Clinical trial NCT04018664
Conditions: Nalbuphine Opioid Abuse
Keywords: nalbuphine abuse potential
Sponsor: Trevi Therapeutics
Start date: 2018-05-29; Completion date: 2020-06-02
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to measure the effects of a drug called nalbuphine (an opioid drug) compared with the effects of hydromorphone (an opioid drug) and placebo (contains no active drug ingredients). The amount of nalbuphine levels in the blood will also be measured and the safety of the study drugs will be evaluated.

This study has 2 parts: Part A and Part B.

Detailed description:
This study will be a single-dose, randomized, double-blind, active- and placebo-controlled, double dummy, 2-part, 7-way crossover study to determine the abuse potential of orally administered nalbuphine solution and nalbuphine ER intact tablets relative to hydromorphone solution and placebo, in non-dependent, recreational opioid users. The study will be conducted in a single clinical research unit (CRU).

The purpose of Part A is to find the appropriate doses (a low, intermediate, and high dose) of nalbuphine solution to use in Part B. Part A of the study has two visits to the research clinic: a screening visit and dose selection visit. The visits will involve a 2-night stay (3 days total) in the research clinic.

In the Main Study Treatment Phase in Part B, the total estimated duration between each dose of study drug is approximately up to 7 days, of which the subject will spend 3 days/2 nights in the research clinic and approximately up to 4 days at home.

The primary objective of the Main Study is to evaluate the abuse potential of orally administered nalbuphine solution and nalbuphine ER intact tablets relative to hydromorphone solution (the active comparator) and placebo in non-dependent, recreational opioid users.

Arms: arm 1: Placebo

150 mL flavored beverage arm 2: 90 mg nalbuphine HCl solution

9 mL × 10 mg/mL hydromorphone HCl + 141 mL flavored beverage arm 3: 120 mg nalbuphine HCl solution

12 mL × 10 mg/mL hydromorphone HCl + 138 mL flavored beverage arm 4: 150 mg nalbuphine HCl solution

15 mL × 10 mg/mL hydromorphone HCl + 135 mL flavored beverage arm 5: 180 mg nalbuphine HCl solution

18 mL × 10 mg/mL hydromorphone HCl + 132 mL flavored beverage arm 6: 270 mg nalbuphine HCl solution

27 mL × 10 mg/mL hydromorphone HCl + 123 mL flavored beverage arm 7: Up to 405 mg nalbuphine HCl solution

Up to 40.5 mL × 10 mg/mL hydromorphone HCl + at least 109.5 mL flavored beverage arm 8: Up to 540 mg nalbuphine HCl solution

Up to 54 mL × 10 mg/mL hydromorphone HCl + at least 96 mL flavored beverage
Interventions: intervention 1: Nalbuphine HCl solution intervention 2: Placebo solution
Intervention descriptions: intervention 1: nalbuphine solution administered at various strengths intervention 2: Placebo

Protocol documents:
Prot_001.pdf: 
CONFIDENTIAL 
This protocol is the confidential information of Trevi Therapeutics, Inc. and is intended solely for the 
guidance of the clinical investigation. This protocol may not be disclosed to parties not associated with the 
clinical investigation or used for any purpose without the prior written consent of Trevi Therapeutics, Inc. 
 
 
 
Clinical Study Protocol TR08 
A Randomized, Double-Blind, Double-Dummy,  
Active- and Placebo-Controlled, Two-Part, 7-Way 
Crossover Study to Evaluate the Oral Abuse Potential 
of Nalbuphine Solution and Extended-Release Intact 
Tablets Relative to Hydromorphone Solution and 
Placebo in Non-Dependent, Recreational Opioid Users 
INC Research Project #1008910 
Initial protocol: Version 1.0, 09-Apr-2018 
Protocol Amendment 1: Version 2.0, 18-May-2018 
Protocol Amendment 2: Version 3.0, 10-Sep-2018 
 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
Confidential 
Page 2 of 102 
 
Short Title 
Oral Abuse Potential Study of Nalbuphine 
Protocol Number 
TR08 
INC Research 
Project Number 
1008910 
Phase 
Phase I 
Sponsor 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, CT, United States  06510 
Test Products 
Part A 
 
Nalbuphine hydrochloride (HCl) 10 mg/mL (equivalent to 9 mg/mL of 
the free base) 
Part B 
 
Nalbuphine HCl 10 mg/mL (equivalent to 9 mg/mL of the free base) 
 
Nalbuphine extended-release (ER) tablets, 162 mg 
 
Nalbuphine matching placebo tablets 
 
Hydromorphone HCl, 2 mg/mL 
Dose/Route of 
Administration 
Oral administration 
 
Nalbuphine single doses from 81 mg (corresponding to 90 mg of the 
HCl salt) up to a maximum safe dose (MSD) coadministered with a 
flavored beverage as a 150 mL solution 
 
Nalbuphine  ER single dose 162 mg (1 × 162 mg ER tablet) 
 
Hydromorphone HCl single dose 8 mg, 12 mg, and 16 mg (4 mL, 
6 mL, and 8 mL × 2 mg/mL, respectively) coadministered with a 
flavored beverage as a 150 mL solution 
CRO/Study Center 
INC Research Toronto, Inc. 
(part of Syneos HealthTM) 
720 King Street West, Suite 700 
Toronto, Ontario, Canada  M5V 2T3 
Clinical Laboratory 
(Safety) 
Dynacare Medical Laboratories 
115 Midair Court 
Brampton, Ontario, Canada  L6T 5M3 
Bioanalytical 
Laboratory 
(Pharmacokinetic) 
Covance 
2202 Ellis Road, Suite D 
Durham, NC, United States  27703 
 
 
 
 
 
 
 
 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
Confidential 
Page 3 of 102 
 
Medical Monitor 
Thomas Sciascia, M.D. 
Trevi Therapeutics 
195 Church Street 
New Haven, CT, United States  06510 
Version 
3.0 
Date 
10-Sep-2018 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
Confidential 
Page 4 of 102 
 
CONFIDENTIALITY STATEMENT 
This protocol contains information that is confidential and proprietary to Trevi Therapeutics, Inc. 
This information is being provided to you for the purpose of conducting a clinical study for Trevi 
Therapeutics, Inc. You may disclose the contents of this protocol to study personnel under your 
supervision who need to know the contents for this purpose, as well as to your Institutional 
Review Board(s) or Ethics Committee(s), subject to the following condition: The contents of this 
protocol may not be disclosed to any person or entity without the prior written permission of 
Trevi Therapeutics, Inc. and may not be used for any purpose other than the conduct of this 
study. The foregoing shall not apply to disclosure required by governmental regulations or laws; 
however, you will give prompt notice to Trevi Therapeutics, Inc. of any such disclosure. 
Any supplemental information that may be added to this document is also confidential and 
proprietary to Trevi Therapeutics, Inc. and must be kept in confidence in the same manner as the 
contents of this protocol. 
Any person who receives this protocol without due authorization from Trevi Therapeutics, Inc. is 
requested to return it to Trevi Therapeutics, Inc. or to promptly destroy it. 
 








Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
Confidential 
Page 7 of 102 
 
TABLE OF CONTENTS 
Sponsor Approval Page ............................................................................................................. 5 
Principal Investigator Protocol Agreement Page .................................................................... 6 
Amendment Summary .............................................................................................................. 12 
Acronyms & Abbreviations ...................................................................................................... 13 
1. Study Background .............................................................................................................. 16 
1.1 
Previous Human Experience ............................................................................................ 16 
1.2 
Study Rationale ................................................................................................................ 18 
2. Study Objectives and Endpoints ...................................................................................... 18 
2.1 
Study Objectives ............................................................................................................... 18 
2.1.1 
Primary Objective ............................................................................................................. 19 
2.1.2 
Secondary Objectives ....................................................................................................... 19 
2.1.3 
Exploratory Objectives ...................................................................................................... 19 
2.2 
Endpoints .......................................................................................................................... 19 
2.2.1 
Primary Endpoint .............................................................................................................. 19 
2.2.2 
Key Secondary Endpoints ................................................................................................. 19 
2.2.3 
Other Secondary Endpoints .............................................................................................. 19 
2.2.4 
Exploratory Endpoints ....................................................................................................... 21 
3. Investigational Plan ............................................................................................................ 22 
3.1 
Study Design .................................................................................................................... 22 
3.1.1 
Screening (Part A and Part B) ........................................................................................... 22 
3.1.2 
Dose Selection Study (Part A) .......................................................................................... 23 
3.1.3 
Qualification Phase (Part B) .............................................................................................. 24 
3.1.4 
Treatment Phase (Part B) ................................................................................................. 24 
3.1.5 
Follow-up Visit (Part B) ..................................................................................................... 26 
3.1.6 
Study Duration .................................................................................................................. 26 
3.1.7 
Study Schematic and Time and Events Schedules ........................................................... 26 
3.2 
Discussion of Study Design .............................................................................................. 38 
3.2.1 
Selection of Hydromorphone Positive Control .................................................................. 39 
3.2.2 
Nalbuphine Treatment....................................................................................................... 39 
4. Study Population ................................................................................................................ 40 
4.1 
Number of Subjects .......................................................................................................... 40 
4.2 
Inclusion Criteria ............................................................................................................... 41 
4.3 
Exclusion Criteria .............................................................................................................. 41 
4.4 
Naloxone Challenge (Part A and Part B) .......................................................................... 43 
4.5 
Qualification Criteria (Part B) ............................................................................................ 44 
4.6 
Study Restrictions ............................................................................................................. 44 
4.6.1 
Prohibited Medications...................................................................................................... 44 


Clinical Trial Protocol 
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Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
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4.6.2 
Contraceptive Precautions ................................................................................................ 45 
4.6.3 
Dietary and Other Restrictions .......................................................................................... 46 
4.7 
Rescue Medication ........................................................................................................... 47 
4.8 
Subject Discontinuation/Stopping Criteria ........................................................................ 47 
4.9 
Dose Escalation Procedures and Stopping Criteria (Part A) ............................................ 49 
4.9.1 
Data Review Committee ................................................................................................... 49 
4.9.2 
Dose Escalation and Stopping Rules ................................................................................ 49 
5. Study Drug Information ..................................................................................................... 50 
5.1 
Study Drug Administration ................................................................................................ 50 
5.1.1 
Dose Selection Phase (Part A) ......................................................................................... 50 
5.1.2 
Qualification Phase (Part B) .............................................................................................. 51 
5.1.3 
Treatment Phase (Part B) ................................................................................................. 52 
5.2 
Study Drug Identification................................................................................................... 54 
5.2.1 
Nalbuphine ........................................................................................................................ 54 
5.2.2 
Hydromorphone Hydrochloride ......................................................................................... 54 
5.2.3 
Placebo ............................................................................................................................. 54 
5.2.4 
Naloxone Hydrochloride (Naloxone Challenge Test - Qualification Phase) ....................... 54 
5.2.5 
Packaging and Labeling.................................................................................................... 54 
5.2.6 
Handling, Storage, and Accountability .............................................................................. 55 
5.2.7 
Dispensing ........................................................................................................................ 56 
5.3 
Method of Assigning Subjects to Treatment Groups ........................................................ 56 
5.3.1 
Qualification Phase Treatment Sequences (Part B) .......................................................... 56 
5.3.2 
Treatment Phase Treatment Sequences (Part B) ............................................................. 57 
5.4 
Selection of Doses ............................................................................................................ 58 
5.4.1 
Nalbuphine Dose Selection ............................................................................................... 58 
5.4.2 
Hydromorphone Dose Selection ....................................................................................... 58 
5.5 
Blinding and Unblinding Procedures ................................................................................ 59 
5.5.1 
Dose Selection Phase (Part A) ......................................................................................... 59 
5.5.2 
Qualification Phase (Part B) .............................................................................................. 59 
5.5.3 
Treatment Phase (Part B) ................................................................................................. 59 
5.6 
Treatment Compliance ..................................................................................................... 60 
6. Study Procedures and Assessments ............................................................................... 60 
6.1 
Pharmacodynamic Assessments ...................................................................................... 60 
6.1.1 
Visual Analog Scale .......................................................................................................... 60 
6.1.2 
Divided Attention Test ....................................................................................................... 63 
6.1.3 
Digit Symbol Substitution Test .......................................................................................... 64 
6.1.4 
Sternberg Short-Term Memory ......................................................................................... 65 
6.1.5 
Pupillometry ...................................................................................................................... 65 
6.2 
Pharmacokinetic Assessments ......................................................................................... 65 
6.3 
Safety Assessments ......................................................................................................... 66 
6.3.1 
Medical History ................................................................................................................. 66 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
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6.3.2 
Medication History and Recreational Drug and Alcohol Use ............................................. 66 
6.3.3 
Physical Examination ........................................................................................................ 67 
6.3.4 
Electrocardiograms ........................................................................................................... 67 
6.3.5 
Vital Signs ......................................................................................................................... 67 
6.3.6 
Continuous Pulse Oximetry .............................................................................................. 67 
6.3.7 
Columbia-Suicide Severity Rating Scale........................................................................... 67 
6.3.8 
Clinical Laboratory Assessments ...................................................................................... 68 
6.3.9 
Clinical Opioid Withdrawal Scale ...................................................................................... 69 
6.3.10 
Screening Assessments for Subjects who Participate in both Part A and Part B .............. 69 
6.4 
Appropriateness of Measures ........................................................................................... 70 
7. Adverse Events and Serious Adverse Events................................................................. 71 
7.1 
Definitions ......................................................................................................................... 71 
7.1.1 
Adverse Events ................................................................................................................. 71 
7.1.2 
Serious Adverse Events and Serious Unexpected Adverse Events .................................. 71 
7.1.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments ............................... 72 
7.2 
Evaluation of Adverse Events and Serious Adverse Events ............................................ 72 
7.2.1 
Classification of Adverse Event Intensity .......................................................................... 72 
7.2.2 
Classification of Adverse Event Causality ......................................................................... 73 
7.2.3 
Classification of Adverse Event Outcome ......................................................................... 75 
7.3 
Reporting Procedures ....................................................................................................... 75 
7.3.1 
Serious Adverse Events and Serious Unexpected Adverse Events .................................. 75 
7.3.2 
Any Adverse Event ........................................................................................................... 76 
7.3.3 
Pregnancy ......................................................................................................................... 76 
7.4 
Follow-up of Adverse Events and Serious Adverse Events .............................................. 76 
8. Data Analysis and Statistical Considerations ................................................................. 77 
8.1 
Statistical and Analytical Plans ......................................................................................... 77 
8.1.1 
Analysis Populations ......................................................................................................... 77 
8.1.2 
General Statistical Considerations .................................................................................... 78 
8.1.3 
Planned Analyses of Primary and Secondary Pharmacodynamic Assessments (Part 
B) ...................................................................................................................................... 78 
8.1.4 
Analysis of Pharmacokinetics ........................................................................................... 82 
8.1.5 
Analysis of Safety Assessments ....................................................................................... 82 
8.1.6 
Interim Analyses ............................................................................................................... 83 
8.1.7 
Missing Data ..................................................................................................................... 83 
8.1.8 
Demographics and Other Baseline Characteristics .......................................................... 83 
8.2 
Determination of Sample Size .......................................................................................... 84 
9. Study Administration ......................................................................................................... 85 
9.1 
Study Identification Card................................................................................................... 85 
9.2 
Data Collection and Electronic Data Capture ................................................................... 85 
9.3 
Regulatory and Ethical Considerations ............................................................................ 86 
9.3.1 
Ethical Conduct of the Study ............................................................................................. 86 


Clinical Trial Protocol 
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Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
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9.3.2 
Regulatory Authority Approval ........................................................................................... 86 
9.3.3 
Ethics Approval ................................................................................................................. 86 
9.3.4 
Subject Informed Consent ................................................................................................ 86 
9.3.5 
Principal Investigator Reporting Requirements ................................................................. 87 
9.4 
Privacy .............................................................................................................................. 87 
9.4.1 
Subject Identifiers ............................................................................................................. 87 
9.4.2 
Purpose of Collecting Personal Information and Use ....................................................... 87 
9.4.3 
Access and Disclosure of Personal Information ................................................................ 87 
9.4.4 
Release of Subject Information ......................................................................................... 88 
9.4.5 
Consent for Collection, Access, Use and Disclosure of Subject Information ..................... 88 
9.5 
Study Monitoring ............................................................................................................... 88 
9.5.1 
Study Monitoring by Sponsor and/or Third Party Monitor ................................................. 88 
9.6 
Principal Investigator’s Data Responsibility ...................................................................... 89 
9.7 
Data Quality Assurance .................................................................................................... 89 
9.8 
Study and Site Closure ..................................................................................................... 90 
9.9 
Records Retention ............................................................................................................ 90 
10. References .......................................................................................................................... 92 
11. Appendices ......................................................................................................................... 95 
11.1 Amount of Blood Drawn per Study Visit: Dose Selection Study (Part A) ......................... 95 
11.2 Amount of Blood Drawn per Study Visit: Main Study (Part B) .......................................... 96 
11.3 Clinical Opiate Withdrawal Scale ...................................................................................... 97 
12. Protocol Amendments ....................................................................................................... 99 
12.1 Protocol Amendment 1 ..................................................................................................... 99 
12.2 Protocol Amendment 2 ................................................................................................... 100 
 
Table of Tables 
Table 1 
Part A - Time and Events Schedule: Screening and Dose Selection Phase ...... 30 
Table 2 
Part B - Time and Events Schedule: Screening and Qualification Phase .......... 32 
Table 3 
Part B - Time and Events Schedule: Treatment Phase and Follow-Up ............. 35 
Table 4 
Medically Acceptable Forms of Contraception and Duration of Use for 
Females of Childbearing Potential with Male Partners ...................................... 45 
Table 5 
Planned Oral Doses of Nalbuphine Hydrochloride Solution in the Dose 
Selection Phase ................................................................................................. 51 
Table 6 
Double-blind Treatments Administered in the Drug Discrimination Test ............ 52 
Table 7 
Double-Blind Administration of Doses During the Treatment Phase.................. 53 
Table 8 
Treatment Sequences in the Qualification Phase .............................................. 56 
Table 9 
Treatment Sequences in the Treatment Phase .................................................. 57 
Table 10 
Description of Subjective Effects Visual Analog Scales ..................................... 61 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
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Table 11 
Description of Drug Similarity Visual Analog Scales .......................................... 62 
Table 12 
Classification of Adverse Event Intensity ........................................................... 73 
Table 13 
Classification of Adverse Event Causality .......................................................... 74 
Table 14 
Classifications for Adverse Event Outcomes ..................................................... 75 
 
Table of Figures 
Figure 1 
Study Schematic for Part A (Dose Selection Study) .......................................... 27 
Figure 2 
Study Schematic for Part B (Main Study) ........................................................... 29 
Figure 3 
Sample Screen Images for Visual Analog Scale Presentation .......................... 62 
Figure 4 
Sample Screen Image for the Divided Attention Test ......................................... 64 
Figure 5 
Sample Screen Image for the Digit Symbol Substitution Test ............................ 65 
 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
Confidential 
Page 12 of 102 
 
AMENDMENT SUMMARY 
 
Version 
Date 
Description 
1.0 
09-Apr-2018 
Initial release 
2.0 
18-May-2018 
Amendment 1. The protocol was amended based on 
feedback from Health Canada on contraception use for 
male subjects and dose escalation stopping rules. Minor 
clarifications were also incorporated into the protocol. 
Details of all changes and the rationale are provided in 
Section 12.1. 
3.0 
10-Sep-2018 
Amendment 2. The dose escalation scheme in Part A was 
amended to allow an incremental increase in the dose of 
nalbuphine based on a percentage of up to 50% from the 
last dose (rather than an absolute 27 mg dose increase), if 
supported by the safety data of the preceding cohorts up to 
a 2-3-fold the therapeutic dose. Doses of nalbuphine are 
not to exceed 486 mg (ie, 3-fold the therapeutic dose). 
 
The amendment is proposed based on the preliminary 
safety results of the first 4 cohorts indicating a lower than 
expected incidence of adverse events and mildness (all 
Grade 1 except for 1 event of Grade 2 nausea) of the 
adverse event profile up to a dose of 162 mg nalbuphine.  
 
Any episode of vomiting (instead of Grade 2 or higher) 
will be considered as a possible signal of intolerance in the 
evaluation of the maximum safe dose. In addition, an 
option to use both pharmacokinetic and safety data to 
identify the maximum safe dose was included.  
 
Additional protocol clarifications were also added 
regarding urine drug screens, the statistical analyses of the 
pharmacodynamic data in Part B, and data listings of the 
Columbia-Suicide Severity Rating Scale. 
 
Details of all changes and the rationale are provided in 
Section 12.2. 
 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
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Page 13 of 102 
 
ACRONYMS & ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
Alu 
aluminum 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-inf or 
AUCinf 
area under the plasma drug concentration time curve extrapolated to infinity 
AUClast 
area under the plasma drug concentration time curve from the time of dosing to 
the last measurable concentration 
BID 
2 times daily 
BLQ 
below the limit of quantification 
BMI 
body mass index 
bpm 
beats per minute 
CI 
confidence interval 
CL/F 
apparent clearance 
Cmax 
maximum observed plasma drug concentration 
CNS 
central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
case report form (electronic or paper) 
CRU 
clinical research unit 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DAT 
divided attention test 
DRC 
Data Review Committee 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition – Text 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
Confidential 
Page 14 of 102 
 
Revision 
DSST 
digit symbol substitution test 
ECG 
electrocardiogram 
EDC 
electronic data capture 
Emax 
maximum effect 
Emin 
minimum effect 
ER 
extended-release 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HAP 
human abuse potential 
HCl 
hydrochloride 
HIV 
IB 
human immunodeficiency virus 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IR 
immediate release 
IRB 
Institutional Review Board 
IV 
intravenous 
kel 
first-order elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPC 
maximum pupil constriction 
MSD 
Maximum Safe Dose 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
Q1 
first quartile 
Q3 
third quartile 
QD 
once per day 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
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RMS 
root mean square 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SpO2 
blood oxygen saturation 
SSTM 
Sternberg short-term memory test 
t½ 
elimination half-life 
TA_AUE 
time-averaged area under the effect curve 
TA_PAOC 
time-averaged pupillometry area over the curve  
TBD 
to be determined 
TEAE 
treatment-emergent adverse event 
TEmax 
time to maximum effect 
TEmin 
time to minimum effect 
Tmax 
time to maximum observed plasma drug concentration 
TMPC 
time to maximum pupil constriction 
THC 
tetrahydrocannabinol 
VAS 
visual analog scale 
Vd/F 
apparent volume of distribution 
 


Clinical Trial Protocol 
TR08 
Trevi Therapeutics, Inc. 
Oral Abuse Potential Study of Nalbuphine 
 
Version: 3.0, 10-Sep-2018 
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1. 
STUDY BACKGROUND 
Nalbuphine is a derivative of 14-hydroxymorphine and is structurally related to the opioid μ-
receptor agonist oxymorphone and the opioid μ-receptor antagonist naloxone.1 Nalbuphine is a 
competitive antagonist of the μ-opioid receptor while producing agonist effects at the κ-opioid 
receptor and is therefore classified as an 'opioid agonist-antagonist'. Unlike morphine and other 
potent mu-agonists, nalbuphine produces an agonist-antagonist “ceiling effect” and does not 
produce a dose-dependent increase in respiratory depression as the dose is increased.2 
In the US, nalbuphine was approved in 1979 as nalbuphine hydrochloride (HCl) for injection 
(originally marketed as Nubain®) and is medically indicated to treat moderate to severe pain, a 
supplement to balanced anesthesia, for pre-operative and post-operative analgesia and obstetrical 
analgesia during labor and delivery. No oral formulations of nalbuphine have been approved for 
any indication; the drug is available only in generic, parenteral formulations. Presently, 
nalbuphine is not a controlled substance under the Controlled Substances Act (CSA; 21 U.S.C. 
812) in the US3 and is a Schedule IV controlled drug substance under the Controlled Drugs and 
Substances Act in Canada.4  
Trevi Therapeutics, Inc. is developing an oral, extended-release (ER) tablet formulation of 
nalbuphine. Nalbuphine has not been studied in an oral abuse potential study. From the literature, 
the abuse potential of parenteral formulations of nalbuphine has been evaluated in dependent and 
non-dependent opioid users1 and results from some of these studies showed that nalbuphine 
produced abuse-related positive subjective responses that were similar to those of the opioid, 
morphine. In a randomized, placebo-controlled, double-blind, crossover trial,5 16 healthy 
volunteers not dependent on opioids received injections of 2.5, 5.0 or 10 mg/70 kg nalbuphine, 
10 mg/70 kg morphine, or saline over a 15-second interval. Subjective and objective measures 
were tested between 5 and 300 minutes post-injection. The results demonstrated that the 
administration of nalbuphine produced dose-related effects on subjective, psychomotor and 
physiological variables. The profiles of subjective and physiological responses were similar 
between the 10 mg/70 kg doses of nalbuphine and morphine: both produced statistically 
significant (P < 0.001) differences in subjective effects (eg, drug liking), pupil constriction, and 
induced impaired psychomotor performance (number of digit symbols drawn) when compared to 
saline. In another study conducted in 8 subjects not dependent on opioids and with a history of 
opioid abuse, parenteral doses of 8 mg/70 kg nalbuphine produced pupil constriction comparable 
to 10 mg/70 kg morphine; however, increasing the dose of nalbuphine up to 72 mg/70 kg (a nine-
fold dose increase) did not result in a dose-dependent increase in pupil constriction (equivalent 
higher doses of morphine were not tested).6 
1.1 
Previous Human Experience 
The sponsor has completed 13 clinical studies with oral nalbuphine to date. A total of 
706 subjects have received at least one dose of nalbuphine. Trevi has conducted 7 Phase 1 
clinical studies of nalbuphine ER tablets (6 studies in healthy volunteers and 1 study in 
hemodialysis patients with age-, gender- and weight-matched healthy subjects). Two analgesic 
efficacy and safety studies have been conducted.1 Two (2) anti-pruritic efficacy and safety 


Clinical Trial Protocol 
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Oral Abuse Potential Study of Nalbuphine 
 
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studies in hemodialysis patients with uremic pruritus have been conducted1 and 2 anti-pruritic 
efficacy and safety studies in prurigo nodularis subjects.1 No human abuse potential studies of 
nalbuphine ER tablets have been conducted.  
The most common adverse events (AEs) following single or multiples doses of nalbuphine ER 
tablets were known to occur with other drugs with opioid pharmacologic properties and were 
primarily in the system organ categories related to nervous system disorders (eg, dizziness, 
headache, somnolence) and gastrointestinal disorders (eg, nausea and vomiting).1 Most of the 
AEs were mild to moderate in severity.1 In order to minimize these AEs, in-clinical efficacy 
patients were titrated from a low dose of 27 mg to the highest clinical tested dose of 162 mg over 
a 2-week period. However, when administered as a single 108 mg or 162 mg oral dose, the 
incidence of these AEs was relatively high (approximately 20 to 40% dose). Specifically, when 
administered as a single dose nalbuphine ER ranging between 27 mg and 162 mg in studies in 
healthy subjects, the incidence of AEs increased with increasing dose.1 Most of these single dose 
related AEs were mild or moderate in AE grade intensity. One subject administered a single 
108 mg oral dose of nalbuphine ER tablets under fasting conditions experienced sedation 
(ie, unresponsive to pain and verbal stimuli but had normal blood pressure and respiration) that 
was reported as a serious adverse event (SAE) attributed to drug-related sedation effects. The 
subject received treatment with naltrexone (2 x 0.4 mg intramuscular [IM] injections) and 
recovered.  
One (1) study (NAL 20) evaluated opiate withdrawal-related effects in subjects with 
osteoarthritis after administration of nalbuphine ER tablets for 21 days followed by abrupt study 
drug discontinuation.1 The objective opiate withdrawal scale (OOWS) scores obtained from the 
study showed an absence of any physical withdrawal symptoms in most active arm subjects 
scored (85% of subjects scored) or minimal evidence of physical withdrawal symptoms. 
Nalbuphine was well absorbed following oral administration of nalbuphine ER tablets in healthy 
volunteers.1 The median time of observed peak concentrations (Tmax) was 3 to 6 hours after oral 
doses of up to 162 mg nalbuphine ER tablets, while the median Tmax of nalbuphine was 0.5 hours 
after oral administration of 54 mg nalbuphine as a solution (Nubain®) (equivalent to 60 mg 
nalbuphine HCl solution). Exposure (area under the curve; AUC) of nalbuphine after single dose 
administration of Nalbuphine ER tablet and oral solution was shown to be comparable with a 
relative bioavailability of 94% under fasting conditions. However, as expected, the rate of 
absorption for the ER tablet is slower than the rate of the oral solution with a reduced maximum 
observed plasma drug concentration (Cmax) and delayed Tmax  (5.8 hours compared to 0.5 hours, 
respectively), which would be expected from the ER mechanism of this formulation. 
Coadministration of nalbuphine ER tablets with a high caloric meal did not affect Tmax but Cmax 
values were approximately 1.5-fold higher compared to dosing under fasting conditions (Study 
NAL 06). However when administered as a nalbuphine solution, the food effect was less 
pronounced with an 11% decrease in Cmax and approximately 24% increase in AUC under fed 
relative to fasting conditions. 
The mean elimination half-life (t1/2) of nalbuphine varied between 6.6 and 9.6 hours across 
clinical studies. Nalbuphine is metabolized by the liver, possibly undergoes enterohepatic 
circulation, and is excreted via the kidneys. Nalbuphine metabolites are reported to be 
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Following a single oral dose, nalbuphine exposure was dose-dependent and increased with 
increasing dose in a near dose proportional manner in healthy subjects. The mean exposure of 
nalbuphine ranged between 4.13 to 21.6 ng/mL and 58.8 to 328 ng.hr/mL for Cmax and the area 
under the curve extrapolated to infinity (AUC0-inf), respectively, over the 27 mg to 162 mg dose 
range. Drug exposure in healthy female subjects was consistently higher (~ 1.3-1.6 fold at the 
162 mg dose) than that in male subjects; however, the differences were not statistically 
significant (P value > 0.05) (Study NAL07). The t1/2 was similar between males (8 to 9 hours) 
and females (7 to 11 hours), and was independent of dose and gender. In an open-label multiple 
escalating dose study of nalbuphine ER (TR01), 15 hemodialysis patients with pruritus and 
9-matched healthy subjects were evaluated. Subjects were titrated every 3-4 days from 27 mg 
once per day (QD) on Day 1 to 27 mg 2 times daily (BID) then 54 mg BID, 108 mg BID and 
finally 162 mg BID over a 13-day period. Exposure (Cmax and are under the curve over the 
dosing interval [AUCtau]) increased in a dose proportional fashion over the 27-mg to 162-mg 
BID dose range: 2-, 4-, and 6-fold increases in dose resulted in approximately 2-, 5-, and 6-fold 
increases, respectively, in mean Cmax, and AUCtau.7 
1.2 
Study Rationale 
Nalbuphine is an opioid agonist-antagonist and produces effects related to the central nervous 
system (CNS). Drug products with CNS activity are associated with abuse potential.8 Therefore, 
this protocol will evaluate the abuse potential, as well as the pharmacokinetics (PK) and safety, 
of nalbuphine solution and intact ER tablets administered orally in non-dependent, recreational 
opioid users. The abuse potential of nalbuphine will be evaluated against placebo and the 
μ-agonist opioid analgesic hydromorphone HCl solution administered orally. The active drugs 
(ie, nalbuphine and hydromorphone) will be administered as solutions in order to maximize the 
peak exposure (Cmax). As described in the Food and Drug Administration (FDA) Guidance for 
Industry,8 the assessment of abuse potential requires the examination of doses ranging from 
minimally effective to supratherapeutic; however, a maximum (supratherapeutic) dose of 
nalbuphine that can be safely administered in a healthy population has not been identified. 
Therefore, this study will include a Dose Selection Study (Part A) in order to identify the 
appropriate doses of nalbuphine to administer in the Main Study (Part B). 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
The primary and secondary study objectives will be addressed in the Main Study (Part B). The 
exploratory objectives will be addressed in the Dose Selection Study (Part A). 


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2.1.1 Primary Objective 
The primary objective of the Main Study is to evaluate the abuse potential of orally administered 
nalbuphine solution and nalbuphine ER intact tablets relative to hydromorphone solution (the 
active comparator) and placebo in non-dependent, recreational opioid users. 
2.1.2 Secondary Objectives 
The secondary objectives of the Main Study are: 
 To assess the cognitive and psychomotor effects of orally administered nalbuphine 
solution and nalbuphine ER intact tablets relative to hydromorphone solution and placebo 
in non-dependent, recreational opioid users. 
 To assess the PK of orally-administered nalbuphine solution and nalbuphine ER tablets in 
non-dependent, recreational opioid users. 
 To assess the safety and tolerability of orally-administered nalbuphine solution and 
nalbuphine ER tablets relative to hydromorphone solution and placebo in non-dependent, 
recreational opioid users. 
2.1.3 Exploratory Objectives 
The exploratory objectives that will be evaluated in the Dose Selection Study are: 
 To assess the safety and tolerability of various doses of orally-administered nalbuphine 
solution and determine the maximum safe dose (MSD) in non-dependent, recreational 
opioid users. 
 To assess the PK and pharmacodynamics (PD; pupillometry) of various doses of orally-
administered nalbuphine solution in non-dependent, recreational opioid users. 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
The primary endpoint for the Main Study is the peak (maximum) effect (Emax) for Drug Liking 
(“at this moment”), assessed on a bipolar, 0 to 100 point visual analog scale (VAS). 
2.2.2 Key Secondary Endpoints 
The key secondary endpoints for the Main Study are the following measures of global effects: 
 Overall Drug Liking VAS (Emax and peak minimum effect [Emin]) 
 Take Drug Again VAS (Emax) 
2.2.3 Other Secondary Endpoints 
The other secondary endpoints for the Main Study are described below. 


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2.2.3.1 Pharmacodynamic Endpoints 
 Balance of effects: 
– Drug Liking VAS (Emin, time to maximum/minimum effect [TEmax/TEmin], and 
time-averaged area under the effect curve [TA_ AUE]) 
 Positive drug effects: 
– High VAS (Emax, TEmax, and TA_AUE) 
– Good Drug Effects VAS (Emax, TEmax, and TA_AUE) 
 Negative drug effects: 
– Bad Drug Effects VAS (Emax, TEmax, and TA_AUE) 
 Other effects: 
– Hallucination VAS (Emax, TEmax, and TA_AUE) 
– Any Drug Effects (Emax, TEmax, and TA_AUE) 
– Drowsiness/Alertness VAS (Emin, TEmin and TA_AUE) 
– Bowdle VAS (Emax, TEmax, and TA_AUE) 
– Drug Similarity VAS (score at 12 hours) 
 Objective measure: 
– Pupillometry (maximum pupil constriction [MPC], time to MPC [TMPC], and 
time-averaged pupillometry area over the curve [TA_PAOC]) 
 Cognitive and psychomotor effects: 
– Divided Attention Test (DAT) 
– Root mean square (RMS) distance: the RMS distance from the center of 
the road (pixels) (Emax) 
– Percentage over road: percentage of time over the road (%); (Emin) 
– Greatest distance: the maximum distance from the center of the road 
(pixels) (Emax)  
– Response latency of correct responses (msec) (Emax) 
– Average number of false alarms (Emax) 
– Percentage of target hits (%) (Emin) 
– Digit Symbol Substitution Test (DSST) 
– Number of symbols completed (Emin) 
– Number of errors (symbols completed incorrectly) (Emax) 


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– Sternberg Short-Term Memory Test (SSTM) 
– d'Prime (d’) pooled, for all valid responses (Emin) 
– Mean reaction time pooled, for all valid responses (Emax) 
2.2.3.2 Pharmacokinetic Endpoints 
The PK parameters that will be evaluated for nalbuphine, as applicable, include: 
 Cmax: maximum observed plasma concentration 
 Tmax: time to maximum observed plasma concentration 
 AUClast: area under the plasma concentration time curve from 0 to last measurable 
concentration 
The following parameters will be derived for nalbuphine if sufficient data are available: 
 AUCinf: area under the plasma concentration versus time curve extrapolated to infinity 
 kel: first-order elimination rate constant associated with the terminal (log-linear) portion 
of the curve 
 t½: apparent first-order terminal elimination half-life will be calculated as 0.693/kel 
 CL/F: apparent clearance 
 Vd/F: apparent volume of distribution 
2.2.3.3 Safety Endpoints 
 AEs (type, incidence, and severity) 
 Vital signs (blood pressure, respiratory rate, heart rate, oxygen saturation [SpO2], and oral 
temperature) 
 Electrocardiograms (ECGs) (heart rate and the PR, QRS, QT, QTcB, and QTcF intervals) 
 Clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
 Physical examination 
2.2.4 Exploratory Endpoints 
 Safety Assessments: AEs, vital signs (blood pressure, respiratory rate, heart rate, SpO2, 
and oral temperature), ECGs (heart rate and the PR, QRS, QT, QTcB, and QTcF 
intervals), clinical laboratory tests (hematology, clinical chemistry, urinalysis), and 
physical examination 
 Identification of an MSD of nalbuphine administered as nalbuphine oral solution  
 Concentration-versus-time profiles of nalbuphine in plasma and PK parameters Cmax, 
Tmax, and AUClast. If data allow then the PK parameters AUCinf, kel, t1/2, CL/F and Vd/F 
will be calculated. 
 Pupillometry (MPC, TMPC, and TA_PAOC) 


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3. 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This study will be a single-dose, randomized, double-blind, active- and placebo-controlled, 
double-dummy, 2-part, 7-way crossover study to determine the abuse potential of orally 
administered nalbuphine solution and nalbuphine ER intact tablets relative to hydromorphone 
solution and placebo, in non-dependent, recreational opioid users. The study will be conducted in 
a single clinical research unit (CRU). 
In order to determine the appropriate MSD of nalbuphine solution to be used in the main study, 
the study will be conducted in 2 parts: Part A (Dose Selection Study) and Part B (Main Study). 
The purpose of Part A will be to conduct an exploratory dose selection study to identify the 
appropriate low, intermediate, and high doses of nalbuphine solution to be administered as single 
doses in the Treatment Phase of the Main Study (Part B). 
In the Main Study Treatment Phase in Part B, the total estimated duration between each dose of 
study drug is approximately up to 7 days, of which the subject will spend 3 days/2 nights in the 
CRU and approximately up to 4 days at home. 
The study will comprise the following visits: 
Dose Selection Study (Part A) 
 Screening Visit (Visit 1) 
 Dose Selection Phase (naloxone challenge and dose selection) (3-days/2-nights; Visit 2) 
Main Study (Part B) 
 Screening Visit (Visit 1) 
 Qualification Phase (naloxone challenge and drug discrimination test) (4-days/3-nights; 
Visit 2) 
 Treatment Phase; treatment periods 1-7 (3-days/2-nights; Visits 3-9) 
 Follow-up Visit (Visit 10) 
3.1.1 Screening (Part A and Part B) 
Subjects will undergo a screening visit, which will include a review of their medical history and 
recreational drug use history against the study inclusion and exclusion criteria (Section 4.2 and 
Section 4.3, respectively). The same screening procedures and requirements will be applicable to 
both Part A and Part B of this study.  
Eligible subjects who participate in Part A may also participate in Part B (after informed consent 
to participate in Part B is obtained) and will only require re-screening if a duration of 60 days or 
greater has passed between the screening visit in Part A and the first visit in Part B. If a duration 
of more than 4 days and less than 60 days has passed between the screening visit in Part A and 


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the first visit in Part B, then the following assessments will be performed: blood samples will be 
collected from these subjects for clinical laboratory tests of hemoglobin, hematocrit, and liver 
enzymes (ie, alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), serology 
(human immunodeficiency virus [HIV], hepatitis B and hepatitis C), and, for females only, a 
serum pregnancy test. 
New subjects enrolling into Part B of this study will be required to undergo all screening 
procedures. 
3.1.2 Dose Selection Study (Part A) 
Within 30 days of Screening, eligible subjects will enter the Dose Selection Phase that will 
include 1) a naloxone challenge to confirm that subjects are not opioid dependent, and 2) a dose 
escalation scheme to evaluate the safety and tolerability of single escalating oral doses of 
nalbuphine solution to non-dependent, recreational drug users. 
During the naloxone challenge, subjects will receive 0.2 mg of naloxone via an intravenous (IV) 
bolus followed by 0.6 mg naloxone IV if no withdrawal signs are observed, as described in 
Section 4.4. The Clinical Opiate Withdrawal Scale (COWS) will be administered to confirm non-
dependence. Subjects with a COWS score of <5 will be eligible to continue participation in the 
Dose Selection Phase. 
At least 12 hours after completing the naloxone challenge, eligible subjects will receive a single 
oral dose of nalbuphine or placebo solution in a randomized, double-blind manner, after at least 
an 8-hour overnight fast, as described in Section 5.1.1. Each dosing cohort will comprise 
8 unique subjects who will be randomized to nalbuphine or placebo in a ratio of 6:2 
nalbuphine:placebo. All subjects within a cohort will receive the same dose of nalbuphine if 
randomized to active study drug.  
At least 5 unique dosing cohorts are planned and the proposed single doses of nalbuphine 
solution will increase by at least 27 mg increments or will increase in an amount up to 50% of 
the dose administered in the previous cohort, as deemed appropriate by the safety and tolerability 
data: eg, 81 mg, 108 mg, 135 mg, 162 mg, and 243 mg (corresponding to 90 mg, 120 mg, 
150 mg, 180 mg, and 270 mg of the HCl salt, respectively) or until an MSD is reached. Doses of 
nalbuphine solution are not to exceed 486 mg (ie, 3-fold the therapeutic dose). Dose reductions 
and intermediate doses may also be considered based on the results obtained in previous 
cohort(s). The rationale for the dosing cohorts planned is provided in Section 5.4, Selection of 
Doses. 
Safety, PK, and PD (ie, pupillometry) assessments will be conducted for up to 24 hours after 
dosing or longer, at the discretion of the investigator or designee. Subjects will remain in the 
CRU until approximately 24 hours after administration of the study drug and after all final 
assessments are completed (or longer, at the discretion of the investigator or designee). 
Following completion of each cohort, safety data will be unblinded and reviewed by the Data 
Review Committee (DRC). PK and PD data may be unblinded for review if it is available in a 
timely manner, but will not serve as the basis for determining dose escalation. Dose escalation 
will only occur if an MSD has not been identified and the previous dose level was deemed to be 


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safe and well tolerated. Escalation to the next dose level will continue until the MSD is 
identified. If the DRC observes a plateau in the incidence and severity of AEs, which do not meet 
the stopping criteria described in Section 4.9, then the PK data may be reviewed to determine if 
there is a plateau in the exposure of nalbuphine despite dose escalation. 
Additional cohorts of 8 subjects per cohort may be added if a given dose level is repeated to 
provide additional data or if a dose level, intermediate to those proposed, is considered necessary 
for safety or tolerability reasons, or a dose higher than those planned is required to be tested, 
based on supporting safety and tolerability data. Dose escalation or reduction decisions by the 
DRC and the rationale in support of each dose selection will be documented. Dose escalation 
procedures, stopping criteria, and details about the DRC are provided in Section 4.9. 
3.1.3 Qualification Phase (Part B) 
Within 30 days of screening, a sufficient number of eligible subjects will participate in the 
Qualification Phase in order to randomize an estimated 56 subjects in the Treatment Phase. The 
Qualification Phase will include 1) a naloxone challenge to confirm that subjects are not opioid 
dependent, and 2) a drug discrimination test to ensure that subjects can distinguish between the 
active control (hydromorphone) and placebo. 
The same procedures used for the naloxone challenge in Part A will performed in Part B: 
subjects will receive 0.2 mg of naloxone via an IV bolus followed by 0.6 mg naloxone IV if no 
withdrawal signs are observed, as described in Section 4.4. Subjects with a COWS score of <5 
will be eligible to continue with the drug discrimination test. For those subjects who successfully 
complete the naloxone challenge in Part A and elect to participate in Part B, a naloxone re-
challenge will only be required if more than 60 days has passed between the first challenge and 
admission to the Qualification Phase in Part B. 
During the drug discrimination test, doses will be administered in a randomized, double-blind, 
single-dummy, crossover manner following a fasting period of at least 8 hours. Subjects will 
receive a single oral dose of 12 mg hydromorphone HCl solution and placebo solution on 
consecutive days (Days 1 and 2), approximately 24 hours apart, to ensure that they are able to 
discriminate the positive drug effects of the active comparator. Each subject will drink 
approximately 200 mL of solution on each day. The 12 mg dose of hydromorphone HCl (6 mL of 
2 mg/mL) will be added to a flavored beverage (approximately 144 mL) to prepare the 150 mL 
dosing solution. The placebo solution will consist of a flavored beverage administered to subjects 
in a volume of 150 mL. After subjects drink the 150 mL dosing solution, an additional 50 mL 
flavored beverage will be added to the dosing container as a rinse and then administered to the 
subjects. Study drug administration is described in Section 5.1.2. 
Pharmacodynamic and safety assessments will be conducted prior to dosing and until at least 
8 hours after dosing. Data will be reviewed to determine subject eligibility, as described in 
Section 4.5. 
3.1.4 Treatment Phase (Part B) 
An estimated 56 eligible subjects will be randomized in the Treatment Phase. The last drug 
administration in the Qualification Phase and the first drug administration in the Treatment Phase 


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will be separated by a washout interval of at least 72 hours (exceeding 5 times the expected half-
life of hydromorphone). During the 7 treatment periods, subjects will receive single oral doses of 
each treatment in a randomized, double-blind, double-dummy fashion, as described in 
Section 5.1.3. Each treatment will consist of a dosing solution of 150 mL of oral solution 
(nalbuphine, hydromorphone, or placebo [flavored beverage]) and one intact tablet (nalbuphine 
ER or matching placebo). After subjects drink the 150 mL dosing solution, an additional 50 mL 
flavored beverage will be added to the dosing container as a rinse and then administered to the 
subjects. 
The selection of the low, intermediate, and high doses of nalbuphine solution planned for the 
Treatment Phase will be determined (“TBD”) based on the results obtained in Part A, as 
described in Section 4.9. However, the total volume of dosing solution to be administered in each 
treatment period will be identical (ie, 150 mL dosing solution comprised of an appropriate 
amount of active drug and/or flavored beverage) in order to maintain the blind. 
The following treatments will be administered: 
 Treatment A: Placebo  
150 mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
 Treatment B: Hydromorphone HCl 8 mg solution 
4 mL × 2 mg/mL hydromorphone HCl + 146 mL flavored beverage +  
1 × nalbuphine matching placebo tablet 
 Treatment C: Hydromorphone HCl 16 mg solution 
8 mL × 2 mg/mL hydromorphone HCl + 142 mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
 Treatment D: Nalbuphine HCl low dose solution  
low dose nalbuphine HCl solution + TBD mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
 Treatment E: Nalbuphine HCl intermediate dose solution  
Intermediate dose nalbuphine HCl solution + TBD mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
 Treatment F: Nalbuphine HCl high dose solution  
high dose nalbuphine HCl solution + TBD mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
 Treatment G: Nalbuphine 162 mg ER intact tablet 
150 mL flavored beverage + 
1 × 162 mg nalbuphine ER tablet 
Drug administration will occur on Day 1 of each treatment period, followed by PD, PK, and 
safety assessments for up to 24 hours post-dose. Subjects will be discharged on Day 2, 
approximately 24 hours after dosing, at the discretion of the investigator or designee to ensure 
subject safety. Each treatment will be separated by a washout interval of at least 4 days.  


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3.1.5 Follow-up Visit (Part B) 
Subjects will return for an end-of-study safety follow-up visit approximately 7 to 14 days 
following the last drug administration in the Treatment Phase, or at the time of early withdrawal. 
3.1.6 Study Duration 
Subjects who enroll in Part A will participate in the study for a maximum of 4.5 weeks. This 
includes up to 30 days for the Screening visit and 3 days in the Dose Selection Phase. 
Subjects who enroll in Part B will participate in the study for up to 14 weeks. This includes up to 
30 days for the Screening visit, up to 3 days in the Qualification Phase followed by at least a 
72-hour washout, 42 days in the Treatment Phase (assuming up to a 7-day washout between each 
dose of study drug), and up to 14 days for the Follow-up visit. 
Subjects who participate in both Part A and Part B of the study may participate for a maximum 
duration of approximately 19 weeks. 
3.1.7 Study Schematic and Time and Events Schedules 
Study schematics are presented in Figure 1 (Part A) and Figure 2 (Part B). Study assessments 
will be performed at the visits and time points outlined in the Time and Events Schedules, as 
follows: 
Table 1 Part A: Screening and Dose Selection Phase 
Table 2 Part B: Screening and Qualification Phase 
Table 3 Part B: Treatment Phase and Follow-up 


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Figure 1 
Study Schematic for Part A (Dose Selection Study) 
Screening
Visit
SCREENING
PHASE
Dose Selection Phase
Cohort 1 
90 mg nalbuphine HCl solution
(equivalent to 81 mg of the free base)
(9 mL × 10 mg/mL + 141 mL flavored beverage or 150 mL flavored beverage)
Visit 2
Visit 1
Within 30 days of Screening visit
Up to 0.8 mg
 naloxone IV
Naloxone Challenge
Cohort 2 
120 mg nalbuphine HCl solution
(equivalent to 108 mg of the free base) 
(12 mL × 10 mg/mL + 138 mL flavored beverage or 150 mL flavored beverage)
Cohort 3 
150 mg nalbuphine HCl solution
(equivalent to 135 mg of the free base) 
(15 mL × 10 mg/mL + 135 mL flavored beverage or 150 mL flavored beverage) 
Cohort 4 
180 mg nalbuphine HCl solution
(equivalent to 162 mg of the free base)
(18 mL × 10 mg/mL + 132 mL flavored beverage or 150 mL flavored beverage)
Cohort 5 
270 mg nalbuphine HCl solution
(equivalent to 243 mg of the free base)
(27 mL × 10 mg/mL + 123 mL flavored beverage or 150 mL flavored beverage)
At least 12 hours after the naloxone challenge
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Yes
Yes
Yes
Yes
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Yes
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose Selection
Cohort 6 
up to 405 mg nalbuphine HCl solution
(equivalent to up to 365 mg of the free base)
(up to 40.5 mL × 10 mg/mL + at least 109.5 mL of flavored beverage or 150 mL flavored beverage)
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Yes
Dose 
escalation 
Stop
Cohort 7 
up to 540 mg nalbuphine HCl solution
(equivalent to up to 486 mg of the free base)
(up to 54 mL × 10 mg/mL + at least 96 mL of flavored beverage or 150 mL flavored beverage)
Dose 
escalation 
Stop
 


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Footnotes Figure 1: 
DRC=data review committee; ER=extended release; HCl=hydrochloride; IV=intravenous; MSD=maximum safe dose. 
At each dosing of active drug, the dose will be added to a flavored beverage to prepare a dosing volume of 150 mL. An additional 
50 mL of a flavored beverage will be added as a rinse to the empty dosing container that contained the 150 mL solution and then 
administered to the subjects.  
At least 12 hours after completing the naloxone challenge, eligible subjects will receive a single oral dose of nalbuphine HCl solution 
or placebo solution in a randomized, double-blind manner. Each cohort will comprise 8 unique subjects who will be randomized to 
nalbuphine HCl (n=6) or placebo (n=2).  
Following completion of each cohort, safety data will be unblinded and reviewed by the DRC. Escalation to the next dose level will 
continue until the MSD is identified. Dose reductions and intermediate doses may be considered based on the results obtained in 
previous cohort(s). Additional cohorts of subjects may be added until the MSD is identified, or if additional data are required at a 
given dose level or at a dose intermediate to those specified, or a dose higher than those planned is required to be tested, based 
on supportive safety data. If a dose higher than planned will be tested, the dose to be administered will be up to 50% greater than 
the dose administered in the previous cohort, based on supporting safety data. 


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Figure 2 
Study Schematic for Part B (Main Study) 
Screening
Visit
SCREENING
PHASE
QUALIFICATION
PHASE
Treatment Y:
Hydromorphone HCl 12 mg solution
Treatment X:
Placebo solution
TREATMENT PHASE
At least 72 hours after the last dose in the Qualification Phase
Treatment A: Placebo 
150 mL flavored beverage
+ 1 × nalbuphine matching placebo tablet
Washout at least 4 days
FOLLOW-UP
PHASE
Follow-up/
Early Withdrawal
Visit
Visit 2
Visit 1
Visit 3 to Visit 9
Visit 10
Within 30 days of Screening visit
Up to 0.8 mg 
naloxone IV
Drug Discrimination Test
Naloxone Challenge
Treatment D: Nalbuphine HCl low dose solution
low dose nalbuphine HCl solution + TBD mL flavored beverage
+ 1 × nalbuphine matching placebo tablet
Washout at least 4 days
Treatment E: Nalbuphine HCl intermediate dose solution
Intermediate dose nalbuphine HCl solution + TBD mL flavored beverage
+ 1 × nalbuphine matching placebo tablet
Washout at least 4 days
Treatment F: Nalbuphine HCl  high dose solution
high dose nalbuphine HCl solution + TBD mL flavored beverage
+ 1 × nalbuphine matching placebo tablet
Washout at least 4 days
Treatment G: Nalbuphine 162 mg ER intact tablet
150 mL flavored beverage
+ 1 × 162 mg nalbuphine ER tablet
Washout at least 4 days
Treatment B: Hydromorphone HCl 8 mg solution
4 mL × 2 mg/mL hydromorphone HCl + 146 mL flavored beverage
+ 1 × nalbuphine matching placebo tablet
Approximately 7 to 14 days after the last dose administration or 
early withdrawal
24-hour washout
Washout at least 4 days
Treatment C: Hydromorphone HCl 16 mg solution
8 mL × 2 mg/mL hydromorphone HCl + 142 mL flavored beverage
+ 1 × nalbuphine matching placebo tablet
 
ER=extended release; HCl=hydrochloride; IR=immediate release; IV=intravenous; TBD=to be determined. 
At each dosing of active drug, the dose will be added to a flavored beverage to prepare a dosing volume of 150 mL. An additional 
50 mL of a flavored beverage will be added as a rinse to the empty dosing container that contained the 150 mL solution and then 
administered to the subjects. 
In the Qualification Phase, the drug discrimination test will be administered to eligible subjects at least 12 hours after the naloxone 
challenge. Each treatment will be administered orally in a randomized, double-blind manner and separated by a 24-hour washout 
interval. Placebo solution will comprise 150 mL flavored beverage and hydromorphone HCl solution will comprise 6 mL x 2 mg/mL 
hydromorphone HCl + 144 mL flavored beverage. 
In the Treatment Phase, each treatment will be administered orally in a randomized, double-blind, double-dummy manner and doses 
will be separated by at least a 4-day washout interval. Low, intermediate, and high doses of nalbuphine HCl solution will be 
determined in Part A. 


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Table 1 
Part A - Time and Events Schedule: Screening and Dose Selection Phase 
 
Screening 
Visit 
Dose Selection Phase 
Naloxone 
Challenge 
Dose Selection Cohorts 
Visit: 
1 
2 
Day: 
–30 to –2 
−1 
1 
2 
 
 
 
Assessment time points relative to dosing (hours) 
Subject Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication and Recreational 
Drug and Alcohol Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Restrictions Review 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSM-IV-TR  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS (Baseline version) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Height, Weight, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B, Hepatitis C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsc 
X 
Xd 
Pre 
 
 
 
1 
 
2 
 
3 
4 
5 
6 
 
7 
8 
10 
12 
24 
 
a Focusing on any changes since the last visit.  
b  Symptom-directed physical examination 
c  Vital signs will include blood pressure, heart rate, and respiratory rate. Vital signs will also include measurements of oxygen saturation after continuous pulse oximetry monitoring is 
complete.  
d Pre-naloxone challenge and at 10 minutes and 1 hour post-naloxone challenge, as indicated in Section 4.4. 


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Screening 
Visit 
Dose Selection Phase 
Naloxone 
Challenge 
Dose Selection Cohorts 
Visit: 
1 
2 
Day: 
–30 to –2 
−1 
1 
2 
 
 
 
Assessment time points relative to dosing (hours) 
Oral Temperature 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Electrocardiogram 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continuous Pulse Oximetrye 
 
 
Predose until at least 6 hours post-dose 
 
Clinical Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Concomitant Medications 
 
 
< -- recorded throughout -- > 
Adverse Event Monitoringf 
X 
X 
< -- recorded throughout -- > 
COWS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
Nalbuphine 
 
 
Pre 
 
0.25 
0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
 
 
8 
10 
12 
24 
Pharmacodynamics 
 
 
 
 
 
Pupillometry 
 
 
Pre 
 
0.25 
0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
 
 
8 
10 
12 
24 
Study Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Naloxone Administration 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
preh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dischargei 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE=adverse event; BMI=body mass index; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia-Suicide Severity Rating Scale; DSM-IV-TR=Diagnostic and Statistical Manual 
of Mental Disorders – Fourth Edition – Text Revision; ECG=electrocardiogram; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; pre=pre-dose
 
e  Oxygen saturation will be monitored continuously via telemetry for at least 6 hours post-dose or longer, if deemed necessary by the investigator or designee to ensure subject safety. 
f  Spontaneous AE reporting is continuous throughout the study; however, AE questioning may be performed using a non-leading question at discretion of the clinical staff. 
g  Naloxone challenge procedures are described in Section 4.4. For female subjects, the results of the urine pregnancy test are required prior to the naloxone challenge; results of the 
serum pregnancy test will not be required prior to the naloxone challenge. 
h  Day 1 only. 
i  Subjects will be discharged after assessments on Day 2 are complete and at the discretion of the investigator or designee to ensure subject safety. 


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Table 2 
Part B - Time and Events Schedule: Screening and Qualification Phase 
 
Screening  
Visita 
Qualification Phase 
Naloxone 
Challengeb 
Drug Discrimination Test 
Visit: 
1 
2 
Day: 
–30 to –2 
–1 
1 and 2 
3c 
 
 
 
Assessment time points relative to dosing (hours) 
 
Subject Review 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
Medication and Recreational 
Drug and Alcohol Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Restrictions Review 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
DSM-IV-TR 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS (Baseline version) 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
Physical Examination 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
Height, Weight, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
 
X 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B, Hepatitis C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
a For subjects who completed screening assessments in Part A, abbreviated screening assessments may be performed as described in Section 6.3.10. 
b For subjects who successfully completed the naloxone challenge in Part A, a naloxone re-challenge will only be required if more than 60 days has passed between the first challenge 
and admission to the Qualification Phase in Part B. 
c Day 3 assessments are performed approximately 24 hours post last dose 
d Focusing on any changes since the last visit 
e Symptom-directed physical examination performed  


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Screening  
Visita 
Qualification Phase 
Naloxone 
Challengeb 
Drug Discrimination Test 
Visit: 
1 
2 
Day: 
–30 to –2 
–1 
1 and 2 
3c 
 
 
 
Assessment time points relative to dosing (hours) 
 
Vital Signsf 
X 
Xg 
pre 
 
1 
 
2 
3 
 
6 
8 
X 
Oral Temperature 
X 
X 
 
 
 
 
 
 
 
 
 
 
COWS 
 
Xh 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol 
X 
X 
 
 
 
 
 
 
 
 
 
 
Continuous Pulse Oximetry 
 
 
From pre-dose until at least 4 hours post-dose 
 
 
Clinical Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
< -- recorded throughout -- > 
X 
Adverse Event Monitoringi 
X 
X 
< -- recorded throughout -- > 
X 
Pharmacodynamics 
 
 
 
Training/Practicej 
 
X 
 
 
 
 
 
 
 
 
 
 
Drug-Specific VASk 
 
 
 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
 
Other VASl 
 
 
pre 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
 
ODL, TDA VAS 
 
 
 
 
 
 
 
 
 
 
8 
 
Study Administration 
 
 
 
 
Naloxone Challenge 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
pren 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
f  Vital signs will include blood pressure, heart rate, and respiratory rate. Oxygen saturation will be measured after continuous pulse oximetry monitoring is complete. 
g   Pre-naloxone challenge and at 10 minutes and 1 hour post-naloxone challenge, as indicated in Section 4.4. 
h  COWS will be done at admission (prior to the naloxone challenge) and during the naloxone challenge.  
i  Spontaneous AE reporting is continuous throughout the study; however, AE questioning may be performed using a non-leading question at discretion of the clinical staff. 
j  Complete training and practice session 
k  Drug Liking VAS, Good Drug Effects VAS, and Bad Drug Effects VAS 
l  High and Drowsiness/Alertness VAS 
m  Naloxone challenge procedures are described in Section 4.4. For female subjects, the results of the urine pregnancy test are required prior to the naloxone challenge; results of the 
serum pregnancy test will not be required prior to the naloxone challenge. 
n  Day 1 only. 


Clinical Trial Protocol 
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Screening  
Visita 
Qualification Phase 
Naloxone 
Challengeb 
Drug Discrimination Test 
Visit: 
1 
2 
Day: 
–30 to –2 
–1 
1 and 2 
3c 
 
 
 
Assessment time points relative to dosing (hours) 
 
Study Drug Administration 
 
 
 
0 
 
 
 
 
 
 
 
 
 
Dispense Subject ID Card 
 
 
 
 
 
 
 
 
 
 
 
X 
Dischargeo 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
AE=adverse event; BMI=body mass index; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia-Suicide Severity Rating Scale; DSM-IV-TR=Diagnostic and Statistical Manual of Mental 
Disorders – Fourth Edition – Text Revision; ECG=electrocardiogram; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; ID=identification; ODL=Overall Drug Liking; pre=pre-
dose; TDA=Take Drug Again; VAS=visual analog scale 
 
 
o Subjects will be discharged after assessments on Day 3 are complete and at the discretion of the investigator or designee to ensure subject safety. 


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Table 3 
Part B - Time and Events Schedule: Treatment Phase and Follow-Up 
 
TREATMENT PHASE 
FU 
or 
EW 
Treatment Periods 1 to 7 
Visit: 
3 to 9 
10 
Day: 
–1 
1 
2 
— 
 
 
Assessment time points (hours) 
 
Subject Review 
 
 
 
Study Restrictions Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical History 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xa 
C-SSRS (Since Last Visit) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety 
 
 
 
Physical Examination 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Serum Pregnancy 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsd 
X 
pre 
 
 
0.5 
1 
1.5 
2 
3 
4 
5 
 
6 
 
7 
8 
10 
12 
24 
X 
Oral Temperature 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
COWSe 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a  Focusing on any changes since the last visit 
b  Symptom-directed physical examination performed 
c  Serum pregnancy at Treatment periods 1 and 7 only; urine pregnancy at Treatment periods 2, 3, 4, 5, and 6 
d  Vital signs will include blood pressure, heart rate, and respiratory rate. Oxygen saturation will be measured after continuous pulse oximetry monitoring is complete. 
e  COWS may be administered adhoc during the Treatment phase, at the investigator’s discretion, based on any observed or reported AEs that may indicate signs or symptoms of 
withdrawal. 
f  Subjects must have both a negative UDS result and a COWS score < 5 to continue the study. Subjects who have a positive UDS result and score < 5 on the COWS may be 
rescheduled at the discretion of the investigator. Subjects who have a COWS score ≥ 5, with or without a positive UDS result, will be discontinued from the study and receive 
appropriate medical care for at least 4 hours or longer until the investigator determines that the subject can be safely discharged from the clinical unit.  


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TREATMENT PHASE 
FU 
or 
EW 
Treatment Periods 1 to 7 
Visit: 
3 to 9 
10 
Day: 
–1 
1 
2 
— 
 
 
Assessment time points (hours) 
 
Continuous Pulse Oximetry 
 
From pre-dose until at least 6 hours post-dose 
 
 
Clinical Laboratory 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medicationsh 
X 
<--------------------------------- Recorded throughout ---------------------------------> 
X 
AE Monitoringi 
X 
<--------------------------------- Recorded throughout ---------------------------------> 
X 
Pharmacodynamics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training/Practice  
Xj 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug-Specific VASl  
 
 
 
 
0.5 
1 
1.5 
2 
3 
4 
5 
5.5 
6 
6.5 
7 
8 
9 
12 
24 
 
Other VASm  
 
pre 
 
 
0.5 
1 
1.5 
2 
3 
4 
5 
5.5 
6 
6.5 
7 
8 
9 
12 
24 
 
ODL, TDA VAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 
24 
 
Drug Similarity VAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 
 
 
DAT, DSST, SSTM 
 
pre 
 
 
0.5 
1 
1.5 
2 
3 
4 
5 
5.5 
6 
6.5 
7 
8 
9 
12 
24 
 
Pupillometry 
 
pre 
 
 
0.5 
1 
1.5 
2 
3 
4 
5 
5.5 
6 
6.5 
7 
8 
9 
12 
24 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nalbuphine 
 
pre 
 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
5.5 
6 
6.5 
7 
 
9 
12 
24 
 
 
g  Hematology, clinical chemistry, and urinalysis 
h  Concomitant medications will be recorded throughout the study; however, specific questioning will be performed at admission(s) and Follow-up 
i  Spontaneous AE reporting is continuous throughout the study; however, AE questioning may be performed using a non-leading question at discretion of the clinical staff.  
j  Pharmacodynamic training and practice session 
k  Pharmacodynamic refresher session for DAT, DSST, and SSTM 
l  Drug Liking VAS, Good Drug Effects VAS, Bad Drug Effects VAS, Any Drug Effects VAS 
m  High, Drowsiness/Alertness, Hallucination, Bowdle VAS 


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TREATMENT PHASE 
FU 
or 
EW 
Treatment Periods 1 to 7 
Visit: 
3 to 9 
10 
Day: 
–1 
1 
2 
— 
 
 
Assessment time points (hours) 
 
Study Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
pren 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Administration 
 
 
0o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dischargep 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE=adverse event; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia-Suicide Severity Rating Scale; DAT=Divided Attention Test; DSST= Digit Symbol Substitution Test; 
ECG=electrocardiogram; EW=early withdrawal; FU=follow up; ODL=Overall Drug Liking; pre=pre-dose; SSTM= Sternberg Short-Term Memory; TDA=Take Drug Again; VAS=visual 
analog scale 
 
 
n  Treatment period 1 only 
o  Day 1 of each Treatment period; each drug administration will be separated by at least 4 days 
p  Approximately 24 hours post-dose in each treatment period (unless subject has a COWS score ≥ 5; see footnote f above), after the completion of assessments, at the discretion of 
the investigator or designee 


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3.2 
Discussion of Study Design 
The overall study design is consistent with guidelines for the assessment of abuse potential in 
humans.8,9 In accordance with these guidelines, subjects will be healthy individuals who are non-
dependent recreational opioid users. 
For this study, nalbuphine will be compared to hydromorphone and placebo. Details for the 
rationale for selecting the positive control can be found in Section 3.2.1 and the rationale for the 
specific doses selected can be found in Section 5.4. 
Due to inter-individual variability in subjective responses, human abuse potential studies are 
typically conducted using a double-blind crossover design, where each subject receives several 
doses of comparator and the investigational drug, as well as placebo. Thus, each subject acts as 
his/her own control. Subjects will be healthy individuals, with previous non-therapeutic 
(recreational) experience with opioids. These subjects are the most face-valid population to study 
because they represent the population at greatest risk for abuse of a novel compound with abuse 
potential, and they can provide meaningful ratings of the drug experiences with a lower risk of 
false negative results. In an abuse potential study, a negative result with a non-drug-using 
population can be considered inconclusive, since these subjects often do not like the effects of 
drugs that are readily abused by substance users. 
In addition to the requirement that subjects be “history qualified” (ie, have a history of 
recreational opioid use), this study uses a pharmacologic qualification to ensure that subjects 
who meet the drug use history criteria can also distinguish and like the subjective effects of the 
positive control drugs. In previous qualifications performed at the investigational site, 
approximately 40% to 60% of history-qualified subjects could not adequately distinguish or 
report positive drug effects of the test drug. Therefore, the pharmacologic qualification procedure 
provides more objective confirmation of drug use history and ensures that subjects can respond 
appropriately in a research clinic setting.  
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (eg, demographics and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. 
A placebo control is used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment as well as to minimize subject and 
investigator bias. Blinded treatment, including the use of double-blind and double-dummy 
procedures, will be used to reduce potential bias during data collection and evaluation of clinical 
endpoints. 
Assessing abuse potential requires a relative comparison to an active drug with known abuse 
potential and one that does not (placebo). The positive control should have measurable abuse 
potential previously established through experimental studies and epidemiological data, and 
should be a drug of abuse in the same pharmacological class as the test drug. 


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3.2.1 Selection of Hydromorphone Positive Control 
Hydromorphone is a C-II scheduled opioid with known abuse potential10 following both oral and 
IV administration and was selected as the active control for this study.  
The abuse potential of hydromorphone has been demonstrated through experimental studies and 
epidemiological data, and is a drug of abuse in the same pharmacological class as the test drug, 
nalbuphine. From an abuse potential perspective, opioids (eg, hydromorphone, hydrocodone, 
oxycodone, and morphine) are expected to produce significant effects in recreational drug users 
and hydromorphone is a potent opioid that is expected produce significant effects when 
appropriate doses are selected for the recreational, non-dependent population.10,11,12 Therefore 
the type of opioid may be less relevant as an active control as compared to the selection of 
appropriate doses. 
In this study, hydromorphone is included in the drug discrimination test in the Qualification 
Phase and in the Treatment Phase. Justification of the hydromorphone doses is provided in 
Section 5.4, Selection of Doses. In the Qualification Phase, subjects will be qualified on 12 mg 
hydromorphone HCl solution, to ensure that subjects can both tolerate and are able to 
differentiate the pharmacological effects of hydromorphone relative to placebo during the Main 
Study (Part B). For hydromorphone (12 mg dose), a minimum 15-point difference (minimum 
score ≥ 65) will be required on the measure of Drug Liking in the Qualification Phase, in 
accordance with the FDA guidance.13 In the Treatment Phase, 2 doses (8 mg and 16 mg) of 
hydromorphone will be administered to qualified subjects. A minimum 11-point difference will 
be required on the measure of Drug Liking between hydromorphone and placebo (including Emax 
to validate the study) because a 15-point difference may not be detected at the lower 8 mg dose 
of hydromorphone but would still be clinically important. An 11-point difference will also be 
used for the analysis of Drug Liking between nalbuphine and placebo. Of note, a 10-point 
difference on a VAS scale has been previously cited as being clinically relevant as a suitable 
threshold in terms of abuse potential.14 The requirements for drug discrimination are outlined in 
Section 4.5. Since hydromorphone is the primary control for this study and has high abuse 
potential, study validity will be confirmed for hydromorphone. 
The doses of hydromorphone HCl in this study, ranging from 8 mg to 16 mg can be safely 
administered to screen non-dependent, recreational opioid users and are expected to produce 
significant effects on PD measures related to abuse potential. The most frequently observed 
adverse effects associated with hydromorphone are similar to those of other opioids and include 
constipation, lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. 15 
Except for the significantly faster oral elimination half-life (2.6 hours), compared to nalbuphine, 
hydromorphone has comparable bioavailability (~20% versus 16% for nalbuphine) with a 
marked first-pass hepatic and no pharmacologically active metabolites.  Tmax following oral 
administration of an oral solution is 0.7 hours for hydromorphone compared to 0.5 hours for 
nalbuphine solution. 
3.2.2 Nalbuphine Treatment 
It is recommended that human abuse potential studies examine several doses of an 
investigational drug, ranging from minimally effective to supratherapeutic, provided that the 


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safety is known and precautions are taken to address safety concerns.8 The safety and tolerability 
of nalbuphine ER tablets at single doses greater than 162 mg or daily doses greater than 162 mg 
BID has not been established in a healthy population.1 Notable adverse effects such as vomiting 
and nausea are observed when doses of nalbuphine are escalated up to 162 mg in healthy 
volunteers. Therefore, the Dose Selection Phase in Part A of this study is designed to evaluate 
escalating doses of nalbuphine using a solution formulation, with the intent to identify a low, 
intermediate, and high (eg, supratherapeutic) doses that are considered safe to administer in 
Part B. Nalbuphine will be administered orally as a solution in order to maximize peak 
concentrations (Cmax), without the confounder of an ER mechanism, and evaluate the abuse 
potential of nalbuphine at peak exposure levels that are determined to be safe in the recreational 
opioid user population.  
Based on the safety data summarized in Section 5.4, dose selection of nalbuphine HCl in Part A 
will begin at 81 mg (equivalent to 90 mg of the HCl salt) and range until an MSD is determined. 
Sequential dosing cohorts of 8 unique non-dependent, recreational opioid users will be 
randomized so that subjects will receive either a single dose of nalbuphine (n=6) or placebo 
(n=2) in order to identify an MSD. Safety measures are included in the design to ensure that 
subjects are adequately monitored during the Dose Selection Phase. This will include the 
unblinding of the safety data following completion of dosing of each cohort and review by the 
DRC (see Section 4.9.1 Data Review Committee). Dose escalation for the active arm subjects in 
the next cohort will only occur if an MSD has not been identified and the previous nalbuphine 
dose level was deemed safe and well tolerated. In addition, subjects will not be discharged from 
the CRU until they are no longer impaired by drugs administered during the study, at the 
discretion of the investigator or designee.  
The median Tmax of nalbuphine is expected to occur between 0.5 and 1.5 hours post-dose after 
oral administration of nalbuphine solution, while the median Tmax is expected to occur between 3 
and 6 hours post-dose after nalbuphine ER tablets.1 The PK sampling in the Treatment Phase was 
developed to capture the expected Tmax of nalbuphine of both nalbuphine formulations. The mean 
Tmax for orally-administered hydromorphone HCl solution is expected to occur at approximately 
0.7 hours.16 In addition, the t1/2 of nalbuphine ranges from 6.6-9.6 hours, whereas the t1/2 for 
hydromorphone is approximately 2.3 hours. Based on this, a 24-hour assessment period and 24-
hour post-dose discharge for each treatment visit is considered safe for the subjects, and at this 
time the PD measures are expected to return to approximately baseline. A minimum 4-day 
washout between each dose in the Treatment Phase is considered acceptable based on the t1/2 of 
the active agents to be used in this study, as it is a duration that is longer that five times the 
maximum t1/2 of the longest acting drug in the study, as recommended in the FDA guidance.8 
4. 
STUDY POPULATION 
4.1 
Number of Subjects 
In Part A, approximately 5 cohorts of approximately 8 unique subjects per cohort is planned or 
until the MSD is identified. Additional cohorts may be added, at the sponsor's and investigator's 
discretion, if additional data at a dose level are needed or if a dose level, intermediate to those 


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proposed, needs to be considered for safety or tolerability reasons, or a dose higher than those 
planned is required to be tested, based on supporting safety data. 
In Part B, a sufficient number of subjects will participate in the Qualification Phase in order to 
randomize an estimated 56 subjects into the Treatment Phase, with the intent to complete 
approximately 42 subjects. Replacement subjects may be added at the sponsor’s and 
investigator’s discretion to ensure that sufficient data are collected to meet the main study 
objectives. 
4.2 
Inclusion Criteria 
Subjects will be considered eligible to participate in this study, for either Part A or Part B, if each 
one of the following inclusion criteria is satisfied at Screening: 
1. Healthy male or female subjects 18 to 55 years of age, inclusive. 
2. Body mass index (BMI) within the range of 18.0 to 33.0 kg/m2, inclusive, and a minimum 
weight of 50.0 kg. 
3. Current opioid users who have used opioids for recreational (non-therapeutic) purposes 
(ie, for psychoactive effects) at least 10 times in the past year and used opioids at least 
once in the 8 weeks before Screening. 
4. Female subjects of childbearing potential with male sexual partners must be using and 
willing to continue using medically acceptable contraception (as specified in Section 4.6.2) 
for at least 1 month prior to Screening (at least 3 months for oral and transdermal 
contraceptives) and for at least 1 month after last study drug administration. 
Female subjects of non-childbearing potential must meet the criteria specified in 
Section 4.6.2. 
Male subjects with female sexual partners of childbearing potential must be using and 
willing to continue using medically acceptable contraception (as specified in Section 4.6.2) 
from Screening and for at least 1 month after the last study drug administration. 
5. Must provide written informed consent prior to the initiation of any protocol-specific 
procedures. 
4.3 
Exclusion Criteria 
Subjects will not be considered eligible to participate in this study, for either Part A or Part B, if 
any one of the following exclusion criteria is satisfied at Screening: 
1. Self-reported substance or alcohol dependence (excluding nicotine and caffeine) within the 
past 2 years, as defined by the Diagnostic and Statistical Manual of Mental Disorders – 
Fourth Edition – Text Revision (DSM-IV-TR), and/or has ever participated or plans to 
participate in a substance or alcohol rehabilitation program to treat their substance or 
alcohol dependence. 


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2. Heavy smoker (≥ 20 cigarettes per day) and/or who is unable to abstain from smoking for 
at least 8 hours during the in-clinic periods. Unable to abstain from using other nicotine-
containing products (eg, gum, patch, e-cigarettes) during the in-clinic periods. 
3. History or presence of clinically significant abnormality as assessed by physical 
examination, medical history, ECGs, vital signs, or laboratory values, which in the opinion 
of the investigator would jeopardize the safety of the subject or the validity of the study 
results. 
4. History or presence of any clinically significant illness (eg, cardiovascular, pulmonary, 
hepatic, renal, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, 
oncologic, musculoskeletal, psychiatric) or any condition, which, in the opinion of the 
investigator or designee, would jeopardize the safety of the subject or the validity of the 
study results. 
5. History of major mental illness that in the opinion of the investigator may affect the ability 
of the subject to participate in the study. Institutionalized subjects will not be eligible for 
participation. 
6. Clinically significant infection/injury/illness within 1 month prior to Screening, as assessed 
by the investigator or designee. 
7. Positive for hepatitis B, hepatitis C, or HIV. 
8. Donation or loss of more than 500 mL whole blood within 30 days preceding entry into the 
Treatment Phase. 
9. Difficulty with venous access or unsuitable or unwilling to undergo catheter insertion. 
10. Female subjects who are currently pregnant (have a positive pregnancy test) or lactating or 
who are planning to become pregnant within 30 days of last study drug administration. 
11. History of severe allergic reaction (including anaphylaxis) to any substance, or previous 
status asthmaticus, or food allergies/intolerances/restrictions, or special dietary needs 
which, in the judgment of the investigator, contraindicates the subject’s participation in the 
study. 
12. History of allergy or hypersensitivity to hydromorphone, nalbuphine, or related drugs 
(eg, other opioids) or naltrexone or related drugs (eg, other antagonists) or to any known 
excipients (eg, lactose).  
13. Subjects with any lifetime history of suicidal ideation or suicidal behavior, as assessed by 
the C-SSRS (baseline version). 
14. Documented history of, or currently active, seizure disorder or history of clinically 
significant head injury (including surgery) or syncope of unknown origin. 
15. Use of a prohibited medication, as specified in Section 4.6.1. 
16. Treatment with an investigational drug within 5 times the elimination t1/2, if known (eg, a 
marketed product) or within 30 days (if the elimination t1/2 is unknown) prior to first drug 
administration or is concurrently enrolled in any research, judged not to be scientifically or 
medically compatible with this study (exclusion is not applicable to subjects who 
participate in Part B after they have participated and received study drug in Part A of this 
study). 


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17. An employee of the sponsor or research site personnel directly affiliated with this study or 
their immediate family member defined as a spouse, parent, child or sibling, whether 
biological or legally adopted. 
18. A subject who, in the opinion of the investigator or designee, is considered unsuitable or 
unlikely to comply with the study protocol for any reason. 
19. Subject has current pending legal charges or is currently on probation based on self-report 
at Screening. 
4.4 
Naloxone Challenge (Part A and Part B) 
Eligible subjects who meet Screening criteria will undergo a naloxone challenge test at least 
12 hours prior to study drug administration in the Dose Selection Phase in Part A and prior to the 
first drug administration in the Drug Discrimination Test in Part B. For female subjects, results of 
the urine pregnancy test will be required prior to the naloxone challenge; results of the serum 
pregnancy test will not be required prior to the naloxone challenge. For those subjects who 
successfully complete the naloxone challenge in Part A and elect to participate in Part B, a 
naloxone re-challenge will only be required if more than 60 days has passed between the first 
challenge and admission to the Qualification Phase in Part B. 
Baseline vital signs and the COWS17 will be assessed before administration of the first naloxone 
dose. The naloxone doses selected for the challenge are consistent with doses commonly 
administered to confirm opioid non-dependence. 
The test will be administered as follows: 
Step 1: Naloxone 0.2 mg will be given via IV bolus followed by a 2 mL to 3 mL saline 
flush. The subject will be observed for 1 minute after the bolus administration for 
signs and symptoms of withdrawal using the COWS. 
Step 2: If the subject develops signs or symptoms of withdrawal following the first IV 
bolus (COWS score ≥5), the second bolus will not be administered and the subject 
will be medically managed.   
If there is no evidence of withdrawal after 1 minute (COWS score <5), a second IV 
bolus of naloxone 0.6 mg will be given within 5 minutes of the first administration, 
followed by a 2 mL to 3 mL saline flush. The subject will be observed and an 
additional COWS assessment will be conducted at 5 minutes after the second 
naloxone dose. Vital signs will be assessed at 10 minutes (± 5 minutes) and 
60 minutes (± 10 minutes) following the second naloxone dose. Additional COWS 
and/or vital sign assessments may be conducted if medically necessary. 
A sample form of the COWS is presented in Appendix 11.3. 
Subjects who present with signs or symptoms of withdrawal following administration of the 
naloxone challenge (ie, COWS score ≥5) will be excluded from the study and will not be eligible 
to participate in the Drug Discrimination Test. Subjects who develop signs or symptoms of 


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withdrawal will be medically managed for at least 4 hours and will be discharged at the 
discretion of the investigator or medically qualified designee. 
Refer to Section 6.3.9 for COWS assessments to be performed during the Treatment Phase in 
Part B. 
4.5 
Qualification Criteria (Part B) 
Subjects must meet the following qualification criteria to be eligible to enter the Treatment 
Phase: 
1. Peak score (Emax) of ≥65 on the Drug Liking VAS and greater than that of placebo by at 
least 15 points in response to 12 mg hydromorphone.  
2. Drug Liking VAS scores over time that are consistent with the known pharmacology of 
12 mg hydromorphone. 
3. Acceptable placebo response on Drug Liking VAS (score between 40 and 60, inclusive). 
4. Ability to complete the PD assessments and have acceptable overall responses for placebo 
and hydromorphone based on all other measures that are consistent with the known 
pharmacology of the drugs administered, as judged by the investigator or designee.  
5. Able to tolerate 12 mg hydromorphone, as judged by the investigator or designee based on 
available safety and PD data (eg, no episodes of vomiting within the first 4 hours post-
dose). 
6. General behavior suggests that the subject could successfully complete the study, as judged 
by the research site staff. 
4.6 
Study Restrictions 
4.6.1 Prohibited Medications 
Subjects will be required to avoid using non-prescription medication (except nicotine-containing 
substances and acetaminophen up to 2000 mg per day) within 7 days prior to first drug 
administration and throughout the study, unless in the opinion of the medical monitor, in 
consultation with the investigator or designee, the product will not interfere with the study 
procedures or data integrity or compromise the safety of the subject. 
Subjects will be required to avoid using prescription medications or natural health products 
(except vitamin or mineral supplements, acceptable forms of birth control, and hormone 
replacement) within 14 days prior to first drug administration and throughout the study, unless in 
the opinion of the investigator or designee, the product will not interfere with the study 
procedures or data integrity or compromise the safety of the subject. 
Concomitant medications are prohibited in this study unless prescribed by the investigator to 
treat clinical events or exempted by the investigator on a case-by-case basis because they would 
be unlikely to affect the study results or subject safety (eg, topical medications). All medications 
taken by subjects after Screening until the completion of the Follow-up visit will be documented 


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as concomitant medications. The reported medications will be reviewed and evaluated by the 
investigator to determine if they affect a subject’s eligibility or continued participation in the 
study. 
4.6.2 Contraceptive Precautions 
For women of childbearing potential with male sexual partners, examples of medically 
acceptable forms of contraception are provided in Table 4. Subjects must agree to use medically 
acceptable contraception for at least 1 month prior to screening (at least 3 months for oral and 
transdermal contraceptives) and for at least 1 month after last study drug administration. Women 
must also abstain from ovum donation from screening and for at least 1 month after last study 
drug administration. 
Women of childbearing potential without male sexual partners must be willing to maintain their 
sexual status (including abstinence) throughout the study. 
Women who are not of childbearing potential must be surgically sterile (hysterectomy and/or 
bilateral oophorectomy/salpingo-oophorectomy, as determined by subject medical history) or 
congenitally sterile, or must be post-menopausal. Post-menopausal is defined as being 
amenorrheic for at least 1 year without another cause and a follicle-stimulating hormone (FSH) 
level ≥26 IU/L. 
Table 4 
Medically Acceptable Forms of Contraception and Duration of Use for Females of 
Childbearing Potential with Male Partners 
Medically Acceptable Forms of Contraception 
Prior to Screening 
During the Study 
Combined oral pill 
3 months 
Throughout the study. 
Subjects will be 
advised to continue 
using acceptable 
contraception for at 
least 1 month after the 
last study drug 
administration. 
Patch 
Vaginal ring 
True abstinence 
1 month 
Intrauterine device or system 
Progestin implant or injection 
Bilateral tubal ligation 
Double-barrier methods 
(ie, male condom in addition to a diaphragm, cervical 
cap, or contraceptive sponge) 
 
For male subjects with female sexual partners of childbearing potential, examples of medically 
acceptable forms of contraception include true abstinence, vasectomy, or male condom for 
subjects plus an additional method of contraception for their female partners. 


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4.6.3 Dietary and Other Restrictions 
In addition to the inclusion and exclusion criteria listed in Section 4.2 and Section 4.3, the 
subject must agree to abide by each of the following restrictions for the specified time: 
 Subjects will be asked to abstain from alcohol for 24 hours prior to each study visit. 
 Subjects will be asked to abstain from recreational drug use throughout the study, from 
Screening until after the last treatment visit. 
 Subjects in both Part A and Part B will be required to abstain from smoking for at least 
2 hours prior to dosing and at least 15 minutes before each breath alcohol measurement.  
Subjects in Part A will also be required to abstain from smoking for at least 6 hours after 
dosing in the Dose Selection Phase.  
Subjects in Part B will also be required to abstain from smoking for at least 4 hours after 
dosing in the drug discrimination test and for at least 6 hours after dosing in each Treatment 
period. Smoking will be permitted at short breaks, at the discretion of the research site staff, 
at times other than the restricted time intervals described above. 
The use of other nicotine-containing substances (eg, gum, patch, e-cigarettes) is not 
permitted during inpatient stays at the CRU. 
 Subjects in both Part A and Part B will be required to fast (abstain from food) for at least 
8 hours prior to dosing and for at least 4 hours post-dosing during the Dose Selection Phase 
in Part A and during the drug discrimination test and Treatment Phase in Part B. Water will 
be permitted ad libitum except for at least 1 hour prior to dosing and for at least 1 hour 
post-dosing, with the exception of any liquids administered as part of dosing procedures. 
 Subjects will be asked to abstain from the following foods from 1 week prior to the Dose 
Selection Phase in Part A and Qualification Phase in Part B until after the last treatment 
visit: 
o grapefruit, pomegranate, pomelo, and star fruit and their juices/products;  
o poppy seeds and Seville oranges and foods containing them (eg, orange 
marmalade); 
o leafy green portion from vegetables of the mustard green family (eg, kale, 
broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard greens); 
however, lettuce and white cabbage are allowed in limited quantities; 
o drinks/foods containing quinine (ie, tonic water). 
 Subjects will be asked not to consume more than 450 mg of caffeine per day 
(eg, approximately 5 cups of tea or 3 cups of regular coffee or 8 cans of cola or 2 energy 
drinks) from 1 week prior to the Dose Selection Phase in Part A and Qualification Phase in 
Part B until after the last treatment visit. Subjects will not be permitted to consume 
caffeine-containing beverages while housed at the research site.  
 Subjects will be asked to refrain from driving, operating machinery, or engaging in 
hazardous activities until they and the investigator are sure the study drug is not impairing 
their judgment and/or ability to perform skilled tasks. Subjects will be informed that 
driving under the influence is a criminal offense and that if they are caught driving under 
the influence, they may be prosecuted to the fullest extent of the law.  


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 Subjects will be asked to abstain from strenuous physical activity for 48 hours prior to each 
study visit. Subjects will not be permitted to engage in strenuous exercise during inpatient 
stays at the research site. 
 Subjects will be required to abstain from blood donation during the study and for 30 days 
after the Follow-up visit. 
 Subjects will be required to follow the informed consent form (ICF) and the clinic code of 
conduct. 
4.7 
Rescue Medication 
Subjects will receive all standard medical treatment, including administration of rescue 
medication, should subjects experience severe (Grade 3 or higher) AEs. Standard safety 
medication (eg, IV naloxone, antihistamine [eg, Benadryl®], epinephrine, solumedrol, ranitidine, 
advanced cardiac life support [ACLS] rescue medication, etc.) will be administered, if required. 
If a subject requires treatment for nausea and vomiting, antiemetic medications (eg, ondansetron 
4 to 8 mg q8h PO and dimenhydrinate 25 to 75 mg q4-6h PO) may be administered, if not 
medically contraindicated for the subject. 
The principal investigator or designee will be on site during all dosing until at least the 
continuous oxygen monitoring period is complete (at least 6 hours post-dose in Part A, and at 
least 4 hours post-dose during the drug discrimination test and at least 6 hours post-dose during 
each Treatment period in Part B). The investigator or designee will be on-call or on-site 
thereafter. Dedicated ACLS nurses or paramedics will be assigned to the study during drug 
administration to monitor AEs and perform safety measures (ie, vital signs). 
Subjects will be supervised by staff nurses and paramedics for the duration of the study. In case 
of emergency or SAEs that require emergency care, the study site is equipped with fully-stocked 
crash carts, oxygen, suction, and defibrillator. If needed, subjects will be transported to the 
nearest emergency room to receive more intensive or continuing treatment. 
4.8 
Subject Discontinuation/Stopping Criteria 
Any subject who voluntarily withdraws consent or is discontinued (eg, because of an AE) from 
the study prior to completion will be considered as withdrawn from the study. Subjects may be 
discontinued from the study under any of the following circumstances: 
 Occurrence of intolerable AE, as assessed by the investigator or designee  
 Clinically significant abnormality on vital signs, ECG, clinical laboratory, or physical 
examination assessments, as assessed by the investigator or designee 
 Withdrawal of consent  
 Lost to follow-up 
 Administrative reasons (eg, sponsor decision)  
 Major violation of the protocol  
 If in the opinion of the qualified investigator, it is in the best interest of the subject 


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 Pregnancy 
 Non-compliance with study requirements and restrictions 
 Use of a concomitant medication that, in the opinion of the investigator or designee, 
could interfere with the study procedures or data integrity or compromise the safety of the 
subject 
 Positive urine drug screen at  
o Admission to the Dose Selection Phase in Part A or Qualification Phase in Part B: 
If a subject presents with a positive urine drug screen at any visit, the urine drug 
screen may be repeated and/or the subject may be rescheduled at the discretion of 
the investigator or designee. If benzodiazepines or THC are positive, inclusion 
will be at the discretion of the investigator, for example, if drug levels are stable at 
low concentrations or decreasing due to the long half-lives of parent compounds 
and/or metabolites. THC levels that have increased from the time of the last visit 
may be acceptable, at the discretion of the investigator or designee, provided that 
there are no visible signs of impairment and/or intoxication due to THC exposure 
(eg, euphoria, dry mouth, slowed reflexes, excessive drowsiness, increased 
appetite, red eyes, paranoia, anxiety, hallucinations, tachycardia, emitting odor of 
marijuana). 
o Admission to any Treatment Period in Part B: Subjects who have a positive urine 
drug screen and a COWS score < 5 may be rescheduled at the discretion of the 
investigator or designee. If benzodiazepines or THC are positive, inclusion will be 
at the discretion of the investigator, for example, if drug levels are stable at low 
concentrations or decreasing due to the long half-lives of parent compounds 
and/or metabolites. THC levels that have increased from the time of the last visit 
may be acceptable, at the discretion of the investigator or designee, provided that 
there are no visible signs of impairment and/or intoxication due to THC exposure 
(eg, euphoria, dry mouth, slowed reflexes, excessive drowsiness, increased 
appetite, red eyes, paranoia, anxiety, hallucinations, tachycardia, emitting odor of 
marijuana). 
 COWS score ≥ 5. Subjects will be medically managed for at least 4 hours or longer until 
the investigator determines that the subject can be safety discharged from the CRU. 
 Positive breath alcohol test at admission to the Dose Selection Phase in Part A or 
Qualification Phase or any Treatment Period in Part B. Subjects with a positive result at 
Screening or admission to any visit may be rescheduled at the discretion of the 
investigator or designee. 
 Termination of the study 
 Subject did not meet the qualification criteria outlined in Section 4.5. 
 Dose escalation (Part A) has been stopped according to the criteria outlined in 
Section 4.9.  
When an event such as a family emergency, a transient intercurrent illness (such as a cold) 
unrelated to study drug, or a remediable act of non-compliance prevents a subject from 
participating in a scheduled visit, but the subject wishes to continue in the study, with the 


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permission of the sponsor/medical monitor and in consultation with the investigator the research 
site staff may attempt to reschedule the visit and retain the subject in the study.  
If a subject is prematurely discontinued from participation in the study for any reason after study 
drug administration, the investigator or designee must make every effort to perform the 
assessments scheduled for the Follow-up visit. The reason for withdrawal will be recorded in the 
case report form (CRF) and the subject’s source medical record. 
Replacement subjects may be added at the sponsor’s discretion, in agreement with the principal 
investigator. Each replacement subject will be assigned to the same treatment sequence as the 
subject who is replaced. 
4.9 
Dose Escalation Procedures and Stopping Criteria (Part A) 
4.9.1 Data Review Committee 
During the Dose Selection Phase in Part A, the safety data and, if available, PK data will be 
unblinded after completion of each dose cohort and reviewed by the DRC. The DRC will 
comprise, at a minimum, the sponsor representative, medical monitor (drug safety 
representative), and the investigator (or designee). Other representatives may be involved in data 
review and dose selection, as appropriate. 
Dose escalation for the next cohort will proceed if the dose administered in the previous cohort 
was deemed to be safe and well tolerated by the DRC. The PK data will be unblinded and 
evaluated if available in a timely manner, but will not be required for dose escalation decisions. 
In addition, the results from the Dose Selection Phase will be reviewed and considered by the 
DRC for dose selection in the Treatment Phase in Part B.  
4.9.2 Dose Escalation and Stopping Rules 
Dose escalation may proceed when the DRC have reviewed the available safety data for a cohort 
(and all preceding cohorts, as applicable) and agree that the safety profile supports proceeding 
with the evaluation of the next higher dose level. Escalation to the next dose level will continue 
until the MSD is identified (doses of nalbuphine solution will not exceed 486 mg, which 
corresponds to 3-fold the therapeutic dose) and only if it is supported by the safety data review 
by the DRC. 
Dose escalation will be stopped if the following is observed in 3 or more subjects who received 
nalbuphine solution in a cohort experience the following AEs within 4 hours of dosing: 
 Grade 3 or higher nausea or, 
 Any episode of vomiting or, 
 Grade 3 or higher somnolence 
Furthermore, dose escalation will be stopped if any of the following is observed in at least 
1 subject in a cohort who received nalbuphine solution: 


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 Sustained (~30 seconds) respiratory depression that results in SpO2 reduction below 92% 
that requires significant intervention (eg, naloxone administration).  
 QTc prolongation (>500 ms or >60 ms above the baseline). 
 Any Grade 3 or higher AE or an SAE that is considered by the investigator to be related 
to nalbuphine and clinically significant, or, any AE deemed by the investigator to be 
dose-limiting. 
If the DRC observe a plateau in the incidence and severity of AEs, which do not meet the 
stopping criteria described above, then the PK data may be reviewed to determine if there is a 
plateau in the exposure of nalbuphine despite dose escalation. If a plateau is observed in the PK 
data, the MSD will be identified based on the available safety and PK exposure data. 
5. 
STUDY DRUG INFORMATION 
5.1 
Study Drug Administration 
Nalbuphine solution and ER tablets are manufactured using nalbuphine HCl salt. The dose 
strength of the ER tablet refers to the content of the free base active moiety rather than the 
nalbuphine salt. For the nalbuphine HCl ER tablet, 162 mg is equivalent to 180 mg nalbuphine 
HCl salt and 1 mL of 10 mg/mL nalbuphine HCl is equivalent to 9 mg nalbuphine free base. 
Flavored beverage: The doses of study drug will be administered with a flavored, low caloric, 
artificially sweetened, non-carbonated beverage (eg, diet cranberry cocktail).  
5.1.1 Dose Selection Phase (Part A) 
During the Dose Selection Phase, subjects in each cohort will receive a single oral dose of 
nalbuphine HCl solution or matching placebo in a randomized, double-blind fashion (Table 5) 
after at least an 8-hour fast. The actual doses administered in each cohort may be adjusted 
(increased, decreased, or repeated) based on the evaluation of safety data obtained in previous 
cohorts. Additional cohorts of subjects may be added to those planned in Table 5 until the MSD 
is identified. Higher doses can be up to 50% greater (but not to exceed 486 mg (3-fold the 
therapeutic dose) than the dose administered in the previous cohort based on supporting safety 
data.  
The dosing solution (150 mL) will be administered in a dark bottle. After subjects drink the 
dosing solution, an additional 50 mL of flavored beverage will be added to the dosing container 
as a rinse and then administered to the subjects. The start of dosing will be considered time zero 
and subjects will be informed that the duration allocated for dosing will be 5 minutes. All dosing 
administration procedures will be outlined in the study specific procedures. 
All subjects within a cohort will receive the same dose of nalbuphine HCl solution if randomized 
to the active drug. Dose escalation procedures are described in Section 4.9. 


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Table 5 
Planned Oral Doses of Nalbuphine Hydrochloride Solution in the Dose Selection Phase 
Cohort 
(n=8) 
Nalbuphine 
Free Base 
Dose Level 
Nalbuphine HCl  
Equivalent 
Dose 
Nalbuphine HCl 
Solution 
(n=6) 
Placebo 
Solution 
(n=2) 
1 
81 mg 
90 mg 
9 mL × 10 mg/mL +  
141 mL flavored beverage 
150 mL flavored beverage 
2 
108 mg 
120 mg 
12 mL × 10 mg/mL +  
138 mL flavored beverage 
150 mL flavored beverage 
3 
135 mg 
150 mg 
15 mL × 10 mg/mL + 
135 mL flavored beverage 
150 mL flavored beverage 
4 
162 mg 
180 mg 
18 mL × 10 mg/mL + 
132 mL flavored beverage 
150 mL flavored beverage 
5 
243 mg 
270 mg  
27 mL × 10 mg/mL + 
123 mL flavored beverage 
150 mL flavored beverage 
6a 
up to 365 mg 
up to 405 mg 
up to 40.5 mL × 10 mg/mL + 
109.5 mL or required volume 
of flavored beverage for a 
total volume of 150 mL 
solution 
150 mL flavored beverage 
7a 
up to 486 mg 
up to 540 mg 
up to 54 mL × 10 mg/mL + 
96 mL or required volume of 
flavored beverage for a total 
volume of 150 mL solution 
150 mL flavored beverage 
HCl=hydrochloride. 
a The dose of nalbuphine free base in Cohorts 6 and 7 may increase up to a 50% increase from  the preceding dose 
but not to exceed 486 mg (3-fold the therapeutic dose) based on the evaluation of safety data in the previous 
cohorts. 
For the nalbuphine solution, the dose will be added to a flavored beverage to prepare a dosing solution of 150 mL. 
For both nalbuphine and placebo treatments, after subjects drink the 150 mL dosing solution, an additional 50 mL of 
flavored beverage will be added to the dosing container as a rinse and then administered to the subjects. Dosing 
procedures will be specified in study specific procedures. 
Actual doses may be adjusted according to the evaluation of safety data from Part A. Dose reductions, intermediate 
doses, or higher doses up to 50% greater than the dose administered in the previous cohort may be considered 
based on the safety results obtained in previous cohorts. Additional cohorts of subjects may be added until the 
MSD is identified or until lack of linearity is observed in the nalbuphine plasma PK profile (see Section 4.9 for 
details).  
5.1.2 Qualification Phase (Part B) 
During the Qualification Phase, hydromorphone HCl and placebo solution (Table 6) will be 
administered orally in a randomized, double-blind fashion after at least an 8-hour fast. Each 
treatment will be separated by a washout of approximately 24 hours. 
The dosing solution (150 mL) will be administered in a dark bottle. After subjects drink the 
dosing solution, an additional 50 mL of flavored beverage will be added to the dosing container 
as a rinse and then administered to the subjects. The start of dosing will be considered time zero 
and subjects will be informed that the duration allocated for dosing will be 5 minutes. All dosing 
administration procedures will be outlined in the study specific procedures. 


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Table 6 
Double-blind Treatments Administered in the Drug Discrimination Test 
Treatment 
Hydromorphone HCl 
Solution 
Placebo  
Solution 
Treatment X: Placebo Solution 
— 
150 mL flavored beverage 
Treatment Y: Hydromorphone HCl 
12 mg Solution 
6 mL × 2 mg/mL +  
144 mL flavored beverage 
— 
HCl=hydrochloride 
For the hydromorphone solution, the dose will be added to a flavored beverage to prepare a dosing volume of 
150 mL. For both hydromorphone and placebo treatments, after subjects drink the 150 mL dosing solution, an 
additional 50 mL of flavored beverage will be added to the dosing container as a rinse and then administered to the 
subjects. Dosing procedures will be specified in study specific procedures. 
5.1.3 Treatment Phase (Part B) 
Treatments A through G are described in Table 7. During the Treatment Phase, subjects will 
receive single oral doses of each treatment in a randomized, double-blind, double-dummy 
fashion after at least an 8-hour fast. Each treatment administered in the Treatment Phase will 
consist of 150 mL oral dosing solution (containing nalbuphine, hydromorphone or placebo 
[flavored beverage]) and 1 tablet (containing nalbuphine or placebo). 
For the nalbuphine solution, the low, intermediate, and high doses will be determined by the 
DRC based on the results obtained from the Dose Selection Phase in Part A, as described in 
Section 4.9. However, the total volume of solution to be administered in each treatment period 
will be identical (ie, 150 mL solution comprised of an appropriate amount of active drug and/or 
flavored beverage) in order to maintain the blind. 


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Table 7 
Double-Blind Administration of Doses During the Treatment Phase 
Tx 
Placebo 
Solution 
Hydromorphone 
HCl Solution 
Nalbuphine 
HCl Solution 
Low 
Dose 
Nalbuphine 
HCl Solution 
Intermediate 
Dose 
Nalbuphine 
HCl Solution 
High 
Dose 
Nalbuphine 
ER Intact  
Tablet 
Nalbuphine 
ER 
Matching 
Placebo 
Tablet 
A 
150 mL 
flavored 
beverage 
— 
— 
— 
— 
— 
1 tablet 
B 
— 
4 mL × 2 mg/mL 
+ 146 mL 
flavored beverage 
— 
— 
— 
— 
1 tablet 
C 
— 
8 mL × 2 mg/mL 
+ 142 mL 
flavored beverage 
 
 
 
 
1 tablet 
D 
— 
— 
TBD 
— 
— 
— 
1 tablet 
E 
— 
— 
— 
TBD 
— 
— 
1 tablet 
F 
— 
— 
— 
— 
TBD 
— 
1 tablet 
G 
150 mL 
flavored 
beverage 
— 
— 
— 
— 
1 × 162 mg 
tablet 
— 
DRC=data review committee; ER=extended release; HCl=hydrochloride; TBD=to be determined; Tx=treatment 
Treatment A: Placebo 
Treatment B: Hydromorphone HCl 8 mg solution 
Treatment C: Hydromorphone HCl 16 mg solution 
Treatment D: Nalbuphine HCl low dose solution 
Treatment E: Nalbuphine HCl intermediate dose solution 
Treatment F: Nalbuphine HCl high dose solution 
Treatment G: Nalbuphine ER tablet 162 mg  
The selection of the low, intermediate, and high doses of nalbuphine HCl will be determined by the DRC based on the 
results obtained from the Dose Selection Phase in Part A. 
For the nalbuphine and hydromorphone solution, the dose will be added to a flavored beverage to prepare a dosing 
volume of 150 mL. For all treatments, after subjects drink the 150 mL dosing solution, an additional 50 mL of 
flavored beverage will be added to the dosing container as a rinse and then administered to the subjects. Dosing 
procedures will be specified in study specific procedures. 
The dosing solution will be administered in a dark bottle. For each treatment, subjects will be 
instructed to ingest the tablet with the 150 mL of solution. After subjects drink the dosing 
solution, an additional 50 mL of flavored beverage will be added to the dosing container as a 
rinse and then administered to the subjects. The start of dosing will be considered time zero and 
subjects will be informed that the duration allocated for dosing will be 5 minutes. All dosing 
administration procedures will be outlined in the study specific procedures. 


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5.2 
Study Drug Identification 
5.2.1 Nalbuphine 
Nalbuphine HCl solution 
Each 1 mL contains 10 mg nalbuphine HCl (equivalent to 9 mg of the free base), 2 mg sodium 
chloride, 9.41 mg sodium citrate dihydrate, 12.62 mg citric acid, and water for injection; pH 
adjusted with hydrochloric acid. Nalbuphine HCl solution (10 mg/mL) will be provided by the 
CRU. 
Nalbuphine ER Tablets 
Nalbuphine ER tablets 162 mg will be provided by the sponsor. 
5.2.2 Hydromorphone Hydrochloride  
Each 1 mL contains hydromorphone HCl 2 mg, citric acid 2 mg, sodium citrate 2 mg, sodium 
chloride 7.48 mg, hydrochloric acid and/or sodium hydroxide to adjust pH, and water for 
injection.15 
Hydromorphone HCl (2 mg/mL) will be provided by the CRU. 
5.2.3 Placebo 
Matching nalbuphine placebo tablets will be provided by the sponsor.  
Placebo solution will consist of a flavored beverage provided by the CRU. 
5.2.4 Naloxone Hydrochloride (Naloxone Challenge Test - Qualification Phase) 
Naloxone HCl will be supplied in concentration of 0.4 mg/mL, and 1 mL vials/ampoules 
(sourced by the clinical site). Each box will be labeled with a label containing information in 
compliance with regulatory and safety requirements. 
Naloxone will be provided by the CRU. 
5.2.5 Packaging and Labeling 
Nalbuphine HCl solution is available in 1 mL ampoules. 
Nalbuphine ER tablets and matching placebo will be packaged in HDPE bottles with induction 
seal child-resistant closures containing 70 tablets each. Tablets should be stored at 20°C-25°C 
(68°F-77°F) with excursions permitted between 15°C and 30°C (between 59°F and 86°F).  
Each container of study drug will be clearly labeled with study-specific information meeting all 
the applicable regulatory requirements. 


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Clinical trial drug supply labels will bear the following information: 
a) a statement indicating that the drug is an investigational drug to be used only by a qualified 
investigator; 
b) the name, number, or identifying mark of the drug and quantity of drug in each unit; 
c) the expiration date of the drug; 
d) the recommended storage conditions of the drug; 
e) the lot number of the drug; 
f) the name and address of the sponsor;  
g) the protocol code or study identification; and  
h) the quantity of drug per package. 
Clinical study drug supplies will be labeled in both French and English. 
5.2.6 Handling, Storage, and Accountability 
All study drugs will be transported, received, stored, and handled strictly in accordance with the 
container or product label. The investigator will ensure that the study drug is stored and 
dispensed in accordance with ICH QE6(R1) (Guideline for Good Clinical Practice), the 
instructions supplied to the research site and its designated pharmacy, and the Guidelines for 
Temperature Control of Drug Products during Storage and Transportation, (GUIDE-0069). 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug.  
Upon receipt by the study site, the research pharmacy staff will examine the shipment and 
temperature monitoring devices (if applicable) to verify the study drugs were received in 
acceptable condition. Once inspected, the study drugs will be promptly transferred to the 
appropriate environmentally-controlled storage area. Study drugs will be stored in a restricted 
access, secured area, with access limited to authorized research site staff, under physical 
conditions consistent with investigational product’s specific requirements. 
The research site’s pharmacist or delegate is responsible for ensuring that all study drug received 
at the site is inventoried and accounted for throughout the study. The investigator is ultimately 
responsible for ensuring that the site and/or Pharmacy maintain accurate records of the receipt of 
all study drug shipped to the site including, but not limited to: the date received, lot number, 
expiration date, quantity received, and the disposition of all investigational product(s). 
Current dispensing records will be maintained for each subject, including but not limited to, the 
date and quantity of drug dispensed. 
All original containers, whether empty or containing study drug will be returned to the pharmacy. 
Returned study drugs will be neither dispensed again (even to the same subject) nor relabeled or 
reassigned for use by other subjects. Study drugs returned by study subjects will be stored and 
disposed of according to the sponsor’s instructions. Contents of the study drug containers will 
not be combined. Unused study drugs and study drugs returned by the subjects will be available 
for verification by the sponsor’s site monitor. 


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5.2.7 Dispensing 
The study drug will be dispensed or administered according to applicable regulations and 
protocol instructions. Details regarding the preparation and administration of the study drugs will 
be outlined in study-specific procedures. Only eligible subjects participating in the study will 
receive the study drug. Only authorized research site staff may supply or administer the study 
drugs. 
During the Dose Selection Phase in Part A and Qualification Phase in Part B, the solution will be 
swallowed by the subjects under the supervision of study personnel.  
During the Treatment Phase, subjects will ingest the solution and tablet under the supervision of 
study personnel.  
5.3 
Method of Assigning Subjects to Treatment Groups 
Randomization will be used to avoid bias in the assignment of subjects to treatment sequences, to 
increase the likelihood that known and unknown subject attributes (eg, demographics and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups.  
Each potential subject will be assigned a unique number (Subject Number) in the screening 
process. This number will be used to identify the subject throughout the study. Subjects who 
enter the Treatment Phase will be assigned a unique Randomization Number to identify their 
sequence of study treatments. Once any subject number is assigned, it cannot be reassigned to 
any other subject. 
All randomization codes will be generated by the sponsor/designated unblinded statistician(s) at 
INC Research before the start of the study. Sealed code break envelopes will be provided before 
the start of the study. 
5.3.1 Qualification Phase Treatment Sequences (Part B) 
Subjects who enter the Qualification Phase will be assigned, in ascending order, a qualification 
randomization number to identify the sequence of their treatments (Table 8). 
Table 8 
Treatment Sequences in the Qualification Phase 
Treatment Sequence 
Day 1 
Day 2 
XY 
X 
Y 
YX 
Y 
X 
HCl=hydrochloride 
Treatment X: Placebo 
Treatment Y: Hydromorphone HCl 12 mg solution 


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5.3.2 Treatment Phase Treatment Sequences (Part B) 
For the treatment phase, qualified subjects will be randomized to 1 of 14 treatment sequences 
based on a computer-generated randomization schedule. The study drug will be prepared for 
each subject based on their randomization code. Subjects will receive all 7 treatments in the 
order specified by the treatment sequence according to a two 7×7 Williams square design  
(Table 9). 
Table 9 
Treatment Sequences in the Treatment Phase 
Treatment 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
Period 5 
Period 6 
Period 7 
ABGCFDE 
A 
B 
G 
C 
F 
D 
E 
BCADGEF 
B 
C 
A 
D 
G 
E 
F 
CDBEAFG 
C 
D 
B 
E 
A 
F 
G 
DECFBGA 
D 
E 
C 
F 
B 
G 
A 
EFDGCAB 
E 
F 
D 
G 
C 
A 
B 
FGEADBC 
F 
G 
E 
A 
D 
B 
C 
GAFBECD 
G 
A 
F 
B 
E 
C 
D 
EDFCGBA 
E 
D 
F 
C 
G 
B 
A 
FEGDACB 
F 
E 
G 
D 
A 
C 
B 
GFAEBDC 
G 
F 
A 
E 
B 
D 
C 
AGBFCED 
A 
G 
B 
F 
C 
E 
D 
BACGDFE 
B 
A 
C 
G 
D 
F 
E 
CBDAEGF 
C 
B 
D 
A 
E 
G 
F 
DCEBFAG 
D 
C 
E 
B 
F 
A 
G 
ER=extended release; HCl=hydrochloride 
Treatment A: Placebo 
Treatment B: Hydromorphone HCl 8 mg solution 
Treatment C: Hydromorphone HCl 16 mg solution 
Treatment D: Nalbuphine HCl low dose solution 
Treatment E: Nalbuphine HCl intermediate dose solution 
Treatment F: Nalbuphine HCl high dose solution 
Treatment G: Nalbuphine 162 mg ER intact tablet 


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5.4 
Selection of Doses 
5.4.1 Nalbuphine Dose Selection 
The Dose Selection Phase (Part A) is designed to evaluate escalating doses of nalbuphine 
solution, with the intent to identify an MSD and, in accordance with regulatory 
recommendations, select low, intermediate, and high doses for administration in Part B.8 The 
proposed starting dose is 81 mg nalbuphine solution (equivalent to 90 mg of the HCl salt). While 
doses up to 162 mg have been previously studied in healthy subjects as a solid dosage form, 
adverse effects following escalating nalbuphine single doses administered as an oral solution has 
not been investigated beyond the 54 mg dose level. 
The solution formulation was selected for administration of nalbuphine as it provides flexibility 
in dose strength selection. Furthermore, the solution will maximize Cmax, while maintaining the 
same AUC exposure as following an nalbuphine ER tablet. Food effect on exposure is also 
relatively lower compared with the ER tablet (Section 1.2). 
The incidence of nausea and vomiting was observed, respectively, in single doses of 54 mg 
solution (5.9% nausea/5.9% vomiting) and 108 mg intact tablets (30% nausea/25% vomiting). 
All AEs were mild and both doses were well tolerated. None of the subjects administered the 
54 mg dose of nalbuphine (equivalent to 60 mg of the HCl salt) as a solution reported 
somnolence. Therefore, considering that this dose was well tolerated in healthy subjects, and that 
the opioid-experienced population tend to be more tolerant of opioid-related AEs, the starting 
dose of 81 mg (equivalent to 90 mg of the HCl salt) was selected in Part A. Sequential dosing of 
cohorts of non-dependent, recreational opioid users will be administered a single dose of 
nalbuphine solution ranging from 81 mg (equivalent to 90 mg of the HCl salt) up to an MSD (if 
the dose levels are determined to be safe by the DRC) or placebo in order to identify an MSD 
(Section 4.9). The proposed doses may be reduced or escalated by 27 mg increments (equivalent 
to 30 mg increments of the HCl salt) or up to 50% greater than the dose administered in the 
previous cohort as described in Section 5.1.1. 
To support the objectives of the main study and given that nausea and vomiting may limit the 
signals of abuse potential (eg, drug liking), a dose range (low dose, intermediate dose, and high 
dose) of nalbuphine solution will be selected based on the safety results obtained in Part A. Dose 
selection in Part A is designed to adequately evaluate doses that can be well tolerated and are 
expected to minimize the influence of negative drug effects on subjective scales. 
A dose of 162 mg nalbuphine ER administered orally as an intact tablet will be included in the 
Treatment Phase (Part B) to evaluate the PD effects of nalbuphine under conditions of intended 
drug product administration. Nalbuphine ER 162 mg tablet is the highest to be marketed tablet 
strength. 
5.4.2 Hydromorphone Dose Selection 
Hydromorphone doses of 8 mg and 16 mg are expected to produce significant effects on Drug 
Liking and other measures related to abuse potential, while not being at a level where tolerability 
may become a limitation. Doses of hydromorphone immediate-release formulations between 
8 mg and 25 mg have been shown to produce sufficient responses on subjective drug measures, 


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including Drug Liking.11,14 Based on experience at the CRU and data in the literature,18 doses of 
hydromorphone less than 8 mg (ie, 4 mg and 6 mg) did not differentiate sufficiently from 
placebo on subjective PD measures. In addition, ceiling effects have been observed for the 
objective measure pupillometry at the 17.5 mg dose. 14 Hence, the doses of 8 mg and 16 mg 
hydromorphone selected in this study are within the range expected to produce significant drug 
effects and minimize negative effects that could potentially decrease subjective scores. Opioids 
such as hydromorphone are characterized by a dose-response profile that results in greater 
subjective effects (eg, drug liking) with greater doses, until they are no longer tolerated due to 
dose-related increases in adverse effects. 
For the Qualification Phase, the dose of hydromorphone (ie, 12 mg) will be an intermediate dose 
of those used in the main study (ie, 8 mg and 16 mg), to ensure both appropriate responses 
compared with placebo and tolerability of the higher dose. This will ensure that subjects can 
tolerate doses and have an increased likelihood to have appropriate PD responses to the doses 
selected for analysis.  
5.5 
Blinding and Unblinding Procedures 
5.5.1 Dose Selection Phase (Part A) 
For each dosing cohort, an unblinded statistician from INC Research, not otherwise involved in 
the study, will prepare a list of subject randomization numbers. These randomization numbers 
will be used to prepare individual subject doses. Sealed qualification code break envelopes will 
be available for each subject in case of emergency. 
Upon completion of each cohort of subjects, the randomization codes for the completed subjects 
will be unblinded by the CRU pharmacy. After unblinding, the safety data will be reviewed to 
determine if dosing can proceed for the next planned dosing cohort, as described in Section 4.9. 
5.5.2 Qualification Phase (Part B) 
For each qualification group, an unblinded statistician from INC Research, not otherwise 
involved in the study, will prepare a list of subject randomization numbers. These randomization 
numbers will be used to prepare individual subject doses. Sealed qualification code break 
envelopes will be available for each subject in case of emergency.  
Upon completion of each group of subjects, the randomization codes for the completed subjects 
will be unblinded by the CRU pharmacy, and the eligibility of subjects to participate in the 
Treatment Phase will be assessed as described in Section 4.5. 
5.5.3 Treatment Phase (Part B) 
The only persons with access to the blinding schema during the Treatment Phase will be the 
designated pharmacy personnel who are responsible for the dispensing of study drug, the 
compliance auditor(s) who verify conformity to study procedures, and the unblinded statisticians 
who generate the code. Under normal circumstances, the blind will not be broken until all 
subjects have completed all treatments. During the Treatment Phase, blinded dosing information 


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will be broken only in an emergency where knowledge of dosing information could impact 
further treatment decisions or aid in the emergency treatment of a subject. Individual blinded 
dosing information can be broken by opening a subject’s sealed code break envelope, thereby, 
not compromising the blind for the remaining subjects. Individual code breaks by the 
investigator or designee will result in the withdrawal of the subject from the study. The date, 
time, and reason for the unblinding will be documented in the appropriate section of the CRF and 
in the source documents. 
5.6 
Treatment Compliance 
Study drugs will be administered under the supervision of study personnel and treatment 
compliance will be verified according to protocol requirements. 
6. 
STUDY PROCEDURES AND ASSESSMENTS 
All study assessments will be performed at the visits and time points outlined in the Time and 
Events Schedule (Section 3.1.7). Study drug administration will be considered as time zero. 
Other logistical considerations (eg, sequence of events, assessment windows) will be outlined in 
study-specific procedures. 
6.1 
Pharmacodynamic Assessments 
All subjects will undergo a training and practice regimen prior to completion of the computerized 
subjective measures. Subjects will also receive PD refresher sessions prior to dosing in the 
Treatment Phase. Measures will be administered and data will be captured electronically using 
proprietary computerized software (PsychometRx®; INC Research Toronto, Inc.). 
Testing conditions for PD assessments should remain as consistent as possible for each treatment 
period. Subjects will be monitored carefully to ensure that they are completing the assessments 
appropriately. See Section 9.4 for details regarding the anonymity of subject information. 
6.1.1 Visual Analog Scale 
Table 10 shows the VAS items administered in this study. Each VAS is scored as an integer from 
0 to 100. The use of a unipolar or bipolar scale is determined by the nature of the subjective 
effect being measured. Unipolar VASs (eg, High, Good Drug Effects, Bad Drug Effects, Any 
Drug Effects, and Hallucinations) are presented with anchors such as “Not at all” (score = 0) to 
“Extremely” (score = 100), where the neutral point equals 0. Note that scales that refer 
specifically to drug (eg, Good Drug Effects, Bad Drug Effects, Any Drug Effects) are not 
administered pre-dose. When appropriate, VASs will be administered as bipolar measures, 
meaning that the neutral point equals 50 (eg, Drug Liking, Overall Drug Liking, Take drug 
Again, and Drowsiness/Alertness VAS). The neutral point will also be labeled with an anchor, 
such as “neither like nor dislike”. 
Eligible subjects who appear to have difficulty differentiating between bipolar and unipolar 
scales (eg, making errors such as selecting 50 as neutral for a unipolar scale) during the 


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Qualification Phase will undergo additional practice training on the difference between the scale 
types. 
Table 10 
Description of Subjective Effects Visual Analog Scales 
Scale 
Interpretation 
Exclude 
Pre-dose 
Description 
Question Text 
Response 
Anchors 
Balance 
Yes 
Drug Liking 
At this moment, my liking for this drug is 
0: Strong disliking 
50: Neither like nor 
dislike 
100: Strong liking 
Global 
Yes 
Overall Drug Liking 
Overall, my liking for this drug is 
Global 
Yes 
Take Drug Again 
I would take this drug again 
0: Definitely not 
50: Neutral 
100: Definitely so 
Positive 
Yes 
Good Drug Effects 
At this moment, I feel good drug effects 
0: Not at all 
100: Extremely 
Positive 
No 
High 
At this moment, I feel high 
Negative 
Yes 
Bad Drug Effects 
At this moment, I feel bad drug effects 
Other effects 
No 
Hallucinations 
I am experiencing hallucinations 
Other effects 
Yes 
Any Drug Effects 
At this moment, I feel any drug effect 
Other effects 
No 
Drowsiness/Alertness 
At this moment, my mental state is 
0: Very drowsy 
50: Neither drowsy 
nor alert 
100: Very alert 
Scales have 5 possible interpretations: (1) “Positive” subjective effects, (2) “Negative” subjective effects, (3) the 
“Balance” between positive and negative effects, (4) “Other effects” (ie, pharmacologic effects that indicate an active 
substance, which may be perceived as either positive or negative depending on the context), and (5) "Global" 
(ie, end-of-day assessment or next day overall assessment). 
The overall appearance of all VAS items is similar to the screen images below. Figure 3A 
presents the display for a typical question. Using a mouse, the subject must position the cursor 
over the small vertical box (a “slider”) and click on it to move it left or right. To register the 
response, the subject must then press the “OK” button that appears below the horizontal line 
(Figure 3B). This multi-step procedure was designed to reduce the possibility of either accidental 
or automatic responding to such scales. The questions and anchors will be modified 
appropriately to reflect study-specific questions. 


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Figure 3 
Sample Screen Images for Visual Analog Scale Presentation 
A. 
 B. 
 
6.1.1.1 Drug Similarity VAS 
The Drug Similarity VASs provide an estimate of the drug class with which drug users identify 
the test drug. The same VAS procedures used to assess subjective drug responses will be used to 
assess perceived drug similarity. Subjects will be asked to compare the drug they received to a 
comparison drug on a scale ranging from “Not at all similar” to “Very similar” (Table 11). Each 
scale is scored as an integer from 0 to 100, where the position of the subject’s response on the 
scale represents a defined integer. Drugs that a subject has not personally experienced often 
enough to use as a standard of comparison (based on the screening assessment) will not be 
included in his or her questionnaire. 
Table 11 
Description of Drug Similarity Visual Analog Scales 
Description 
Question Text 
Response Anchors 
Drug similarity 
How similar is the drug you most 
recently received to [drug name]? 
0: Not at all similar 
100: Very similar 
where the question will be repeated for each [drug name] in the following list: 
Phencyclidine (PCP) 
Caffeine 
Cocaine (including crack) 
Codeine, morphine, 
oxycodone, hydrocodone, 
hydromorphone 
Ecstasy (MDMA) 
Heroin 
LSD 
Methadone 
Nicotine 
Placebo 
D-amphetamine (“Speed”) or 
methamphetamine 
Pseudoephedrine (Sudafed) 
Halcion, Xanax, or Valium 
Ketamine (“Special K”)  
THC (marijuana, cannabis, 
hash) 
At the conclusion of the list of specific drugs, a general question will appear: 
Overall Familiarity 
How familiar was the effect of the 
drug you most recently received? 
0: Very unfamiliar 
100: Very familiar 


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6.1.1.2 Bowdle VAS 
The Bowdle VAS19 consists of 13 items for which the subject is asked to rate his or her current 
feelings. An adapted computerized version of Bowdle VAS will be administered with 11 items 
examining internal and external perception sub-scales. Each VAS will be scored from 0 to 100, 
with 0 reflecting “Not at all” and 100 reflecting “Extremely.” Lower individual and overall 
scores indicate fewer psychedelic effects. 
The individual items of the questionnaire are listed below: 
1. My body or body parts seemed to change their shape or position (BODY) 
2. My surroundings seemed to change in size, depth, or shape (SURROUNDINGS) 
3. The passing of time was altered (TIME) 
4. I had feelings of unreality (REALITY) 
5. It was difficult to control my thoughts (THOUGHTS) 
6. The intensity of colors changed (COLORS) 
7. The intensity of sound changed (SOUND) 
8. I heard voices or sounds that were not real (VOICES) 
9. I had the idea that events, objects, or other people had particular meaning that was specific 
for me (MEANING) 
10. I had suspicious ideas or the belief that others were against me (SUSPICIOUS) 
11. I felt anxious (ANXIOUS) 
Items 1, 2, 3, 5, 6, and 7 are combined to assess the derived variable “subjective external 
perception.” Items 4, 8, 9, 10, and 11 are combined to assess the derived variable “subjective 
internal perception.”  
If one of the items is missing, the related score will not be calculated. 
6.1.2 Divided Attention Test 
The Divided Attention Test (DAT) is a manual-tracking test with a simultaneous visual target 
detection component. The subject is provided with a joystick with a trigger to execute this 
measure. During testing, the subject is presented with the image of an airplane and a randomly 
curving road (Figure 4). As the road moves down the screen, the subject is to try and position the 
image of the airplane over the center of the road.20 At random times during this process, a visual 
target will briefly present itself at random positions on the screen and immediately disappear. 
The subject is to respond to the visual target as fast as possible by pressing a button on the 
joystick. There are 16 targets presented during each trial. Each test consists of three 1-minute 
trials over different road courses. Performance is measured based on the subject’s ability to keep 
the image of the airplane over the road, and the subject’s ability to respond to the visual target. 
The following outcome measures will be used to assess performance on this task: 
 Root mean square (RMS) distance: the RMS distance from the center of the road (pixels) 
 Greatest distance: the maximum distance from the center of the road (pixels) 


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 Response latency of correct responses (msec) 
 Average number of false alarms  
 Percentage over road: percentage of time over the road (%) 
 Percentage of target hits (%) 
Figure 4 
Sample Screen Image for the Divided Attention Test 
 
6.1.3 Digit Symbol Substitution Test 
The Digit Symbol Substitution Test (DSST) (modified) is a test of processing speed and visual-
motor coordination. Subjects are presented with a legend or key at the top of the screen, which 
shows 10 digits displayed with 10 different associated symbols (Figure 5A). Just below the 
center of the screen, a single digit appears with a 3 × 3 grid of 9 squares presented below. Inside 
the grid, subjects must draw the symbol associated with the digit displayed on the screen 
(Figure 5B). When they have drawn the appropriate symbol, a new single digit and workspace 
appear. The goal is for the subject to complete as many symbols correctly as they can in the 
amount of time determined in the measure configuration (typically 90 seconds). Each time 
subjects perform this task, the same 10 symbols will be used, but the order of the symbols across 
the top of the screen and the corresponding digit will change. The task is scored for the number 
of symbols completed and the number of errors (symbols completed incorrectly). 


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Figure 5 
Sample Screen Image for the Digit Symbol Substitution Test 
A. 
B. 
 
 
6.1.4 Sternberg Short-Term Memory 
The Sternberg Short-Term Memory (SSTM) task21 is a measure of immediate memory in which 
subjects are asked to remember a series of digits that are rapidly presented on a computer screen.  
The SSTM task involves rapid presentation of target lists of 2, 4, and 6 stimulus digits 
(1.2 seconds/digit). Two seconds after presentation of each list of digits, a series of 24 probe 
digits is presented. The subject is to identify as quickly as possible whether or not each probe 
appeared in the target list by pressing buttons on a response box meaning “YES” or “NO.” 
Probes that appeared on the target list are called “positive”, while probes that did not appear on 
the target list are called “negative.” 
The test consists of 3 trials with digit sequence size lengths of 2, 4, and 6. Performance is 
assessed by measures of response latency and accuracy. 
6.1.5 Pupillometry 
Pupillometry will be used as an objective physiological PD measure as it is a sensitive measure 
of central opioid/stimulant action and appears to be resistant to tolerance development with 
repeated administration. An electronic pupillometer (NeuroOptics) will be used to measure pupil 
diameter. Data from a series of frames will be used in the calculation, and the final display will 
show the weighted average and standard deviation (SD) of the pupil size. Measurements will be 
collected under mesopic lighting conditions. For each subject, every effort will be made to use 
the same eye for all assessments throughout the study. 
6.2 
Pharmacokinetic Assessments 
In Part A and Part B, venous blood samples (2 mL) will be collected to determine the plasma 
concentrations of nalbuphine following oral administration of nalbuphine solution and 
nalbuphine ER tablet. Samples will be collected, processed, and shipped according to the 


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instructions provided in the laboratory manual and instructions from the sponsor or bioanalytical 
laboratory. 
The PK sample collection timepoints are included in Table 1 for Part A and Table 3 for Part B. 
Blood volumes required for PK sampling are available in Appendix 11.1 (Part A) and in 
Appendix 11.2 (Part B). 
The plasma samples will be analyzed for nalbuphine and metabolites by Covance using validated 
methods.  
Plasma samples will be shipped frozen on dry ice from the research site to Covance at the 
address provided in the laboratory manual. Samples will not be shipped without prior 
arrangement with the bioanalytical laboratory and notification to the sponsor. 
Drug concentration information that may unblind the study will not be reported to the study site 
or blinded personnel until the study has been unblinded. 
6.3 
Safety Assessments 
Safety will be determined by an ongoing evaluation of the following: 
 AEs 
 Vital sign measurements 
 ECGs 
 Clinical laboratory tests 
 Physical Examination 
 COWS 
6.3.1 Medical History 
Medical histories will be obtained during screening (Part A and Part B) and will include 
demographic data (date of birth, sex, race, and ethnicity); histories of acute, chronic, and 
infectious disease; contraception use, surgical and oncologic histories; and any reported 
conditions affecting major body systems. All findings on medical history will be evaluated by the 
investigator for clinical significance. 
The DSM-IV-TR modules will be used to screen for alcohol and substance dependence. 
6.3.2 Medication History and Recreational Drug and Alcohol Use 
All medications (prescription and non-prescription, herbal medications/natural health products, 
or investigational drugs) taken by the subjects during the 30 days prior to Screening (Part A and 
Part B) will be recorded in the source documentation as medication history.  
A history of all drugs used for recreational/non-medicinal purposes (ie, psychoactive effects) and 
alcohol use will also be collected during the screening visit(s). 


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6.3.3 Physical Examination 
A complete physical examination, assessing the subject’s overall health and physical condition, 
will be performed at the Screening visit including height, weight, and BMI. Subsequent physical 
examinations will be performed per the Schedule of Events and may be performed by physicians 
or mid-level providers, such as advanced practice nurses and physician assistants, if they are 
appropriately licensed and credentialed to perform these examinations in accordance with local 
requirements and/or regulations.  
Any clinically significant worsening after the start of study drug will be reported as an AE. 
Clinically significant findings observed prior to start of Study Drug treatment will be recorded as 
part of the medical history. 
6.3.4 Electrocardiograms 
12-Lead ECGs will be performed by the site and interpreted by the investigator or other 
appropriately credentialed designee. The ECGs will be performed with the electrodes positioned 
on the torso after the subject has been resting in a supine or semi-supine position for at least 
3 minutes. The ECG will electronically measure and calculate ventricular heart rate and the PR, 
QRS, QT, QTcB, and QTcF intervals. The QTcF will be used for clinical evaluations. 
6.3.5 Vital Signs 
Vital signs will be measured after subjects have been at rest for approximately 3 minutes at the 
time points specified in the Schedule of Events. Vital signs will consist of systolic and diastolic 
blood pressure (mmHg), heart rate (bpm), and respiratory rate (breaths/min). Oral temperature 
(°C) will also be taken at some time points. In addition, pulse oximetry measurements will be 
taken with the vital signs monitoring system (eg, Dinamap) at designated time points and 
recorded after the continuous monitoring period (Section 6.3.6). 
6.3.6 Continuous Pulse Oximetry 
Continuous pulse oximetry will be performed by telemetry from pre-dose until at least 4 hours 
post-dose during the Qualification Phase in Part B and at least 6 hours post-dose during the Dose 
Selection Phase in Part A and the Treatment Phase in Part B, or longer, based on the discretion of 
the investigator or designee. 
Continuous monitoring will include real-time measurements of SpO2. Oxygen saturation 
readings will be recorded at designated time points. After the continuous monitoring period, 
pulse oximetry measurements will be taken with the vital signs monitoring system (eg, Dinamap) 
at designated time points and recorded. 
6.3.7 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a unique, simple, and short method of assessing both behavior and ideation that 
tracks all suicidal events, and provides a summary of suicidal ideation and behavior. It assesses 
the lethality of attempts and other features of ideation (frequency, duration, controllability, 
reasons for ideation, and deterrents), all of which are significantly predictive of completed 
suicide.  


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Two versions of the C-SSRS will be used in this study: the Baseline version assesses lifetime 
suicidal ideation and behavior, and the Since Last Visit version assesses suicidal thoughts or 
behaviors the subject may have had since the last time the C-SSRS was administered.  
Occurrence of suicidal ideation after baseline is defined as having answered “yes” to at least 1 of 
the 5 suicidal ideation subcategories (ie, wish to be dead; non-specific active suicidal thoughts; 
active suicidal ideation with any methods [no plan] without intent to act; active suicidal ideation 
with some intent to act [without specific plan]; and active suicidal ideation with specific plan and 
intent) at any post-baseline evaluation. Occurrence of suicidal behavior after baseline is defined 
as having answered “yes” to at least 1 of the 4 suicidal behavior subcategories (ie, actual attempt, 
interrupted attempt, aborted attempt, and preparatory acts or behavior) at any post-baseline 
evaluation. 
A trained rater will record the clinical observations on the scale, which will be used as the source 
document.  
6.3.8 Clinical Laboratory Assessments 
Blood and urine samples will be collected, processed, and shipped according to the instructions 
provided in the laboratory manual. All laboratory safety data will be reviewed by the investigator 
or designee for clinical significance. See Section 9.4 for details regarding the anonymity of 
subject information. 
Blood volumes required per laboratory test and study period/phase are provided in 
Appendix 11.1 (Part A) and in Appendix 11.2 (Part B).  
Clinical Chemistry: Quantitative analysis will be performed for the following analytes: alkaline 
phosphatase, calcium, chloride, creatinine, random glucose, potassium, alanine aminotransferase, 
aspartate aminotransferase, gamma-glutamyl transpeptidase, sodium, total bilirubin, and urea. 
Hematology: A peripheral blood smear will be performed to assess blood cell morphology. 
Quantitative analysis will be performed for at least the following analytes: hemoglobin, 
hematocrit, red blood cell (RBC) count, white blood cell (WBC) count, WBC differential 
(absolute counts), and numerical platelet count. 
Urinalysis: Qualitative or quantitative analysis will be performed for the following analytes, as 
appropriate: specific gravity, pH, ketones, random glucose, nitrite, blood, leukocyte esterase, 
protein, urobilinogen, and bilirubin. If nitrite, blood, or protein tests are positive, a microscopic 
examination will be performed. 
Pregnancy: Pregnancy tests for female subjects will test for the presence of β-Human Chorionic 
Gonadotropin (HCG) in blood serum or urine. Results of blood serum and urine pregnancy tests 
will be reported and determined to be negative prior to study continuation and/or dosing. 
FSH: Post-menopausal status for female subjects, as applicable, will be confirmed by FSH 
testing at Screening. 


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Viral Screen: Serology will screen for hepatitis B, hepatitis C, and HIV. Only subjects with 
negative viral serology tests will be eligible for the study. Positive results will be managed 
according to local regulatory requirements. 
Breath Alcohol: Breath alcohol testing will be performed. If there is any doubt or concern 
regarding alcohol use, research site staff may request a breath alcohol test at any time during the 
study. 
Drugs of Abuse Screen: The urine drug screen will test for the following drugs of abuse: THC, 
oxycodone, other opiates (ie, the opiate panel will test for the presence of codeine, hydrocodone, 
hydromorphone, morphine, and oxymorphone), amphetamines (ie, amphetamine and 
methamphetamine), cocaine, and benzodiazepines. Refer to Section 4.8 for subject 
discontinuation rules in the event of a positive urine drug screen. 
6.3.9 Clinical Opioid Withdrawal Scale 
A sample form of the COWS is presented in Appendix 11.3. 
6.3.9.1 Treatment Phase Admission 
At each admission to a Treatment period (Periods 1 through 7), subjects will undergo an 
assessment for signs or symptoms of withdrawal based on the COWS: 
 Subjects with a COWS score < 5 will be allowed to continue participating in the study 
period. 
 Subjects with a COWS score ≥ 5) will be discontinued from the study and medically 
managed for at least 4 hours or longer until the investigator determines that the subject 
can be safely discharged from the CRU.  
6.3.9.2 Adhoc Assessments 
The COWS may be administered adhoc during the Treatment Phase, at the investigator’s 
discretion, based on any observed or reported AEs that may indicate signs or symptoms of 
withdrawal.  
Subjects with an adhoc COWS score < 5 will be allowed to continue participating in the study.  
Subjects with an adhoc COWS score ≥ 5 will be discontinued from the study and medically 
managed for at least 4 hours or longer until the investigator determines that the subject can be 
safely discharged from the CRU. 
6.3.10 Screening Assessments for Subjects who Participate in both Part A and Part B 
Eligible subjects who participate in Part A may also participate in Part B (after informed consent 
to participate in Part B is obtained) and will only require re-screening (ie, completion of all 
screening assessments) if a duration of 60 days or greater has passed between the screening visit 
in Part A and the first visit (admission to the Qualification Phase) in Part B. 


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If a duration of at least 4 days but less than 60 days has passed from the screening visit in Part A 
and the first visit (admission to the Qualification Phase) in Part B, the following assessments will 
be performed for the subject: 
 Blood samples will be collected for evaluation of hemoglobin, hematocrit, and liver 
enzymes (ie, ALT and AST) levels. 
 Blood samples will be collected for HIV, hepatitis B and hepatitis C tests. 
 Serum pregnancy test (females only). 
6.4 
Appropriateness of Measures 
The selected PD measures will assess positive and negative subjective drug effects associated 
with the abuse potential of a drug, as well as objective measures evaluating the cognitive and 
opiate effects. A number of concurrent measures will be used in this study to assess the abuse 
potential of nalbuphine relative to hydromorphone and placebo. These measures are grouped as 
follows:  
 Measures of balance of effects (eg, rating of "at the moment" drug liking) 
 Measures of global effects (eg, willingness to take the drug again) 
 Measures of positive effects (eg, good effects, high) 
 Measures of negative effects (eg, bad effects) 
 Measures of stimulant and sedative effects (eg, drowsiness/alertness) 
 Measures of perceptual disturbances (eg, hallucinations, Bowdle VAS) 
 Measures of cognitive effects (eg, DAT, DSST, SSTM) 
 Measure of opiate effect (eg, pupil size) 
The selection of subjective abuse potential measures in this study, including the use of a bipolar 
Drug Liking VAS as the primary endpoint, is consistent with regulatory and literature 
guidelines.8,22,23 The assessment of drug liking has been chosen as the primary measure in the 
current study because the degree of subject liking is considered one of the most sensitive indices 
of abuse liability.12 The Drug Liking VAS and the Overall Drug Liking VAS assess slightly 
different aspects of drug liking. Drug Liking VAS assesses the subject’s liking of the drug at the 
moment the question is asked, may be less subject to recall bias, and is useful for understanding 
the time-course of the effects. The Overall Drug Liking VAS is thought to assess ‘global’ drug 
effects (ie, subjective effects over the whole course of the experience including any carry-over 
effects), and has the additional advantage that the subject is generally sober by the time of the 
assessment (ie, end of day and/or next day). Other VAS items will measure positive, negative, 
and other subjective effects to assess the pharmacologic response to the study drugs. The Take 
Drug Again VAS will provide a global measure of drug effects and indicate the subject’s 
willingness to take the drug again. 
Pupillometry will be used as an objective physiological PD measure as it is a sensitive measure 
of central opioid action and appears to be resistant to tolerance development with repeated 
administration. Impairing effects will be evaluated on various measures of cognition evaluating 
divided attention, visual spatial processing speed, and short-term memory. 


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PK samples will be evaluated for plasma concentrations of nalbuphine. Standard safety 
assessments, such as AE reporting, vital signs (including oxygen saturation monitoring), physical 
examination, and ECGs will be included in this study. 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The investigator or designee and research site staff are responsible for the detection, 
documentation, classification, reporting, and follow-up of events meeting the definition of an AE 
or SAE.  
Spontaneously reported or observed AEs will be recorded throughout the study, beginning at the 
time the subject gives informed consent. Subjects will be monitored throughout confinement for 
AEs and AEs may be elicited using a non-leading question at the discretion of the clinical staff. 
Regardless of seriousness, intensity, or presumed relationship to study drug, all AEs will be 
recorded in the source documentation from the time of first contact with the subject (eg, 
Screening) until the end of the Follow-up period of the study. AEs that occur after screening and 
prior to administration of the first dose of study drug will be recorded in the source 
documentation as baseline signs and symptoms. All measures required for management of AEs 
will be recorded in the source documentation. 
7.1 
Definitions 
7.1.1 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and may not necessarily have a causal relationship with 
the administered treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant laboratory abnormality, for example), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. During the study, an AE can also occur outside 
the time that the investigational product(s) was given (eg, during a washout period).  
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs. 
Pre-existing conditions, diseases, or disorders are not considered AEs unless there is a change in 
intensity, frequency, or quality. 
7.1.2 Serious Adverse Events and Serious Unexpected Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening (at the time of the event), 


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 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in 
the risk information set out in the IB or on the label of the drug. 
7.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Abnormal laboratory findings (eg, from clinical chemistry, hematology, or urinalysis) and other 
abnormal assessments (eg, from vital signs or ECGs) judged as clinically significant by the 
investigator or designee will be recorded as AEs or SAEs if they meet the definitions provided in 
Section 7.1.1 and Section 7.1.2. Furthermore, abnormal laboratory findings and other abnormal 
assessments present at baseline that significantly worsen following the start of the study 
(ie, become clinically significant) will be reported as AEs or SAEs. However, abnormal 
laboratory findings present at the start of the study that do not worsen will not be reported as AEs 
or SAEs. 
The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
7.2 
Evaluation of Adverse Events and Serious Adverse Events 
The investigator or designee is responsible for making an assessment as to the seriousness, 
intensity, causality, and outcome of an AE. 
7.2.1 Classification of Adverse Event Intensity 
For each recorded AE or SAE, the investigator or designee must make an assessment of intensity 
based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
(Table 12). If there is insufficient information to determine intensity, the AE must still be 
reported. 


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Table 12 
Classification of Adverse Event Intensity 
Classification 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death. 
Source: National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) available for 
download at: https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
7.2.2 Classification of Adverse Event Causality 
For each recorded AE or SAE, the investigator or designee must make an assessment of causality 
based on the criteria in Table 13 to determine the relationship between the AE and the study 
drug. 


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Table 13 
Classification of Adverse Event Causality 
Classification 
Definition 
Unrelated 
The AE or SAE is judged to be clearly and incontrovertibly due only to 
extraneous causes (eg, disease, environment) and does not meet the 
criteria for study drug relationship listed under probable, possible, or 
unlikely. 
Unlikely 
The AE or SAE is unlikely related to the study drug, when the AE or SAE 
 does not follow a reasonable temporal sequence from administration 
of the study drug 
 may readily have been produced by the subject’s clinical state, 
environmental, or toxic factors, or other modes of therapy 
administered to the subject 
 does not follow a known pattern of response to the study drug 
 does not reappear or worsen when the study drug is re-administered 
Possible 
The AE or SAE is possibly related to the study drug, when the connection 
to the study drug appears unlikely but cannot be ruled out with certainty. 
This causal relationship is assigned when the AE or SAE 
 follows a reasonable temporal sequence from administration of the 
study drug 
 may have been produced by the subject’s clinical state, 
environmental, or toxic factors, or other modes of therapy 
administered to the subject 
 follows a pattern of response to the suspected study drug 
Probable 
The AE or SAE is probably related to the study drug, when the connection 
to study drug can be made with a high degree of certainty. This causal 
relationship is assigned when the AE or SAE 
 follows a reasonable temporal sequence from administration of the 
study drug 
 cannot be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental, or toxic factors, or other 
modes of therapy administered to the subject 
 disappears or decreases upon cessation or reduction in dose (note 
that there are important exceptions when an AE or SAE does not 
disappear upon discontinuation of the study drug, yet drug 
relatedness clearly exists, eg, bone marrow depression or tardive 
dyskinesias) 
 follows a known pattern of response to the suspected study drug 
 reappears upon re-challenge 


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7.2.3 Classification of Adverse Event Outcome 
For each recorded AE or SAE, the investigator or designee must make an assessment of outcome 
at the time of last observation. The outcome of AEs or SAEs will be documented as outlined in 
Table 14. 
Table 14 
Classifications for Adverse Event Outcomes 
Classification 
Definition 
Fatal 
The subject died. 
Resolved 
The AE or SAE has ended. 
Resolved with 
Sequelae 
The AE or SAE has ended but changes are noted from baseline. 
Unresolved 
The AE has not ended.  
An AE outcome can only be categorized as unresolved, if the AE is 
 ongoing at the end of the reporting period (ie, 14 days after the final 
Follow-up visit) and the investigator deems that further follow-up is 
not medically required 
 lost to follow-up after repeated unsuccessful attempts to contact the 
subject 
 ongoing and referred to the subject’s physician or a specialist 
7.3 
Reporting Procedures 
7.3.1 Serious Adverse Events and Serious Unexpected Adverse Events 
Any SAE—expected or unexpected, irrespective of relationship to study treatments, including 
death due to any cause—experienced by a study subject will be reported to INC Research Safety 
and Pharmacovigilance by the investigator or designee within 24 hours of learning of the event.  
The contact information for the INC Research Safety and Pharmacovigilance is as follows: 
Name 
INC Research Safety and Pharmacovigilance 
Email 
INCDrugSafety@incresearch.com 
Fax 
1-877-464-7787  
Any SAEs occurring during the trial will be reported in an expedited manner to the regulatory 
authorities. INC Research assumes responsibility for appropriate reporting of SAEs to the 
regulatory authorities (eg, Health Canada). Information regarding the SAE, and all follow-up 
evaluations, will be transmitted to Trevi Therapeutics, Inc. by email (hard copy of documents to 
be scanned and attached to the email). 


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Contact information for the Medical Monitor in this study is as follows: 
Name 
Thomas Sciascia, M.D. 
Telephone 
203-903-9894 
Fax 
203-562-0266 
Email 
Thomas.Sciascia@trevitherapeutics.com 
INC Research assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities (eg, Health Canada).  
Trevi Therapeutics, Inc. will report to the investigator all SAEs that are unlisted and associated 
with the use of the study drug. The investigator must report these events to the appropriate 
Institutional Review Board (IRB) that approved the protocol (unless otherwise required and 
documented by the IRB). 
All additional follow-up evaluations for SAEs will be reported to Trevi Therapeutics, Inc. 
7.3.2 Any Adverse Event 
Regardless of seriousness, intensity, or presumed relationship to study drug, all AEs will be 
recorded in the source documentation. Whenever possible, diagnoses will be recorded, when 
signs and symptoms are due to a common etiology. In addition, the investigator must record his 
or her opinion as to the intensity of the AE and whether the AE is related to study drug. All 
measures required for management of the AE will be recorded in the source documentation. 
7.3.3 Pregnancy 
In the event of a subject pregnancy, research site staff will report the pregnancy to INC Research 
Safety and Pharmacovigilance within 24 hours of learning of the event. Any subject who 
becomes pregnant during the study will be immediately withdrawn. 
Follow-up information regarding the course and outcome of the pregnancy, including any post-
natal sequelae in the infant, will be obtained where possible (ie, with the consent of the subject or 
subject’s partner). 
7.4 
Follow-up of Adverse Events and Serious Adverse Events 
All unresolved AEs, that were reported by the investigator to have a “probable” causal 
relationship to study drug, will be followed for a minimum of 14 days after the subject’s final 
study visit, the events are resolved, the patient is lost to follow-up, or the AE has stabilized, 
unless the investigator’s judgment dictates otherwise, the event has resolved or stabilized before 
the 14-day period, or the subject is lost to follow-up.  
All AEs and SAEs that result in discontinuation will be followed until one of the following 
occurs: 
 The event resolves 


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 The event stabilizes 
 The event returns to a baseline value, if a baseline value is available 
 The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
When it becomes unlikely that any additional information can be obtained (eg, subject or health 
care practitioner fails to provide additional information, the subject is lost to follow-up), the 
investigator or designee will ensure that the follow-up includes any pertinent supplemental 
investigations (eg, laboratory tests or investigations, histopathological examinations or 
consultation with other health care professionals) to elucidate the nature and/or causality of the 
AE or SAE. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects that occur 
following the follow-up period.  
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1 
Statistical and Analytical Plans 
8.1.1 Analysis Populations 
8.1.1.1 Dose Selection Phase (Part A) 
The following analysis populations will be used for Part A: 
 Dose Selection Randomized Population: All subjects who are assigned a randomization 
number in the Dose Selection Phase. 
 Dose Selection Safety Population: All subjects in the Dose Selection Randomized 
Population who receive any Dose Selection treatment. These subjects will be included in 
the safety analysis for this phase. 
 Dose Selection PK Population: All subjects in the Dose Selection Randomized population 
who received a dose of nalbuphine and have evaluable PK data. These subjects will be 
used in the PK analysis for this phase.  
8.1.1.2 Qualification and Treatment Phase (Part B) 
 Qualification Safety Population: All subjects who receive at least one dose of study 
medication during the Qualification Phase. 
 Randomized Population: All subjects who are assigned a randomization number in the 
Treatment Phase. 
 Safety Population: All randomized subjects who receive any study treatment in the 
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 Completers Population: All subjects in the Safety population who receive all study 
treatments and complete all treatment periods in the Treatment Phase regardless whether 
they have protocol deviations. Subjects must have at least one response on Drug Liking 
VAS within 2 hours of Tmax for each treatment in the study. 
 PK Population: All subjects in the Randomized population who receive at least 1 dose of 
nalbuphine from whom at least 1 PK sample is obtained after dosing, and who have no 
protocol deviations or other circumstances that would exclude the subjects from analysis. 
Details of subject evaluability criteria will be determined prior to study unblinding. 
8.1.2 General Statistical Considerations 
Complete details of the statistical analyses to be performed by INC Research will be documented 
in a statistical analysis plan (SAP), which will be completed prior to unblinding of the study data. 
This document will include more detail of the analysis populations, summary strategies, and of 
any amendments to the proposed analyses listed here, if necessary. Any changes to the SAP will 
be outlined in the final clinical study report (CSR).  
The PK analyses will be performed by INC Research using Phoenix WinNonlin (release 6.4 or 
higher) and other statistical analyses will be performed using SAS® (release 9.3 or higher). 
8.1.3 Planned Analyses of Primary and Secondary Pharmacodynamic Assessments (Part B) 
PD data will be analyzed for the Completers population. The primary endpoint is Drug Liking 
VAS Emax, and the key secondary endpoints are Overall Drug Liking VAS Emax, and Take Drug 
Again VAS Emax. 
For the Qualification Phase, Drug Liking VAS Emax will be summarized by treatment and paired 
difference for the Completers population using descriptive statistics. 
For the Treatment Phase, PD data at each time point will be summarized by descriptive statistics 
including mean, standard error (SE), minimum, first quartile (Q1), median, third quartile (Q3) 
and maximum. PD data will be presented graphically (where appropriate) for the Completers 
population. Derived endpoints will be summarized by treatment and paired difference using 
descriptive statistics. PD endpoints will be provided in both tables and figures (as applicable). 
Outliers will be listed by measure and parameter. 
PD endpoints for the Treatment Phase (Emax, Emin, and TA_AUE, as appropriate) will be analyzed 
using a mixed-effect model if the distribution of the residuals is normally distributed. The model 
will include treatment, period, sequence and first-order carryover effect (where applicable) as 
fixed effects, baseline (pre-dose) measurement as a covariate (where applicable), and subject 
nested within treatment sequence as random effect. First, the residuals from each mixed-effect 
model, excluding carryover effects, will be investigated for normality using the Shapiro-Wilk W-
test. Parameters will be analyzed under the assumption of a normal distribution if the P value of 
the test is ≥ 0.01. 24 The null and alternative hypotheses for this analysis are shown below: 
H0: The distribution of residuals is normal versus Ha: The distribution of residuals is not normal 


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If the normality assumption of a model is satisfied, it will be determined if carryover effects 
should be included. When conducting drug abuse potential studies, Chen and Tsong (2007)25 
have recommended the inclusion of first-order carryover as a fixed effect in the mixed-effects 
model. The adoption of this conservative approach would address possible effects associated 
with the subjective nature of these studies. Carryover effects are defined as the treatment 
administered in the previous treatment period; for Treatment Period 1, placebo (Treatment A) 
will be used. If the carryover effect is found to be non-significant at alpha=0.25, then the term 
will be dropped from the analysis model. 
If the normality assumption of the model is satisfied, least square means, SE, and 95% 
confidence intervals (CIs) for treatments and treatment differences will be derived from the 
mixed-effects model. P values will be provided for the effects and the contrasts. CIs and P values 
will be one-sided for the primary endpoint and key secondary endpoints. CIs and P values will 
be two-sided for all other secondary PD parameters. 
If the normality assumption of the model is not satisfied, the distribution of the paired difference 
for each contrast will be examined. Each paired difference will be investigated for normality 
using the Shapiro-Wilk W-test. If the P value for the distribution of the paired difference is 
≥ 0.01 or the distribution is quite symmetric (skewness = −1 to 1), a paired t-test will be used. 
Means, SE, and 95% CIs for paired treatment differences will be presented. Otherwise, the sign 
test will be used. The median, first quantile and third quantile, 95% CI and P value for the paired 
difference will be presented. 
The primary objective of a human abuse potential (HAP) study is to provide information on the 
relative abuse potential of a test drug in humans. The statistical analysis of a HAP study should 
address the following questions: 
1. Does the known drug of abuse (positive control) produce reliable abuse-related responses 
compared to placebo (study validity)? 
2. Does the test drug produce abuse-related responses that are smaller than those of the 
positive control? 
3. Does the test drug produce abuse-related responses that are similar to placebo? 
To address these issues, the following hypotheses must be tested: 
1. Validation test of the sensitivity and integrity of the study: Does the positive control (C) 
produce mean responses that show greater abuse potential compared to placebo (P)? This 
question may be expressed using the following hypothesis: 
H0: μC - μP ≤ δ1 versus Ha: μC - μP > δ1 where δ1 > 0 
2. Does the test drug (T) produce mean responses that show less abuse potential compared to 
positive control (C)? 
H0: μC – μT ≤ δ2 versus Ha: μC – μT > δ2 where δ2 ≥ 0 
3. Does the test drug (T) produce mean responses that show similar abuse potential 
compared to placebo (P)? 


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H0: μT - μP ≥ δ3 versus Ha: μT - μP < δ3 where δ3 > 0 
These hypotheses will be applied to the primary and key secondary endpoints. A 10-point 
difference was reported to be clinically meaningful for Drug Liking26 and High VAS,27 however 
these differences have not been validated.27 Nalbuphine has not been previously evaluated in 
HAP studies, and therefore, its effect size on the primary measure of Drug Liking and other study 
measures is unknown. Appropriate and clinically significant margins for nalbuphine have not 
been previously defined. The evaluation of nalbuphine in this study is exploratory and 
considered a safety study. Nalbuphine is a new chemical entity (NCE); the statistical methods 
proposed herein are novel based on the newly issued guidance8, and clinically meaningful point 
differences have not be established for the other VAS scales being measured. A minimum 15-
point difference between hydromorphone 12 mg and placebo is required in the Qualification 
Phase. However, hydromorphone 8 mg will be administered in the Treatment Phase. As a 15-
point difference may not be detected in the lower dose of hydromorphone, δ1, will be set to 11. 
Due to the exploratory nature of this study, δ2 will be set to 0 for comparisons of nalbuphine with 
hydromorphone; δ3 will be set to 11.28  
For study validity purposes, the primary endpoint, Emax for Drug Liking VAS, will be compared 
for the positive controls, hydromorphone 8 and 16 mg, and placebo. The comparison will assess 
the null hypothesis that the mean difference in Drug Liking Emax between hydromorphone and 
placebo is less than or equal to 11 against the alternative hypothesis that the mean difference in 
Drug Liking Emax between hydromorphone and placebo is greater than 11. If statistically 
significant, it will confirm the sensitivity of the study and allow for the comparison of the other 
pairwise comparisons shown below. The hypotheses can be expressed as follows: 
H0: μC - μP ≤ 11 versus Ha: μC - μP > 11 
where 𝜇𝜇C is the mean for the positive controls, hydromorphone 8 and 16 mg, and 𝜇𝜇𝑃𝑃 is the 
mean for placebo and will be applied to the following contrasts: 
 Treatment B: Hydromorphone 8 mg versus Treatment A: Placebo 
 Treatment C: Hydromorphone 16 mg versus Treatment A: Placebo 
The primary hypothesis for the comparison will assess the null hypothesis that the mean 
difference in Drug Liking Emax between hydromorphone and nalbuphine is less than or equal to 0 
against the alternative hypothesis that the mean difference in Drug Liking Emax between 
hydromorphone and nalbuphine is greater than 0. 
Comparison between the test drug, nalbuphine, and the positive control, hydromorphone 
8 and 16 mg, will be: 
H0: μC – μT ≤ 0 versus Ha: μC – μT > 0 
where 𝜇𝜇C is the mean for the positive control, hydromorphone, and 𝜇𝜇T is the mean for 
nalbuphine and will be applied to the following contrasts: 
 Treatment B: Hydromorphone 8 mg versus Treatment D: Nalbuphine low dose 
 Treatment B: Hydromorphone 8 mg versus Treatment E: Nalbuphine intermediate dose 
 Treatment B: Hydromorphone 8 mg versus Treatment F: Nalbuphine high dose 


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 Treatment B: Hydromorphone 8 mg versus Treatment G: Nalbuphine 162 mg ER intact 
 Treatment C: Hydromorphone 16 mg versus Treatment D: Nalbuphine low dose 
 Treatment C: Hydromorphone 16 mg versus Treatment E: Nalbuphine intermediate dose 
 Treatment C: Hydromorphone 16 mg versus Treatment F: Nalbuphine high dose 
 Treatment C: Hydromorphone 16 mg versus Treatment G: Nalbuphine 162 mg ER intact 
For VAS scales, the hypothesis for the comparison between nalbuphine and placebo will be: 
Ho: μT - μP ≥ 11 versus Ha: μT - μP < 11 
where, 𝜇𝜇T is the mean for nalbuphine and 𝜇𝜇𝑃𝑃 is the mean for placebo and will be applied to the 
following contrasts: 
 Treatment D: Nalbuphine low dose versus Treatment A: Placebo 
 Treatment E: Nalbuphine intermediate dose versus Treatment A: Placebo 
 Treatment F: Nalbuphine high dose versus Treatment A: Placebo 
 Treatment G: Nalbuphine 162 mg ER intact versus Treatment A: Placebo 
No clinically meaningful differences have been defined for any of the other PD measures and 
thus, assigning a δ margin is not applicable. Furthermore, changes observed on measures of 
cognition or performance do not inherently imply that the drug has abuse potential, but rather 
provide important information related to the drug’s CNS pharmacology.8 For PD endpoints that 
have not been defined as primary or key secondary, the following 3 hypotheses will be used to 
provide information on the relative abuse potential of the test drug in humans: 
1. H0: μC - μP = 0 versus Ha: μC - μP ≠ 0 
2. H0: μC - μT = 0 versus Ha: μC - μT ≠ 0 
3. H0: μT - μP = 0 versus Ha: μT - μP ≠ 0 
A significance level of 0.05 will be used for all individual one-sided and two-sided hypothesis 
tests. Multiple comparison adjustments will not be made. 
The abuse potential of nalbuphine will be assessed through evaluation and integrative 
interpretation of the pattern of results across the various types of measures: measures of positive 
response (ie, measures most predictive of the drug’s abuse potential and reinforcing properties), 
measures of negative response (ie, measures that potentially mitigate against abuse potential), 
measures of stimulant effects, measures of other effects and measures of cognitive and 
psychomotor effects. The treatment comparisons will support evaluation of the importance of the 
steepness of the dose-response curves and the similarity of responses to nalbuphine, as compared 
to the responses to hydromorphone and placebo. 
Sensitivity Analysis 
Inclusion criteria for Part B of the Qualification Phase include having a peak score (Emax) on the 
Drug Liking VAS greater than that of placebo by at least 15 points in response to 12 mg 
hydromorphone. In order to assess the robustness of this 15-point difference, a sensitivity 


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analysis will be conducted in the Treatment Phase to assess the null hypothesis that the mean 
difference in Drug Liking VAS Emax between the positive controls, hydromorphone 8 and 16 mg, 
and placebo is less than or equal to 15 against the alternative hypothesis that the mean difference 
in Drug Liking VAS Emax between hydromorphone and placebo is greater than 15. The 
hypothesis can be expressed as:   
H0: μc − μP ≤ 15 versus Ha: μc − μP > 15 
8.1.4 Analysis of Pharmacokinetics 
Pharmacokinetic analyses will be performed using the Dose Selection PK population in Part A 
and the PK population in Part B.  
The PK parameters for plasma nalbuphine and (Part A only) its metabolites will be calculated 
using non-compartmental analysis and will be summarized by dose level in Part A and by 
treatment in Part B. Graphs of the concentration (original and log transformed) versus time will 
be generated. Descriptive statistics, including n, mean, SD, coefficient of variation (CV), 
minimum, median, and maximum will be calculated by dose level (Part A) and treatment 
(Part B) and time point for each study drug. Concentrations below the limit of quantification 
(BLQ) will be set to zero for the generation of summary statistics for concentrations and the 
generation of mean concentration-time plots. 
For the calculation of the PK parameters, concentration-time data will be treated as follows: 
BLQ concentrations before the first quantifiable concentration will be set to zero; BLQ 
concentrations after the first quantifiable concentration will be treated as missing; and pre-dose 
sampling times relative to dosing will be set to zero. Descriptive statistics, including n, mean, 
SD, geometric mean, geometric CV, minimum, median, and maximum, will be calculated by 
dose level and treatment group for all PK parameters except Tmax , t½, and kel. Time to maximum 
observed plasma concentration data will be summarized with minimum, median, maximum, Q1 
and Q3. The t½ and kel data will be summarized with n, mean, SD, CV, minimum, median, and 
maximum. 
PK profiles will be analyzed for all subjects, even if some PK sampling time points are missed. 
The PK parameters will be subject to quality control criteria. If quality control criteria are met, 
the PK parameters will be used in analyses and models. Quality control criteria for PK will be 
sufficient to eliminate unreliable data. Details will be provided in the SAP. 
The PK parameters summary will be presented separately for a subset (if applicable) of subjects 
who do not vomit within 12 hours of dosing in Part A and Part B of the study. 
8.1.5 Analysis of Safety Assessments 
For Part A, the analysis of safety assessments will be performed using the Dose Selection Safety 
population. For Part B, the analysis of safety assessments will be performed using the Safety 
population. 
Assessment of safety will be based on the incidence of AEs, AEs resulting in discontinuation, 
and SAEs by treatment. AE summaries will be provided showing the number and percentage of 
subjects who experienced at least one AE. AEs will also be tabulated by maximum severity and 


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by maximum relationship to study drug. These summaries will be presented by body system and 
preferred term (Medical Dictionary for Regulatory Activities [MedDRA] 20.0 or higher). SAEs 
and AEs resulting in discontinuation will be summarized separately. Adverse event data from the 
Qualification Phase will be listed by subject for the Randomized population but not summarized 
further. 
Clinical laboratory data collected during the Treatment Phase will be summarized by the type of 
laboratory test and visit. Descriptive statistics (mean, SD, minimum, median and maximum) and 
the number of subjects with laboratory test results below, within, and above normal ranges will 
be tabulated by visit. Abnormal findings in laboratory data will be listed. 
Treatment Phase vital signs (blood pressure, respiratory rate, heart rate, SpO2) will be analyzed 
as minimum, maximum, and final post-dose values, since the analyses of these extremes are 
more meaningful than analyses of individual time points. 
The ECG data (absolute values in heart rate and the PR, QRS, QT, QTcB and QTcF intervals) 
will be summarized using descriptive statistics for data collected in the Treatment Phase. 
Physical examination abnormal results will be listed by subject and visit. Baseline and since last 
visit C-SSRS results will be listed. No summaries will be provided. 
8.1.6 Interim Analyses 
No interim analyses are planned for this study; however, based on a review of the results from 
cohorts in the Dose Selection Phase in Part A, low, intermediate, and high doses of nalbuphine 
will be selected by the DRC for the Treatment Phase in Part B. Therefore, dose selection 
decisions and conclusions made by the DRC will be documented and included in the appendix of 
the CSR. 
8.1.7 Missing Data 
For PD and PK analyses, missing data for subjects who are administered all scheduled study 
treatments for all the treatment sessions will be considered as random non-informative missing 
for analysis purposes. Missing values will be examined on a case-by-case basis. Further details 
on missing values imputation for descriptive statistics and endpoints derivations will be provided 
in the SAP. 
8.1.8 Demographics and Other Baseline Characteristics 
For Part A and Part B, demographics and baseline characteristics (age, sex, race, ethnicity, 
recreational drug and alcohol use history, body weight, height, and BMI) will be summarized 
using descriptive statistics (number of subjects, mean, SD, minimum, median and maximum for 
continuous variables, and the proportion of subjects for categorical variables) for the 
Randomized population. No formal statistical comparison between the groups will be performed. 
Medical history will be listed by subject. Medical history will be coded into the most recent 
version of MedDRA available (version 20.0 or later). 


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Prior and concomitant medications will be coded using the most recent version of the World 
Health Organization drug codes available (WHO Drug). Prior and concomitant medications will 
be listed by subject. The incidence of concomitant antiemetic medication use in will be tabulated 
by cohort (ie, dose level) and treatment (active drug or placebo) for Part A and by treatment for 
Part B. 
The number of subjects in each treatment group will be presented, in addition to the number of 
subjects who complete each visit. The reasons for all post-randomization discontinuations will be 
tabulated and grouped by treatment and major reason. All deviations related to study inclusion or 
exclusion criteria, conduct of the trial, subject management, or subject assessment will be 
described. 
8.2 
Determination of Sample Size 
In Part A, cohorts of 8 subjects in a ratio of 6:2 nalbuphine:placebo will be considered a 
sufficient sample size for the Dose Selection Phase based on dose escalation paradigms used 
historically for HAP studies. The proposed single doses of nalbuphine solution for the first 
cohort will be 81 mg (equivalent to 90 mg of the HCl salt). Dose escalation will only occur for 
each subsequent cohort if an MSD has not been identified and the previous dose level was 
deemed to be safe and well tolerated. Escalation to the next dose level will continue until the 
maximum safe dose is identified or the highest proposed dose level of nalbuphine is achieved. 
Additional cohorts of 8 subjects may be added if a given dose level will be repeated to provide 
additional data or if a dose level, intermediate to those proposed, needs to be considered for 
safety or tolerability reasons. 
In Part B, 56 healthy male and female subjects with a history of recreational opioid drug use will 
be enrolled in the Treatment Phase, with the intent to complete 42 subjects. 
The sample size calculation was conducted based on unpublished Drug Liking VAS Emax (bipolar 
scale) data collected at the investigational site, which included hydromorphone 8 mg as the 
investigational positive control. Based on this data, the mean paired difference between 
hydromorphone and placebo was 24.6. Within-group SDs were 18.4 for hydromorphone and 18.0 
for placebo. As determined by a published algorithm,29 adjusting for 7 periods and 14 sequences, 
with a 1-sided significance level of 0.05 and δ1 = 11, a sample size of 42 subjects will have at 
least 90% power to detect a difference in Drug Liking VAS Emax (bipolar scale). Assuming an 
approximate 25% dropout rate, 56 subjects (4 subjects per sequence) will be randomized into the 
Treatment Phase, with the intention to complete approximately 42 subjects (3 subjects per 
sequence). 


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9. 
STUDY ADMINISTRATION 
9.1 
Study Identification Card 
Eligible subjects will be given a study identification card during the Qualification Phase (Part B) 
that confirms they are participants in a research trial with hydromorphone, nalbuphine solution, 
and an investigational drug.  
Subjects will be provided with immediate medical care contact information that can be used 
during out-patient days between treatments. The card should contain trial site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. Subjects should 
be instructed to carry the card with them at all times until the end of their participation in the 
study. 
9.2 
Data Collection and Electronic Data Capture 
The investigator or designee will record all required subject data using the specified data 
collection method agreed upon by INC Research Toronto, Inc. and Trevi Therapeutics, Inc. 
(ie, paper source and/or the electronic data capture [EDC] system). 
The study site will use a validated EDC system to enter subject data onto electronic case report 
forms (eCRFs). Data will be collected using the EDC system and entered into a quality 
controlled clinical database. Prior to the commencement of the study, items to be included in the 
clinical database will be determined and suitable paper source documents will be created to 
ensure the appropriate collection of all required data. Clinical staff conducting the study will 
enter the required data onto source documents and generally different staff (who have been 
trained to do so) will enter the data from source documents into the clinical database, although 
there may be some staff overlap. All entries, corrections, and alterations will be made by the 
investigator or other authorized study personnel, and all data entries will be verified for accuracy 
and correctness. The EDC system is optimized for manual keying and review (including review 
by independent monitors) and maintains a full audit trail.  
For subjects who do not qualify for the Treatment Phase of the study, demographic data collected 
during the Screening and Qualification visits will be entered into the clinical database. 
Clinical laboratory and/or PK data will be transmitted electronically from external vendors to 
INC Research Data Management and reconciled against the clinical database. PsychometRx™ 
data will be captured electronically and imported into the clinical database. 
The study file and all source data will be retained at the clinical site until notification is given by 
the sponsor for destruction. 


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9.3 
Regulatory and Ethical Considerations 
9.3.1 Ethical Conduct of the Study 
The investigator will conduct the study in accordance with Good Clinical Practice (GCP) and all 
applicable regulations, including, where applicable, the Declaration of Helsinki. The study will 
also be carried out in keeping with applicable national and local laws and regulations. This may 
include an inspection by the sponsor’s representatives and/or regulatory authority’s 
representatives at any time. 
9.3.2 Regulatory Authority Approval 
In accordance with applicable local regulations, the sponsor or designee will obtain approval 
from the appropriate regulatory agency prior to a site initiating the study in that country or 
jurisdiction. 
9.3.3 Ethics Approval 
The investigator will ensure that this protocol is reviewed and approved by the appropriate IRB. 
The IRB will also review and approve the site’s ICFs (Part A and Part B) and any other written 
information provided to the subject, including any advertisements used for subject recruitment. 
Prior to the enrollment of subjects, the investigator or designee will forward copies of the IRB 
approval and approved study documentation to the sponsor for their records. 
If, during the study, it is necessary to amend study documentation (eg, protocol, ICF), the 
investigator or designee will be responsible for ensuring that the IRB reviews and approves these 
amended documents. IRB approval of an amended ICF must be obtained before new subjects 
consent to take part in the study using the amended form. Copies of the IRB approval of the 
amended study documentation and the approved materials will be forwarded to the sponsor as 
soon as available. 
9.3.4 Subject Informed Consent 
The investigator or designee will inform the subject or, where applicable, the subject’s legally 
authorized representative (eg, parent, guardian, next of kin, other individual, other body with 
appropriate jurisdiction) of all aspects pertaining to the subject’s participation in the study. 
The process for obtaining subject informed consent will be in accordance with all applicable 
regulatory requirements. The investigator or designee and the subject or the subject’s legally 
acceptable representative will both sign and date the ICF before the subject can participate in the 
study. Informed consent will be obtained from each subject before entry into each part of the 
study (ie, subjects will sign and date an ICF for Part A and an ICF for Part B). 
In the ICF for Part B, subjects will be blinded on how they will receive the study drugs 
(hydromorphone and placebo) in the drug discrimination test. Subjects will not know whether 
they will be receiving one of these study drugs on 2 occasions or each drug on 1 occasion during 
the 2-day test period of the Qualification Phase. This will mitigate subject expectations of drug-
related effects. 


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The subject or subject’s legally acceptable representative will receive a copy of the consent 
form(s), and the original form(s) will be retained in the site study records. The subject’s decision 
regarding participation in the study will be entirely voluntary. The investigator or designee will 
emphasize to the subject or the subject’s legally acceptable representative that consent regarding 
study participation may be withdrawn at any time, without penalty or loss of benefits to which 
the subject is otherwise entitled. 
If the ICF is amended during the study, the investigator will follow all applicable regulatory 
requirements pertaining to the implementation and use of the amended ICF, including use for 
previously consented subjects. 
9.3.5 Principal Investigator Reporting Requirements 
In accordance with applicable local regulatory requirements, the investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his or her research site and 
notification of study closure to the IRB. Such periodic safety updates and notifications are the 
responsibility of the investigator and not of the sponsor. The sponsor will be provided with 
copies of all notifications sent to the IRB. 
9.4 
Privacy 
9.4.1 Subject Identifiers 
To ensure subject anonymity and to limit disclosure, subjects will be assigned a unique subject 
identifier at their first assessment. This subject identifier will be cross-referenced in the subject’s 
chart. The subject identifier will not contain any potentially identifiable information. A subject 
identifier log will be maintained, by the investigator, linking each subject’s name to the 
corresponding subject identifier. 
9.4.2 Purpose of Collecting Personal Information and Use 
The purpose of collecting personal information from subjects (including health and medical 
information) during this study is for scientific research and/or as supportive evidence for drug-
related submissions to regulatory authorities, in compliance with legal or regulatory 
requirements. 
By signing the study protocol, the investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by Trevi Therapeutics. If necessary, the authorities will 
be notified of the investigator’s name, address, qualifications, and extent of involvement. 
9.4.3 Access and Disclosure of Personal Information 
The knowledge gained through this study is the property of Trevi Therapeutics, Inc.. The 
sponsor, representatives and affiliated companies of the sponsor, the IRB, Health Canada, and 
other regulatory agencies (such as the United States Food and Drug Administration) may inspect 
subject medical records related to the study to check the validity and accuracy of the data 


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gathered in this study. Subject names will not be supplied to the Sponsor. Only the subject 
number and subject initials will be recorded in the CRF (unless not allowed by local regulations), 
and if the subject name appears on any other document (eg, laboratory report), it must be 
obliterated before a copy of the document is supplied to the sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The subject will be told 
that representatives of the sponsor, IRB/IEC, or regulatory authorities may inspect their medical 
records to verify the information collected and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws.  
With the agreement of the subject, the investigator may inform the subject’s primary care 
physician about his or her participation in the study and will forward any clinically significant 
findings from clinical tests such as ECGs and laboratory tests. The primary care physician may 
contact the investigator for any further information regarding the subject’s participation in the 
study. The subject has the right to request access to and request corrections of his or her medical 
record. 
9.4.4 Release of Subject Information 
The results of this study will be reported in such a manner that subjects will not be identifiable in 
any way. Published reports or presentations will refer to grouped data or coded individual data 
and not to any identifiable individuals. Study reports sent to the sponsor or drug regulatory 
agencies (eg, Health Canada) will not include subject names. 
9.4.5 Consent for Collection, Access, Use and Disclosure of Subject Information 
By signing the ICF, the subject consents to the collection, access, use, and disclosure of his or her 
information as described in the ICF document. If a subject withdraws consent, some of the 
subject’s information may still be collected, used, and disclosed by those involved in this study 
per applicable laws. 
9.5 
Study Monitoring 
9.5.1 Study Monitoring by Sponsor and/or Third Party Monitor 
The study will be monitored by Trevi Therapeutics or its designee. Monitoring and auditing 
procedures will be conducted in accordance with applicable regulations, GCP guidelines, the 
study monitoring plan, and sponsor procedures.  
In addition, the investigator will permit inspection of the study files by authorized representatives 
of Trevi Therapeutics or the regulatory agencies. Domestic and foreign regulatory authorities, the 
IRB/IEC, and an auditor authorized by the sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities. Medical records and other study documents may be copied during audit or 
inspection provided that patient names are obliterated on the copies to ensure confidentiality. 


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Throughout the course of the study, the study monitor will make frequent contact with the 
investigator. This will include telephone calls and on-site visits. The investigator or designee will 
ensure that the study monitor has access to the on-site study documentation and medical records 
for the duration of the study. 
During the on-site visits, the CRF will be reviewed for completeness and adherence to the 
protocol. The study monitor will also perform drug accountability checks and perform a review 
of the regulatory records to ensure completeness of documentation. 
Activities to be completed during the monitoring visits include, but are not limited to, the 
following: 
 Check and assess the progress of the study 
 Review study data collected 
 Conduct source document verification  
 Identify any issues and address their resolution 
This will be done in order to verify that 
 The data are authentic, accurate, and complete;  
 The safety and rights of subjects are being protected; and 
 The study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate the investigator’s time and/or time of research site staff to the monitor to discuss 
findings and any relevant issues. 
In addition to contact during the study, the monitor will also contact the site prior to the start of 
the study to discuss the protocol and data collection procedures with research site personnel. 
At study closure, monitors will also conduct all activities as indicated in Section 9.8, Study and 
Site Closure. 
9.6 
Principal Investigator’s Data Responsibility 
The completed CRFs will be reviewed against source documents by the monitor at each 
monitoring visit. If any data, signatures, or forms are missing or incorrect, the investigator or 
designee will be informed and corrections will be made. Case report forms will be collected from 
the study site at the termination of the study after all monitoring visits and data queries are 
completed. 
9.7 
Data Quality Assurance 
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study center; the review of protocol procedures with the 
investigator and associated study personnel prior to study start; the use of suitable source 


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documents, as well as periodic site monitoring by the sponsor. Written instructions will be 
provided for the collection, preparation, and shipment of blood, plasma, and urine samples. The 
sponsor or designee will review source documents for accuracy and completeness during on-site 
monitoring visits and after their return to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. The data will be entered into the clinical study database 
and any queries will be resolved by site staff. 
9.8 
Study and Site Closure 
Upon completion of the study, the following activities, when applicable, will be conducted by the 
study monitor, in conjunction with the investigator or designee, as appropriate: 
 Return of all study data to the sponsor 
 Data clarifications or resolutions 
 Accounting, reconciliation, and final disposition of used and unused study drugs and 
emergency code break envelopes 
 Review of site study records for completeness 
 Return of treatment codes to the sponsor  
In addition, the sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason. If such action is taken, the sponsor will discuss this with 
the investigator (including the reasons for taking such action) at that time. The sponsor will 
promptly inform any other investigators and/or institutions conducting the study if the study is 
suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the investigator will promptly inform the IRB and provide the study subjects with 
the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data will be returned to the sponsor. In 
addition, the site will conduct final disposition of all unused study drugs in accordance with the 
sponsor’s procedures for the study. 
9.9 
Records Retention 
Following closure of the study, the investigator will maintain a copy of all site study records in 
their original format in a safe and secure location in accordance with applicable regulatory 
requirements (for 25 years in Canada).  
Essential documents include: 
 Signed informed consent documents for all subjects 
 Subject identification code list, screening log (if applicable), and enrollment log 
 Record of all communications between the investigator and the IRB 
 Copies of CRFs and of documentation of corrections for all subjects 
 Investigational product accountability records 


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 All other source documents (subject medical records, hospital records, laboratory records, 
etc.) 
 All other documents as listed in Section 8 of the ICH E6 Guideline for Good Clinical 
Practice (Essential Documents for the Conduct of a Clinical Trial) 
Normally, these records will be held in the investigator’s archives. If the investigator is unable to 
meet this obligation, he or she will ask the sponsor for permission to make alternative 
arrangements. Details of these arrangements will be documented. 


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10. 
REFERENCES 
 
1 
Investigator Brochure for Nalbuphine Hydrochloride Extended-Release Tablets, 9th ed., 
Apr-2018. 
2 
U.S. Department of Justice, Drug Enforcement Administration, Office of Diversion 
Control, Drug & Chemical Evaluation Section, Nalbuphine Hydrochloride (Trade Name: 
Nubain®). Aug-2013. Access on 12-Dec-2015. Available at: 
http://www.deadiversion.usdoj.gov/drug_chem_info/nalbuphine.pdf. 
3 
U.S. Department of Justice, Drug Enforcement Administration, Office of Diversion 
Control, Drug & Chemical Evaluation Section, Lists of: Scheduling Actions Controlled 
Substances Regulated Chemicals. Nov-2015. Accessed on 12-Dec-2015. Available at: 
http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf 
4 
Canadian Controlled Drugs and Substances Act, Minister of Justice, last amended 16-Jul-
2015. Accessed on 26-Feb-2018. Available at: http://laws.justice.gc.ca/PDF/C-38.8.pdf. 
5 
Zacny, JP, Conley K, and Marks S. Comparing the subjective, psychomotor and 
physiological effects of intravenous nalbuphine and morphine in healthy volunteers. 
JPET 1997;280:1159–1169. 
6 
Jasinski DR, Mansky PA. Evaluation of nalbuphine for abuse potential. Clin Pharmacol 
Ther. 1972;13(1):78-90. 
7  
Hawi A, Alcorn Jr H, Berg J, Hines C, Hait H and Sciascia T. Pharmacokinetics of 
nalbuphine hydrochloride extended release tablets in hemodialysis patients with 
exploratory effect on pruritus. BMC Nephrol. 2015;16:47. 
8 
U.S. Department of Health and Human Services. Food and Drug Administration. Center 
for Drug Evaluation and Research. Guidance for Industry: Assessment of Abuse Potential 
of Drugs. January 2017. 
9 
Balster RL, Bigelow GE. Guidelines and methodological reviews concerning drug abuse 
liability assessment. Drug Alcohol Depend. 2003;70(3 Suppl):S13–40. 
10  
Walsh SL, Nuzzoa PA, Lofwall MR, Holtman Jr JR. The relative abuse liability of oral 
oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. 
Drug Alcohol Depend 2008;98:191–202. 
11  
Shram MJ, Sathyan G, Khanna S, Tudor IC, Nath R, Thipphawong J, Sellers EM. 
Evaluation of the abuse potential of extended release hydromorphone versus immediate 
release hydromorphone. J Clin Psychopharmacol 2010;30(1):25-33. 
12  
Bigelow GE. Human drug abuse liability assessment: opioids and analgesics. Br J Addict. 
1991;86:1615-1628 
 


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13 
U.S. Department of Health and Human Services.  Food and Drug Administration.  Center 
for Drug Evaluation and Research. Guidance for Industry: Abuse-Deterrent Opioids: 
Evaluation and Labeling. April 2015.  
14 
Eaton TA, Comer SD, Revicki DA, Trudeau JJ, van Inwegen RG, Stauffer JW, Katz NP. 
Determining the clinically important difference in visual analog scale scores in abuse 
liability studies evaluating novel opioid formulations. Qual Life Res. 2012;21(6):975-81.  
15 
NHYDROmorphone (hydromorphone hydrochloride injection USP) Prescribing 
Information. Sandoz Canada Inc. 08 Mar 2018. Available at: 
https://pdf.hres.ca/dpd_pm/00016264.pdf 
16 
DILAUDID® (hydromorphone hydrochloride) oral solution and tablet. Prescribing 
Information. Purdue Pharma LP. Dec 2016. Accessed at: 
http://app.purduepharma.com/xmlpublishing/pi.aspx?id=dt 
17 
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new 
rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13(3):293–308. 
18  
Stoops WW, Glaser PEA, Rush CR. Miotic and Subject-Rated Effects of Therapeutic 
Doses of Tapentadol, Tramadol and Hydromorphone in Occasional Opioid Users. 
Psychopharmacology (Berl). 2013 July;228(2): 255–262. 
19 
Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. 
Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma 
concentrations. Anesthesiology. 1998;88(1):82–8. 
20 
Kaplan HL. Representation of on-line questionnaires in an editable, auditable database. 
Behaviour Research Models, Instruments & Computers. 1992;24:373–84. 
21 
Sternberg, S. High-speed scanning in human memory. Science. 1966;153(3736):652–4. 
22 
Schoedel KA, Sellers EM.Assessing abuse liability during drug development: changing 
standards and expectations. Clin Pharmacol Ther. 2008 Apr;83(4):622-6. doi: 
10.1038/sj.clpt.6100492. Epub 2008 Jan 23. 
23 
Griffiths RR, Bigelow GE, Ator NA. Principles of initial experimental drug abuse 
liability assessment in humans. Drug Alcohol Depend. 2003 Jun 5;70(3 Suppl):S41-54. 
24  
Chen L. An Overview of Regulatory Recommendations for Statistical Approaches to 
Evaluate Human Abuse Potential Study Data. Presented: Meeting on the Advancement in 
Abuse Potential Assessments – Building on the FDA Draft Guidance for Industry. 
Organized by the Cross Company Abuse Liability Council (CCALC), North Bethesda, 
MD, April 16-17, 2015. 
25  
Chen L, Tsong Y. Design and Analysis for Drug Abuse Potential Studies: Issues and 
Strategies for Implementing a Crossover Design. DIA Journal 2007; 41: 481-9. 
 


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26  
Schoedel K, Shram M, Levy-Cooperman N et al. Defining clinically important 
differences in subjective abuse potential measures. Presented: 74th Annual Meeting of the 
College on Problems of Drug Dependence, Palm Springs, CA, 2012. 
27  
Eaton TA, Comer SD, Revicki DA, Trudeau JJ, van Inwegen RG, Stauffer JW et al. 
Determining the clinically important difference in visual analog scale scores in abuse 
liability studies evaluating novel opioid formulations. Qual Life Res. 2012 Aug; 
21(6):975–981. 
28  
Chen L, Bonson K. An equivalence test for the comparison between a test drug and 
placebo in human abuse potential studies. J Biopharm Stat. 2013; 23:294-306. 
29.  
Sun P. Using Proc Power To Perform Model-Based Power Analysis For Clinical 
Pharmacology Studies. PharmaSUG2010 – Paper SP05. 
 


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11. 
APPENDICES 
11.1 Amount of Blood Drawn per Study Visit: Dose Selection Study (Part A) 
 
Pharmacokinetic 
Sampling 
Safety 
Total 
Clinical 
Chemistry 
Hematology 
Serology 
Blood Volume (mL) [Number of Samples] 
Approximate 
volume per 
sample (mL) 
2 mL 
5 mL 
4 mL 
5 mL 
 
Screening 
 
5 [1] 
4 [1] 
5 [1] 
14 [3] 
Dose Selection 
Phase  
 
 
 
 
 
Males 
2 [15] 
5 [1] 
4 [1] 
 
39 [17] 
Females 
2 [15] 
10 [2] 
4 [1] 
 
44 [18] 
Total 
 
 
 
 
 
Males 
30 [15] 
10 [2] 
8 [2] 
5 [1] 
53 [20] 
Females 
30 [15] 
15 [3] 
8 [2] 
5 [1] 
58 [21] 
Blood volumes shown in the table are approximate. Additional blood samples may be taken if needed to follow-up on 
individual subject safety. 


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11.2 Amount of Blood Drawn per Study Visit: Main Study (Part B) 
 
Pharmacokinetic 
Sampling 
Safety 
Total 
Clinical 
Chemistry 
Hematology 
Serology 
Blood Volume (mL) [Number of Samples] 
Approximate 
volume per 
sample (mL) 
2 mL 
5 mL 
4 mL 
5 mL 
 
Screening 
 
5 [1] 
4 [1] 
5 [1] 
14 [3] 
Qualification 
Phase 
 
 
 
 
 
Day -1 
(Females only) 
 
5 [1] 
 
 
5 [1] 
Treatment Period  
1 
2 [16] 
5 [1] 
4 [1] 
 
41 [18] 
2 
2 [16] 
5 [1] 
4 [1] 
 
41 [18] 
3 
2 [16] 
5 [1] 
4 [1] 
 
41 [18] 
4 
2 [16] 
5 [1] 
4 [1] 
 
41 [18] 
5 
2 [16] 
5 [1] 
4 [1] 
 
41 [18] 
6 
2 [16] 
5 [1] 
4 [1] 
 
41 [18] 
7 
2 [16] 
5 [1] 
4 [1] 
 
41 [18] 
Follow-up 
 
5 [1] 
4 [1] 
 
9 [2] 
Total 
 
 
 
 
 
Males 
224 [112] 
45 [9] 
36 [9] 
5 [1] 
310 [131] 
Females 
224 [112] 
50 [10] 
36 [9] 
5 [1] 
315 [132] 
Blood volumes are approximate. Additional blood samples may be taken if needed to follow-up on subject safety. 


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11.3 Clinical Opiate Withdrawal Scale 
The COWS will be used to record the signs and symptoms of withdrawal observed in Step 1 and 
Step 2 of the naloxone challenge test (Section 4.4). 
The scores for each item are added to obtain the total score. 
Subject Number: 
Date/Time:  
INSTRUCTIONS: For each item, circle the number that best describes the subject’s signs or symptom. Rate on just the apparent relationship to 
opiate withdrawal. Add the numbers for each item to obtain the total score. 
 
Signs 
Measures 
1 
Resting Pulse Rate:  
     ________ beats/min 
Measured after subject is sitting or lying for 1 minute 
0 pulse rate 80 or below 
1 pulse rate 81–100 
2 pulse rate 101–120 
4 
pulse rate greater than 120 
2 
Sweating 
Over past ½ hour not accounted for by room temperature or subject 
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 
3 
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 
4 
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 
5 
Bone or joint aches 
If subject was having pain previously, only the additional component 
attributed to opiates withdrawal is scored 
0 
not present 
1 
mild diffuse discomfort 
2 
subject reports severe diffuse aching of joints/muscles 
4 
subject is rubbing joints or muscles and is unable to sit still 
because of discomfort 
6 
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 
7 
GI upset 
Over ½ hour 


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Subject Number: 
Date/Time:  
INSTRUCTIONS: For each item, circle the number that best describes the subject’s signs or symptom. Rate on just the apparent relationship to 
opiate withdrawal. Add the numbers for each item to obtain the total score. 
 
Signs 
Measures 
0 
no GI symptoms 
1 
stomach cramps 
2 
nausea or loose stool 
3 
vomiting or diarrhoea 
5 
multiple episodes of diarrhoea or vomiting 
8 
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 
9 
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 
 
10 
Anxiety or irritability 
0 
none 
1 
subject reports increasing irritability or anxiousness 
2 
subject obviously irritable or anxious 
4 
subject so irritable or anxious that participation in the assessment 
is difficult 
11 
Gooseflesh skin 
0 
skin is smooth 
3 
piloerection of skin can be felt or hairs standing up on arms 
5 
prominent piloerection 
Total Score: 
 
Initials of individual completing assessment:  
 
 
 
 


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12. 
PROTOCOL AMENDMENTS 
12.1 Protocol Amendment 1 
The protocol was amended based on feedback from Health Canada to include contraception use 
for male subjects and modify the dose escalation stopping rule for QTc prolongation criteria 
compared to baseline. Minor clarifications were also incorporated into the protocol.  
Details of all changes following feedback from Health Canada and the rationale are provided 
below: 
 Section 4.2, Inclusion Criterion #4: added paragraph for contraception use by male 
subjects. Subjects must be using and willing to continue using medically acceptable 
contraception from Screening and for at least 1 month after the last study drug 
administration. 
 Section 4.6.2 Contraception Precautions: added examples of medically acceptable forms 
of contraception to include true abstinence, vasectomy, or male condom for subjects plus 
an additional method of contraception for their female partners. 
 Section 4.8, Subject Discontinuation/Stopping Rules: bullet for QTc prolongation 
criterion was modified from >70 ms above the baseline to >60 ms above the baseline as 
suggested in the ICH E14 guideline as a commonly used threshold. 
Details of the minor clarifications incorporated into the protocol and the rationale are provided 
below: 
 Section 3.1.7, Table 3 Part B Time and Events Schedule: Treatment Phase and Follow-
Up: Corrected footnote “c” to include urine pregnancy test at admission to Treatment 
Period 6 and add serum pregnancy test to Treatment Period 7. Revised footnote text: 
“serum pregnancy at Treatment periods 1 and 7 only; urine pregnancy at Treatment 
periods 2, 3, 4, 5, and 6.” 
 Section 4.8, Subject Discontinuation/Stopping Rules: clarified the timing of positive 
breath alcohol test results in which a subject may be rescheduled at the discretion of the 
investigator or designee. The following text “at Screening or admission to any visit” was 
added to the sentence: “Subjects with a positive result at Screening or admission to any 
visit may be rescheduled at the discretion of the investigator or designee.” 
 Section 5.2.5, Packaging and Labeling: corrected the number of tablets that will be 
packaged in HDPE bottles from 60 to 70 tablets. Updated protocol text: Nalbuphine ER 
tablets and matching placebo will be packaged in HDPE bottles with induction seal child-
resistant closures containing 70 tablets each. 


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12.2 Protocol Amendment 2 
The dose escalation scheme in Part A was amended to allow an incremental increase in the dose 
of nalbuphine based on a percentage of up to 50% from the last dose (rather than an absolute 
27 mg dose increase), if supported by the safety data of the preceding cohorts.  
The amendment is proposed based on the safety results of the first 4 cohorts indicating a lower 
than expected incidence of AEs and severity up to the 162 mg nalbuphine. Data indicated that -
unlike healthy subjects- nalbuphine is much better tolerated in the non-dependent recreational 
opioid population and that the dose-AE response was flat over the selected dose range. At the 
162 mg therapeutic dose (Cohort 4) only one Grade 2 AE was observed out of a total of 14 AEs. 
Subjects dosed at 81 mg had very mild AEs (2 out of 6 subjects had Grade 1 somnolence) with 
no nausea or vomiting compared to 5.9% in healthy subjects. Grade 1 vomiting and nausea were 
observed in one subject out of 6 at 135 mg while doubling the dose from 81 mg to 162 mg 
resulted in a single AE of Grade 2 nausea reported in one out of 6 drug treated subjects. This is 
in contrast to the observed incidence of vomiting (32%), nausea (41%) AEs in healthy subjects at 
the 162 mg dose. There was no effect on oxygen saturation (spO2 > 95%), ECG parameters, or 
any other vital signs over 24 hours post-dose in any individual subject up to 162 mg dose.   
In view of the “flat” dose-response observed in this subject population, the protocol was 
amended to allow an incremental increase in the dose of nalbuphine based on a percentage of up 
to 50% from the previous dose (rather than an absolute 27 mg dose increase). The 50% increase 
was selected to ensure a sufficient differentiation between the doses while keeping in perspective 
the potential safety of the subjects as the doses are escalated to the higher doses. Given the high 
inter-subject variability of 54% in nalbuphine plasma Cmax and 46% in AUC, a 50% increase 
seemed further justified. 
In addition, an option to use both PK and safety data to identify the MSD was included to reduce 
the potential unnecessary exposure to escalating doses of study drug in the study population. 
Nalbuphine exposure increases with increasing dose in a proportional fashion over the 27 mg to 
162 mg doses, the highest tested dose in healthy subjects. On the other hand, PK in the uremic 
pruritus subjects on hemodialysis indicated a plateau in exposure when the dose was increased 
from 162 mg to 216 mg (mean Cmax = 83 ng/mL and AUC=761 h∙ng/mL compared to 80 ng/mL 
and 770 h∙ng/mL, respectively) (Study TR01). Therefore it would be reasonable to assume that 
as doses of nalbuphine increase, the exposure in the current otherwise healthy subjects would 
also start to deviate from proportionality and/or plateau at doses higher than 162 mg. If this were 
to be the case, then further increases in doses would not be expected to have a significant impact 
on the safety or tolerability of the drug.  
Thus the option to review the PK data to determine if a plateau in the exposure of nalbuphine is 
reached despite dose escalation was added in Section 4.9.2. Dose Escalation and Stopping Rules. 
If a plateau is observed in the PK data, the MSD will be identified based on the available safety 
and PK exposure data. This option is intended to reduce the potential unnecessary exposure to 
escalating doses of study drug in the study population. 
The proposed amendment for the dose escalation will involve at least a Cohort 5 at a dose of 
243 mg dose (1.5 × 162 mg). As per the amended protocol, the option to dose additional cohorts 
may be considered proposed if the stopping rules in Section 4.9.2 are not met in Cohort 5.  


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Typically, human abuse liability studies evaluate the highest proposed therapeutic dose of the test 
drug as well as doses that are multiples of the highest proposed therapeutic dose (usually 2-3 
times greater, if this can be done safely) in comparison to a positive control(s) and placebo. Our 
intent is to increase the dose until a 2- to 3-fold the therapeutic dose is reached assuming the dose 
stopping rules are not met. Doses are not to exceed 486 mg (3-fold the therapeutic dose). 
Figure 1 and Table 5 have been updated accordingly in the protocol to clarify the planned dose 
escalation scheme. 
Additional protocol clarifications were also added regarding urine drug screens, the statistical 
analyses of the PD data in Part B, and data listings of the C-SSRS. 
Details of all changes to the protocol and the rationale are provided below: 
 Section 3.1.2, Dose Selection Study (Part A), modified text to indicate that at least 
5 cohorts are planned and doses may escalate in an amount up to 50% of the dose 
administered in the previous cohort, as deemed appropriate by the safety and tolerability 
data. Additional cohorts may be added if a dose higher than those planned is required to 
be tested based on supportive safety data. Added that the doses of nalbuphine solution 
tested are not to exceed 486 mg (ie, 3-fold the therapeutic dose). If the DRC observes a 
plateau in the incidence and severity of AEs, which do not meet the stopping criteria 
described in Section 4.9, then the PK data may be reviewed to determine if there is a 
plateau in the exposure of nalbuphine despite dose escalation. The changes in dose 
escalation procedures were added based on the preliminary safety data observed in the 
initial cohorts enrolled in Part A. 
 Figure 1, Study Schematic for Part A (Dose Selection Study), footnote, indicated that a 
dose higher than planned may be required to be tested based on supportive safety data. 
The higher dose selected may be up to 50% greater than the dose administered in the 
previous cohort based on supportive safety data. 
 Section 4.1, Number of Subjects, indicated that additional cohorts may be added in Part A 
if a dose higher than those planned is also required to be tested based on supportive safety 
data. 
 Section 4.8, Subject Discontinuation/Stopping Criteria, urine drug screen results 
exclusions were modified to current standards at the CRU for the recreational drug user 
population as described in the note-to-file entitled Urine Drug Testing and Positive THC - 
Directive for Interpretation and Eligibility Considerations for Non-Dependent 
Recreational Drug Users dated 17-Jul-2018. 
 Section 4.9.2, Dose Escalation and Stopping Rules, modified the criterion for vomiting 
from “Grade 2 or higher” to “any episode” of vomiting within the 4-hour post-dose 
interval. The change was implemented to indicate that any vomiting episode will be 
considered as a signal of possible intolerance during the safety data review by the DRC. 
In addition, added an option to use both PK and safety data to identify the MSD. If the 
DRC observe a plateau in the incidence and severity of AEs, which do not meet the 
stopping criteria described in this section, then the PK data may be reviewed to determine 
if there is a plateau in the exposure of nalbuphine despite dose escalation. If a plateau is 
observed in the PK data, the MSD will be identified based on the available safety and PK 


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exposure data. This option is intended to reduce the potential unnecessary exposure to 
escalating doses of study drug in the study population. 
Specified that the doses of nalbuphine solution will not exceed 486 mg, which 
corresponds to 3-fold the therapeutic dose 
 Section 5.1.1, Dose Selection Phase (Part A), clarified in the text and the footnote of 
Table 5 that the actual doses administered in each cohort may be adjusted (increased, 
decreased, or repeated) based on the evaluation of safety data obtained in previous 
cohorts. Additional cohorts of subjects may be added to those planned (Table 5) until the 
MSD is identified. Higher doses can be up to 50% greater (but not to exceed 486 mg) 
than the dose administered in the previous cohort based on supporting safety data.  
 Section 5.4.1, Nalbuphine Dose Selection, clarified that the proposed doses may be 
reduced or escalated by 27 mg increments (equivalent to 30 mg increments of the HCl 
salt) or up to 50% greater than the dose administered in the previous cohort as described 
in Section 5.1.1. 
 Section 8.1.3, Planned Analyses of the Primary and Secondary Pharmacodynamic 
Assessments (Part B), parameters will be analyzed under the assumption of a normal 
distribution if the P value of the test is ≥ 0.01 (modified from P value ≥ 0.05). In cases 
where the normality of the distribution of the residuals is not satisfied and the Shapiro-
Wilk W-test is applied, a paired t-test will be used if the P value is ≥ 0.01 (modified from 
P value ≥ 0.05) and the skewness = -1 to 1 (modified from -0.5 to 0.5). The change 
reflects current standards established at the CRU based on scientific conferences attended 
by the FDA. In addition, in the second-to-last paragraph, the first sentence had been 
included in error and was corrected to indicate that a P value of 0.05 will be used to 
denote statistical significance for both one-sided and two-sided hypothesis tests.  
Inclusion criteria for Part B of the Qualification Phase include having a peak score (Emax) 
on the Drug Liking VAS greater than that of placebo by at least 15 points in response to 
12 mg hydromorphone. In order to assess the robustness of this 15-point difference, a 
sensitivity analysis was added to the planned analysis for the Treatment Phase to assess 
the null hypothesis that the mean difference in Drug Liking VAS Emax between the 
positive controls, hydromorphone 8 and 16 mg, and placebo is less than or equal to 15 
against the alternative hypothesis that the mean difference in Drug Liking VAS Emax 
between hydromorphone and placebo is greater than 15. 
 Section 8.1.5, Analysis of Safety Assessments, clarified that the results from both the 
since last visit and baseline versions of the C-SSRS will be included in the data listings. 
On Page 2, the sponsor address zip code was corrected from 06150 to 06510. Minor formatting 
changes are not described. 

SAP_000.pdf: 
Statistical Analysis 
Plan 
Final Version 1.1 
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Protocol # TR08 
 
Syneos Health # 1008910 
 
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Sponsor Name: 
Trevi Therapeutics, Inc. 
Protocol Number and Title: 
 
TR08 
A Randomized, Double-Blind, Double-Dummy,  
Active- and Placebo-Controlled, Two-Part, 7-
Way Crossover Study to Evaluate the Oral 
Abuse Potential of Nalbuphine Solution and 
Extended-Release Intact Tablets Relative to 
Hydromorphone Solution and Placebo in Non-
Dependent, Recreational Opioid Users 
Protocol Version and Date: 
3.0, 13-Aug-2018  
2.0, 18-May-2018 
1.0, 09-Apr-2018 
Syneos Health Project 
Code: 
1008910 
Author: 
Philippa Rook, Biostatistician II 
SAP Version: 
Final 1.1 
SAP Version Date:  
08-Aug-2019 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Trevi Therapeutics, Inc. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Trevi Therapeutics, Inc. However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, Syneos Health should be notified 
promptly. 


Statistical Analysis 
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Revision History 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Draft 
Version 
0.3 
 
17Jul2018 
Philippa Rook 
Initial release version – draft version 
0.3 
Draft 
Version 
1.0 
 
14Aug2018 
Philippa Rook 
Updated draft version 1.0 
Final 
Version 
1.0 
24Aug2018 
Philippa Rook 
Final version 1.0 
Final 
Version 
1.1 
08Aug2019 
Philippa Rook 
Updated Final version 1.1 for the 
removal of Part B 
 
 


Statistical Analysis 
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I confirm that I have reviewed this document and agree with the content. 
APPROVALS 
Syneos Health 
 
 
 
Lead Biostatistician 
Philippa Rook 
Biostatistician II 
 
Date (dd-Mmm-yyyy) 
Senior Reviewing Biostatistician 
Georgia Gourgioti 
Manager, Biostatistics 
 
Date (dd-Mmm-yyyy) 
Lead Statistical Programmer 
Rohit Srivastava 
Associate Director, Statistical Programming 
 
 
Date (dd-Mmm-yyyy) 
Hiren Mehta 
Senior Pharmacokineticist, Pharmacokinetics 
 
Date (dd-Mmm-yyyy) 
 
 


Statistical Analysis 
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APPROVALS 
Trevi Therapeutics, Inc. 
 
 
 
Thomas Sciascia, MD 
Chief Medical Officer 
 
Date (dd-Mmm-yyyy) 
 
 


Statistical Analysis 
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TABLE OF CONTENTS 
CONTENTS 
REVISION HISTORY ................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................. 5 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................. 9 
2. 
PURPOSE ...................................................................................................... 12 
2.1. 
Responsibilities ................................................................................................................. 12 
2.2. 
Timings of Analyses .......................................................................................................... 12 
3. 
STUDY OBJECTIVES ................................................................................... 13 
3.1. 
Exploratory Objectives ...................................................................................................... 13 
3.2. 
Brief Description ................................................................................................................ 13 
3.3. 
Subject Selection ............................................................................................................... 15 
3.3.1. 
Inclusion Criteria ......................................................................................................... 15 
3.3.2. 
Exclusion Criteria ........................................................................................................ 16 
3.3.3. 
Naloxone Challenge .................................................................................................... 18 
3.4. 
Determination of Sample Size .......................................................................................... 19 
3.5. 
Treatment Assignment & Blinding ................................................................................... 19 
3.6. 
Administration of Study Medication ................................................................................ 20 
3.7. 
Study Procedures and Flowchart ..................................................................................... 23 
4. 
ENDPOINTS .................................................................................................. 29 
4.1.1. 
Pharmacokinetic Endpoints ......................................................................................... 29 
4.1.2. 
Safety Endpoints ......................................................................................................... 29 
4.1.3. 
Exploratory Endpoints ................................................................................................. 29 
5. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................. 31 


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6. 
ANALYSIS POPULATIONS .......................................................................... 32 
6.1. 
Dose Selection Randomized Population ......................................................................... 32 
6.2. 
Dose Selection Safety Population .................................................................................... 32 
6.3. 
Dose Selection PK Population ......................................................................................... 32 
6.4. 
Protocol Deviations ........................................................................................................... 32 
7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 33 
7.1. 
General Methods ................................................................................................................ 33 
7.2. 
Key Definitions ................................................................................................................... 33 
7.3. 
Missing Data ....................................................................................................................... 34 
7.4. 
Visit Windows ..................................................................................................................... 36 
7.4.1. 
Pharmacodynamic (PD) Assessments ....................................................................... 36 
7.4.2. 
Pharmacokinetic (PK) Sample Collection ................................................................... 36 
7.5. 
Pooling of Centers ............................................................................................................. 36 
7.6. 
Subgroups .......................................................................................................................... 36 
8. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION................................................................................................. 37 
8.1. 
Subject Disposition and Withdrawals .............................................................................. 37 
8.2. 
Demographic and Other Baseline Characteristics ......................................................... 37 
8.3. 
Other Baseline Characteristics ........................................................................................ 37 
8.3.1. 
Recreational Drug and Alcohol Use History ................................................................ 37 
8.3.2. 
Nicotine Use ................................................................................................................ 38 
8.4. 
Medical History .................................................................................................................. 38 
8.5. 
Prior and Concomitant Medication .................................................................................. 38 
9. 
PHARMACODYNAMICS ASSESSMENTS AND ANALYSIS ....................... 40 
9.1. 
Pharmacodynamic Assessments ..................................................................................... 40 
9.1.1. 
Pupillometry................................................................................................................. 40 
9.1.2. 
Derived and Imputed Data .......................................................................................... 40 


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10. ANALYSIS OF PHARMACOKINETICS ........................................................ 42 
10.1. 
Measurements .................................................................................................................... 42 
10.2. 
PK Sampling Schedule ...................................................................................................... 42 
10.3. 
Derived and Imputed Data ................................................................................................ 42 
10.4. 
Handling of Missing Data .................................................................................................. 43 
10.5. 
Data Summarization and Presentation ............................................................................ 43 
11. SAFETY ......................................................................................................... 45 
11.1. 
Extent of Exposure ............................................................................................................ 45 
11.2. 
Treatment Compliance ...................................................................................................... 45 
11.3. 
Adverse Events / Adverse Drug Reactions ..................................................................... 45 
11.4. 
Laboratory Evaluations ..................................................................................................... 45 
11.5. 
Vital Signs ........................................................................................................................... 47 
11.6. 
ECG ..................................................................................................................................... 47 
11.7. 
Physical Examination ........................................................................................................ 47 
11.8. 
Other Safety ........................................................................................................................ 48 
11.9. 
Interim Analyses ................................................................................................................ 48 
12. REFERENCE LIST ........................................................................................ 49 
13. PROGRAMMING CONSIDERATIONS .......................................................... 50 
13.1. 
General Considerations .................................................................................................... 50 
13.2. 
Table, Listing, and Figure Format .................................................................................... 50 
13.2.1. 
General ........................................................................................................................ 50 
13.2.2. 
Headers ....................................................................................................................... 50 
13.2.3. 
Display Titles ............................................................................................................... 51 
13.2.4. 
Column Headers ......................................................................................................... 51 
13.2.5. 
Body of the Data Display ............................................................................................. 51 
13.2.6. 
Footnotes .................................................................................................................... 54 
14. QUALITY CONTROL ..................................................................................... 55 


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15. INDEX OF TABLES ....................................................................................... 56 
16. INDEX OF LISTINGS ..................................................................................... 58 
17. INDEX OF FIGURES ..................................................................................... 60 
18. APPENDICES ................................................................................................ 61 
19. MOCK-UPS .................................................................................................... 65 
 
 
 
 
 
 
 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUCinf 
Area Under the Plasma Concentration versus -Time Curve from 
Time 0 Extrapolated to Infinity 
AUClast 
Area Under the Plasma Concentration versus -Time Curve from 
Time 0 to the last measurable concentration 
AUE 
Area Under the Effect curve 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CL/F 
Apparent Clearance 
CM 
Concomitant Medication 
Cmax 
Maximum Observed Plasma Concentration 
COWS 
Clinical Opiate Withdrawal Scale 
CRF or eCRF 
Case Report Form or electronic Case Report Form 
CRU 
Clinical Research Unit 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
DAT 
Divided Attention Test 
DRC 
Data Review Committee 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders - Fourth 
Edition – Text Revision 
DSST 
Digit Symbol Substitution Test 
ECG 
Electrocardiogram 
Emax 
Maximum (peak) Effect 
Emin 
Minimum (peak) Effect 
ER 
Extended-Release 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 


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Abbreviation 
Description 
HAP 
Human Abuse Potential 
HCl 
Hydrochloride 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
IQR 
Inter-Quartile Range 
IV 
Intravenous 
kel 
First-Order Elimination Rate Constant Associated with the 
Terminal (Log-Linear) Portion of the Curve 
LNH 
Low/Normal/High (classification) 
LLOQ 
Lower Limit of Quantification 
LSM 
Least Square Mean 
MSD 
Maximum Safe Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPC 
Maximum Pupil Constriction 
NA 
Not Applicable 
NCE 
New Chemical Entity 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
Q1 
1st Quartile or 25th Percentile 
Q3 
3rd Quartile or 75th Percentile 
QTcB 
QT Interval Corrected by Bazett Formula 
QTcF 
QT Interval Corrected by Fridericia Formula 
RBC 
Red Blood Cell 
RMS 
Root Mean Square 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard Deviation 
SE 
Standard Error 


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Abbreviation 
Description 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Oxygen Saturation 
SSTM 
Sternberg Short-Term Memory Test 
t1/2 
Terminal Elimination Half Life 
TBD 
To Be Determined 
tmax 
Time to Maximum Observed Plasma Concentration 
TA_AUE 
Time-Averaged Area Under the Effect Curve 
TA_PAOC 
Time-Averaged Pupillometry Area Over the Curve 
TEAE 
Treatment-Emergent Adverse Event 
TEmax 
Time to Maximum Effect 
TEmin 
Time to Minimum Effect 
TLF 
Table, Listing and Figure 
TMPC 
Time to MPC 
VAS 
Visual Analogue Scale 
Vd/F 
Apparent Volume of Distribution 
WBC 
White Blood Cell (count) 
WHO-DD 
World Health Organization- Drug Dictionary 


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2. 
PURPOSE 
The purpose of this Statistical Analysis Plan (SAP) is to ensure that the data listings, 
summary tables and figures that will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. 
2.1. 
RESPONSIBILITIES 
The Syneos Health biostatistics team will perform the statistical analyses and is 
responsible for developing the randomization plan, randomization schedule, and 
statistical analysis plan (SAP) including table, listing and figure (TLF) shells, quality 
control plan as well as the production and quality control of all TLFs, including results 
for the safety, pharmacodynamics (PD) and pharmacokinetics (PK) endpoints. 
Due to the unexpected closure of the investigational site following completion of Part 
A, but before commencement of Part B, the scope of this analysis plan is limited to Part 
A only (see Section 5). While the study Protocol provides full documentation of the plan 
for Part B undertaking, no reference to Part B in this SAP will be included. In addition, 
any exclusion to specific reference to Part A implies that the proposed methods are 
applicable to Part A, i.e., specifically referring to Part A hereon in is redundant. In 
addition, the use of the term “Dose Selection Phase” and “Part A” are interchangeable. 
2.2. 
TIMINGS OF ANALYSES 
The primary analysis of safety, PD and PK will be conducted after all subjects complete 
the final study visit or terminate early from the study and after the database is locked. 
No interim analysis is planned for this study. 


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3. 
STUDY OBJECTIVES 
3.1. 
EXPLORATORY OBJECTIVES 
The exploratory objectives that will be evaluated in the Dose Selection Phase (referred 
to as Part A in the Protocol) are the following: 
 
To assess the safety and tolerability of various doses of orally-administered 
nalbuphine solution and determine the maximum safe dose (MSD) in non-
dependent, recreational opioid users. 
 
To assess the PK and pharmacodynamics (PD; pupillometry) of various doses of 
orally-administered nalbuphine solution in non-dependent, recreational opioid 
users. 
3.2. 
BRIEF DESCRIPTION 
This study will be a single-dose, randomized, double-blind, active- and placebo-
controlled, double-dummy, 2-part, 7-way crossover study. The abuse potential of orally 
administered nalbuphine solution and nalbuphine ER intact tablets will be assessed 
relative to that of hydromorphone solution and placebo, in non-dependent, recreational 
opioid users. The study will be conducted in a single clinical research unit (CRU). 
The study is limited to Part A (Dose Selection Phase) as described in the Protocol. The 
purpose will be to conduct an exploratory dose selection phase to identify the 
appropriate low, intermediate, and high doses of nalbuphine solution administered as 
single doses in the Treatment Phase of the eventual planned Main Study (Part B). 
Part A will be a randomized, double-blind, placebo-controlled dose escalation study and 
will include the following:  
o Screening (Visit 1) 
o Dose Selection Phase (naloxone challenge and dose selection) (3 days/2 
nights; Visit 2). 
Screening will be an outpatient visit during which informed consent will be obtained and 
screening assessments will be completed, including a review of medical history and 
recreational drug use history against inclusion and exclusion criteria to determine 
subject eligibility for the study.  
The dose selection phase is a randomized, double-blind, placebo-controlled dose 
escalation to determine the MSD of nalbuphine. Within 30 days of Screening, eligible 
subjects will enter the Dose Selection Phase that will include 1) a naloxone challenge to 
confirm that subjects are not opioid dependent, and 2) a dose escalation scheme to 


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evaluate the safety and tolerability of single escalating oral doses of nalbuphine 
solution to non-dependent, recreational drug users. 
During the naloxone challenge, subjects will receive 0.2 mg of naloxone via an 
intravenous (IV) bolus followed by 0.6 mg naloxone IV if no withdrawal signs are 
observed. The Clinical Opiate Withdrawal Scale (COWS) will be administered to confirm 
non-dependence. Subjects with a COWS score of <5 will be eligible to continue 
participation in the Dose Selection Phase. 
At least 12 hours after completing the naloxone challenge, eligible subjects will receive 
a single oral dose of nalbuphine or placebo solution. At least 5 unique dosing cohorts are 
planned and the proposed single doses of nalbuphine solution will increase by at least 
27 mg increments or will increase in an amount up to 50% of the dose administered in 
the previous cohort, as deemed appropriate by the safety and tolerability data: e.g., 81 
mg, 108 mg, 135 mg, 162 mg, and 243 mg (corresponding to 90 mg, 120 mg, 150 mg, 
180 mg, and 270 mg of the hydrochloride (HCl) salt, respectively) or until an MSD is 
reached. There are 5 planned unique cohorts; however, additional cohorts of subjects 
may be added until the MSD is identified, or if additional data are required at a given 
dose level or at a dose intermediate to those specified, or if a dose higher than those 
planned is required to be tested, based on supporting safety data. Each cohort will 
enroll 8 subjects (6 active, 2 placebo). Subjects will participate in a single cohort and 
will receive single oral doses of nalbuphine or placebo.  
PK, PD (i.e., pupillometry) and safety assessments will be conducted pre-dose and up to 
24 hours post-dose or longer, at the discretion of the investigator or designee. Subjects 
will be discharged approximately 24 hours after drug administration, at the discretion of 
the investigator or designee. Following the completion of each cohort, safety data will 
be unblinded and reviewed by the Data Review Committee (DRC) to determine if dose 
escalation is required. PK and PD data may be unblinded for review if it is available in a 
timely manner but will not serve as the basis for determining dose escalation. 
The following treatments will be administered: 
o Treatment A: Placebo  
150 mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
o Treatment B: Hydromorphone HCl 8 mg solution 
4 mL × 2 mg/mL hydromorphone HCl + 146 mL flavored beverage +  
1 × nalbuphine matching placebo tablet 
o Treatment C: Hydromorphone HCl 16 mg solution 
8 mL × 2 mg/mL hydromorphone HCl + 142 mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
o Treatment D: Nalbuphine HCl low dose solution  
low dose nalbuphine HCl solution + TBD mL flavored beverage + 
1 × nalbuphine matching placebo tablet 


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o Treatment E: Nalbuphine HCl intermediate dose solution  
Intermediate dose nalbuphine HCl solution + TBD mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
o Treatment F: Nalbuphine HCl high dose solution  
high dose nalbuphine HCl solution + TBD mL flavored beverage + 
1 × nalbuphine matching placebo tablet 
 
Treatment G: Nalbuphine 162 mg ER intact tablet 
150 mL flavored beverage + 
1 × 162 mg nalbuphine ER tablet 
Subjects will be discharged approximately 24 hours after each drug administration 
(following completion of all post-dose procedures), at the discretion of the investigator 
or designee. 
The follow-up visit will be conducted approximately 7 to 14 days after the last drug 
administration in the treatment phase or at the time of early withdrawal from the study 
and will include standard safety assessments. 
An overview of the study design is shown in Error! Reference source not found.. Study 
assessments will be performed at the visits and time points outlined in the Time and 
Events Schedule (Table 2).  
3.3. 
SUBJECT SELECTION 
Approximately 5 cohorts of approximately 8 unique subjects per cohort is planned or 
until the MSD is identified. Additional cohorts may be added, at the sponsor's and 
investigator's discretion, if additional data at a dose level are needed or if a dose level, 
intermediate to those proposed, needs to be considered for safety or tolerability 
reasons, or a dose higher than those planned is required to be tested, based on 
supporting safety and tolerability data. 
3.3.1. 
Inclusion Criteria 
Subjects will be considered eligible to participate in this study if each one of the 
following inclusion criteria is satisfied at Screening: 
1. Healthy male or female subjects 18 to 55 years of age, inclusive. 
2. Body mass index (BMI) within the range of 18.0 to 33.0 kg/m2, inclusive, and a 
minimum weight of 50.0 kg. 
3. Current opioid users who have used opioids for recreational (non-therapeutic) 
purposes (i.e., for psychoactive effects) at least 10 times in the past year and 
used opioids at least once in the 8 weeks before Screening. 
4. Female subjects of childbearing potential with male sexual partners must be 
using and willing to continue using medically acceptable contraception (as 


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specified in Section 4.6.2 of the Protocol) for at least 1 month prior to Screening 
(at least 3 months for oral and transdermal contraceptives) and for at least 
1 month after last study drug administration. 
Female subjects of non-childbearing potential must meet the criteria specified 
in Section 4.6.2 of the Protocol. 
5. Male subjects with female sexual partners of childbearing potential must be 
using and willing to continue using medically acceptable contraception (as 
specified in Section 4.6.2 of the Protocol) from Screening and for at least 
1 month after the last study drug administration. 
6. Must provide written informed consent prior to the initiation of any Protocol-
specific procedures. 
3.3.2. 
Exclusion Criteria 
Subjects will not be considered eligible to participate in this study if any one of the 
following exclusion criteria is satisfied at Screening: 
1. Self-reported substance or alcohol dependence (excluding nicotine and caffeine) 
within the past 2 years, as defined by the Diagnostic and Statistical Manual of 
Mental Disorders - Fourth Edition – Text Revision (DSM-IV-TR), and/or has ever 
participated or plans to participate in a substance or alcohol rehabilitation 
program to treat their substance or alcohol dependence. 
2. Heavy smoker (≥ 20 cigarettes per day) and/or who is unable to abstain from 
smoking for at least 8 hours during the in-clinic periods. Unable to abstain from 
using other nicotine-containing products (e.g., gum, patch, e-cigarettes) during 
the in-clinic periods. 
3. History or presence of clinically significant abnormality as assessed by physical 
examination, medical history, electrocardiograms (ECGs), vital signs, or 
laboratory values, which in the opinion of the investigator would jeopardize the 
safety of the subject or the validity of the study results. 
4. History or presence of any clinically significant illness (e.g., cardiovascular, 
pulmonary, hepatic, renal, gastrointestinal, endocrine, immunologic, 
dermatologic, neurologic, oncologic, musculoskeletal, psychiatric) or any 
condition, which, in the opinion of the investigator or designee, would 
jeopardize the safety of the subject or the validity of the study results. 
5. History of major mental illness that in the opinion of the investigator may affect 
the ability of the subject to participate in the study. Institutionalized subjects 
will not be eligible for participation. 
6. Clinically significant infection/injury/illness within 1 month prior to Screening, 
as assessed by the investigator or designee. 


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7. Positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). 
8. Donation or loss of more than 500 mL whole blood within 30 days preceding 
entry into the Treatment Phase. 
9. Difficulty with venous access or unsuitable or unwilling to undergo catheter 
insertion. 
10. Female subjects who are currently pregnant (have a positive pregnancy test) or 
lactating or who are planning to become pregnant within 30 days of last study 
drug administration. 
11. History of severe allergic reaction (including anaphylaxis) to any substance, or 
previous status asthmaticus, or food allergies/intolerances/restrictions, or 
special dietary needs which, in the judgment of the investigator, contraindicates 
the subject’s participation in the study. 
12. History of allergy or hypersensitivity to hydromorphone, nalbuphine, or related 
drugs (e.g., other opioids) or naltrexone or related drugs (e.g., other 
antagonists) or to any known excipients (e.g., lactose).  
13. Subjects with any lifetime history of suicidal ideation or suicidal behavior, as 
assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS; baseline 
version). 
14. Documented history of, or currently active, seizure disorder or history of 
clinically significant head injury (including surgery) or syncope of unknown 
origin. 
15. Use of a prohibited medication, as specified in Section 4.6.1 of the Protocol. 
16. Treatment with an investigational drug within 5 times the elimination half-life 
(t1/2), if known (e.g., a marketed product) or within 30 days (if the elimination 
t1/2 is unknown) prior to first drug administration or is concurrently enrolled in 
any research, judged not to be scientifically or medically compatible with this 
study (exclusion is not applicable to subjects who participate in Part B after they 
have participated and received study drug in Part A of this study). 
17. An employee of the sponsor or research site personnel directly affiliated with 
this study or their immediate family member defined as a spouse, parent, child 
or sibling, whether biological or legally adopted. 
18. A subject who, in the opinion of the investigator or designee, is considered 
unsuitable or unlikely to comply with the study Protocol for any reason. 
19. Subject has current pending legal charges or is currently on probation based on 
self-report at Screening. 


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3.3.3. 
Naloxone Challenge  
Eligible subjects who meet Screening criteria will undergo a naloxone challenge test at 
least 12 hours prior to study drug administration. For female subjects, results of the 
urine pregnancy test will be required prior to the naloxone challenge; results of the 
serum pregnancy test will not be required prior to the naloxone challenge.  
Baseline vital signs and the COWS will be assessed before administration of the first 
naloxone dose. The naloxone doses selected for the challenge are consistent with doses 
commonly administered to confirm opioid non-dependence. 
The test will be administered as follows: 
Step 1: Naloxone 0.2 mg will be given via IV bolus followed by a 2 mL to 3 mL 
saline flush. The subject will be observed for 1 minute after the bolus 
administration for signs and symptoms of withdrawal using the COWS. 
Step 2: If the subject develops signs or symptoms of withdrawal following the 
first IV bolus (COWS score ≥5), the second bolus will not be administered and the 
subject will be medically managed.   
If there is no evidence of withdrawal after 1 minute (COWS score <5), a second 
IV bolus of naloxone 0.6 mg will be given within 5 minutes of the first 
administration, followed by a 2 mL to 3 mL saline flush. The subject will be 
observed and an additional COWS assessment will be conducted at 5 minutes 
after the second naloxone dose. Vital signs will be assessed at 10 minutes (± 5 
minutes) and 60 minutes (± 10 minutes) following the second naloxone dose. 
Additional COWS and/or vital sign assessments may be conducted if medically 
necessary. 
A sample form of the COWS is presented in Appendix 11.3 of the Protocol. 
Subjects who present with signs or symptoms of withdrawal following administration of 
the naloxone challenge (i.e., COWS score ≥5) will be excluded from the study and will 
not be eligible to participate in the Drug Discrimination Test. Subjects who develop 
signs or symptoms of withdrawal will be medically managed for at least 4 hours and will 
be discharged at the discretion of the investigator or medically qualified designee. 
 
 


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3.4. 
DETERMINATION OF SAMPLE SIZE 
Approximately 5 cohorts of 8 subjects in a ratio of 6:2 nalbuphine:placebo will be 
considered a sufficient sample size for the Dose Selection Phase based on dose 
escalation paradigms used historically for human abuse potential (HAP) studies. The 
proposed single doses of nalbuphine solution for the first cohort will be 81 mg 
(equivalent to 90 mg of the HCl salt). Dose escalation will only occur for each 
subsequent cohort if an MSD has not been identified and the previous dose level was 
deemed to be safe and well tolerated. Escalation to the next dose level will continue 
until the MSD is identified. If the DRC observes a plateau in the incidence and severity 
of AEs, which do not meet the stopping criteria (Section 4.9 of the Protocol), then the 
PK data may be reviewed to determine if there is a plateau in the exposure of 
nalbuphine despite dose escalation. 
Additional cohorts of 8 subjects may be added if a given dose level will be repeated to 
provide additional data or if a dose level, intermediate to those proposed, needs to be 
considered for safety or tolerability reasons, or a dose higher than those planned is 
required to be tested, based on supporting safety and tolerability data. 
3.5. 
TREATMENT ASSIGNMENT & BLINDING 
Randomization will be used to avoid bias in the assignment of subjects to treatment 
sequences, to increase the likelihood that known and unknown subject attributes 
(e.g., demographics and baseline characteristics) are evenly balanced across treatment 
groups, and to enhance the validity of statistical comparisons across treatment groups. 
Each potential subject will be assigned a unique number in the screening process 
(subject number). This number will be used to identify the subject throughout the 
study. Subjects who enter the Treatment Phase will be assigned a unique randomization 
number to identify their sequence of study treatments. Once any subject number is 
assigned, it cannot be reassigned to any other subject. 
All randomization codes will be generated by the designated unblinded statistician(s) at 
Syneos Health before the start of the study. Sealed code break envelopes will be 
provided before the start of the study. 
Each subject will participate in a naloxone challenge, by which subjects will receive 0.2 
mg of naloxone via an IV bolus followed by 0.6 mg naloxone IV if no withdrawal signs are 
observed. At least 12 hours after the naloxone challenge, eligible subjects will be 
randomized to either placebo or active treatment (allocation 6 Active: 2 Placebo) in a 
double-blind manner according to the randomization schedule.  For each dose selection 
cohort, an unblinded statistician from Syneos Health, not otherwise involved in the 
study, will prepare a list of subject randomization numbers. These randomization 
numbers will be used to prepare individual subject doses. Sealed dose selection code 
break envelopes will be available for each subject in case of emergency. Upon 
completion of each cohort of subjects, the randomization codes for the completed 


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subjects will be unblinded, and the PD and safety data will be reviewed to determine if 
dose escalation to the next cohort should occur. 
3.6. 
ADMINISTRATION OF STUDY MEDICATION 
Subjects will be administered study drug with a flavored, low caloric, artificially 
sweetened, non-carbonated beverage (e.g., diet cranberry cocktail). Each subject will 
receive a single oral dose of either nalbuphine HCl solution or matching placebo after at 
least an 8-hour fast. The actual doses administered in each cohort may be adjusted 
(increased, decreased or repeated) based on the evaluation of safety data obtained in 
previous cohorts. Additional cohorts of subjects may be added to those planned in Table 
1 until the MSD is identified. Higher doses can be up to 50% greater than the dose 
administered in the previous cohort, based on supporting safety data. The dosing 
solution (150 mL) will be administered in a dark bottle. After subjects drink the dosing 
solution, an additional 50 mL of flavored beverage will be added to the dosing container 
as a rinse and then administered to the subjects. The start of dosing will be considered 
time zero and subjects will be informed that the duration allocated for dosing will be 5 
minutes. 
There are 7 planned cohorts (Table 1). All subjects within a cohort will receive the 
same dose of nalbuphine HCl solution if randomized to the active drug. Dose escalation 
procedures are described in Section 4.9 of the Protocol. 
 
 


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Table 1 
Planned Oral Doses of Nalbuphine Hydrochloride Solution in the Dose 
Selection Phase 
Cohort 
(n=8) 
Nalbuphine 
Free Base 
Dose Level 
Nalbuphine 
HCl  
Equivalent 
Dose 
Nalbuphine HCl 
Solution 
(n=6) 
Placebo 
Solution 
(n=2) 
1 
81 mg 
90 mg 
9 mL × 10 mg/mL +  
141 mL flavored 
beverage 
150 mL flavored 
beverage 
2 
108 mg 
120 mg 
12 mL × 10 mg/mL +  
138 mL flavored 
beverage 
150 mL flavored 
beverage 
3 
135 mg 
150 mg 
15 mL × 10 mg/mL + 
135 mL flavored 
beverage 
150 mL flavored 
beverage 
4 
162 mg 
180 mg 
18 mL × 10 mg/mL + 
132 mL flavored 
beverage 
150 mL flavored 
beverage 
5 
243 mg 
270 mg 
27 mL × 10 mg/mL + 
123 mL flavored 
beverage 
150 mL flavored 
beverage 
6a 
Up to 365 mg 
405 mg 
40.5 mL × 10 mg/mL + 
109.5 mL flavored 
beverage 
150 mL flavored 
beverage 
7a 
Up to 486 mg 
540 mg 
54 mL × 10 mg/mL + 
96 mL flavored 
beverage 
150 mL flavored 
beverage 
HCl=hydrochloride. 
a The dose of nalbuphine free base in Cohorts 6 and 7 may increase up to a 50% increase from  the preceding 
dose but not to exceed 486 mg (3 fold the therapeutic dose) based on the evaluation of safety data in the 
previous cohorts. 
For the nalbuphine solution, the dose will be added to a flavored beverage to prepare a dosing solution of 
150 mL. 
For both nalbuphine and placebo treatments, after subjects drink the 150 mL dosing solution, an additional 
50 mL of flavored beverage will be added to the dosing container as a rinse and then administered to the 
subjects. Dosing procedures will be specified in study specific procedures. 
Actual doses may be adjusted according to the evaluation of safety data. Dose reductions, intermediate 
doses, or higher doses up to 50% greater than the dose administered in the previous cohort may be 
considered based on the safety results obtained in previous cohorts. Additional cohorts of subjects may be 


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added until the MSD is identified, or until lack of linearity is observed in the nalbuphine plasma PK profile (see 
Section 4.9 of the Protocol for details). 
 
 


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3.7. 
STUDY PROCEDURES AND FLOWCHART 
An overview of the study design is shown in Figure 1. Study assessments will be 
performed at the visits and time points outlined in the Time and Events Schedule (Table 
2). 
 
 
 
 
 
 
 


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Figure 1 
Study Schematic 
Screening
Visit
SCREENING
PHASE
Dose Selection Phase
Cohort 1 
90 mg nalbuphine HCl solution
(equivalent to 81 mg of the free base)
(9 mL × 10 mg/mL + 141 mL flavored beverage or 150 mL flavored beverage)
Visit 2
Visit 1
Within 30 days of Screening visit
Up to 0.8 mg
 naloxone IV
Naloxone Challenge
Cohort 2 
120 mg nalbuphine HCl solution
(equivalent to 108 mg of the free base) 
(12 mL × 10 mg/mL + 138 mL flavored beverage or 150 mL flavored beverage)
Cohort 3 
150 mg nalbuphine HCl solution
(equivalent to 135 mg of the free base) 
(15 mL × 10 mg/mL + 135 mL flavored beverage or 150 mL flavored beverage) 
Cohort 4 
180 mg nalbuphine HCl solution
(equivalent to 162 mg of the free base)
(18 mL × 10 mg/mL + 132 mL flavored beverage or 150 mL flavored beverage)
Cohort 5 
270 mg nalbuphine HCl solution
(equivalent to 243 mg of the free base)
(27 mL × 10 mg/mL + 123 mL flavored beverage or 150 mL flavored beverage)
At least 12 hours after the naloxone challenge
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Yes
Yes
Yes
Yes
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Yes
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose 
escalation 
Stop
Dose Selection
Cohort 6 
up to 405 mg nalbuphine HCl solution
(equivalent to up to 365 mg of the free base)
(up to 40.5 mL × 10 mg/mL + at least 109.5 mL of flavored beverage or 150 mL flavored beverage)
Independent assessment of 
unblinded safety data by DRC
Is the MSD identified?
Yes
Dose 
escalation 
Stop
Cohort 7 
up to 540 mg nalbuphine HCl solution
(equivalent to up to 486 mg of the free base)
(up to 54 mL × 10 mg/mL + at least 96 mL of flavored beverage or 150 mL flavored beverage)
Dose 
escalation 
Stop
  


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DRC=data review committee; ER=extended release; HCl=hydrochloride; IV=intravenous; MSD=maximum safe dose. 
At each dosing of active drug, the dose will be added to a flavored beverage to prepare a dosing volume of 150 mL. An additional 50 
mL of a flavored beverage will be added as a rinse to the empty dosing container that contained the 150 mL solution and then 
administered to the subjects.  
At least 12 hours after completing the naloxone challenge, eligible subjects will receive a single oral dose of nalbuphine HCl solution 
or placebo solution in a randomized, double-blind manner. Each cohort will comprise 8 unique subjects who will be randomized to 
nalbuphine HCl (n=6) or placebo (n=2).  
Following completion of each cohort, safety data will be unblinded and reviewed by the DRC. Escalation to the next dose level will 
continue until the MSD is identified. Dose reductions and intermediate doses may be considered based on the results obtained in 
previous cohort(s). Additional cohorts of subjects may be added until the MSD is identified, or if additional data are required at a 
given dose level or at a dose intermediate to those specified, or a dose higher than those planned is required to be tested, based on 
supportive safety data. If a dose higher than planned will be tested, the dose to be administered will be up to 50% greater than the 
dose administered in the previous cohort, based on supporting safety data.. 


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Table 2 
Time and Events Schedule 
 
Screening 
Visit 
Dose Selection Phase 
Naloxone 
Challenge 
Dose Selection Cohorts 
Visit: 
1 
2 
Day: 
–30 to –2 
−1 
1 
2 
 
 
 
Assessment time points relative to dosing (hours) 
Subject Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication and Recreational 
Drug and Alcohol Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Restrictions Review 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSM-IV-TR  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS (Baseline version) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Height, Weight, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B, Hepatitis C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
a Focusing on any changes since the last visit.  
b  Symptom-directed physical examination 


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Screening 
Visit 
Dose Selection Phase 
Naloxone 
Challenge 
Dose Selection Cohorts 
Visit: 
1 
2 
Day: 
–30 to –2 
−1 
1 
2 
 
 
 
Assessment time points relative to dosing (hours) 
Vital Signsc 
X 
Xd 
Pre 
 
 
 
1 
 
2 
 
3 
4 
5 
6 
 
7 
8 
10 
12 
24 
Oral Temperature 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Electrocardiogram 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continuous Pulse Oximetrye 
 
 
Predose until at least 6 hours post-dose 
 
Clinical Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Concomitant Medications 
 
 
< -- recorded throughout -- > 
Adverse Event Monitoringf 
X 
X 
< -- recorded throughout -- > 
COWS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
Nalbuphine 
 
 
Pre 
 
0.25 
0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
 
 
8 
10 
12 
24 
Pharmacodynamics 
 
 
 
 
 
Pupillometry 
 
 
Pre 
 
0.25 
0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
 
 
8 
10 
12 
24 
Study Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Naloxone Administration 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
preh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
c  Vital signs will include blood pressure, heartrate, and respiratory rate. Vital signs will also include measurements of oxygen saturation after continuous pulse oximetry monitoring is 
complete.  
d Pre-naloxone challenge and at 10 minutes and 1 hour post-naloxone challenge, as indicated in Section 4.4 of the Protocol. 
e  Oxygen saturation will be monitored continuously via telemetry for at least 6 hours post-dose or longer, if deemed necessary by the investigator or designee to ensure subject safety. 
f  Spontaneous AE reporting is continuous throughout the study; however, AE questioning may be performed using a non-leading question at discretion of the clinical staff. 
g  Naloxone challenge procedures are described in Section 4.4 of the Protocol. For female subjects, the results of the urine pregnancy test are required prior to the naloxone 
challenge; results of the serum pregnancy test will not be required prior to the naloxone challenge. 
h  Day 1 only. 


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Screening 
Visit 
Dose Selection Phase 
Naloxone 
Challenge 
Dose Selection Cohorts 
Visit: 
1 
2 
Day: 
–30 to –2 
−1 
1 
2 
 
 
 
Assessment time points relative to dosing (hours) 
Study Drug Administration 
 
 
 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dischargei 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
                                                 
i  Subjects will be discharged after assessments on Day 2 are complete and at the discretion of the investigator or designee to ensure subject safety. 


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4. 
ENDPOINTS 
4.1.1. 
Pharmacokinetic Endpoints 
The PK parameters that will be evaluated for nalbuphine, as applicable, include: 
 
Cmax: maximum observed plasma concentration 
 
tmax: time to maximum observed plasma concentration 
 
AUClast: area under the plasma concentration versus time curve from time 0 to 
the last measurable concentration 
The following parameters will be derived for nalbuphine if sufficient data are available: 
 
AUCinf: area under the plasma concentration versus time curve extrapolated to 
infinity 
 
kel: first-order elimination rate constant associated with the terminal (log-linear) 
portion of the curve 
 
t½: apparent first-order terminal elimination half-life will be calculated as 
0.693/kel 
 
CL/F: apparent clearance 
 
Vd/F: apparent volume of distribution 
4.1.2. 
Safety Endpoints 
The safety endpoints will include the following: 
 
Type, incidence, and severity of adverse events (AEs) 
 
Vital signs (blood pressure, respiratory rate, heart rate, oxygen saturation 
[SpO2], and oral temperature) 
 
ECGs (heart rate and the PR, QRS, QT, QTcB, and QTcF intervals) 
 
Clinical laboratory tests (hematology, clinical chemistry, urinalysis) 
 
Physical examination findings 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints for this study are: 
 
Identification of a MSD of nalbuphine administered as nalbuphine oral solution. 


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 
Concentration-versus-time profiles of nalbuphine in plasma and PK parameters 
Cmax, tmax, and AUClast. If data allow then the PK parameters AUCinf, kel, t1/2, CL/F 
and Vd/F will be calculated. 
 
Pupillometry (maximum pupil constriction [MPC], time to MPC [TMPC], and time-
averaged pupillometry area over the curve [TA_PAOC]). 
 


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5. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Due to the unexpected closure of the investigational site prior to the initiation of Part B 
of this study, only Part A was completed. Part B will be placed with a new investigation 
site sometime in the future. As a result, only those endpoints associated with Part A will 
be summarized and evaluated. Consequently, this updated SAP provides a detailed 
description of planned assessments for Part A only. 


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6. 
ANALYSIS POPULATIONS 
The study analysis populations will consist of the following: 
 
Dose Selection Randomized Population 
 
Dose Selection Safety Population 
 
Dose Selection PK Population 
Details of subject evaluability criteria will be determined prior to study unblinding. 
6.1. 
DOSE SELECTION RANDOMIZED POPULATION 
The Dose Selection Randomized Population will include all subjects who are assigned a 
randomization number in the Dose Selection Phase. Unless specified otherwise, this 
population will be used for subject listings and for summaries of subject disposition for 
this phase. 
6.2. 
DOSE SELECTION SAFETY POPULATION 
The Dose Selection Safety Population will include all subjects in the Dose Selection 
Randomized Population who receive any Dose Selection treatment. The Dose Selection 
Safety Population will be used for all analyses of safety endpoints, the listing of PK 
concentration data and for the analyses of PD pupillometry data in this phase. 
6.3. 
DOSE SELECTION PK POPULATION 
The Dose Selection PK Population will include all subjects in Dose Selection Randomized 
Population who receive a dose of nalbuphine and have evaluable PK data, and who have 
no protocol deviations or other circumstances that would exclude them from analysis. 
Details of subject inclusion in the Dose Selection PK Population will be determined prior 
to study unblinding. The Dose Selection PK Population will be used for all PK analyses and 
for the listing of derived PK parameters in this phase. 
6.4. 
PROTOCOL DEVIATIONS 
All protocol deviations related to study inclusion or exclusion criteria, conduct of the 
trial, subject management or subject assessment will be listed. Protocol deviations will 
be reviewed by the Sponsor, the principal investigator, the lead statistician and the 
study scientist and will be finalized before unblinding the study. All deviations will be 
listed. 


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7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
7.1. 
GENERAL METHODS 
Study data will be reported in subject data listings and summary tables. Descriptive 
statistics will be provided by cohort or treatment group and observation time (visit) of 
interest, as appropriate. If not specified otherwise, the standard summary statistics 
that will be calculated for quantitative and qualitative variables are: 
Continuous: 
number of subjects (N), mean, SD or standard error (SE), minimum, 
median, and maximum  
Categorical: 
number of subjects, absolute and relative frequencies per class 
(denominators for relative frequencies will be described in the tables)  
Frequency counts of 0 will be reported as "0" with no percentage. 
Data collected pre- and post-treatment during the Dose Selection Phase will be 
summarized by time point and cohort (PD [i.e., pupillometry], PK plasma 
concentrations) or as maximum, minimum and final post-dose individual values by 
cohort (vital signs). 
Data collected at other “off-treatment” times (e.g., baseline, admission and follow-up) 
will be summarized by cohort. These data include demography, baseline conditions, and 
safety evaluations (lab, ECG). 
7.2. 
KEY DEFINITIONS 
Administration of the first dose of study drug during the Dose Selection Phase is defined 
as Study Day 1. Study Day -1 is the day before dosing and all assessments prior to Study 
Day 1, including Screening will have negative study days. Nominal Time is the scheduled 
measurement time relative to time 0. Time 0 is the time of dosing on Day 1. Time 0 is 
precisely defined for each analysis below. For data collected pre- and post-
administration, baseline is the last observed measurement prior to the administration of 
study drug. Hence, we have one possible baseline. 
For AEs and concomitant medications (CMs), time since dose will be calculated as the 
difference between the event or medication start date/time and the date/time of the 
treatment dose of each period. Time since dose will be expressed in days, hours and 
minutes. If onset time is in seconds, it will be expressed as “<1 min”. If time is missing, 
duration will be expressed in days. Methods for handling partial start date/times of AEs 
and CMs are described in Section 7.3. 
Duration will be calculated for AEs that resolve as the difference between the 
resolution date/time and onset date/time and will be expressed in days, hours and 
minutes. If duration is in seconds, it will be express as “<1 min”. If time is missing, 
duration will be expressed in days. Methods for handling partial resolution and onset 
dates of AEs and CMs onset are described in Section 7.3. 


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Age is calculated based on the date of birth and date of full informed consent on the 
database level and this value will be used in analyses. In case date of birth was provided 
as year only, age is calculated as difference of 01Jan<year of birth> and date of informed 
consent.  
A subject will be defined as “completed” if s/he completes the Follow-up Visit 10. 
Termination at a different time point will be considered as discontinuation. This applies 
only for the Treatment Phase. 
Subjects will be defined as “completed” if s/he completes Visit 2. Termination at a 
different time point will be considered as discontinuation. 
Nominal Time is the scheduled measurement time of the time point relative to the dose 
time. 
Time since dose is the actual elapsed time from the first administration of study drug in 
a cohort. So, for example, if study drug is administered at 08:00 on Day 1, 10:30 on Day 
1 represents a Time Since Dose of 2:30 or 2.5 hours. 
7.3. 
MISSING DATA 
For PD and PK analyses, missing data for subjects who are administered all scheduled 
study treatments for all the treatment periods will be considered as random 
non-informative missing for analysis purposes. Missing values will be examined on a 
case-by-case basis to confirm this. Missing values for PD assessments will not be 
imputed. The handling of missing PK data is detailed in Section 10.4. 
AEs and medications with incomplete start dates and times will be considered as 
treatment-emergent or prior/concomitant, respectively, according to the following 
algorithm: 
1. If the AE occurrence type is specified for the AE on the eCRF, it will be used to 
determine treatment-emergence. If the AE occurrence type is ‘Treatment Period 
X’ then the AE will be assigned as treatment-emergent. This will be verified using 
the algorithms below (steps 3 through 7). 
2. If a medication started and stopped prior to the start of study treatment the 
medication will be considered prior. This will be verified using the algorithms 
below (steps 3 through 7). 
3. Comments will be reviewed for additional information when treatment emergence 
is ambiguous. 
4. Only the start year is reported: If the year is after or the same as the year of the 
first dose date, then the event will be considered treatment-emergent. 


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5. Only the start month and year are reported: If the month/year is after or the same 
as the month/year of the first dose date, then the event will be considered 
treatment-emergent. 
6. Only the start time is missing: If the event occurred or medication was started on 
or after the date of the first dose date, then the event will be considered 
treatment-emergent and the event will be attributed to that treatment; if it 
occurred before the first dose in the treatment period (e.g., at admission), it will 
be attributed to the treatment administered in the previous period. 
7. For AEs with missing or incomplete start dates, if it can be determined based on 
the available start date components or the stop date to which treatment group(s) 
the AE should be assigned to then the AE will be assigned to the appropriate 
treatment group. If it cannot be determined, then the AE will be assigned to all 
treatment groups received. 
For treatment-emergent AEs (TEAEs), time since dose will be expressed in days, hours 
and minutes. If either time is missing, time since dose will be expressed in days. 
Duration will be calculated for AEs that resolve as the difference between the 
resolution date and time and onset date and time and will be expressed in days, hours 
and minutes. If either time is missing, duration will be expressed in days. 
Time since dose and duration will only be calculated when both dates are complete. 
 
 


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7.4. 
VISIT WINDOWS 
7.4.1. 
Pharmacodynamic (PD) Assessments 
PK samples will be collected after the completion of all PD assessments within the 
following allowable windows: 
Table 3 
Acceptable Collection Window for PD Assessments 
Time Point (hours) 
Acceptable Collection Window 
Pre-dose 
Within 2 hours prior to study drug 
administration  
Post-dose time points 0.25h, 0.5h, 1h, 1.5h 
±5 minutes of nominal time 
 
7.4.2. 
Pharmacokinetic (PK) Sample Collection 
PK samples will be collected after the completion of all PD assessments within the 
following allowable windows: 
Table 4 
Acceptable Collection Window for PK Blood Sample Collection 
Time Point (hours) 
Acceptable Collection Window 
Pre-dose 
Within 60 minutes prior to study drug 
administration  
Post-dose time points 0.25h, 0.5h, 1h, 1.5h 
Within + 2 minutes of the completion of PD 
assessments 
Post-dose time points 2.0h, 2.5h, 3.0h, 4.0h, 
5.0h, 6.0h, 8.0h, 10.0h, 12.0h 
Within + 5 minutes of the completion of PD 
assessments 
Post-dose time point 24.0h 
Within + 15 minutes of the completion of PD 
assessments 
7.5. 
POOLING OF CENTERS 
This is a single center study, therefore pooling of centers is Not Applicable (NA). 
7.6. 
SUBGROUPS 
No subgroups will be evaluated. 


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8. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
8.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition will be summarized by treatment. The number of subjects in each 
cohort will be presented, in addition to the number of subjects who completed, the 
number of subjects who discontinued the study early along with the reasons for all post-
randomization discontinuations. 
The number and percentage of subjects in the analysis populations will be presented in 
the subject disposition tables. 
The denominators for the percent calculations will be the number of subjects 
randomized.  
A listing of subjects who participated in the study will also be presented, including 
participation (yes/no) and treatment received. 
Listings of subjects excluded from the analysis sets will also be produced. 
Inclusion/exclusion criteria definitions and all deviations will be listed. If no 
inclusion/exclusion criteria are reported, this will be noted in place of the listing. 
8.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics (age, sex, race, ethnicity, body weight, 
height, and BMI) will be summarized using descriptive statistics (n, mean, SD, minimum, 
median and maximum, for continuous variables, and the proportion of subjects for 
categorical variables). Summaries will be presented by treatment for the Dose Selection 
Randomized Population. No formal statistical comparison between the groups will be 
performed. 
8.3. 
OTHER BASELINE CHARACTERISTICS 
8.3.1. 
Recreational Drug and Alcohol Use History 
A history of all drugs used for recreational/non-medicinal purposes (i.e., psychoactive 
effects) and alcohol use will be collected during the Screening visit(s) and listed by 
subject for Dose Selection Randomized Population. 
The number and percent of subjects with history in each drug class (cannabinoids, 
depressants, dissociative anesthetics, hallucinogens, opioids and morphine derivatives, 
stimulants and other compounds) will be presented by treatment for the Dose Selection 
Randomized Population. For each drug class, the proportion of subjects with a history of 
the given drug class are summarized. 
For all recreational drugs, the following questions will be tabulated using standard 
summary statistics: 


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 
Number of times used in past 2 years 
 
Number of recreational drugs used in past 2 years (1, 2, 3 or ≥4) 
For the opioids drug class, the following two additional questions will be tabulated using 
standard summary statistics: 
 
Number of times opioids used in the past 8 weeks prior to Screening visit 
 
Number of times opioids used in the past 12 months  
For subjects reporting more than one drug per drug class, number of times used will be 
summed over all drugs in that class. 
The number and percentage of subjects reporting drinking alcohol will be presented by 
treatment for the Dose Selection Randomized Population. The average number of drinks 
in the past 2 years will be tabulated using standard summary statistics. 
8.3.2. 
Nicotine Use 
Nicotine use will be collected at Screening and listed only by subject for the Dose 
Selection Randomized Population. 
8.4. 
MEDICAL HISTORY 
Medical history will be listed by subject for the Dose Selection Randomized Population. 
Medical history will be coded into the most recent version of Medical Dictionary for 
Regulatory Activities (MedDRA) available (version 20.0 or later). All findings on medical 
history will be evaluated by the investigator for clinical significance. 
The DSM-IV-TR modules will be used to screen for alcohol and substance dependence 
but shall not be listed. 
8.5. 
PRIOR AND CONCOMITANT MEDICATION 
Prior medication is defined as medication taken up to 30 days before the first screening 
date. Non-study medication taken from the first Screening visit until the completion of 
the Follow-up visit will be considered as concomitant. Prior and concomitant 
medications will be assigned a 12-digit code using the most recent version of the World 
Health Organization drug codes available (WHO Drug). The original verbatim terms 
collected in the electronic Case Report Form (eCRF) for prior and concomitant 
medications will be coded using the World Health Organization Drug Dictionary (WHO-
DD) into drug class (Anatomical Therapeutic Chemical [ATC] Classification level 2) and 
preferred term (PT).  
Prior and concomitant medications will be listed chronologically by subject including all 
data collected in the eCRF, along with coded variables for Dose Selection Randomized 


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Population. The incidence of concomitant antiemetic medication use will be tabulated 
by cohort (i.e., dose level) and treatment (active drug or placebo). 


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9. 
PHARMACODYNAMICS ASSESSMENTS AND ANALYSIS 
The abuse potential of nalbuphine will be assessed through evaluation and integrative 
interpretation of the pattern of results across the various types of measures: measures 
of positive response (i.e., measures most predictive of the drug’s abuse potential and 
reinforcing properties), measures of negative response (i.e., measures that potentially 
mitigate against abuse potential), measures of stimulant effects, measures of other 
effects and measures of cognitive and psychomotor effects. 
9.1. 
PHARMACODYNAMIC ASSESSMENTS 
9.1.1. 
Pupillometry 
Pupillometry will be used as an objective physiological PD measure as it is a sensitive 
measure of central opioid/stimulant action and appears to be resistant to tolerance 
development with repeated administration. An electronic pupillometer (NeuroOptics) 
will be used to measure pupil diameter. Data from a series of frames will be used in the 
calculation, and the final display will show the weighted average and SD of the pupil 
size. Measurements will be collected under mesopic lighting conditions. For each 
subject, every effort will be made to use the same eye for all assessments throughout 
the study. 
Pupillometry will be recorded at the following time points: 
 
Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-
dose. 
PD pupillometry data in the Dose Selection Phase will be analyzed for the Dose 
Selection Safety Population. The exploratory endpoints are MPC, TMPC, and TA_PAOC. 
9.1.2. 
Derived and Imputed Data 
For each subject and treatment period, the parameters will be derived using the 
following rules: 
 Analyses will be based on actual assessment times, except for pre-dose (baseline) 
times, which will automatically be considered as time 0 as appropriate for analysis. 
If the actual time is missing, the nominal time will be used. 
 TMPC will be calculated as the time from time 0 to MPC. 
 TA_PAOC is calculated as the area over the curve (AOC) divided by the time from 
time 0 (or the 0.25 hour time point if the VAS is not collected pre-dose) to the 24 
hour time point. AOC is calculated using the linear trapezoidal rule applied to non-
missing data. 


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 Missing data for subjects who are administered all scheduled study treatments for 
all the treatment periods will be considered as random non-informative missing for 
analysis purposes. Missing values will be examined on a case-by-case basis to 
confirm this. Reasons for missing data will be displayed in the listings. No further 
imputation will be applied to any missing values. 
Assessments done outside the assessment windows may be excluded from by-time point 
summary statistics; this will be determined prior to unblinding. 


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10. 
ANALYSIS OF PHARMACOKINETICS 
10.1. 
MEASUREMENTS 
The Dose Selection Safety Population will be used for all individual plasma 
concentration listings, whilst all listings and summaries and pharmacokinetic analyses of 
PK data will be performed using the Dose Selection PK Population. 
PK endpoints include plasma concentrations of nalbuphine and its corresponding 
metabolites (M1, M3, M4, and M5) at each collection time point and the derived PK 
parameters listed in Section 4.2.3. 
10.2. 
PK SAMPLING SCHEDULE 
During the Dose Selection Phase, blood samples will be collected at the following time 
points: 
 
Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-
dose. 
10.3. 
DERIVED AND IMPUTED DATA 
 
PK parameters (Cmax, tmax, AUClast, AUCinf, t½, kel, CL/F and Vd/F) will be 
determined for nalbuphine and its metabolites based on concentrations in 
plasma and actual sampling times via non-compartmental analysis using 
validated Phoenix WinNonlin Version 6.4 or higher. For each subject, the PK 
parameters will be derived as follows: The apparent Cmax and the corresponding 
tmax will be read directly from the concentration-time plot (observed data, not 
predicted data by the program);  
 
AUClast and AUCinf will be calculated using the linear up log down trapezoidal 
method; 
 
The elimination rate constant (kel) will be determined by log-linear regression 
obtained on at least the three last quantifiable concentrations;  
 
The Terminal elimination half-life (t½) will be calculated as 0.693/kel. 
 
AUCinf is calculated by the program as: 
AUCinf = AUClast + AUCt-inf where t is the sampling time point of the last 
measurable concentration (tlast). AUCt-inf is calculated by the program as: Clast/kel, 
where Clast is the last measurable concentration at time t and kel is the 
elimination rate constant during the terminal elimination phase;  
 
CL/F will be derived by Dose/AUCinf and Vd/F will be derived as CL/F divided by 
kel. 
The following reliability criteria will be used for the PK parameters: 


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 
The adjusted square of the correlation coefficient (Rsquare adj.) for the 
goodness of fit of the regression line through the data points must be at least 
0.80 for the kel value to be considered reliable; 
 
The AUC extrapolation to infinity (AUCt-inf ) must be ≤20% of the total area for 
AUCinf to be considered reliable; 
For subjects with unreliable kel (e.g. Rsquare adjusted ≤0.80), kel, t1/2 and AUCinf will be 
flagged in the individual data Listings. For subjects with unreliable AUCinf (because of 
extrapolation >20%), AUCinf, CL/F and Vd/F will be flagged in the individual data 
Listings. Flagged PK parameters will be excluded from summarization and statistical 
analyses. 
10.4. 
HANDLING OF MISSING DATA 
Missing concentration data for subjects who were administered scheduled study 
treatments will be considered as random non-informative missing for analysis purposes 
and will not be imputed. Missing values will be examined on a case-by-case basis to 
confirm this.  
 
The data will be handled as follows for the graphical presentation of individual 
plasma concentrations and for the derivation of the PK parameters (using actual 
sampling times): The time of collection of the pre-dose sample will be set to 
zero (time 0); 
 
Actual post-dose sampling times are expressed relative to the time of dosing (if 
the actual time of sampling is missing, the planned time will be used); 
 
Pre-dose plasma concentrations below the lower limit of quantification (LLOQ) 
will be treated as zero for the derivation of PK parameters; 
 
Concentration values below LLOQ prior to the first quantifiable concentration 
will be treated as zero for the derivation of PK parameters. 
 
Post-dose below limit of quantification (BLQ) values after the first quantifiable 
time point will be set to missing for the derivation of PK parameters. 
 
For the summary and graphical presentation of plasma concentrations, any 
plasma concentrations that are BLQ will be treated as zero. 
 
If all samples are BLQ for a given concentration-time profile, PK parameters will 
not be derived for that profile. 
 
No further imputation will be applied to any missing values. 
10.5. 
DATA SUMMARIZATION AND PRESENTATION 
PK sample collection data, plasma concentrations and the derived PK parameters for 
nalbuphine and its metabolites (M1, M3, M4, and M5) will be listed by subject. Plasma 
concentration data and the PK parameters for the nalbuphine treatments and its 
metabolites will be summarized by dose level using the following statistics (Table 5): 


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Table 5 
Summary Statistics for PK Analyses 
Variable 
Summarized with: 
Plasma 
concentration at 
each time point 
n; number of missing (if not zero); number and percent BLQ values; arithmetic 
mean, SD and coefficient of variation (CV%, calculated as 100*SD/mean); 
minimum, median and maximum 
Cmax, AUClast, AUCinf, 
CL/F, Vd/F 
n; number of missing (if not zero); arithmetic mean, SD and coefficient of 
variation (CV%, calculated as 100*SD/mean); minimum, median, and maximum; 
geometric mean and geometric CV% (calculated as 100% 
, where z2 
is the variance of the log-transformed data) 
tmax 
n; number of missing (if not zero); median, minimum, maximum, first quartile 
(Q1) add third quartile (Q3). 
t1/2, kel 
n; number of missing (if not zero); arithmetic mean, SD and CV (%); minimum, 
median, and maximum 
AUC = area under the curve; BLQ = below the limit of quantification; Cmax = maximum observed plasma 
concentration; CV = coefficient of variation; SD = standard deviation; tmax = time to maximum plasma 
concentration; t1/2 = terminal elimination half-life; kel = first-order elimination rate constant. 
If more than 50% of values are BLQ or are missing, then only n, n (%) BLQ, minimum, 
median and maximum will be calculated and reported. If the calculated mean/median 
value is less than LLOQ, then that time point will be ignored for plotting the mean PK 
profiles. 
The following graphical presentations will be made for nalbuphine: 
 
Mean PK plasma concentrations plotted vs time curve by dose level within the 
same figure using both linear and log-linear scales. 
 
Box-whisker plots of PK parameters including Cmax and AUClast by dose level using 
linear scale. 
 
By-subject time-concentration curves by dose level within the same figure using 
both linear and log-linear scales. 
The PK parameters summary will be presented separately for a subset (if applicable) of 
subjects who do not vomit within 12 hours of dosing. 
 
 


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11. 
SAFETY 
All safety analyses will be done using the Dose Selection Safety Population. 
11.1. EXTENT OF EXPOSURE 
Drug administration data for the Dose Selection Phase will be listed for the Dose 
Selection Randomized Population. 
11.2. TREATMENT COMPLIANCE 
Not Applicable (NA). 
11.3. ADVERSE EVENTS / ADVERSE DRUG REACTIONS 
Analysis of safety assessments will be performed using the Dose Selection Safety 
Population. Assessment of safety will be based on the incidence of AEs, AEs resulting in 
discontinuation, and SAEs by treatment. AE summaries will be provided showing the 
number and percentage of subjects who experienced at least one TEAE. TEAEs will also 
be tabulated by maximum severity and by maximum relationship to study drug. These 
summaries will be presented by body system and PT (MedDRA, version 20.0 or higher). 
SAEs and AEs resulting in discontinuation will be summarized separately. All AEs will be 
listed by subject for the Dose Selection Randomized Population.  
Any AE occurring after treatment start will be considered as a TEAE. Rules related to 
assigning TEAEs to treatment and imputation related to missing data are described in 
the Section 7.3. 
Subjects may be counted under multiple system organ classes (SOCs) and PTs, but for 
each SOC and PT, subjects are only counted once. 
The number and percentages of subjects with TEAEs as well as the number of events 
will be displayed. SOCs will be sorted by descending frequency of subjects. Within each 
SOC the PTs will be sorted by descending frequency of subjects. 
Imputation related to missing AE data is described in the Section 7.3. 
11.4. LABORATORY EVALUATIONS 
Blood and urine samples for hematology, clinical chemistry, and urinalysis (referred to 
collectively as safety laboratory data) will be collected according to the Time and 
Events Schedule (Table 2).  
The following tests are included: 
 
Clinical Chemistry: alkaline phosphatase (ALP), calcium, chloride, creatinine, 
random glucose, potassium, alanine aminotransferase (ALT), aspartate 


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aminotransferase (AST), gamma-glutamyl transpeptidase, sodium, total bilirubin, 
and urea. 
 
Hematology: A peripheral blood smear to assess blood cell morphology, 
hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) 
count, WBC differential (absolute counts), and numerical platelet count. 
 
Urinalysis: specific gravity, pH, ketones, random glucose, nitrite, blood, 
leukocyte esterase, protein, urobilinogen, and bilirubin. If nitrite, blood, or 
protein tests are positive, a microscopic examination will be performed. 
 
Pregnancy: presence of β-Human Chorionic Gonadotropin (HCG) in the blood 
serum or urine of all female subjects. Results of blood serum and urine 
pregnancy tests will be reported and determined to be negative prior to study 
continuation and/or dosing. 
 
Follicle-Stimulating Hormone (FSH): Post-menopausal status for female 
subjects will be confirmed by FSH testing at Screening. 
 
Viral Screen: Serology will screen for hepatitis B, hepatitis C, and HIV. Only 
subjects with negative viral serology tests will be eligible for the study. 
 
Breath Alcohol: If there is any doubt or concern regarding alcohol use, research 
site staff may request a breath alcohol test at any time during the study. 
 
Drugs of Abuse Screen: Urine samples will be tested for the following drugs of 
abuse: THC, oxycodone and other opiates (i.e., the opiate panel will test for the 
presence of codeine, hydrocodone, hydromorphone, morphine, and 
oxymorphone), amphetamines (i.e., amphetamines and methamphetamines), 
cocaine, and benzodiazepines.  
Laboratory data collected during the Dose Selection Phase will be summarized by the 
type of laboratory test and visit. Descriptive statistics (n, mean, SD, minimum, median 
and maximum) and the number of subjects with laboratory test results below, within, 
and above normal ranges will be tabulated by visit. 
Continuous laboratory test results will be assigned a low/high/normal (LNH) 
classification by the central lab according to whether the value was below (L: Low), 
within (N: Normal), or above (H: High) the laboratory parameter’s normal range; 
categorical laboratory test results were classified as normal (N) or abnormal (A). 
Abnormal findings in laboratory data will be listed. Abnormal values, classified as 
Low/Normal/High (LNH), and clinically significant abnormalities (as determined by the 
investigator) will be flagged. Laboratory listings will be provided for the Dose Selection 
Randomized Population. 
All laboratory test results will be reported in Standard International System of Units (SI) 
units. 


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11.5. VITAL SIGNS 
Vital signs consist of systolic and diastolic blood pressure (mmHg), heart rate (beats per 
minute [bpm]), and respiratory rate (breaths/minute). Oral temperature (°C) will also 
be taken at some time points according to the Time and Events Schedules (Table  [Dose 
Selection]).  
In addition, pulse oximetry measurements (SpO2) will be taken at designated time points 
after the continuous monitoring period. 
Dose Selection Phase vital signs (blood pressure, respiratory rate, heart rate, SpO2) will 
be analyzed as minimum, maximum, and final post-dose (i.e. 24 hours) values and 
summarized using descriptive statistics (n, mean, SD, minimum, median and maximum), 
since the analyses of these extremes are more meaningful than the analyses of 
individual time points. The individual time points and all off-treatment vital signs (i.e., 
Screening, and Follow-up) will be listed for the Dose Selection Randomized Population 
but not otherwise analyzed. Abnormal findings in vital signs data will be listed. In the 
Dose Selection Phase, baseline will be determined as the last observed measurement 
prior to the administration of study drug. In addition, minimum, maximum, and final 
post-dose individual values will be derived and individual data will be presented in data 
listings. 
11.6. ECG 
12-lead ECGs will be performed by the site according to the Time and Events Schedules 
(Table  [Dose Selection]). The ECG will electronically measure and calculate ventricular 
heart rate and the PR, QRS, QT, QTcB, and QTcF intervals. ECG data will be classified as 
“Normal”, “Abnormal, Not Clinically Significant” or “Abnormal, Clinically Significant”. 
12-lead ECG data (absolute values in heart rate and PR, QRS, QT, QTcB, and QTcF 
intervals) will be summarized by parameter and visit using descriptive statistics (n, mean, 
SD, minimum, median and maximum). Abnormal findings in ECG data will be listed. A 
summary table of overall ECG interpretation will show the number and percentage of 
subjects with normal, abnormal non-clinically significant (NCS) or abnormal clinically 
significant (CS) findings at each visit. ECG data will be listed for the Dose Selection 
Randomized Population. 
11.7. PHYSICAL EXAMINATION 
A complete physical examination including general appearance, eye, ear, nose and 
throat, head and neck, respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, peripheral vascular, lymphatic, neurological, mental status and other 
body system status, will be performed at Screening. Subsequent symptom-directed 
physical examinations will be performed according to the Time and Events Schedule 
(Table 2), and may be performed by physicians or mid-level providers, such as advanced 
practice nurses and physician assistants, if they are appropriately licensed and 
credentialed to perform these examinations in accordance with local requirements 
and/or regulations. Height, weight, and BMI will be recorded at Screening only. 


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Physical examination abnormal results will be listed by subject and visit for the Dose 
Selection Randomized Population. 
11.8. OTHER SAFETY 
Two versions of the Columbia-Suicide Severity Rating Scale (C-SSRS) will be used in this 
study: the Baseline version to assess lifetime suicidal ideation and behavior at 
Screening, and the Since Last Visit version to assess suicidal thoughts or behaviors the 
subject may have had since the last time the C-SSRS was administered.  
The Baseline and Since Last Visit C-SSRS results will be listed for the Dose Selection 
Randomized Population. 
11.9. INTERIM ANALYSES 
No interim analysis is planned for this trial. 


Statistical Analysis Plan 
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Protocol # TR08 
 
Syneos Health # 1008910 
 
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12. 
REFERENCE LIST 
1. U.S. Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. Guidance for Industry: Assessment of 
Abuse Potential of Drugs. January 2017. 
2. Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. 
Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state 
plasma concentrations. Anesthesiology. 1998;88(1):82–8. 
3. Kaplan HL. Representation of on-line questionnaires in an editable, auditable 
database. Behaviour Research Models, Instruments & Computers. 1992;24:373–84. 
4. Sternberg, S. High-speed scanning in human memory. Science. 1966;153(3736):652–
4. 
5. Chen L. An Overview of Regulatory Recommendations for Statistical Approaches to 
Evaluate Human Abuse Potential Study Data. Presented: Meeting on the 
Advancement in Abuse Potential Assessments – Building on the FDA Draft Guidance 
for Industry. Organized by the Cross Company Abuse Liability Council (CCALC), North 
Bethesda, MD, April 16-17, 2015. 
6. Chen L, Tsong Y. Design and Analysis for Drug Abuse Potential Studies: Issues and 
Strategies for Implementing a Crossover Design. DIA Journal 2007; 41: 481-9. 
7. Schoedel K, Shram M, Levy-Cooperman N et al. Defining clinically important 
differences in subjective abuse potential measures. Presented: 74th Annual Meeting 
of the College on Problems of Drug Dependence, Palm Springs, CA, 2012. 
8. Eaton TA, Comer SD, Revicki DA, Trudeau JJ, van Inwegen RG, Stauffer JW et al. 
Determining the clinically important difference in visual analog scale scores in abuse 
liability studies evaluating novel opioid formulations. Qual Life Res. 2012 Aug; 
21(6):975–981. 
9. Chen L, Bonson K. An equivalence test for the comparison between a test drug and 
placebo in human abuse potential studies. J Biopharm Stat. 2013; 23:294-306. 
10. Sun P. Using Proc Power To Perform Model-Based Power Analysis For Clinical 
Pharmacology Studies. PharmaSUG2010 – Paper SP05. 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
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13. 
PROGRAMMING CONSIDERATIONS 
All TLFs and statistical analyses will be generated using SAS® for Windows, Release 9.4 
(SAS® Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure 
output will adhere to the following specifications. 
The PK analyses will be performed by Syneos Health using Phoenix WinNonlin® version 
6.4 or higher (Certara USA, Inc., Princeton, NJ, USA). 
13.1. GENERAL CONSIDERATIONS 
 
A separate SAS program will be created for each output. 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Word format. TLFs will be bundled separately with a 
table of contents for each. 
 
Numbering of TLFs will follow International Council for Harmonisation (ICH E3 
guidance 
13.2. TABLE, LISTING, AND FIGURE FORMAT 
13.2.1. 
General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8. 
 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
TLFs will be in black and white (no color), unless otherwise specified 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
13.2.2. 
Headers 
 
All output will have the following header at the top left of each page: 


Statistical Analysis Plan 
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Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
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Trevi Therapeutics Inc. Protocol TR08 (Syneos Health Study Number 1008910) 
Draft/Final Run DDMMMYYYY 
 
All output will have Page n of N at the top or bottom right corner of each page. TLFs 
will be internally paginated in relation to the total length (i.e., the page number 
should appear sequentially as page n of N, where N is the total number of pages in 
the table). 
 
The date output was generated will appear along with the program name as a footer 
on each page. 
13.2.3. 
Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
A decimal system (x.y and x.y.z) will be used to identify TLFs with related contents. 
The title is centered. The analysis population will be identified on the line 
immediately following the title. The title and table designation are single spaced. A 
solid line spanning the margins will separate the display titles from the Column 
headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Analysis Population 
13.2.4. 
Column Headers 
 
Column headings will be displayed immediately below the solid line described above 
in initial upper-case characters.  
 
In the case of PD tables, the variable (or characteristic) column will be on the far 
left followed by the treatment group columns and total column (if applicable). P-
values will be presented under the total column or in separate P-value column (if 
applicable). Within-treatment comparisons may have P-values presented in a row 
beneath the summary statistics for that treatment. 
 
For numeric variables, include “unit” in column or row heading when appropriate. 
 
Analysis population sizes will be presented for each treatment group in the column 
heading as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ 
used for the descriptive statistics representing the number of subjects in the 
analysis population. 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active comparator 
trials, followed by a total column (if applicable). 
13.2.5. 
Body of the Data Display 
13.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
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03.007A.03     
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• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
13.2.5.2. Table Conventions 
 
Units will be included where available 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
mild 
3 
moderate 
8 
severe 
0 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and the SD 
should be printed out to 2 more significant digits than the original values. The 
minimum and maximum should report the same significant digits as the original 
values. For example, for systolic blood pressure: 
n 
  xx 
Mean (SD) 
xxx.x (x.xx) 
Median 
xxx.x 
Minimum, Maximum 
xxx, xxx 
 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any P-value less than 0.001 will be presented as <0.001. If the P-
value should be less than 0.0001 then present as <0.0001. If the P-value is returned 
as >0.999 then present as >0.999 
 
Percentage values will be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise 
noted, for all percentages, the number of subjects in the analysis population for the 
treatment group who have an observation will be the denominator. Percentages 
after zero counts will not be displayed and percentages equating to 100% will be 
presented as 100%, without any decimal places.  


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
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 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of AE data should be presented by the body system, treatment 
class, or SOC with the highest occurrence in the active treatment group in 
decreasing order, assuming all terms are coded. Within the body system, drug class 
and SOC, medical history (by PT), drugs (by ATC1 code), and AEs (by PT) should be 
displayed in decreasing order. If incidence for more than 1 term is identical, they 
should then be sorted alphabetically. Missing descriptive statistics or P-values which 
cannot be estimated should be reported as “-”. 
 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis 
population presented. However, careful consideration is required in many instances 
due to the complicated nature of selecting the denominator, usually the appropriate 
number of subjects exposed. Describe details of this in footnotes or programming 
notes. 
 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject will be included in the summary statistics for all relevant categories or 
just 1 category and the criteria for selecting the criteria. 
 
Where a category with a subheading (such as SOC) has to be split over more than one 
page, output the subheading followed by “(Cont.)” at the top of each subsequent 
page.  The overall summary statistics for the subheading will only be output on the 
first relevant page. 
13.2.5.3. Listing Conventions 
 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
 
Missing data will be represented on subject listings as either a hyphen (“-”) with a 
corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
 
Dates will be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates will be represented on subject listings as dashes (--JUL2000). Dates 
that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
 
All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS 
format (e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as 
part of the study. 
 
Units will be included where available 
13.2.5.4. Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
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13.2.6. 
Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes. 
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes will always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
 
Subject specific footnotes will be avoided, where possible. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page. 
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
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14. 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary tables, 
data listings, figures or statistical analyses. Syneos Health Standard Operating Procedures 
(SOPs) 03.010 and 03.013 provide an overview of the development of such SAS programs. 
Syneos Health SOP 03.016.02 provides an overview of the pharmacokinetic data analyses 
and reporting. 
Syneos Health SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the output 
by checking for their logic, efficiency and commenting and by review of the produced 
output. 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
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15. 
INDEX OF TABLES 
The following tables will be produced (table numbers and titles may be different in the 
final versions): 
Header 
Table 
Number 
Name 
Analysis 
Population 
Template 
14. 
 
Tables, Figures, and Graphs Referred to but not Included in 
the Text 
 
 
14.1 
 
Subject Disposition and Demographic Data Summary Tables 
 
 
14.1.1 
 
Subject Disposition 
 
 
 
14.1.1.1 
Disposition of Subjects – Dose Selection Phase, Part A 
Dose 
Selection 
Randomized 
T1.1 
 
14.1.1.2 
Subject Populations – Dose Selection Phase, Part A 
Dose 
Selection 
Randomized 
T1.2 
14.1.2 
 
Demographic and Baseline Characteristics 
 
 
 
14.1.2.1 
Demographic and Baseline Characteristics – Dose Selection 
Phase, Part A 
Dose 
Selection 
Randomized 
T1.3 
 
14.1.2.2 
Recreational Drug Use History – Dose Selection Phase, Part A 
Dose 
Selection 
Randomized 
T1.4 
 
14.1.2.3 
Alcohol Use History – Dose Selection Phase, Part A 
Dose 
Selection 
Randomized 
T1.5 
14.2 
 
Pharmacokinetic and Pharmacodynamic Data Summary 
Tables and Figures 
 
 
14.2.1 
 
Pharmacodynamic Data Summary Tables and Figures 
 
 
14.2.1.1 
 
Pharmacodynamic Data in the Dose Selection Phase 
 
 
 
14.2.1.1 
Pupillometry – Pharmacodynamic Parameters – Dose 
Selection Phase, Part A 
Dose 
Selection 
Safety 
T2.1 
14.2.2 
 
Pharmacokinetic Data Summary Tables and Figures 
 
 
 
14.2.2.1 
Plasma Concentrations of Nalbuphine and its Metabolites M1, 
M3, M4, and M5 (ng/mL) Over Time by Treatment - Dose 
Selection Phase, Part A 
Dose 
Selection PK 
T3.1 
 
14.2.2.2 
Pharmacokinetic Parameters of Nalbuphine and its 
Metabolites M1, M3, M4, and M5 (ng/mL) by Dose – Dose 
Selection Phase, Part A 
Dose 
Selection PK 
T3.2 
14.3 
 
Safety Data Summary Tables 
 
 
14.3.1 
 
Display of Adverse Events 
 
 
 
14.3.1.1 
Treatment-Emergent Adverse Events (TEAEs) – Overall 
Summary - Dose Selection Phase, Part A 
Dose 
Selection 
Safety 
T4.1 
 
14.3.1.2 
Treatment-Emergent Adverse Events (TEAEs) by System 
Organ Class and Preferred Term - Dose Selection Phase, Part 
A 
Dose 
Selection 
Safety 
T4.2 
 
14.3.1.3 
Treatment-Emergent Adverse Events (TEAEs) by System 
Organ Class, Preferred Term, and Maximum Intensity - Dose 
Selection Phase, Part A 
Dose 
Selection 
Safety 
T4. 
 
14.3.1.4 
Treatment-Emergent Adverse Events (TEAEs) by System 
Organ Class, Preferred Term, and Maximum Relationship - 
Dose Selection Phase, Part A 
Dose 
Selection 
Safety 
T4.4 


Statistical Analysis Plan 
Final Version 1.1 
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Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
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Header 
Table 
Number 
Name 
Analysis 
Population 
Template 
 
14.3.2 
Listings of Deaths, Other Serious and Significant Adverse 
Events - Dose Selection Phase, Part A 
Dose 
Selection 
Safety 
T4.5 
14.3.4 
 
Other Safety Data 
 
 
14.3.4.1 
 
Clinical Laboratory Data 
 
 
14.3.4.1.1 
 
Clinical Chemistry Data 
 
 
 
14.3.4.1.1.1 
Clinical Chemistry: Summary – Dose Selection Phase, Part A 
Dose 
Selection 
Safety 
T5.1 
 
14.3.4.1.1.2 
Clinical Chemistry: Abnormal Results - Listing – Dose 
Selection Phase, Part A 
Dose 
Selection 
Safety 
T5.3 
14.3.4.1.2 
 
Hematology Data 
 
 
 
14.3.4.1.2.1 
Hematology: Summary – Dose Selection Phase, Part A 
Dose 
Selection 
Safety 
T5.1 
 
14.3.4.1.2.2 
Hematology: Abnormal Results - Listing – Dose Selection 
Phase, Part A 
Dose 
Selection 
Safety 
T5.3 
14.3.4.1.3 
 
Urinalysis Data 
 
 
 
14.3.4.1.3.1 
Urinalysis: Summary of Continuous Tests – Dose Selection 
Phase, Part A 
Dose 
Selection 
Safety 
T5.1 
 
14.3.4.1.3.2 
Urinalysis: Summary of Categorical Tests – Dose Selection 
Phase, Part A 
Dose 
Selection 
Safety 
T5.2 
 
14.3.4.1.3.3 
Urinalysis: Abnormal Results - Listing – Dose Selection Phase, 
Part A 
Dose 
Selection 
Safety 
T5.3 
14.3.4.2 
 
Vital Signs 
 
 
 
14.3.4.2.1 
Summary of Vital Signs – Dose Selection Phase, Part A 
Dose 
Selection 
Safety 
T6.1 
 
14.3.4.2.2 
Vital Signs: Abnormal Results – Listing – Dose Selection 
Phase, Part A 
Dose 
Selection 
Safety 
T6.2 
14.3.4.3 
 
Electrocardiogram (ECG) Data 
 
 
 
14.3.4.3.1 
Summary of Overall ECG Interpretation – Dose Selection 
Phase, Part A 
Dose 
Selection 
Safety 
T6.3 
 
14.3.4.3.2 
Summary of ECG Continuous Data – Dose Selection Phase, 
Part A 
Dose 
Selection 
Safety 
T6.4 
 
14.3.4.3.3 
ECG: Abnormal Results – Listing – Dose Selection Phase, Part 
A 
Dose 
Selection 
Safety 
T6.5 
Templates are provided in Section 19.1.  
 
 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
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03.007A.03     
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16. 
INDEX OF LISTINGS 
The following listings will be produced (listing numbers and titles may be different in 
the final versions):  
Header 
Listing 
Number 
Name 
Analysis 
Population 
Template 
16.1.7 
 
 
 
 
 
16.1.7 
Randomization Scheme and Code – Dose Selection 
Phase, Part A 
Dose Selection 
Randomized 
L1.1 
 
16.1.8 
Subjects Randomized in Part A 
Dose Selection 
Randomized 
L1.2 
16.2 
 
Subject Data Listings 
 
 
 
16.2.1 
Subject Disposition and Completion / Discontinuation – 
Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L2 
 
16.2.2 
Protocol Deviations – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L3.1 
16.2.3 
 
Subjects Excluded from Analysis 
 
 
 
16.2.3.1 
Inclusion/Exclusion Criteria 
 
L3.2 
 
16.2.3.2 
Inclusion/Exclusion Criteria Violations – Dose Selection 
Phase, Part A 
Dose Selection 
Randomized 
L3.3 
 
16.2.3.3 
Subject Exclusions from Analysis Populations – Dose 
Selection Phase, Part A 
Dose Selection 
Randomized 
L4 
16.2.4 
 
Demographics and Other Baseline Characteristics 
 
 
16.2.4.1 
 
Demographic Data 
 
 
 
16.2.4.1 
Demographics and Informed Consent – Dose Selection 
Phase, Part A 
Dose Selection 
Randomized 
L5.1 
16.2.4.2 
 
Medical History 
 
 
 
16.2.4.2 
Medical History – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L5.2 
16.2.4.3 
 
Baseline Characteristics 
 
 
 
16.2.4.3.1 
Recreational Drug Use History – Dose Selection Phase, 
Part A 
Dose Selection 
Randomized 
L5.3 
 
16.2.4.3.2 
Alcohol Use History – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L5.4 
 
16.2.4.3.3 
Nicotine Use – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L5.5 
16.2.4.4 
 
Prior and Concomitant Medications 
 
 
 
16.2.4.4 
Prior and Concomitant Medications – Dose Selection 
Phase, Part A 
Dose Selection 
Randomized 
L5.6 
16.2.5 
 
Study Drug Administration 
 
 
 
16.2.5 
Study Drug Administration – Dose Selection Phase, Part 
A 
Dose Selection 
Randomized 
L6.1 
16.2.6 
 
Pharmacodynamic and Pharmacokinetic Data 
 
 
16.2.6.1 
 
Pharmacodynamic Data – Dose Selection Phase 
 
 
 
16.2.6.1 
Pupillometry Data – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L7.1 
16.2.6.2 
 
Pharmacokinetic Data 
 
 
 
16.2.6.2.1 
Pharmacokinetic Sample Collection Data and Plasma 
Concentration Data for Nalbuphine and its Metabolites 
M1, M3, M4, and M5 (ng/mL) – Dose Selection Phase, 
Part A 
Dose Selection 
Safety 
L7.2 


Statistical Analysis Plan 
Final Version 1.1 
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Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
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Header 
Listing 
Number 
Name 
Analysis 
Population 
Template 
 
16.2.6.2.2 
Pharmacokinetic Parameters for Nalbuphine and its 
Metabolites M1, M3, M4, and M5 – Dose Selection 
Phase, Part A 
Dose Selection PK 
L7.3 
16.2.7 
 
Adverse Event Listings 
 
 
 
16.2.7 
Adverse Events – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L8a 
16.2.8 
 
Listing of Individual Laboratory Measurements by 
Patient 
 
 
16.2.8.1 
 
Clinical Laboratory Data 
 
 
 
16.2.8.1.1 
Clinical Chemistry – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L9.1 
 
16.2.8.1.2 
Hematology – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L9.1 
 
16.2.8.1.3 
Urinalysis – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L9.1 
 
16.2.8.1.4 
Pregnancy and FSH Tests – Dose Selection Phase, Part 
A 
Dose Selection 
Randomized 
L9.2 
 
16.2.8.1.5 
Viral Screen – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L9.3 
 
16.2.8.1.6 
Urine Drugs of Abuse Screen – Dose Selection Phase, 
Part A 
Dose Selection 
Randomized 
L9.4 
 
16.2.8.1.7 
Breath Alcohol Test – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L9.5 
16.2.8.2 
 
Other Safety Data 
 
 
 
16.2.8.2.1 
Vital Signs – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L10.1 
 
16.2.8.2.2 
ECG Data – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L10.2 
 
16.2.8.2.3 
Physical Examination Abnormalities – Dose Selection 
Phase, Part A 
Dose Selection 
Randomized 
L10.3 
 
16.2.8.2.4 
Baseline Columbia-Suicide Severity Rating Scale (C-
SSRS) – Dose Selection Phase, Part A 
Dose Selection 
Randomized 
L10.4 
Templates are provided in Section 19.2. These templates show what information will be 
contained in the listing, but the actual layout (e.g., order of columns, additional 
columns) may change to reflect what is actually received. Listings may be split into 
multiple listings if there are too many data points to fit on one page.  Numbering of 
listings may be adjusted to accommodate split listings, listings that are added, listings 
that are omitted due to no records.


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
  Syneos Health 
Page 60 of 65 
17. 
INDEX OF FIGURES 
The following figures will be produced (figure numbers and titles may be different in 
the final versions): 
Header 
Figure 
Number* 
Figure Title 
Analysis Population 
Tem-
plate 
14.2.2 
 
Pharmacokinetic Data Summary Tables and Figures 
 
 
 
14.2.2.1.1.1 
Mean (± SD) Plasma Concentration Curves for Nalbuphine 
and its Metabolites M1, M3, M4, and M5 (ng/mL) by Dose – 
Linear Scale – Dose Selection Phase, Part A 
Dose Selection PK 
F2.1 
 
14.2.2.1.1.2 
Mean (± SD) Plasma Concentration Curves for Nalbuphine 
and its Metabolites M1, M3, M4, and M5 (ng/mL)  by Dose – 
Log-linear Scale – Dose Selection Phase, Part A 
Dose Selection PK 
F2.1 
 
14.2.2.1.2.1 
Individual Plasma Concentration Curves for Nalbuphine and 
its Metabolites M1, M3, M4, and M5 (ng/mL)  by Dose – 
Linear Scale – Dose Selection Phase, Part A 
Dose Selection PK 
F2.2 
 
14.2.2.1.2.2 
Individual Plasma Concentration Curves for Nalbuphine and 
its Metabolites M1, M3, M4, and M5 (ng/mL) by Dose – Log-
linear Scale – Dose Selection Phase, Part A 
Dose Selection PK 
F2.2 
 
14.2.2.2.1 
Box Plot of Cmax for Nalbuphine and its Metabolites M1, M3, 
M4, and M5 – Dose Selection Phase, Part A 
Dose Selection PK 
F2.3 
 
14.2.2.2.2 
Box Plot of  AUClastfor Nalbuphine and its Metabolites M1, 
M3, M4, and M5 – Dose Selection Phase, Part A 
Dose Selection PK 
F2.3 
Templates are provided in Section 19.3. 
 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
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18. 
APPENDICES 
APPENDIX A: CALCULATIONS 
Derived Variable 
Variables used 
Calculation 
Notes 
General: 
Age (years) 
Date of Informed Consent (ICdate) 
Date of birth (DOB) 
If Informed Consent Form (IC) signed on 
birthday, then  
Age = year(ICdate)-year(DOB); 
Otherwise, 
Age = INT(ICdate-DOB)/365.25)  
The latter formula is only ~60% 
accurate on birthdays 
Body Mass Index (BMI) 
(kg/m2) 
Weight (WT) (kg) 
Height (HT) (m) 
BMI = WT / HT2 
 
AE Duration (DD:HH:MM) 
Onset date & time (start_dtm) 
Resolution date & time (stop_dtm) 
Duration = stop_dtm - start_dtm 
Calculated only for AEs which are 
resolved and start and stop times are 
known. If duration is in seconds, then 
it will be reported as “<1 min”. 
AE Duration (Days) 
Onset date (start_date) 
Resolution date (stop_date) 
Duration = stop_date - start_date+1 
Calculated only for AEs that are 
resolved and start and/or stop times 
are unknown 
Geometric Coefficient of 
Variation, CV (%) 
Data xi 
, where z2 is 
the variance of ln(xi) 
 
Derived PK parameters: 
Cmax 
Concentration at time i (Ci) over 
one inter-dosing interval 
Max i {Ci} 
Missing data are ignored 
tmax 
Concentrations Ci at times ti over 
one inter-dosing interval 
Smallest ti at which Cmax was observed 
 
The first time of peak concentration 
is used if the peak is obtained more 
than once 
1
%
100
2 


ze
CV


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 62 of 65 
Derived Variable 
Variables used 
Calculation 
Notes 
AUClast 
 
Concentrations Ci at times ti  
The area under the plasma concentration 
vs time curve from time 0 to last 
measurable concentration (AUClast) is 
calculated using the formula: 
𝐴𝑈𝐶last = ∑
𝐴𝑈𝐶(𝑡𝑖−𝑡𝑖+1)
𝑛−1
𝑖=1
, where 
t1 = 0 and tn = t. Concentrations Ci are 
measured at times ti, i=1,…,n. 
Method:  
 Sections with increasing or equal 
concentrations (Ci+1 ≥ Ci) calculated by 
linear trapezoidal rule: 
𝐴𝑈𝐶(𝑡𝑖−𝑡𝑖+1) = 1
2 ∗(𝐶𝑖+ 𝐶𝑖+1)
∗(𝑡𝑖+1 −𝑡𝑖)  
 Sections 
with 
decreasing 
concentrations (Ci+1 < Ci) calculated by 
log-linear trapezoidal rule: 
𝐴𝑈𝐶(𝑡𝑖−𝑡𝑖+1)
= (𝐶𝑖−𝐶𝑖+1) ∗(𝑡𝑖+1 −𝑡𝑖)
(ln 𝐶𝑖−ln 𝐶𝑖+1)
  
The area under the serum 
concentration-time curve will be 
calculated using the linear up/ log 
down trapezoidal rule. 
AUCinf  
Concentrations Ci at times ti; 
Clast and kel 
𝐴𝑈𝐶inf = 𝐴𝑈𝐶last + 𝐴𝑈𝐶t−inf, 
where t is the sampling time point of the 
last measurable concentration. AUCt-inf is 
calculated as: Clast/kel, where Clast is the last 
measurable concentration taken directly 
from the raw data.
The AUCt-inf must be ≤ 20% of the 
total area for AUCinf to be considered 
reliable. For subjects with unreliable 
AUCinf (because of 
extrapolation >20%), AUCinf will be 
flagged in the individual data.  
kel 
Concentrations Ci at times ti 
 
First order elimination rate constant (kel) 
associated with the terminal (log-linear) 
portion of the curve (the negative gradient 
At least three samples are needed 
during the terminal log-linear phase 
in order to reliably estimate the 
terminal rate constant. The adjusted 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
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Derived Variable 
Variables used 
Calculation 
Notes 
of the regression of log-concentration 
versus time in the elimination phase).  
 
square of the correlation coefficient 
(R-square adjusted) for the goodness 
of fit of the regression line through 
the data points must be at least 0.85 
for the kel value to be considered 
reliable. kel, t1/2 and AUCinf  will be 
flagged in the individual data 
Listings if kel value is not reliable. 
t½ 
Concentrations Ci at times ti 
 
Half-life (t½), the time for half the drug to 
be eliminated is calculated as ln(2)/kel 
Terminal elimination half-life, 
calculated as ln(2)/kel. 
If the time interval between the lower 
and upper time points used for the 
regression spans is less than the 
derived half-life itself then kel and 
the associated t½ will be considered 
unreliable. kel, t1/2 and AUCinf  will be 
flagged in the individual data listings 
if kel and the associated t½ value are 
not reliable. 
Flagged PK parameters will be 
excluded from summarization and 
statistical analyses. 
Derived PD parameters: 
Emax 
Response at time i (Ei) over one 
inter-dosing interval 
Max I {Ei} 
Missing data are ignored 
Emin 
Response at time i (Ei) over one 
inter-dosing interval 
Min I {Ei} 
Missing data are ignored 


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
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Derived Variable 
Variables used 
Calculation 
Notes 
TEmax 
Response at time i (Ei) at times ti 
over one inter-dosing interval 
Time at time i (
) 
 
The first time of peak response is 
used if the peak is obtained more 
than once 
TEmin 
Response at time i (Ei) at times ti 
over one inter-dosing  
Interval 
Time at time i (
) 
 
The first time of trough response is 
used if the trough is obtained more 
than once 
TA_AUE (AUE) 
PD effect score Ei at actual elapsed 
times ti over one inter-dosing 
interval. 
 
Then: 
, summation over all 
time intervals until the last non-missing 
PD score. 
Trapezoidal rule used to the 2 
consecutive non-missing data points 
Missing data are ignored. The actual 
elapsed time t0 for the pre-dose value 
is set to 0. 
 
i
time

i
E
E
t
TE
i
j
j
j



|
max
max
i
time

i
E
E
t
TE
i
j
j
j



|
min
min



2
1
1





i
i
i
i
i
E
E
t
t
AUE



n
i
i
AUE
AUE
1


Statistical Analysis Plan 
Final Version 1.1 
Trevi Therapeutics, Inc. 
Protocol # TR08 
 
Syneos Health # 1008910 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 65 of 65 
19. 
MOCK-UPS 
Attachment: Trevi TR08_1008910_SAP_Mock TLFs_Final_v1.1_08Aug19