HCl
hydrochloride
IR
immediate release
INR
international normalized ratio
PD
pharmacodynamic(s)
PR
pulse rate
PT
prothrombin time
QTc
corrected QT
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
RBC
red blood cell
WBC
white blood cell
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


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