Conditions: Prurigo Nodularis Nodularis Prurigo Prurigo
Keywords: Itch Chronic Itch Nalbupine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the overall safety of nalbuphine HCL ER tablets during a treatment period of up to 50 weeks.

Detailed description:

Arms:
arm 1: nalbuphine HCl ER

Interventions: intervention 1: nalbuphine HCl ER
Intervention descriptions: intervention 1: nalbuphine HCl ER BID for up to 50 weeks

Protocol document:
Prot_001.pdf: 
Trevi Therapeutics, Inc. 
Nalbuphine hydrochloride 
Protocol: TR03ext 
Clinical study report 
16.1.1 
Protocol and Protocol Amendments 
This section contains the following documents: 
Original protocol version 1.0 dated 24 June 2014 
Protocol Amendment 1 version 2.0 dated 11 March 2015 
Protocol Amendment 2 version 3.0 dated 02 June 2016 
 
Page 1


 
 
Page 1 of 97 
CLINICAL PROTOCOL 
 
Protocol Number: 
TR03ext 
 
Version Number: 
1.0 
Version Date: 
24 June 2014 
EudraCT No. 
2013-005628-41 
Protocol Title: 
An Open Label Extension Study of the Safety and Anti-
Pruritic Efficacy of Nalbuphine HCl ER Tablets in 
Prurigo Nodularis Patients  
Study Sponsor: 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, Connecticut 06510 
United States 
Phone: (203) 304-2499 
www.trevitherapeutics.com 
 
 
CONFIDENTIAL 
 
This document is the confidential and proprietary information of Trevi Therapeutics, Inc. By 
reviewing this document, you agree to keep it confidential and to use and disclose it solely for the 
purpose of assessing whether your organization will participate in and/or the performance of the 
proposed clinical study. Any permitted disclosures will be made only on a confidential 
“need-to-know” basis within your organization or to your independent ethics committee(s). Any other 
use, copying, disclosure, or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by Trevi Therapeutics, Inc. Any supplemental information (e.g., amendments) 
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 document. Any person who 
receives this document without due authorization from Trevi Therapeutics, Inc., is requested to return 
it to Trevi Therapeutics, Inc., or promptly destroy it. All other rights reserved. This study is to be 
performed in accordance with Good Clinical Practice (GCP), the ethical principles that have their 
origin in the Declaration of Helsinki, International Conference on Harmonisation (ICH) E6, and Title 
21 of the Code of Federal Regulations (CFR), Parts 50, 56, and 312 (or equivalent regulatory body 
regulations/guidelines, as applicable). 
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Investigators:  
 
 
 
Multicenter 
 
 
 
 
 
 
 
 
Research Facilities:  
 
 
Multicenter 
 
 
 
 
 
 
 
 
Institutional Review Board/ 
Independent Ethics Committee: Multicenter 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR: 
 
 
 
Trevi Therapeutics, Inc.  
 
 
 
 
 
 
195 Church Street, 14th Floor  
 
 
 
 
 
 
 
New Haven, CT 06510 
 
 
 
 
Office Phone: (203) 304-2499 
 
Office Fax: 
(203) 526-0266 
 
 
 
 
 
SPONSOR CONTACT:  
Thomas Sciascia, M.D. 
Chief Medical Officer 
Trevi Therapeutics, Inc. 
 
 
 
 
 
 
195 Church Street, 14th Floor 
New Haven, CT 06510 
Office Phone    (203) 304-2499 
Office Fax:       (203) 526-0266  
 
 
 
 
 
 
 
 
 
 
 
 
MEDICAL MONITOR:  
Edward Matheis, MD, PPD Medical Monitor 
 
 
 
 
 
 
Telephone:  
(888) 483-7729 
 
 
 
 
 
 
Fax:   
 
(888) 529-3580 
 
 
Serious Adverse Event Fax number:  
(888) 529-3580 
 
  
 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
 
I have read the attached protocol entitled A Randomized, Double-Blind, Placebo-Controlled, Parallel, 3- 
Arm Study of the Safety and Anti-Pruritic Efficacy of nalbuphine HCl ER Tablets in Prurigo Nodularis 
Patients dated 24 JUNE 2014 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on Good 
Clinical Practice and applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 
Title 21 of the CFR, Parts 11, 50, 54, 56, and 312 or equivalent regulatory body regulations/guidelines, as 
applicable. 
 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
Myself (including, if applicable, my spouse [or legal partner], and dependent children) 
• 
My subinvestigators (including, if applicable, their spouses [or legal partners], and dependent children) 
The Financial Disclosure Statements will be completed before study initiation, during the study if there are 
changes that affect my financial disclosure status, and after the study is completed. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Trevi Therapeutics, Inc. 
 
 
 
 
 
 
 
Principal Investigator: 
__________________________________ 
___________ 
 
Name of Principal Investigator 
 
 
Date 
 
__________________________________ 
 
 
Institution or Clinical Practice 
 
 
 
 
__________________________________ 
 
 
 
 
 
      Signature 
 
 
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1 STUDY SYNOPSIS 
 
Title 
An Open Label Extension Study of the Safety and Anti-
Pruritic Efficacy of Nalbuphine HCl ER Tablets in Prurigo 
Nodularis Patients  
Sponsor 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, Connecticut  06510 
United States 
Phone: (203) 304-2499 
www.trevitherapeutics.com 
Protocol Number 
TR03ext 
Version and Date 
Version 1.0 dated 23 JUNE 2014 
Indication 
Prurigo Nodularis (PN) 
Investigational Product  
nalbuphine hydrochloride (HCl) extended-release (ER) 
tablets 
Active Ingredient 
nalbuphine hydrochloride 
Route of Administration  
Oral 
Duration of Study 
The total study duration for any individual patient will be up 
to 52 weeks.  Patients will receive drug treatment for up to 
50 weeks. 
Study Phase 
Phase 2/3  
Study Design 
Open label 
Planned Sample Size 
No a priori planned sample size is designated for this study.  
Eligible patients who have successfully completed the TR03 
study and wish to participate in TR03ext may be enrolled, 
treated, and analyzed. The maximum number of patients will 
not exceed the number of patients who complete the TR03 
study  (i.e., up to 60 patients) 
Total Number of Centers 
Up to 7 sites in North America and Europe  
Primary Objective 
• 
To evaluate the safety and tolerability of nalbuphine 
HCL ER tablets during a drug treatment period of up 
to 50 weeks. 
Secondary Objectives 
• 
To evaluate the safety of nalbuphine by achieved 
maintenance dose at the end of Treatment Period 
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Week 4.  
• 
Assess skin lesion improvement using the metrics of 
the PAS  
• 
Changes in Patient-Reported Outcome measures 
(worst
• 
the percentage of patients utilizing various doses of 
nalbuphine ER tablets by Study Week 
 itch NRS, average daily itch intensity NRS, 
VRS (itchy, burning and stinging), ItchyQoL, MOS 
Sleep-R, HADS and PBI-P) during the Treatment 
Period 
• 
the frequency and reasons for down-titration and 
treatment discontinuation during the study 
• 
the changes in the PRO measurements during the 
Washout Period after cessation of treatment of 
nalbuphine HCl ER tablets 
• 
the number of days of use of rescue medications for 
itching. 
Exploratory Objectives 
The exploratory objectives of the study are to evaluate the 
effect of nalbuphine HCl ER tablets on: 
• 
The potential of nalbuphine HCl ER tablets to impact 
on the measurement of nerve fiber density 
(histology) and MOR/KOR density (histology, 
Western Blot) in skin biopsies taken at the last 
Treatment Period Visit when compared to biopsy 
material assessed during study TR03 (selected sites 
only). 
Selection Criteria 
Inclusion Criteria: 
Patients must meet all of the following criteria to be eligible: 
1. Have been adequately informed of the nature and 
risks of the study and have given written informed 
consent at or prior to Visit 1a. 
2. Have completed participation in the TR03 study. 
Completion of participation in the TR03 study is 
defined as completion of Study Drug treatment 
through TR03 Visit 5 and completion of the TR03 
Visit 6.  
3. Agree to comply with the contraception requirements 
as below: 
Female patients of childbearing potential are 
required to use one barrier method (e.g., condom, 
cervical cap, or diaphragm) of contraception in 
addition to one other method (e.g., intrauterine 
device [IUD], hormonal contraception, tubal ligation, 
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Essure procedure, or spermicide).  
4. Ability and acceptance to provide written informed 
consent. 
5. Willing and able to comply with study requirements 
and restrictions  
6. Agree to the confidential use and storage of all data 
(including photography) and use of all anonymized 
data for publication including scientific publication. 
Selection Criteria 
Exclusion Criteria: 
If a patient meets any of the following criteria, he or she is 
not eligible: 
1. Significant medical condition or other factors that in 
the opinion of the Investigator may interfere with the 
conduct of the study. 
2. Known hypersensitivity or allergy to nalbuphine or 
formulation components.  
3. Is a pregnant or lactating female. 
Study Treatment 
Allocation 
All patients who are enrolled into the study will receive 
active treatment with nalbuphine HCl ER tablets. 
Study Procedures 
 
 
Visit 1a of the TR03ext study is temporally the same visit as 
TR03 Visit 6. Informed consent for this study will be 
obtained during Study TR03 Visit 6, or earlier.  Subjects who 
do not consent by the end of the TR03 study visit 6 are no 
longer eligible for the extension study.  Study TR03 Visit 6 
procedures in common with Study TR03ext Visit 1a 
procedures do not have to be repeated.   
For all patients, TR03 extension study Visits (both during the 
Treatment Period and Observation Period) will include 
recording of vital signs, completion of PRO questionnaires, 
assessment of AEs, and recording of concomitant 
medications.  
For All Patients: 
On Visit 1a, patients will either enter directly into the drug 
Treatment Period or into a no-drug Observation Period based 
on their reported worst itch NRS scores on that Visit day.  
Patients with 
Patients with NRS >2 enter the Treatment Period: 
worst itch NRS > 2 at Visit 1a will start in the 
drug Treatment Period of the study and will receive Study 
Drug starting with an evening 30 mg dose (to be taken at 
home), after the Treatment Visit 1a procedures have been 
completed. Receipt of the first dose of study drug will define 
Treatment Period Day 1. Treatment Visit 1a for these 
patients is also Treatment visit 1 (TV1).  Subsequent visits 
will be defined as TV2, TV3, etc.  In addition, during the 
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time period of dose titration, information will be obtained via 
telephone communication; these will be defined as TC1, and 
TC2. 
The dose will be titrated for up to 4 weeks, after which time 
the dose achieved (90mg BID, 120mg BID or 180 mg BID) 
as of the end of Treatment Week 4 will be maintained up to 
an additional 46 weeks (with the exception of a single 
allowable down titration permitted). Patients requiring a 
second down-titration after Treatment Period week 4 must be 
discontinued from the study (see Table 3 dosing schedule). 
For patients transitioning from the Observation period, the 
total time in the Treatment Period plus any time in the 
Observation Period will be a total of 50 weeks.   
Safety laboratory data and blood for PK, ECGs, and physical 
examinations including the PAS assessment will be 
performed periodically according to the Schedule of Events 
(See Appendix 1). Schematic descriptions of the study can be 
found in Appendix 2. 
All patients on drug treatment will enter a 2-week wash-out 
and safety follow up period following end of the Treatment 
Period with procedures conducted according to the 
Schedule of Events (See Appendix 1). 
Patients with NRS ≤ 2 at Visit 1a will enter into an extended 
screening period, the Observation Period (no drug treatment), 
of the study and will be followed for up to 12 weeks. Visit 1a 
for these patients is also Observational Visit 1 (OV1).  
Subsequent visits will be defined as OV2, OV3 and OV4 and 
will occur at approximately monthly intervals for the next 3 
months.   
Patients with NRS ≤ 2 enter the Observation Period: 
During this Observation period, patients who report NRS 
score increases to >2 at any one of their Observation Visits 
will be eligible to enroll immediately into the Treatment 
Period of the study and that same visit is now referred to as 
Visit1b.  Patients will receive open-label Study Drug starting 
with an evening 30 mg dose (to be taken at home), after the 
Visit 1b procedures have been completed.  Receipt of the 
first drug will indicate the start of their Treatment Period and 
enrollment into the study. The duration of the Treatment 
Period for such a patient will equal 50 weeks minus the 
number of weeks spent in the Observation Period (i.e., the 
sum of time in the Observation Period and Treatment Period 
will not exceed 50 weeks). 
Patients in the Observation Period whose NRS scores 
remain ≤2 over the 12 weeks will be screen failed from 
the study at the end of that time period. 
Safety Assessments 
Safety will be assessed based on adverse events (AEs), 
clinical laboratory measurements, 12-lead electrocardiogram 
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(ECG), vital signs and physical examinations. 
Efficacy Assessments 
Efficacy Measurements: 
• 
worst
• 
average itch intensity (from NRS)  
 itch intensity (from NRS) 
• 
VRS (itchy, burning and stinging) 
• 
ItchyQoL  
• 
MOS Sleep-R 
• 
HADS 
• 
PAS  
• 
PBI-P 
• 
Frequency, pattern, and reasons for dose titration 
• 
Use of rescue medications for itching 
At selected sites: 
• 
Nerve fiber density (histology) at Baseline and at 
the final Treatment Period visit 
• 
MOR/KOR density (histology, Western Blot) at 
Baseline and at the final Treatment Period visit. 
Pharmacokinetic 
Assessments 
Blood samples for nalbuphine plasma concentration (and 
metabolites as needed) will be collected periodically 
according to the Schedule of Events (Appendix 1).  
Study  Endpoints 
Primary Endpoint: 
• 
A description of the incidence and nature of TEAEs 
during Treatment Weeks 5- 50 
Secondary Endpoints 
Visit 1a or 1b will serve as the baseline visit for efficacy 
endpoints. Visit 1a will be the baseline for patients 
directly entering the Treatment Period as of Visit 1a.  
Visit 1b will be the baseline for patients entering the 
Treatment Period after participating in the Observation 
Period for any length of time. 
• 
Assess skin lesion improvement using the metrics of 
the PAS  
• 
Change from Baseline in Patient-Reported Outcome 
measures (worst
• 
Change between Baseline and final Treatment Period 
visit in PBI-P 
 itch NRS, average daily itch 
intensity NRS, VRS (itchy, burning and stinging), 
MOS Sleep-R, ItchyQoL, HADS) by Treatment 
Period study visit and Baseline NRS score categories 
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• 
A description of the percentage of patients utilizing 
various doses of nalbuphine HCl ER tablets by Study 
Week 
• 
A description of the frequency and reasons for dose 
up- and down-titration and treatment discontinuation 
during the study 
• 
To describe the changes in the PRO measurements 
during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets 
• 
The number of days of use of rescue medications for 
itching. 
Exploratory Endpoint 
Impact on the measurement of nerve fiber density (histology) 
and MOR/KOR density (histology, Western Blot) in skin 
biopsies taken at the last Treatment Period Visit when 
compared to biopsy material assessed during study TR03. 
(selected sites only). 
Statistical Methodology 
Efficacy:  
All efficacy endpoints will be evaluated through the 
generation of summary statistics.  For continuous variables, 
the mean, standard deviation, median, minimum, and 
maximum will be presented for a particular visit and for the 
change from baseline (Visit 1a or 1b).  For categorical 
variables, the number and percentage of patients within each 
category of classification will be summarized by study visit.  
No formal statistical testing will be conducted. 
Safety: 
The incidence of AEs will be summarized through the 
presentation of proportions by MedDRA body system 
classification and preferred term.  Vital signs and laboratory 
data will be summarized using continuous-based descriptive 
statistics (n, mean, SD, median, minimum, maximum).  The 
extent and duration of use of rescue medications will be 
similarly summarized using descriptive statistics.  Summary 
statistics for AEs with onset during the Observation Period 
will be separately summarized. No formal statistical analysis 
will be performed on safety outcomes; inferences, if any, will 
be derived through clinical review and interpretation. 
 
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Table of Contents 
1 
STUDY SYNOPSIS ................................................................................................. 5 
LIST OF TABLES .......................................................................................................... 14 
LIST OF FIGURES ........................................................................................................ 14 
2 
LIST OF ABBREVIATIONS ............................................................................... 15 
3 
INTRODUCTION ................................................................................................. 17 
3.1 
PRURIGO NODULARIS AND STUDY RATIONALE .................................................. 17 
3.1.1 
General Information on Prurigo Nodularis ........................................................ 17 
3.1.2 
Potential Mechanism of Prurigo Nodularis Pathophysiology............................ 19 
3.1.3 
Rationale for Investigating Nalbuphine HCl ER in Prurigo Nodularis ............. 22 
3.2 
NALBUPHINE ......................................................................................................... 26 
3.3 
NALBUPHINE HCL ER TABLET CLINICAL DEVELOPMENT ............................... 26 
3.3.1 
Overall Summary ............................................................................................... 26 
3.3.2 
Clinical Study TR01 in Hemodialysis Patients and Healthy Volunteers........... 27 
3.3.3 
Additional Nalbuphine HCl ER Tablet Clinical Data ....................................... 29 
4 
STUDY OBJECTIVES.......................................................................................... 30 
4.1 
PRIMARY OBJECTIVE ........................................................................................... 30 
4.2 
SECONDARY OBJECTIVES ..................................................................................... 30 
4.3 
EXPLORATORY OBJECTIVES ................................................................................ 30 
5 
STUDY ENDPOINTS............................................................................................ 31 
5.1 
PRIMARY ENDPOINT ............................................................................................. 31 
5.2 
SECONDARY ENDPOINTS ...................................................................................... 31 
5.3 
EXPLORATORY ENDPOINTS.................................................................................. 31 
6 
NUMBER OF SITES AND PATIENTS .............................................................. 31 
7 
ESTIMATED STUDY DURATION .................................................................... 32 
8 
SELECTION CRITERIA ..................................................................................... 32 
8.1 
STUDY POPULATION ............................................................................................. 32 
8.2 
INCLUSION CRITERIA ........................................................................................... 32 
8.3 
EXCLUSION CRITERIA .......................................................................................... 32 
9 
STUDY PLAN ........................................................................................................ 33 
9.1 
GENERAL STUDY DESIGN ..................................................................................... 33 
9.2 
RATIONALE FOR STUDY DESIGN .......................................................................... 33 
9.3 
SAFETY MONITORING PLAN ................................................................................ 34 
9.4 
RISK-BENEFITS ..................................................................................................... 36 
9.5 
STUDY OVERVIEW ................................................................................................ 36 
9.6 
STUDY PROCEDURES ............................................................................................ 37 
9.6.1 
Visit 1a (Day 1 of Study Week 1)...................................................................... 38 
9.6.2 
Treatment Period (Study Weeks 1-50) .............................................................. 40 
9.6.3 
Washout and Safety Follow-Up Period (Week 52) ........................................... 44 
9.6.4 
Early Termination Visit ..................................................................................... 45 
9.6.5 
Observation Period (Study Weeks 1-12) ........................................................... 45 
9.6.6 
Unscheduled Visits ............................................................................................ 48 
9.6.7 
Schedule of Events............................................................................................. 48 
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9.7 
STUDY DRUG TREATMENT AND DRUG ACCOUNTABILITY .................................. 48 
9.7.1 
Study Drug Dosing ............................................................................................ 48 
9.7.2 
Down-Titration .................................................................................................. 50 
9.7.3 
Overdose ............................................................................................................ 50 
9.7.4 
Treatment Compliance ....................................................................................... 50 
9.7.5 
Rescue Medications, Concomitant Medications, Prohibited Medications, and 
Pre-Medications ................................................................................................................ 50 
9.7.6 
Efficacy Assessments ........................................................................................ 51 
9.7.7 
Safety Assessments ............................................................................................ 54 
10 
STUDY DRUG ....................................................................................................... 54 
10.1 
FORMULATION, PACKAGING AND LABELING ...................................................... 54 
10.2 
SHIPPING, STORAGE AND HANDLING .................................................................. 54 
10.3 
UNBLINDING ......................................................................................................... 54 
10.4 
DRUG ACCOUNTABILITY ...................................................................................... 55 
11 
PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT ... 55 
12 
PREMATURE WITHDRAWL OF PATIENTS FROM THE STUDY ........... 55 
13 
WARNINGS AND PRECAUTIONS ................................................................... 56 
14 
EFFICACY EVALUATIONS .............................................................................. 56 
14.1 
EXPLORATORY ..................................................................................................... 56 
15 
COLLECTION, HANDLING, AND ANALYSIS OF PHARMACOKINETIC 
BLOOD SAMPLES ............................................................................................... 57 
15.1 
BLOOD SAMPLE COLLECTION ............................................................................. 57 
15.2 
CENTRAL LABORATORY ...................................................................................... 57 
15.3 
PHARMACOKINETIC SAMPLES ............................................................................. 57 
15.4 
PREPARATION, STORAGE, AND HANDLING FOR PHARMACOKINETIC SAMPLES 57 
15.5 
ANALYTICAL ......................................................................................................... 58 
16 
TISSUE SAMPLES AND HISTOLOGY ............................................................ 58 
17 
SAFETY EVALUATIONS ................................................................................... 58 
17.1 
PHYSICAL EXAMINATION ..................................................................................... 58 
17.2 
VITAL SIGN MEASUREMENTS .............................................................................. 58 
17.3 
LABORATORY EVALUATIONS ............................................................................... 59 
17.4 
ELECTROCARDIOGRAM .............................................................................. 59 
17.5 
ADVERSE EVENTS ................................................................................................. 59 
17.5.1 
Adverse Event Definition .................................................................................. 59 
17.5.2 
Serious Adverse Events ..................................................................................... 60 
17.5.3 
Non-Serious Adverse Events ............................................................................. 61 
17.5.4 
Definition of Relationship to Study Medication ................................................ 61 
17.5.5 
Definition of Severity ........................................................................................ 62 
17.5.6 
Definition of Unexpected Adverse Event .......................................................... 62 
18 
EMERGENCY PROCEDURES .......................................................................... 62 
18.1 
EMERGENCY SPONSOR CONTACT ........................................................................ 62 
19 
CONSIDERATION, ANALYSIS PLAN AND DETERMINATION OF 
SAMPLE SIZE ....................................................................................................... 63 
19.1 
GENERAL .............................................................................................................. 63 
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19.2 
INTERIM ANALYSES .............................................................................................. 63 
19.3 
METHODS FOR HANDLING MISSING DATA .......................................................... 63 
19.4 
PATIENT DISPOSITION .......................................................................................... 63 
19.5 
BASELINE CHARACTERISTICS .............................................................................. 63 
19.6 
CONCOMITANT MEDICATIONS............................................................................. 63 
19.7 
STUDY DRUG DOSING ............................................................................................ 63 
19.8 
EFFICACY ANALYSES ............................................................................................ 63 
19.8.1 
Efficacy Population............................................................................................ 63 
19.8.2 
Premature Discontinuation Due to Lack of Efficacy or Adverse Events .......... 64 
19.9 
SAFETY ANALYSES ............................................................................................... 64 
19.9.1 
Safety Population ............................................................................................... 64 
19.9.2 
Adverse Events .................................................................................................. 64 
19.9.3 
Vital Signs.......................................................................................................... 64 
19.9.4 
Laboratory Evaluations ...................................................................................... 64 
19.9.5 
Physical Examinations ....................................................................................... 65 
19.9.6 
Electrocardiograms ............................................................................................ 65 
19.10 DETERMINATION OF SAMPLE SIZE ...................................................................... 65 
19.11 PHARMACOKINETIC AND PHARMACOKINETIC / 
PHARMACODYNAMIC ANALYSES ............................................................. 65 
20 
ETHICS .................................................................................................................. 65 
20.1 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD ........ 65 
20.2 
ETHICAL CONDUCT OF THE STUDY ..................................................................... 66 
20.3 
PATIENT INFORMATION AND INFORMED CONSENT ............................................ 66 
21 
STUDY ADMINISTRATION .............................................................................. 66 
21.1 
CLINICAL MONITORING ....................................................................................... 66 
21.2 
DATA QUALITY ASSURANCE ................................................................................ 67 
21.3 
RETENTION OF STUDY RECORDS ......................................................................... 67 
21.4 
CONFIDENTIALITY ................................................................................................ 68 
21.5 
DOCUMENTATION OF STUDY RESULTS ................................................................ 68 
21.6 
USE OF STUDY RESULTS ....................................................................................... 69 
22 
REFERENCES....................................................................................................... 70 
APPENDICES ................................................................................................................. 76 
APPENDIX 1: 
SCHEDULE OF EVENTS ......................................................................... 77 
APPENDIX 2: 
STUDY SCHEMATIC FLOW CHARTS ..................................................... 83 
APPENDIX 3: 
CLINICAL LABORATORY TESTS ........................................................... 86 
APPENDIX 4:  
PATIENT REPORTED OUTCOMES ......................................................... 87 
Medical Outcomes Sleep Scale (Revised MOS Sleep-R)................................................. 88 
ItchyQoLTM ....................................................................................................................... 90 
Prurigo Activity Score (PAS) ........................................................................................... 93 
Patient Benefit Index, Pruritus Version (PBI-P) ............................................................... 94 
Numerical Rating Scale (Worst Itch) ................................................................................ 96 
Numerical Rating Scale (Average-Itch)............................................................................ 96 
Verbal Rating Scale .......................................................................................................... 96 
Hospital Anxiety and Depression Scale (HADS) ............................................................. 97 
 
 
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LIST OF TABLES 
TABLE 1: 
ETIOLOGY OF CHRONIC PRURITUS REPORTED IN PRURIGO NODULARIS 
PATIENTS (N=108)..................................................................................................... 18 
TABLE 2:  
TR03EXT STUDY PERIODS ............................................................................ 37 
TABLE 3: 
 DOSING SCHEDULE FOR TR03EXT ............................................................... 49 
TABLE 4: SCHEDULE OF EVENTS FOR VISITS 1A AND 1B .................................................... 77 
TABLE 5:  
TREATMENT PERIOD WEEKS 2-4 ................................................................... 78 
TABLE 6: TREATMENT PERIOD VISITS12 DURING STUDY WEEKS 5-50 AND 
WASHOUT/SAFETY FOLLOW-UP VISIT OR TREATMENT PERIOD EARLY TERMINATION 
VISIT .......................................................................................................................... 79 
TABLE 7:  
OBSERVATION PERIOD VISITS5 ..................................................................... 80 
TABLE 8:  
SCHEDULE OF NEXT TREATMENT PERIOD VISITS FOR PATIENTS 
TRANSITIONED FROM THE OBSERVATION PERIOD AND WHO COMPLETE TITRATION .. 81 
TABLE 9: RESCUE MEDICATIONS FOR ITCHING .................................................................. 82 
 
LIST OF FIGURES 
 
FIGURE 1:  
MEAN VAS SCORE (SD) FOR ALL PATIENTS AS A FUNCTION OF NALBUPHINE 
HCL DOSE ADMINISTERED AS NALBUPHINE HCL ER TABLETS.  N= 14 EXCEPT FOR 180 
MG (N=13) AND 240 MG (N=4).  SOURCE: NAL.001.TR01.PD
 
 ................................. 25
FIGURE 2:  
OVERVIEW OF TR03-EXT STUDY DESIGN
 
 ................................................... 83
FIGURE 3:  
EXAMPLES ILLUSTRATING POSSIBLE OBSERVATION AND TREATMENT PERIODS 
SCENARIOS IN TR03-EXT
 
 .......................................................................................... 84
FIGURE 4:  
DOSING SCHEDULE IN TR03EXT
 
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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic and Therapeutic Class 
BID 
Twice daily 
BMI 
Body Mass Index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
e-diary 
Electronic daily patient diary 
ER 
Extended release 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&E 
Hematoxylin and eosin 
HADS 
Hospital Anxiety and Depression Scale 
HCG 
Human chorionic gonadotropin 
HCl 
Hydrochloric acid 
HD 
Hemodialysis 
H pylori 
Helicobacter pylori 
HR 
Heart rate 
ICF 
Informed consent form 
ICD-10 
International Classification of Diseases, 10th revision  
ICH 
International Conference on Harmonization 
IFSI 
International Forum for the Study of Itch  
IRB 
Institutional Review Board 
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Abbreviation 
Definition 
IUD 
Intra-uterine device 
KOR 
Kappa Opiate Receptor 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOR 
Mu Opiate Receptor 
MOS 
Medical Outcomes Study 
MITT 
Modified Intent-To-Treat 
NONMEM 
Non-linear mixed effects modeling 
NRS 
Numerical Rating Scale 
OV 
Observation Period Visit 
OTC 
Over-the-counter 
PAS 
Prurigo Activity Score 
PBI-P 
Patient Benefit Index, pruritus version 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic 
PN 
Prurigo Nodularis 
PRO 
Patient-Reported Outcome; In this study, PRO instruments 
administered at the site are as follows: NRS, VRS, ItchyQoL, 
PBI-P, MOS Sleep-R, HADS 
QoL 
Quality of Life 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SD 
Standard deviation 
TC 
Telephone Call 
TV 
Treatment Period Visit 
UP 
Uremic Pruritus 
VRS 
Verbal Rating Scale 
WHO 
World Health Organization 
 
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3 INTRODUCTION 
3.1 
PRURIGO NODULARIS AND STUDY RATIONALE 
3.1.1 General Information on Prurigo Nodularis 
Prurigo Nodularis (PN) is an intensely pruritic dermatologic condition with the presence of 
papules as well as nodules with excoriations and ulcerations.  The basis of PN is a pre-
existing severe and chronic pruritus of various etiologies (see Table 1). The pruritus leads 
to scratching. However, the etiology or predisposing factors leading to the development of 
papules and nodules of PN are largely unknown (Eigelshoven et al 2009; Valdya and 
Schwartz 2008; Lee and Shumack 2005). Iking et al (2012) reports that in the past few 
years the hypothesis for the etiology of PN as being a reaction pattern due to a “vicious 
cycle of repeated itching and scratching” is gaining wider acceptance in the medical 
community. 
 
With regard to the types of pre-existing chronic pruritus conditions that have been reported 
in PN patients, Table 1 summarizes data reported by Iking et al (2012) in their study of PN 
patients (N=108). Pruritus secondary to multi-factorial etiologies (“Mixed Origin”) was the 
most common source attributed to the cause of the chronic pruritus. The majority of the 
“mixed origin” patients had a combination of dermatological and systemic diseases or a 
combination of several systemic disorders. 
 
Iking et al (2012) did not attribute any cases of PN to an underlying diagnosis that was 
solely psychological in origin.  In the subjects who were diagnosed with PN from mixed 
origin etiologies (summarized in Table 1), the authors attributed psychological factors 
related to chronic pruritus etiology to be present in 5.6% of the PN subjects categorized as 
having mixed (multi-factorial) origin pruritus.  In a study focused on understanding 
psychosomatic/psychiatric dimensions related to chronic itch, Schneider et al (2006) 
reported on 44 PN patients.  The authors stated that 34% of subjects had no accompanying 
psychiatric diagnosis and 46.8% were given a diagnosis of “psychological or behavioral 
factors associated with disorders classified elsewhere” (ICD-10 code F54) –indicating that 
psychological factors may play a role in the development and course of the condition. 
Payne et al (1985) reported psycho-social problems may have been relevant in about 33% 
of the studied 42 subjects that were adequately questioned. 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1: Etiology of Chronic Pruritus Reported in Prurigo Nodularis Patients 
(N=108) 
Origin of Pruritus by 
Organ System 
Number 
of 
Patients (%) 
 %  Mixed with Organ 
Category Contribution to 
Chronic Pruritus 
Most Common 
Disease 
 
 
 
 
 
 
 
Mixed 
(pruritus 
of 
multi-factorial 
etiologies) 
 
 
 
 
 
 
 
64  (59.3%) 
 
 
Dermatological Disease 
(19.4%) 
Atopic diathesis 
 
 
 
Systemic Diseases 
(70.9%) 
Sorbitol 
Intolerance 
Lactose 
Intolerance 
Iron Deficiency 
H pylori 
Infection 
Diabetes 
Mellitus 
Renal Failure 
Neurological Disease 
(4.1%) 
Chronic pain 
Syndrome 
Neuropathy 
PUVA-pain 
Psychological Factors 
(5.6%) 
Psychological 
Factors (non-
specific) 
Origin of Pruritus by 
Organ System 
Number 
of 
Patients (%) 
      Most Common Disease 
Dermatological 
20  (18.5%) 
Atopic diathesis/dermatitis 
 
 
 
 
Systemic 
 
 
 
 
8    (7.4%) 
Sorbitol Intolerance 
Lactose Intolerance 
Hepatitis C 
H pylori infection 
Iron Deficiency 
Diabetes Mellitus 
Unknown 
14   (13%) 
- 
Neurological 
2    (1.9%) 
Brachio-radial Pruritus 
Psychological  
0      (0%) 
- 
Source: Iking et al (2012) 
 
Iking et al (2012) reported that the median value of the NRS average intensity pruritus 
measured 8 on a rating scale with anchor points of zero (no pruritus)-10 (worst imaginable 
pruritus).  Itch intensity scores ≥ 7 are considered severe in terms of itch intensity and itch 
intensity scores ≥ 3 are considered moderate in terms of itch intensity (Stander et al 2013).  
Accioly-Filho et al (2000) reports that once the cycle of pruritus-excoriation-pruritus 
begins, it is difficult to stop as PN is very resistant to therapeutic intervention strategies.  
Papoiu et al (2013) report a central nervous system relationship to the itch-scratch cycle. 
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The authors showed that there is a complex interaction of sensory, motor and emotional 
components based on their investigation of using real-time flare brain MRI imaging and 
psychophysical ratings of itch relief or pleasurability of scratching conducted in healthy 
volunteer experimental subjects. 
 
Eigelshoven et al (2009) reports that patients present with excruciating pruritus that is 
usually anatomically symmetrical and mainly involves the extensor aspects of the 
extremities, the shoulders, chest and sacral regions with the appearance of typical lesions. 
Payne et al (1985) reported in a study of 46 subjects that the patients came from all social 
classes and racial groups, almost equally divided by gender and with a mean age of 39.5 
years at the time of PN onset.  Iking et al (2012) reported in their study that the patients 
were distributed in age between 11.9 years - 95.6 years with a median age of 61.9 years and 
there were more females than males affected by the disease.  
 
Weigelt et al (2010) summarized the characteristic histological findings in PN that include 
the presence of thick compact orthohyperkeratosis; folliculosebaceous units in nonvolar 
skin in conjunction with a thick and compact cornified layer; irregular epidermal 
hyperplasia or pseudoepitheliomatous hyperplasia; focal parakeratosis; hypergranulosis; 
fibrosis of the papillary dermis with vertically arranged collagen fibers; increased number 
of fibroblasts and capillaries; a superficial, perivascular and/or interstitial inflammatory 
infiltrate of lymphocytes, macrophages and, to a lesser extent, eosinophils and neutrophils. 
 
In terms of treatment options for PN, there have been a variety of medical interventions 
discussed.  Hogan et al (2012) recently reviewed the therapies discussed in the literature 
that included topical, systemic and intra-lesion steroids administration; antihistamines; 
anxiolytics; opiate receptor antagonists; thalidomide; gabapentin; capsaicin cream; topical 
anesthetics; occlusive therapies; ultraviolet light; and reports that they had “mild to 
moderate success at best”.  The authors also comment on the potential imbalance in the 
mu-kappa opiate receptor system and mention the possibility of studying the kappa agonist 
nalfurafine (see section 3.1.3.1, where nalfurafine was used as a positive control in 
Sponsor’s preclinical substance P mouse model of itch investigation).  Spring et al (2014) 
reported on the use of methotrexate and the need for chemotherapeutic related regular 
medical monitoring.   Liu et al (2013) and Kanavy (et al 2012) both reported on 
lenalidomide is case reports, but the drug led to side effect of a reversible myopathy in one 
of the subjects.  Accioly-Filho (2000) reported the condition is “notoriously resistant to 
therapy”.  Iking et al (2012) and Valdya and Schwartz (2008) reported a significant impact 
on the patient’s quality of life (2008).  Spring et al (2014) report PN to be debilitating 
condition and a therapeutic challenge where conventional treatments with steroids, 
standard anti-pruritic agents, phototherapy and immune-suppressors often fail.   
3.1.2 Potential Mechanism of Prurigo Nodularis Pathophysiology 
3.1.2.1 Opiate Neurobiology 
The initiating biological event in the skin is unclear but assumed to patho-physiologically 
result from a complex cross talk of different skin cells.  The neurobiology of opioid 
peptides may be involved at the peripheral level as part of a reaction to the skin tissue 
injury.  Therapeutic intervention at the peripheral level through opioid pharmacology to 
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break the scratch-itch cycle via interrupting positive feedback loops that have developed 
between elements of the peripheral nervous system, immune system and various skin cell 
interactive dynamics may be possible.  In addition, central nervous system opiate 
neurobiology may be involved in a positive feedback loop between the tremendous urge to 
scratch and the pleasurable anti-pruritic relief gotten from scratching that could also be a 
level of therapeutic intervention using opioid pharmacology. 
3.1.2.2 Systems Biology Hypothesis to Prurigo Nodularis Etiology  
Diseases that arise from an abnormal interaction between integrated body system networks 
and exhibit the concept of a positive feedback cycle which lead to an amplification of a 
biological signal can be discussed using concepts from systems biology (Kitano 2004). The 
physiological phenomena of a “scratch-itch cycle” (“positive feedback loop”) underlying 
the patient’s behavior, the intense (“amplified”) nature of the pruritus and the large areas of 
body surface involvement in the absence of an active dermatosis suggest a “generalized” 
process either potentially due to central nervous system circuitry pathophysiology and/or 
widespread derangement of the dermal-immune-nervous system component interactions. 
PN may be analogous to chronic regional pain syndrome – a condition where there may or 
may not be an initiating etiological event, the intensity of pain is severe, the sensation of 
pain spreads to wide areas of the body surface and the condition is regarded as a systemic 
disease that involves both the central and peripheral components of the nervous system 
along with interactions with the immune system (Schwartzman et al 2009).  C omplex 
regional pain syndrome is completely independent of any potential nociceptive initiating 
event.  Schmelz (2005) reviewed the literature on t he evidence of similar biological 
patterns occurring in chronic pain and chronic itch conditions.  Iking et al (2012) reported 
that on onset, PN was localized in 68.5% of patients with only 31.5% having generalized 
PN. In the majority of patients (56.5%), a secondary generalization of PN was observed. In 
the course of PN, only 12.0% still suffered from a localized form of PN. 
3.1.2.3 Relevant Cutaneous Peripheral Neurobiology in the Skin 
The complex neurochemical/neurohumoral interactions between the cutaneous resident 
mast cells and epidermal keratinocytes with peripheral non-myelinated type C nerve 
endings responsible for initiating the behavior of scratching as an evolved protective 
response to exogenous invading skin irritants is well summarized by Raap et al (2011) and 
the current understanding of the peripheral neuroanatomy-spinal cord synaptic connections 
underlying itch is well summarized by Dhand et al (2014).  Selected aspects of this 
neurobiology as they relate to the development of some specifics of the known pathology 
in PN will be summarized.   
 
The cellular initiation of itch can begin with the mast cell release of histamine that binds to 
H1 receptors on nerve fibers (Raap et al 2011).  Endorphins and other opiate peptides are 
known to cause histamine mast cell release (Barke et al 1993).  Endorphin itch initiation 
biology may be more direct.  Bigiliardi and Bigliardi-Qi (2004) observed that while 
histamine interaction with nerve fibers may be a source of itch sensation, they summarize 
evidence for direct opiate peptide interaction with nerve fiber endings expressing 
endorphin receptors as a contributor to itch sensation initiation.   
 
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With regard to the skin cells themselves, keratinocytes are known to produce different 
neuropeptides that include proopiomelanocortin (POMC), which is a precursor for the 
opiate peptide beta-endorphin (Bigliardi et al 1998).  In addition, mast cell activation can 
initiate the itch process via non-histamine mediated processes that that lead to substance P 
presence in the interstitium (Raap et al 2011).  Substance P, a neuropeptide member of the 
tachykinin family, is thought to induce itching in humans via histamine degranulation from 
mast cells (Potenzieri et al 2012).  Keratinocytes are known to express Substance P 
receptors (Peters et al 2006) and opiate receptors (Bigliardi et al 1998). 
 
There is also a close link between endorphins and substance P in nerve fibers innervating 
the epidermis.  Opioid receptors destined for insertion onto the distal portions of Type C 
cutaneous nerve fiber membrane and the neuropeptides (such as substance P) that are 
capable of release into the interstitium are both synthesized in the same dorsal root 
ganglion nerve cells and transported to the peripheral nerve processes in the skin (Stein et 
al 2003).   
3.1.2.4 Abnormal endogenous opiates in the skin of PN patients: 
Bigiliardi and Bigliardi-Qi (2004) reported that in PN human skin tissue samples there was 
a down regulation of the mu-opiate receptor expression in the epidermis compared to 
normal skin.  The down regulation was thought to be a biological response to abnormal 
tissue exposure to large amounts of endogenous opioid ligands such as endorphins.  The 
authors comment that the epidermal skin cells such as the keratinocytes that are no longer 
binding the opioid ligands possibly leave the ligands available to bind to epidermal nerve 
endings and thus induce a nerve transmission mediated signal to the CNS resulting in a 
pruritus sensation.   
3.1.2.5 Abnormal substance P level in the skin of PN patients: 
Haas et al (2010) reported data showing significantly increased density of dermal substance 
P nerve fibers both in lesion skin samples as well as normal appearing skin samples from 
PN patients.  The authors concluded that the hyper-innervation by substance P containing 
sensory nerves may have a role in the itch sensation found in these patients. Molina et al 
(1992) reports increased nerve fibers containing substance P in PN subjects compared to 
control group that could be related to the intense pruritus. 
3.1.2.6 Inflammatory Component to PN Histology: 
Neurogenic inflammation refers to the manifestation of skin diseases related to the 
malfunctioning of the nervous system – immune system interaction (Steinhoff et al 2003, 
Peters et al 2006, and Potenzieri et al 2012).  Bigliardi et al (1998) conclude that the 
presence of receptor systems for endorphins and substance P molecules is evidence of an 
interaction between skin, immune and nervous system.  Given the abnormal biology of 
substance P and endorphins in the skin of PN patients just discussed above, the hypothesis 
that the induction of an inflammatory component in PN is etiologically related to 
endorphin-substance P pathobiology is based on the following biological facts: 
In addition to being a pruitogen, substance P also has pro-inflammatory and immune-
stimulatory activity (Peters et al 2006).  Steinhoff et al (2003), Peters et al (2006), and 
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Potenzieri et al (2012) state that substance P may be an important mediator of 
cutaneous neurogenic inflammation.  T he immune cells that migrate under a pro-
inflammatory signal from released substance P are an important source of opioid 
ligands.  The opioid ligand containing immune cells consist of T and B lymphocytes, 
granulocytes, and monocytes/macrophages (Sehgal et al 2011).  As noted by Weigelt et 
al (2010), part of the characteristic PN histological findings is a superficial, 
perivascular and/or interstitial inflammatory infiltrate of lymphocytes, macrophages 
and, to a lesser extent, eosinophils and neutrophils (granulocytes).  The opioid ligands 
released by immune cells interact with peripheral opioid receptors located on t he 
cutaneous nerves (Stein et al 2003).  Otherwise stated, the cutaneous nerve induced 
signaling from opioid ligands released by immune cells may be a source of the pruritic 
signal to the brain.   
3.1.3 Rationale for Investigating Nalbuphine HCl ER in Prurigo Nodularis  
3.1.3.1 Pre-clinical Animal Data 
A preclinical investigation (Covance Study No. 8265903) was undertaken to demonstrate 
the effects of nalbuphine HCl on substance-P (SubP) induced scratching behavior in the 
mouse, a standard animal model (Kuraishi et al. 1995).  Scratching behavior induced by 
peripheral stimulation by the pruritogen SubP mimics the characteristics of itch-related 
scratches in humans (Kuraishi et al. 1995) and Andoh et al 1998).  In addition, the SubP 
induced scratching behavior is not inhibited by the histamine H1 receptor antagonist and 
elicits responses even in mast cell-deficient mice.  Thus, SubP-induced scratches are likely 
to represent antihistamine-resistant pruritus.  The model is relevant to antihistamine-
resistant pruritus (Togashi et al 2002 and references cited therein). 
 
The SubP itch mouse model was successfully established and its viability confirmed by 
assessing the responses using vehicle (phosphate buffered saline, PBS) only group 
(VEH/VEH) and nalfurafine HCl, a positive comparative control group (PCC/SubP)  
relative to untreated group (VEH/SubP) group.  Briefly, studies were conducted in male 
C57BL/6 mice.  Animals were acclimated to the facility at least three days prior to dosing.  
On the test day, mice were acclimated to the observation cages for one hour prior to dosing.  
Mice were then randomly assigned to treatment groups and subcutaneously (SC) dosed 
with vehicle (PBS), PCC (0.01 or 0.02mg/kg), or the test article nalbuphine (10 or 
30mg/kg) (NAL/SubP group), and video recorded for 30 minutes to establish baseline 
scratching behavior.  After the 30-minute baseline recording, mice received either vehicle 
(0.05 mL PBS) or SubP (250 nM in 0.050 mL) injected intradermally (ID) into the rostral 
part of the back and video recording continued immediately for an additional hour.   
 
Itching was scored by reviewing the recording and counting the number of scratches over 
30 minute periods following SubP (or vehicle) challenge.  Itching was defined as 
scratching with the hind paw at the intradermal injection site (upper right shoulder area).  
Continuous scratching over one second was counted as one scratch event and paused 
scratches were considered separate scratching events.  Scratching of other sites such as ears 
and face were not recorded.   
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Baseline scratching (pre-SubP) was similar for all treatment groups.  Following SubP 
administration in the untreated mice, itching began within 3-5 minutes from administration 
of the pruritogen.  The itch intensity was the highest in the first 30 minutes post-dose.  By 
60 minutes post-dose, the effect of the SubP injection began to wear off as scratching 
returned towards baseline levels. 
As expected, PCC significantly (p< 0.001) decreased the SubP-induced scratching 
supporting the validity of the itch model.  Subcutaneous pre-treatment with PCC resulted in 
a reduction of 42 and 63% reduction at the 0.01 and 0.02mg/kg dose (from 107 to 62 or 40 
scratches, respectively).  
Significant reduction in itch (p< 0.001) was noted following nalbuphine SC administration 
with about 43% reduction in itch at the 10 mg/kg dose (from 107 to 61 scratches) and 52% 
at the 30 mg/kg dose (from 107 to 52 scratches).  Though there was a trend for a dose 
dependence on itch reduction, there was no statistical difference between the tested 
nalbuphine doses. 
In this study, nalbuphine was as effective as PCC (nalfurafine) at reducing SubP-induced 
itch with no statistical difference between nalbuphine and PCC effect, regardless of the 
dose. 
Ambulation was not suppressed in mice injected with nalbuphine dosed at 10 or 30 mg/kg 
indicating that attenuation of the scratching was not due to decreased locomotor activity. 
3.1.3.2 Neuropharmacologic Basis of the Rationale of Investigating Nalbuphine for the 
Treatment of Prurigo Nodularis 
Gutstein et al (2001) reports that nalbuphine exerts its clinical pharmacologic action by 
competitively antagonizing the opioid μ-receptor and simultaneously acting as an agonist at 
the opioid κ-receptor, and thus is a member of the  “opioid agonist-antagonist” class of 
drugs that mechanistically work through this dual pharmacologic process.  T here is no 
published literature on the use of the moiety nalbuphine in PN.  Nalbuphine was shown to 
be effective in reducing morphine induced pruritus, a well-known clinical pruritic condition 
induced by morphine administration.  In several published clinical well controlled studies 
(which are reviewed in detail in the Investigator Brochure Section 5.8), nalbuphine was 
either equally effective or superior in efficacy when compared to naltrexone or naloxone 
(both are pure u-antagonists) for the management of morphine induced pruritus.  
Neurogenic inflammation (as discussed in Section 3.1.2.6) may induce the secondary 
phenomena of “central sensitization” (Woolf et al 2011).  Central sensitization is a central 
nervous system pathologic neurobiology change in cell circuitry that results from abnormal 
peripheral nerve signaling and/or peripheral nerve injury. The net effect of central 
sensitization is that there is a lowering of neural excitation threshold to external stimulus 
whereby either nociceptive or low intensity pruritogen cutaneous stimuli induce a h igh 
intensity sensation of pruritus (Paus et al 2006).  Schmelz (2005) reports on the evidence 
that there is a mu-kappa opiate gating circuitry in the spinal cord whereby kappa agonist 
activity would inhibit mu opiate receptor containing cell activation mediated signaling that 
brings to consciousness the sensation of pruritus.  The analysis by Schmelz may be an 
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example of what Pan (1998) reports as a potentially very general opioid μ-receptor 
antagonizing function by the opioid κ-receptor.  The author reviews the literature on central 
neural networks where the opioid κ-receptors are located in cell groups that are distinct 
from the cell groups that contain the opioid μ-receptors and summarizes the evidence that 
agonism at the pharmacological level of the opioid κ-receptor antagonizes various opioid 
μ-receptor agonist mediated actions in the brain. This central gating mechanism could be 
important in countering any potential pruritogenic induced sensation from a peripheral 
neurogenic inflammatory initiating event in PN. 
 
As discussed in Section 3.1.2.5, there is histological evidence of abnormal substance P 
presence in skin samples of PN patients. In that regard, an experiment conducted by Trevi 
Therapeutics indicated that nalbuphine administered subcutaneously significantly 
(p<0.001) suppressed the substance P induced scratching in mice (see Section 3.1.3.1 study 
summary). 
 
Metze et al (1999) reported that 9 out of 17 patients with PN who were treated with the mu 
antagonist medication naltrexone reported a decrease in pruritus intensity of at least 50%.  
Reduced scratching as well as skin lesion healing was reported over a time period of up to 
20 months on drug.  This clinical observation potentially has different anatomical locations 
for the mechanistic drug effect.  S ince Stein et al (2003) reported that inflammation 
increases both the number of sensory nerve terminals (“sprouting”) and disrupts the 
perineural barrier –thus facilitating opioid access to receptors, there is the possibility that 
peripherally acting mu antagonist naltrexone action reduced the neural membrane 
excitation by blocking actions of endogenous endorphins reported by Bigiliardi and 
Bigliardi-Qi (2004) to be present in the epidermis.  In fact, Bigiliardi and Bigliardi-Qi 
(2004) suggest an opiate antagonist be therapeutically investigated for this reason and also 
comment on the evidence that mu opiate receptors on epidermal cells may be have a role in 
skin healing. 
 
However, consideration must also be given to central nervous system opioid pharmacology 
as a contributing antipruritic effect elicited by naltrexone. At the spinal cord level, Schmelz 
(2005) commented that the explanation for opiate mu antagonists being capable of 
reversing experimentally induced itch may be related to the neurobiology of spinal cord 
level neuronal kappa-mu opioid gating circuits where either a mu antagonist or kappa 
agonist drug may act to have a pruritus suppressing effect.  Supraspinal brain level action 
related to interference of the circuits related to reward behavior cannot be excluded given 
that it is known that naltrexone, like nalbuphine, can abolish morphine induced pruritus 
from morphine administered intrathecally.  In addition, opiate receptor neuronal systems 
are known to be related to the physiological psychology of human reward behaviour and 
mu antagonist opioid class drugs are known to block the phenomena (Le Merrer et al 
2009).  Nalbuphine is known to block the effects of mu agonist drugs and induce the opioid 
withdrawal syndrome (Nubain® label). 
3.1.3.3 Nalbuphine Clinical Data in Uremic Pruritus 
Mannenti et al (2009) summarized potential pathophysiologic mechanisms for the etiology 
of uremic pruritus.  Included among the postulated uremia induced mechanisms to explain 
uremic pruritus is neurophysiologic central sensitization “wind up” phenomena related to 
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immune-inflammatory skin pathology.  Mettang and Kremer (2014) in their review of 
uremic pruritus comment on the recent focus given to the mechanistic hypothesis related to 
peripheral neuropathic changes and central nervous system pathobiology along with 
evidence for cutaneous micro-inflammation. The authors state that a therapeutic option 
may be systemic treatment with mu-opioid receptor antagonist and kappa-opioid receptor 
agonist.  The proposed etiology of uremic pruritus pathobiology may be similar in origin to 
the neuroinflammatory process discussed in Section 3.1.2.6 as part of the mechanism 
postulated for the underlying process involved in inducing PN.  In should be noted that Lee 
and Shumack (2005) reported prurigo nodularis occurring in patients with renal failure and 
Iking et al (2012) report renal failure as a contributing source of chronic pruritus with PN 
that was attributed to mix origin chronic pruritic conditions (see Table 1). 
 
In clinical study TR01, the effect of oral nalbuphine on pr uritus in hemodialysis (HD) 
patients with uremic pruritus was explored. The results indicated that nalbuphine HCl ER 
tablets demonstrated ability to suppress itch in a dose response fashion (see Figure 1)  
 
 
Figure 1:  
Mean VAS score (SD) for all patients as a function of nalbuphine HCl 
dose administered as nalbuphine HCl ER tablets.  N= 14 except for 180 
mg (N=13) and 240 mg (N=4).  Source: NAL.001.TR01.PD 
 
The TR01 study is summarized in the Investigator Brochure Section 5.4.3. 
Considering the potential similarity in the underlying postulated mechanism between 
uremic pruritus and PN, nalbuphine would also be expected to be therapeutic in PN 
patients.  As such, Study TR01 in HD patients can be regarded as a proof of concept study 
for PN.   
Based on the clinical evidence of nalbuphine to suppress itch in uremic pruritus, morphine 
induced pruritus, the substance P induced itch in a pre-clinical study, results and the 
mechanistic link between the opioid receptors and substance P with the pathophysiology of 
PN, a cl inical investigation of efficacy of nalbuphine on i tch in the PN population is 
justified. 
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3.2 
NALBUPHINE 
Nalbuphine HCl is currently available only as a generic medication in an injectable form.  
An injectable form of nalbuphine is a commercially available approved drug product in the 
United States since 1979 and originally marketed as Nubain®, on which the presently sold 
generic injectable formulations are based.  It is currently approved for use in the United 
States for the relief of moderate to severe pain, a supplement to balanced anesthesia, for 
pre-operative and post-operative analgesia and obstetrical analgesia during labor and 
delivery.  The European Union marketing experience with the injectable form of 
nalbuphine dates back to 1986 and this was recently reviewed (Nalbuphine -Medicines 
Evaluation Board in the Netherlands Public Assessment Report 2010). 
Nalbuphine is not a controlled drug in the United States.  An oral dosage form of the drug 
is not commercially available.  Nalbuphine HCl ER is an extended release oral tablet that is 
currently being developed for the treatment of pruritus. 
Nalbuphine is a synthetic opioid with mixed μ antagonist/κ agonist opioid properties.  
Structurally, nalbuphine is a derivative of 14-hydroxymorphine and is related to the opioid 
μ-receptor agonist oxymorphone and the opioid μ-receptor antagonist naloxone.  
Nalbuphine exerts its clinical pharmacologic action by competitively antagonizing the 
opioid μ-receptor while simultaneously acting as an agonist at the opioid κ-receptor 
(Gutstein 2001; Gharagozlou 2003 and 2006).  
3.3 
NALBUPHINE HCL ER TABLET CLINICAL DEVELOPMENT  
3.3.1 Overall Summary 
The safety, tolerability and pharmacokinetics of nalbuphine HCl ER tablets have been 
characterized following single and multiple ascending dose studies in healthy male and 
female human subjects, in a single dose study conducted in a dental pain patient 
population, a multi-dose study conducted in a patient population experiencing osteoarthritic 
related joint pain and in a multi-dose study conducted in both hemodialysis (HD) 
population experiencing uremic pruritus and healthy subjects.  Studies were conducted with 
nalbuphine HCl ER tablets or oral solution following single dose administration from 30 
mg up to 180 mg and multiple doses ranging between 30 mg BID and 180 mg BID in 
subjects with normal renal function (up to 3 weeks) and in the hemodialysis population in 
multiple doses ranging from 30 mg BID to 240 mg BID (up to 15 days). 
In subchronic and chronic dose toxicology studies, the CNS was identified as the only 
target organ when unformulated (neat) nalbuphine was given to dogs at high doses.  High 
systemic drug exposures in dogs caused CNS toxicity (tremors and convulsions) leading to 
deaths in some cases.  It should be noted that the convulsions at high doses of nalbuphine 
in dogs were most likely Cmax-related.  In toxicology studies in which dogs were given 
high doses of nalbuphine formulated with release-rate controlling excipients that blunt the 
Cmax, no CNS signs of toxicity were observed.  Using the most conservative (lowest) 
margin of safety determined in all toxicity studies, a minimum 12.4-fold safety margin was 
calculated respectively for the mean plasma Cmax in subjects with normal renal function at 
the highest projected clinical dose of nalbuphine (180 mg BID) relative to the plasma 
Cmax at the lowest NOAEL in dogs given unformulated nalbuphine.  Convulsions were 
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not observed in any of the clinical trials conducted with nalbuphine HCl ER oral tablets in 
subjects with normal renal function at doses up to 180 mg BID (360 mg daily dose) or in 
HD patients at doses up to 240 mg BID (480 mg daily dose).  
In the course of development, 355 subjects received at least one dose of oral nalbuphine 
HCl.  The most frequently reported adverse events were primarily in the Central Nervous 
System (CNS) and Gastrointestinal (GI) organ system categories. All these side effects are 
known to occur with drugs with opioid pharmacologic properties.  Most of the side effects 
noted in the study program were mild to moderate in severity.  Initiating drug dosing in 
both HD patients and healthy subjects at the 30 mg BID dose resulted in good tolerability 
for subsequent titration related dose escalation. 
No drug abuse issues were reported during any of the investigations. The incidence of 
opiate withdrawal effects noted at drug discontinuation in the patients was investigated in 
the osteoarthritis pain treatment study when nalbuphine dosing was abruptly stopped 
following the end-of-study participation. There was an absence of any objective evidence 
of physical withdrawal symptoms in 85% of the patients and only mild evidence of 
physical withdrawal symptoms in the remainder of the patients. 
3.3.2 Clinical Study TR01 in Hemodialysis Patients and Healthy Volunteers 
Pruritus is a frequently identified sign and symptoms of uremia (“uremic pruritus”) and is 
thus a common symptom in patients receiving hemodialysis (Pisoni et al 2006 and Narita et 
al 2006).  Study TR01 was undertaken to assess the safety, PK, and the open label effects 
on pruritus intensity in hemodialysis subjects.  PK and safety was compared to matched 
healthy control subjects. 
Study TR01 was a single site, open label, non-randomized, parallel group, escalating dose 
study in hemodialysis patients with pruritus of at least mild intermittent intensity receiving 
intermittent hemodialysis three times a week compared to matched healthy control patients. 
All subjects were in house during the entire dosing period.  Nalbuphine HCl ER tablets 
were administered orally for up to a 15 day period in hemodialysis patients and 13 days in 
healthy subjects.  Doses were sequentially escalated from 30 mg QD on Day 1 to 30mg 
BID then to 60 mg BID, 120 mg BID, 180 mg BID and 240 mg BID with dose escalation 
predicated on PK, safety, and tolerability of the preceding dose.  HD Patients remained at 
each dose level for 2-3 days for a minimum of 4-5 consecutive doses.  Healthy subjects 
remained at each dose level for 3-4 days for a minimum of 5 consecutive doses.   
Study subjects were separated into 2 cohorts:  Of the 15 hemodialysis patients in Cohort 1, 
11 were assigned to dose escalate up to 180 mg BID and 4 were assigned to dose escalate 
up to 240 mg BID.  13 patients (11 males and 2 females) completed the study.  One male 
patient discontinued secondary to non-drug related disease progression diagnosis of pleural 
effusion at the 30 mg BID dose level and a female patient discontinued following a Grade 3 
AE of vertigo at the 240 mg BID dose level. Cohort 2 were healthy subjects who were 
assigned to dose escalate up to 180 mg BID.  Cohort 2 consisted of 8 healthy subjects (6 
males and 2 female) who completed the study and one male subject who discontinued at 
the 120 mg BID dosing level with only Grade 1 intensity AEs. All study subjects were 
closely monitored for AEs throughout the study.    
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In healthy subjects, the dosing regimen resulted in mainly Grade 1 AEs and the dose 
escalation was tolerable in 8/9 subjects dosed.  Of the nine healthy subjects enrolled, one 
subject withdrew from the study secondary to AE Grade 1 level gastrointestinal reflux, 
nausea/vomiting and vertigo symptoms at the 120 mg BD dosing level.  The subject 
recovered from the AE following drug discontinuation.  AEs that occurred in greater than 
two subjects were somnolence (N=2), headaches (N=2), flatulence (N=2) and constipation 
(N=3).   
In the HD subjects, there were no deaths or drug-related serious AEs.  There were no dose-
limiting AEs reported as defined as two hemodialysis patients experiencing a drug-related 
AE of Grade 3. A total of 72 AEs were reported in the 15 dialysis patients of Cohort 1. The 
nervous and gastrointestinal organ systems had the highest incidence of AEs. The most 
frequently occurring AEs were nausea and somnolence. Of the 13 hemodialysis patients 
who completed the study (10 HD patients assigned to dose up to 180 mg BID and 3 HD 
patients assigned to dose up to 240 mg BID), 12 patients completed the trial per protocol 
and 1 patient completed the study but did not dose titrate beyond 120 mg BID.   
With regard to the gastrointestinal organ system, of the 14 hemodialysis patients who 
completed 13 days of dosing (1 patient at 120 mg BID and 13 patients at 180 mg BID), 
4/14 (29%) experienced no nausea during the study and 7/14 (50%) experienced Grade 1 
intensity nausea that was self-limited and only occurred at the initiation dose of 30 mg.  
One patient (1/14, 7%) experienced Grade 2 nausea starting from the 60 mg BID through 
the 180 mg BID dose. Three patients (3/14, 21%) only developed nausea at the 180 mg 
dose level.   
With regard to the nervous system AEs, of the 14 subjects who completed the 13 days of 
dosing, 5/14 (36%) did not experience somnolence, 4/14 (29%) experienced somnolence 
that was self-limited and only occurred at the initiation dose of 30 mg.  With regard to AE 
intensity, two patients (2/14, 14%) experienced somnolence of Grade 2 intensity at dosing 
levels above 30 mg BID.  Only one drug-related Grade 3 AE (vertigo) was reported in one 
patient at the 240 mg dose which resolved completely following drug termination.  No 
clinically relevant findings in vital signs, blood pressure (BP), ECGs or physical 
examinations were noted during the study.  Oxygen saturation was also monitored via pulse 
oximetry as a safety precaution.  The oximetry readings were taken at regular intervals 
during the daytime and continuously monitored during the nighttime hours over the 15 
days of drug dosing and up to a maximal dose of 240 mg BID.  No clinically significant 
decrease in daytime readings were recorded in the oximetry readings except in the one 
male HD subject previously mentioned who discontinued from the study at the time of the 
development of a pleural effusion.  There was no clinically significant decrease in the 
nocturnal oxygen saturation level below the pre-dosing baseline nocturnal oxygen 
saturation level in any HD subject.  
The Investigator Brochure and Section 5.4.4.4; Table 21 and Section 5.4.4.2.2; Table 17 
summarize the AE profile of the TR01 HD subjects and healthy subjects respectively. 
During the course of TR01, the 15 HD subjects that were enrolled were on multiple 
concomitant medications.  Common concomitant medications included heparin, vitamin D, 
aspirin, iron, hyperphosphatemia management with sevelemar, erythropoiesis-stimulating 
agent, secondary hyperparathyroidism management with cinacalcet, neuropathic pain 
management with gabapentin; antihypertensive medications such as amlodipine (calcium 
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channel blocker), carvedilol (beta and alpha-1 blocker), metoprolol (beta blocker), 
linosopril (ACE inhibitor); gastrointestinal medications: omeprazole, pantoprazole, 
ranitidine and renal vitamins and supplements. These medications seem to be commonly 
used by HD patients both in the US and the EU (Schmid et al 2010).  There was no 
clinically significant difference in the adverse event profile observed based on concomitant 
medication use or obvious pharmacodynamic interaction over the course of the study. 
 
Data on Itch Intensity was obtained in an unblinded fashion from the hemodialysis patients 
enrolled in the open-label single arm Study TR01 using a 0 (none) to 10 mm (maximal 
possible intensity) itch Visual Analogue Scale (VAS) recording “worst itch” intensity.  
From a baseline mean daytime VAS of 4.4±2.3 mm and nighttime of 2.8±2. mm, the mean 
VAS decreased over a 13-day dosing period by -3.6±2.5 mm and by -1.8±2.1 mm, 
respectively. 
Please see the Investigator Brochure for more details on the TR01 study. 
3.3.3 Additional Nalbuphine HCl ER Tablet Clinical Data 
In addition to the subjects in the TR01 study, a total of 331 subjects have been exposed to 
nalbuphine HCl during the course of 8 previous clinical studies. 
Four Phase 1 studies were early biopharmaceuticals studies conducted in healthy subjects 
mainly for formulation selection and as such they support the safety of the drug product.  In 
addition, two Phase 1 studies were conducted with the current clinical formulations and 
each consisted of a single dose study assessing the safety, tolerability, and PK of the 
current tablet formulations in the 30mg -180 mg range.  
A safety and efficacy analgesic study was conducted in subjects with dental-pain following 
third molar extractions following a single dose (placebo or 60 mg or 120 mg).  The subjects 
were otherwise healthy male and female subjects.  The study also contained PK-PD 
analysis demonstrating an analgesic dose-response relationship, with clear differentiation 
between the nalbuphine dose groups and placebo group. 
Oxygen saturation was monitored via pulse oximetry as a safety precaution during Phase 1 
studies and in the single dose third molar extraction dental pain treatment study.  All 
subjects who received the drug had oxygen saturation levels within the 90%-100% range 
during the studies. 
A safety and efficacy analgesic study was conducted in a patient population experiencing 
osteoarthritic related joint pain using the current nalbuphine HCl ER 60 mg tablet.  The 
population was demographically older with the mean age of 57 years and a range extending 
from age 40-70 years.  Patients were dosed continuously for up to 3 weeks starting at 
60 mg BID up to a dose of 180 mg BID.  Patients who tolerated the initial dosing were 
titrated up in weekly increments of 60 mg BID to the maximal dose of 180 mg BID.  The 
AEs that developed mainly had their onset at the initiation of dosing with no new type of 
AE developing in any statistically significant incidence during the course of dose 
escalation.  
In these eight clinical studies overall, the most frequently reported AEs in the single dose 
and multi-dose studies were CNS events, namely dizziness, headache, and somnolence.  
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Gastrointestinal system AEs were mainly nausea and vomiting.  Most of the AEs noted in 
the clinical study program were mild to moderate in severity.   
In the case of single dose Phase 1 nalbuphine HCl ER tablet administration, there was a 
dose relationship to the incidence of AEs and there was minimal AEs observed at the 30 
mg dose compared to initiating dosing at the higher doses.  As a result, a titration to higher 
doses from a starting dose of 30 mg was selected for subsequent studies that also included 
TR01 in order to improve the tolerability of the drug. 
Section 5 of the Investigator Brochure summarizes the results of the clinical development 
program in detail. 
4 STUDY OBJECTIVES 
4.1 
PRIMARY OBJECTIVE 
The primary objective of the study is: 
• To evaluate the safety and tolerability of nalbuphine HCL ER tablets during a drug 
treatment period of up to 50 weeks. 
4.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to evaluate the effect of two doses of nalbuphine 
HCl ER tablets on: 
• To evaluate the safety of nalbuphine by achieved maintenance dose at the end of 
Treatment Period Week 4.  
• Assess skin lesion improvement using the metrics of the PAS  
• Changes in Patient-Reported Outcome measures (worst
• The percentage of patients utilizing various doses of nalbuphine HCl ER tablets by 
Study Week 
 itch NRS, average daily 
itch intensity NRS, VRS (itchy, burning and stinging), ItchyQoL, MOS Sleep-R, 
HADS and PBI-P) during the Treatment Period 
• The frequency and reasons for down-titration and treatment discontinuation during 
the study 
• The changes in the PRO measurements during the Washout Period after cessation 
of treatment of nalbuphine HCl ER tablets 
• 
The number of days of use of rescue medications. 
4.3 
EXPLORATORY OBJECTIVES 
• The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve 
fiber density (histology) and MOR/KOR density (histology, Western Blot) in skin 
biopsies taken at the last Treatment Period Visit when compared to biopsy material 
assessed during study TR03 (selected sites only). 
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5 STUDY ENDPOINTS 
5.1 
PRIMARY ENDPOINT 
• A description of the incidence and nature of TEAEs during Treatment Weeks 5- 
50 
5.2 
SECONDARY ENDPOINTS 
Visit 1a or 1b will serve as the baseline visit for efficacy endpoints. Visit 1a will be 
the baseline for patients directly entering the Treatment Period as of Visit 1a.  Visit 
1b will be the baseline for patients entering the Treatment Period after participating 
in the Observation Period for any length of time. 
• Assess skin lesion improvement using the metrics of the PAS  
• Change from Baseline in Patient-Reported Outcome measures (worst
• Change between Baseline and final Treatment Period visit in PBI-PA 
description of the percentage of patients utilizing various doses of nalbuphine 
HCl ER tablets by Study Week 
 itch NRS, 
average daily itch intensity NRS, VRS (itchy, burning and stinging), MOS 
Sleep-R, ItchyQoL, HADS) by Treatment Period visit and Baseline NRS score 
categories 
• A description of the frequency and reasons for dose up- and down-titration and 
treatment discontinuation during the study 
• To describe the changes in the PRO measurements during the Washout Period 
after cessation of treatment of nalbuphine HCl ER tablets 
• 
A description of the number of days of use of rescue medications for itching.  
5.3 
EXPLORATORY ENDPOINTS 
The exploratory objectives of the study are to evaluate the effect of nalbuphine HCl ER 
tablets on: 
• The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve 
fiber density (histology) and MOR/KOR density (histology, Western Blot) in skin 
biopsies taken at the last Treatment Period Visit when compared to biopsy material 
assessed during study TR03 (selected sites only). 
6 NUMBER OF SITES AND PATIENTS 
Up to 7 sites in the North America and Europe are planned to participate in this study.  
Eligible patients who have successfully completed the TR03 study and wish to participate 
in TR03ext may be enrolled, treated, and analyzed. The maximum number of patients will 
not exceed the number of patients who complete the TR03 study  (i.e., up to 60 patients). 
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7 ESTIMATED STUDY DURATION 
The total study duration for any individual patient will be up to 52 weeks.  Patients will 
receive drug treatment for up to 50 weeks. Followed by two week washout period. 
8 SELECTION CRITERIA 
8.1 
STUDY POPULATION 
Patients with prurigo nodularis who completed the TR03 study and have met 
Inclusion/Exclusion eligibility requirements for TR03ext (see Section 8.2).    
8.2 
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be eligible: 
1. Have been adequately informed of the nature and risks of the study and have given 
written informed consent at or prior to Visit 1a. 
2. Have completed participation in the TR03 study. 
Completion of participation in the TR03 study is defined as completion of Study 
Drug treatment through TR03 Visit 5 and completion of the TR03 Visit 6.  
3. Agree to comply with the contraception requirements as below: 
Female patients of childbearing potential are required to use one barrier method 
(e.g., condom, cervical cap, or diaphragm) of contraception in addition to one other 
method (e.g., intrauterine device [IUD], hormonal contraception, tubal ligation, 
Essure procedure, or spermicide).  
4. Ability and acceptance to provide written informed consent. 
5. Willing and able to comply with study requirements and restrictions  
6. Agree to the confidential use and storage of all data (including photography) and 
use of all anonymized data for publication including scientific publication. 
8.3 
EXCLUSION CRITERIA 
If a patient meets any of the following criteria, he or she is not eligible: 
1. Significant medical condition or other factors that in the opinion of the Investigator 
may interfere with the conduct of the study 
2. Known hypersensitivity or allergy to nalbuphine or formulation components  
3. Is a pregnant or lactating female. 
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9 STUDY PLAN 
9.1 
GENERAL STUDY DESIGN 
This is an open label extension study for patients who have completed the TR03 study. 
9.2 
RATIONALE FOR STUDY DESIGN 
The primary objective of this TR03ext study is to evaluate the safety of nalbuphine HCL 
ER tablets in patients with prurigo nodularis for up to 50 weeks on drug.  The TR03ext 
study is 52 weeks in duration. The open label design allows all patients who have 
completed the parent study TR03, an opportunity to receive active treatment for the 
assessment of the safety of nalbuphine HCl ER tablets over a longer term. A maximum of 
50 weeks on study drug was chosen as a reasonable time frame that would add 
substantially to the understanding of nalbuphine ER HCl tablets chronic use in prurigo 
nodularis. 
 
Metze et al (1999) reported that 9 out of 17 patients with PN who were treated with the mu 
antagonist medication naltrexone reported a decrease in pruritus intensity of at least 50%.  
Reduced scratching as well as skin lesion healing was reported over a time period of up to 
20 months on drug.  Based on these clinical observations, TR03ext was designed to be of 
sufficient duration in order to observe any possible effects that potential anti-pruritic 
suppressive effects of study drug may have on impacting scratching behavior and thus 
potentially skin lesion healing.  Furthermore, the TR03ext study design anticipates 
potential sustained anti-pruritic effect that may outlast the actual dosing of study drug in 
TR03.  Thus there is an Observation Period incorporated into TR03ext to follow patients 
for up to 12 weeks in order to measure the duration of any possible sustained anti-pruritic 
effect and to allow patients to receive study drug if pruritus returns within the 12 week time 
period. 
 
This study will allow evaluation of a titration algorithm that mimics the manner in which 
opioid medications are often used in clinical practice (i.e., stepwise, titration to effect). To 
facilitate evaluation by achieved dose, the dose to which the patient has been titrated at the 
end of Treatment Period week 4 will be maintained through Study Week 50, with the 
exception of one allowable down-titration (See Table 3 for dosing schedule). Patients who 
require a second down-titration after Treatment Period week 4 must be discontinued from 
the study.  
 
Patients can enroll into TR03ext and receive drug as early as approximately 2 weeks 
following their last dose of study drug in the parent study TR03. Approximately one-third 
of patients are expected to enter the study after having received placebo in TR03. These 
patients are expected to have a high level of pruritus intensity.  On the other hand, patients 
who have received active treatment in TR03 may still have residual anti-pruritic effects 
from active arm drug treatment as they enter the TR03ext study at the time of the last TR03 
study visit when a signed informed consent for TR03ext is required.  To allow for various 
starting levels of pruritus intensity, patients who have an NRS that is > 2 will enter the 
Treatment Period upon completion of Visit 1a.  Patients whose NRS scores are ≤ 2 will be 
entered into an extended screening period, no-treatment Observation Period for up to 12 
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weeks or until they develop a higher level of pruritus (i.e., NRS >2), at which point they 
will transition to the Treatment Period upon completion of Visit 1b.  All patients entering 
the Treatment Period, whether immediately upon study entry or following a period of time 
in the Observation Period, will initially be titrated to a dose that can be as high as 180 mg 
BID during the first 4 weeks of the Treatment Period (See Table 3 for dosing schedule). 
Patients who continue in the Observation Period and maintain an NRS score of ≤ 2 will be 
screen failed from the study at the end of the 12-week period. While patients remain in the 
Observation Period, they will not be considered as enrolled into the study, but as 
participating in an extended screening process until they are eligible for treatment. 
In the parent study, TR03, the two target doses (90 mg and 180 mg) of nalbuphine HCl are 
both within the dose range that was well tolerated in hemodialysis patients and healthy 
volunteers subjects from study TR01 (30 mg to 240 mg BID for up to 15 days). 
Additionally, data from TR01 suggested a decrease in itching intensity in this dose range. 
Further, the safety profile of nalbuphine following injection is well documented. Injectable 
nalbuphine has been commercially available in the United States since 1979 and there has 
been marketing experience within the European Union dating back to 1986 (See 
Nalbuphine -Medicines Evaluation Board in the Netherlands Public Assessment Report 
(2010) for a recent review). 
In order to facilitate analysis of the clinical safety data and efficacy data, patients in the 
present study will begin titration at the 30 mg QD dose and titrate to only one of three 
maintenance doses:  90 mg BID, 120 mg BID or 180 mg BID.  The 60 mg BID dose is 
believed to be only a marginally effective dose based on available TR01 data.  However 
since there is a one time dose reduction permitted in all subjects during Treatment Period 
weeks 5-50 (see Table 3) to the next lower allowed dose, a subject at the 90 mg BID 
maintenance dose will be permitted a dose reduction to 60 mg BID and maintained at that  
dose level for the remainder of the study. 
The study population being evaluated is an intended target population for oral nalbuphine 
HCl ER tablets: prurigo nodularis patients. 
 
Patients will be closely monitored for safety. All patients will be seen at the Investigator 
site (See Schedule of Events in Appendix 1). Adverse events and vital signs will be 
recorded. Additionally, 12-lead ECGs, physical examinations, and clinical laboratory 
testing will be conducted to monitor safety on patients receiving study drug.   Safety 
monitoring will be done to address the primary objective of evaluating the longer term 
safety of study drug exposure.   The primary endpoint is a description of adverse events 
during up to 50-weeks of treatment with nalbuphine HCl ER tablets. An important 
secondary endpoint objective of the study is to use recorded PAS metrics to assess the 
potential of any possible study drug anti-pruritic suppression to affect scratching behavior 
of the subject and result in skin lesion improvement.  Changes in patient-reported outcome 
measures: Worst
9.3 
SAFETY MONITORING PLAN 
 itch NRS, Average daily itch intensity NRS, VRS (itchy, burning and 
stinging), ItchyQoL, MOS Sleep-R, HADS and PBI-P will be explored.  
All the clinical studies conducted with nalbuphine HCl ER oral tablets to date have 
indicated that the most common AEs are gastrointestinal and nervous system-related.  
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To mitigate opioid-related side effects, nalbuphine will be titrated over 4 weeks based on a 
combination of efficacy and tolerability to a dose that is between 90 mg BID to 180 mg 
BID (see Table 3). Titration is a clinical management strategy consistent with dosing of 
opioids in general (Jovey 2003). The titration regimen planned in this study is similar to the 
regimen used in study TR01, in which doses in the planned range were well tolerated 
(Section 3.3.2).   In this study, the combination of a low starting dosing (30 mg on the first 
day) followed by a relatively slow titration (dose escalation after six consecutive doses 
over approximately 3 days) is expected to minimize treatment-limiting opioid adverse 
effects.  See Table 3 for the drug titration scheme. The time interval between dose 
escalations is consistent with the “three day tolerance check” suggested by the National 
Opioid Use Guideline Group of Canada (2010) for outpatient clinical practice management 
of opioid drug titration as part of monitoring patient side effects. 
Nalbuphine has µ-opioid antagonist pharmacological properties.  To minimize the 
possibility of acute opiate withdrawal occurring at drug initiation in a physically dependent 
subject, patients receiving daily doses of opiates are excluded from the study.  Patients who 
require ongoing non-daily opiates concurrently with nalbuphine should be monitored 
carefully for additive opiate effects.  If patients develop a new need for daily opiates during 
the study, the Investigator is required to contact the Medical Monitor to discuss the 
specifics of the situation. 
It is known from prior studies, that gastrointestinal opioid-like adverse effects (e.g., nausea, 
vomiting, and constipation) occur early and can be treatment-limiting.  In anticipation of 
the possible occurrence of these effects, pre-medications for nausea will be permitted and 
Investigators will be advised to use pharmacologic or non-pharmacologic means to avoid 
constipation as clinically indicated.  In anticipation of the possible occurrence of central 
nervous system (CNS) AEs such as somnolence, patients will be instructed to be aware of 
possible CNS AEs that may occur.  The evening doses during the Titration Period should 
be taken at home.  The first dose of any new titration step will occur with an evening dose 
(see Table 3). Patients will be additionally instructed that if any significant CNS AEs 
occur, they are to avoid activities such as driving and operation of dangerous machinery 
until the effect of the Study Drug can be assessed by the Investigator. Additionally, 
concomitant use of daily opioids during the course of the study, other than for short-term 
use, can be undertaken with the approval of the Medical Monitor.  Overdoses or opioid-
related significant central nervous system adverse effects may be reversed with opioid 
antagonists if clinically indicated. 
Although psychological dependence or abuse can develop to chronically administered 
opioid drugs, the risk for psychological dependence or abuse in this study is judged to be 
low based on previous clinical studies with nalbuphine HCl ER oral tablets.  To date, there 
have been no reported cases of psychological dependence or abuse reported following 
dosing for 3 weeks up to 180 mg BID and dosing for 15 days up to 240 mg BID.  See the 
Investigator Brochure for details. Nevertheless, the nalbuphine HCl injection package 
insert for the product sold in the United States states that “individuals with a prior history 
of opioid or other substance abuse or dependence may be at greater risk for the 
development of drug abuse and dependence”. 
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9.4 
RISK-BENEFITS 
The selected doses for study in TR03ext of 90 mg BID, 120 mg BID and 180 mg BID were 
chosen given the safety profile summarized in Section 3.3.2 and discussed further in 
Section 9.2 as well as detailed in the Investigator Brochure.  As summarized in, Section 
3.1.3.3, open label data from the TR01 study showed that pruritus suppression in the HD 
patients was noted with drug administration within the dose range that is planned for the 
current study.  
Data obtained from a previous study in osteoarthritis patients dosed up to 180 mg BID with 
nalbuphine HCl ER tablets showed that objective opioid withdrawal symptoms at the 
termination of 3 weeks of therapy were absent or mild in degree (See the Investigator 
Brochure Section 5.4.4.5 for details).   
It should be noted that the commercially available nalbuphine HCl for Injection product in 
the United States (Nalbuphine HCl package insert) has a usual recommended dose of 10 
mg for a 70 kg adult, administered subcutaneously, intramuscularly, or intravenously, 
which may be repeated every 3 to 6 hours as necessary (ie, up to a daily dose of 40-80 mg 
IV); and, in non-tolerant individuals, the recommended single maximum dose is 20 mg, 
with a maximum total daily dose of 160 mg.  Exposure following IV administration is 
approximately 6-fold higher than following oral administration (estimated oral 
bioavailability of nalbuphine HCl = 16%).  Therefore, a 10-mg, 20-mg, or 160-mg IV dose 
would correspond to approximately 60 mg, 120 mg, and 960 mg oral nalbuphine, 
respectively.  The highest dose proposed in the TR03 study is 180 mg BID (360 mg daily 
dose), and this oral dose is well below the highest recommended daily treatment of 160 mg 
IV (equivalent to 960 mg oral) for the current marketed product. 
The risk for patients participating in the study is judged to be low based on previous 
experience with nalbuphine oral tablets.  In addition, in the current study, there will be a 
low initiation dose of 30 mg, a slow dose titration rate, and careful safety monitoring of 
patients during the clinical study. 
There is no approved therapy for prurigo nodularis related pruritus in the United States or 
Europe.  Should nalbuphine prove effective, patients with purigo nodularis could 
potentially see benefit.  
9.5 
STUDY OVERVIEW 
This is an open label safety and tolerability extension study for patients who have 
completed study TR03.  Patients will either enter directly a drug Treatment Period (NRS 
>2) or a enter an extended screening period of a no-drug Observation Period (NRS ≤ 
The total study duration for any individual patient will be up to 52 weeks. For patients who 
enter directly into the Treatment Period, the total amount of time on drug will not exceed 
50 weeks.  Patients who enter the Treatment Period from the Observation Period, the total 
2) 
based on their reported NRS scores on the first Visit (Visit 1a).   For up to 12 study weeks, 
patients in the no-drug Observation Period may also transition into the drug Treatment 
Period if their NRS increases to NRS>2. 
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amount of time spent in the combined two periods of the study cannot exceed 50 weeks. 
All patients on drug treatment will have a 2-week washout and safety follow-up period at 
the end of the dosing period.   
The total amount of time in the Observation Period cannot exceed 12 weeks. After 12 
weeks, subjects not eligible for the Treatment Period are screen failed from the study. The 
study periods are summarized below in Table 2.   
 
Table 2:  
TR03ext Study Periods 
Study Period 
Study Weeks 
Duration 
Observation Period 
Patients followed in Observation Period visits for 
up to 12 weeks.  During this time, the patient 
either enters the Treatment Period or screen fails 
for entry to the Treatment Period at 12 weeks and 
participation in the study ends. 
Up to 12 weeks 
Treatment Period 
For patient directly entering the Treatment Period 
as of Visit 1a, the Treatment Period begins with 
Study Week 1 (Visit 1a) and ends with Study 
Week 50  
For patients entering the Treatment Period after 
being followed in the Observation Period, the 
Treatment Period still ends at Study Week 50, 
thus Table 8 calculates the TV assignment for any 
patient entering the Treatment Period from the 
respective Observation Period visits. 
Up to   
50 weeks 
Washout and Safety 
Follow-Up Period 
Weeks 51-52 
2 weeks 
 
9.6 
STUDY PROCEDURES 
Before the initiation of study-specific procedures the patient must be given a complete 
explanation of the purpose of the study, evaluations to be conducted, and risks/benefits for 
study participation.  Patients must understand the requirements of the study, provide 
informed consent (See Section 9.6.1 and Section 20.3), agree to the study restrictions, and 
agree to return for the required assessments.  After review of the informed consent is 
documented, the patient must give witnessed verbal and written consent. For this study, 
patients will retain their study number from study TR03. 
 
With the exception of Visits 1a and 1b, windows for all visits will be +/-3 Days.  Please see 
the Schedule of Events in Appendix 1 for details of the Titration Period assessments and 
the Study Schematics Flow Charts in Appendix 2. See Section 9.7.1 for details of Study 
Drug administration and Section 9.7.5.4 for information on the use of pre-medications with 
the Study Drug.  
 
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Visit 1a has procedures to be done as summarized in Section 9.6.1 regardless of the 
patient’s pruritus intensity score.  Following a set of common procedures, only patients 
who qualify for the Treatment Period based on meeting the pruritus intensity criteria will 
be eligible to receive study drug; Visit 1a corresponds to TV1.  For patients who during the 
final visit of TR03 did not meet the pruritus intensity criteria to enter the TR03ext 
Treatment Period, Visit 1a corresponds to OV1, the first visit of the Observation Period.  If 
during a subsequent observation period visit to the site, the patient meets the pruritus 
intensity criteria, then that observation visit immediately transitions into Visit 1b (it also 
corresponds to TV1 since it is now the first Treatment Period visit) – See Section 9.6.5.3.  
 
For subjects who transition to the Treatment Period from the Observation Period, Table 8 
provides details on the treatment visit schedule based on the study week that the subject 
transitioned from the Observation Period to the Treatment Period. The subject will follow 
the treatment visit schedule until they reach Study Week 50, at which time they will skip to 
the last treatment visit TV14 described in Section 9.6.2.2.4. 
 
Figure 2 and Figure 3 visually display the relationship between TR03ext study weeks, 
Treatment Period weeks and Observation Period weeks. 
9.6.1 Visit 1a (Day 1 of Study Week 1)  
See Table 4 for summary of Visit 1a procedures. 
 
Study TR03 Visit 6 procedures in common with Study TR03 extension Visit 1a procedures 
do not have to be repeated. 
 
• obtain informed consent  
• confirm eligibility  
• obtain vital signs 
• conduct a physical examination  
• collect central laboratory samples (hematology and chemistry) 
• collect serum pregnancy sample in women of childbearing potential (done at the 
central laboratory)*  
• collect urine for central lab urinalysis 
• collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)* 
* If the urine pregnancy test result is negative and the serum pregnancy test result is 
positive, the patient is to be contacted and the following actions are to take place: 
• instruct the patient to discontinue taking study drug 
• schedule the patient for an unscheduled visit to collect another serum 
pregnancy test  
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment.  See section 17.5.2.1 regarding how pregnancies 
are to be handled in this study. 
• obtain blood for PK 
• obtain a 12-lead ECG  
• record AEs  
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• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins; also obtain the TR03 re 
• retrieve any remaining study drug from the parent study TR03 
• administer Worst
a) If NRS scores are ≤ 2 (Worst Itch NRS), start the Observation Period.  
Do NOT initiate study drug treatment at this visit  
 itch NRS and review score for eligibility to either enter the 
Treatment Period or to continue in screening under the Observation Period 
b) If NRS scores is >2 (Worst Itch NRS) start Treatment Period 
immediately  
The Worst
For patients qualifying for drug Treatment Period only (Visit 1a is also study visit 
TV1): 
 Itch NRS must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual) 
• complete PAS 
• administer PRO measurements:  
o Average daily itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
o PBI-P 
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual) 
• 
dispense Study Drug to the patient required until return at TV2. 
• instruct patients to self-administer the first dose on the evening of Visit 1a at home  
• instruct patients to notify the Investigator if any significant CNS AEs occur, and not 
to drive or operate dangerous machinery until the effect of the Study Drug can be 
assessed by the Investigator, see Section 9.3 
• 
instruct the patient to take the Study Drug twice daily at approximately the same 
times of day and how to escalate from 30mg to 60mg BID. 
• instruct patients to bring all remaining Study Drug to the Investigator site for each 
study visit. 
 
For patients starting the Treatment Period, the next visit will be TV2.  
 
For patients not qualifying for drug Treatment Period only (Visit 1a is also study visit 
OV1), the patient will enter the Observation Period and the next visit will be OV2. 
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9.6.2 Treatment Period (Study Weeks 1-50) 
Patients who enter the Treatment Period on Visit 1a will be in the Treatment Period for 50 
weeks and thus are eligible to receive study drug for up to 50 weeks.   
Patients who enter the Treatment Period from the Observation Period will be in the 
Treatment Period anywhere from 38-46 study weeks.  Patients enter the Treatment Period 
from an Observation Visit (OV) when their worst itch NRS >2. 
Regardless of how many treatment weeks the patient was on study drug, for all patients 
study week 50 will coincide with TV14 when end of study drug procedures are conducted. 
Since all patients must titrate to their maintenance dose over the first four weeks of the 
Treatment Period, Visits 1a/Visits 1b (TV 1) and TV 2 over the first four weeks of the 
Treatment Period will be common to all subjects in TR03ext regardless of the study week 
entry into the Treatment Period.  Patients who transition from the Observation Period to the 
Treatment Period at a respective OV will follow a TV schedule outlined in Table 8 in order 
for the patient to complete the TV 14 visit during week 50.   
9.6.2.1  Treatment Period Weeks 2-4 (Titration Phase of Study Drug) 
The first week in the Titration phase is initiated as part of Visit 1a/1b (Day 1 Treatment 
period Week 1, see Section 9.6.1 above).  Subsequently, the following events TC1, TV2 
and TC2 will be conducted during the remainder of the titration phase.  See Table 5 for the 
Schedule of Events during the titration phase. 
9.6.2.1.1 
Telephone Contact Number 1 (TC1, Treatment Period Week 2) 
The patient is to be contacted by phone and the following are to take place: 
• Record AEs  
• Reinforce compliance 
• Confirm that patient has titrated drug up to 60 mg BID following the dosing 
schedule of Table 3 
• Document tolerability/intolerability to study drug and decision to continue dose 
escalation following the dosing schedule of Table 3 
• Discontinue patients who could not tolerate 60 mg dose and schedule patients for an 
Early Termination Visit (See Section 9.6.4). 
9.6.2.1.2 
Treatment Visit 2 (TV2, Treatment Period Week 3) 
The following procedures are to take place at this visit: 
• obtain vital signs 
• collect urine for pregnancy (must be confirmed negative prior to dispensing study 
drug) 
• collect blood for PK 
• administer PRO measurements:  
o Worst itch NRS 
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o Average daily itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS. 
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
• record AEs (including tolerability to study drug) 
• review 
concomitant 
medications, 
including 
over-the-counter 
medications, 
nutritional supplements, and vitamins  
• reinforce compliance 
• perform Study Drug accountability, retrieve previously dispensed Study Drug  
• dispense the Study Drug to the patient required until return at TV3 (Treatment 
Week 5) 
• Document tolerability/intolerability to study drug and decision to maintain dose at 
180 mg or decrease dose to either 120 m g or 90 m g BID following the dosing 
schedule of Table 3. 
9.6.2.1.3 
Telephone Contact Number 2 (TC2, Treatment Period Week 4) 
The patient is to be contacted by phone and the following are to take place: 
• record AEs 
• reinforce compliance 
• for patients who report intolerable side effects at the 180 mg BID decrease dose to 
either 120 mg BID or 90 mg BID 
• for Patients who report intolerable side effects at the 120 mg BID decrease dose to 
90 mg BID 
• record patient dose as maintenance dose 
• patients dosed at 90 mg BID for the previous week and report intolerable AEs, the 
subject is to be discontinued and scheduled for an Early Termination Visit (See 
Section 9.6.4). 
9.6.2.2 Treatment Period Weeks 5-50  
During this period of the study, the patient continues on the maintenance dose established 
by the end of Treatment Period week 4 for the remainder of the study with the exception of 
a single allowable dose reduction is permitted during Treatment Period Weeks 5 – 50  (a 
patient at 90 mg BID can be reduced to 60 mg BID). If a second dose reduction is needed, 
the patient should be discontinued from the study (See Table 3).   
 
See Table 6 for the Schedule of Events for Treatment Period weeks 5-50. 
 
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9.6.2.2.1 
Treatment Visits 3-7 (TV3-TV7, Treatment Period Weeks 5-21) 
The following procedures are to take place at these visits: 
• obtain vital signs 
• collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug) 
• collect blood for PK 
• administer PRO measurements:  
o Worst
o Average daily itch intensity NRS 
 itch NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce compliance 
• perform study drug accountability, retrieve previously dispensed Study Drug  
• Dispense the study drug to the patient required until next TV 
 
9.6.2.2.2 
Treatment Visit 8 (TV 8, Treatment Period Week 26) 
The following procedures are to take place at this visit: 
• obtain vital signs 
• perform physical examination 
• complete the PAS 
• perform 12-lead ECG 
• collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug) 
• collect urine for urinalysis for central lab 
• collect blood for central laboratory (hematology and chemistry) and for PK 
• administer PRO measurements:  
o Worst
o Average daily itch intensity NRS 
 itch NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
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The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
• record AEs  
• review 
concomitant 
medications, 
including 
over-the-counter 
medications, 
nutritional supplements, and vitamins  
• reinforce compliance 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense study drug to the patient required until next TV 
 
9.6.2.2.3 
Treatment Visits 9-13 (TV 9-TV13, Treatment Period Weeks 30-46) 
The following procedures are to take place at this visit: 
• obtain vital signs 
• collect urine for pregnancy (must be confirmed negative prior to dispensing study 
drug) 
• collect blood for PK 
• administer PRO measurements:  
o Worst
o Average daily itch intensity NRS 
 itch NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce compliance 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense the study drug to the patient required until next TV 
 
9.6.2.2.4 
Treatment Visit 14 (TV 14, Last Treatment Period Visit – Study Week 
50) 
The following procedures are to take place at this visit: 
• obtain vital signs 
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• perform physical examination 
• complete the PAS 
• perform 12-lead ECG 
• collect blood for central laboratory (hematology and chemistry) and serum 
pregnancy test for central laboratory 
• collect urine for urinalysis at the central laboratory 
• collect blood for PK 
• perform skin biopsy for histological studies (selected sites only) 
• administer PRO measurements:  
 
o Worst
o Average daily itch intensity NRS 
 itch NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
 
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• perform study drug accountability, final retrieval of any dispensed study drug  
9.6.3 Washout and Safety Follow-Up Period (Week 52) 
All patients on Treatment will have a 2-week Washout and Safety Follow-Up Period 
following TV14.  During this visit, the PRO questionnaires must be administered at the 
study site under supervision by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual). Please see the Schedule of Events in 
Appendix 1 for details of the Washout and Safety Follow-Up Period assessments.  
Additional information for this visit is provided below. 
 
The following procedures are to take place at this visit: 
• obtain vital signs 
• perform 12-lead ECG 
• collect blood for central laboratory measurements and PK 
• administer PRO measurements:  
o Worst
o Average daily itch intensity NRS 
 itch NRS 
o VRS 
o ItchyQoL 
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o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
 
• AEs and concomitant medications (including rescue medications) will be recorded 
• collect the Rescue Medication Log will be collected from the patient at this visit 
• retrieve any remaining study drug that the patient did not previously turn in 
9.6.4 Early Termination Visit 
The following procedures are to take place at this visit: 
• obtain vital signs 
• perform physical examination 
• collect blood for central laboratory (hematology and chemistry) and serum 
pregnancy test at the central laboratory 
• collect blood for PK 
• perform 12-lead ECG 
• collect urine for urinalysis at central lab 
• administer PRO measurements:  
o Worst
o Average daily itch intensity NRS 
 itch NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• perform study drug accountability, final retrieval of any dispensed study drug 
9.6.5 Observation Period (Study Weeks 1-12) 
Only patients with Visit 1a worst itch NRS score of ≤2  (Visit 1a for these patients is 
considered OV1) should enter the Observation Period, which includes subsequent study 
visits OV 2-4 at approximately one month intervals over the next 12 study weeks 
(See Table 7). While patients remain in the Observation Period, they will not be considered 
enrolled into the study, but as participating in an extended screening process until they are 
eligible for enrollment. Patients evaluated at OV 2-4 and who record worst itch NRS>2 and 
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are otherwise eligible can immediately begin Visit 1b and transition into the Treatment 
Period. 
For these patients, the sum of time in the Observation Period and Treatment Period will not 
exceed 50 weeks. As a result, both the Observation Period and Treatment Period will differ 
in length for different patients.  
9.6.5.1 Observation Visit 2 at Study Week 4 and Observation Visit 3 at Study Week 8 
To ensure that the total number of study weeks does not 
exceed 50 weeks, that all patients complete proper titration of study drug up to the 
assessment of TV 2 during Treatment Period Week 3, and that the final Treatment Period 
visit is always TV14, multiple interim Treatment Visits will be skipped as indicated in 
Table 8. 
The following procedures are to take place at this visit: 
• administer the Worst itch NRS; if >2, patient must undergo Visit 1b procedures 
• obtain vital signs 
• record AEs 
• record concomitant medications 
9.6.5.2 Observation Visit 4 at Study Week 12 
The following procedures are to take place at this visit: 
• administer the Worst itch NRS; if >2, patient must undergo Visit 1b procedures 
• obtain vital signs 
• record AEs 
• record concomitant medications 
If subject screen fails and does not transition to Visit 1b, conduct the following: 
o Average daily itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
9.6.5.3 Visit 1b 
See Table 4 for summary of Visit 1b procedures. 
Patients evaluated at OV 2-4 who record worst itch NRS>2 and are otherwise eligible can 
immediately begin Visit 1b.  This patient then transitions into the Treatment Period and 
will undergo the following procedures: 
• obtain vital signs 
• conduct a physical examination  
• collect central laboratory samples (hematology and chemistry) 
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• collect serum pregnancy sample in women of childbearing potential (done at the 
central laboratory)*  
• collect urine for central lab urinalysis 
• urine for pregnancy (must be confirmed negative prior to dispensing study drug)* 
* If the urine pregnancy test result is negative and the serum pregnancy test result is 
positive, the patient is to be contacted and the following actions are to take place: 
• instruct the patient to discontinue taking study drug 
• schedule the patient for an unscheduled visit to collect another serum 
pregnancy test  
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment.  See section 17.5.2.1 regarding how pregnancies 
are to be handled in this study. 
 
• obtain blood for PK 
• obtain a 12-lead ECG  
• administer PRO measurements:  
 
o Worst
o Average daily itch intensity NRS 
 itch NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
o PBI-P 
The PRO questionnaires must be administered at the study site under supervision by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• complete the PAS 
• dispense Study Drug to the patient required until return at TV2 
• instruct patients to self-administer the first dose on the evening of Visit 1b at home  
• instruct patients to notify the Investigator if any significant CNS AEs occur, and not 
to drive or operate dangerous machinery until the effect of the Study Drug can be 
assessed by the Investigator, see Section 9.3 
• 
instruct the patient to take the Study Drug twice daily at approximately the same 
times of day  
• instruct patients to bring all remaining Study Drug to the Investigator site for each 
study visit. 
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The next study visit will be Treatment Visit 2 (TV2).  However, to ensure that the total 
number of study weeks does not exceed 50 weeks, that all patients complete proper 
titration of study drug and that the final Treatment Period visit is always TV14, multiple 
interim Treatment Visits will be skipped as indicated in Table 8. 
9.6.6 Unscheduled Visits 
If a patient needs to be evaluated in relation to the study on a day other than one of the 
study visit days, that day will be considered an Unscheduled Visit. The reason for each 
unscheduled visit will be recorded and the following procedures will be performed: vital 
signs (BP, HR, RR, temperature), assessment for AEs, review of concomitant medications, 
and Study Drug accountability. Additional procedures such as central or local laboratory 
sample collection may also take place, if clinically indicated.   All unscheduled visits will 
be recorded on the Unscheduled Visit CRF.   
9.6.7 Schedule of Events 
The Schedule of Events is shown in Appendix 1 and is described in Section 9.6. 
9.7 
STUDY DRUG TREATMENT AND DRUG ACCOUNTABILITY 
Please see the Study Reference Manual for additional information on Study Drug supplies, 
packaging, storage, dispensation, and accountability. 
9.7.1 Study Drug Dosing 
Study drug can be taken with or without food.  Patients will be instructed to take the AM 
and PM Study Drug tablets at the same times of the day, approximately 12 hours apart, 
preferably with 240 mL (approximately 8 ounces) of water. If the patient does not take a 
particular dose at the planned time he or she may take it up to 2 hours later.  For example, 
if a patient is taking the Study Drug at 9 AM and 9 PM but forgets to take the 9 AM dose, 
he may take the 9 AM dose as late as 11 AM.  After that time, the patient should skip the 9 
AM dose and, instead, take the regularly scheduled next dose at 9 PM.   
The Study Drug will be titrated to their maintenance dose during the titration phase of the 
Treatment Period according to the schedule in Table 3 below and graphically displayed in 
Figure 4. 
 
 
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Table 3: 
 Dosing Schedule for TR03ext 
Week of Treatment Period1 
(TV or TC) 
Tolerance 
Day 
Dose2  
Week 1 
 
 
(TV1/Visit1a or 1b) 
N/A 
Day 1 
30 mg (PM dose) 
2 
None (0 mg) AM; 
30 mg PM 
3-4 
30 mg BID 
5 
30 mg AM;  
60 mg PM 
6-7 
60 mg BID 
Week 22 
 
(TC #1) 
Unacceptable3 
1 
Discontinue Patient 
Acceptable 
1 
60 mg AM;  
90 mg PM 
2-3 
90 mg BID 
4 
90 mg AM 
120 mg PM 
5-6 
120 mg BID 
7 
120 mg BID 
Week 32 
 
(TV2) 
Acceptable 
1 
 
  120 mg AM;     
180 mg PM 
2-7 
180 mg BID 
Unacceptable3 
1-7 
Reduce dose and 
maintain at 90 mg BID 
Week 42 
(TC#2) 
Uncceptable3 
1-7 
Decrease dose to either 
120 mg BID or 90 mg 
BID4 
Acceptable 
1-7 
Maintain dose (either 90 
mg BID, 120 mg BID or 
180 mg BID) 
Treatment Period Week 55 up 
to Treatment Period Week 50 
(TV3-TV 14) 
Acceptable5 
1-7 
Maintain dose at either 
90 mg BID; 120 mg BID 
or 180 mg BID 
through TV146 
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1The decision to enter the patient into the Titration Period is based on Worst Itch NRS score NRS >2 obtained from 
the patient on Visit 1a or 1b 
2The titration decision will be made based on tolerance to study drug 
3Tolerance level is unacceptable to either the patient and/or investigator. 
4Patients who were dosing at 90 mg BID for the previous week and could not tolerate the study drug are to be 
discontinued 
5 The number of Treatment Period weeks prior to TV 14 will vary for patients previously in the Observation Period 
depending upon the number of weeks spent in the Observation Period. See Table 8 
 
6The achieved dose attained as of the end of Treatment Period Week 4 will be maintained throughout the rest of the 
Treatment Period. This dose will be defined as the patient’s “maintenance dose”. A one time dose reduction to the 
next lower allowed dose is permitted during Treatment Period Weeks 5 – 50  (a patient at 90 mg BID can be reduced 
to 60 mg BID). If a second dose reduction is needed, the patient should be discontinued from the study. 
 
9.7.2 Down-Titration 
Down-titration is not permitted except as discussed in Section 9.7.1 
9.7.3 Overdose  
The effects of nalbuphine may be reversed with opioid antagonists such as naloxone. 
Please see Guidance to the Investigator section of the Investigator Brochure for additional 
information. 
9.7.4 Treatment Compliance 
Returned study drug tablets will be used to assess compliance at each visit. Medication 
compliance will be recorded on the CRF for each designated visit (See Appendix 1). 
Patient compliance with the study dosing schedule will be assessed as part of the planned 
study analyses. 
9.7.5 Rescue Medications, Concomitant Medications, Prohibited Medications, and 
Pre-Medications 
9.7.5.1 Rescue Medications 
A secondary objective of the study is to quantitate the number of days of rescue medication 
use for itching during the course of nalbuphine HCl ER treatment.  Rescue medications 
will be defined as those drugs, when used for the purpose of treating itch, that were 
required to be washed out prior to entry into TR03 (See Table 9).  For the purposes of this 
study, any UV light treatment received will also be defined as a rescue medication.   
9.7.5.2 Concomitant Medications 
Any medication taken by a patient following the signing of informed consent during the 
course of the study and the reason for use of the medication will be recorded on the case 
report form (CRF).  Each patient will be instructed to report the use of all medication to the 
Investigator, including over-the-counter [OTC] medications, herbal medications, vitamins, 
and nutritional supplements.  Patients will also be instructed about the importance of not 
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taking any new medications during the study (including OTC medications) without 
consulting the Investigator. 
9.7.5.3 Prohibited Medications 
Initiating use of opiate medications during the study should be done with caution with 
assessment of the patient for potential additive opiate AEs. If an enrolled patient requires 
daily treatment with opioid medications during the study (e.g., for post-surgical pain), 
please contact the Medical Monitor. Use of acetaminophen, non-steroidal anti-
inflammatory medications, and aspirin is permitted. 
Concomitant use of opioid antagonists (e.g. naloxone, naltrexone) are also prohibited 
during the study, unless required for urgent reversal of opioid adverse effects or opioid 
overdose.  
Use of all other investigational drugs are prohibited during the study.  A subject who 
initiates an investigational drug during the study should be discontinued. 
9.7.5.4 Pre-Medications 
Nalbuphine use may be associated with nausea, vomiting, and/or constipation, particularly 
as the dose is escalated or upon initiation of treatment.  At the Investigator’s discretion, 
anti-emetics such as ondanestron may be administered prophylactically, prior to taking the 
Study Drug or, as needed, for treatment.  Dietary and other prophylactic measures to avoid 
constipation should also be considered as clinically indicated. 
9.7.6 Efficacy Assessments 
The below PRO instruments will be administered at the site at the site and under 
supervision by trained study staff, strictly adhering to PRO Administration Instructions (see 
Study Reference Manual) according the Schedule of Events  (see Appendix 1). 
9.7.6.1 Numerical Rating Scale (NRS)  
The NRS is a patient-reported outcome instrument, designed to quantify the intensity of 
worst itching experienced during a 24-hour period.  The scale is a set of boxes, one for 
each number, from 0 (no itching) to 10 (worst possible itching).  The NRS is a widely used 
instrument recommended by IFSI for quantifying itch intensity as well as a useful 
instrument for grouping patients into categories of itch intensity described as mild, 
moderate or severe (Stander et al 2013).  The itch NRS has been investigated in patients 
with chronic pruritus of a variety of origins and has a high reliability and concurrent 
validity was found (Phan et al 2012).  
In this study, patients will be asked to record two NRS values:  
• rate itching on average 
• rate 
over the past 24 hours 
most severe 
This instrument can be found in 
itching over the past 24 hours 
Appendix 4. 
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9.7.6.2 Verbal Rating Scale (VRS) 
The VRS scale to be used in this study has three dimensions, each dimension coded with 
graduated adjectives (from 0 = none; to 5 = very severe) for the skin sensations of itchy, 
burning and stinging.  
 
In this study, patients will be asked to record the VRS value: 
• 
How is your skin sensation today?   
 
This instrument can be found in the Appendix 4. 
9.7.6.3 Hospital Anxiety and Depression Scale (HADS) 
The HADS instrument includes 14 multiple-choice questions, each with 4 possible choices, 
scored between 0 and 3. This instrument can be found in Appendix 4.    
9.7.6.4 ItchyQoLTM 
The ItchyQoLTM consists of 22 pruritus-specific items measuring how pruritus affects 
patients’ QOL in the area of symptoms related to the itch condition (6 questions), 
functional limitations (7 questions), and emotions (9 questions). The subject scores each 
question never =1, rarely=2, sometimes=3, often=4, all the time=5.  The instrument can be 
found in Appendix 4.  
9.7.6.5 Medical Outcomes Sleep Scale –Revised (MOS Sleep-R) 
MOS Sleep Scale-R measure is a 12-item self-report sleep measure that was developed to 
assess sleep quality and quantity. It is a multi-dimensional assessment of sleep parameters 
with scoring results in six subscales or domains: sleep disturbance (4 items), snoring (1 
item), awaken short of breath or with headache (1 item), quantity of sleep (1 item), optimal 
sleep (1 item), sleep adequacy (2 items), and daytime somnolence (3 items).  
 
Additionally, a 9-item Sleep Problems Index (“Sleep Problem Index I”) can be generated 
which assesses overall sleep problems that includes the 4 sleep disturbance and the 2 sleep 
adequacy items, 2 of the somnolence items, and awakening short of breath/headache; 
higher scores indicate greater sleep impairment, and this index is often used in clinical 
trials as an indication of sleep quality.  The instrument can be found in Appendix 4.   
9.7.6.6 Patient Benefit Index (PBI-P) 
The PBI-P questionnaire assesses the importance of treatment objectives to the individual. 
Before and at the end of drug treatment in this study, the patient completes the same 
questionnaire and rates the extent to which the treatment objectives have been achieved. 
The instrument consists of 27 multiple choice questions that can be answered “not at all”, 
“somewhat”, “moderately”, “quite” and “very”. The instrument can be found in 
Appendix 4. 
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9.7.6.7 Prurigo Activity Score (PAS)  
The PAS consists of 7 quantitative and quantitative measurements related to the 
examination of the skin.  Type, number, distribution, affected body parts, and quantitative 
number of lesions in a representative body part are documented.  The biggest lesion and the 
most representative lesion are monitored with documentation of height and area 
measurements.  Prurigo lesion activity is recorded as a percentages based on their stage (0-
4).  Photographs of the body are conducted with monitored lesions marked. The instrument 
can be found in Appendix 4. 
9.7.6.8 Exploratory Histological Endpoints (at selected sites) 
Punch biopsy skin material for measurement of nerve fiber density (histology) and 
MOR/KOR density (histology, Western Blot) analysis was obtained during TR03 (at 
selected sites).  Punch biopsy will be obtained (at selected sites) during TV 14 for a 
comparative analysis with the results of the histological results of pre-dosing TR03 and end 
of study TR03 results. 
 
9.7.6.8.1 
MOR/KOR density and Nerve Fiber Density  
The potential of nalbuphine HCl ER tablets to impact on the Measurement of nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot) in skin biopsies taken 
at Baseline visit and the Evaluation visit will be investigated at selected sites. 
In addition to skin biopsy tissue obtained prior to drug treatment for H&E and analysis by a 
central reading dermatopathologist, at selected sites additional skin biopsy material 
obtained before and at the end of drug treatment will be compared to investigate, in an 
exploratory manner, any evidence of change in expression of MOR and KOR and nerve 
fiber density in relation to any noted changes in clinical study endpoints.  
 
Bigliardi et al (2007) reports that in normal skin, keratinocytes express high amounts of 
MOR and it is therefore concluded that endogenous ligands are bound primarily to opioid 
receptors on keratinocytes and thus the endogenous opiate ligands are not binding to opioid 
receptors located on nerve endings –the net result is at most a weak itch signal to the 
central nervous system in the normal state. In chronic pruritic skin disorders, most opioid 
receptors on keratinocytes are reported as internalized; therefore there are many opioid 
ligands available to bind to opioid receptors on sensory nerve endings. This state leads, 
together with the changed morphology of the epidermal nerve endings, to a strong itch 
signal to the CNS.  The authors reported that topical administration of the opioid mu 
receptor antagonist naltrexone in subjects with atopic dermatitis, lichen simplex chronicus 
or prurigo simplex showed an antipruritic effect.  In addition, there was also an 
upregulation of epidermal MOR expression following two weeks of treatment, but no 
MOR upregulation in subjects who did not experience an antipruritic response. Bigiliardi 
and Bigliardi-Qi (2004) reported that in PN human skin tissue samples there was a down 
regulation of the mu-opiate receptor (MOR) expression in the epidermis compared to 
normal skin.   
 
Bigliardi-Qi et al (2009) reports that while it is widely accepted that KOR signaling 
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suppresses itch, there is currently no animal, behavioral or human data relating the 
regulation of skin KOR expression to pruritus. Salemi et al 2007 however reported high 
upregulation of KOR in the skin of fibromyalgia subjects that was thought to correlate with 
reported complaints of pain symptoms. 
 
With regard to peripheral sensory nerve fiber density in the skin, Bigliardi et al (2009, 
2007) report that epidermal nerve endings of pruritic skin in prurigo are thinner when 
compared to normal skin.  In addition, the nerve fibers have a different morphology which 
may relate to initiating the sensation of pruritus because of the altered anatomical 
relationship to the various cellular elements of the skin.   
9.7.7   Safety Assessments 
Safety will be determined by evaluation of the following: 
• AEs 
• Vital signs including weight, BP, heart rate (HR), respiratory rate (RR), and body 
temperature 
• Physical examination  
• Clinical laboratory data  (see Appendix 3 for list of analytes) 
• 12 Lead-ECG. 
10 STUDY DRUG 
Please see the Study Reference Manual for additional information on Study Drug supplies, 
packaging, storage, dispensation, and accountability. 
10.1 FORMULATION, PACKAGING AND LABELING 
The Study Drug in this trial is nalbuphine HCl ER tablets. Nalbuphine HCl ER tablets are 
white to off white film-coated round tablet containing either 30 mg or 60 mg nalbuphine 
HCl.   
All study medication will be supplied by the Sponsor. Following confirmation of eligibility 
to start the Treatment Period, the patient will receive bottles of study drug tablets 
containing 60 tablets each. Bottles will be labeled with at minimum: contents, storage 
conditions, expiration date, clinical trial statement, and the name and lot number of the 
study drug Sponsor (Trevi Therapeutics). 
10.2 SHIPPING, STORAGE AND HANDLING 
The Investigator will ensure that the Study Drug is stored and dispensed in accordance with 
FDA and EU regulations concerning the storage and administration of investigational 
drugs.  Nalbuphine HCl ER tablets should be stored at 20°C-25°C (68°F-77°F) with 
excursions permitted between 15°C and 30°C (59° to 86°F). The Study Drug should be 
stored away from any extreme conditions of temperature, light, or excess humidity. 
10.3 UNBLINDING 
Not applicable.  This is an open-label study. 
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10.4 DRUG ACCOUNTABILITY 
The Investigator must ensure that all drug supplies are kept in a secure locked area with 
access limited to those authorized by the Investigator.  The Investigator must maintain 
accurate records of the receipt of all Study Drug shipped by the sponsor or the sponsor’s 
representative, including but not limited to the date received, lot number, expiration date, 
amount received, and the disposition of all Study Drug.  Current dispensing records will 
also be maintained including the date and amount of drug dispensed and the patient 
receiving the drug.  All remaining drug not required by regulations to be held by the 
clinical facility will be destroyed on site at the end of the study. 
11 PREMATURE DISCONTINUATION OF STUDY DRUG 
TREATMENT 
Patients who complete Study Drug treatment through Treatment Visit 14 (even if some 
doses have been missed or if the patient was followed in the Observation Period before 
receiving study drug treatment) are considered to have completed Study Drug treatment. 
Patients discontinuing Study Drug treatment prior to Treatment Visit 14 will be 
considered to have prematurely discontinued Study Drug treatment. Patients removed 
from the study after enrollment and who have received a dose of study drug will not be 
replaced. 
Some reasons for premature discontinuation of Study Drug treatment include: 
• Withdrawal of consent to continue Study Drug treatment 
• Intercurrent Illness 
• Any intolerable AE that cannot be ameliorated or safely managed with 
medical intervention or one that poses undue risk to the subject if Study 
Drug treatment were continued in the opinion of the Medical Monitor or 
Investigator. 
12 PREMATURE WITHDRAWL OF PATIENTS FROM THE STUDY 
Patients who complete study visits through the Evaluation visit of Week 10, even if there 
have been intervening missed visits, are considered to have completed the study.  
All patients who receive study treatment should remain in the study whenever possible. 
Reasons for withdrawal of the patient from the study include: 
• Withdrawal of consent for study participation 
• Premature discontinuation of Study Drug treatment  
• Sponsor terminates the study for any reason 
• Investigator decision 
The Investigator may withdraw any patient from the study if, in the Investigator’s 
opinion, it is not in the patient’s best interest to continue on the study. 
• Death of the patient 
• Change in eligibility to participate in the study.  
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Any patient whose condition significantly changes after entering the study should be 
carefully evaluated by the Investigator and discussed with the Medical Monitor.  Such 
patients should be withdrawn from the study if continuing would place them at risk or 
compromise the results of the study. 
Patients who prematurely discontinue from the study will be asked to undergo and have 
completed all evaluations that may be necessary to ensure that the patient is free of 
untoward effects and to seek appropriate follow-up for any continuing problems.  The date 
on which the patient is withdrawn from the study and the reason for discontinuation will be 
recorded on the CRF.  When a patient is withdrawn prematurely from the study, (regardless 
of the reason), all evaluations required at the Early Termination visit will be performed.  
Patients who withdraw from the study will not be replaced. 
13 WARNINGS AND PRECAUTIONS 
Please refer to the accompanying Investigator’s Brochure for more details summarizing the 
safety data on nalbuphine HCl ER tablets.  In addition, see the Warnings and Precautions 
sections of the parenteral nalbuphine HCl package insert for safety-related information.  
The package insert is contained in the Study Reference Manual. 
14 EFFICACY EVALUATIONS 
Efficacy measurements will be evaluated as exploratory endpoints in this study. The 
measurements include: 
• Worst
• Average daily itch intensity baseline. 
 itch intensity NRS  
• VRS (itchy, burning and stinging)  
• ItchyQoL  
• MOS Sleep-R  
• HADS 
• Prurigo Activity Score (PAS)  
• Patient Benefit Index, pruritus version (PBI-P)  
• Frequency, pattern, and reasons for dose titration 
• Use of rescue medications. 
14.1 EXPLORATORY 
The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot) in skin biopsies taken 
during TR03 and the the last week on study drug during TR03ext  (at selected sites only). 
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15 COLLECTION, HANDLING, AND ANALYSIS OF 
PHARMACOKINETIC BLOOD SAMPLES 
15.1 BLOOD SAMPLE COLLECTION 
Blood samples will be collected for safety, pharmacokinetic and CYP analysis.  At the time 
of sample collection and processing, study patient information will be anonymized.  Only 
the patient’s identification number, assigned by an IVR/IWR system, and a sample barcode 
aligned to the lab requisition form will be noted on the tube/vial.   
See the study Laboratory Manual for specimen collection, handling and shipping details.  
15.2 CENTRAL LABORATORY 
Blood samples, including chemistry, serum pregnancy test, and hematology, and urine for 
urinalysis  obtained for the study will be analyzed at a central laboratory.  
Urine pregnancy testing will be conducted at the site. 
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment should the urine and serum pregnancy test results differ.  
See section 17.5.2.1 regarding how pregnancies are to be handled in this study. 
15.3 PHARMACOKINETIC SAMPLES 
To determine Study Drug content in plasma, blood samples will be collected at various 
time intervals over the duration of the study. 
15.4 PREPARATION, STORAGE, AND HANDLING FOR PHARMACOKINETIC SAMPLES 
Immediately after blood sample collection, the tubes will be gently inverted several times 
to mix the anticoagulant with the blood sample and placed on ice (4 to 8°C) until 
centrifuged.  
The plasma fraction will be separated by centrifugation of the collection tube. It is 
preferable that a refrigerated (4 to 8°C) centrifuge be used.  Centrifugation will be 
conducted in a manner to yield approximately 2 x1 mL of plasma (e.g., 10 minutes at 1,500 
x g).  The plasma fraction will be withdrawn by pipette and divided into 2 evenly 
proportioned aliquots in polypropylene freezing tubes.  All sample collection and freezing 
tubes will be clearly labeled in a fashion that identifies the patient identification number, 
the study dose, and the collection date and time. 
Labels will be fixed to freezing tubes in a manner that will prevent the label from becoming 
detached after freezing.  All plasma samples will be processed and placed into either a 
minus 70°C or minus 20°C refrigerator within 1 hour after collection.  Tube labels for PK 
samples will be provided in the Central Laboratory kits.  Each label will contain the study 
number, patient number, study day of sample, and time of sample.  The actual date and 
time of blood collection will be recorded in the patient’s CRF.  
All plasma samples will be stored frozen (at either -70ºC or -20°C) until they are shipped 
for storage and analysis. 
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15.5 ANALYTICAL 
Plasma samples will be analyzed for Study Drug using a validated liquid chromatography 
mass spectrometry (LC-MS/MS) method developed at Tandem Lab/s-RTP, Durham, North 
Carolina. The units for nalbuphine will be in ng/mL. In addition, metabolite concentrations 
will be assessed in these samples using an exploratory analytical LC-MS/MS method. 
Analysis and reporting of results will be conducted according to the current Standard 
Operating Procedures for bioanalysis at Tandem labs Durham, North Carolina. Details of 
the sample analysis, including a bioanalytical study report, will be included with the final 
clinical study report. 
16 TISSUE SAMPLES AND HISTOLOGY 
At selected sites only, three 3 mm punch skin biopsy samples will be obtained at TV 14. 
One sample will be fixed in formalin and then paraffin for routine histology (H&E) and 
immunohistochemical examination of inflammatory cells and pro-inflammatory mediators. 
One sample will be fixed in 4% paraformaldehyde for 2 h to 5 days, and then kept in 5% 
sucrose overnight, buffered in 10% and 20% sucrose and after 6 h stored in liquid nitrogen. 
This tissue will serve for the determination of the nerve fiber density. One sample will be 
used for RNA and protein extraction for the quantification of MOR/KOR by PCR and 
western blot.  Analysis will be performed at the University of Munster, Munster, Germany.  
See the study Laboratory Manual for specimen collection, handling and shipping details. 
17 SAFETY EVALUATIONS 
Safety evaluations will include physical examination findings, changes in vital signs and 
ECGs, findings from clinical laboratory studies and the incidence of AEs 
17.1 PHYSICAL EXAMINATION 
A complete physical examination will be performed at the Screening Visit and 
subsequently according to the Schedule of Events (Appendix 1).  Physical examinations 
may be performed by physicians or mid-level providers such as advanced practice nurses 
and physician assistants with the Sponsor’s approval. Any clinically significant worsening 
after the start of Study Drug treatment 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.  
17.2 VITAL SIGN MEASUREMENTS 
Blood pressure and HR will be taken while sitting or semi-recumbent/recumbent for at 
least 5 minutes. Temperature may be taken by any standard method (e.g., oral, tympanic, 
rectal, etc), but the method must be recorded. 
Vital signs (BP, HR, RR, body temperature, and weight will be obtained according to the 
Schedule of Events (Appendix 1). The height, weight and BMI will be recorded only on 
Visit 1. 
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17.3 LABORATORY EVALUATIONS 
A complete series of laboratory evaluations (including hematology, serum chemistry, 
serum pregnancy and urine pregnancy (both if applicable) and urinalysis will be obtained 
according to the Schedule of Events (Appendix 1).  The required clinical laboratory tests 
are listed in Appendix 3.  
Clinically-significant worsening in laboratory findings following start of Study Drug 
treatment will be recorded as AEs and these will be repeated for verification. Clinically-
significant findings noted prior to the start of Study Drug treatment will be recorded as 
Medical History. The recorded AE will indicate the underlying abnormality or diagnosis as 
opposed to the observed deviation in laboratory results if the diagnosis is known (e.g. 
“acute Hepatitis A” is preferable to “ALT increased”).   
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal result or to monitor the course of an AE will be obtained when clinically 
indicated.  In particular, if a clinically significant abnormal result is observed that is not 
resolved by the final study visit, tests will be repeated to document resolution or stability of 
the abnormality. 
17.4 ELECTROCARDIOGRAM 
A standard 12-lead ECG will be obtained according to the Schedule of Events 
(Appendix 1). Electrocardiograms will be read locally for ECG intervals (PR, RR, QRS, 
and QT), rate, rhythm, and other clinically significant abnormalities such as left ventricular 
hypertrophy, pathological Q-waves, etc. Clinically-significant worsening in ECG findings 
following start of Study Drug treatment will be recorded as AEs. Clinically-significant 
findings noted prior to the start of Study Drug treatment will be recorded as Medical 
History. 
17.5 ADVERSE EVENTS  
Adverse events will be recorded starting with the signing of the first informed consent. All 
AEs will be collected through the Washout and Safety follow up visit (or Early 
Termination Visit). Adverse events that have not been directly reported to the Investigator 
will be promptly conveyed to the Investigator by the study staff. Investigators will 
additionally review any AE source documents and the patient’s medical records, on a 
regular basis during the course of the study. 
Following the Washout and Safety follow up visit (or Early Termination Visit), all 
unresolved AEs that were reported by the Investigator to be probably drug related should 
be followed by the Investigator until the events are resolved, the patient is lost to follow-
up, or the adverse event has stabilized. 
17.5.1 Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
reported on or after the first screening date.  A treatment-emergent AE (TEAE) is any 
untoward medical occurrence in a clinical investigation patient or patient administered a 
pharmaceutical product on or after the initial administration of study medication on the 
evening of Visit 7. An AE does not necessarily have to have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
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abnormal laboratory finding), symptom whether or not related to the medicinal 
(investigational) product, or disease temporally associated with the use of a medicinal 
(investigational) product. 
The AE may be any of the following: 
• a new illness 
• worsening of a pre-existing condition  
• worsening of a sign or symptom of the condition under treatment or of a 
concomitant illness 
• an effect of the study medication, including comparator 
• a combination of 2 or more of these factors. 
No causal relationship with the study medication or with the clinical study itself is implied 
by the use of the term “AE.” 
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. 
Adverse events fall into the categories “non-serious” and “serious.” 
17.5.2 Serious Adverse Events 
The reporting period for serious AEs is the same as for AEs. Serious AEs must be 
submitted to the Sponsor within 24 hours of their discovery, even if the full information 
about the event is not yet available. These events should also be reported to the IRB/IEC as 
needed based on local requirements. Fax SAE forms to the following number: 
Serious AE Fax #: 888-529-3580 
Also notify the PPD Medical Monitor at (888) 483-7729. 
17.5.2.1 Serious Adverse Event Definition 
An SAE is one that, at any dose, results in any of the following: 
• Death 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect. 
A hospitalization is defined as an inpatient admission lasting 24 hours or more. Visits to 
urgent care centers and emergency departments that do not result in admission to a hospital 
for >24 hours will not be considered hospitalizations. Hospitalizations for elective 
procedures, defined as any procedure that was planned prior to signing of the informed 
consent will not, in and of themselves, be considered to fulfill criteria for an SAE. For 
example, for patients on the kidney transplant waiting list prior to signing the ICF who 
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subsequently are hospitalized for a transplant, the hospitalization would be considered 
elective.  
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at immediate risk of death at the time of the SAE. It does not refer to a SAE 
that hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether other AEs, such 
as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed above. These should also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Female patients who become pregnant should be immediately discontinued from the study 
if they have not yet received Study Drug. If a patient is found to be pregnant after they 
have received Study Drug, she should discontinue dosing, complete all end-of-study 
procedures, and be followed to determine the outcome of the pregnancy. Generally, follow-
up will be no longer than 6 to 8 weeks following the estimated delivery date. While 
pregnancy itself is not considered an AE or SAE, any pregnancy complications or less than 
a healthy, normal outcome will be recorded as an AE or SAE.   
Clarification on the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
17.5.3 Non-Serious Adverse Events 
A non-serious AE is any AE not meeting the SAE criteria. 
17.5.4 Definition of Relationship to Study Medication 
Association or relatedness to the study medication will be graded as either “probably,” 
“possibly,” or “unlikely.”  Determination of relatedness includes: 
PROBABLY – The AE: 
• follows a reasonable temporal sequence from drug administration; 
• abates upon discontinuation of the drug; 
• cannot be reasonably explained by the known characteristics of the patient’s clinical 
state. 
POSSIBLY – The AE: 
• follows a reasonable temporal sequence from drug administration; 
• could have been produced by the patient’s clinical state or by other modes of 
therapy administered to the patient. 
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UNLIKELY – The AE: 
• does not follow a reasonable temporal sequence from drug administration; 
• is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient. 
17.5.5 Definition of Severity 
All AEs will be graded, if possible, by the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 [http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf].   This is also provided in the Study Reference Manual for 
reference purposes. 
The severity of AEs that cannot be graded by the most current version of CTCAE will be 
categorized as follows: 
• Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
• Grade 2 – Mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required. 
• Grade 3 – Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required hospitalizations possible. 
• Grade 4 – Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required hospitalization or hospice care probable. 
• Grade 5 – Death. 
17.5.6 Definition of Unexpected Adverse Event 
Any AE, the specificity or severity of which is not consistent with the current Investigator 
Brochure, rather than from the perspective of such experience not being anticipated from 
the pharmacological properties of the drug. 
18 EMERGENCY PROCEDURES 
In case of study-related medical questions, or if a pregnancy is confirmed in a trial patient, 
the Investigator should contact the designated Medical Monitor. 
18.1 EMERGENCY SPONSOR CONTACT 
In emergency situations, the Investigator should contact the designated sponsor 
representative at the following address: 
Thomas Sciascia, MD 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, CT 06510 USA 
Telephone:   (203) 304-2499 
Mobile:   
(617) 913-6808 
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19 CONSIDERATION, ANALYSIS PLAN AND DETERMINATION 
OF SAMPLE SIZE 
19.1 GENERAL 
As a companion to this protocol and in an effort to provide a more detailed explanation of 
the statistical methodology to be used for this study, which will consist of data summaries, 
a statistical analysis plan (SAP) will be developed prior to locking the data base. 
No formal statistical testing is planned for this study.  Data summaries will provide the 
basis for clinical interpretation of efficacy and safety outcomes 
19.2 INTERIM ANALYSES 
There is no interim analysis planned in this study. 
19.3 METHODS FOR HANDLING MISSING DATA 
No replacement or imputation of missing data will be conducted for this study.  
19.4 PATIENT DISPOSITION 
Patient disposition will be summarized, including the reasons for discontinuation.  The 
number of patients in each analysis population will be displayed and an accounting of 
exclusions from each study population will be provided. 
19.5 BASELINE CHARACTERISTICS 
Demographics, medical history, laboratory data, and physical examination findings will be 
summarized. 
19.6 CONCOMITANT MEDICATIONS 
Concomitant medications will be tabulated by Anatomic and Therapeutic Class (ATC) of 
WHO drug, preferred term, and treatment group.  A medication’s usage will be considered 
concomitant if it was started or continued after administration of the study medication.  If 
the start date is missing, it will be assumed that the medication was used concomitantly.   
Rescue and opioid medication usage will be tabulated separately from all other 
concomitant medications. 
19.7 STUDY DRUG DOSING 
The percentage of patients reaching various achieved doses at the end of Treatment Week 4 
and through Study Week 50 will be summarized. The mean dose during the Treatment 
Period and the dose distribution by Treatment Period Visit will be reported. Descriptive 
statistics will be used to describe the mean daily dose by Visit. 
19.8 EFFICACY ANALYSES 
19.8.1 Efficacy Population 
The Safety population, consisting of all enrolled patients who have received a single dose 
of study medication, will be used to evaluate the efficacy endpoints defined for this study.  
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Eligibility for analysis of a particular endpoint will require only that the patient have a 
baseline value and at least one post-baseline value for the endpoint of interest, so that a 
change from baseline calculation can be obtained.  All efficacy endpoints will be evaluated 
through the generation of descriptive summary statistics.  For continuous variables, the 
mean, standard deviation, median, minimum, and maximum will be presented for a 
particular visit and for the change from baseline (Visit 1a or 1b).  For categorical variables, 
the number and percentage of patients within each category of classification will be 
summarized by study visit.  No formal statistical testing will be conducted. 
19.8.2 Premature Discontinuation Due to Lack of Efficacy or Adverse Events 
The distribution of patients who prematurely discontinue due to lack of efficacy or adverse 
events will be summarized.  Patients who prematurely discontinue after having been 
followed in the Observation Period only will be also be summarized.  
19.9 SAFETY ANALYSES 
19.9.1  Safety Population 
The Safety Population will consist of all patients who have received a single dose of study 
medication, i.e., this same population will be used both for the efficacy and safety 
evaluations. The Safety Population will be used in all safety analyses. 
19.9.2  Adverse Events 
All treatment emergent AEs will be summarized overall and for each body system and 
preferred term by treatment group, relationship to study medication, and severity.  For 
tabulations by severity, only a patient’s most severe event within the category (e.g., overall, 
body system, or preferred term) will be counted. Adverse events will be dichotomized into 
“related” (probably and possibly) and “unrelated” (unlikely). “Treatment-emergent” will be 
defined as starting or worsening after the first dose of study medication.  If the start date is 
missing, the event is assumed to be treatment emergent. All SAEs will be tabulated as well. 
Although nalbuphine is not a controlled substance in the United States, adverse events of 
special interest that suggest a possible addiction or abuse potential or withdrawal will be 
specifically analyzed to screen for these effects. The list of MedDRA preferred terms for 
adverse events of special interest will be described in the Statistical Analysis Plan.  
19.9.3  Vital Signs 
Vital signs, including BP, HR, body temperature, and RR, and weight will be summarized 
by treatment group at Baseline and at each assessment time point during the post dosing 
period. 
19.9.4 Laboratory Evaluations 
Clinical safety laboratory data will be summarized descriptively by treatment group at 
baseline and at each scheduled visit. Summaries of safety laboratory parameters will 
include the first measurement of each scheduled assessment but repeat assessments done at 
the same study time point will not be included in summary calculations.  Lab data will also 
be listed by treatment, patient, and visit. Listings will include scheduled, unscheduled, and 
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repeat evaluations. A listing of markedly abnormal values, as defined in the Statistical 
Analysis Plan, will additionally be generated. 
19.9.5  Physical Examinations 
Abnormal physical examination findings that suggest a clinically significant worsening will 
be reported as AEs and analyzed as such. Clinically significant findings noted prior to start 
of Study Drug treatment will be recorded as medical history and analyzed as such. 
19.9.6  Electrocardiograms 
A standard 12-lead ECG will be obtained on Visit 1a/1b and subsequently, according to the 
Schedule of Events in Appendix 1. Electrocardiogram intervals (PR, RR, QTcF) will be 
summarized with descriptive statistics. All findings, including any follow-up ECGs as a 
result of any significant abnormal results, will be listed by treatment, patient, and visit. 
19.10 DETERMINATION OF SAMPLE SIZE 
As this is a safety extension study for which patients will be recruited from patients who 
have completed parent study TR03, the sample size cannot be predicted. No formal sample 
size calculations have been performed and no inferential statistics are planned. The 
maximum number of patients will not exceed the number of patients who completed TR03 
(i.e., up to 60 patients). 
19.11 PHARMACOKINETIC AND PHARMACOKINETIC / 
PHARMACODYNAMIC ANALYSES 
The Study Drug plasma concentration data will be provided as data listings and will be 
summarized descriptively (mean, median, SD, minimum, and maximum) by collection time 
and nalbuphine dose.  Additionally, these PK data may be analyzed through population, 
nonlinear mixed effects modeling (NONMEM), using the software package NONMEM 
(Version V, Level 1.1 or higher; GloboMax LLC, Hanover, MD). 
20 ETHICS 
20.1 INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD  
Prior to initiation of the study, the Investigator will submit the study protocol, sample ICF, 
and any other documents that pertain to patient information, recruitment methods such as 
patient diaries, and advertisements, to the Institutional Review Board/Independent Ethics 
Committee (IRB/ IEC).  The Investigator must also submit any other information that may 
be requested to the IRB/IEC for review and approval.  The Investigator will request that the 
IRB/IEC provide written approval of the study and will keep on file records of approval of 
all documents pertaining to this study.  A letter confirming the approval must be forwarded 
to the Study Monitor prior to initiation of this study.  This letter will be forwarded to the 
Sponsor prior to the initiation of the study. 
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC for 
all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the IRB/IEC of deviations from the protocol or SAEs occurring at the site, as well as 
other AE reports received the Sponsor, in accordance with local procedures. 
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The Investigator will be responsible for obtaining annual IRB/IEC approval or renewal 
throughout the duration of the study.   
20.2 ETHICAL CONDUCT OF THE STUDY 
This study is to be conducted according to globally accepted standards of good clinical 
practice (as defined in the ICH E6 Guideline for Good Clinical Practice [GCP], 1 May 
1996), in agreement with the latest revision of the Declaration of Helsinki and in keeping 
with local regulations. 
The Investigator should ensure that all persons assisting with the trial are adequately 
qualified, informed about the protocol, any amendments to the protocol, the study 
treatments, and their trial-related duties and functions. 
The Investigator should maintain a list of Subinvestigators and other appropriately 
qualified persons to whom he or she has delegated significant trial-related duties.  Should 
the Investigator delegate the supervision of the investigational product administration to a 
designated person, this individual must have the appropriate medical qualifications to 
effectively conduct or supervise any potential resuscitation procedures. 
20.3 PATIENT INFORMATION AND INFORMED CONSENT 
Patients  must provide written consent to participate after the nature, scope, and possible 
consequences of the clinical study have been explained in a form understandable to them. 
An ICF that includes information about the study will be prepared and given to the patient..  
This document will contain all the elements required by the ICH E6 Guideline for GCP and 
any additional elements required by local regulations.  The document must be in a language 
understandable to the patient and must specify who informed the patient..  Where required 
by local law, the person who informs the patient must be a physician. 
After reading the ICF, the patient must give consent in writing.  The patient’s consent must 
be confirmed at the time of consent by the personally dated signature of the patient and by 
the personally dated signature of the person conducting the informed consent discussions. 
A copy of the signed ICFs must be given to the patient.  The original signed ICFs will be 
retained by the Investigator.  
The Investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained.  
21 STUDY ADMINISTRATION 
21.1 CLINICAL MONITORING 
Monitoring and auditing procedures, developed or endorsed by Trevi Therapeutics will be 
followed to comply with GCP guidelines.  Access to the on-site study documentation and 
medical records will be ensured. 
The study will be monitored by Trevi Therapeutics or its designee.  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.  During the on-site visits, the CRF will be 
reviewed for completeness and adherence to the protocol.  As part of the data audit, source 
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documents must be made available to the Study Monitor for review.  The Study Monitor 
will also perform drug accountability checks and will request to perform a review of the 
Investigator study file to ensure completeness of documentation in all respects of clinical 
study conduct. 
Upon completion of the study, the Study Monitor will arrange for a final review of the 
study files, after which the files should be secured for the appropriate time period.  The 
Investigator, or appointed delegate, will meet with the Study Monitor during the on-site 
visits and will cooperate in providing the documents for inspection and responding to 
inquiries.  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. 
21.2 DATA QUALITY ASSURANCE 
The Investigator, or designee, will enter study data required by the protocol into an 
electronic data capture (EDC) system.  The clinical research associates will visit each study 
site, at a frequency documented in the monitoring plan, to review the electronic CRF 
(eCRF) for completeness and accuracy.  Any discrepancies found between source 
documents and completed eCRF will be entered as a discrepancy in the EDC system by the 
clinical research associate.  Appropriate study site personnel should then address those 
discrepancies in the EDC system. Uniform procedures for eCRF correction (queries) will 
be discussed during the study site initiation visits and will be documented in the study 
operations manual. 
Data from eCRF and other external data sources will be entered into a clinical database as 
specified in the data management plan.  Quality control and data validation procedures will 
be applied to ensure the validity and accuracy of the clinical database.  
Computerized and manual procedures should be used to review and check data from eCRF 
and data from other external sources for omissions, apparent errors, and values that may 
require further clarification.  Data queries requiring clarification should be documented, 
and the study site should be requested to review and resolve the queries.  Only authorized 
personnel can make corrections to the clinical database, and all corrections should be 
documented in an audit trail. 
Adverse events will be coded using the most current MedDRA version.  Prior and 
concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Dictionary. 
21.3 RETENTION OF STUDY RECORDS 
The following records must be retained by the Investigator for a minimum of 2 years after 
the Sponsor has notified the FDA that investigations have been discontinued or after the 
FDA has approved the new drug application:  
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• Signed ICFs for all patients 
• Patient identification code list, screening log (if applicable), and enrollment log 
• Record of all communications between the Investigator and the IRB/IEC 
• Composition of the IRB/IEC or other applicable statement  
• Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
• List of Subinvestigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in 
the study and their signatures 
• Copies of CRFs and of documentation of corrections for all patients  
• Drug accountability records 
• Record of any body fluids or tissue samples retained 
• All other source documents (patient records, hospital records, laboratory records, 
etc.) 
• All other documents as listed in Section 8 of the ICH consolidated guideline on 
GCP (Essential Documents for the Conduct of a Clinical Trial) 
However, because of international regulatory requirements, the Sponsor may request 
retention for a longer period of time.  The Investigator must therefore obtain approval in 
writing from the Sponsor prior to destruction of any records. 
Normally, these records will be held in the Investigator's archives.  If the Investigator is 
unable to meet this obligation, he or she must ask the Sponsor for permission to make 
alternative arrangements.  Details of these arrangements should be documented. 
21.4 CONFIDENTIALITY 
Patient names will not be supplied to the Sponsor.  Only the patient number and patient 
initials will be recorded in CRF (unless not allowed by local regulations), and if the patient 
name appears on any other document (e.g., pathologist 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 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. 
The Investigator will maintain a personal patient identification list (patient numbers with 
the corresponding patient  names) to enable records to be identified. 
21.5 DOCUMENTATION OF STUDY RESULTS 
As part of the responsibilities assumed by participating in the study, the Investigator or 
Subinvestigator agrees to maintain adequate case histories for the patients treated as part of 
the research under this protocol. The Investigator or Subinvestigator agrees to maintain 
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accurate eCRF and source documentation as part of the case histories.  These source 
documents may include laboratory reports and ECG recordings. 
The Investigator or designees must enter all results collected during the clinical study into 
the eCRF.  Guidelines for completion of the eCRF will be reviewed with study-site 
personnel at the site initiation visits.  There is a 2-part process to review and collect the 
eCRF data.  Study-site personnel will enter the data from each study visit.  The Investigator 
is responsible for approval of the entered/corrected data.  The eCRF responsibilities of the 
study team members will be documented on the site delegation log, which will be collected 
at the closeout visits. 
The Investigator can authorize Sub-investigators to sign and approve the eCRF if they are 
designated on Form FDA 1572 as Sub-investigators, have been trained on the EDC system, 
and have their own user name and password.  The Investigators or designees must review 
and approve the data before database lock. 
21.6 USE OF STUDY RESULTS 
All information concerning the product, as well as any matter concerning the operation of 
Trevi Therapeutics (such as clinical indications for the drug, its formula, methods of 
manufacture, and other scientific data relating to it, that have been provided by Trevi 
Therapeutics and are unpublished) are confidential and must remain the sole property of 
Trevi Therapeutics.  The Investigator and participating vendors will agree to use the 
information only for the purposes of carrying out this study and for no other purpose unless 
prior written permission from Trevi Therapeutics is obtained.  The Sponsor has full 
ownership of the CRFs completed as part of the study. 
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. 
 
 
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International results from the Dialysis Practice Patterns and Outcomes Study 
(DOPPS). Nephrol, Dial, Transplant 2006; 3495-3505.  
56. Potenzieri C, Undem BJ. Basic mechanisms of itch. Clin Exp Allergy. 2012 
Jan;42(1):8-19 
57. Raap U, Ständer S, Metz M. Pathophysiology of itch and new treatments. Curr 
Opin Allergy Clin Immunol. 2011 Oct;11(5):420-7 
58. Sadosky A, Dukes E, Evans C. Reliability of a 1-week recall period for the Medical 
Outcomes Study Sleep Scale (MOS-SS) in patients with fibromyalgia. Health and 
Quality of Life Outcomes 2009, 7:12 
59.  Salemi S, Aeschlimann A, Wollina U et al. Up-regulation of delta-opioid receptors 
and kappa-opioid receptors in the skin of fibromyalgia patients. Arthritis Rheum 
2007: 56: 2464–2466. 
60. Schedel F, Schurmann C, Augustin M, Metze D, Blome C, Zeidler C, Stander S. 
Prurigo Nodularis: Introduction of a Re-defined Classification and Prurigo Activity 
Score (PAS). Acta Derm Venerol 2013; 93:610 and Presentation at 7th World 
Congress on Itch. September 21-23, 2013.   
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61. Schmid H, Schiffl H, Lederer SR. Pharmacotherapy of end-stage renal disease. 
Expert Opin Pharmacother. 2010 Mar;11(4):597-61 
62. Schwartzman RJ, Erwin KL, Alexander GM. The natural history of complex 
regional pain syndrome. Clin J Pain. 2009 May;25(4):273-80 
63. Sehgal N, Smith HS, Manchikanti L.  Peripherally acting opioids and clinical 
implications for pain control. Pain Physician. 2011 May-Jun;14(3):249-58 
64. Schmelz M.  Itch and Pain. Dermatologic Therapy, Vol. 18, 2005, 304–307 
65. Schmidt WK, Tam SW, Shotzberger GS, Smith DH Jr, Clark R, Vernier VG. 
Nalbuphine. Drug Alcohol Depend. 1985 Feb;14(3-4):339-62 
66. Schneider G, Driesch G, Heuft G, Evers S, Luger TA, Ständer S. Psychosomatic 
cofactors and psychiatric comorbidity in patients with chronic itch. Clin Exp 
Dermatol. 2006 Nov;31(6):762-7.  
67. Sher L, Chang J, Patel I, Balkrishnan R, Fleischer A. Relieving the Pruritus of 
Atopic Dermatitis:A Meta-analysis. Acta Derm Venerol 2012; 92:445-461. 
68. Spring P, Gschwind I, Gilliet M. Prurigo nodularis: retrospective study of 13 cases 
managed with methotrexate. Clin Exp Dermatol. 2014 Jun;39(4):468-73. 
69. Ständer S, Augustin M, Reich A, Blome C, Ebata T, Phan NQ, Szepietowski JC; 
International Forum for the Study of Itch Special Interest Group Scoring Itch in 
Clinical Trials. Pruritus assessment in clinical trials: consensus recommendations 
from the International Forum for the Study of Itch (IFSI) Special Interest Group 
Scoring Itch in Clinical Trials. Acta Derm Venereol. 2013 Sep 4;93(5):509-14. 
70. Stein C, Schäfer M, Machelska H. Attacking pain at its source: new perspectives on 
opioids. Nat Med. 2003 Aug;9(8):1003-8. 
71. Steinhoff M, Ständer S, Seeliger S, Ansel JC, Schmelz M, Luger T. Modern aspects 
of cutaneous neurogenic inflammation. Arch Dermatol. 2003 Nov;139(11):1479-88. 
72. Togashi, Y.; Umeuchi, H.; Okano, K.; Ando, N.; Yoshizawa, Y.; Honda, T.; 
Kawamura, K.; Endoh, T.; Utsumi, J.; Kamei, J.; Tanaka, T. & Nagase, H. 
Antipruritic activity of the k-opioid receptor agonist, TRK-820, Eur. J. Pharmacol. 
435:259-264, 2002.  
73. Umeuchi H, Togashi Y, Honda T, et al. Involvement of central k-opioid system in 
the scratching behavior in mice, and the suppression of it by the activation of k-
opioid system. Eur J Pharmacol. 2003;477:29- 35.   
74. Vaidya DC, Schwartz RA. Prurigo nodularis: a benign dermatosis derived from a 
persistent pruritus. Acta Dermatovenerol Croat. 2008;16(1):38-44.  
75. Weigelt N, Metze D, Ständer S. Prurigo nodularis: systematic analysis of 58 
histological criteria in 136 patients. J Cutan Pathol. 2010 May;37(5):578-86 
76. Weisbord SD, Fried LF, Mor MK, et al. Renal Provider Recognition of Symptoms 
in Patients on Maintenance Hemodialysis. Clin J Am Soci Nephrol 2007; 960-967. 
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77. Wikstrom B, Gellert R, Ladefoged D, et al. κ -Opioid System in Uremic Pruritus: 
Multicenter, Randomized, Double-Blind, Placebo-Controlled Studies. J Am Soc 
Nephrol 2005; 3742-7. 
78. Wolfe F, Michaud K, Li T. Sleep disturbance in patients with rheumatoid arthritis: 
evaluation by medical outcomes study and visual analog sleep scales. J Rheumatol. 
2006 Oct;33(10):1942-51. 
79. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of 
pain. Pain. 2011 Mar;152(3 Suppl):S2-15. 
 
 
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APPENDICES 
Appendices 1 through 4 are provided on the following pages. 
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Appendix 1: Schedule of Events 
 
Table 4: Schedule of Events for Visits 1a and 1b 
(Day 1 of Week 1 of Treatment Period)  
 
 
 
 
 
 
1Study TR03 Visit 6 procedures in 
common with Study TR03 
extension Visit 1a procedures do 
not have to be repeated. 
2 To be completed any time before 
start of Visit 1a procedures 
3BP and HR (sitting or semi-
recumbent), RR, temperature, and  
pre-dialysis weight 
4 Visit 1b is the first visit of the 
Treatment Period for patients 
transitioning from the Observation 
Period to the Treatment Period.   
5Hematology and chemistry 
6Females of Childbearing potential 
only 
7Questionnaires must be 
administered strictly adhering to 
instructions (see Study Reference 
Manual)  
8Includes review of patient TR03 
Rescue Medication Log 
9Study procedures only conducted 
if patient qualifies to enter the 
Treatment Period based on worst 
itch NRS>2 
10Titrate study drug according to 
the schedule in Table 3;  
The first dose of study drug 
treatment will define enrollment 
into the study 
11 For female patients of child-
bearing potential, a urine 
pregnancy test must be negative 
prior to dispensing study drug.   
Visit 
1a1 
1b4 
 
Informed Consent2 
X 
 
 
Confirm Eligibility 
X 
 
 
Vital Signs3 
X 
X 
 
Physical Examination 
X 
X 
 
Central Clinical Labs5 & serum 
PregnancyTest6 
X 
X 
 
Urinalysis 
X 
X 
 
Urine for pregnancy test11 
X 
X 
 
Blood for PK 
X 
X 
 
12-lead ECG 
X 
X 
 
Worst
X 
 itch Numerical Rating Scale 
(NRS)7 
X 
 
Average daily itch intensity Numerical 
Rating Scale (NRS)7 
X9 
X 
 
Verbal Rating Scale (VRS)7 
X9 
X 
 
ItchyQoL7 
X9 
X 
 
MOS Sleep-R7 
X9 
X 
 
Hospital Anxiety and Depression Scales 
(HADS)7 
X9 
X 
 
Patient Benefit Index Pruritus (PBI-P)7 
X9 
X 
 
Prurigo Activity Score (PAS) 
X9 
X 
 
Record AEs  
X 
X 
 
Review Rescue Medications and 
Concomitant Medications 
X8 
X 
 
Study Drug Retrieval and 
Accountability for TR03 
X 
 
 
Dispense Study Drug for TR03ext 
X9 
X 
 
First dose of Study Drug for TR03ext10 
X9 
X 
 
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Table 5:  Treatment Period Weeks 2-4  
 
TC 11 
TV 21 
TC 21 
Treatment Period Week  
2 
3 
4 
Dispense Study Drug3 
 
X 
 
Titrate Study Drug2 
X 
X 
 
Confirm Maintenance Dose 
 
 
X5 
Vital Signs4 
 
X 
 
Urine pregnancy test7 
 
X 
 
Blood for PK 
 
X 
 
12-lead ECG 
 
 
 
Worst
 
 itch NRS6 
X 
 
Average daily itch intensity NRS6 
 
X 
 
VRS6 
 
X 
 
MOS Sleep-R6 
 
X 
 
HADS6 
 
X 
 
ItchyQoL6 
 
X 
 
PBI-P6 
 
 
 
PAS 
 
 
 
Study Drug BID 
X 
Record AEs  
 X 
X 
X 
Record Concomitant Medications 
  
X 
 
Reinforce Compliance 
X 
X 
X 
Study Drug Accountability  
 
X 
 
1 The window for TC 1-2 and TV2 is +/-3 days 
2Titrate study drug according to the schedule in Table 3 
3At TV 2 dispense a single 60 mg tablet bottle for the 120 mg BID and 180 BID dosing patients; Dispense 30 mg 
bottle for the 90 mg BID dosing patients.  
and assess tolerability/intolerability to study drug; determine 
if to continue dose escalation   
4 BP and HR (sitting or semi-recumbent), RR, temperature. 
5 Down titrate only if necessary and only down titration from the 180 mg BID and 120 mg BID groups are allowed.  
If 90 mg BID is intolerable, the subject is discontinued.  See Table 3. 
6Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual) 
7 For female patients of child-bearing potential, a urine pregnancy test must be negative prior to dispensing additional 
study drug.   
 
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Table 6: Treatment Period Visits12 During Study Weeks 5-50 and Washout/Safety Follow-up Visit or Treatment Period Early 
Termination Visit 
Treatment Period 
Weeks 5-521,3 
TV
3 
TV
4 
TV
5 
TV
6 
TV
7 
TV
8 
TV
9 
TV
10 
TV
11 
TV
12 
TV
13 
TV
14 
Washout / Safety 
Follow-up Period 
ET9 
Treatment Period Week 
5 
9 
13 
17 
21 
26 
30 
34 
38 
42 
46 
502 
52 
Physical Examination 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Central Clinical Labs6 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Serum pregnancy test to central lab11 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Urinalysis to central lab 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
PAS 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
PBI-P7 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
12-lead ECG 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Skin biopsy 
 
 
 
 
 
 
 
 
 
 
 
X10 
 
 
Blood for PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Urine pregnancy test5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Worst
X 
 itch NRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Average daily itch intensity NRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ItchyQoL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MOS Sleep-R7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HADS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record  Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Reinforce Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug Accountability  
X 
X 
X 
X 
X 
X8 
X 
X 
X 
X 
X 
X 
 
X8 
Study Drug BID 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
1Patients who were previously in the Observation Period should start the Treatment Period at Visit 1b and continue in the study for 38-46 weeks; the total number of weeks in the 
combined Observation and Treatment Periods is no more than 50 weeks. The last scheduled visit on study drug for patients previously in the Observation Period should be TV 14 
regardless of the study week. 
2 The number of Treatment Period weeks prior to TV 14 will vary for patients previously in the Observation Period depending upon the number of weeks spent in the Observation 
Period. See Table 8 
3A single allowable dose reduction is permitted during Treatment Period Weeks 5 – 50  (a patient at 90 mg BID can be reduced to 60 mg BID). If a second dose reduction is needed, the 
patient should be discontinued from the study. 
4 BP and HR (sitting or semi-recumbent), RR, temperature 
5For female patients of child-bearing potential, a urine pregnancy test must be negative prior to dispensing additional study drug. 
6 Hematology and chemistry. 
7Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual) 
8 Retrieve remaining study drug at TV 14 or ET Visit 
9 ET Visit is conducted within 2 weeks of study drug termination 
10 Skin biopsy material for nerve fiber density (histology) and MOR/KOR density to be performed only at select sites 
11Females of Childbearing potential only 
12 Visit windows will be +/-3 Days 
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Table 7:  
Observation Period Visits5 
 
Observation Visit 
OV 
2 
OV 
3 
OV 
4 
Observation Study Week 
4 
8 
121 
Check Worst itch NRS2: If >2, patient must undergo Visit 1b  
X4 
X4 
X4 
Vital Signs3 
X 
X 
X 
Average daily itch intensity NRS2 
 
 
X 
VRS2 
 
 
X 
MOS Sleep-R2 
 
 
X 
HADS2 
 
 
X 
ItchyQoL2 
 
 
X 
Record AEs  
 X 
X 
 X 
Record concomitant medications 
X 
X 
X 
1Patients whose NRS is <2 at OV 4 should be screen failed from the study.  
2 Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual) 
3BP and HR (sitting or semi-recumbent), RR, temperature 
4If patient’s NRS>2 proceed to Visit1b procedures and no need to record any further data under OV visit 
procedures 
5Visit windows will be +/-3 Days 
 
 
 
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Table 8:  
Schedule of Next Treatment Period Visits for Patients Transitioned from 
the Observation Period and who complete titration 
 
 
Study Week of 
Visit 1b  
Study Week of 
 TV2 
Next Treatment 
Period Visit1,2,3 
OV2 
Week 4 
Week 6 
TV4, Week 9 
OV3 
Week 8 
Week 10 
TV5, Week 13 
OV4 
Week 12 
Week 14 
TV6, Week 17 
1 See Table 6 
2 Schedule modifications will take place for patients entering the Treatment Period 
from the Observation Period.  These patients will not have specific visits depending 
on when they enter the Treatment Period 
• For patients entering at OV2, TV3 will not take place  
• For patients entering at OV3, TV4 will not take place  
• For patients entering at OV4, TV5 will not take place  
2 Patients will be provided with adequate study drug to take them from TV2 to the 
next Treatment Period visit listed 
 
 
 
 
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Table 9: Rescue Medications for Itching 
Rescue Medication 
Only intended for anti-
pruritic treatment 
Examples 
Opioid receptor antagonists  
 
naltrexone, naloxone 
Antihistamines   
  
topical or systemic 
Topical calcineurin inhibitors  
  
tacrolimus 
Topical antibiotics 
  
--- 
Topical steroids 
  
--- 
Topical capsaicin 
  
--- 
Anti-septic baths and anti-septic 
cleansing lotions  
  
--- 
Anti-convulsant class drugs 
  
gabapentin or pregabalin 
Systemic Steroids 
  
--- 
cyclosporin A and other 
immunosuppressants 
  
--- 
antidepressant medications  
  
paroxetine, fluvoxamine, 
amitriptyline 
Malignant tumor related active 
treatment with a systemic drug 
  
--- 
UV Therapy 
  
--- 
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Appendix 2: Study Schematic Flow Charts  
 
Figure 2:  
Overview of TR03-EXT Study Design 
 
 
 
 
 
 
 
 
 
 
 
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Figure 3:  
Examples illustrating possible Observation and Treatment periods Scenarios in TR03-Ext 
 
 
 
 
 
 
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Figure 4:  
Dosing Schedule in TR03ext 
 
 
 
 
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Appendix 3: Clinical Laboratory Tests 
 
Hematology: 
Serum Chemistry: 
 
 
Hemoglobin 
Potassium 
Hematocrit 
Chloride 
Red Blood Cell Count 
Carbon Dioxide 
White Blood Cell Count 
Blood Urea Nitrogen (BUN) 
White Blood Cell Differential 
Creatinine 
Platelet Count 
Calcium 
 
Phosphorus 
 
Total Protein 
Urine: 
Albumin 
 
Total Bilirubin 
Urinalysis 
AST 
Pregnancy 
ALT 
 
Alkaline Phosphatase 
 
LDH 
Serum Pregnancy: 
Glucose 
β-Human Chorionic  
Gonadotropin (HCG) (women of 
childbearing potential) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 4:  Patient Reported Outcomes 
 
The Patient Reported Outcomes are provided on the subsequent pages. 
 
 
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Medical Outcomes Sleep Scale (Revised MOS Sleep-R) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
Your Sleep 
 
For each of the following questions, please mark an 
 in the one box that best describes your 
answer. 
 
1. How long did it usually take for you to fall asleep during the past 4 weeks
0-15 
minutes 
? 
16-30 
minutes 
31-45 
minutes 
46-60 
minutes 
More than 60 
minutes 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
2. On the average, how many hours did you sleep each night during the past 4 
weeks
 
Write in number of hours per night:  
? 
 
3. How often during the past 4 weeks
 
 did you… 
Copyright, 1986, RAND. 
MOS 12-Item Sleep Scale – Revised 2010 
United States (English) 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
a 
feel that your sleep was not quiet 
(moving restlessly, feeling tense, 
speaking, etc., while sleeping)? ...........
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
b 
get enough sleep to feel rested  
upon waking in the morning? .............
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
c 
awaken short of breath or with 
a headache? .................................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
d 
feel drowsy or sleepy during  
the day? ......................................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
e 
have trouble falling asleep? ................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
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Medical Outcomes Sleep Scale (Revised MOS Sleep-R) (cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
How often during the past 4 weeks
 
 did you… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright, 1986, RAND. 
MOS 12-Item Sleep Scale – Revised 2010 
United States (English) 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
f 
awaken during your sleep time  
and have trouble falling asleep 
again? .........................................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
g 
have trouble staying awake  
during the day? ..............................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
h 
snore during your sleep? ................... 
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
i 
take naps (5 minutes or longer)  
during the day? ..............................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
j 
get the amount of sleep you  
needed? ......................................
 1 ........... 
 2 ...........
 3 ........... 
 4 ...........
 5 
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ItchyQoLTM 
 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
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ItchyQoLTM (cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
 
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ItchyQoLTM (cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
 
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Prurigo Activity Score (PAS) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
SST-Pr-10-2007, Amendment 9, PAS, Version 0.7; 11.09.2013 
 
 
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Patient Benefit Index, Pruritus Version (PBI-P) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
PBI-Patient Benefit Index (index of benefits and needs in therapy), Augustin 2006 
 
 
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PBI-P (Cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
PBI-Patient Benefit Index (index of benefits and needs in therapy), Augustin 2006 
 
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Numerical Rating Scale (Worst Itch) 
 
How would you rate your most severe 
 
itching over the past 24 hours? 
 
 
 
 
Numerical Rating Scale (Average-Itch) 
 
How would you rate your itching on average 
 
over the past 24 hours? 
 
 
Verbal Rating Scale 
 
How is your skin sensation today?   
 
0:  
not 
present 
1:  
mild 
present 
2: 
moderately 
present 
3: 
severely 
present 
4:  
very severely 
present 
Itchy 
 
 
 
 
 
Burning 
 
 
 
 
 
Stinging 
 
 
 
 
 
 
 
 
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Hospital Anxiety and Depression Scale (HADS) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
 
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Page 1 of 122
CLINICAL PROTOCOL
Protocol Number:
TR03ext
Version Number:
2.0
Version Date:
11 March 2015
EudraCT No.
2013-005628-41
Protocol Title:
An Open Label Extension Study of the Safety and Anti-
Pruritic Efficacy of Nalbuphine HCl ER Tablets in 
Prurigo Nodularis Patients
Study Sponsor:
Trevi Therapeutics, Inc.
195 Church Street, 14th Floor
New Haven, Connecticut 06510
United States
Phone: (203) 304-2499
www.trevitherapeutics.com
CONFIDENTIAL
This document is the confidential and proprietary information of Trevi Therapeutics, Inc. By 
reviewing this document, you agree to keep it confidential and to use and disclose it solely for the 
purpose of assessing whether your organization will participate in and/or the performance of the 
proposed clinical study. Any permitted disclosures will be made only on a confidential 
“need-to-know” basis within your organization or to your independent ethics committee(s). Any other 
use, copying, disclosure, or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by Trevi Therapeutics, Inc. Any supplemental information (e.g., amendments) 
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 document. Any person who 
receives this document without due authorization from Trevi Therapeutics, Inc., is requested to return 
it to Trevi Therapeutics, Inc., or promptly destroy it. All other rights reserved. This study is to be 
performed in accordance with Good Clinical Practice (GCP), the ethical principles that have their 
origin in the Declaration of Helsinki, International Conference on Harmonisation (ICH) E6, and Title 
21 of the Code of Federal Regulations (CFR), Parts 50, 56, and 312 and European Union Directive 
2001/20/EC, (or equivalent regulatory body regulations/guidelines, as applicable).
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Investigators:
Multicenter
Research Facilities:
Multicenter
Institutional Review Board/
Independent Ethics Committee: Multicenter
SPONSOR:
Trevi Therapeutics, Inc.
195 Church Street, 14th Floor
New Haven, CT 06510
Office Phone: (203) 304-2499
Office Fax:
(203) 526-0266
SPONSOR CONTACT:
Thomas Sciascia, M.D.
Chief Medical Officer
Trevi Therapeutics, Inc.
195 Church Street, 14th Floor
New Haven, CT 06510
Office Phone    (203) 304-2499
Office Fax:       (203) 526-0266
MEDICAL MONITOR:
Edward Matheis, MD, PPD Medical Monitor
Telephone:
(888) 483-7729
Fax:
(888) 529-3580
Serious Adverse Event Fax number:
(888) 529-3580
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INVESTIGATOR SIGNATURE PAGE
I have read the attached protocol entitled A Randomized, Double-Blind, Placebo-Controlled, Parallel, 3-
Arm Study of the Safety and Anti-Pruritic Efficacy of nalbuphine HCl ER Tablets in Prurigo Nodularis 
Patients dated 11 MARCH 2015 and agree to abide by all provisions set forth therein.
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on Good 
Clinical Practice and applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 
Title 21 of the CFR, Parts 11, 50, 54, 56, and 312 and European Union Directive 2001/20/EC or equivalent 
regulatory body regulations/guidelines, as applicable.
I agree to ensure that Financial Disclosure Statements will be completed by:

Myself (including, if applicable, my spouse [or legal partner], and dependent children)

My subinvestigators (including, if applicable, their spouses [or legal partners], and dependent children)
The Financial Disclosure Statements will be completed before study initiation, during the study if there are 
changes that affect my financial disclosure status, and after the study is completed.
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Trevi Therapeutics, Inc.
Principal Investigator:
__________________________________
___________
Name of Principal Investigator
Date
__________________________________
Institution or Clinical Practice
__________________________________
Signature
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1
STUDY SYNOPSIS
Title
An Open Label Extension Study of the Safety and Anti-
Pruritic Efficacy of Nalbuphine HCl ER Tablets in Prurigo 
Nodularis Patients 
Sponsor
Trevi Therapeutics, Inc.
195 Church Street, 14th Floor
New Haven, Connecticut  06510
United States
Phone: (203) 304-2499
www.trevitherapeutics.com
Protocol Number
TR03ext
Version and Date
Amendment 1: Version 2.0 dated 11 MARCH 2015
Version 1.0 dated 24 JUNE 2014
Indication
Prurigo Nodularis (PN)
Investigational Product 
nalbuphine hydrochloride (HCl) extended-release (ER) 
tablets
Active Ingredient
nalbuphine hydrochloride
Route of Administration 
Oral
Duration of Study
The total study duration for any individual patient will be up 
to 53 weeks.  Patients will receive drug treatment for up to 
50 weeks.
Study Phase
Phase 2/3
Study Design
Open label
Planned Sample Size
No a priori planned sample size is designated for this study.  
Eligible patients who have successfully completed the TR03
study and wish to participate in TR03ext may be enrolled, 
treated, and analyzed. The maximum number of patients will 
not exceed the number of patients who complete the TR03 
study  (i.e., up to 60 patients)
Total Number of Centers
Up to 10 sites in North America and Europe 
Primary Objective

To evaluate the safety and tolerability of nalbuphine 
HCl ER tablets during a drug treatment period of up 
to 50 weeks.
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Secondary Objectives

To evaluate the safety of nalbuphine by achieved
maintenance dose at the end of Treatment Week 4. 

Assess skin lesion improvement using the metrics of 
the PAS 

Change from Baseline in Patient-Reported Outcome 
measures Worst (i.e., most severe itching over the 
past 24 hours) itch NRS, average itch intensity NRS, 
VRS (itchy, burning and stinging), MOS Sleep-R, 
ItchyQoL, HADS by the final Treatment Period Visit

Change between Baseline and the final Treatment 
Period Visit in PBI-P

A description of the frequency and reasons for dose 
up- and down-titration and treatment discontinuation 
during the study

Frequency and distribution by time on study of 
patients determined to meet failure-to-improve 
criteria 

Changes in the PRO measurements during the 
Washout Period after cessation of treatment of 
nalbuphine HCl ER tablets

Time to first use of rescue medications and the 
number of days of use of rescue medications for 
itching

To evaluate the daily changes in the Subjective 
Opiate Withdrawal Scale (SOWS) during the 
Washout Period after cessation of treatment of 
nalbuphine HCl ER tablets.
Exploratory Objectives
A single exploratory objective of the study is to evaluate:

The potential of nalbuphine HCl ER tablets to impact 
on the measurement of nerve fiber density 
(histology) and MOR/KOR density (histology, 
Western Blot), as well as histological (H&E) 
changes in skin biopsies taken at Baseline and by the 
final Treatment Period Visit to investigate possible 
correlation with any clinical response and also 
compared to biopsy material assessed during study 
TR03 (optional procedures at select sites only).
Selection Criteria
Inclusion Criteria:
Patients must meet all of the following criteria to be eligible:
1.
Have been adequately informed of the nature and 
risks of the study and have given written informed 
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consent at or prior to Visit 1a.
2.
Have completed participation in the TR03 study.
Completion of participation in the TR03 study is 
defined as completion of Study Drug treatment 
through TR03 Visit 5 and completion of the TR03 
Visit 6. 
3.
Agree to comply with the contraception requirements 
as below:
Female patients of childbearing potential are 
required to use one barrier method (e.g., condom, 
cervical cap, or diaphragm) of contraception in 
addition to one other method (e.g., intrauterine 
device [IUD], hormonal contraception, tubal ligation, 
Essure procedure, or spermicide). 
For the purpose of this study, all females are 
considered to be of childbearing potential unless they 
are post-menopausal (i.e., at least 1 year since last 
menses and age >50 years) or surgically sterile (i.e., 
tubal ligation, hysterectomy and/or bilateral 
oophorectomy).
4.
Ability and acceptance to provide written informed 
consent.
5.
Willing and able to comply with study requirements 
and restrictions 
6.
Agree to the confidential use and storage of all data 
(including photography) and use of all anonymized 
data for publication including scientific publication.
Selection Criteria
Exclusion Criteria:
If a patient meets any of the following criteria, he or she is 
not eligible:
1.
Patients with a history of congestive heart failure of 
Class 2 or higher as graded using the New York 
Heart Association scale (scale provided in Appendix 
5)
2.
Patients with a history of angina pectoris grade 2 or 
higher as graded using the Canadian Cardiovascular 
Society grading scale (scale provided in Appendix 5)
3.
History of ventricular tachycardia, torsade de 
pointes, family history of sudden death, myocardial 
infarction or acute coronary syndrome within the 
previous 3 months, as reported by the patient.
4.
Serum potassium below the laboratory lower limit of 
normality.  Potassium supplementation can be 
prescribed and the serum potassium level repeated
5.
QTcF interval >450ms on screening EKG
6.
Heart rate <50 BPM on screening
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7.
Use of a medication known to be associated with risk 
of torsade de pointes (see Section 9.7.8, Safety 
Assessments, for hyperlink to the CredibleMeds 
Filtered QTDrug List for cardiovascular related 
prohibited medications with a known associated risk 
of Torsade de Pointes) 
8.
History of substance abuse within the past year as 
determined by the Investigator
9.
Significant medical condition or other factors that in 
the opinion of the Investigator may interfere with the 
conduct of the study
10. Known hypersensitivity or allergy to nalbuphine or 
formulation components
11. Is a pregnant or lactating female
Study Treatment 
Allocation
All patients who are enrolled into the study will receive 
active treatment with nalbuphine HCl ER tablets.
Study Procedures
Visit 1a of the TR03ext study is temporally the same visit as 
TR03 Visit 6. Subjects who do not consent by the end of the 
TR03 study visit 6 are no longer eligible for the extension 
study.  Study TR03 Visit 6 procedures in common with 
Study TR03ext Visit 1a procedures do not have to be 
repeated.  
For All Patients:
For all patients, TR03ext Visits (both during the Treatment 
Period and Observation Period) will include recording of 
vital signs, completion of PRO questionnaires, assessment of 
AEs, and recording of concomitant medications. 
On Visit 1a, patients will either enter directly into the drug 
Treatment Period or into a no-drug Observation Period based 
on their reported Worst itch NRS scores (defined as most 
severe itching over the past 24 hours) on that Visit day. 
Patients with a Worst Itch NRS score greater than or 
equal to 5 () 5 enter the Treatment Period:
Patients with Worst itch NRS  at Visit 1a will start in the 
drug Treatment Period of the study and will receive Study 
Drug starting with an evening 30 mg dose (to be taken at 
home), after the Treatment Visit 1a procedures have been 
completed. Receipt of the first dose of study drug will define 
Treatment Period Day 1. Treatment Visit 1a for these 
patients is also Treatment Visit 1 (TV1). Subsequent visits 
will be defined as TV2, TV3, etc. In addition, during the 
time period of dose titration, information will be obtained via 
telephone communication; these will be defined as TC1, and 
TC2.
The dose will be titrated for up to 4 weeks based on 
tolerability, after which time the dose achieved (as of the end 
of Treatment Week 4) will be maintained up to an additional 
46 weeks (with the exception of permitted down titrations);
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see Table 3 Study Drug Dosing schedule.
For patients transitioning from the Observation period, the 
total time in the Treatment Period plus any time in the 
Observation Period will be a total of 50 weeks.  
Safety laboratory data and blood for PK, ECGs (locally and 
centrally read), and physical examinations including the PAS 
assessment will be performed periodically according to the 
Schedule of Events (See Appendix 1). Schematic 
descriptions of the study can be found in Appendix 2.
All patients on drug treatment will enter a 2-week wash-out 
and safety follow up period following end of the Treatment 
Period with procedures conducted according to the Schedule 
of Events (See Appendix 1).
Patients with a Worst Itch NRS score less than 5 (< 5)
enter the Observation Period:
Patients with a Worst Itch NRS score < 5 at Visit 1a will 
enter into an extended screening period, Observation Period 
(no drug treatment), of the study and will be followed for up 
to 12 weeks (extended screening weeks). Visit 1a for these 
patients is also Observational Visit 1 (OV1).  Subsequent 
visits will be defined as OV2, OV3 and OV4 and will occur 
at approximately monthly intervals for the next 3 months.
During this Observation period, patients who report an
increase in their Worst Itch NRS with a score of  at any 
one of their Observation Visits and meet all other eligibility 
criteria will be able to enroll immediately into the Treatment 
Period of the study and Visit1b procedures are to be 
performed.  Patients will receive open-label Study Drug 
starting with an evening 30 mg dose (to be taken at home), 
after the Visit 1b procedures have been completed.  Receipt 
of the first drug will indicate the start of their Treatment 
Period and enrollment into the study. The duration of the 
Treatment Period for such a patient will vary depending upon 
the visit at which they transition from the Observation Period 
to the Treatment Period.
Patients in the Observation Period whose Worst Itch NRS 
score remains <5 over the 12 extended screening weeks will 
be screen failed from the study at the end of that time period.
Failure to Improve Criteria:
Beginning on TV 3 and at every subsequent Treatment Visit, 
patients with a Worst itch NRS equal to or greater than 
the Worst Itch NRS at Visit 1a (or at Visit 1b in the case of 
patient who require the Observation Visit period) will be 
discontinued from taking study drug. Subjects discontinued 
from taking study drug are to undergo the End of Treatment 
Visit (TV14), the Washout/Safety Follow-up Period 
assessment in two weeks and receive a follow-up Telephone 
Contact 30 days following end of study drug for final safety 
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assessment.
Safety Assessments
Safety will be assessed based on adverse events (AEs), 
clinical laboratory measurements, Investigator review and 
central cardiac core laboratory read-12-lead 
electrocardiogram (ECG), vital signs and physical 
examinations.
An unblinded, independent Data Safety Monitoring Board 
(DSMB) will periodically review safety data.  The frequency 
of data review and DSMB processes are outlined in the 
DSMB charter.
Efficacy Assessments
Efficacy Measurements:

Worst itch intensity (from NRS)

Average itch intensity (from NRS)

VRS (itchy, burning and stinging)

ItchyQoL

MOS Sleep-R

HADS

PAS 

PBI-P

Frequency, pattern, and reasons for dose titration

Use of rescue medications for itching
At selected sites (optional procedures):

Nerve fiber density (histology) at Baseline and 
the final Treatment Period Visit

MOR/KOR density (histology, Western Blot) at 
Baseline and the final Treatment Period Visit

Histological analysis (H&E) at Baseline and the 
final Treatment Period Visit
Pharmacokinetic 
Assessments
Blood samples for nalbuphine plasma concentration (and 
metabolites as needed) will be collected periodically 
according to the Schedule of Events (Appendix 1). 
Study  Endpoints
Primary Endpoint:

A description of the incidence and nature of TEAEs 
during Treatment Weeks 5- 50
Secondary Endpoints
Visit 1a or 1b will serve as the baseline visit for efficacy 
endpoints. Visit 1a will be the baseline for patients 
directly entering the Treatment Period as of Visit 1a. 
Visit 1b will be the baseline for patients entering the 
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Treatment Period after participating in the Observation 
Period for any length of time.

Assess skin lesion improvement using the metrics of 
the PAS 

Change from Baseline in Patient-Reported Outcome 
measures Worst itch NRS, average itch intensity
NRS, VRS (itchy, burning and stinging), MOS 
Sleep-R, ItchyQoL, HADS) by Treatment Period 
study visit and Baseline NRS score

Change between Baseline and final Treatment Period 
visit in PBI-P

A description of the percentage of patients utilizing 
various doses of nalbuphine HCl ER tablets by Study 
Week

A description of the frequency and reasons for dose 
up- and down-titration and treatment discontinuation
during the study

Frequency and distribution by time on study of 
patients determined to meet failure to improve 
criteria

Changes in the PRO measurements during the 
Washout Period after cessation of treatment of 
nalbuphine HCl ER tablets

Time to the first use of rescue medications and the 
number of days of use of rescue medications for 
itching

To evaluate the daily changes in the Subjective 
Opiate Withdrawal Scale (SOWS) during the 
Washout Period after cessation of treatment of 
nalbuphine HCl ER tablets
Exploratory Endpoint

Impact on the measurement of nerve fiber density 
(histology) and MOR/KOR density (histology, 
Western Blot), as well as histological (H&E) 
changes in skin biopsies taken at Baseline and the 
final Treatment Period Visit to investigate possible 
correlation with any clinical response and also 
compared to biopsy material assessed during study 
TR03 (optional procedures at select sites only).
Statistical Methodology
Efficacy: 
All efficacy endpoints will be evaluated through the 
generation of summary statistics.  For continuous variables, 
the mean, standard deviation, median, minimum, and 
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maximum will be presented for a particular visit and for the 
change from baseline (Visit 1a or 1b).  For categorical 
variables, the number and percentage of patients within each 
category of classification will be summarized by study visit.  
No formal statistical testing will be conducted.
Safety:
The incidence of AEs will be summarized through the 
presentation of proportions by MedDRA body system 
classification and preferred term.  Vital signs and laboratory 
data will be summarized using continuous-based descriptive 
statistics (n, mean, SD, median, minimum, maximum).  The 
extent and duration of use of rescue medications will be 
similarly summarized using descriptive statistics.  Summary 
statistics for AEs with onset during the Observation Period 
will be separately summarized. No formal statistical analysis 
will be performed on safety outcomes; inferences, if any, will 
be derived through clinical review and interpretation.
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TABLE OF CONTENTS
1 
STUDY SYNOPSIS ................................................................................................. 5 
TABLE OF CONTENTS ............................................................................................... 13 
LIST OF TABLES.......................................................................................................... 16 
LIST OF FIGURES........................................................................................................ 16 
2 
LIST OF ABBREVIATIONS ............................................................................... 17 
3 
INTRODUCTION ................................................................................................. 19 
3.1 
PRURIGO NODULARIS AND STUDY RATIONALE .................................................. 19 
3.1.1 
General Information on Prurigo Nodularis........................................................ 19 
3.1.2 
Potential Mechanism of Prurigo Nodularis Pathophysiology............................ 21 
3.1.3 
Rationale for Investigating Nalbuphine HCl ER in Prurigo Nodularis ............. 24 
3.2 
NALBUPHINE......................................................................................................... 27 
3.3 
NALBUPHINE HCL ER TABLET CLINICAL DEVELOPMENT ............................... 28 
3.3.1 
Overall Summary............................................................................................... 28 
3.3.2 
Clinical Study TR01 in Hemodialysis Patients and Healthy Volunteers........... 29 
3.3.3 
Additional Nalbuphine HCl ER Tablet Clinical Data ....................................... 31 
4 
STUDY OBJECTIVES.......................................................................................... 32 
4.1 
PRIMARY OBJECTIVE........................................................................................... 32 
4.2 
SECONDARY OBJECTIVES ..................................................................................... 32 
4.3 
EXPLORATORY OBJECTIVES ................................................................................ 32 
5 
STUDY ENDPOINTS............................................................................................ 33 
5.1 
PRIMARY ENDPOINT............................................................................................. 33 
5.2 
SECONDARY ENDPOINTS ...................................................................................... 33 
5.3 
EXPLORATORY ENDPOINTS.................................................................................. 33 
6 
NUMBER OF SITES AND PATIENTS.............................................................. 34 
7 
ESTIMATED STUDY DURATION.................................................................... 34 
8 
SELECTION CRITERIA..................................................................................... 34 
8.1 
STUDY POPULATION............................................................................................. 34 
8.2 
INCLUSION CRITERIA........................................................................................... 34 
8.3 
EXCLUSION CRITERIA.......................................................................................... 35 
9 
STUDY PLAN........................................................................................................ 35 
9.1 
GENERAL STUDY DESIGN..................................................................................... 35 
9.2 
RATIONALE FOR STUDY DESIGN.......................................................................... 35 
9.3 
SAFETY MONITORING PLAN ................................................................................ 37 
9.4 
RISK-BENEFITS..................................................................................................... 39 
9.5 
STUDY OVERVIEW................................................................................................ 40 
9.6 
STUDY PROCEDURES ............................................................................................ 42 
9.6.1 
Visit 1a (Day 1 of Study Week 1)...................................................................... 43 
9.6.2 
Treatment Period (Treatment Weeks 1-50) ....................................................... 45 
9.6.3 
Observation Period (Extended Screening Weeks 1-12) .................................... 58 
9.6.4 
Transition to Treatment Period (Visit 1b).......................................................... 59 
9.6.5 
Washout and Safety Follow-Up Period ............................................................. 61 
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9.6.6 
Premature Discontinuation of Study Drug Follow-up Telephone Contact Visit62 
9.6.7 
Early Termination Visit for Patients who Withdraw Consent........................... 62 
9.6.8 
Unscheduled Visits ............................................................................................ 63 
9.6.9 
Schedule of Events............................................................................................. 63 
9.7 
STUDY DRUG TREATMENT AND DRUG ACCOUNTABILITY.................................. 63 
9.7.1 
Study Drug Dosing ............................................................................................ 63 
9.7.2 
Down-Titration .................................................................................................. 66 
9.7.3 
Multiple Missed Doses ...................................................................................... 66 
9.7.4 
Overdose............................................................................................................ 66 
9.7.5 
Treatment Compliance....................................................................................... 66 
9.7.6 
Rescue Medications, Concomitant Medications, Prohibited Medications, and 
Pre-Medications ................................................................................................................ 66 
9.7.7 
Efficacy Assessments ........................................................................................ 67 
9.7.8 
Safety Assessments............................................................................................ 70 
10 
STUDY DRUG....................................................................................................... 72 
10.1 
FORMULATION, PACKAGING AND LABELING...................................................... 72 
10.2 
SHIPPING, STORAGE AND HANDLING.................................................................. 72 
10.3 
UNBLINDING ......................................................................................................... 72 
10.4 
DRUG ACCOUNTABILITY...................................................................................... 73 
11 
PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT ... 73 
11.1 
PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT ASSOCIATED 
WITH FAILURE-TO-IMPROVE CRITERIA.............................................................. 73 
11.2 
PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT FOR REASONS 
OTHER THAN FAILURE-TO-IMPROVE.................................................................. 74 
12 
PREMATURE WITHDRAWAL OF PATIENTS FROM THE STUDY ........ 74 
13 
WARNINGS AND PRECAUTIONS ................................................................... 75 
14 
EFFICACY EVALUATIONS .............................................................................. 75 
14.1 
EXPLORATORY ..................................................................................................... 75 
15 
COLLECTION, HANDLING, AND ANALYSIS OF PHARMACOKINETIC 
BLOOD SAMPLES............................................................................................... 76 
15.1 
BLOOD SAMPLE COLLECTION ............................................................................. 76 
15.2 
CENTRAL LABORATORY ...................................................................................... 76 
15.3 
PHARMACOKINETIC SAMPLES............................................................................. 76 
15.4 
PREPARATION, STORAGE, AND HANDLING FOR PHARMACOKINETIC SAMPLES 76 
15.5 
ANALYTICAL......................................................................................................... 77 
16 
TISSUE SAMPLES AND HISTOLOGY ............................................................ 77 
17 
SAFETY EVALUATIONS ................................................................................... 77 
17.1 
PHYSICAL EXAMINATION..................................................................................... 77 
17.2 
VITAL SIGN MEASUREMENTS .............................................................................. 78 
17.3 
LABORATORY EVALUATIONS............................................................................... 78 
17.4 
ELECTROCARDIOGRAM........................................................................................ 78 
17.5 
ADVERSE EVENTS................................................................................................. 79 
17.5.1 
Adverse Event Definition .................................................................................. 79 
17.5.2 
Serious Adverse Events ..................................................................................... 79 
17.5.3 
Non-Serious Adverse Events............................................................................. 80 
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17.5.4 
Definition of Relationship to Study Medication................................................ 81 
17.5.5 
Definition of Severity ........................................................................................ 81 
17.5.6 
Definition of Unexpected Adverse Event.......................................................... 81 
17.6 
DATA SAFETY MONITORING BOARD................................................................... 82 
18 
EMERGENCY PROCEDURES .......................................................................... 82 
18.1 
EMERGENCY SPONSOR CONTACT........................................................................ 82 
19 
CONSIDERATION, ANALYSIS PLAN AND DETERMINATION OF 
SAMPLE SIZE....................................................................................................... 82 
19.1 
GENERAL .............................................................................................................. 82 
19.2 
INTERIM ANALYSES.............................................................................................. 82 
19.3 
METHODS FOR HANDLING MISSING DATA.......................................................... 82 
19.4 
PATIENT DISPOSITION.......................................................................................... 82 
19.5 
BASELINE CHARACTERISTICS.............................................................................. 83 
19.6 
CONCOMITANT MEDICATIONS............................................................................. 83 
19.7 
STUDY DRUG DOSING............................................................................................ 83 
19.8 
EFFICACY ANALYSES............................................................................................ 83 
19.8.1 
Efficacy Population............................................................................................ 83 
19.8.2 
Premature Discontinuation Due to Lack of Efficacy or Adverse Events .......... 83 
19.9 
SAFETY ANALYSES ............................................................................................... 83 
19.9.1 
Safety Population............................................................................................... 83 
19.9.2 
Adverse Events .................................................................................................. 84 
19.9.3 
Vital Signs.......................................................................................................... 84 
19.9.4 
Laboratory Evaluations...................................................................................... 84 
19.9.5 
Physical Examinations....................................................................................... 84 
19.9.6 
Electrocardiograms ............................................................................................ 84 
19.10 DETERMINATION OF SAMPLE SIZE...................................................................... 84 
19.11 PHARMACOKINETIC AND PHARMACOKINETIC /
PHARMACODYNAMIC ANALYSES............................................................. 85 
20 
ETHICS .................................................................................................................. 85 
20.1 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD ........ 85 
20.2 
ETHICAL CONDUCT OF THE STUDY ..................................................................... 85 
20.3 
PATIENT INFORMATION AND INFORMED CONSENT ............................................ 86 
21 
STUDY ADMINISTRATION .............................................................................. 86 
21.1 
CLINICAL MONITORING....................................................................................... 86 
21.2 
DATA QUALITY ASSURANCE................................................................................ 87 
21.3 
RETENTION OF STUDY RECORDS......................................................................... 87 
21.4 
CONFIDENTIALITY................................................................................................ 88 
21.5 
DOCUMENTATION OF STUDY RESULTS................................................................ 88 
21.6 
USE OF STUDY RESULTS....................................................................................... 89 
22 
REFERENCES....................................................................................................... 90 
APPENDICES................................................................................................................. 96 
APPENDIX 1: 
SCHEDULE OF EVENTS ......................................................................... 97 
APPENDIX 2: 
STUDY SCHEMATIC FLOW CHARTS................................................... 104 
APPENDIX 3: 
CLINICAL LABORATORY TESTS......................................................... 107 
APPENDIX 4:  
PATIENT REPORTED OUTCOMES....................................................... 108 
Medical Outcomes Sleep Scale (Revised MOS Sleep-R)................................... 109 
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ItchyQoLTM......................................................................................................... 111 
Prurigo Activity Score (PAS) ............................................................................. 114 
Patient Benefit Index, Pruritus Version (PBI-P)................................................. 115 
Numerical Rating Scale (Worst Itch).................................................................. 117 
Numerical Rating Scale (Average-Itch).............................................................. 117 
Verbal Rating Scale ............................................................................................ 117 
Hospital Anxiety and Depression Scale (HADS)............................................... 118 
Subjective Opiate Withdrawal Scale (SOWS).................................................... 119 
APPENDIX 5:  
CARDIOVASCULAR RELATED PROHIBITED MEDICATIONS AND 
CARDIOLOGICAL ASSESSMENTS........................................................................ 120 
Canadian Cardiovascular Society Grading of Angina Pectoris......................... 121 
NYHA FUNCTIONAL CLASSIFICATION ......................................................... 122 
ACC/AHA CLASSIFICATION OF CHF............................................................. 122 
LIST OF TABLES
TABLE 1: 
ETIOLOGY OF CHRONIC PRURITUS REPORTED IN PRURIGO NODULARIS 
PATIENTS (N=108)..................................................................................................... 20 
TABLE 2:  
TR03EXT STUDY PERIODS............................................................................ 41 
TABLE 3: 
DOSING SCHEDULE FOR TR03EXT ............................................................... 65 
TABLE 4: SCHEDULE OF EVENTS FOR VISITS 1A AND 1B.................................................... 97 
TABLE 5:  
TREATMENT WEEKS 2-4 ............................................................................... 98 
TABLE 6: TREATMENT PERIOD VISITS12 DURING STUDY WEEKS 5-50 AND 
WASHOUT/SAFETY FOLLOW-UP VISIT OR TREATMENT PERIOD EARLY TERMINATION 
VISIT.......................................................................................................................... 99 
TABLE 7:  
OBSERVATION PERIOD VISITS5 ................................................................... 101 
TABLE 8: TREATMENT VISIT SCHEDULE FOR PATIENTS ENTERING TREATMENT VIA VISIT 
1B ............................................................................................................................ 102 
TABLE 9: RESCUE MEDICATIONS FOR ITCHING................................................................ 103 
LIST OF FIGURES
FIGURE 1:  
MEAN VAS SCORE (SD) FOR ALL PATIENTS AS A FUNCTION OF NALBUPHINE 
HCL DOSE ADMINISTERED AS NALBUPHINE HCL ER TABLETS. N= 14 EXCEPT FOR 180
MG (N=13) AND 240 MG (N=4). SOURCE: NAL.001.TR01.PD................................. 27 
FIGURE 2:  
OVERVIEW OF TR03-EXT STUDY DESIGN ................................................. 104 
FIGURE 3:  
EXAMPLES ILLUSTRATING POSSIBLE OBSERVATION AND TREATMENT PERIODS 
SCENARIOS IN TR03-EXT ........................................................................................ 105 
FIGURE 4:  
DOSING SCHEDULE IN TR03EXT................................................................. 106 
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2
LIST OF ABBREVIATIONS
Abbreviation
Definition
ACC
American College of Cardiology
AE
Adverse event
AHA
American Heart Association
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
ATC
Anatomic and Therapeutic Class
BID
Twice daily
BMI
Body Mass Index
BP
Blood pressure
BPM
Beats per minute
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CHF
Congestive Heart Failure
CNS
Central nervous system
CRF
Case report form
CRO
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
ER
Extended release
FDA
Food and Drug Administration
GCP
Good Clinical Practice
H&E
Hematoxylin and eosin
HADS
Hospital Anxiety and Depression Scale
HCG
Human chorionic gonadotropin
HCl
Hydrochloric acid
HD
Hemodialysis
H pylori
Helicobacter pylori
HR
Heart rate
ICF
Informed consent form
ICD-10
International Classification of Diseases, 10th revision 
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Abbreviation
Definition
ICH
International Conference on Harmonization
IFSI
International Forum for the Study of Itch 
IRB
Institutional Review Board
IUD
Intra-uterine device
KOR
Kappa Opiate Receptor
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
MOR
Mu Opiate Receptor
MOS
Medical Outcomes Study
MITT
Modified Intent-To-Treat
NONMEM
Non-linear mixed effects modeling
NRS
Numerical Rating Scale
NYHA
New York Heart Association
OV
Observation Period Visit
OTC
Over-the-counter
PAS
Prurigo Activity Score
PBI-P
Patient Benefit Index, pruritus version
PD
Pharmacodynamic(s)
PK
Pharmacokinetic
PN
Prurigo Nodularis
PRO
Patient-Reported Outcome; In this study, PRO instruments
administered at the site are as follows: NRS, VRS, ItchyQoL, 
PBI-P, MOS Sleep-R, HADS, SOWs
QoL
Quality of Life
RR
Respiratory rate
SAE
Serious adverse event
SD
Standard deviation
SOWS
Subjective Opiate Withdrawal Scale
TC
Telephone Call
TdP
Torsade  de Pointes
TV
Treatment Period Visit
UP
Uremic Pruritus
VRS
Verbal Rating Scale
WHO
World Health Organization
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3
INTRODUCTION
3.1
PRURIGO NODULARIS AND STUDY RATIONALE
3.1.1
General Information on Prurigo Nodularis
Prurigo Nodularis (PN) is an intensely pruritic dermatologic condition with the presence of 
papules as well as nodules with excoriations and ulcerations. The basis of PN is a pre-
existing severe and chronic pruritus of various etiologies (see Table 1). The pruritus leads 
to scratching. However, the etiology or predisposing factors leading to the development of 
papules and nodules of PN are largely unknown (Eigelshoven et al 2009; Valdya and 
Schwartz 2008; Lee and Shumack 2005). Iking et al (2012) reports that in the past few 
years the hypothesis for the etiology of PN as being a reaction pattern due to a “vicious 
cycle of repeated itching and scratching” is gaining wider acceptance in the medical 
community.
With regard to the types of pre-existing chronic pruritus conditions that have been reported 
in PN patients, Table 1 summarizes data reported by Iking et al (2012) in their study of PN 
patients (N=108). Pruritus secondary to multi-factorial etiologies (“Mixed Origin”) was 
the most common source attributed to the cause of the chronic pruritus. The majority of 
the “mixed origin” patients had a combination of dermatological and systemic diseases or a 
combination of several systemic disorders.
Iking et al (2012) did not attribute any cases of PN to an underlying diagnosis that was 
solely psychological in origin.  In the subjects who were diagnosed with PN from mixed 
origin etiologies (summarized in Table 1), the authors attributed psychological factors 
related to chronic pruritus etiology to be present in 5.6% of the PN subjects categorized as 
having mixed (multi-factorial) origin pruritus.  In a study focused on understanding 
psychosomatic/psychiatric dimensions related to chronic itch, Schneider et al (2006) 
reported on 44 PN patients.  The authors stated that 34% of subjects had no accompanying 
psychiatric diagnosis and 46.8% were given a diagnosis of “psychological or behavioral 
factors associated with disorders classified elsewhere” (ICD-10 code F54) –indicating that 
psychological factors may play a role in the development and course of the condition.
Payne et al (1985) reported psycho-social problems may have been relevant in about 33% 
of the studied 42 subjects that were adequately questioned.
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Table 1:
Etiology of Chronic Pruritus Reported in Prurigo Nodularis Patients
(N=108)
Origin of Pruritus by 
Organ System
Number 
of 
Patients (%)
%  Mixed with Organ 
Category Contribution to 
Chronic Pruritus
Most Common 
Disease
Mixed 
(pruritus 
of 
multi-factorial 
etiologies)
64  (59.3%)
Dermatological Disease 
(19.4%)
Atopic diathesis
Systemic Diseases
(70.9%)
Sorbitol 
Intolerance
Lactose 
Intolerance
Iron Deficiency
H pylori 
Infection
Diabetes 
Mellitus
Renal Failure
Neurological Disease
(4.1%)
Chronic pain 
Syndrome
Neuropathy
PUVA-pain
Psychological Factors
(5.6%)
Psychological 
Factors (non-
specific)
Origin of Pruritus by 
Organ System
Number 
of 
Patients (%)
Most Common Disease
Dermatological
20  (18.5%)
Atopic diathesis/dermatitis
Systemic
8    (7.4%)
Sorbitol Intolerance
Lactose Intolerance
Hepatitis C
H pylori infection
Iron Deficiency
Diabetes Mellitus
Unknown
14   (13%)
-
Neurological
2    (1.9%)
Brachio-radial Pruritus
Psychological 
0      (0%)
-
Source: Iking et al (2012)
Iking et al (2012) reported that the median value of the NRS average intensity pruritus 
measured 8 on a rating scale with anchor points of zero (no pruritus)-10 (worst imaginable 
pruritus). Itch intensity scores  7 are considered severe in terms of itch intensity and itch 
intensity scores  3 are considered moderate in terms of itch intensity (Stander et al 2013).
Accioly-Filho et al (2000) reports that once the cycle of pruritus-excoriation-pruritus 
begins, it is difficult to stop as PN is very resistant to therapeutic intervention strategies. 
Papoiu et al (2013) report a central nervous system relationship to the itch-scratch cycle. 
The authors showed that there is a complex interaction of sensory, motor and emotional 
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components based on their investigation of using real-time flare brain MRI imaging and 
psychophysical ratings of itch relief or pleasurability of scratching conducted in healthy 
volunteer experimental subjects.
Eigelshoven et al (2009) reports that patients present with excruciating pruritus that is 
usually anatomically symmetrical and mainly involves the extensor aspects of the 
extremities, the shoulders, chest and sacral regions with the appearance of typical lesions.
Payne et al (1985) reported in a study of 46 subjects that the patients came from all social 
classes and racial groups, almost equally divided by gender and with a mean age of 39.5 
years at the time of PN onset. Iking et al (2012) reported in their study that the patients 
were distributed in age between 11.9 years - 95.6 years with a median age of 61.9 years and 
there were more females than males affected by the disease.
Weigelt et al (2010) summarized the characteristic histological findings in PN that include 
the presence of thick compact orthohyperkeratosis; folliculosebaceous units in nonvolar 
skin in conjunction with a thick and compact cornified layer; irregular epidermal 
hyperplasia or pseudoepitheliomatous hyperplasia; focal parakeratosis; hypergranulosis; 
fibrosis of the papillary dermis with vertically arranged collagen fibers; increased number 
of fibroblasts and capillaries; a superficial, perivascular and/or interstitial inflammatory 
infiltrate of lymphocytes, macrophages and, to a lesser extent, eosinophils and neutrophils.
In terms of treatment options for PN, there have been a variety of medical interventions 
discussed. Hogan et al (2012) recently reviewed the therapies discussed in the literature 
that included topical, systemic and intra-lesion steroids administration; antihistamines; 
anxiolytics; opiate receptor antagonists; thalidomide; gabapentin; capsaicin cream; topical 
anesthetics; occlusive therapies; ultraviolet light; and reports that they had “mild to 
moderate success at best”.  The authors also comment on the potential imbalance in the 
mu-kappa opiate receptor system and mention the possibility of studying the kappa agonist 
nalfurafine (see section 3.1.3.1, where nalfurafine was used as a positive control in 
Sponsor’s preclinical substance P mouse model of itch investigation). Spring et al (2014) 
reported on the use of methotrexate and the need for chemotherapeutic related regular 
medical monitoring. Liu et al (2013) and Kanavy (et al 2012) both reported on 
lenalidomide is case reports, but the drug led to side effect of a reversible myopathy in one 
of the subjects.  Accioly-Filho (2000) reported the condition is “notoriously resistant to 
therapy”. Iking et al (2012) and Valdya and Schwartz (2008) reported a significant impact 
on the patient’s quality of life (2008). Spring et al (2014) report PN to be debilitating 
condition and a therapeutic challenge where conventional treatments with steroids, 
standard anti-pruritic agents, phototherapy and immune-suppressors often fail.  
3.1.2
Potential Mechanism of Prurigo Nodularis Pathophysiology
3.1.2.1
Opiate Neurobiology
The initiating biological event in the skin is unclear but assumed to patho-physiologically 
result from a complex cross talk of different skin cells. The neurobiology of opioid 
peptides may be involved at the peripheral level as part of a reaction to the skin tissue 
injury. Therapeutic intervention at the peripheral level through opioid pharmacology to 
break the scratch-itch cycle via interrupting positive feedback loops that have developed 
between elements of the peripheral nervous system, immune system and various skin cell 
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interactive dynamics may be possible. 
In addition, central nervous system opiate 
neurobiology may be involved in a positive feedback loop between the tremendous urge to 
scratch and the pleasurable anti-pruritic relief gotten from scratching that could also be a 
level of therapeutic intervention using opioid pharmacology.
3.1.2.2
Systems Biology Hypothesis to Prurigo Nodularis Etiology 
Diseases that arise from an abnormal interaction between integrated body system networks
and exhibit the concept of a positive feedback cycle which lead to an amplification of a 
biological signal can be discussed using concepts from systems biology (Kitano 2004).
The physiological phenomena of a “scratch-itch cycle” (“positive feedback loop”) 
underlying the patient’s behavior, the intense (“amplified”) nature of the pruritus and the 
large areas of body surface involvement in the absence of an active dermatosis suggest a 
“generalized” process either potentially due to
central nervous system
circuitry 
pathophysiology and/or widespread derangement of the dermal-immune-nervous system 
component interactions.
PN may be analogous to chronic regional pain syndrome – a
condition where there may or may not be an initiating etiological event, the intensity of 
pain is severe, the sensation of pain spreads to wide areas of the body surface and the 
condition is regarded as a systemic disease that involves both the central and peripheral 
components of the nervous system along with interactions with the immune system 
(Schwartzman et al 2009).  Complex regional pain syndrome is completely independent of 
any potential nociceptive initiating event.  Schmelz (2005) reviewed the literature on the 
evidence of similar biological patterns occurring in chronic pain and chronic itch 
conditions. Iking et al (2012) reported that on onset, PN was localized in 68.5% of patients 
with only 31.5% having generalized PN. In the majority of patients (56.5%), a secondary 
generalization of PN was observed. In the course of PN, only 12.0% still suffered from a 
localized form of PN.
3.1.2.3
Relevant Cutaneous Peripheral Neurobiology in the Skin
The complex neurochemical/neurohumoral interactions between the cutaneous resident 
mast cells and epidermal keratinocytes with peripheral non-myelinated type C nerve 
endings responsible for initiating the behavior of scratching as an evolved protective 
response to exogenous invading skin irritants is well summarized by Raap et al (2011) and 
the current understanding of the peripheral neuroanatomy-spinal cord synaptic connections 
underlying itch is well summarized by Dhand et al (2014). Selected aspects of this 
neurobiology as they relate to the development of some specifics of the known pathology 
in PN will be summarized.  
The cellular initiation of itch can begin with the mast cell release of histamine that binds to 
H1 receptors on nerve fibers (Raap et al 2011).  Endorphins and other opiate peptides are 
known to cause histamine mast cell release (Barke et al 1993).  Endorphin itch initiation 
biology may be more direct.  Bigiliardi and Bigliardi-Qi (2004) observed that while 
histamine interaction with nerve fibers may be a source of itch sensation, they summarize 
evidence for direct opiate peptide interaction with nerve fiber endings expressing 
endorphin receptors as a contributor to itch sensation initiation.  
With regard to the skin cells themselves, keratinocytes are known to produce different 
neuropeptides that include proopiomelanocortin (POMC), which is a precursor for the 
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opiate peptide beta-endorphin (Bigliardi et al 1998).  In addition, mast cell activation can 
initiate the itch process via non-histamine mediated processes that that lead to substance P 
presence in the interstitium (Raap et al 2011).  Substance P, a neuropeptide member of the 
tachykinin family, is thought to induce itching in humans via histamine degranulation from 
mast cells (Potenzieri et al 2012). Keratinocytes are known to express Substance P 
receptors (Peters et al 2006) and opiate receptors (Bigliardi et al 1998).
There is also a close link between endorphins and substance P in nerve fibers innervating 
the epidermis.  Opioid receptors destined for insertion onto the distal portions of Type C 
cutaneous nerve fiber membrane and the neuropeptides (such as substance P) that are 
capable of release into the interstitium are both synthesized in the same dorsal root 
ganglion nerve cells and transported to the peripheral nerve processes in the skin (Stein et 
al 2003).  
3.1.2.4
Abnormal endogenous opiates in the skin of PN patients:
Bigiliardi and Bigliardi-Qi (2004) reported that in PN human skin tissue samples there was 
a down regulation of the mu-opiate receptor expression in the epidermis compared to 
normal skin.  The down regulation was thought to be a biological response to abnormal 
tissue exposure to large amounts of endogenous opioid ligands such as endorphins.  The 
authors comment that the epidermal skin cells such as the keratinocytes that are no longer 
binding the opioid ligands possibly leave the ligands available to bind to epidermal nerve 
endings and thus induce a nerve transmission mediated signal to the CNS resulting in a 
pruritus sensation.  
3.1.2.5
Abnormal substance P level in the skin of PN patients:
Haas et al (2010) reported data showing significantly increased density of dermal substance 
P nerve fibers both in lesion skin samples as well as normal appearing skin samples from 
PN patients.  The authors concluded that the hyper-innervation by substance P containing 
sensory nerves may have a role in the itch sensation found in these patients. Molina et al 
(1992) reports increased nerve fibers containing substance P in PN subjects compared to 
control group that could be related to the intense pruritus.
3.1.2.6
Inflammatory Component to PN Histology:
Neurogenic inflammation refers to the manifestation of skin diseases related to the 
malfunctioning of the nervous system – immune system interaction (Steinhoff et al 2003, 
Peters et al 2006, and Potenzieri et al 2012). Bigliardi et al (1998) conclude that the 
presence of receptor systems for endorphins and substance P molecules is evidence of an 
interaction between skin, immune and nervous system.  Given the abnormal biology of 
substance P and endorphins in the skin of PN patients just discussed above, the hypothesis 
that the induction of an inflammatory component in PN is etiologically related to 
endorphin-substance P pathobiology is based on the following biological facts:
In addition to being a pruitogen, substance P also has pro-inflammatory and immune-
stimulatory activity (Peters et al 2006).  Steinhoff et al (2003), Peters et al (2006), and 
Potenzieri et al (2012) state that substance P may be an important mediator of 
cutaneous neurogenic inflammation.  The immune cells that migrate under a pro-
inflammatory signal from released substance P are an important source of opioid 
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ligands. The opioid ligand containing immune cells consist of T and B lymphocytes, 
granulocytes, and monocytes/macrophages (Sehgal et al 2011).  As noted by Weigelt et 
al (2010), part of the characteristic PN histological findings is a superficial, 
perivascular and/or interstitial inflammatory infiltrate of lymphocytes, macrophages 
and, to a lesser extent, eosinophils and neutrophils (granulocytes).  The opioid ligands 
released by immune cells interact with peripheral opioid receptors located on the 
cutaneous nerves (Stein et al 2003). Otherwise stated, the cutaneous nerve induced 
signaling from opioid ligands released by immune cells may be a source of the pruritic 
signal to the brain.  
3.1.3
Rationale for Investigating Nalbuphine HCl ER in Prurigo 
Nodularis 
3.1.3.1
Pre-clinical Animal Data
A preclinical investigation (Covance Study No. 8265903) was undertaken to demonstrate 
the effects of nalbuphine HCl on substance-P (SubP) induced scratching behavior in the 
mouse, a standard animal model (Kuraishi et al. 1995).  Scratching behavior induced by
peripheral stimulation by the pruritogen SubP mimics the characteristics of itch-related 
scratches in humans (Kuraishi et al. 1995) and Andoh et al 1998).  In addition, the SubP 
induced scratching behavior is not inhibited by the histamine H1 receptor antagonist and 
elicits responses even in mast cell-deficient mice.  Thus, SubP-induced scratches are likely 
to represent antihistamine-resistant pruritus.  The model is relevant to antihistamine-
resistant pruritus (Togashi et al 2002 and references cited therein).
The SubP itch mouse model was successfully established and its viability confirmed by 
assessing the responses using vehicle (phosphate buffered saline, PBS) only group
(VEH/VEH) and nalfurafine HCl, a positive comparative control group (PCC/SubP)  
relative to untreated group (VEH/SubP) group.  Briefly, studies were conducted in male 
C57BL/6 mice.  Animals were acclimated to the facility at least three days prior to dosing.  
On the test day, mice were acclimated to the observation cages for one hour prior to dosing.  
Mice were then randomly assigned to treatment groups and subcutaneously (SC) dosed 
with vehicle (PBS), PCC (0.01 or 0.02mg/kg), or the test article nalbuphine (10 or 
30mg/kg) (NAL/SubP group), and video recorded for 30 minutes to establish baseline 
scratching behavior.  After the 30-minute baseline recording, mice received either vehicle 
(0.05 mL PBS) or SubP (250 nM in 0.050 mL) injected intradermally (ID) into the rostral 
part of the back and video recording continued immediately for an additional hour.  
Itching was scored by reviewing the recording and counting the number of scratches over 
30 minute periods following SubP (or vehicle) challenge.  Itching was defined as 
scratching with the hind paw at the intradermal injection site (upper right shoulder area).  
Continuous scratching over one second was counted as one scratch event and paused 
scratches were considered separate scratching events.  Scratching of other sites such as ears 
and face were not recorded.  
Baseline scratching (pre-SubP) was similar for all treatment groups.  Following SubP 
administration in the untreated mice, itching began within 3-5 minutes from administration 
of the pruritogen.  The itch intensity was the highest in the first 30 minutes post-dose.  By 
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60 minutes post-dose, the effect of the SubP injection began to wear off as scratching 
returned towards baseline levels.
As expected, PCC significantly (p< 0.001) decreased the SubP-induced scratching 
supporting the validity of the itch model.  Subcutaneous pre-treatment with PCC resulted in 
a reduction of 42 and 63% reduction at the 0.01 and 0.02mg/kg dose (from 107 to 62 or 40 
scratches, respectively).
Significant reduction in itch (p< 0.001) was noted following nalbuphine SC administration 
with about 43% reduction in itch at the 10 mg/kg dose (from 107 to 61 scratches) and 52% 
at the 30 mg/kg dose (from 107 to 52 scratches).  Though there was a trend for a dose 
dependence on itch reduction, there was no statistical difference between the tested 
nalbuphine doses.
In this study, nalbuphine was as effective as PCC (nalfurafine) at reducing SubP-induced 
itch with no statistical difference between nalbuphine and PCC effect, regardless of the 
dose.
Ambulation was not suppressed in mice injected with nalbuphine dosed at 10 or 30 mg/kg 
indicating that attenuation of the scratching was not due to decreased locomotor activity.
3.1.3.2
Neuropharmacologic Basis of the Rationale of Investigating Nalbuphine for the 
Treatment of Prurigo Nodularis
Gutstein et al (2001) reports that nalbuphine exerts its clinical pharmacologic action by 
competitively antagonizing the opioid -receptor and simultaneously acting as an agonist at 
the opioid -receptor, and thus is a member of the  “opioid agonist-antagonist” class of 
drugs that mechanistically work through this dual pharmacologic process.  There is no 
published literature on the use of the moiety nalbuphine in PN.  Nalbuphine was shown to 
be effective in reducing morphine induced pruritus, a well-known clinical pruritic condition 
induced by morphine administration. In several published clinical well controlled studies 
(which are reviewed in detail in the Investigator Brochure Section 5.8), nalbuphine was 
either equally effective or superior in efficacy when compared to naltrexone or naloxone 
(both are pure u-antagonists) for the management of morphine induced pruritus. 
Neurogenic inflammation (as discussed in Section 3.1.2.6) may induce the secondary 
phenomena of “central sensitization” (Woolf et al 2011).  Central sensitization is a central 
nervous system pathologic neurobiology change in cell circuitry that results from abnormal 
peripheral nerve signaling and/or peripheral nerve injury.
The net effect of central 
sensitization is that there is a lowering of neural excitation threshold to external stimulus 
whereby either nociceptive or low intensity pruritogen cutaneous stimuli induce a high 
intensity sensation of pruritus (Paus et al 2006). Schmelz (2005) reports on the evidence 
that there is a mu-kappa opiate gating circuitry in the spinal cord whereby kappa agonist 
activity would inhibit mu opiate receptor containing cell activation mediated signaling that 
brings to consciousness the sensation of pruritus. The analysis by Schmelz may be an 
example of what Pan (1998) reports as a potentially very general opioid -receptor 
antagonizing function by the opioid -receptor. The author reviews the literature on central 
neural networks where the opioid -receptors are located in cell groups that are distinct 
from the cell groups that contain the opioid -receptors and summarizes the evidence that 
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agonism at the pharmacological level of the opioid -receptor antagonizes various opioid 
-receptor agonist mediated actions in the brain. This central gating mechanism could be 
important in countering any potential pruritogenic induced sensation from a peripheral 
neurogenic inflammatory initiating event in PN.
As discussed in Section 3.1.2.5, there is histological evidence of abnormal substance P 
presence in skin samples of PN patients. In that regard, an experiment conducted by Trevi
Therapeutics indicated that nalbuphine administered subcutaneously significantly 
(p<0.001) suppressed the substance P induced scratching in mice (see Section 3.1.3.1 study
summary).
Metze et al (1999) reported that 9 out of 17 patients with PN who were treated with the mu 
antagonist medication naltrexone reported a decrease in pruritus intensity of at least 50%.  
Reduced scratching as well as skin lesion healing was reported over a time period of up to 
20 months on drug.  This clinical observation potentially has different anatomical locations 
for the mechanistic drug effect.  Since Stein et al (2003) reported that inflammation 
increases both the number of sensory nerve terminals (“sprouting”) and disrupts the 
perineural barrier –thus facilitating opioid access to receptors, there is the possibility that 
peripherally acting mu antagonist naltrexone action reduced the neural membrane 
excitation by blocking actions of endogenous endorphins reported by Bigiliardi and 
Bigliardi-Qi (2004) to be present in the epidermis.  In fact, Bigiliardi and Bigliardi-Qi 
(2004) suggest an opiate antagonist be therapeutically investigated for this reason and also 
comment on the evidence that mu opiate receptors on epidermal cells may be have a role in 
skin healing.
However, consideration must also be given to central nervous system opioid pharmacology 
as a contributing antipruritic effect elicited by naltrexone.
At the spinal cord level, 
Schmelz (2005) commented that the explanation for opiate mu antagonists being capable of 
reversing experimentally induced itch may be related to the neurobiology of spinal cord 
level neuronal kappa-mu opioid gating circuits where either a mu antagonist or kappa 
agonist drug may act to have a pruritus suppressing effect. Supraspinal brain level action
related to interference of the circuits related to reward behavior cannot be excluded given 
that it is known that naltrexone, like nalbuphine, can abolish morphine induced pruritus 
from morphine administered intrathecally.  In addition, opiate receptor neuronal systems 
are known to be related to the physiological psychology of human reward behaviour and 
mu antagonist opioid class drugs are known to block the phenomena (Le Merrer et al 
2009).  Nalbuphine is known to block the effects of mu agonist drugs and induce the opioid 
withdrawal syndrome (Nubain® label).
3.1.3.3
Nalbuphine Clinical Data in Uremic Pruritus
Mannenti et al (2009) summarized potential pathophysiologic mechanisms for the etiology 
of uremic pruritus. Included among the postulated uremia induced mechanisms to explain 
uremic pruritus is neurophysiologic central sensitization “wind up” phenomena related to 
immune-inflammatory skin pathology.  Mettang and Kremer (2014) in their review of 
uremic pruritus comment on the recent focus given to the mechanistic hypothesis related to 
peripheral neuropathic changes and central nervous system pathobiology along with 
evidence for cutaneous micro-inflammation.
The authors state that a therapeutic option 
may be systemic treatment with mu-opioid receptor antagonist and kappa-opioid receptor 
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agonist.  The proposed etiology of uremic pruritus pathobiology may be similar in origin to
the neuroinflammatory process discussed in Section 3.1.2.6 as part of the mechanism
postulated for the underlying process involved in inducing PN. In should be noted that Lee 
and Shumack (2005) reported prurigo nodularis occurring in patients with renal failure and 
Iking et al (2012) report renal failure as a contributing source of chronic pruritus with PN 
that was attributed to mix origin chronic pruritic conditions (see Table 1).
In clinical study TR01, the effect of oral nalbuphine on pruritus in hemodialysis (HD)
patients with uremic pruritus was explored. The results indicated that nalbuphine HCl ER 
tablets demonstrated ability to suppress itch in a dose response fashion (see Figure 1)
Figure 1:
Mean VAS score (SD) for all patients as a function of nalbuphine HCl 
dose administered as nalbuphine HCl ER tablets.  N= 14 except for 180 
mg (N=13) and 240 mg (N=4).  Source: NAL.001.TR01.PD
The TR01 study is summarized in the Investigator Brochure Section 5.4.3.
Considering the potential similarity in the underlying postulated mechanism between 
uremic pruritus and PN, nalbuphine would also be expected to be therapeutic in PN 
patients.  As such, Study TR01 in HD patients can be regarded as a proof of concept study 
for PN.  
Based on the clinical evidence of nalbuphine to suppress itch in uremic pruritus, morphine 
induced pruritus, the substance P induced itch in a pre-clinical study, results and the 
mechanistic link between the opioid receptors and substance P with the pathophysiology of 
PN, a clinical investigation of efficacy of nalbuphine on itch in the PN population is 
justified.
3.2
NALBUPHINE
Nalbuphine HCl is currently available only as a generic medication in an injectable form.  
An injectable form of nalbuphine is a commercially available approved drug product in the 
United States since 1979 and originally marketed as Nubain®, on which the presently sold 
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generic injectable formulations are based.  It is currently approved for use in the United 
States for the relief of moderate to severe pain, a supplement to balanced anesthesia, for 
pre-operative and post-operative analgesia and obstetrical analgesia during labor and 
delivery.  The European Union marketing experience with the injectable form of 
nalbuphine dates back to 1986 and this was recently reviewed (Nalbuphine -Medicines 
Evaluation Board in the Netherlands Public Assessment Report 2010).
Nalbuphine is not a controlled drug in the United States. An oral dosage form of the drug 
is not commercially available.  Nalbuphine HCl ER is an extended release oral tablet that is 
currently being developed for the treatment of pruritus.
Nalbuphine is 	
		
	


Structurally, nalbuphine is a derivative of 14-hydroxymorphine and is related to the opioid 
-	
	-receptor antagonist naloxone.  
Nalbuphine exerts its clinical pharmacologic action by competitively antagonizing the 
-
	
		
		
	-receptor 
(Gutstein 2001; Gharagozlou 2003 and 2006). 
3.3
NALBUPHINE HCL ER TABLET CLINICAL DEVELOPMENT 
3.3.1
Overall Summary
The safety, tolerability and pharmacokinetics of nalbuphine HCl ER tablets have been 
characterized following single and multiple ascending dose studies in healthy male and 
female human subjects, in a single dose study conducted in a dental pain patient 
population, a multi-dose study conducted in a patient population experiencing osteoarthritic 
related joint pain and in a multi-dose study conducted in both hemodialysis (HD) 
population experiencing uremic pruritus and healthy subjects. Studies were conducted with 
nalbuphine HCl ER tablets or oral solution following single dose administration from 30 
mg up to 180 mg and multiple doses ranging between 30 mg BID and 180 mg BID in 
subjects with normal renal function (up to 3 weeks) and in the hemodialysis population in 
multiple doses ranging from 30 mg BID to 240 mg BID (up to 15 days).
In subchronic and chronic dose toxicology studies, the CNS was identified as the only 
target organ when unformulated (neat) nalbuphine was given to dogs at high doses. High 
systemic drug exposures in dogs caused CNS toxicity (tremors and convulsions) leading to 
deaths in some cases. It should be noted that the convulsions at high doses of nalbuphine 
in dogs were most likely Cmax-related. In toxicology studies in which dogs were given 
high doses of nalbuphine formulated with release-rate controlling excipients that blunt the 
Cmax, no CNS signs of toxicity were observed. Using the most conservative (lowest) 
margin of safety determined in all toxicity studies, a minimum 12.4-fold safety margin was 
calculated respectively for the mean plasma Cmax in subjects with normal renal function at 
the highest projected clinical dose of nalbuphine (180 mg BID) relative to the plasma 
Cmax at the lowest NOAEL in dogs given unformulated nalbuphine.  Convulsions were 
not observed in any of the clinical trials conducted with nalbuphine HCl ER oral tablets in 
subjects with normal renal function at doses up to 180 mg BID (360 mg daily dose) or in 
HD patients at doses up to 240 mg BID (480 mg daily dose). 
In the course of development, 355 subjects received at least one dose of oral nalbuphine 
HCl. The most frequently reported adverse events were primarily in the Central Nervous 
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System (CNS) and Gastrointestinal (GI) organ system categories. All these side effects are 
known to occur with drugs with opioid pharmacologic properties. Most of the side effects 
noted in the study program were mild to moderate in severity.  Initiating drug dosing in 
both HD patients and healthy subjects at the 30 mg BID dose resulted in good tolerability 
for subsequent titration related dose escalation.
No drug abuse issues were reported during any of the investigations. The incidence of 
opiate withdrawal effects noted at drug discontinuation in the patients was investigated in 
the osteoarthritis pain treatment study when nalbuphine dosing was abruptly stopped 
following the end-of-study participation. There was an absence of any objective evidence 
of physical withdrawal symptoms in 85% of the patients and only mild evidence of 
physical withdrawal symptoms in the remainder of the patients.
3.3.2
Clinical Study TR01 in Hemodialysis Patients and Healthy 
Volunteers
Pruritus is a frequently identified sign and symptoms of uremia (“uremic pruritus”) and is 
thus a common symptom in patients receiving hemodialysis (Pisoni et al 2006 and Narita et 
al 2006).  Study TR01 was undertaken to assess the safety, PK, and the open label effects 
on pruritus intensity in hemodialysis subjects. PK and safety was compared to matched 
healthy control subjects.
Study TR01 was a single site, open label, non-randomized, parallel group, escalating dose 
study in hemodialysis patients with pruritus of at least mild intermittent intensity receiving 
intermittent hemodialysis three times a week compared to matched healthy control patients.
All subjects were in house during the entire dosing period. Nalbuphine HCl ER tablets 
were administered orally for up to a 15 day period in HD subjects and 13 days in healthy 
subjects. Doses were sequentially escalated from 30 mg QD on Day 1 to 30mg BID then to 
60 mg BID, 120 mg BID, 180 mg BID and 240 mg BID with dose escalation predicated on 
PK, safety, and tolerability of the preceding dose.  HD subjects remained at each dose level 
for 2-3 days for a minimum of 4-5 consecutive doses.  Healthy subjects remained at each 
dose level for 3-4 days for a minimum of 5 consecutive doses.  
Study subjects were separated into 2 cohorts:  Of the 15 HD subjects in enrolled into 
Cohort 1, 11 were assigned to dose escalate up to 180 mg BID and 4 were assigned to dose 
escalate up to 240 mg BID.  13 subjects (11 males and 2 females) completed the study.
One male subject discontinued secondary to non-drug related disease progression diagnosis 
of pleural effusion at the 30 mg BID dose level and a female subject discontinued 
following a Grade 3 AE of vertigo at the 240 mg BID dose level. Cohort 2 were healthy 
subjects who were assigned to dose escalate up to 180 mg BID.  Cohort 2 consisted of 8 
healthy subjects (6 males and 2 female) who completed the study and one male subject 
who discontinued at the 120 mg BID dosing level with only Grade 1 intensity AEs. All 
study subjects were closely monitored for AEs throughout the study.   
In healthy subjects, the dosing regimen resulted in mainly Grade 1 AEs and the dose 
escalation was tolerable in 8/9 subjects dosed. Of the nine healthy subjects enrolled, one 
subject withdrew from the study secondary to AE Grade 1 level gastrointestinal reflux, 
nausea/vomiting and vertigo symptoms at the 120 mg BD dosing level.  The subject 
recovered from the AE following drug discontinuation. AEs that occurred in greater than 
two subjects were somnolence (N=2), headaches (N=2), flatulence (N=2) and constipation 
(N=3).  
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In the HD subjects, there were no deaths or drug-related serious AEs.  There were no dose-
limiting AEs reported as defined as two HD subjects experiencing a drug-related AE of 
Grade 3. A total of 72 AEs were reported in the 15 HD subjects of Cohort 1. The nervous 
and gastrointestinal organ systems had the highest incidence of AEs. The most frequently 
occurring AEs were nausea and somnolence. Of the 13 HD subjects who completed the 
study (10 HD patients assigned to dose up to 180 mg BID and 3 HD subjects assigned to 
dose up to 240 mg BID), 12 subjects completed the trial per protocol and 1 subject
completed the study but did not dose titrate beyond 120 mg BID.  
With regard to the gastrointestinal organ system, of the 14 HD subjects who completed 13 
days of dosing (1 subject at 120 mg BID and 13 subjects at 180 mg BID), 4/14 (29%) 
experienced no nausea during the study and 7/14 (50%) experienced Grade 1 intensity 
nausea that was self-limited and only occurred at the initiation dose of 30 mg. One subject 
(1/14, 7%) experienced Grade 2 nausea starting from the 60 mg BID through the 180 mg 
BID dose. Three subjects (3/14, 21%) only developed nausea at the 180 mg dose level.  
With regard to the nervous system AEs, of the 14 HD subjects who completed the 13 days 
of dosing, 5/14 (36%) did not experience somnolence, 4/14 (29%) experienced somnolence
that was self-limited and only occurred at the initiation dose of 30 mg.  With regard to AE 
intensity, two subjects (2/14, 14%) experienced somnolence of Grade 2 intensity at dosing 
levels above 30 mg BID. Only one drug-related Grade 3 AE (vertigo) was reported in one 
subject at the 240 mg dose which resolved completely following drug termination. No 
clinically relevant findings in vital signs, blood pressure (BP), ECGs or physical 
examinations were noted during the study.  Oxygen saturation was also monitored via pulse 
oximetry as a safety precaution.  The oximetry readings were taken at regular intervals 
during the daytime and continuously monitored during the nighttime hours over the 15 
days of drug dosing and up to a maximal dose of 240 mg BID.  
In both the HD and healthy subjects, no clinically significant decrease in daytime readings 
were recorded in the oximetry readings except in the one male HD subject previously 
mentioned who discontinued from the study at the time of the development of a pleural 
effusion. There was no clinically significant decrease in the nocturnal oxygen saturation 
level below the pre-dosing baseline nocturnal oxygen saturation level in any HD subject. 
The Investigator Brochure and Section 5.4.4.4; Table 21 and Section 5.4.4.2.2; Table 17 
summarize the AE profile of the TR01 HD subjects and healthy subjects respectively.
During the course of TR01, the 15 HD subjects that were enrolled were on multiple 
concomitant medications.  Common concomitant medications included heparin, vitamin D, 
aspirin, iron, hyperphosphatemia management with sevelemar, erythropoiesis-stimulating 
agent, secondary hyperparathyroidism management with cinacalcet, neuropathic pain 
management with gabapentin; antihypertensive medications such as amlodipine (calcium 
channel blocker), carvedilol (beta and alpha-1 blocker), metoprolol (beta blocker), 
linosopril (ACE inhibitor); gastrointestinal medications: omeprazole, pantoprazole, 
ranitidine and renal vitamins and supplements. These medications seem to be commonly 
used by HD patients both in the US and the EU (Schmid et al 2010).  There was no 
clinically significant difference in the adverse event profile observed based on concomitant 
medication use or obvious pharmacodynamic interaction over the course of the study.
Data on Itch Intensity was obtained in an unblinded fashion from the HD subjects enrolled 
in the open-label single arm Study TR01 using a 0 (none) to 10 cm (maximal possible 
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intensity) itch Visual Analogue Scale (VAS) recording “worst itch” intensity. From a 
baseline mean daytime VAS of 4.4±2.3 cm and nighttime of 2.8±2. cm, the mean VAS 
decreased over a 13-day dosing period by -3.6±2.5 cm and by -1.8±2.1 cm, respectively.
Please see the Investigator Brochure for more details on the TR01 study.
3.3.3
Additional Nalbuphine HCl ER Tablet Clinical Data
In addition to the subjects in the TR01 study, a total of 331 subjects have been exposed to 
nalbuphine HCl during the course of 8 previous clinical studies.
Four Phase 1 studies were early biopharmaceuticals studies conducted in healthy subjects 
mainly for formulation selection and as such they support the safety of the drug product. In 
addition, two Phase 1 studies were conducted with the current clinical formulations and 
each consisted of a single dose study assessing the safety, tolerability, and PK of the 
current tablet formulations in the 30 mg -180 mg range. 
A safety and efficacy analgesic study was conducted in subjects with dental-pain following 
third molar extractions following a single dose (placebo or 60 mg or 120 mg).  The subjects 
were otherwise healthy male and female subjects. The study also contained PK-PD 
analysis demonstrating an analgesic dose-response relationship, with clear differentiation 
between the nalbuphine dose groups and placebo group.
Oxygen saturation was monitored via pulse oximetry as a safety precaution during Phase 1 
studies and in the single dose third molar extraction dental pain treatment study. All 
subjects who received the drug had oxygen saturation levels within the 90%-100% range 
during the studies.
A safety and efficacy analgesic study was conducted in a patient population experiencing 
osteoarthritic related joint pain using the current nalbuphine HCl ER 60 mg tablet.  The 
population was demographically older with the mean age of 57 years and a range extending 
from age 40-70 years.  Subjects were dosed continuously for up to 3 weeks starting at 
60 mg BID up to a dose of 180 mg BID. Subjects who tolerated the initial dosing were 
titrated up in weekly increments of 60 mg BID to the maximal dose of 180 mg BID.  The 
AEs that developed mainly had their onset at the initiation of dosing with no new type of 
AE developing in any statistically significant incidence during the course of dose 
escalation.
In both genders, the most frequently reported adverse events were primarily in the Central 
Nervous System and Gastrointestinal organ system categories.  A higher incidence of AEs 
was noted in females during week one of dosing with the gender asymmetry in AE 
generation lessening as a function of time.  This difference in AE incidence may be related 
to the tendency of females to have higher plasma levels than males (about 1.7 and 1.3 fold 
higher for Cmax and AUC, respectively). 
In these eight clinical studies overall, the most frequently reported AEs in the single dose 
and multi-dose studies were CNS events, namely dizziness, headache, and somnolence.  
Gastrointestinal system AEs were mainly nausea and vomiting.  Most of the AEs noted in 
the clinical study program were mild to moderate in severity.  
In the case of single dose Phase 1 nalbuphine HCl ER tablet administration, there was a
dose relationship to the incidence of AEs and there was minimal AEs observed at the 30 
mg dose compared to initiating dosing at the higher doses.  As a result, a titration to higher 
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doses from a starting dose of 30 mg was selected for subsequent studies that also included 
TR01 in order to improve the tolerability of the drug.
Section 5 of the Investigator Brochure summarizes the results of the clinical development 
program in detail.
4
STUDY OBJECTIVES
4.1
PRIMARY OBJECTIVE
The primary objective of the study is:

To evaluate the safety and tolerability of nalbuphine HC1 ER tablets during a drug 
treatment period of up to 50 weeks.
4.2
SECONDARY OBJECTIVES
The secondary objectives of the study are to evaluate the effect of nalbuphine HCl ER 
tablets on:

To evaluate the safety of nalbuphine by achieved maintenance dose at the end of 
Treatment Week 4 

Assess skin lesion improvement using the metrics of the PAS 

Change from Baseline in Patient-Reported Outcome measures Worst (i.e., most 
severe itching over the past 24 hours) itch NRS, average itch intensity NRS, VRS 
(itchy, burning and stinging), MOS Sleep-R, ItchyQoL, HADS by the final 
Treatment Period Visit

Change between Baseline and the final Treatment Period Visit in PBI-P

A description of the percentage of patients utilizing various doses of nalbuphine 
HCl ER tablets by Study Week

A description of the frequency and reasons for dose up- and down-titration and 
treatment discontinuation during the study

Frequency and distribution by time on study of patients determined to meet failure-
to-improve criteria

Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets

Time to first use of rescue medications and the number of days of use of rescue 
medications for itching

To evaluate the daily changes in the Subjective Opiate Withdrawal Scale (SOWS) 
during the Washout Period after cessation of treatment of nalbuphine HCl ER 
tablets
4.3
EXPLORATORY OBJECTIVES

The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve 
fiber density (histology) and MOR/KOR density (histology, Western Blot) and 
Histological (H&E) changes in skin biopsies taken Baseline and the final Treatment 
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Period Visit to investigate possible correlation with any clinical response and also 
compared to biopsy material assessed during study TR03 (optional period at select 
sites only).
5
STUDY ENDPOINTS
5.1
PRIMARY ENDPOINT

A description of the incidence and nature of TEAEs during Treatment Weeks 5-
50
5.2
SECONDARY ENDPOINTS
Visit 1a or 1b will serve as the baseline visit for efficacy endpoints. Visit 1a will be 
the baseline for patients directly entering the Treatment Period as of Visit 1a.  Visit 
1b will be the baseline for patients entering the Treatment Period after participating 
in the Observation Period for any length of time.

Assess skin lesion improvement using the metrics of the PAS 

Change from Baseline in Patient-Reported Outcome measures Worst itch NRS, 
average itch intensity NRS, VRS (itchy, burning and stinging), MOS Sleep-R, 
ItchyQoL, HADS) by Treatment Period study visit and Baseline NRS score 

Change between Baseline and the final Treatment Period visit in PBI-P

A description of the percentage of patients utilizing various doses of nalbuphine 
HCl ER tablets by Study Week

A description of the frequency and reasons for dose up- and down-titration and 
treatment discontinuation during the study

Frequency and distribution by time on study of patients determined to meet 
failure-to-improve criteria

Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets

Time to first use of rescue medications and the number of days of use of rescue 
medications for itching

To evaluate the daily changes in the Subjective Opiate Withdrawal Scale 
(SOWS) during the Washout Period after cessation of treatment of nalbuphine 
HCl ER tablets.
5.3
EXPLORATORY ENDPOINTS
The exploratory objectives of the study are to evaluate the effect of nalbuphine HCl ER 
tablets on:

The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve 
fiber density (histology) and MOR/KOR density (histology, Western Blot), as well 
as histological (H&E) changes in skin biopsies taken at Baseline and the final
Treatment Period Visit when compared to biopsy material assessed during study 
TR03 (optional procedure at select sites only).
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6
NUMBER OF SITES AND PATIENTS
Up to 10 sites in the North America and Europe are planned to participate in this study.
Eligible patients who have successfully completed the TR03 study and wish to participate 
in TR03ext may be enrolled, treated, and analyzed. The maximum number of patients will 
not exceed the number of patients who complete the TR03 study (i.e., up to 60 patients).
7
ESTIMATED STUDY DURATION
The total study duration for any individual patient will be up to 53 weeks.  Patients will 
receive drug treatment for up to 50 weeks, followed by a two week washout period.
8
SELECTION CRITERIA
8.1
STUDY POPULATION
Patients with prurigo nodularis who completed the TR03 study and have met 
Inclusion/Exclusion eligibility requirements for TR03ext (see Section 8.2 and Section 8.3).
8.2
INCLUSION CRITERIA
Patients must meet all of the following criteria to be eligible:
1. Have been adequately informed of the nature and risks of the study and have given 
written informed consent by Visit 1a.
2. Have completed participation in the TR03 study.
Completion of participation in the TR03 study is defined as completion of Study 
Drug treatment through TR03 Visit 5 and completion of the TR03 Visit 6. 
3. Agree to comply with the contraception requirements as below:
Female patients of childbearing potential are required to use one barrier method 
(e.g., condom, cervical cap, or diaphragm) of contraception in addition to one other 
method (e.g., intrauterine device [IUD], hormonal contraception, tubal ligation, 
Essure procedure, or spermicide). 
For the purpose of this study, all females are considered to be of childbearing 
potential unless they are post-menopausal (i.e., at least 1 year since last menses and 
age >50 years) or surgically sterile (i.e., tubal ligation, hysterectomy and/or bilateral 
oophorectomy).
4. Ability and acceptance to provide written informed consent.
5. Willing and able to comply with study requirements and restrictions 
6. Agree to the confidential use and storage of all data (including photography) and 
use of all anonymized data for publication including scientific publication.
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8.3
EXCLUSION CRITERIA
If a patient meets any of the following criteria, he or she is not eligible:
1. Patients with a history of congestive heart failure of Class 2 or higher as graded
using the New York Heart Association scale (scale provided in Appendix 5)
2. Patients with a history of angina pectoris grade 2 or higher as graded using the 
Canadian Cardiovascular Society grading scale (scale provided in Appendix 5)
3. History of ventricular tachycardia, torsade de pointes, family history of sudden 
death, myocardial infarction or acute coronary syndrome within the previous 3 
months, as reported by the patient.
4. Serum potassium below the laboratory lower limit of normality.  Potassium 
supplementation can be prescribed and the serum potassium level repeated
5. QTcF interval >450ms on screening EKG
6. Heart rate <50 BPM on screening
7. Use of a medication known to be associated with risk of torsade de pointes 
(see Section 9.7.8, Safety Assessments, for hyperlink to the CredibleMeds Filtered 
QTDrug List for cardiovascular related prohibited medications with a known 
associated risk of Torsade de Pointes)
8. History of substance abuse within the past year as determined by the Investigator
9. Significant medical condition or other factors that in the opinion of the Investigator 
may interfere with the conduct of the study
10. Known hypersensitivity or allergy to nalbuphine or formulation components 
11. Is a pregnant or lactating female.
9
STUDY PLAN
9.1
GENERAL STUDY DESIGN
This is an open label extension study for patients who have completed the TR03 study.
9.2
RATIONALE FOR STUDY DESIGN
The primary objective of this TR03ext study is to evaluate the safety of nalbuphine HCl ER 
tablets in patients with prurigo nodularis for up to 50 weeks on drug, followed by a two 
week washout period for a total of up to 53 weeks of study duration. The open label design 
allows all patients, who have completed the parent study TR03, an opportunity to receive 
active treatment for the assessment of the safety of nalbuphine HCl ER tablets over a 
longer term and follow the effect of skin lesion healing in addition to reducing itch. A
maximum of 50 weeks on study drug was chosen as a reasonable time frame that would 
add substantially to the understanding of chronic use of nalbuphine HCl ER tablets chronic 
use in prurigo nodularis.
Metze et al (1999) reported that 9 out of 17 patients with PN who were treated with the mu 
antagonist medication naltrexone reported a decrease in pruritus intensity of at least 50%.  
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Reduced scratching as well as skin lesion healing was reported over a time period of up to 
20 months on drug.  Based on these clinical observations, TR03ext was designed to be of 
sufficient duration to observe potential anti-pruritic suppressive effects of study drug on
scratching behavior and thus potentially skin lesion healing.  Furthermore, the TR03ext 
study design anticipates potential sustained anti-pruritic effect that may outlast the actual 
dosing of study drug in TR03.  Thus an Observation Period has been incorporated to follow 
patients whose Worst Itch NRS has been significantly reduced for up to 12 weeks in order 
to measure the durability of the anti-pruritic effect and to allow patients to receive study 
drug if pruritus intensity increases within the 12 week time period.
This study will also allow evaluation of a titration algorithm that mimics the manner in 
which opioid medications are often used in clinical practice (i.e., stepwise titration) to a
tolerable dose with an improvement in worst itch intensity. To facilitate evaluation by 
achieved dose, the dose to which the patient has been titrated at the end of Treatment Week 
4 will be maintained through Study Week 50, with the exception of two allowable down-
titration (See Table 3 for dosing schedule). Patients who require a third down-titration 
after Treatment Week 4 must be discontinued from the study.
Patients can enroll into TR03ext and receive drug as early as approximately 2 weeks 
following their last dose of study drug in the parent study TR03. Approximately one-third 
of patients are expected to enter the study after having received placebo in TR03. These 
patients are expected to have a high level of pruritus intensity. On the other hand, some 
patients who have received active treatment in TR03 may still have either reverted to their 
original pruritic conditions or may have a residual anti-pruritic effects from the drug 
treatment even following the 2-week wash out period. To allow for various starting levels 
of pruritus intensity, patients who have Worst Itch NRS that is 5 will enter the Treatment 
Period upon completion of Visit 1a.  Patients whose Worst Itch NRS score is < 5 will be 
entered into an extended screening period, no-treatment criteria Observation Period for up 
to 12 weeks or until they develop a higher level of pruritus (i.e., Worst Itch NRS ), at 
which point they will transition to the Treatment Period upon completion of Visit 1b.  All 
patients entering the Treatment Period, whether immediately upon study entry or following 
a period of time in the Observation Period, will initially be titrated to a dose that can be as 
high as 180 mg BID during the first 4 weeks of the Treatment Period (See Table 3 for 
dosing schedule). Patients who continue in the Observation Period and maintain a Worst
Itch NRS score of < 5 will be screen failed from the study at the end of the 12-week period.
While patients remain in the Observation Period, they will not be considered as enrolled 
into the study, but as participating in an extended screening process until they are eligible 
for treatment.
Patients who fail to improve, as defined by the failure-to-improve criteria, will be taken off 
study drug treatment. A failure-to-improve criteria is implemented beginning on TV 3 and 
at every subsequent Treatment Visit, and is described in Section 11.1. The rationale for the 
failure-to-improve criteria is based on the following: Following a maximal titration period 
of up to 3-weeks, an approximate 2-week window on stable drug dose should be sufficient 
for the drug to start eliciting a beneficial effect. The subject’s self-reporting of pruritus 
intensity at each visits beginning at TV 3 will be compared to the baseline value of the 
patient’s pruritus intensity upon entry to TR03ext. The premise of the failure-to-improve
criteria is that patients will not be allowed to continue to receive study drug for an extended 
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period of time if there is no demonstration of diminishment in pruritus intensity. Subjects 
discontinued from treatment are to participate in the Washout and Safety Follow-up Period,
unless consent is withdrawn.  These patients will also receive a Telephone Contact 30 days 
(+2 weeks) post the completion of study drug to collect safety information related to 
previous drug exposure.
In the parent study, TR03, the two target doses (90 mg and 180 mg) of nalbuphine HCl ER 
are both within the dose range that was well tolerated in HD subjects and healthy 
volunteers subjects from study TR01 (30 mg to 240 mg BID for up to 15 days).
Additionally, data from TR01 suggested a decrease in itching intensity in this dose range.
Further, the safety profile of nalbuphine following injection is well documented. Injectable 
nalbuphine has been commercially available in the United States since 1979 and there has 
been marketing experience within the European Union dating back to 1986 (See 
Nalbuphine -Medicines Evaluation Board in the Netherlands Public Assessment Report 
(2010) for a recent review).
In order to facilitate analysis of the clinical safety data and efficacy data, patients in the 
present study will begin titration at the 30 mg QD dose and titrate to only a maintenance
dose ranging between 30 mg BID and 180 mg BID. The 30 mg BID and 60 mg BID doses
are believed to be only marginally effective doses based on available TR01 data.  However 
there is a two time dose reduction permitted for all subjects during Treatment Weeks 5-50
(see Table 3) to the next lower allowed dose (e.g., a subject at the 90 mg BID maintenance 
dose will be permitted a dose reduction to 60 mg BID or subsequently to 30 mg BID and 
then be maintained at that dose level for the remainder of the study).
The study population being evaluated is an intended target population for oral nalbuphine
HCl ER tablets: prurigo nodularis patients.
Patients will be closely monitored for safety. All patients will be seen at the Investigator 
site (See Schedule of Events in Appendix 1). Adverse events and vital signs will be 
recorded. Additionally, 12-lead ECGs (locally and centrally read), physical examinations, 
and clinical laboratory testing will be conducted to monitor safety on patients receiving 
study drug. Safety monitoring will be done to address the primary objective of evaluating 
the longer term safety of study drug exposure. The primary endpoint is a description of 
adverse events during up to 50-weeks of treatment with nalbuphine HCl ER tablets. An 
important secondary endpoint objective of the study is to use recorded PAS metrics to 
assess the study drug anti-pruritic suppression of the scratching behavior of the subject and
impact on skin lesion improvement. Changes in patient-reported outcome measures: Worst
itch NRS, Average itch intensity NRS, VRS (itchy, burning and stinging), ItchyQoL, MOS 
Sleep-R, HADS and PBI-P will be explored. 
9.3
SAFETY MONITORING PLAN
Patients will be closely monitored for safety. Adverse events will be continuously 
evaluated throughout the study (and in particular AEs of special interest: nausea, vomiting, 
constipation, somnolence, sedation, dizziness, and vertigo) and vital signs, locally and 
central cardiac core laboratory read 12-lead ECGs, physical examinations, and clinical 
laboratory testing will be conducted to monitor patient safety. 
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An independent Data Safety Monitoring Board (DSMB) will periodically review safety 
data.  The frequency of data review and DSMB processes are outlined in the DSMB 
charter.
Patients with apparent failure-to-improve to a stable dose of study drug will be taken off 
study drug.
As with all subjects who are discontinued from study drug, the patient will complete a daily 
SOWS scale for the two weeks following the last dose of study drug.  The SOWS is a self-
administered scale for grading opioid withdrawal symptoms. If the subject is experiencing 
any symptoms on the SOW scale to a moderate degree, the subject will be instructed to 
contact the site.  If a subject is determined to be experiencing significant subjective 
withdrawal symptoms (at the Investigator’s discretion), the subject will be offered 
treatment.
As summarized in Section 6.2.7 of the Investigator Brochure, the CNS has been identified 
as the only target organ when nalbuphine was given to animals at high doses.  In addition, 
the most frequently reported adverse events reported in the nalbuphine HCl ER tablet 
dosing studies were primarily in the nervous system and gastrointestinal organ system 
categories.  .
To mitigate opioid-related side effects, nalbuphine will be titrated over 4 weeks based on 
tolerability to a dose that is between 30 mg BID to 180 mg BID (see Table 3). Titration is 
a clinical management strategy consistent with dosing of opioids in general (Jovey 2003).
The titration regimen planned in this study is similar to the regimen used in study TR01, in 
which doses in the planned range were well tolerated (Section 3.3.2) except uptitration is 
not a forced titration. This will provide flexibility for each patient to assess tolerability. In 
this study, the combination of a low starting dosing (30 mg on the first day) followed by a 
relatively slow titration (dose escalation after a minimum of six consecutive doses over 
approximately 3 days) is expected to minimize treatment-limiting opioid adverse effects.  
See Table 3 for the drug titration scheme. The time interval between dose escalations is 
consistent with the “three day tolerance check” suggested by the National Opioid Use 
Guideline Group of Canada (2010) for outpatient clinical practice management of opioid 
drug titration as part of monitoring patient side effects.
Nalbuphine has -opioid antagonist pharmacological properties.  To minimize the 
possibility of acute opiate withdrawal occurring at drug initiation in a physically dependent 
subject, patients receiving daily doses of opiates are excluded from the study.  Patients who 
require ongoing non-daily opiates concurrently with nalbuphine should be monitored 
carefully for additive opiate effects.  If patients develop a new need for daily opiates during 
the study, the Investigator is required to contact the Medical Monitor to discuss the 
specifics of the situation.
It is known from prior studies, that gastrointestinal opioid-like adverse effects (e.g., nausea, 
vomiting, and constipation) occur early and can be treatment-limiting.  In anticipation of 
the possible occurrence of these effects, pre-medications for nausea will be permitted and 
Investigators will be advised to use pharmacologic or non-pharmacologic means to avoid 
constipation as clinically indicated.  In anticipation of the possible occurrence of central 
nervous system (CNS) AEs such as somnolence, patients will be instructed to be aware of 
possible CNS AEs that may occur.  The evening doses during the Titration Period should 
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be taken at home.  The first dose of any new titration step will occur with an evening dose 
(see Table 3). In order to monitor any potential CNS related side effects, a brief 
neurological assessment will be conducted at each study visit as well as a focused 
neurological medical history will be obtained at enrollment.
Patients will be additionally instructed that if any significant CNS AEs occur, they are to 
avoid activities such as driving and operation of dangerous machinery until the effect of the 
Study Drug can be assessed by the Investigator. Additionally, concomitant use of daily
opioids during the course of the study, other than for short-term use, can be undertaken 
with the approval of the Medical Monitor.  Overdoses or opioid-related significant central 
nervous system adverse effects may be reversed with opioid antagonists if clinically 
indicated.
Although psychological dependence or abuse can develop to chronically administered 
opioid drugs, the risk for psychological dependence or abuse in this study is judged to be 
low based on previous clinical studies with nalbuphine HCl ER oral tablets.  To date, there 
have been no reported cases of psychological dependence or abuse reported following 
dosing for 3 weeks up to 180 mg BID and dosing for 15 days up to 240 mg BID.  See the 
Investigator Brochure for details. Nevertheless, the nalbuphine HCl injection package 
insert for the product sold in the United States states that “individuals with a prior history 
of opioid or other substance abuse or dependence may be at greater risk for the 
development of drug abuse and dependence”.
9.4
RISK-BENEFITS
The selected dose range for study in TR03ext of 30 mg BID to 180 mg BID were chosen 
given the safety profile summarized in Section 3.3.2 and discussed further in Section 9.2 as 
well as detailed in the Investigator Brochure. As summarized in, Section 3.1.3.3, open 
label data from the TR01 study showed that pruritus suppression in the HD patients was 
noted with drug administration within the dose range that is planned for the current study. 
Data obtained from a previous study in osteoarthritis patients dosed up to 180 mg BID with 
nalbuphine HCl ER tablets showed that objective opioid withdrawal symptoms at the 
termination of 3 weeks of therapy were absent or mild in degree (See the Investigator 
Brochure Section 5.4.4.5 for details).
It should be noted that the commercially available nalbuphine HCl for Injection product in 
the United States (Nalbuphine HCl package insert) has a usual recommended dose of 10 
mg for a 70 kg adult, administered subcutaneously, intramuscularly, or intravenously, 
which may be repeated every 3 to 6 hours as necessary (i.e., up to a daily dose of 40-80 mg 
IV); and, in non-tolerant individuals, the recommended single maximum dose is 20 mg, 
with a maximum total daily dose of 160 mg. Exposure following IV administration is 
approximately 6-fold higher than following oral administration (estimated oral 
bioavailability of nalbuphine HCl = 16%). Therefore, a 10-mg, 20-mg, or 160-mg IV dose 
would correspond to approximately 60 mg, 120 mg, and 960 mg oral nalbuphine, 
respectively.  The highest dose proposed in the TR03 study is 180 mg BID (360 mg daily 
dose), and this oral dose is well below the highest recommended daily treatment of 160 mg 
IV (equivalent to 960 mg oral) for the current marketed product.
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The risk for patients participating in the study is judged to be low based on previous 
experience with nalbuphine oral tablets. In addition, in the current study, there will be a 
low initiation dose of 30 mg, a slow dose titration rate, and careful safety monitoring of 
patients during the clinical study.
There is no approved therapy for prurigo nodularis related pruritus in the United States or 
Europe.  Should nalbuphine prove effective, patients with prurigo nodularis could 
potentially see benefit.
9.5
STUDY OVERVIEW
This is an open label safety and tolerability extension study for patients who have 
completed study TR03.  Patients will either enter directly a drug Treatment Period (Worst
Itch NRS greater than or equal to 5 ()) or enter an extended screening period of a no-
drug Observation Period (Worst Itch NRS less than 5 (<5)) based on their reported NRS 
scores on the first Visit (Visit 1a). For up to 12 extended screening weeks, patients in the 
no-drug Observation Period may also transition into the drug Treatment Period if their 
Worst Itch NRS increases to greater than or equal to 5 ().
The total study duration for any individual patient will be up to 53 weeks. For patients who 
enter directly into the Treatment Period, the total amount of time on drug will not exceed 
50 weeks.  For patients who enter the Treatment Period from the Observation Period, the 
total amount of time spent in the combined two periods of the study cannot exceed 50
weeks. All patients who received drug treatment will have a 2-week Washout and Safety 
Follow-up period at the end of the dosing period, unless consent is withdrawn.
The total amount of time in the Observation Period cannot exceed 12 weeks. After 12
extended screening weeks, subjects not eligible for the Treatment Period are screen failed
from the study. The study periods are summarized below in Table 2.
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Table 2:
TR03ext Study Periods
Study Period
Study Weeks
Duration
Observation Period
Patients who do not meet the criteria to start 
Treatment are followed in Observation Period 
visits for up to 12 extended screening weeks.  
During this time, the patient may meet criteria and 
become eligible to enter the Treatment Period.  If 
the patient does not meet the criteria to enter the 
Treatment Period by the end of 12 extended 
screening weeks (OV12), participation in the 
study ends and the patient is screen failed.
Up to 12
extended 
screening weeks
Treatment Period
For patient directly entering the Treatment Period 
as of Visit 1a, the Treatment Period begins with 
Study Week 1 (Visit 1a) and ends with Study 
Week 50 
For patients entering the Treatment Period after 
being followed in the Observation Period, the 
number of weeks on treatment and the end of the 
Treatment Period varies; Table 8 calculates the 
Treatment Visit assignments for any patient 
entering the Treatment Period from the respective 
Observation Period visits.
The End of Treatment Visit will take place after 
the patient completes the last week of study drug.
Up to  
50 weeks
Washout and Safety 
Follow-Up Period
The Washout and Safety Follow-up Period is two 
(2) weeks in duration.  
For patients directly entering the Treatment Period 
as of Visit 1a and completing 50 weeks of study 
drug treatment, the Washout and Safety Follow-
up Period should take place during weeks 51 and 
52.
For patients entering the Treatment Period after 
being followed in the Observation Period, the 
number of weeks on treatment and the end of the 
Treatment Period varies; Table 8 calculates the 
Treatment Visit assignments for any patient 
entering the Treatment Period from the respective 
Observation Period visits.  The Washout and 
Safety Follow-up Period will take place during the 
two (2) weeks after the patients completes the last 
week of study drug.
The Washout and Safety Follow-up Period Visit 
will take place in the week following the 
completion of the two (2) week Washout and 
Safety Follow-up Period.
2 weeks
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9.6
STUDY PROCEDURES
Before the initiation of study-specific procedures the patient must be given a complete 
explanation of the purpose of the study, evaluations to be conducted, and risks/benefits for 
study participation. Patients must understand the requirements of the study, provide 
informed consent (See Section 9.6.1 and Section 20.3), agree to the study restrictions, and 
agree to return for the required assessments. After review of the informed consent is 
documented, the patient must give witnessed verbal and written consent. For this study, 
patients will retain their study number from study TR03.
With the exception of Visits 1a and 1b, windows for all visits will be +/-3 Days. Please see 
the Schedule of Events in Appendix 1 for details of the Titration Period assessments and 
the Study Schematics Flow Charts in Appendix 2. See Section 9.7.1 for details of Study 
Drug Dosing and Section 9.7.6.4 for information on the use of pre-medications with the 
Study Drug. Visit 6 of TR03 will serve as TR03ext Visit 1a.
Visit 1a has procedures to be done as summarized in Section 9.6.1 regardless of the 
patient’s pruritus intensity score.  Following a set of common procedures, only patients 
who qualify for the Treatment Period based on meeting the pruritus intensity criteria will 
be eligible to receive study drug; Visit 1a corresponds to TV1. For patients who, during 
the final visit of TR03, did not meet the pruritus intensity criteria to enter the TR03ext 
Treatment Period, Visit 1a corresponds to OV1, the first visit of the Observation Period. If 
during a subsequent observation period visit to the site, the patient meets the pruritus 
intensity criteria, then that observation visit immediately transitions into Visit 1b (it also 
corresponds to TV1 since it is now the first Treatment Period visit) – See Section 9.6.3.3
and Section 9.6.4.
For subjects who transition to the Treatment Period from the Observation Period, Table 8
provides details on the treatment visit schedule based on the study week that the subject 
transitioned from the Observation Period to the Treatment Period. The subject will follow 
the Treatment Visit schedule outlined on the Schedule of Events (Appendix 1).
For clarity,
Patients with a Worst Itch NRS greater than 5 ( ) enter the Treatment Period
and will receive Study Drug starting with an evening 30 mg dose (to be taken at home), 
after the Visit 1a (or Visit 1b) procedures have been completed.
Receipt of the first dose of study drug will define Day 1. Visit 1a or Visit 1b for these 
patients is also Treatment Visit 1 (TV1). Subsequent visits will be defined as TV2, 
TV3, etc.
Patients with a Worst Itch NRS less than 5 (<5) enter the Observation Period and 
will not receive study drug treatment.  Visit 1a for these patients is also 
Observational Visit 1 (OV1). Subsequent visits will be defined as OV2, OV3, etc.
Patients in the observation period can be followed for up to 12 weeks.  
If during the Observation Period, a patient’s Worst Itch NRS increases to greater 
than or equal to 5 () and the patient meets all other eligibility criteria, Visit 1b 
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procedures are to be performed.  The patient’s next visit will be Treatment Visit 2 
(TV2).  Do not repeat the Worst Itch NRS during Visit 1b.   
If, however, at Observation Visit 12 the patient does not have a Worst Itch NRS
greater than or equal to 5 (), the patient will be screen failed without having 
initiated treatment with nalbuphine.
Figure 2, Figure 3 and Figure 4 visually display the relationship between TR03ext study 
weeks, Treatment Period weeks and Observation Period weeks.
9.6.1
Visit 1a (Day 1 of Study Week 1)
See Table 4 for summary of Visit 1a procedures. See Section 20.3 regarding the informed 
consent process that must take place prior to any study procedures.
Study TR03 Visit 6 procedures in common with Study TR03 extension Visit 1a procedures 
do not have to be repeated.

obtain informed consent 

confirm eligibility 

obtain vital signs

conduct a physical examination 

conduct a neurological exam

collect central laboratory samples (hematology and chemistry)

collect serum pregnancy sample in women of childbearing potential (done at the 
central laboratory)*

collect urine for central lab urinalysis

collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)*
* If the urine pregnancy test result is negative and the serum pregnancy test result is 
positive, the patient is to be contacted and the following actions are to take place:

instruct the patient to discontinue taking study drug

schedule the patient for an unscheduled visit to collect another serum 
pregnancy test 
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment.  See section 17.5.2.1 regarding how pregnancies 
are to be handled in this study.

obtain blood for PK

at select sites only, perform skin biopsy (optional).  Obtain 3 samples (i.e., H&E, 
nerve fiber density (histology) and MOR/KOR density (histology, Western Blot)); 
see the Lab and Study Reference Manuals for details

perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins; also collect the TR03 rescue medication log
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retrieve any remaining study drug from the parent study TR03

administer the Worst itch NRS and review score for eligibility to either enter the 
Treatment Period or to continue in screening under the Observation Period
a) If the Worst Itch NRS score is < 5, start the Observation Period. Do 
NOT initiate study drug treatment at this visit
b) If Worst Itch NRS score is  5, confirm eligibility and start the 
Treatment Period (see below, ‘For patients qualifying for drug 
Treatment Period only’).
The Worst Itch NRS must be administered at the study site under the supervision of 
and by trained study staff, strictly adhering to PRO Administration Instructions (see 
Study Reference Manual)
For patients qualifying for the drug Treatment Period only (Visit 1a is also study visit 
TV1):

complete PAS

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
o
PBI-P
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual)

At selected sites only, perform skin biopsy (optional).  Obtain 3 samples (i.e., H&E, 
nerve fiber density (histology) and MOR/KOR density (histology, Western Blot)); 
see the Lab and Study Reference Manuals for details

dispense Study Drug to the patient required until return at Treatment Visit 2, TV2

dispense the Dosing Diary and instruct the patient on how to complete it

dispense the Rescue Medication Log and instruct the patient on how to complete it

instruct patients to self-administer the first dose on the evening of Visit 1a at home 

instruct patients to notify the Investigator if any significant CNS AEs occur, and not 
to drive or operate dangerous machinery until the effect of the Study Drug can be 
assessed by the Investigator, see Section 9.3

instruct the patient to take the Study Drug twice daily at approximately the same 
times of day.  All patients should be instructed to titrate to their most tolerated dose.  
See Table 3 Drug Dosing Schedule for more information.  Here is the 
recommended Week 1 titration schedule for patients who tolerate study drug:
Day 1 (the first day that study drug the patient receives a study drug dose): No 
dose in the AM and 30 mg in the PM
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Day 2: No dose in the AM and 30 mg in the PM
Day 3: 30 mg in the AM and 30 mg in the PM
Day 4: 30 mg in the AM and 30 mg in the PM
Day 5: 30 mg in the AM and 60 mg in the PM
Day 6: 60 mg in the AM and 60 mg in the PM
Day 7: 60 mg in the AM and 60 mg in the PM

instruct patients to bring all remaining Study Drug to the Investigator site for each 
study visit

If a patient misses 3 or more consecutive doses, contact the Medical Monitor.
For patients starting the Treatment Period, the next visit will be TV2, Treatment Week 3.
For patients not qualifying for the drug Treatment Period only (Visit 1a is also study 
visit OV1), the patient will enter the Observation Period and the next visit will be OV2,
Extending Screening Week 4 (see section 9.6.3 Observation Period (Extended Screening
Weeks 1-12))
9.6.2
Treatment Period (Treatment Weeks 1-50)
Patients who enter the Treatment Period on Visit 1a will be in the Treatment Period for up
to 50 weeks and thus are eligible to receive study drug for up to 50 weeks.  
Patients who enter the Treatment Period from the Observation Period will be in the 
Treatment Period for up to 46 Treatment Weeks.  Patients enter the Treatment Period from 
an Observation Visit (OV) when their Worst itch NRS is greater than or equal to 5 ().
Regardless of how many treatment weeks the patient was on study drug, all patients who 
enter the Treatment Period will complete End of Treatment Visit TV14. Since all patients 
must titrate to their maintenance dose over the first four weeks of the Treatment Period,
Visits 1a/Visits 1b (TV 1) and TV 2 over the first four weeks of the Treatment Period will 
be common to all subjects in TR03ext regardless of when they enter into the Treatment 
Period.  Patients who transition from the Observation Period to the Treatment Period at a 
respective Observation Visit will follow the Treatment Visit schedule outlined in Table 8.
9.6.2.1
Treatment Period Weeks 2-4 (Titration Phase of Study Drug)
The first week in the Titration phase is initiated as part of Visit 1a/1b (Day 1 Treatment 
Week 1, see Section 9.6.1 and Section 9.6.4).  Subsequently, the following events TC1, 
TV2 and TC2 will be conducted during the remainder of the titration phase. See Table 5
for the Schedule of Events during the titration phase.
9.6.2.1.1 Telephone Contact Number 1 (TC1, Treatment Week 2)
The patient is to be contacted by phone and the following are to take place:

Record AEs

Reinforce compliance

Confirm that patient has titrated drug in accordance with the dosing schedule 
on Table 3
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Document tolerability/intolerability to study drug and decision to continue dose 
titration/maintenance following the dosing schedule of Table 3

Discontinue study medication in patients who could not tolerate 30 mg BID dose 
and complete the End of Treatment Visit, TV14 (See Section 9.6.2.2.12 and Section 
11)
9.6.2.1.2 TV 2 (Treatment Week 3)
The following procedures are to take place at this visit:

obtain vital signs

collect urine for pregnancy (must be confirmed negative prior to dispensing study 
drug)

collect blood for PK

perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

perform brief neurological assessment

administer PRO measurements:
o
Worst itch NRS
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS.
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual).

record AEs (including tolerability to study drug)

review 
concomitant 
medications, 
including 
over-the-counter 
medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform Study Drug accountability, retrieve previously dispensed Study Drug

dispense the Study Drug to the patient required until return at TV3 (Treatment 
Week 5)

Document tolerability/intolerability to study drug and titration decision based 
on Table 3

Discontinue study medication in patients who could not tolerate 30 mg BID dose 
and complete the End of Treatment Visit, TV14 (See Section 9.6.2.2.12 and Section 
11)
9.6.2.1.3 Telephone Contact Number 2 (TC2, Treatment Week 4)
The patient is to be contacted by phone and the following are to take place:

record AEs
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reinforce compliance

instruct the patient on dose titration/maintenance based on Table 3

patients reporting intolerable side effects at their current dose should titrate down to 
a tolerable preceding dose and this should be record as the patient’s maintenance 
dose

patients at any dose who reported intolerable AEs for the previous week (Week 3 
on drug) and continue to report intolerable AEs on this visit, should be discontinued 
from study drug and scheduled for the End of Treatment Visit, TV14 (See Section 
9.6.2.2.12 and Section 11)
9.6.2.2
Treatment Period Weeks 5-50
During this period of the study, the patient continues on the maintenance dose established 
by the end of Treatment Week 4 for the remainder of the study with the exception of two
allowable dose reductions permitted during Treatment Weeks 5 – 50 (e.g., a patient at 90 
mg BID can be reduced to 60 mg BID and then subsequently to 30 mg BID). If a third
dose reduction is needed, the patient should be discontinued from the study (See Table 
3, Section 9.6.2.2.12 and Section 11). Patients who are on the 30 mg BID dose will be 
discontinued if a dose reduction is required.
See Table 6 for the Schedule of Events for Treatment Weeks 5-50.
9.6.2.2.1
TV 3 (Treatment Week 5)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve criteria, perform the following 
procedures

obtain vital signs

collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform 12-Lead ECG after at least 5 minutes in a supine position (See the
Study Reference Manual for ECG procedures, section 17.4 Electrocardiograms 
for the handling of Cardiovascular adverse events)

perform brief neurological assessment

administer PRO measurements:
o
Average itch intensity NRS
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o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense the study drug to the patient required until the next Treatment Visit
9.6.2.2.2
TV 4 (Treatment Week 9)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform 12-Lead ECG after at least 5 minutes in a supine position (See the
Study Reference Manual for ECG procedures, section 17.4 Electrocardiograms 
for the handling of Cardiovascular adverse events)

perform brief neurological assessment

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).
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record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed Study Drug

dispense study drug required until the patient returns for the next Treatment 
Visit
9.6.2.2.3
TV 5 (Treatment Week 13)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform 12-Lead ECG after at least 5 minutes in a supine position (See the
Study Reference Manual for ECG procedures, section 17.4 Electrocardiograms 
for the handling of Cardiovascular adverse events)

perform brief neurological assessment

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense the study drug to the patient required until the next Treatment Visit
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9.6.2.2.4
TV 6 (Treatment Week 17)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform 12-Lead ECG after at least 5 minutes in a supine position (See the
Study Reference Manual for ECG procedures, section 17.4 Electrocardiograms 
for the handling of Cardiovascular adverse events)

perform brief neurological assessment

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense the study drug to the patient required until the next Treatment Visit
9.6.2.2.5
TV 7 (Treatment Week 21)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
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o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform 12-Lead ECG after at least 5 minutes in a supine position (See the
Study Reference Manual for ECG procedures, section 17.4 Electrocardiograms 
for the handling of Cardiovascular adverse events)

perform brief neurological assessment

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability,

retrieve previously dispensed Study Drug

dispense the study drug to the patient required until next Treatment Visit 
9.6.2.2.6 TV 8 (Treatment Week 26)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs
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perform physical examination

perform brief neurological assessment

complete the PAS

perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

collect urine for pregnancy test (must be confirmed negative prior to dispensing 
study drug)

collect urine for urinalysis for central lab

collect blood for central laboratory (hematology and chemistry) and for PK

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense study drug to the patient required until the next Treatment Visit
9.6.2.2.7 TV 9 (Treatment Week 30)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DID NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy (must be confirmed negative prior to dispensing 
study drug)
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collect blood for PK

perform brief neurological assessment

perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense the study drug to the patient required until the next Treatment Visit
9.6.2.2.8 TV 10 (Treatment Week 34)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform brief neurological assessment

perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)
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administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense the study drug to the patient required until the next Treatment Visit
9.6.2.2.9 TV 11 (Treatment Week 38)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform brief neurological assessment

perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
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o
HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense the study drug to the patient required until the next Treatment Visit
9.6.2.2.10 TV 12 (Treatment Week 42)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform brief neurological assessment

perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 
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review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug

dispense the study drug to the patient required until the next Treatment Visit
9.6.2.2.11 TV 13 (Treatment Week 46)
The following procedures are to take place at this visit:

Administer the Worst Itch NRS and evaluate against the Failure-to-Improve criteria 
(see Section 11.1)

For patients who MEET the Failure-to Improve criteria
o
Stop study medication
o
Perform End of Treatment Visit (TV14) procedures

For patients who DO NOT meet Failure-to-Improve perform the following 
procedures

obtain vital signs

collect urine for pregnancy (must be confirmed negative prior to dispensing 
study drug)

collect blood for PK

perform brief neurological assessment

perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

reinforce compliance

perform study drug accountability, retrieve previously dispensed study drug
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dispense the study drug to the patient required until the next Treatment Visit
9.6.2.2.12 TV 14 (End of Treatment Visit)
This visit applies to all patients who completed TV13; including patients who met Failure-
to-Improve criteria at any Treatment Visit during the study.
For patients who DID NOT meet Failure-to-Improve criteria during the conduct of the 
study, this visit (TV14) takes place after the patient has completed study medication.   

For patients who entered the Treatment Period at Visit 1a, TV14 would take place 
during week 51; four (4) weeks after TV13, as these patients should complete 50
weeks of treatment prior to TV14

For patients who entered the Treatment Period at Visit 1b see Table 8 for 
information on when TV14 is to take place
The following procedures are to take place at this visit:

obtain vital signs

perform physical examination

perform brief neurological assessment

complete the PAS

perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

collect blood for central laboratory (hematology and chemistry) and serum 
pregnancy test for central laboratory

collect urine for urinalysis at the central laboratory

collect blood for PK

at select sites only, perform skin biopsy (optional).  Obtain 3 samples (i.e., H&E, 
nerve fiber density (histology) and MOR/KOR density (histology, Western Blot)); 
see the Lab and Study Reference Manuals for details

administer PRO measurements:
o
Worst itch NRS
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
o
SOWS
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual).

record AEs 
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review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

perform study drug accountability, final retrieval of any dispensed study drug

retrieve the Dosing Diary

Dispense the 14 Day SOWS packet, instruct the patient on how to complete the 
scales and to complete the scales daily for 14 days

Schedule the patient for the Washout and Safety Follow-up Period Visit
9.6.3
Observation Period (Extended Screening Weeks 1-12)
Only patients with Visit 1a Worst itch NRS score of less than 5 (<5) (Visit 1a for these 
patients is considered OV1) should enter the Observation Period, which includes 
subsequent study visits OV 2-4 at approximately one month intervals over the next 12 
extended screening weeks (See Table 7). While patients remain in the Observation Period, 
they will not be considered enrolled into the study, but as participating in an extended 
screening process until they are eligible for enrollment. Patients evaluated at OV 2-4 and 
who record Worst itch NRS greater than or equal to 5 (), and are otherwise eligible, can 
immediately begin Visit 1b and transition into the Treatment Period.
For these patients, the sum of time in the Observation Period and Treatment Period will not 
exceed 50 weeks. As a result, both the Observation Period and Treatment Period will 
differ in length for different patients.  To ensure that the total number of study weeks does 
not exceed 50 weeks, that all patients complete proper titration of study drug up to the 
assessment of TV 2 during Treatment Week 3, and that the final Treatment Period visit is 
always TV14, see Table 8 for visit details. As such, visits during this period are not 
equivalent to Treatment Weeks.  During the Observation Period, patients are participating 
in Extended Screening Weeks.
9.6.3.1
Observation Visit 2 at Extended Screening Week 4 and Observation Visit 3 at 
Extended Screening Week 8
The following procedures are to take place at this visit:

administer the Worst itch NRS
o
If the Worst Itch NRS is less than 5 (<5), perform the following Observation 
Visit procedures at any time during the visit  

obtain vital signs

record AEs

record concomitant medications
o
If the Worst Itch NRS 
			transition the patient 
to the Treatment Period and conduct Visit 1b procedures (described 
in Section 9.6.4) on the same day as this visit.  See Table 8 for a summary 
related to future Treatment Period Visits.
9.6.3.2
Observation Visit 4 at Extended Screening Week 12
The following procedures are to take place at this visit:
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administer the Worst itch NRS
o
If Worst Itch NRS is less than 5 (<5), perform the following Observation 
Visit procedures at any time during the visit  

obtain vital signs

administer the following

Average itch intensity NRS

VRS

ItchyQoL

MOS Sleep-R

HADS

record AEs

record concomitant medications
o
If the Worst Itch !"#
			transition the patient 
to the Treatment Period and conduct Visit 1b procedures (described 
in Section 9.6.4) on the same day as this visit.  See Table 8 for a summary 
related to future Treatment Period Visits.
Patients whose Worst Itch NRS is less than 5 (<5) at the OV4 should be screen failed from 
the study. No Washout/Safety follow-up visit is to take place.
9.6.3.3
Transitioning from the Observation Period to the Treatment Period 

For patients who have a Worst NRS score that is greater than 	) at 
Observation Visit 2, 3, or 4, complete Visit 1b procedures (see Section 9.6.4).

These patients will receive up to 46 weeks of study medication treatment.

See Table 8 for the Treatment Period Visits to be completed post Visit 1b, as well 
as the number of weeks of study drug to dispense at each Treatment Visit and when 
to schedule the End of Treatment Visit 14, TV14, to take place.

See Section 9.6.2 and the Schedule of Events (Appendix 1) for procedures to be 
performed at each applicable Treatment Visit.
9.6.4
Transition to Treatment Period (Visit 1b)
Confirm each patient’s eligibility (see Sections 8.2 and 8.3) prior to performing any Visit 
1b procedures.  If the patient does not meet eligibility requirements, do not perform any 
Visit 1b procedures; the patient is to be screen failed.
See Table 4 for summary of Visit 1b procedures.
Patients evaluated at OV 2-4 who record a Worst itch NRS greater than or equal to 5 ()
and, are otherwise eligible, can immediately begin Visit 1b.  This patient then transitions 
into the Treatment Period and will undergo the following procedures:

obtain vital signs

conduct a physical examination 

collect central laboratory samples (hematology and chemistry)
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collect serum pregnancy sample in women of childbearing potential (done at the 
central laboratory)*

collect urine for central lab urinalysis

urine for pregnancy (must be confirmed negative prior to dispensing study drug)*
* If the urine pregnancy test result is negative and the serum pregnancy test result is 
positive, the patient is to be contacted and the following actions are to take place:

instruct the patient to discontinue taking study drug

schedule the patient for an unscheduled visit to collect another serum 
pregnancy test 
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment.  See section 17.5.2.1 regarding how pregnancies 
are to be handled in this study.

obtain blood for PK

Perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

administer PRO measurements:
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS
o
PBI-P
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

complete the PAS

dispense Study Drug to the patient required until return at Treatment Visit 2, TV2

instruct patients to self-administer the first dose on the evening of Visit 1b at home 

instruct patients to notify the Investigator if any significant CNS AEs occur, and not 
to drive or operate dangerous machinery until the effect of the Study Drug can be 
assessed by the Investigator, see Section 9.3

all patients should be instructed to titrate to their most tolerated dose.  See Table 3
Drug Dosing Schedule for more information.  Here is the recommended Week 1 
titration schedule for patients who tolerate study drug:
Day 1(the first day that study drug is dispensed to a patient on treatment): No
dose in the AM and 30 mg in the PM
Day 2: No dose in the AM and 30 mg in the PM
Day 3: 30 mg in the AM and 30 mg in the PM
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Day 4: 30 mg in the AM and 30 mg in the PM
Day 5: 30 mg in the AM and 60 mg in the PM
Day 6: 60 mg in the AM and 60 mg in the PM
Day 7: 60 mg in the AM and 60 mg in the PM

Instruct patients to bring all remaining Study Drug to the dialysis unit for each 
subsequent treatment period study visits.

If a patient misses 3 or more consecutive doses, contact the Medical Monitor.
The next study visit will be Treatment Visit 2 (TV2).  However, to ensure that the total 
number of study weeks does not exceed 50 weeks, that all patients complete proper 
titration of study drug and that the End of Treatment Visit is always TV14, see Table 8 for 
more information.
The next visit will be Treatment Visit 2 (Section 9.6.2.1.2). See Appendix 1, Schedule of 
Event and Table 8 for the Treatment Visit Schedule for Patients Entering Treatment via 
Visit 1b. 
9.6.5 Washout and Safety Follow-Up Period 
All patients who received Treatment, but did not withdraw consent, will have a 2-week 
Washout and Safety Follow-Up Period following TV14.  During this visit, the PRO 
questionnaires must be administered at the study site under the supervision of and by 
trained study staff, strictly adhering to PRO Administration Instructions (see Study 
Reference Manual). Please see the Schedule of Events in Appendix 1 for details of the 
Washout and Safety Follow-Up Period assessments. Additional information for this visit is 
provided below.
For patients who entered the Treatment Period at Visit 1a, the Washout and Safety Follow-
Up Period Visit would take place during week 53, post TV14. However, for a patient who
enters the Treatment Period at Visit 1b, the Washout and Safety Follow-up Period Visit 
will take place 14 days (plus the visit window) post TV14.
For patients who met Failure-to-Improve criteria or who discontinue treatment for other 
reasons (see Section 11.1), this visit is to take place 14 days (+ 7 days) after TV14.
The following procedures are to take place at this visit:

obtain vital signs

perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

perform brief neurological assessment

collect blood for central laboratory measurements and PK

administer PRO measurements:
o
Worst itch NRS
o
Average itch intensity NRS
o
VRS
o
ItchyQoL
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o
MOS Sleep-R
o
HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual).

AEs and concomitant medications (including rescue medications) will be recorded

collect the Rescue Medication Log will be collected from the patient at this visit

retrieve any remaining study drug not previously returned by the patient

retrieve the 14 day SOWS packet
For patients who prematurely discontinued study medication for reasons other than 
withdrawal of consent, schedule the Premature Discontinuation of Study Drug Follow-up
Telephone Contact visit.  
9.6.6
Premature Discontinuation of Study Drug Follow-up Telephone 
Contact Visit
Patients who prematurely discontinued study drug during the study, for reasons other than 
withdrawal of consent, will have completed TV14 and the Washout and Follow-up Safety 
Period Visit.  These patients are to be contacted by telephone 30 days (+ 2 weeks) after the 
visit that the patient met the Failure-to-Improve criteria and stopped medication.
During this Telephone Contact, record AEs and changes in concomitant medications since 
the completion of the Washout and Follow-up Safety Period Visit.
Document any additional efforts that take place to reach a patient who is non-responsive to 
telephone contact.  
9.6.7
Early Termination Visit for Patients who Withdraw Consent
Patients may withdraw consent from the study at any time.  However, if feasible for the 
patient, the following procedures should take place as part of an Early Termination Visit:

obtain vital signs

perform physical examination

complete the PAS

perform brief neurological assessment

collect blood for central laboratory (hematology and chemistry) and serum 
pregnancy test at the central laboratory

collect blood for PK

Perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events)

collect urine for urinalysis at central lab

administer PRO measurements:
o
Worst itch NRS
o
Average itch intensity NRS
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o
VRS
o
ItchyQoL
o
MOS Sleep-R
o
HADS 
o
SOWS
o
PBI-P
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual).

record AEs 

review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 

perform study drug accountability, final retrieval of any dispensed study drug
9.6.8
Unscheduled Visits
If a patient needs to be evaluated in relation to the study on a day other than one of the 
study visit days, that day will be considered an Unscheduled Visit. The reason for each 
unscheduled visit will be recorded and the following procedures will be performed: vital 
signs (BP, HR, RR, temperature), assessment for AEs, review of concomitant medications
(including rescue medications), and Study Drug accountability. Additional procedures 
such as central or local laboratory sample collection may also take place, if clinically 
indicated. All unscheduled visits will be recorded on the Unscheduled Visit CRF.
9.6.9
Schedule of Events
The Schedule of Events is shown in Appendix 1 and is described in Section 9.6.
9.7
STUDY DRUG TREATMENT AND DRUG ACCOUNTABILITY
Please see the Study Reference Manual for additional information on Study Drug supplies, 
packaging, storage, dispensation, and accountability.
9.7.1
Study Drug Dosing
Following enrollment, the patient will receive 30 mg open-label tablets. At each visit at 
which study drug is to be dispensed, enough study drug should be supplied to ensure a 
sufficient number of tablets until the next visit plus an additional 8 tablets to allow for visit 
windows and/or possibility of a missed visit. Bottles can be re-dispensed, as appropriate.
Study drug can be taken with or without food.  Patients will be instructed to take the AM 
and PM Study Drug tablets at the same times of the day, approximately 12 hours apart,
preferably with 240 mL (approximately 8 ounces) of water. If the patient does not take a 
particular dose at the planned time he or she may take it up to 2 hours later. For example, 
if a patient is taking the Study Drug at 9 AM and 9 PM but forgets to take the 9 AM dose, 
he may take the 9 AM dose as late as 11 AM. After that time, the patient should skip the 9 
AM dose and, instead, take the regularly scheduled next dose at 9 PM.
The first dosing day will be on either Visit 1a or Visit 1b.  Titration will be based on
tolerability. If the patient is experiencing a study-drug related AE or an AE that may be 
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aggravated by study drug uptitration, the study drug dose should not be increased,
regardless of the NRS score.
The Study Drug will be titrated during the Treatment Weeks 1 - 4, according to the 
schedule in Table 3 to a final dose of 30 mg BID up to 180 mg BID. The dosing for 
Treatment Week 1 is further described in Section 9.6.1 (Visit 1a) and Section 9.6.4 (Visit 
1b).
Patients will titrate to tolerability beginning with a 30 mg dose on Day 1 (Visit 1a or Visit 
1b) with a dose increase of 30 mg BID not more often than every 3 to 4 days in order to 
attain steady-state plasma concentrations of nalbuphine at each dose.
The achieved dose attained as of the end of Treatment Week 4 will be maintained 
throughout the rest of the Treatment Period. This dose will be defined as the patient’s 
“maintenance dose”. A single dose reduction or dose hold per patient is permitted during 
Treatment Period at the investigator’s discretion. If subsequent dose reductions or dose 
interruptions are needed, the Medical Monitor must be contacted. The duration of any dose 
hold must be discussed with the Medical Monitor.
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Table 3:
Dosing Schedule for TR03ext
Week of 
Treatment 
Period1
(TV or TC)
Day
Drug Tolerance
Discontinuation 
Acceptable
Unacceptable3
Week 1
(TV1/Visit1a
/1b)
TC#1
1
30 mg (PM dose)
--
2
0 mg (AM dose)
30 mg (PM dose) 
--
3-4
30 mg BID
5-7
Titrate patients to tolerability with 
dose increases of 30 mg BID.
Maintain dose for at least 3 to 4 
days up to next dose level
Reduce dose 
incrementally by 30 
mg
NA
The highest possible titration dose by the end of Treatment Week 1 is 60 mg BID
Week 22
1-7
Continue incremental increase in 
dose and maintaining at each dosed 
level for 3 to 4 days
Reduce dose 
incrementally by 30 
mg
If 30 mg BID is not 
tolerated within 
one week, 
discontinue subject
The highest possible titration dose by the end of Treatment Week 2 is 120 mg BID
Week 32
1-7
Continue dose increase
Reduce dose by 30 mg 
BID and maintain 
If 30 mg BID is not 
tolerated within 
one week, 
discontinue subject
The highest possible titration dose by the end of Treatment Week 3 is 180 mg BID
Week 42
(TC#2)
1-7
Maintain dose at highest dose level 
reached on Week 3 Day 7
Reduce dose reached 
on Week 3 Day 7
by either 30 or 60 mg 
and maintain
NA
Treatment 
Week 54 up
to Treatment 
Week 50
(TV3-TV 14)
1-7
Maintain dose from Week 4 
through TV145,6
Patient may down 
titrate twice over 
remaining duration of 
study 
Patient 
discontinued if a 
3rd time down-
titration is needed.
1The decision to enter the patient into the Titration Period is based on Worst Itch NRS score NRS  obtained from the 
patient on Visit 1a or 1b
2The titration decision will be made based on tolerance to study drug
3Tolerance level is unacceptable to either the patient and/or investigator.
4 The number of Treatment Weeks prior to TV 14 will vary for patients previously in the Observation Period depending 
upon the number of weeks spent in the Observation Period.  See Table 8
5The achieved dose attained as of the end of Treatment Week 4 will be maintained throughout the rest of the Treatment 
Period.  This dose will be defined as the patient’s “maintenance dose”. Two dose reductions to the next lower allowed 
dose are permitted during Treatment Weeks 5 – 50 (e.g., a patient at 90 mg BID can be reduced to 60 mg BID).  If a third
dose reduction is needed, the patient should be discontinued from the study.
6 Beginning on TV 3 and at every subsequent Treatment Visit, patients with a Worst !"#Worst itch NRS at 
Visit 1a (or at Visit 1b in the case of patient who require the OV period) will be discontinued from study drug, complete the 
End of Treatment Visit 14, the Washout and Safety Follow-up Period and Visit, and a Telephone Contact Visit 30 days 
after the last dose of study drug.
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9.7.2
Down-Titration
Down-titration is not permitted except as discussed in Section 9.7.1.
9.7.3
Multiple Missed Doses
If a patient misses multiple doses of the Study Drug, please follow the procedures below.
In no case should patients take additional doses of Study Drug to make up for missed 
doses.  If Study Drug is re-started after missed doses, the patient should be instructed to 
take Study Drug from the tablets designated for the visit during which Study Drug is being 
re-started rather than from the visits during which Study Drug doses were missed.

During the Titration Period
If a patient misses 3 (or more) consecutive doses, please contact the study Medical 
Monitor.

During the Stable Dose Period
If a patient misses 6 (or more) consecutive doses, please contact the study Medical 
Monitor. If authorized by the Medical Monitor, patients who miss more than 6 consecutive 
doses may be allowed to continue on study. In such situations, patients should receive the 
Study Drug only once daily (i.e., the AM or PM dose only) for the first 3 days before 
returning to the full (BID) target dose.
9.7.4
Overdose 
The effects of nalbuphine may be reversed with opioid antagonists such as naloxone.
Please see Guidance to the Investigator section of the Investigator Brochure for additional 
information.
9.7.5
Treatment Compliance
Returned study drug tablets will be used to assess compliance at each visit. Medication 
compliance will be recorded on the CRF for each designated visit (See Appendix 1).
Patient compliance with the study dosing schedule will be assessed as part of the planned 
study analyses.
9.7.6
Rescue Medications, Concomitant Medications, Prohibited 
Medications, and Pre-Medications
9.7.6.1
Rescue Medications
A secondary objective of the study is to quantitate the number of days of rescue medication 
use for itching during the course of nalbuphine HCl ER treatment.  Rescue medications 
will be defined as those drugs, when used for the purpose of treating itch, that were 
required to be washed out prior to entry into TR03 (See Table 9).  For the purposes of this 
study, any UV light treatment received will also be defined as a rescue medication.
If a medication is prescribed for chronic anti-pruritic use of greater than 2 weeks, the 
subject should be discontinued (see Section 11.2).
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9.7.6.2
Concomitant Medications
Any medication taken by a patient following the signing of informed consent during the 
course of the study and the reason for use of the medication will be recorded on the case 
report form (CRF). Each patient will be instructed to report the use of all medication to the 
Investigator, including over-the-counter [OTC] medications, herbal medications, vitamins, 
and nutritional supplements.  Patients will also be instructed about the importance of not 
taking any new medications during the study (including OTC medications) without 
consulting the Investigator.
9.7.6.3
Prohibited Medications
Initiating use of opiate medications during the study should be done with caution with 
assessment of the patient for potential additive opiate AEs. If an enrolled patient requires 
daily treatment with opioid medications during the study (e.g., for post-surgical pain), 
please contact the Medical Monitor. Use of acetaminophen, non-steroidal anti-
inflammatory medications, and aspirin is permitted. If an opioid medication is introduced 
in anticipation for chronic use of greater than 2 weeks, the subject should be discontinued.
Concomitant use of opioid antagonists (e.g. naloxone, naltrexone) are also prohibited
during the study, unless required for urgent reversal of opioid adverse effects or opioid 
overdose.
Use of all other investigational drugs are prohibited during the study. A subject who 
initiates an investigational drug during the study should be discontinued.
If the patient is prescribed a medication(s) included on the list of those with a known risk 
of Torsade de Pointes (see Section 9.7.8, Safety Assessments, for hyperlink to the 
CredibleMeds Filtered QTDrug List for cardiovascular related prohibited medications with 
a known associated risk of Torsade de Pointes), contact the Medical Monitor.
9.7.6.4
Pre-Medications
Nalbuphine use may be associated with nausea, vomiting, and/or constipation, particularly 
as the dose is escalated or upon initiation of treatment. At the Investigator’s discretion, 
anti-emetics such as ondanestron may be administered prophylactically, prior to taking the 
Study Drug or, as needed, for treatment. Dietary and other prophylactic measures to avoid 
constipation should also be considered as clinically indicated (see Section 9.7.8, Safety 
Assessments, for hyperlink to the CredibleMeds Filtered QTDrug List for cardiovascular 
related prohibited medications with a known associated risk of Torsade de Pointes).
9.7.7
Efficacy Assessments
The below PRO instruments will be administered at the site at the site and under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual) according the Schedule of Events  
(see Appendix 1).
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9.7.7.1
Numerical Rating Scale (NRS)
The NRS is a patient-reported outcome instrument, designed to quantify the intensity of 
worst itching experienced during a 24-hour period. The scale is a set of boxes, one for 
each number, from 0 (no itching) to 10 (worst possible itching). The NRS is a widely used
instrument recommended by IFSI for quantifying itch intensity as well as a useful 
instrument for grouping patients into categories of itch intensity described as mild,
moderate or severe (Stander et al 2013). The itch NRS has been investigated in patients 
with chronic pruritus of a variety of origins and has a high reliability and concurrent 
validity was found (Phan et al 2012). 
In this study, patients will be asked to record two NRS values: 

rate itching on average over the past 24 hours

rate worst itching over the past 24 hours
This instrument can be found in Appendix 4.
9.7.7.2
Verbal Rating Scale (VRS)
The VRS scale to be used in this study has three dimensions, each dimension coded with 
graduated adjectives (from 0 = none; to 5 = very severe) for the skin sensations of itchy,
burning and stinging. 
In this study, patients will be asked to record the VRS value:

How is your skin sensation today?
This instrument can be found in the Appendix 4.
9.7.7.3
Hospital Anxiety and Depression Scale (HADS)
The HADS instrument includes 14 multiple-choice questions, each with 4 possible choices,
scored between 0 and 3. This instrument can be found in Appendix 4.
9.7.7.4
ItchyQoLTM
The ItchyQoLTM consists of 22 pruritus-specific items measuring how pruritus affects 
patients’ QOL in the area of symptoms related to the itch condition (6 questions),
functional limitations (7 questions), and emotions (9 questions). The subject scores each 
question never =1, rarely=2, sometimes=3, often=4, all the time=5. The instrument can be 
found in Appendix 4.
9.7.7.5
Medical Outcomes Sleep Scale –Revised (MOS Sleep-R)
MOS Sleep Scale-R measure is a 12-item self-report sleep measure that was developed to 
assess sleep quality and quantity. It is a multi-dimensional assessment of sleep parameters 
with scoring results in six subscales or domains: sleep disturbance (4 items), snoring (1 
item), awaken short of breath or with headache (1 item), quantity of sleep (1 item), optimal 
sleep (1 item), sleep adequacy (2 items), and daytime somnolence (3 items). 
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Additionally, a 9-item Sleep Problems Index (“Sleep Problem Index I”) can be generated 
which assesses overall sleep problems that includes the 4 sleep disturbance and the 2 sleep 
adequacy items, 2 of the somnolence items, and awakening short of breath/headache; 
higher scores indicate greater sleep impairment, and this index is often used in clinical 
trials as an indication of sleep quality. The instrument can be found in Appendix 4.
9.7.7.6
Patient Benefit Index (PBI-P)
The PBI-P questionnaire assesses the importance of treatment objectives to the individual.
Before and at the end of drug treatment in this study, the patient completes the same 
questionnaire and rates the extent to which the treatment objectives have been achieved.
The instrument consists of 27 multiple choice questions that can be answered “not at all”, 
“somewhat”, “moderately”, “quite” and “very”. The instrument can be found 
in Appendix 4.
9.7.7.7
Prurigo Activity Score (PAS)
The PAS consists of 7 quantitative and quantitative measurements related to the 
examination of the skin.  Type, number, distribution, affected body parts, and quantitative 
number of lesions in a representative body part are documented.  The biggest lesion and the 
most representative lesion are monitored with documentation of height and area 
measurements. Prurigo lesion activity is recorded as a percentages based on their stage (0-
4).  Photographs of the body are conducted with monitored lesions marked. The instrument 
can be found in Appendix 4. Please see the Study Reference Manual for instructions for 
obtaining and storing photographs collected in conjunction with the PAS.
9.7.7.8
Exploratory Histological Endpoints (optional)
Punch biopsy skin material for measurement of routine histology (H&E), nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot) analysis was obtained 
during TR03 (optional procedure at select sites).  Punch biopsy may be obtained (optional 
at select sites) at Visit 1a/1b and End of Treatment Visit of TR03ext for a comparative 
analysis with the results of the histological results of pre-dosing TR03 and end of study 
TR03 results.
9.7.7.8.1 MOR/KOR density and Nerve Fiber Density
The potential of nalbuphine HCl ER tablets to impact on the Measurement of nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot) in skin biopsies taken 
at Baseline visit and the Evaluation visit will be investigated at select sites.
In addition to skin biopsy tissue obtained prior to drug treatment for H&E and analysis by a 
central reading dermatopathologist, at select sites additional skin biopsy material obtained 
before and at the end of drug treatment will be compared to investigate, in an exploratory 
manner, any evidence of change in expression of MOR and KOR and nerve fiber density in 
relation to any noted changes in clinical study endpoints. 
Bigliardi et al (2007) reports that in normal skin, keratinocytes express high amounts of 
MOR and it is therefore concluded that endogenous ligands are bound primarily to opioid 
receptors on keratinocytes and thus the endogenous opiate ligands are not binding to opioid 
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receptors located on nerve endings –the net result is at most a weak itch signal to the 
central nervous system in the normal state. In chronic pruritic skin disorders, most opioid
receptors on keratinocytes are reported as internalized; therefore there are many opioid 
ligands available to bind to opioid receptors on sensory nerve endings. This state leads, 
together with the changed morphology of the epidermal nerve endings, to a strong itch 
signal to the CNS. The authors reported that topical administration of the opioid mu 
receptor antagonist naltrexone in subjects with atopic dermatitis, lichen simplex chronicus 
or prurigo simplex showed an antipruritic effect.  In addition, there was also an 
upregulation of epidermal MOR expression following two weeks of treatment, but no 
MOR upregulation in subjects who did not experience an antipruritic response. Bigiliardi 
and Bigliardi-Qi (2004) reported that in PN human skin tissue samples there was a down 
regulation of the mu-opiate receptor (MOR) expression in the epidermis compared to 
normal skin.  
Bigliardi-Qi et al (2009) reports that while it is widely accepted that KOR signaling 
suppresses itch, there is currently no animal, behavioral or human data relating the 
regulation of skin KOR expression to pruritus. Salemi et al 2007 however reported high
upregulation of KOR in the skin of fibromyalgia subjects that was thought to correlate with 
reported complaints of pain symptoms.
With regard to peripheral sensory nerve fiber density in the skin, Bigliardi et al (2009, 
2007) report that epidermal nerve endings of pruritic skin in prurigo are thinner when 
compared to normal skin.  In addition, the nerve fibers have a different morphology which 
may relate to initiating the sensation of pruritus because of the altered anatomical 
relationship to the various cellular elements of the skin.  
9.7.7.8.2
Routine histology (H&E) and immunohistochemical examination of 
inflammatory cells and pro-inflammatory mediators
Weigelt et al (2010) summarized the characteristic histological pattern in PN that include 
the presence of thick compact orthohyperkeratosis; folliculosebaceous units in nonvolar 
skin in conjunction with a thick and compact cornified layer; irregular epidermal 
hyperplasia or pseudoepitheliomatous hyperplasia; focal parakeratosis; hypergranulosis; 
fibrosis of the papillary dermis with vertically arranged collagen fibers; increased number 
of fibroblasts and capillaries; a superficial, perivascular and/or interstitial inflammatory 
infiltrate of lymphocytes, macrophages and, to a lesser extent, eosinophils and neutrophils.
While the skin biopsy from PN patients is reported to show a composite pattern of 
dermatopathologic findings, the condition is not defined internationally by a Dermpath 
expert board. Thus the biopsy obtained at the Baseline Visit and Evaluation Visit will be 
analyzed as an exploratory endpoint by a central dermatopathologist for histological review 
investigating possible correlation of pre-existing histopathological findings (i.e., level of 
inflammation, etc.) with any subsequent clinical response noted on drug
9.7.8
Safety Assessments
As summarized in Section 6.2.7 of the Investigator Brochure, the CNS has been identified 
as the only target organ when nalbuphine was given to animals at high doses.  In addition, 
the most frequently reported adverse events reported in the nalbuphine HCl ER tablet 
dosing studies were primarily in the nervous system and gastrointestinal organ system 
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categories.  In order to monitor any potential CNS related side effects, a brief neurological 
assessment will be conducted at each study visit as well as a focused neurological medical 
history will be obtained at screening.
Safety will be determined by evaluation of the following:

AEs

Vital signs including weight, BP, heart rate (HR), respiratory rate (RR), and body 
temperature

Physical examination 

Clinical laboratory data (see Appendix 3 for list of analytes)

Investigator reviewed ECG and central cardiac core laboratory read 12 Lead-ECG,
cardiovascular grading, and/or cardiovascular related prohibited medications

Subjective Opiate Withdrawal Scale (SOWS)
The SOWS is a self-administered scale for grading opioid withdrawal symptoms. It 
contains 16 symptoms whose intensity the patient rates on a scale of 0 (“not at all”) to 4 
(“extremely”). The instrument can be found in Appendix 4.  In this study, patients will 
complete SOWS daily, starting at TV14, End of Treatment Visit through to the
Washout and Safety Follow-up Period Visit. The SOWS will also be completed at the 
Early Termination Visit. As with all subjects who are discontinued from study drug, 
the patient will complete a daily SOWS scale for the two weeks following the last dose 
of study drug.  The SOWS is a self-administered scale for grading opioid withdrawal 
symptoms. If the subject is experiencing any symptoms on the SOW scale to a 
moderate degree, the subject will be instructed to contact the site.  If a subject is 
determined to be experiencing significant subjective withdrawal symptoms (at the
Investigator’s discretion), the subject will be offered treatment.
The following will be used to assess patient eligibility to continue participation if the 
patient experiences CHF, angina pectoris and/or other cardiovascular exclusion criteria 
(see Section 8.3 for the Exclusion Criteria and Appendix 5 for the grading scales)

The Canadian Cardiovascular Society grading of angina pectoris assessment:  
The Canadian Cardiovascular Society grading of angina pectoris (sometimes 
referred to as the CCS Angina Grading Scale or the CCS Functional 
Classification of Angina) is commonly used for the classification of severity of 
angina

The New York Heart Association (NYHA) Functional Classification:  The New 
York Heart Association Function Classification provides a simple way of 
classifying the extent of heart failure by placing patients in one of four 
categories based on how much they are limited during physical activity; the 
limitations/symptoms are in regard to normal breathing and varying degrees in 
shortness of breath and/or angina pain.
CredibleMeds Filtered QTDrug [List: Known Risk of TdP]:  Cardiovascular related 
prohibited medications are provided on the CredibleMeds Filtered QTDrug List.
Drugs are placed into one of four risk categories based on their relative potential to 
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alter the electrocardiogram (QT prolongation) and/or cause life-threatening ventricular 
arrhythmias. See the following link to the CredibleMeds Filtered QTDrug List for 
cardiovascular related prohibited medications with a known associated risk of Torsade 
de Pointes:  https://www.crediblemeds.org/
10 STUDY DRUG
Please see the Study Reference Manual for additional information on Study Drug supplies, 
packaging, storage, dispensation, and accountability.
10.1 FORMULATION, PACKAGING AND LABELING
The Study Drug in this trial is nalbuphine HCl ER tablets. Nalbuphine HCl ER tablets are 
white to off white film-coated round tablet containing either 30 mg or 60 mg nalbuphine 
HCl. 
All study medication will be supplied by the Sponsor. Following confirmation of 
eligibility to start the Treatment Period, the patient will receive bottles of study drug tablets
containing 60 tablets each. Bottles will be labeled with at minimum: contents, storage 
conditions, expiration date, clinical trial statement, and the name and lot number of the 
study drug Sponsor (Trevi Therapeutics).
10.2 SHIPPING, STORAGE AND HANDLING
The Investigator will ensure that the Study Drug is stored and dispensed in accordance with 
ICH QE6(R1) (Guideline for Good Clinical Practice) and EU Clinical Trial Directive and 
Annex13 regulations concerning the storage and administration of investigational drugs.
Nalbuphine HCl ER tablets and placebo tablets should be stored at 20°C-25°C (68°F-77°F) 
with excursions permitted between 15°C and 30°C (59° to 86°F). The storage conditions 
were established following ICH Q1A(R2) (Stability testing of new drug substances and 
drug product) and the CHMP Guideline CPMP/QWP/122/02, rev 1 corr CHMP Guideline ( 
Stability Testing of existing active substances and related Finished products) for 
assessment and provision of appropriate labelling and storage conditions.
The Study Drug will be stored away from any extreme conditions of temperature, light, or 
humidity as an additional precaution
In the EU, the investigational medicinal products will remain under the control of the 
sponsor until after completion of a two-step procedure: certification by the Qualified 
Person; and release by the sponsor for use in a clinical trial following fulfillment of the 
requirements of Article 9 (Commencement of a clinical trial) of Directive 2001/20/EC.
Both steps will be recorded and retained in the relevant trial files held by or on behalf of 
the sponsor.
10.3 UNBLINDING
Not applicable.  This is an open-label study.
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10.4 DRUG ACCOUNTABILITY
The Investigator must ensure that all drug supplies are kept in a secure locked area with 
access limited to those authorized by the Investigator.  The Investigator must maintain 
accurate records of the receipt of all Study Drug shipped by the sponsor or the sponsor’s 
representative, including but not limited to the date received, lot number, expiration date, 
amount received, and the disposition of all Study Drug.  Current dispensing records will 
also be maintained including the date and amount of drug dispensed and the patient 
receiving the drug.  All remaining drug not required by regulations to be held by the 
clinical facility will be destroyed on site at the end of the study.
11 PREMATURE DISCONTINUATION OF STUDY DRUG 
TREATMENT
Patients who discontinue study drug, for reasons other than withdrawal of consent, will 
completed the following visits

End of Treatment Visit (TV14)

Washout and Safety Follow-up Period Visit

Premature Discontinuation of Study Drug Telephone Contact Visit
11.1 PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT ASSOCIATED WITH 
FAILURE-TO-IMPROVE CRITERIA
Patients who meet failure-to-improve criteria during the conduct of the study, will stop 
taking study medication. The Failure-to-Improve criteria is as follows:
Beginning on TV 3 and at every subsequent Treatment Visit, patients with a Worst
!"#			Worst Itch NRS at Visit 1a (or at Visit 1b 
in the case of patient who require the Observation Visit period) will be discontinued 
on study drug. Subjects discontinued on study drug are to undergo the End of 
Treatment Visit (TV14), the Washout/Safety Follow-up Period assessment in two 
weeks and receive a follow-up Telephone Contact 30 days following end of study 
drug for final safety assessment.
See the examples below:
Examples
Visit
Worst Itch 
NRS
Worst Itch NRS 
Lower/Higher or no 
change from 
V1a/1b
Failure-to-
improve met for 
that visit?
Next Steps
Visit 1a (or Visit 1b)
5
--
--
--
Ex #1
TV3
5
No Change
Yes
Discontinue 
study drug
Ex #2
TV3
4
Lower
No
Maintain 
subject on 
treatment
Ex #3
TV3
6
Higher
Yes
Discontinue 
study drug
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11.2 PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT FOR REASONS 
OTHER THAN FAILURE-TO-IMPROVE
Patients who complete Study Drug treatment according to Section 9.6 (even if some doses 
have been missed or if the patient was followed in the Observation Period before receiving 
study drug treatment) are considered to have completed Study Drug treatment. Patients 
discontinuing Study Drug prior to the maximum allowable number of Treatment Weeks 
based on their entry into the study at either Visit 1a or Visit 1b, will be considered to have 
prematurely discontinued Study Drug treatment. Patients removed from the study after 
enrollment and who have received a dose of study drug will not be replaced.
Some reasons for premature discontinuation of Study Drug treatment include:

Withdrawal of consent to continue Study Drug treatment

Intercurrent Illness

Any intolerable AE that cannot be ameliorated or safely managed with 
medical intervention or one that poses undue risk to the subject if Study 
Drug treatment were continued in the opinion of the Medical Monitor or 
Investigator.

ECG changes as summarized in section 17.4

Opioid medication is introduced in anticipation for chronic use of greater 
than 2 weeks (see Section 9.7.8)

Any medication prescribed for chronic anti-pruritic use of greater than 2 
weeks (see Section 9.7.6.1)

Development of substance abuse as determined by the Investigator
12 PREMATURE WITHDRAWAL OF PATIENTS FROM THE 
STUDY
All patients who receive study treatment should remain in the study whenever possible.
Reasons for withdrawal of the patient from the study, not just discontinuation of study 
drug, include:

Withdrawal of consent for study participation

Sponsor terminates the study for any reason

Investigator decision
The Investigator may withdraw any patient from the study if, in the Investigator’s 
opinion, it is not in the patient’s best interest to continue on the study.

Death of the patient
Any patient whose condition significantly changes after entering the study should be 
carefully evaluated by the Investigator and discussed with the Medical Monitor. Such 
patients should be withdrawn from the study if continuing would place them at risk or 
compromise the results of the study.
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Patients who prematurely discontinue from the study will be asked to undergo and have
completed Early Termination visit procedures and evaluations that may be necessary to 
ensure that the patient is free of untoward effects and to seek appropriate follow-up for any 
continuing problems.  The date on which the patient is withdrawn from the study and the 
reason for discontinuation will be recorded on the CRF.  Patients who withdraw from the 
study will not be replaced.
13 WARNINGS AND PRECAUTIONS
Please refer to the accompanying Investigator’s Brochure for more details summarizing the 
safety data on nalbuphine HCl ER tablets. In addition, see the Warnings and Precautions 
sections of the parenteral nalbuphine HCl package insert for safety-related information.  
The package insert is contained in the Study Reference Manual.
14 EFFICACY EVALUATIONS
Efficacy measurements will be evaluated as secondary endpoints in this study. The 
measurements include:

Worst itch intensity NRS 

Average itch intensity baseline.

VRS (itchy, burning and stinging) 

ItchyQoL 

MOS Sleep-R

HADS

Prurigo Activity Score (PAS) 

Patient Benefit Index, pruritus version (PBI-P) 

Frequency, pattern, and reasons for dose titration

Frequency and distribution by time on study of patients determined to meet failure-
to-improve criteria

Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets

Time to first use of rescue medications and number of days of use of rescue 
medications for itching

To evaluate the daily changes in the Subjective Opiate Withdrawal Scale (SOWS) 
during the Washout Period after cessation of treatment of nalbuphine HCl ER 
tablets.
14.1 EXPLORATORY
The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot), as well as 
histological (H&E) in skin biopsies taken during TR03 and the last week on study drug 
during TR03ext (optional procedures at select sites only).
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15 COLLECTION, HANDLING, AND ANALYSIS OF 
PHARMACOKINETIC BLOOD SAMPLES
15.1 BLOOD SAMPLE COLLECTION
Blood samples will be collected for safety, pharmacokinetic and CYP analysis.  At the time 
of sample collection and processing, study patient information will be anonymized.  Only 
the patient’s identification number, assigned by an IVR/IWR system, and a sample barcode 
aligned to the lab requisition form will be noted on the tube/vial.  
See the study Laboratory Manual for specimen collection, handling and shipping details. 
15.2 CENTRAL LABORATORY
Blood samples, including chemistry, serum pregnancy test, and hematology, and urine for 
urinalysis obtained for the study will be analyzed at a central laboratory. 
Urine pregnancy testing will be conducted at the site.
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment should the urine and serum pregnancy test results differ.  
See section 17.5.2.1 regarding how pregnancies are to be handled in this study.
15.3 PHARMACOKINETIC SAMPLES
To determine Study Drug content in plasma, blood samples will be collected at various 
time intervals over the duration of the study.
15.4 PREPARATION, STORAGE, AND HANDLING FOR PHARMACOKINETIC SAMPLES
Immediately after blood sample collection, the tubes will be gently inverted several times 
to mix the anticoagulant with the blood sample and placed on ice (4 to 8°C) until 
centrifuged.
The plasma fraction will be separated by centrifugation of the collection tube. It is 
preferable that a refrigerated (4 to 8°C) centrifuge be used. Centrifugation will be 
conducted in a manner to yield approximately 2 x1 mL of plasma (e.g., 10 minutes at 1,500 
x g). The plasma fraction will be withdrawn by pipette and divided into 2 evenly 
proportioned aliquots in polypropylene freezing tubes. All sample collection and freezing 
tubes will be clearly labeled in a fashion that identifies the patient identification number, 
the study dose, and the collection date and time.
Labels will be fixed to freezing tubes in a manner that will prevent the label from becoming 
detached after freezing. All plasma samples will be processed and placed into either a
minus 70°C or minus 20°C refrigerator within 1 hour after collection. Tube labels for PK 
samples will be provided in the Central Laboratory kits. Each label will contain the study 
number, patient number, study day of sample, and time of sample. The actual date and 
time of blood collection will be recorded in the patient’s CRF. 
All plasma samples will be stored frozen (at either -70ºC or -20°C) until they are shipped 
for storage and analysis.
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15.5 ANALYTICAL
Plasma samples will be analyzed for Study Drug using a validated liquid chromatography 
mass spectrometry (LC-MS/MS) method developed at Tandem Lab/s-RTP, Durham, North 
Carolina. The units for nalbuphine will be in ng/mL. In addition, metabolite 
concentrations will be assessed in these samples using an exploratory analytical LC-
MS/MS method.
Analysis and reporting of results will be conducted according to the current Standard 
Operating Procedures for bioanalysis at Tandem labs Durham, North Carolina. Details of 
the sample analysis, including a bioanalytical study report, will be included with the final 
clinical study report.
16 TISSUE SAMPLES AND HISTOLOGY
At selected sites only, up to three 3 mm punch skin biopsy samples (optional) will be 
obtained at Visit 1a/1b and the End of Treatment Visit (TV14).

A 3x3 mm punch skin biopsy is taken from an itchy region which will be fixed in 
formalin and then paraffin for routine histology (H&E) and immunohistochemical 
examination of inflammatory cells and pro-inflammatory mediators.

For the other two 3x3 mm punch skin biopsy samples taken from an itchy region,
o
One sample will be fixed in 4% paraformaldehyde for 2 h to 5 days, and 
then kept in 5% sucrose overnight, buffered in 10% and 20% sucrose and 
after 6 h stored in liquid nitrogen. This tissue will serve for the 
determination of the nerve fiber density. 
o
One sample will be used for RNA and protein extraction for the 
quantification of MOR/KOR by PCR and western blot.
Analysis will be performed at the University of Munster, Munster, Germany. 
See the Study Reference Manual and the Laboratory Manual for specimen collection, 
handling and shipping details.
17 SAFETY EVALUATIONS
Safety evaluations will include physical examination findings, changes in vital signs and 
ECGs (locally and centrally read), findings from clinical laboratory studies and the 
incidence of AEs
17.1 PHYSICAL EXAMINATION
A complete physical examination will be performed at the Screening Visit and 
subsequently according to the Schedule of Events (Appendix 1). Any clinically significant 
worsening after the start of Study Drug treatment 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. 
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17.2 VITAL SIGN MEASUREMENTS
Blood pressure and HR will be taken while sitting or semi-recumbent/recumbent for at 
least 5 minutes. Temperature may be taken by any standard method (e.g., oral, tympanic, 
rectal, etc.), but the method must be recorded.
Vital signs (BP, HR, RR, body temperature, and weight will be obtained according to the 
Schedule of Events (Appendix 1). The height, weight and BMI will be recorded only on 
Visit 1a.
17.3 LABORATORY EVALUATIONS
A complete series of laboratory evaluations (including hematology, serum chemistry, 
serum pregnancy and urine pregnancy (both if applicable) and urinalysis will be obtained 
according to the Schedule of Events (Appendix 1).  The required clinical laboratory tests 
are listed in Appendix 3.
Clinically-significant worsening in laboratory findings following start of Study Drug
treatment will be recorded as AEs and these will be repeated for verification. Clinically-
significant findings noted prior to the start of Study Drug treatment will be recorded as 
Medical History. The recorded AE will indicate the underlying abnormality or diagnosis as 
opposed to the observed deviation in laboratory results if the diagnosis is known (e.g. 
“acute Hepatitis A” is preferable to “ALT increased”).
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal result or to monitor the course of an AE will be obtained when clinically 
indicated.  In particular, if a clinically significant abnormal result is observed that is not 
resolved by the final study visit, tests will be repeated to document resolution or stability of 
the abnormality.
17.4 ELECTROCARDIOGRAM
A standard 12-lead ECG will be obtained according to the Schedule of Events (Appendix 
1); see the Study Reference Manual for ECG procedures. Electrocardiograms will be read 
locally by the Principal Investigator for clinical significance and centrally for ECG 
intervals (PR, RR, QRS, QT, and QTcF using nomogram table), rate, rhythm, and other 
clinically significant abnormalities such as left ventricular hypertrophy, pathological Q-
waves, etc. Clinically-significant worsening in ECG findings following start of Study Drug 
treatment will be recorded as AEs. Clinically-significant findings noted prior to the start of 
Study Drug treatment will be recorded as Medical History.
If a patient develops a QTcF >500ms associated with an increase from baseline >60ms, the 
ECG will be repeated at least 30min later.  If these parameters are confirmed on the second 
ECG by the Core ECG laboratory, the subject will be discontinued from the study.
During the conduct of the trial, if a patient develops any other cardiovascular events noted 
as part of the exclusion criteria, the cardiovascular assessments in Appendix 5 are to be 
completed.  See section 17.5 Adverse Events for the handling and follow-up of Adverse 
Events.
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17.5 ADVERSE EVENTS
Adverse events will be recorded starting with the signing of the first informed consent. All 
AEs will be collected through the Washout and Safety follow up visit (or Early 
Termination Visit). Adverse events that have not been directly reported to the Investigator 
will be promptly conveyed to the Investigator by the study staff. Investigators will 
additionally review any AE source documents and the patient’s medical records, on a 
regular basis during the course of the study.
Following the Washout and Safety follow up visit (or Early Termination Visit), all
unresolved AEs that were reported by the Investigator to be probably drug related should 
be followed by the Investigator until the events are resolved, the patient is lost to follow-
up, or the adverse event has stabilized.
17.5.1 Adverse Event Definition
An AE is defined as any untoward medical occurrence in a clinical investigation patient
reported on or after the first screening date.  A treatment-emergent AE (TEAE) is any 
untoward medical occurrence in a clinical investigation patient or patient administered a 
pharmaceutical product on or after the initial administration of study medication. An AE 
does not necessarily have to have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom whether or not related to the medicinal (investigational) product, or 
disease temporally associated with the use of a medicinal (investigational) product.
The AE may be any of the following:

a new illness

worsening of a pre-existing condition

worsening of a sign or symptom of the condition under treatment or of a
concomitant illness

an effect of the study medication, including comparator

a combination of 2 or more of these factors.
No causal relationship with the study medication or with the clinical study itself is implied 
by the use of the term “AE.”
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.
Adverse events fall into the categories “non-serious” and “serious.”
17.5.2 Serious Adverse Events
The reporting period for serious AEs is the same as for AEs. Serious AEs must be 
submitted to the Sponsor within 24 hours of their discovery, even if the full information 
about the event is not yet available. These events should also be reported to the IRB/IEC 
as needed based on local requirements. Fax SAE forms to the following number:
Serious AE Fax #: 888-529-3580
Also notify the PPD Medical Monitor at (888) 483-7729.
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17.5.2.1 Serious Adverse Event Definition
An SAE is one that, at any dose, results in any of the following:

Death

A life-threatening adverse drug experience

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant disability/incapacity

A congenital anomaly/birth defect.
A hospitalization is defined as an inpatient admission lasting 24 hours or more. Visits to 
urgent care centers and emergency departments that do not result in admission to a hospital 
for 24 hours will not be considered hospitalizations. Hospitalizations for elective 
procedures, defined as any procedure that was planned prior to signing of the informed 
consent will not, in and of themselves, be considered to fulfill criteria for an SAE. For 
example, for patients on the kidney transplant waiting list prior to signing the ICF who 
subsequently are hospitalized for a transplant, the hospitalization would be considered 
elective. 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at immediate risk of death at the time of the SAE. It does not refer to a SAE 
that hypothetically might have caused death if it were more severe.
Medical and scientific judgment should be exercised in deciding whether other AEs, such 
as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed above. These should also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
Female patients who become pregnant should be immediately discontinued from the study 
if they have not yet received Study Drug. If a patient is found to be pregnant after they 
have received Study Drug, she should discontinue dosing, complete all end-of-study 
procedures, and be followed to determine the outcome of the pregnancy. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. While
pregnancy itself is not considered an AE or SAE, any pregnancy complications or less than 
a healthy, normal outcome will be recorded as an AE or SAE.
Clarification on the difference in meaning between “severe” and “serious”
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations.
17.5.3 Non-Serious Adverse Events
A non-serious AE is any AE not meeting the SAE criteria.
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17.5.4 Definition of Relationship to Study Medication
Association or relatedness to the study medication will be graded as either “probably,”
“possibly,” or “unlikely.”  Determination of relatedness includes:
PROBABLY – The AE:

follows a reasonable temporal sequence from drug administration;

abates upon discontinuation of the drug;

cannot be reasonably explained by the known characteristics of the patient’s clinical 
state.
POSSIBLY – The AE:

follows a reasonable temporal sequence from drug administration;

could have been produced by the patient’s clinical state or by other modes of 
therapy administered to the patient.
UNLIKELY – The AE:

does not follow a reasonable temporal sequence from drug administration;

is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient.
17.5.5 Definition of Severity
All AEs will be graded, if possible, by the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 [http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf]. This is also provided in the Study Reference Manual for 
reference purposes.
The severity of AEs that cannot be graded by the most current version of CTCAE will be 
categorized as follows:

Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required.

Grade 2 – Mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required.

Grade 3 – Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required hospitalizations possible.

Grade 4 – Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required hospitalization or hospice care probable.

Grade 5 – Death.
17.5.6 Definition of Unexpected Adverse Event
Any AE, the specificity or severity of which is not consistent with the current Investigator 
Brochure, rather than from the perspective of such experience not being anticipated from 
the pharmacological properties of the drug.
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17.6 DATA SAFETY MONITORING BOARD
An unblinded, independent Data Safety Monitoring Board (DSMB) will periodically 
review safety data.  The frequency of data review and DSMB processes are outlined in the 
DSMB charter. The DSMB will periodically review group-unblinded study information 
(on a treatment group level, using random letters instead of actual treatments) during the 
conduct of the study.  If necessary, unblinding of individual subject data and treatment 
groups may be done.
18 EMERGENCY PROCEDURES
In case of study-related medical questions, or if a pregnancy is confirmed in a trial patient,
the Investigator should contact the designated Medical Monitor.
18.1 EMERGENCY SPONSOR CONTACT
In emergency situations, the Investigator should contact the designated sponsor 
representative at the following address:
Thomas Sciascia, MD
Trevi Therapeutics, Inc.
195 Church Street, 14th Floor
New Haven, CT 06510 USA
Telephone:  
(203) 304-2499
Mobile:  
(617) 913-6808
19 CONSIDERATION, ANALYSIS PLAN AND DETERMINATION 
OF SAMPLE SIZE
19.1 GENERAL
As a companion to this protocol and in an effort to provide a more detailed explanation of 
the statistical methodology to be used for this study, which will consist of data summaries, 
a statistical analysis plan (SAP) will be developed prior to locking the data base.
No formal statistical testing is planned for this study.  Data summaries will provide the 
basis for clinical interpretation of efficacy and safety outcomes
19.2 INTERIM ANALYSES
There is no interim analysis planned in this study.
19.3 METHODS FOR HANDLING MISSING DATA
No replacement or imputation of missing data will be conducted for this study.
19.4 PATIENT DISPOSITION
Patient disposition will be summarized, including the reasons for discontinuation.  The 
number of patients in each analysis population will be displayed and an accounting of 
exclusions from each study population will be provided.
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19.5 BASELINE CHARACTERISTICS
Demographics, medical history, laboratory data, and physical examination findings will be 
summarized.
19.6 CONCOMITANT MEDICATIONS
Concomitant medications will be tabulated by Anatomic and Therapeutic Class (ATC) of 
WHO drug, preferred term, and treatment group.  A medication’s usage will be considered 
concomitant if it was started or continued after administration of the study medication.  If 
the start date is missing, it will be assumed that the medication was used concomitantly.
Rescue and opioid medication usage will be tabulated separately from all other 
concomitant medications.
19.7 STUDY DRUG DOSING
The percentage of patients reaching various achieved doses at the end of Treatment Week 4 
and through Study Week 50 will be summarized. The mean dose during the Treatment 
Period and the dose distribution by Treatment Period Visit will be reported. Descriptive 
statistics will be used to describe the mean daily dose by Visit.
19.8 EFFICACY ANALYSES
19.8.1 Efficacy Population
The Safety population, consisting of all enrolled patients who have received a single dose 
of study medication, will be used to evaluate the efficacy endpoints defined for this study.  
Eligibility for analysis of a particular endpoint will require only that the patient have a 
baseline value and at least one post-baseline value for the endpoint of interest, so that a 
change from baseline calculation can be obtained.  All efficacy endpoints will be evaluated 
through the generation of descriptive summary statistics.  For continuous variables, the 
mean, standard deviation, median, minimum, and maximum will be presented for a 
particular visit and for the change from baseline (Visit 1a or 1b).  For categorical variables, 
the number and percentage of patients within each category of classification will be 
summarized by study visit.  No formal statistical testing will be conducted.
19.8.2 Premature Discontinuation Due to Lack of Efficacy or Adverse 
Events
The distribution of patients who prematurely discontinue due to lack of efficacy or adverse 
events will be summarized.  Patients who prematurely discontinue after having been 
followed in the Observation Period only will be also be summarized. 
19.9 SAFETY ANALYSES
19.9.1 Safety Population
The Safety Population will consist of all patients who have received a single dose of study 
medication, i.e., this same population will be used both for the efficacy and safety 
evaluations. The Safety Population will be used in all safety analyses.
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19.9.2 Adverse Events
All treatment emergent AEs will be summarized overall and for each body system and 
preferred term by treatment group, relationship to study medication, and severity.  For 
tabulations by severity, only a patient’s most severe event within the category (e.g., overall, 
body system, or preferred term) will be counted. Adverse events will be dichotomized into 
“related” (probably and possibly) and “unrelated” (unlikely). “Treatment-emergent” will 
be defined as starting or worsening after the first dose of study medication.  If the start date 
is missing, the event is assumed to be treatment emergent. All SAEs will be tabulated as 
well.
Although nalbuphine is not a controlled substance in the United States, adverse events of 
special interest that suggest a possible addiction or abuse potential or withdrawal will be 
specifically analyzed to screen for these effects. The list of MedDRA preferred terms for 
adverse events of special interest will be described in the Statistical Analysis Plan.
19.9.3 Vital Signs
Vital signs, including BP, HR, body temperature, and RR, and weight will be summarized 
by treatment group at Baseline and at each assessment time point during the post dosing 
period.
19.9.4 Laboratory Evaluations
Clinical safety laboratory data will be summarized descriptively by treatment group at 
baseline and at each scheduled visit. Summaries of safety laboratory parameters will 
include the first measurement of each scheduled assessment but repeat assessments done at 
the same study time point will not be included in summary calculations. Lab data will also 
be listed by treatment, patient, and visit. Listings will include scheduled, unscheduled, and 
repeat evaluations. A listing of markedly abnormal values, as defined in the Statistical 
Analysis Plan, will additionally be generated.
19.9.5 Physical Examinations
Abnormal physical examination findings that suggest a clinically significant worsening will 
be reported as AEs and analyzed as such. Clinically significant findings noted prior to start 
of Study Drug treatment will be recorded as medical history and analyzed as such.
19.9.6 Electrocardiograms
A standard 12-lead ECG will be obtained on Visit 1a/1b (pre-treatment) and subsequently, 
according to the Schedule of Events in Appendix 1. Electrocardiogram intervals (PR, RR, 
QTcF) will be summarized with descriptive statistics. All findings, including any follow-
up ECGs as a result of any significant abnormal results, will be listed by treatment, patient, 
and visit.
19.10 DETERMINATION OF SAMPLE SIZE
As this is a safety extension study for which patients will be recruited from patients who 
have completed parent study TR03, the sample size cannot be predicted. No formal sample 
size calculations have been performed and no inferential statistics are planned. The
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maximum number of patients will not exceed the number of patients who completed TR03 
(i.e., up to 60 patients).
19.11PHARMACOKINETIC AND PHARMACOKINETIC /
PHARMACODYNAMIC ANALYSES
The Study Drug plasma concentration data will be provided as data listings and will be 
summarized descriptively (mean, median, SD, minimum, and maximum) by collection time 
and nalbuphine dose.  Additionally, these PK data may be analyzed through population, 
nonlinear mixed effects modeling (NONMEM), using the software package NONMEM 
(Version V, Level 1.1 or higher; GloboMax LLC, Hanover, MD).
20 ETHICS
20.1 INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD
Prior to initiation of the study, the Investigator will submit the study protocol, sample 
informed consent form (ICF), and any other documents that pertain to patient information, 
recruitment methods such as patient diaries, and advertisements, to the Institutional Review 
Board/Independent Ethics Committee (IRB/ IEC).  The Investigator must also submit any 
other information that may be requested to the IRB/IEC for review and approval.  The 
Investigator will request that the IRB/IEC provide written approval of the study and will 
keep on file records of approval of all documents pertaining to this study.  A letter 
confirming the approval must be forwarded to the Study Monitor prior to initiation of this 
study.  This letter will be forwarded to the Sponsor prior to the initiation of the study.
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC for 
all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the IRB/IEC of deviations from the protocol or SAEs occurring at the site, as well as 
other AE reports received the Sponsor, in accordance with local procedures.
The Investigator will be responsible for obtaining annual IRB/IEC approval or renewal 
throughout the duration of the study.  
20.2 ETHICAL CONDUCT OF THE STUDY
This study is to be conducted according to globally accepted standards of good clinical 
practice (as defined in the ICH E6 Guideline for Good Clinical Practice [GCP], 1 May 
1996), in agreement with the latest revision of the Declaration of Helsinki and in keeping 
with local regulations.
The Investigator should ensure that all persons assisting with the trial are adequately 
qualified, informed about the protocol, any amendments to the protocol, the study 
treatments, and their trial-related duties and functions.
The Investigator should maintain a list of Subinvestigators and other appropriately 
qualified persons to whom he or she has delegated significant trial-related duties.  Should 
the Investigator delegate the supervision of the investigational product administration to a 
designated person, this individual must have the appropriate medical qualifications to 
effectively conduct or supervise any potential resuscitation procedures.
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20.3 PATIENT INFORMATION AND INFORMED CONSENT
Patients must provide written consent to participate after the nature, scope, and possible 
consequences of the clinical study have been explained in a form understandable to them.
An ICF that includes information about the study will be prepared and given to the patient.
This document will contain all the elements required by the ICH E6 Guideline for GCP and 
any additional elements required by local regulations.  The document must be in a language 
understandable to the patient and must specify who informed the patient. Where required 
by local law, the person who informs the patient must be a physician.
After reading the ICF, the patient must give consent in writing.  The patient’s consent must 
be confirmed at the time of consent by the personally dated signature of the patient and by 
the personally dated signature of the person conducting the informed consent discussions.
A copy of the signed ICFs must be given to the patient.  The original signed ICFs will be 
retained by the Investigator. 
The Investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained. 
21 STUDY ADMINISTRATION
21.1 CLINICAL MONITORING
Monitoring and auditing procedures, developed or endorsed by Trevi Therapeutics will be 
followed to comply with GCP guidelines.  Access to the on-site study documentation and 
medical records will be ensured.
The study will be monitored by Trevi Therapeutics or its designee.  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.  During the on-site visits, the CRF will be 
reviewed for completeness and adherence to the protocol.  As part of the data audit, source 
documents must be made available to the Study Monitor for review.  The Study Monitor 
will also perform drug accountability checks and will request to perform a review of the 
Investigator study file to ensure completeness of documentation in all respects of clinical 
study conduct.
Upon completion of the study, the Study Monitor will arrange for a final review of the 
study files, after which the files should be secured for the appropriate time period.  The 
Investigator, or appointed delegate, will meet with the Study Monitor during the on-site 
visits and will cooperate in providing the documents for inspection and responding to 
inquiries.  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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21.2 DATA QUALITY ASSURANCE
The Investigator, or designee, will enter study data required by the protocol into an 
electronic data capture (EDC) system. The clinical research associates will visit each study 
site, at a frequency documented in the monitoring plan, to review the electronic CRF 
(eCRF) for completeness and accuracy. Any discrepancies found between source 
documents and completed eCRF will be entered as a discrepancy in the EDC system by the 
clinical research associate. Appropriate study site personnel should then address those
discrepancies in the EDC system. Uniform procedures for eCRF correction (queries) will 
be discussed during the study site initiation visits and will be documented in the study 
operations manual.
Data from eCRF and other external data sources will be entered into a clinical database as 
specified in the data management plan. Quality control and data validation procedures will 
be applied to ensure the validity and accuracy of the clinical database. 
Computerized and manual procedures should be used to review and check data from eCRF 
and data from other external sources for omissions, apparent errors, and values that may 
require further clarification. Data queries requiring clarification should be documented, 
and the study site should be requested to review and resolve the queries. Only authorized 
personnel can make corrections to the clinical database, and all corrections should be 
documented in an audit trail.
Adverse events will be coded using the most current MedDRA version.  Prior and 
concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Dictionary.
21.3 RETENTION OF STUDY RECORDS
The following records must be retained by the Investigator for a minimum of 2 years after 
the Sponsor has notified the FDA that investigations have been discontinued or after the 
FDA has approved the new drug application: 

Signed ICFs for all patients

Patient identification code list, screening log (if applicable), and enrollment log

Record of all communications between the Investigator and the IRB/IEC

Composition of the IRB/IEC or other applicable statement 

Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO])

List of Subinvestigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in 
the study and their signatures

Copies of CRFs and of documentation of corrections for all patients 

Drug accountability records

Record of any body fluids or tissue samples retained

All other source documents (patient records, hospital records, laboratory records, 
etc.)
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All other documents as listed in Section 8 of the ICH consolidated guideline on 
GCP (Essential Documents for the Conduct of a Clinical Trial)
However, because of international regulatory requirements, the Sponsor may request 
retention for a longer period of time.  The Investigator must therefore obtain approval in 
writing from the Sponsor prior to destruction of any records.
Normally, these records will be held in the Investigator's archives.  If the Investigator is 
unable to meet this obligation, he or she must ask the Sponsor for permission to make 
alternative arrangements.  Details of these arrangements should be documented.
21.4 CONFIDENTIALITY
Patient names will not be supplied to the Sponsor.  Only the patient number and patient 
initials will be recorded in CRF (unless not allowed by local regulations), and if the patient 
name appears on any other document (e.g., pathologist 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 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.
The Investigator will maintain a personal patient identification list (patient numbers with 
the corresponding patient names) to enable records to be identified.
21.5 DOCUMENTATION OF STUDY RESULTS
As part of the responsibilities assumed by participating in the study, the Investigator or 
Subinvestigator agrees to maintain adequate case histories for the patients treated as part of
the research under this protocol. The Investigator or Subinvestigator agrees to maintain 
accurate eCRF and source documentation as part of the case histories. These source
documents may include laboratory reports and ECG recordings.
The Investigator or designees must enter all results collected during the clinical study into 
the eCRF. Guidelines for completion of the eCRF will be reviewed with study-site
personnel at the site initiation visits. There is a 2-part process to review and collect the 
eCRF data. Study-site personnel will enter the data from each study visit. The Investigator 
is responsible for approval of the entered/corrected data. The eCRF responsibilities of the 
study team members will be documented on the site delegation log, which will be collected 
at the closeout visits.
The Investigator can authorize Sub-investigators to sign and approve the eCRF if they are 
designated on Form FDA 1572 as Sub-investigators, have been trained on the EDC system, 
and have their own user name and password. The Investigators or designees must review 
and approve the data before database lock.
In the EU, the Investigator agrees to maintain documentation of the data generated by the 
trial so that it complies with the requirements of Directive 2001/20/EC, as amended and 
Directive 2005/28/EC as amended to incorporate recommendations on ‘The Trial Master 
File and Archiving’.
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21.6 USE OF STUDY RESULTS
All information concerning the product, as well as any matter concerning the operation of 
Trevi Therapeutics (such as clinical indications for the drug, its formula, methods of 
manufacture, and other scientific data relating to it, that have been provided by Trevi 
Therapeutics and are unpublished) are confidential and must remain the sole property of 
Trevi Therapeutics.  The Investigator and participating vendors will agree to use the 
information only for the purposes of carrying out this study and for no other purpose unless 
prior written permission from Trevi Therapeutics is obtained.  The Sponsor has full 
ownership of the CRFs completed as part of the study.
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.
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22 REFERENCES
1. Accioly-Filho JW. Nogueira A. Ramos-e-Silva MR. Prurigo Nodularis of Hyde-An 
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APPENDICES
Appendices 1 through 4 are provided on the following pages.
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Appendix 1: Schedule of Events 
Table 4: Schedule of Events for Visits 1a and 1b
(Day 1 of Week 1 of Treatment Period) 
1Study TR03 Visit 6 procedures in 
common with Study TR03 extension 
Visit 1a procedures do not have to be 
repeated.
2 To be completed any time before start 
of Visit 1a procedures
3BP and HR (sitting or semi-
recumbent), RR, temperature, and  
weight
4 Visit 1b is the first visit of the 
Treatment Period for patients 
transitioning from the Observation 
Period to the Treatment Period.  
5Hematology and chemistry
6Females of Childbearing potential 
only
7Questionnaires must be administered 
strictly adhering to instructions (see 
Study Reference Manual) 
8Includes review of patient TR03 
Rescue Medication Log
9Study procedures only conducted if 
patient qualifies to enter the Treatment 
Period based on Worst itch NRS 
10Titrate study drug according to the 
schedule in Table 3; 
The first dose of study drug treatment 
will define enrollment into the study
11 For female patients of child-bearing 
potential, a urine pregnancy test must 
be negative prior to dispensing study 
drug.
12 ECGs are to be performed after the 
patient has been in the supine position 
for at least 5 minutes.  ECGs will be 
read by the Investigators for clinical 
significance and centrally by a core 
ECG laboratory for analytical and 
DSMB safety review
13The first dose of study drug is to be 
taken in the evening, see Section 9.7.1
and Section 9.3
Visit
1a1
1b4
Informed Consent2
X
Confirm Eligibility
X
Vital Signs3
X
X
Physical Examination
X
X
Neurological Exam
X
X
Central Clinical Labs5 & serum 
PregnancyTest6
X
X
Urinalysis
X
X
Urine for pregnancy test11
X
X
Blood for PK
X
X
Perform skin biopsy (only at select sites and 
the procedure is optional)9
X
X
12-lead ECG12
X
X
Worst itch Numerical Rating Scale 
(NRS)7
X
X
Average itch intensity Numerical Rating 
Scale (NRS)7
X9
X
Verbal Rating Scale (VRS)7
X9
X
ItchyQoL7
X9
X
MOS Sleep-R7
X9
X
Hospital Anxiety and Depression Scales
(HADS)7
X9
X
Patient Benefit Index Pruritus (PBI-P)7
X9
X
Prurigo Activity Score (PAS)
X9
X
Record AEs
X
X
Review Rescue Medications and 
Concomitant Medications
X8
X
Retrieve TR03 study drug
X
Dispense Study Drug for TR03ext13
X9
X
Collect Rescue Medication Log for TR03
X
First dose of Study Drug for TR03ext10,13
X9
X
Dispense Drug Dosing Instructions and 
Dosing Diary
X
X
Dispense TR03ext Rescue Medication Log
X
X
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Table 5:
Treatment Weeks 2-4
TC 11
TV 21
TC 21
Treatment Week 
2
3
4
Dispense Study Drug2
X
Titrate Study Drug2
X
X
Confirm Maintenance Dose
X2
Vital Signs3
X
Neurological Assessment
X
Urine pregnancy test5
X
Blood for PK
X
12-lead ECG6
X
Worst itch NRS4
X
Average itch intensity NRS4
X
VRS4
X
MOS Sleep-R4
X
HADS4
X
ItchyQoL4
X
Study Drug BID
X
Record AEs 
X
X
X
Record Concomitant Medications
X
Reinforce Compliance7
X
X
X
Study Drug Accountability
X
Dispense Dosing Diary
X
Dispense Rescue Medication Log
X
1 The window for TC 1-2 and TV2 is +/-3 days
2 Instruct the patient in the dose titration/maintenance according to the schedule in Table 3 and assess 
tolerability/intolerability to study drug
3 BP and HR (sitting or semi-recumbent), RR, temperature.
4Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual)
5 For female patients of child-bearing potential, a urine pregnancy test must be negative prior to dispensing additional 
study drug.  
6 ECGs are to be performed after the patient has been in the supine position for at least 5 minutes.  ECGs will be read 
by the Investigators for clinical significance and centrally by a core ECG laboratory for analytical and DSMB safety 
review
7Includes review of Rescue Medication Log and Drug Dosing Diary for accuracy and completeness.
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Table 6: Treatment Period Visits12 During Study Weeks 5-50 and Washout/Safety Follow-up Visit or Treatment Period Early 
Termination Visit
TV
3
TV
4
TV
5
TV
6
TV
7
TV
8
TV
9
TV
10
TV
11
TV
12
TV
13
End of 
Treatment 
Visit 
(TV14)
Washout /
Safety Follow-
up Period
Premature 
Discontinuation 
of Study Drug 
Telephone 
Contact14
ET9
Treatment Week1,3
5
9
13
17
21
26
30
34
38
42
46
--2
--
--
Physical Examination
X
X
X
Brief Neurological Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central Clinical Labs6
X
X
X
X
Serum pregnancy test to central lab11
X
X
Urinalysis to central lab
X
X
X
PAS
X
X
X
PBI-P7
X
X
12-lead ECG13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Skin biopsy (at select sites and is an 
optional procedure)
X10
X
Blood for PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Failure-to-Improve Evaluation17
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test5
X
X
X
X
X
X
X
X
X
X
X
Vital Signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Worst itch NRS7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Average itch intensity NRS7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ItchyQoL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
VRS7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MOS Sleep-R7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HADS7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SOWS7
X
X
Dispense 14 day SOWS packet15
X
Retrieve 14 day SOWS packet15
X
Record AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record  Concomitant Medications16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Reinforce Compliance
X
X
X
X
X
X
X
X
X
X
X
Study Drug Accountability
X
X
X
X
X
X8
X
X
X
X
X
X
X8
Study Drug BID
X
X
X
X
X
X
X
X
X
X
X
1Patients who were previously in the Observation Period should start the Treatment Period at Visit 1b and continue in the study for 38-46 weeks; the total number of weeks in the 
combined Observation and Treatment Periods is no more than 50 weeks. The last scheduled visit on study drug for patients previously in the Observation Period should be TV 14 
regardless of the study week.
2 The number of Treatment Weeks prior to TV 14 will vary for patients who prematurely discontinue study drug for reasons other than withdrawal of consent see Section 11.
3Two allowable dose reductions are permitted during Treatment Weeks 5 – 50 (a patient can be reduced to 30 mg BID). If a third dose reduction is needed, the patient should be 
discontinued from the study.
4 BP and HR (sitting or semi-recumbent), RR, temperature
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5For female patients of child-bearing potential, a urine pregnancy test must be negative prior to dispensing additional study drug.
6 Hematology and chemistry.
7Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual)
8 Retrieve remaining study drug at TV 14 or ET Visit
9 ET Visit is conducted within 2 weeks of study drug termination, see Section 12
10 Skin biopsy material for nerve fiber density, histology (H&E) and MOR/KOR density to be performed, only at select sites (optional procedure)
11Females of Childbearing potential only
12 Visit windows will be +/-3 Days
13 ECGs are to be performed after the patient has been in the supine position for at least 5 minutes.  ECGs will be read by the Investigators for clinical significance and centrally by a core 
ECG laboratory for analytical and DSMB safety review
14The Premature Study Drug Discontinuation Telephone Contact is to take place for all patients who prematurely discontinue study drug for reasons noted in Section 11.  This telephone 
contact takes place 30 days (+2 weeks) from the last dose of study drug.
15The 14 Day SOW packet is to be completed at home by the patient.  A SOWS is to be completed each day starting at TV14.  The packet is to be retrieved at the Washout and Safety 
Follow-up Period Visit
16Includes review of Rescue Medication Log and Drug Dosing Diary for accuracy and completeness
17See Section 11.1 for the Failure-to-Improve criteria; perform End of Treatment Visit (TV14) procedures for patients that meet the Failure-to-Improve criteria
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Version 2.0, 11 MARCH 2015
Page 101 of 122
Table 7:
Observation Period Visits5
Observation Visit
OV
2
OV
3
OV
4
Observation Study Week
4
8
121
Check Worst itch NRS2: If , patient must undergo Visit 1b 
X4
X4
X4
Vital Signs3
X
X
X
Average itch intensity NRS2
X
VRS2
X
MOS Sleep-R2
X
HADS2
X
ItchyQoL2
X
Record AEs 
X
X
X
Record concomitant medications
X
X
X
1Patients whose NRS is <5 at OV 4 are to be screen failed from the study
2 Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual)
3BP and HR (sitting or semi-recumbent), RR, temperature
4If patient’s NRS is  proceed to Visit1b procedures and no need to record any further data under OV visit 
procedures
5Visit windows will be +/-3 Days
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Version 2.0, 11 MARCH 2015
Page 102 of 122
Table 8:  Treatment Visit Schedule for Patients Entering Treatment via Visit 1b
	
			
	
	
Visit are 
to complete Visit 1b and transition from the Observation Period to the Treatment Period.
If the above criteria are met, Visit 1b procedures are to be completed at the Observation Visit
Visit of 
Transition
OV2
OV3
OV4
Treatment Visits 
to Complete
Visit 1b/TV1, TV2 
through TV12, and 
TV13
Visit 1b/TV1, TV2 
through TV11, and 
TV12
Visit 1b/TV1, TV2 
through TV10, and 
TV11
Last Treatment 
Visit 
TV13
Dispense 1 week of study  
drug 
Week 46 is last week of 
treatment for a patient 
who transitioned to the 
Treatment Period from 
OV2
Conduct the End of 
Treatment Visit (TV14) 
during week 47
TV12
Dispense 1 week of study  
drug 
Week 42 is last week of 
treatment for a patient 
who transitioned to the 
Treatment Period from 
OV3
Conduct the End of 
Treatment Visit (TV14) 
during week 43
TV11
Dispense 1 week of study  
drug 
Week 38 is last week of 
treatment for a patient 
who transitioned to the 
Treatment Period from 
OV4
Conduct the End of 
Treatment Visit (TV14) 
during week 39
Total Potential 
Weeks on 
Treatment
46
42
38
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Protocol No. TR03ext
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Version 2.0, 11 MARCH 2015
Page 103 of 122
Table 9: Rescue Medications for Itching
Rescue Medication
Only intended for anti-
pruritic treatment
Examples
Opioid receptor antagonists
naltrexone, naloxone
Antihistamines 

topical or systemic
Topical calcineurin inhibitors

tacrolimus
Topical antibiotics

---
Topical steroids

---
Topical capsaicin

---
Anti-septic baths and anti-septic 
cleansing lotions 

---
Anti-convulsant class drugs

gabapentin or pregabalin
Systemic Steroids

---
cyclosporin A and other 
immunosuppressants

---
antidepressant medications

paroxetine, fluvoxamine, 
amitriptyline
Malignant tumor related active 
treatment with a systemic drug

---
UV Therapy

---
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Version 2.0, 11 MARCH 2015
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Appendix 2: Study Schematic Flow Charts
Figure 2:
Overview of TR03-EXT Study Design
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Version 2.0, 11 MARCH 2015
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Figure 3:
Examples illustrating possible Observation and Treatment periods Scenarios in TR03-Ext
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Version 2.0, 11 MARCH 2015
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Figure 4:
Dosing Schedule in TR03ext
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 107 of 122
Appendix 3: Clinical Laboratory Tests
Hematology:
Serum Chemistry:
Hemoglobin
Potassium
Hematocrit
Chloride
Red Blood Cell Count
Carbon Dioxide
White Blood Cell Count
Blood Urea Nitrogen (BUN)
White Blood Cell Differential
Creatinine
Platelet Count
Calcium
Phosphorus
Total Protein
Urine:
Albumin
Total Bilirubin
Urinalysis
AST
Pregnancy
ALT
Alkaline Phosphatase
LDH
Serum Pregnancy:
Glucose
-Human Chorionic 
Gonadotropin (HCG) (women of 
childbearing potential)
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No. TR03ext
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Version 2.0, 11 MARCH 2015
Page 108 of 122
Appendix 4:  Patient Reported Outcomes
The Patient Reported Outcomes are provided on the subsequent pages.
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Protocol No. TR03ext
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Version 2.0, 11 MARCH 2015
Page 109 of 122
Medical Outcomes Sleep Scale (Revised MOS Sleep-R)
Sample – actual assessment scale will be provided to the patient at appropriate visits
Your Sleep
For each of the following questions, please mark an 
in the one box that best describes your 
answer.
1.
How long did it usually take for you to fall asleep during the past 4 weeks?
0-15
minutes
16-30
minutes
31-45
minutes
46-60
minutes
More than 60
minutes





  
1
  
2
  
3
  
4
  
5
2.
On the average, how many hours did you sleep each night during the past 4 
weeks?
Write in number of hours per night:
3.
How often during the past 4 weeks did you…
Copyright, 1986, RAND.
MOS 12-Item Sleep Scale – Revised 2010
United States (English)
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time
    
a
feel that your sleep was not quiet
(moving restlessly, feeling tense,
speaking, etc., while sleeping)?...........
1...........
2 ...........
3...........
4 ...........
5
b
get enough sleep to feel rested 
upon waking in the morning? .............
1...........
2 ...........
3...........
4 ...........
5
c
awaken short of breath or with
a headache? .................................
1...........
2 ...........
3...........
4 ...........
5
d
feel drowsy or sleepy during 
the day? ......................................
1...........
2 ...........
3...........
4 ...........
5
e
have trouble falling asleep?................
1...........
2 ...........
3...........
4 ...........
5
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 110 of 122
Medical Outcomes Sleep Scale (Revised MOS Sleep-R) (cont’d)
Sample – actual assessment scale will be provided to the patient at appropriate visits
How often during the past 4 weeks did you…
Copyright, 1986, RAND.
MOS 12-Item Sleep Scale – Revised 2010
United States (English)
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time
    
f
awaken during your sleep time 
and have trouble falling asleep
again?.........................................
1...........
2 ...........
3...........
4 ...........
5
g
have trouble staying awake 
during the day?..............................
1...........
2 ...........
3...........
4 ...........
5
h
snore during your sleep?...................
1...........
2 ...........
3...........
4 ...........
5
i
take naps (5 minutes or longer) 
during the day?..............................
1...........
2 ...........
3...........
4 ...........
5
j
get the amount of sleep you 
needed?......................................
1...........
2 ...........
3...........
4 ...........
5
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Version 2.0, 11 MARCH 2015
Page 111 of 122
ItchyQoLTM
Sample – actual assessment scale will be provided to the patient at appropriate visits
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Version 2.0, 11 MARCH 2015
Page 112 of 122
ItchyQoLTM (cont’d)
Sample – actual assessment scale will be provided to the patient at appropriate visits
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 113 of 122
ItchyQoLTM (cont’d)
Sample – actual assessment scale will be provided to the patient at appropriate visits
 
 
 
 
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 114 of 122
Prurigo Activity Score (PAS)
Sample – actual assessment scale will be provided to the patient at appropriate visits
SST-Pr-10-2007, Amendment 9, PAS, Version 0.7; 11.09.2013
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 115 of 122
Patient Benefit Index, Pruritus Version (PBI-P)
Sample – actual assessment scale will be provided to the patient at appropriate visits
PBI-Patient Benefit Index (index of benefits and needs in therapy), Augustin 2006
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 116 of 122
PBI-P (Cont’d)
Sample – actual assessment scale will be provided to the patient at appropriate visits
PBI-Patient Benefit Index (index of benefits and needs in therapy), Augustin 2006
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 117 of 122
Numerical Rating Scale (Worst Itch)
How would you rate your most severe itching over the past 24 hours?
Numerical Rating Scale (Average-Itch)
How would you rate your itching on average over the past 24 hours?
Verbal Rating Scale
How is your skin sensation today?
0: 
not 
present
1:
mild 
present
2:
moderately 
present
3:
severely 
present
4:
very severely 
present
Itchy
Burning
Stinging
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 118 of 122
Hospital Anxiety and Depression Scale (HADS)
Sample – actual assessment scale will be provided to the patient at appropriate visits
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Protocol No. TR03ext
Trevi Therapeutics, Inc.
Version 2.0, 11 MARCH 2015
Page 119 of 122
Subjective Opiate Withdrawal Scale (SOWS)
Sample – actual assessment scale will be provided to the patient at appropriate visits
PLEASE SCORE EACH OF THE 16 ITEMS BELOW ACCORDING TO HOW YOU FEEL
NOW
(CIRCLE ONE NUMBER)
SYMPTOM
NOT AT ALL
A LITTLE
NOT AT ALL
QUITE A BIT
EXTREMELY
1
I feel anxious
0
1
2
3
4
2
I feel like yawning
0
1
2
3
4
3
I am perspiring
0
1
2
3
4
4
My eyes are teary
0
1
2
3
4
5
My nose is running
0
1
2
3
4
6
I have goosebumps
0
1
2
3
4
7
I am shaking
0
1
2
3
4
8
I have hot flushes
0
1
2
3
4
9
I have cold flushes
0
1
2
3
4
10
My bones and muscles
ache
0
1
2
3
4
11
I feel restless
0
1
2
3
4
12
I feel nauseous
0
1
2
3
4
13
I feel like vomiting
0
1
2
3
4
14
My muscles twitch
0
1
2
3
4
15
I have stomach
cramps
0
1
2
3
4
16
I feel like using now
0
1
2
3
4
Range 0-64. Handelsman, L., Cochrane, K. J., Aronson, M. J. et al. (1987)
Two New Rating Scales for Opiate Withdrawal, American Journal of Alcohol Abuse, 13, 293-308.
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Version 2.0, 11 MARCH 2015
Page 120 of 122
APPENDIX 5: CARDIOVASCULAR RELATED PROHIBITED MEDICATIONS AND CARDIOLOGICAL 
ASSESSMENTS  
The Cardiological Assessments are provided on the subsequent pages.
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Version 2.0, 11 MARCH 2015
Page 121 of 122
Canadian Cardiovascular Society Grading of Angina Pectoris
Sample – actual grading scale will be completed at appropriate visits
Grade
Description
Grade I
Ordinary physical activity does not cause angina, such as walking 
and climbing stairs. Angina with strenuous or rapid or prolonged 
exertion at work or recreation
Grade II
Slight limitation of ordinary activity. Walking or climbing stairs
rapidly, walking uphill, walking or stair climbing after meals, or in
cold, or in wind, or under emotional stress, or only during the few 
hours after awakening. Walking more than two blocks on the level
and climbing more than one flight of ordinary stairs at a normal 
pace and in normal conditions
Grade III
Marked limitation of ordinary physical activity. Walking one or two
blocks on the level and climbing one flight of stairs in normal 
conditions and at normal pace
Grade IV
Inability to carry on any physical activity without discomfort,
anginal syndrome may be present at rest
References
Campeau Lucien. Grading of angina pectoris. Circulation 1976;54:522-3
Available on the Canadian Cardiovascular Society Website at www.ccs.ca
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Protocol No. TR03ext
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Version 2.0, 11 MARCH 2015
Page 122 of 122
NYHA FUNCTIONAL CLASSIFICATION
Sample – actual grading scale will be completed at appropriate visits
The NYHA classifies heart failure into classes based on functional limitations and severity.
Class
Patient Symptoms
Class I
(Normal)
Few observable symptoms, no limitation in ordinary physical activity. 
Class II
(Mild)
Mild observable symptoms and slight limitation during ordinary activity. 
Comfortable at rest.
Class III
(Moderate)
Marked limitation in physical activity due to symptoms even during less-
than-ordinary activity. Comfortable only at rest.
Class IV
(Severe)
End-stage heart failure. Severe limitations. Experience symptoms even 
while at rest.
ACC/AHA CLASSIFICATION OF CHF
The ACC/AHA created four classifications from risk for developing the disease to severe 
disability.
Stage
Description
A
(High risk for developing  CHF)
Hypertension, diabetes mellitus, family history, 
coronary artery disease
B
(Asymptomatic HF)
Previous myocardial infarction (heart attack), 
valvular disorders, left ventricular dysfunction
C
(Symptomatic HF)
Structural heart disease, fatigue, low tolerance 
level for physical activity
D
(Refractory end-stage HF)
Severe limitations. Experience symptoms even 
while at rest.
Source: American Heart Association
Page 220


Page 1 of 126 
 CLINICAL PROTOCOL 
Protocol Number: 
TR03ext 
Version Number: 
3.0 
Version Date: 
02 June 2016 
EudraCT No. 
2013-005628-41 
Protocol Title: 
An Open Label Extension Study of the Safety and Anti-
Pruritic Efficacy of Nalbuphine HCl ER Tablets in 
Prurigo Nodularis Patients  
Study Sponsor: 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, Connecticut 06510 
United States 
Phone: (203) 304-2499 
www.trevitherapeutics.com 
CONFIDENTIAL 
This document is the confidential and proprietary information of Trevi Therapeutics, Inc.  By 
reviewing this document, you agree to keep it confidential and to use and disclose it solely for the 
purpose of assessing whether your organization will participate in and/or the performance of the 
proposed clinical study.  Any permitted disclosures will be made only on a confidential 
“need-to-know” basis within your organization or to your independent ethics committee(s).  Any 
other use, copying, disclosure, or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by Trevi Therapeutics, Inc.  Any supplemental information (e.g., 
amendments) 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 
document.  Any person who receives this document without due authorization from Trevi 
Therapeutics, Inc., is requested to return it to Trevi Therapeutics, Inc., or promptly destroy it.  All 
other rights reserved.  This study is to be performed in accordance with Good Clinical Practice 
(GCP), the ethical principles that have their origin in the Declaration of Helsinki, International 
Conference on Harmonisation (ICH) E6, and Title 21 of the Code of Federal Regulations (CFR), 
Parts 50, 56, and 312 and European Union Directive 2001/20/EC, (or equivalent regulatory body 
regulations/guidelines, as applicable). 
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Protocol No. TR03ext 
Trevi Therapeutics, Inc. 
Version 3.0, 02 JUNE 2016 
          Page 2 of 126 
Investigators: 
Multicenter 
Research Facilities: 
Multicenter 
Institutional Review Board/ 
Independent Ethics Committee:  
Multicenter 
SPONSOR: 
Trevi Therapeutics, Inc.  
195 Church Street, 14th Floor  
New Haven, CT 06510 
 
Office Phone: (203) 304-2499 
Office Fax: 
(203)
526-
0266 
SPONSOR CONTACT: 
Thomas Sciascia, M.D. 
Chief Medical Officer 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, CT 06510 
Office Phone    (203) 304-2499 
Office 
Fax:
(203) 
526-
0266 
PPD MEDICAL MONITOR: 
Edward Matheis, MD, PPD Medical Monitor 
Telephone:  
(888) 483-7729 
Fax:   
 
(888) 529-3580 
Serious Adverse Event Fax number:  
(888) 529-3580 
Page 222


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Protocol No. TR03ext 
Trevi Therapeutics, Inc. 
Version 3.0, 02 JUNE 2016 
          Page 4 of 126 
INVESTIGATOR SIGNATURE PAGE 
I have read the attached protocol entitled:  An Open Label Extension Study of the Safety and Anti-Pruritic 
Efficacy of Nalbuphine HCl ER Tablets in Prurigo Nodularis Patients dated 02 JUNE 2016 and agree to 
abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on Good 
Clinical Practice and applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 
Title 21 of the CFR, Parts 11, 50, 54, 56, and 312 and European Union Directive 2001/20/EC or equivalent 
regulatory body regulations/guidelines, as applicable. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
•
Myself (including, if applicable, my spouse [or legal partner], and dependent children)
•
My sub-investigators (including, if applicable, their spouses [or legal partners], and dependent children)
The Financial Disclosure Statements will be completed before study initiation, during the study if there are 
changes that affect my financial disclosure status, and after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Trevi Therapeutics, Inc. 
Principal Investigator: 
__________________________________ 
___________ 
Name of Principal Investigator 
Date 
__________________________________ 
Institution or Clinical Practice 
__________________________________ 
      Signature 
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Protocol No. TR03ext 
Trevi Therapeutics, Inc. 
Version 3.0, 02 JUNE 2016 
          Page 5 of 126 
1 STUDY SYNOPSIS 
Title 
An Open Label Extension Study of the Safety and Anti-
Pruritic Efficacy of Nalbuphine HCl ER Tablets in Prurigo 
Nodularis Patients  
Sponsor 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, Connecticut  06510 
United States 
Phone: (203) 304-2499 
www.trevitherapeutics.com 
Protocol Number 
TR03ext 
Version and Date 
Amendment 2: Version 3.0 dated 02 JUNE 2016 
Amendment 1: Version 2.0 dated 11 MARCH 2015 
Version 1.0 dated 24 JUNE 2014 
Indication 
Prurigo Nodularis (PN) 
Investigational Product 
nalbuphine hydrochloride (HCl) extended-release (ER) 
tablets 
Active Ingredient 
nalbuphine hydrochloride 
Route of Administration 
Oral 
Duration of Study 
The total study duration for any individual patient will be 
up to 53 weeks.  Patients will receive drug treatment for up 
to 50 weeks. 
Study Phase 
Phase 2/3 
Study Design 
Open label 
Planned Sample Size 
No a priori planned sample size is designated for this 
study.  Eligible patients who have successfully completed 
the TR03 study and wish to participate in TR03ext may be 
enrolled, treated, and analyzed.  The maximum number of 
patients will not exceed the number of patients who 
complete the TR03 study  (i.e., approximately 60 patients) 
Total Number of Centers 
Up to 20 sites in North America and Europe 
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Protocol No. TR03ext 
Trevi Therapeutics, Inc. 
Version 3.0, 02 JUNE 2016 
          Page 6 of 126 
Primary Objective 
•
To evaluate the safety and tolerability of nalbuphine
HCl ER tablets during a drug treatment period of up
to 50 weeks.
Secondary Objectives 
•
To evaluate the safety of nalbuphine by achieved
maintenance dose at the end of Treatment Week 4
•
Assess skin lesion improvement using the metrics
of the PAS
•
Change from Baseline in Patient-Reported
Outcome measures Worst (i.e., most severe itching
over the past 24 hours) itch NRS, average itch
intensity NRS, VRS (itchy, burning and stinging),
MOS Sleep-R, ItchyQoL, HADS by the final
Treatment Period Visit
•
Change between Baseline and the final Treatment
Period Visit in PBI-P
•
A description of the frequency and reasons for dose
up- and down-titration and treatment
discontinuation during the study
•
Frequency and distribution by time on study of
patients determined to meet failure-to-improve
criteria
•
Changes in the PRO measurements during the
Washout Period after cessation of treatment of
nalbuphine HCl ER tablets
•
Time to first use of rescue medications and the
number of days of use of rescue medications for
itching
•
To evaluate the daily changes in the Subjective
Opiate Withdrawal Scale (SOWS) during the
Washout Period after cessation of treatment of
nalbuphine HCl ER tablets.
Exploratory Objectives 
A single exploratory objective of the study is to evaluate: 
The potential of nalbuphine HCl ER tablets to 
impact on the measurement of nerve fiber density 
(histology) and MOR/KOR density (histology, 
Western Blot), as well as histological (H&E) 
changes in skin biopsies taken at Baseline and by 
the final Treatment Period Visit to investigate 
possible correlation with any clinical response and 
also compared to biopsy material assessed during 
study TR03 (optional procedures at select sites 
only) 
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Protocol No. TR03ext 
 
Trevi Therapeutics, Inc. 
Version 3.0, 02 JUNE 2016 
           Page 7 of 126 
 
 
Selection Criteria 
Inclusion Criteria: 
Patients must meet all of the following criteria to be 
eligible: 
1. Have been adequately informed of the nature and 
risks of the study and have given written informed 
consent at the conclusion of TR03 Visit 6 and prior 
to Visit 1a. 
2. Have completed participation in the TR03 study 
Completion of participation in the TR03 study is 
defined as completion of Study Drug treatment 
through TR03 Visit 5 and completion of the TR03 
Visit 6 
3. Agree to comply with the contraception 
requirements as below: 
 
Sexually active female patients of childbearing 
potential are required to use one barrier method 
(e.g., condom, cervical cap, or diaphragm) of 
contraception in addition to one other method (e.g., 
intrauterine device [IUD], hormonal contraception, 
tubal ligation, Essure procedure, or spermicide)  
For the purpose of this study, all females are 
considered to be of childbearing potential unless 
they are post-menopausal (i.e., at least 1 year since 
last menses and age >50 years) or surgically sterile 
(i.e., tubal ligation, hysterectomy and/or bilateral 
oophorectomy) 
Female patients who are abstinent may participate 
in the study, however; they must be counseled on 
the requirement to use appropriate contraception 
should they become sexually active.  This 
counseling should occur at each study visit and 
must be documented in source records 
4. Ability and acceptance to provide written informed 
consent. 
5. Willing and able to comply with study 
requirements and restrictions  
6. Agree to the confidential use and storage of all data 
(including photography) and use of all anonymized 
data for publication including scientific 
publication. 
 
 
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Protocol No. TR03ext 
 
Trevi Therapeutics, Inc. 
Version 3.0, 02 JUNE 2016 
           Page 8 of 126 
 
 
Selection Criteria 
Exclusion Criteria: 
If a patient meets any of the following criteria, he or she is 
not eligible: 
1. Patients with a history of congestive heart failure of 
Class 2 or higher as graded using the New York 
Heart Association scale (scale provided in Appendix 
5) 
2. Patients with a history of angina pectoris grade 2 or 
higher as graded using the Canadian Cardiovascular 
Society grading scale (scale provided in Appendix 
5)  
3. History of ventricular tachycardia, torsade de 
pointes, family history of sudden death, myocardial 
infarction or acute coronary syndrome within the 
previous 3 months, as reported by the patient. 
4. Serum potassium below the laboratory lower limit 
of normality at TR03 Visit 5.  Note: Potassium 
levels below the laboratory lower limit of 
normal at Visit 6/Visit 1a should be repeated 
and potassium supplementation provided as 
appropriate. 
5. QTcF interval >450ms on screening/Visit 1a ECG. 
6. Heart rate <50 BPM on any screening measurement.  
Patients with a resting heart rate of <50 bpm will 
have it repeated once after 5 minutes in the supine 
position, and if it remains <50 bpm during the 
repeat, they will be considered a screen failure. 
7. Use of a medication known to be associated with 
risk of torsade de pointes (see Section 9.7.8, Safety 
Assessments, for hyperlink to the CredibleMeds 
Filtered QTDrug List for cardiovascular related 
prohibited medications with a known associated risk 
of Torsade de Pointes)  
8. History of substance abuse within the past year as 
determined by the Investigator 
9. Significant medical condition or other factors that 
in the opinion of the Investigator may interfere 
with the conduct of the study 
10. Known hypersensitivity or allergy to nalbuphine or 
formulation components 
11. Is a pregnant or lactating female 
Study Treatment 
Allocation 
All patients who are enrolled into the study will receive 
active treatment with nalbuphine HCl ER tablets. 
Study Procedures 
 
 
Visit 1a of the TR03ext study is temporally the same visit 
as TR03 Visit 6.  Patients who do not consent by the end of 
the TR03 study visit 6 are no longer eligible for the 
extension study.  Study TR03 Visit 6 procedures in 
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Protocol No. TR03ext 
 
Trevi Therapeutics, Inc. 
Version 3.0, 02 JUNE 2016 
           Page 9 of 126 
 
 
common with Study TR03ext Visit 1a procedures do not 
have to be repeated.   
For All Patients: 
For all patients, TR03ext Visits (both during the Treatment 
Period and Observation Period) will include recording of 
vital signs, completion of PRO questionnaires, assessment 
of AEs, and recording of concomitant medications.  
On Visit 1a, patients will either enter directly into the drug 
Treatment Period or into a no-drug Observation Period 
based on their reported Worst itch NRS scores (defined as 
most severe itching over the past 24 hours) on that Visit 
day.  
Patients with a Worst Itch NRS score greater than or 
equal to 5 (≥ 5) enter the Treatment Period: 
Patients with Worst itch NRS ≥ 5 at Visit 1a will start in 
the drug Treatment Period of the study and will receive 
Study Drug starting with an evening 30 mg dose (to be 
taken at home), after the Treatment Visit 1a procedures 
have been completed.  Receipt of the first dose of study 
drug will define Treatment Period Day 1.  Treatment Visit 
1a for these patients is also Treatment Visit 1 (TV1).  
Subsequent visits will be defined as TV2, TV3, etc.  In 
addition, during the time period of dose titration, 
information will be obtained via telephone communication; 
these will be defined as TC1, and TC2. 
The dose will be titrated for up to 4 weeks based on 
tolerability, after which time the dose achieved (as of the 
end of Treatment Week 4) will be maintained up to an 
additional 46 weeks (with the exception of permitted down 
titrations); see Table 3 Study Drug Dosing schedule. 
For patients transitioning from the Observation period, the 
total time in the Treatment Period plus any time in the 
Observation Period will be a total of 50 weeks.   
Safety laboratory data and blood for PK, ECGs (locally and 
centrally read), and physical examinations including the 
PAS assessment will be performed periodically according 
to the Schedule of Events (See Appendix 1).  Schematic 
descriptions of the study can be found in Appendix 2. 
All patients on drug treatment will enter a 2-week wash-out 
and safety follow up period following the end of the 
Treatment Period with procedures conducted according to 
the Schedule of Events (See Appendix 1). 
Patients with a Worst Itch NRS score less than 5 (< 5) 
enter the Observation Period: 
Patients with a Worst Itch NRS score < 5 at Visit 1a will 
enter into an extended screening period, Observation Period 
(no drug treatment), of the study and will be followed for 
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up to 12 weeks (extended screening weeks).  Visit 1a for 
these patients is also Observational Visit 1 (OV1).  
Subsequent visits will be defined as OV2, OV3 and OV4 
and will occur at approximately monthly intervals for the 
next 3 months.   
During this Observation period, patients who report an 
increase in their Worst Itch NRS with a score of ≥ 5 at any 
one of their Observation Visits and meet all other eligibility 
criteria will be able to enroll immediately into the 
Treatment Period of the study and Visit1b procedures are to 
be performed.  Patients will receive open-label Study Drug 
starting with an evening 30 mg dose (to be taken at home), 
after the Visit 1b procedures have been completed.  Receipt 
of the first drug will indicate the start of their Treatment 
Period and enrollment into the study.  The duration of the 
Treatment Period for such a patient will vary depending 
upon the visit at which they transition from the Observation 
Period to the Treatment Period. 
Patients in the Observation Period whose Worst Itch NRS 
score remains <5 over the 12 extended screening weeks 
will be screen failed from the study at the end of that time 
period. 
 
Failure to Improve Criteria: 
Beginning on TV 3, and at every subsequent Treatment 
Visit, patients with a Worst itch NRS equal to or greater 
than (≥) the Worst Itch NRS at Visit 1a (or at Visit 1b in 
the case of patients who require the Observation Visit 
period) will be discontinued from taking study 
drug.   Patients discontinued from taking study drug are to 
undergo the End of Treatment Visit (TV14), the 
Washout/Safety Follow-up Period assessment in two 
weeks, and receive a follow-up Telephone Contact 30 days 
following end of study drug dosing for final safety 
assessment. 
Safety Assessments 
Safety will be assessed based on adverse events (AEs), 
clinical laboratory measurements, Investigator review and 
central cardiac core laboratory read-12-lead 
electrocardiogram (ECG), vital signs and physical 
examinations. 
An unblinded, independent Data Safety Monitoring Board 
(DSMB) will periodically review safety data during the 
time period that the blinded part of the nalbuphine HCl 
program remains ongoing.  The frequency of data review 
and DSMB processes are outlined in the DSMB charter. 
Efficacy Assessments 
Efficacy Measurements: 
• 
Worst itch intensity (from NRS) 
• 
Average itch intensity (from NRS)  
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• 
VRS (itchy, burning and stinging) 
• 
ItchyQoL  
• 
MOS Sleep-R 
• 
HADS 
• 
PAS  
• 
PBI-P 
• 
Frequency, pattern, and reasons for dose 
titration 
• 
Use of rescue medications for itching 
Optional Procedures (at select sites only): 
• 
Nerve fiber density (histology) at Baseline and 
the final Treatment Period Visit 
• 
MOR/KOR density (histology, Western Blot) 
at Baseline and the final Treatment Period Visit 
• 
Histological analysis (H&E) at Baseline and 
the final Treatment Period Visit 
Pharmacokinetic 
Assessments 
Blood samples for nalbuphine plasma concentration (and 
metabolites as needed) will be collected periodically 
according to the Schedule of Events (Appendix 1).  
Study Endpoints 
Primary Endpoint: 
• 
A description of the incidence and nature of 
Treatment Emergent Adverse Events (TEAE) 
during Treatment Weeks 5- 50 
Secondary Endpoints 
Visit 1a or 1b will serve as the baseline visit for efficacy 
endpoints.  Visit 1a will be the baseline for patients 
directly entering the Treatment Period as of Visit 1a.  
Visit 1b will be the baseline for patients entering the 
Treatment Period after participating in the Observation 
Period for any length of time. 
• 
Assess skin lesion improvement using the metrics 
of the PAS  
• 
Change from Baseline in Patient-Reported 
Outcome measures Worst itch NRS, average itch 
intensity NRS, VRS (itchy, burning and stinging), 
MOS Sleep-R, ItchyQoL, HADS) by Treatment 
Period study visit and Baseline NRS score 
• 
Change between Baseline and final Treatment 
Period visit in PBI-P 
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• 
A description of the percentage of patients utilizing 
various doses of nalbuphine HCl ER tablets by 
Study Week 
• 
A description of the frequency and reasons for dose 
up and down-titration and treatment 
discontinuation during the study 
• 
Frequency and distribution by time on study of 
patients determined to meet failure to improve 
criteria 
• 
Changes in the PRO measurements during the 
Washout Period after cessation of treatment of 
nalbuphine HCl ER tablets 
• 
Time to the first use of rescue medications and the 
number of days of use of rescue medications for 
itching 
• 
To evaluate the daily changes in the Subjective 
Opiate Withdrawal Scale (SOWS) during the 
Washout Period after cessation of treatment of 
nalbuphine HCl ER tablets 
Exploratory Endpoint 
Impact on the measurement of nerve fiber density 
(histology) and MOR/KOR density (histology, 
Western Blot), as well as histological (H&E) 
changes in skin biopsies taken at Baseline and the 
final Treatment Period Visit to investigate possible 
correlation with any clinical response and also 
compared to biopsy material assessed during study 
TR03 (optional procedures at select sites only). 
 
Statistical Methodology 
Efficacy:  
All efficacy endpoints will be evaluated through the 
generation of summary statistics.  For continuous variables, 
the mean, standard deviation, median, minimum, and 
maximum will be presented for a particular visit and for the 
change from baseline (Visit 1a or 1b).  For categorical 
variables, the number and percentage of patients within 
each category of classification will be summarized by study 
visit.  No formal statistical testing will be conducted. 
Safety: 
The incidence of AEs will be summarized through the 
presentation of proportions by MedDRA body system 
classification and preferred term.  Vital signs and 
laboratory data will be summarized using continuous-based 
descriptive statistics (n, mean, SD, median, minimum, 
maximum).  The extent and duration of use of rescue 
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medications will be similarly summarized using descriptive 
statistics.  Summary statistics for AEs with onset during the 
Observation Period will be separately summarized.  No 
formal statistical analysis will be performed on safety 
outcomes; inferences, if any, will be derived through 
clinical review and interpretation. 
 
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TABLE OF CONTENTS 
1 
STUDY SYNOPSIS ................................................................................................. 5 
TABLE OF CONTENTS ............................................................................................... 14 
LIST OF TABLES .......................................................................................................... 17 
LIST OF FIGURES ........................................................................................................ 17 
2 
LIST OF ABBREVIATIONS ............................................................................... 18 
3 
INTRODUCTION ................................................................................................. 20 
3.1 
PRURIGO NODULARIS AND STUDY RATIONALE .................................................. 20 
3.1.1 
General Information on Prurigo Nodularis ........................................................ 20 
3.1.2 
Potential Mechanism of Prurigo Nodularis Pathophysiology............................ 22 
3.1.3 
Rationale for Investigating Nalbuphine HCl ER in Prurigo Nodularis ............. 25 
3.2 
NALBUPHINE ......................................................................................................... 28 
3.3 
NALBUPHINE HCL ER TABLET CLINICAL DEVELOPMENT ............................... 29 
3.3.1 
Overall Summary ............................................................................................... 29 
3.3.2 
Clinical Study TR01 in Hemodialysis Patients and Healthy Volunteers........... 30 
3.3.3 
Additional Nalbuphine HCl ER Tablet Clinical Data ....................................... 32 
4 
STUDY OBJECTIVES.......................................................................................... 33 
4.1 
PRIMARY OBJECTIVE ........................................................................................... 33 
4.2 
SECONDARY OBJECTIVES ..................................................................................... 33 
4.3 
EXPLORATORY OBJECTIVES ................................................................................ 33 
5 
STUDY ENDPOINTS............................................................................................ 34 
5.1 
PRIMARY ENDPOINT ............................................................................................. 34 
5.2 
SECONDARY ENDPOINTS ...................................................................................... 34 
5.3 
EXPLORATORY ENDPOINTS.................................................................................. 34 
6 
NUMBER OF SITES AND PATIENTS .............................................................. 35 
7 
ESTIMATED STUDY DURATION .................................................................... 35 
8 
SELECTION CRITERIA ..................................................................................... 35 
8.1 
STUDY POPULATION ............................................................................................. 35 
8.2 
INCLUSION CRITERIA ........................................................................................... 35 
8.3 
EXCLUSION CRITERIA .......................................................................................... 36 
9 
STUDY PLAN ........................................................................................................ 36 
9.1 
GENERAL STUDY DESIGN ..................................................................................... 36 
9.2 
RATIONALE FOR STUDY DESIGN .......................................................................... 36 
9.3 
SAFETY MONITORING PLAN ................................................................................ 38 
9.4 
RISK-BENEFITS ..................................................................................................... 40 
9.5 
STUDY OVERVIEW ................................................................................................ 41 
9.6 
STUDY PROCEDURES ............................................................................................ 43 
9.6.1 
Visit 1a (Day 1 of Study Week 1)...................................................................... 44 
9.6.2 
Treatment Period (Treatment Weeks 1-50) ....................................................... 46 
9.6.3 
Observation Period (Extended Screening Weeks 1-12) .................................... 60 
9.6.4 
Transition to Treatment Period (Visit 1b).......................................................... 62 
9.6.5 
Washout and Safety Follow-Up Period ............................................................. 64 
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9.6.6 
Premature Discontinuation of Study Drug Follow-up Telephone Contact Visit 64 
9.6.7 
Early Termination Visit for Patients who Withdraw Consent ........................... 65 
9.6.8 
Unscheduled Visits ............................................................................................ 66 
9.6.9 
Schedule of Events............................................................................................. 66 
9.7 
STUDY DRUG TREATMENT AND DRUG ACCOUNTABILITY .................................. 66 
9.7.1 
Study Drug Dosing ............................................................................................ 66 
9.7.2 
Down-Titration .................................................................................................. 70 
9.7.3 
Multiple Missed Doses ...................................................................................... 70 
9.7.4 
Overdose ............................................................................................................ 70 
9.7.5 
Treatment Compliance ....................................................................................... 70 
9.7.6 
Rescue Medications, Concomitant Medications, Prohibited Medications, and 
Pre-Medications ................................................................................................................ 70 
9.7.7 
Efficacy Assessments ........................................................................................ 71 
9.7.8 
Safety Assessments ............................................................................................ 75 
10 
STUDY DRUG ....................................................................................................... 76 
10.1 
FORMULATION, PACKAGING AND LABELING ...................................................... 76 
10.2 
SHIPPING, STORAGE AND HANDLING .................................................................. 76 
10.3 
UNBLINDING ......................................................................................................... 77 
10.4 
DRUG ACCOUNTABILITY ...................................................................................... 77 
11 
PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT ... 77 
11.1 
PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT ASSOCIATED 
WITH FAILURE-TO-IMPROVE CRITERIA .............................................................. 77 
11.2 
PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT FOR REASONS 
OTHER THAN FAILURE-TO-IMPROVE.................................................................. 78 
12 
PREMATURE WITHDRAWAL OF PATIENTS FROM THE STUDY ........ 78 
13 
WARNINGS AND PRECAUTIONS ................................................................... 79 
14 
EFFICACY EVALUATIONS .............................................................................. 79 
14.1 
EXPLORATORY ..................................................................................................... 80 
15 
COLLECTION, HANDLING, AND ANALYSIS OF PHARMACOKINETIC 
BLOOD SAMPLES ............................................................................................... 80 
15.1 
BLOOD SAMPLE COLLECTION ............................................................................. 80 
15.2 
CENTRAL LABORATORY ...................................................................................... 80 
15.3 
PHARMACOKINETIC SAMPLES ............................................................................. 80 
15.4 
PREPARATION, STORAGE, AND HANDLING FOR PHARMACOKINETIC SAMPLES 80 
15.5 
ANALYTICAL ......................................................................................................... 81 
16 
TISSUE SAMPLES AND HISTOLOGY ............................................................ 81 
17 
SAFETY EVALUATIONS ................................................................................... 82 
17.1 
PHYSICAL EXAMINATION ..................................................................................... 82 
17.2 
VITAL SIGN MEASUREMENTS .............................................................................. 82 
17.3 
LABORATORY EVALUATIONS ............................................................................... 82 
17.4 
ELECTROCARDIOGRAM ........................................................................................ 82 
17.5 
ADVERSE EVENTS ................................................................................................. 83 
17.5.1 
Adverse Event Definition .................................................................................. 83 
17.5.2 
Serious Adverse Events ..................................................................................... 84 
17.5.3 
Non-Serious Adverse Events ............................................................................. 85 
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17.5.4 
Definition of Relationship to Study Medication ................................................ 85 
17.5.5 
Definition of Severity ........................................................................................ 85 
17.5.6 
Definition of Unexpected Adverse Event .......................................................... 86 
17.6 
DATA SAFETY MONITORING BOARD ................................................................... 86 
18 
EMERGENCY PROCEDURES .......................................................................... 86 
18.1 
EMERGENCY SPONSOR CONTACT ........................................................................ 86 
19 
CONSIDERATION, ANALYSIS PLAN AND DETERMINATION OF 
SAMPLE SIZE ....................................................................................................... 86 
19.1 
GENERAL .............................................................................................................. 86 
19.2 
INTERIM ANALYSES .............................................................................................. 87 
19.3 
METHODS FOR HANDLING MISSING DATA .......................................................... 87 
19.4 
PATIENT DISPOSITION .......................................................................................... 87 
19.5 
BASELINE CHARACTERISTICS .............................................................................. 87 
19.6 
CONCOMITANT MEDICATIONS............................................................................. 87 
19.7 
STUDY DRUG DOSING ............................................................................................ 87 
19.8 
EFFICACY ANALYSES ............................................................................................ 87 
19.8.1 
Efficacy Population............................................................................................ 87 
19.8.2 
Premature Discontinuation Due to Lack of Efficacy or Adverse Events .......... 88 
19.9 
SAFETY ANALYSES ............................................................................................... 88 
19.9.1 
Safety Population ............................................................................................... 88 
19.9.2 
Adverse Events .................................................................................................. 88 
19.9.3 
Vital Signs.......................................................................................................... 88 
19.9.4 
Laboratory Evaluations ...................................................................................... 88 
19.9.5 
Physical Examinations ....................................................................................... 88 
19.9.6 
Electrocardiograms ............................................................................................ 89 
19.10 DETERMINATION OF SAMPLE SIZE ...................................................................... 89 
19.11 PHARMACOKINETIC AND PHARMACOKINETIC / 
PHARMACODYNAMIC ANALYSES ............................................................. 89 
20 
ETHICS .................................................................................................................. 89 
20.1 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD ........ 89 
20.2 
ETHICAL CONDUCT OF THE STUDY ..................................................................... 90 
20.3 
PATIENT INFORMATION AND INFORMED CONSENT ............................................ 90 
21 
STUDY ADMINISTRATION .............................................................................. 90 
21.1 
CLINICAL MONITORING ....................................................................................... 90 
21.2 
DATA QUALITY ASSURANCE ................................................................................ 91 
21.3 
RETENTION OF STUDY RECORDS ......................................................................... 91 
21.4 
CONFIDENTIALITY ................................................................................................ 92 
21.5 
DOCUMENTATION OF STUDY RESULTS ................................................................ 92 
21.6 
USE OF STUDY RESULTS ....................................................................................... 93 
22 
REFERENCES....................................................................................................... 94 
APPENDICES ............................................................................................................... 100 
APPENDIX 1: 
SCHEDULE OF EVENTS ....................................................................... 101 
APPENDIX 2: 
STUDY SCHEMATIC FLOW CHARTS ................................................... 108 
APPENDIX 3: 
CLINICAL LABORATORY TESTS ......................................................... 111 
APPENDIX 4:  
PATIENT REPORTED OUTCOMES ....................................................... 112 
Medical Outcomes Sleep Scale (Revised MOS Sleep-R)................................... 113 
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ItchyQoLTM ......................................................................................................... 115 
Prurigo Activity Score (PAS) ............................................................................. 118 
Patient Benefit Index, Pruritus Version (PBI-P) ................................................. 119 
Numerical Rating Scale (Worst Itch) .................................................................. 121 
Numerical Rating Scale (Average-Itch).............................................................. 121 
Verbal Rating Scale ............................................................................................ 121 
Hospital Anxiety and Depression Scale (HADS) ............................................... 122 
Subjective Opiate Withdrawal Scale (SOWS) .................................................... 123 
APPENDIX 5:  
CARDIOVASCULAR RELATED PROHIBITED MEDICATIONS AND 
CARDIOLOGICAL ASSESSMENTS ........................................................................ 124 
Canadian Cardiovascular Society Grading of Angina Pectoris ......................... 125 
NYHA FUNCTIONAL CLASSIFICATION ......................................................... 126 
ACC/AHA CLASSIFICATION OF CHF ............................................................. 126 
 
 
LIST OF TABLES 
TABLE 1: 
ETIOLOGY OF CHRONIC PRURITUS REPORTED IN PRURIGO NODULARIS 
PATIENTS (N=108)..................................................................................................... 21 
TABLE 2:  
TR03EXT STUDY PERIODS ............................................................................ 42 
TABLE 3: 
 DOSING SCHEDULE FOR TR03EXT ............................................................... 69 
TABLE 4: SCHEDULE OF EVENTS FOR VISITS 1A AND 1B .................................................. 101 
TABLE 5:  
TREATMENT WEEKS 2-4 ............................................................................. 102 
TABLE 6: TREATMENT PERIOD VISITS12 DURING STUDY WEEKS 5-50 AND 
WASHOUT/SAFETY FOLLOW-UP VISIT OR TREATMENT PERIOD EARLY TERMINATION 
VISIT ........................................................................................................................ 103 
TABLE 7:  
OBSERVATION PERIOD VISITS5 ................................................................... 105 
TABLE 8:  TREATMENT VISIT SCHEDULE FOR PATIENTS ENTERING TREATMENT VIA VISIT 
1B ............................................................................................................................ 106 
TABLE 9: RESCUE MEDICATIONS FOR ITCHING ................................................................ 107 
 
LIST OF FIGURES 
 
FIGURE 1:  
MEAN VAS SCORE (SD) FOR ALL PATIENTS AS A FUNCTION OF NALBUPHINE 
HCL DOSE ADMINISTERED AS NALBUPHINE HCL ER TABLETS.  N= 14 EXCEPT FOR 180 
MG (N=13) AND 240 MG (N=4).  SOURCE: NAL.001.TR01.PD ................................. 28 
FIGURE 2:  
OVERVIEW OF TR03-EXT STUDY DESIGN ................................................. 108 
FIGURE 3:  
EXAMPLES ILLUSTRATING POSSIBLE OBSERVATION AND TREATMENT PERIODS 
SCENARIOS IN TR03-EXT ........................................................................................ 109 
FIGURE 4:  
DOSING SCHEDULE IN TR03EXT ................................................................. 110 
 
 
 
 
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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACC 
American College of Cardiology 
AE 
Adverse event 
AHA 
American Heart Association 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic and Therapeutic Class 
BID 
Twice daily 
BMI 
Body Mass Index 
BP 
Blood pressure 
BPM 
Beats per minute 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ER 
Extended release 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&E 
Hematoxylin and eosin 
HADS 
Hospital Anxiety and Depression Scale 
HCG 
Human chorionic gonadotropin 
HCl 
Hydrochloric acid 
HD 
Hemodialysis 
H pylori 
Helicobacter pylori 
HR 
Heart rate 
ICF 
Informed consent form 
ICD-10 
International Classification of Diseases, 10th revision  
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Abbreviation 
Definition 
ICH 
International Conference on Harmonization 
IFSI 
International Forum for the Study of Itch  
IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
KOR 
Kappa Opiate Receptor 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOR 
Mu Opiate Receptor 
MOS 
Medical Outcomes Study 
MITT 
Modified Intent-To-Treat 
NONMEM 
Non-linear mixed effects modeling 
NRS 
Numerical Rating Scale 
NYHA 
New York Heart Association 
OV 
Observation Period Visit 
OTC 
Over-the-counter 
PAS 
Prurigo Activity Score 
PBI-P 
Patient Benefit Index, pruritus version 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic 
PN 
Prurigo Nodularis 
PRO 
Patient-Reported Outcome; In this study, PRO instruments 
administered at the site are as follows: NRS, VRS, ItchyQoL, 
PBI-P, MOS Sleep-R, HADS, SOWs 
PUVA 
Psoralen plus Ultraviolet Light A 
QoL 
Quality of Life 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOWS 
Subjective Opiate Withdrawal Scale 
TC 
Telephone Call 
TdP 
Torsade de Pointes 
TV 
Treatment Period Visit 
UP 
Uremic Pruritus 
VRS 
Verbal Rating Scale 
WHO 
World Health Organization 
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3 INTRODUCTION 
3.1 
PRURIGO NODULARIS AND STUDY RATIONALE 
3.1.1 General Information on Prurigo Nodularis 
Prurigo Nodularis (PN) is an intensely pruritic dermatologic condition with the presence of 
papules as well as nodules with excoriations and ulcerations.  The basis of PN is a pre-
existing severe and chronic pruritus of various etiologies (see Table 1).  The pruritus leads 
to scratching.  However, the etiology or predisposing factors leading to the development of 
papules and nodules of PN are largely unknown (Eigelshoven et al 2009; Valdya and 
Schwartz 2008; Lee and Shumack 2005).  Iking et al (2012) reports that in the past few years 
the hypothesis for the etiology of PN as being a reaction pattern due to a “vicious cycle of 
repeated itching and scratching” is gaining wider acceptance in the medical community. 
 
With regard to the types of pre-existing chronic pruritus conditions that have been reported 
in PN patients, Table 1 summarizes data reported by Iking et al (2012) in their study of PN 
patients (N=108).  Pruritus secondary to multi-factorial etiologies (“Mixed Origin”) was 
the most common source attributed to the cause of the chronic pruritus.  The majority of 
the “mixed origin” patients had a combination of dermatological and systemic diseases or a 
combination of several systemic disorders. 
 
Iking et al (2012) did not attribute any cases of PN to an underlying diagnosis that was 
solely psychological in origin.  In the subjects who were diagnosed with PN from mixed 
origin etiologies (summarized in Table 1), the authors attributed psychological factors 
related to chronic pruritus etiology to be present in 5.6% of the PN subjects categorized as 
having mixed (multi-factorial) origin pruritus.  In a study focused on understanding 
psychosomatic/psychiatric dimensions related to chronic itch, Schneider et al (2006) 
reported on 44 PN patients.  The authors stated that 34% of subjects had no accompanying 
psychiatric diagnosis and 46.8% were given a diagnosis of “psychological or behavioral 
factors associated with disorders classified elsewhere” (ICD-10 code F54) –indicating that 
psychological factors may play a role in the development and course of the condition.  
Payne et al (1985) reported psycho-social problems may have been relevant in about 33% 
of the studied 42 subjects that were adequately questioned. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1: Etiology of Chronic Pruritus Reported in Prurigo Nodularis Patients 
(N=108) 
Origin of Pruritus by 
Organ System 
Number 
of 
Patients (%) 
 %  Mixed with Organ 
Category Contribution to 
Chronic Pruritus 
Most Common 
Disease 
 
 
 
 
 
 
 
Mixed 
(pruritus 
of 
multi-factorial 
etiologies) 
 
 
 
 
 
 
 
64  (59.3%) 
 
 
Dermatological Disease 
(19.4%) 
Atopic diathesis 
 
 
 
Systemic Diseases 
(70.9%) 
Sorbitol 
Intolerance 
Lactose 
Intolerance 
Iron Deficiency 
H pylori 
Infection 
Diabetes 
Mellitus 
Renal Failure 
Neurological Disease 
(4.1%) 
Chronic pain 
Syndrome 
Neuropathy 
PUVA-pain 
Psychological Factors 
(5.6%) 
Psychological 
Factors (non-
specific) 
Origin of Pruritus by 
Organ System 
Number 
of 
Patients (%) 
      Most Common Disease 
Dermatological 
20  (18.5%) 
Atopic diathesis/dermatitis 
 
 
 
 
Systemic 
 
 
 
 
8    (7.4%) 
Sorbitol Intolerance 
Lactose Intolerance 
Hepatitis C 
H pylori infection 
Iron Deficiency 
Diabetes Mellitus 
Unknown 
14   (13%) 
- 
Neurological 
2     (1.9%) 
Brachio-radial Pruritus 
Psychological  
0      (0%) 
- 
Source: Iking et al (2012) 
 
Iking et al (2012) reported that the median value of the NRS average intensity pruritus 
measured 8 on a rating scale with anchor points of zero (no pruritus)-10 (worst imaginable 
pruritus).  Itch intensity scores ≥ 7 are considered severe in terms of itch intensity and itch 
intensity scores ≥ 3 are considered moderate in terms of itch intensity (Stander et al 2013).  
Accioly-Filho et al (2000) reports that once the cycle of pruritus-excoriation-pruritus begins, 
it is difficult to stop as PN is very resistant to therapeutic intervention strategies.  Papoiu et 
al (2013) report a central nervous system relationship to the itch-scratch cycle.  The authors 
showed that there is a complex interaction of sensory, motor and emotional components 
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based on their investigation of using real-time flare brain MRI imaging and psychophysical 
ratings of itch relief or pleasurability of scratching conducted in healthy volunteer 
experimental subjects. 
 
Eigelshoven et al (2009) reports that patients present with excruciating pruritus that is usually 
anatomically symmetrical and mainly involves the extensor aspects of the extremities, the 
shoulders, chest and sacral regions with the appearance of typical lesions. 
 
Payne et al (1985) reported in a study of 46 subjects that the patients came from all social 
classes and racial groups, almost equally divided by gender and with a mean age of 39.5 
years at the time of PN onset.  Iking et al (2012) reported in their study that the patients were 
distributed in age between 11.9 years - 95.6 years with a median age of 61.9 years and there 
were more females than males affected by the disease.  
 
Weigelt et al (2010) summarized the characteristic histological findings in PN that include 
the presence of thick compact orthohyperkeratosis; folliculosebaceous units in nonvolar skin 
in conjunction with a thick and compact cornified layer; irregular epidermal hyperplasia or 
pseudoepitheliomatous hyperplasia; focal parakeratosis; hypergranulosis; fibrosis of the 
papillary dermis with vertically arranged collagen fibers; increased number of fibroblasts 
and capillaries; a superficial, perivascular and/or interstitial inflammatory infiltrate of 
lymphocytes, macrophages and, to a lesser extent, eosinophils and neutrophils. 
 
In terms of treatment options for PN, there have been a variety of medical interventions 
discussed.  Hogan et al (2012) recently reviewed the therapies discussed in the literature 
that included topical, systemic and intra-lesion steroids administration; antihistamines; 
anxiolytics; opiate receptor antagonists; thalidomide; gabapentin; capsaicin cream; topical 
anesthetics; occlusive therapies; ultraviolet light; and reports that they had “mild to 
moderate success at best”.  The authors also comment on the potential imbalance in the 
mu-kappa opiate receptor system and mention the possibility of studying the kappa agonist 
nalfurafine (see Section 3.1.3.1, where nalfurafine was used as a positive control in 
Sponsor’s preclinical substance P mouse model of itch investigation).  Spring et al (2014) 
reported on the use of methotrexate and the need for chemotherapeutic related regular 
medical monitoring.  Liu et al (2013) and Kanavy (et al 2012) both reported on 
lenalidomide is case reports, but the drug led to side effect of a reversible myopathy in one 
of the subjects.  Accioly-Filho (2000) reported the condition is “notoriously resistant to 
therapy”.  Iking et al (2012) and Valdya and Schwartz (2008) reported a significant impact 
on the patient’s quality of life (2008).  Spring et al (2014) report PN to be debilitating 
condition and a therapeutic challenge where conventional treatments with steroids, 
standard anti-pruritic agents, phototherapy and immune-suppressors often fail.   
3.1.2 Potential Mechanism of Prurigo Nodularis Pathophysiology 
3.1.2.1 Opiate Neurobiology 
The initiating biological event in the skin is unclear but assumed to patho-physiologically 
result from a complex cross talk of different skin cells.  The neurobiology of opioid peptides 
may be involved at the peripheral level as part of a reaction to the skin tissue injury.  
Therapeutic intervention at the peripheral level through opioid pharmacology to break the 
scratch-itch cycle via interrupting positive feedback loops that have developed between 
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elements of the peripheral nervous system, immune system and various skin cell interactive 
dynamics may be possible.  In addition, central nervous system opiate neurobiology may be 
involved in a positive feedback loop between the tremendous urge to scratch and the 
pleasurable anti-pruritic relief gotten from scratching that could also be a level of therapeutic 
intervention using opioid pharmacology. 
3.1.2.2 Systems Biology Hypothesis to Prurigo Nodularis Etiology  
Diseases that arise from an abnormal interaction between integrated body system networks, 
and exhibit the concept of a positive feedback cycle which lead to an amplification of a 
biological signal; can be discussed using concepts from systems biology (Kitano 2004).  The 
physiological phenomena of a “scratch-itch cycle” (“positive feedback loop”) underlying the 
patient’s behavior, the intense (“amplified”) nature of the pruritus and the large areas of body 
surface involvement in the absence of an active dermatosis suggest a “generalized” process 
either potentially due to central nervous system circuitry pathophysiology and/or widespread 
derangement of the dermal-immune-nervous system component interactions.  PN may be 
analogous to chronic regional pain syndrome – a condition where there may or may not be 
an initiating etiological event, the intensity of pain is severe, the sensation of pain spreads to 
wide areas of the body surface and the condition is regarded as a systemic disease that 
involves both the central and peripheral components of the nervous system along with 
interactions with the immune system (Schwartzman et al 2009).  Complex regional pain 
syndrome is completely independent of any potential nociceptive initiating event.  Schmelz 
(2005) reviewed the literature on the evidence of similar biological patterns occurring in 
chronic pain and chronic itch conditions.  Iking et al (2012) reported that on onset, PN was 
localized in 68.5% of patients with only 31.5% having generalized PN.  In the majority of 
patients (56.5%), a secondary generalization of PN was observed.  In the course of PN, only 
12.0% still suffered from a localized form of PN. 
3.1.2.3 Relevant Cutaneous Peripheral Neurobiology in the Skin 
The complex neurochemical/neurohumoral interactions between the cutaneous resident mast 
cells and epidermal keratinocytes with peripheral non-myelinated type C nerve endings 
responsible for initiating the behavior of scratching as an evolved protective response to 
exogenous invading skin irritants is well summarized by Raap et al (2011) and the current 
understanding of the peripheral neuroanatomy-spinal cord synaptic connections underlying 
itch is well summarized by Dhand et al (2014).  Selected aspects of this neurobiology as they 
relate to the development of some specifics of the known pathology in PN will be 
summarized.   
 
The cellular initiation of itch can begin with the mast cell release of histamine that binds to 
H1 receptors on nerve fibers (Raap et al 2011).  Endorphins and other opiate peptides are 
known to cause histamine mast cell release (Barke et al 1993).  Endorphin itch initiation 
biology may be more direct.  Bigiliardi and Bigliardi-Qi (2004) observed that while 
histamine interaction with nerve fibers may be a source of itch sensation, they summarize 
evidence for direct opiate peptide interaction with nerve fiber endings expressing endorphin 
receptors as a contributor to itch sensation initiation.   
 
With regard to the skin cells themselves, keratinocytes are known to produce different 
neuropeptides that include proopiomelanocortin (POMC), which is a precursor for the opiate 
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peptide beta-endorphin (Bigliardi et al 1998).  In addition, mast cell activation can initiate 
the itch process via non-histamine mediated processes that that lead to substance P presence 
in the interstitium (Raap et al 2011).  Substance P, a neuropeptide member of the tachykinin 
family, is thought to induce itching in humans via histamine degranulation from mast cells 
(Potenzieri et al 2012).  Keratinocytes are known to express Substance P receptors (Peters et 
al 2006) and opiate receptors (Bigliardi et al 1998). 
 
There is also a close link between endorphins and substance P in nerve fibers innervating the 
epidermis.  Opioid receptors destined for insertion onto the distal portions of Type C 
cutaneous nerve fiber membrane and the neuropeptides (such as substance P) that are capable 
of release into the interstitium are both synthesized in the same dorsal root ganglion nerve 
cells and transported to the peripheral nerve processes in the skin (Stein et al 2003).   
3.1.2.4 Abnormal endogenous opiates in the skin of PN patients: 
Bigiliardi and Bigliardi-Qi (2004) reported that in PN human skin tissue samples there was 
a down regulation of the mu-opiate receptor expression in the epidermis compared to normal 
skin.  The down regulation was thought to be a biological response to abnormal tissue 
exposure to large amounts of endogenous opioid ligands such as endorphins.  The authors 
comment that the epidermal skin cells such as the keratinocytes that are no longer binding 
the opioid ligands possibly leave the ligands available to bind to epidermal nerve endings 
and thus induce a nerve transmission mediated signal to the CNS resulting in a pruritus 
sensation.   
3.1.2.5 Abnormal substance P level in the skin of PN patients: 
Haas et al (2010) reported data showing significantly increased density of dermal substance 
P nerve fibers both in lesion skin samples as well as normal appearing skin samples from PN 
patients.  The authors concluded that the hyper-innervation by substance P containing 
sensory nerves may have a role in the itch sensation found in these patients.  Molina et al 
(1992) reports increased nerve fibers containing substance P in PN subjects compared to 
control group that could be related to the intense pruritus. 
3.1.2.6 Inflammatory Component to PN Histology: 
Neurogenic inflammation refers to the manifestation of skin diseases related to the 
malfunctioning of the nervous system – immune system interaction (Steinhoff et al 2003, 
Peters et al 2006, and Potenzieri et al 2012).  Bigliardi et al (1998) conclude that the presence 
of receptor systems for endorphins and substance P molecules is evidence of an interaction 
between skin, immune and nervous system.  Given the abnormal biology of substance P and 
endorphins in the skin of PN patients just discussed above, the hypothesis that the induction 
of an inflammatory component in PN is etiologically related to endorphin-substance P 
pathobiology is based on the following biological facts: 
In addition to being a pruritogen, substance P also has pro-inflammatory and immune-
stimulatory activity (Peters et al 2006).  Steinhoff et al (2003), Peters et al (2006), and 
Potenzieri et al (2012) state that substance P may be an important mediator of cutaneous 
neurogenic inflammation.  The immune cells that migrate under a pro-inflammatory 
signal from released substance P are an important source of opioid ligands.  The opioid 
ligand containing immune cells consist of T and B lymphocytes, granulocytes, and 
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monocytes/macrophages (Sehgal et al 2011).  As noted by Weigelt et al (2010), part of 
the characteristic PN histological findings is a superficial, perivascular and/or interstitial 
inflammatory infiltrate of lymphocytes, macrophages and, to a lesser extent, eosinophils 
and neutrophils (granulocytes).  The opioid ligands released by immune cells interact 
with peripheral opioid receptors located on the cutaneous nerves (Stein et al 2003).  
Otherwise stated, the cutaneous nerve induced signaling from opioid ligands released by 
immune cells may be a source of the pruritic signal to the brain.   
3.1.3 Rationale for Investigating Nalbuphine HCl ER in Prurigo 
Nodularis  
3.1.3.1 Pre-clinical Animal Data 
A preclinical investigation (Covance Study No. 8265903) was undertaken to demonstrate 
the effects of nalbuphine HCl on substance-P (SubP) induced scratching behavior in the 
mouse, a standard animal model (Kuraishi et al. 1995).  Scratching behavior induced by 
peripheral stimulation by the pruritogen SubP mimics the characteristics of itch-related 
scratches in humans (Kuraishi et al. 1995) and Andoh et al 1998).  In addition, the SubP 
induced scratching behavior is not inhibited by the histamine H1 receptor antagonist and 
elicits responses even in mast cell-deficient mice.  Thus, SubP-induced scratches are likely 
to represent antihistamine-resistant pruritus.  The model is relevant to antihistamine-
resistant pruritus (Togashi et al 2002 and references cited therein). 
 
The SubP itch mouse model was successfully established and its viability confirmed by 
assessing the responses using vehicle (phosphate buffered saline, PBS) only group 
(VEH/VEH) and nalfurafine HCl, a positive comparative control group (PCC/SubP)  
relative to untreated group (VEH/SubP) group.  Briefly, studies were conducted in male 
C57BL/6 mice.  Animals were acclimated to the facility at least three days prior to dosing.  
On the test day, mice were acclimated to the observation cages for one hour prior to dosing.  
Mice were then randomly assigned to treatment groups and subcutaneously (SC) dosed 
with vehicle (PBS), PCC (0.01 or 0.02mg/kg), or the test article nalbuphine (10 or 
30mg/kg) (NAL/SubP group), and video recorded for 30 minutes to establish baseline 
scratching behavior.  After the 30-minute baseline recording, mice received either vehicle 
(0.05 mL PBS) or SubP (250 nM in 0.050 mL) injected intradermally (ID) into the rostral 
part of the back and video recording continued immediately for an additional hour.   
 
Itching was scored by reviewing the recording and counting the number of scratches over 
30 minute periods following SubP (or vehicle) challenge.  Itching was defined as 
scratching with the hind paw at the intradermal injection site (upper right shoulder area).  
Continuous scratching over one second was counted as one scratch event and paused 
scratches were considered separate scratching events.  Scratching of other sites such as ears 
and face were not recorded.   
Baseline scratching (pre-SubP) was similar for all treatment groups.  Following SubP 
administration in the untreated mice, itching began within 3-5 minutes from administration 
of the pruritogen.  The itch intensity was the highest in the first 30 minutes post-dose.  By 
60 minutes post-dose, the effect of the SubP injection began to wear off as scratching 
returned towards baseline levels. 
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As expected, PCC significantly (p< 0.001) decreased the SubP-induced scratching 
supporting the validity of the itch model.  Subcutaneous pre-treatment with PCC resulted in 
a reduction of 42 and 63% reduction at the 0.01 and 0.02mg/kg dose (from 107 to 62 or 40 
scratches, respectively).  
Significant reduction in itch (p< 0.001) was noted following nalbuphine SC administration 
with about 43% reduction in itch at the 10 mg/kg dose (from 107 to 61 scratches) and 52% 
at the 30 mg/kg dose (from 107 to 52 scratches).  Though there was a trend for a dose 
dependence on itch reduction, there was no statistical difference between the tested 
nalbuphine doses. 
In this study, nalbuphine was as effective as PCC (nalfurafine) at reducing SubP-induced 
itch with no statistical difference between nalbuphine and PCC effect, regardless of the 
dose. 
Ambulation was not suppressed in mice injected with nalbuphine dosed at 10 or 30 mg/kg 
indicating that attenuation of the scratching was not due to decreased locomotor activity. 
3.1.3.2 Neuropharmacologic Basis of the Rationale of Investigating Nalbuphine for the 
Treatment of Prurigo Nodularis 
Gutstein et al (2001) reports that nalbuphine exerts its clinical pharmacologic action by 
competitively antagonizing the opioid μ-receptor and simultaneously acting as an agonist at 
the opioid κ-receptor, and thus is a member of the  “opioid agonist-antagonist” class of drugs 
that mechanistically work through this dual pharmacologic process.  There is no published 
literature on the use of the moiety nalbuphine in PN.  Nalbuphine was shown to be effective 
in reducing morphine induced pruritus, a well-known clinical pruritic condition induced by 
morphine administration.  In several published clinical well controlled studies (which are 
reviewed in detail in the Investigator’s Brochure Section 5.8), nalbuphine was either equally 
effective or superior in efficacy when compared to naltrexone or naloxone (both are pure u-
antagonists) for the management of morphine induced pruritus.  
Neurogenic inflammation (as discussed in Section 3.1.2.6) may induce the secondary 
phenomena of “central sensitization” (Woolf et al 2011).  Central sensitization is a central 
nervous system pathologic neurobiology change in cell circuitry that results from abnormal 
peripheral nerve signaling and/or peripheral nerve injury.  The net effect of central 
sensitization is that there is a lowering of neural excitation threshold to external stimulus 
whereby either nociceptive or low intensity pruritogen cutaneous stimuli induce a high 
intensity sensation of pruritus (Paus et al 2006).  Schmelz (2005) reports on the evidence that 
there is a mu-kappa opiate gating circuitry in the spinal cord whereby kappa agonist activity 
would inhibit mu opiate receptor containing cell activation mediated signaling that brings to 
consciousness the sensation of pruritus.  The analysis by Schmelz may be an example of 
what Pan (1998) reports as a potentially very general opioid μ-receptor antagonizing function 
by the opioid κ-receptor.  The author reviews the literature on central neural networks where 
the opioid κ-receptors are located in cell groups that are distinct from the cell groups that 
contain the opioid μ-receptors and summarizes the evidence that agonism at the 
pharmacological level of the opioid κ-receptor antagonizes various opioid μ-receptor agonist 
mediated actions in the brain.  This central gating mechanism could be important in 
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countering any potential pruritogenic induced sensation from a peripheral neurogenic 
inflammatory initiating event in PN. 
 
As discussed in Section 3.1.2.5, there is histological evidence of abnormal substance P 
presence in skin samples of PN patients.  In that regard, an experiment conducted by Trevi 
Therapeutics indicated that nalbuphine administered subcutaneously significantly (p<0.001) 
suppressed the substance P induced scratching in mice (see Section 3.1.3.1 study summary). 
 
Metze et al (1999) reported that 9 out of 17 patients with PN who were treated with the mu 
antagonist medication naltrexone reported a decrease in pruritus intensity of at least 50%.  
Reduced scratching as well as skin lesion healing was reported over a time period of up to 
20 months on drug.  This clinical observation potentially has different anatomical locations 
for the mechanistic drug effect.  Since Stein et al (2003) reported that inflammation increases 
both the number of sensory nerve terminals (“sprouting”) and disrupts the perineural barrier 
–thus facilitating opioid access to receptors, there is the possibility that peripherally acting 
mu antagonist naltrexone action reduced the neural membrane excitation by blocking actions 
of endogenous endorphins reported by Bigiliardi and Bigliardi-Qi (2004) to be present in the 
epidermis.  In fact, Bigiliardi and Bigliardi-Qi (2004) suggest an opiate antagonist be 
therapeutically investigated for this reason and also comment on the evidence that mu opiate 
receptors on epidermal cells may be have a role in skin healing. 
 
However, consideration must also be given to central nervous system opioid pharmacology 
as a contributing antipruritic effect elicited by naltrexone.  At the spinal cord level, Schmelz 
(2005) commented that the explanation for opiate mu antagonists being capable of reversing 
experimentally induced itch may be related to the neurobiology of spinal cord level neuronal 
kappa-mu opioid gating circuits where either a mu antagonist or kappa agonist drug may act 
to have a pruritus suppressing effect.  Supraspinal brain level action related to interference 
of the circuits related to reward behavior cannot be excluded given that it is known that 
naltrexone, like nalbuphine, can abolish morphine induced pruritus from morphine 
administered intrathecally.  In addition, opiate receptor neuronal systems are known to be 
related to the physiological psychology of human reward behaviour and mu antagonist opioid 
class drugs are known to block the phenomena (Le Merrer et al 2009).  Nalbuphine is known 
to block the effects of mu agonist drugs and induce the opioid withdrawal syndrome 
(Nubain® label). 
3.1.3.3 Nalbuphine Clinical Data in Uremic Pruritus 
Mannenti et al (2009) summarized potential pathophysiologic mechanisms for the etiology 
of uremic pruritus.  Included among the postulated uremia induced mechanisms to explain 
uremic pruritus is neurophysiologic central sensitization “wind up” phenomena related to 
immune-inflammatory skin pathology.  Mettang and Kremer (2014) in their review of uremic 
pruritus comment on the recent focus given to the mechanistic hypothesis related to 
peripheral neuropathic changes and central nervous system pathobiology along with 
evidence for cutaneous micro-inflammation.  The authors state that a therapeutic option may 
be systemic treatment with mu-opioid receptor antagonist and kappa-opioid receptor agonist.  
The proposed etiology of uremic pruritus pathobiology may be similar in origin to the 
neuroinflammatory process discussed in Section 3.1.2.6 as part of the mechanism postulated 
for the underlying process involved in inducing PN.  In should be noted that Lee and 
Shumack (2005) reported prurigo nodularis occurring in patients with renal failure and Iking 
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et al (2012) report renal failure as a contributing source of chronic pruritus with PN that was 
attributed to mix origin chronic pruritic conditions (see Table 1). 
 
In clinical study TR01, the effect of oral nalbuphine on pruritus in hemodialysis (HD) 
patients with uremic pruritus was explored.  The results indicated that nalbuphine HCl ER 
tablets demonstrated ability to suppress itch in a dose response fashion (see Figure 1)  
 
 
Figure 1:  
Mean VAS score (SD) for all patients as a function of nalbuphine HCl 
dose administered as nalbuphine HCl ER tablets.  N= 14 except for 180 
mg (N=13) and 240 mg (N=4).  Source: NAL.001.TR01.PD 
 
The TR01 study is summarized in the Investigator’s Brochure Section 5.4.3. 
Considering the potential similarity in the underlying postulated mechanism between uremic 
pruritus and PN, nalbuphine would also be expected to be therapeutic in PN patients.  As 
such, Study TR01 in HD patients can be regarded as a proof of concept study for PN.   
Based on the clinical evidence of nalbuphine to suppress itch in uremic pruritus, morphine 
induced pruritus, the substance P induced itch in a pre-clinical study, results and the 
mechanistic link between the opioid receptors and substance P with the pathophysiology of 
PN, a clinical investigation of efficacy of nalbuphine on itch in the PN population is justified. 
3.2 
NALBUPHINE 
Nalbuphine HCl is currently available only as a generic medication in an injectable form.  
An injectable form of nalbuphine is a commercially available approved drug product in the 
United States since 1979 and originally marketed as Nubain®, on which the presently sold 
generic injectable formulations are based.  It is currently approved for use in the United 
States for the relief of moderate to severe pain, a supplement to balanced anesthesia, for 
pre-operative and post-operative analgesia and obstetrical analgesia during labor and 
delivery.  The European Union marketing experience with the injectable form of 
nalbuphine dates back to 1986 and this was recently reviewed (Nalbuphine -Medicines 
Evaluation Board in the Netherlands Public Assessment Report 2010). 
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Nalbuphine is not a controlled drug in the United States.  An oral dosage form of the drug 
is not commercially available.  Nalbuphine HCl ER is an extended release oral tablet that is 
currently being developed for the treatment of pruritus. 
Nalbuphine is a synthetic opioid with mixed μ antagonist/κ agonist opioid properties.  
Structurally, nalbuphine is a derivative of 14-hydroxymorphine and is related to the opioid 
μ-receptor agonist oxymorphone and the opioid μ-receptor antagonist naloxone.  
Nalbuphine exerts its clinical pharmacologic action by competitively antagonizing the 
opioid μ-receptor while simultaneously acting as an agonist at the opioid κ-receptor 
(Gutstein 2001; Gharagozlou 2003 and 2006).  
3.3 
NALBUPHINE HCL ER TABLET CLINICAL DEVELOPMENT  
3.3.1 Overall Summary 
The safety, tolerability and pharmacokinetics of nalbuphine HCl ER tablets have been 
characterized following single and multiple ascending dose studies in healthy male and 
female human subjects, in a single dose study conducted in a dental pain patient 
population, a multi-dose study conducted in a patient population experiencing osteoarthritic 
related joint pain and in a multi-dose study conducted in both hemodialysis (HD) 
population experiencing uremic pruritus and healthy subjects.  Studies were conducted with 
nalbuphine HCl ER tablets or oral solution following single dose administration from 30 
mg up to 180 mg and multiple doses ranging between 30 mg BID and 180 mg BID in 
subjects with normal renal function (up to 3 weeks) and in the hemodialysis population in 
multiple doses ranging from 30 mg BID to 240 mg BID (up to 15 days). 
In subchronic and chronic dose toxicology studies, the CNS was identified as the only 
target organ when unformulated (neat) nalbuphine was given to dogs at high doses.  High 
systemic drug exposures in dogs caused CNS toxicity (tremors and convulsions) leading to 
deaths in some cases.  It should be noted that the convulsions at high doses of nalbuphine 
in dogs were most likely Cmax-related.  In toxicology studies in which dogs were given 
high doses of nalbuphine formulated with release-rate controlling excipients that blunt the 
Cmax, no CNS signs of toxicity were observed.  Using the most conservative (lowest) 
margin of safety determined in all toxicity studies, a minimum 12.4-fold safety margin was 
calculated respectively for the mean plasma Cmax in subjects with normal renal function at 
the highest projected clinical dose of nalbuphine (180 mg BID) relative to the plasma 
Cmax at the lowest NOAEL in dogs given unformulated nalbuphine.  Convulsions were 
not observed in any of the clinical trials conducted with nalbuphine HCl ER oral tablets in 
subjects with normal renal function at doses up to 180 mg BID (360 mg daily dose) or in 
HD patients at doses up to 240 mg BID (480 mg daily dose).  
In the course of development, 355 subjects received at least one dose of oral nalbuphine 
HCl.  The most frequently reported adverse events were primarily in the Central Nervous 
System (CNS) and Gastrointestinal (GI) organ system categories.  All these side effects are 
known to occur with drugs with opioid pharmacologic properties.  Most of the side effects 
noted in the study program were mild to moderate in severity.  Initiating drug dosing in 
both HD patients and healthy subjects at the 30 mg BID dose resulted in good tolerability 
for subsequent titration related dose escalation. 
No drug abuse issues were reported during any of the investigations.  The incidence of 
opiate withdrawal effects noted at drug discontinuation in the patients was investigated in 
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the osteoarthritis pain treatment study when nalbuphine dosing was abruptly stopped 
following the end-of-study participation.  There was an absence of any objective evidence 
of physical withdrawal symptoms in 85% of the patients and only mild evidence of 
physical withdrawal symptoms in the remainder of the patients. 
3.3.2 Clinical Study TR01 in Hemodialysis Patients and Healthy 
Volunteers 
Pruritus is a frequently identified sign and symptoms of uremia (“uremic pruritus”) and is 
thus a common symptom in patients receiving hemodialysis (Pisoni et al 2006 and Narita et 
al 2006).  Study TR01 was undertaken to assess the safety, PK, and the open label effects 
on pruritus intensity in hemodialysis subjects.  PK and safety was compared to matched 
healthy control subjects. 
Study TR01 was a single site, open label, non-randomized, parallel group, escalating dose 
study in hemodialysis patients with pruritus of at least mild intermittent intensity receiving 
intermittent hemodialysis three times a week compared to matched healthy control patients.  
All subjects were in house during the entire dosing period.  Nalbuphine HCl ER tablets 
were administered orally for up to a 15 day period in HD subjects and 13 days in healthy 
subjects.  Doses were sequentially escalated from 30 mg QD on Day 1 to 30mg BID then to 
60 mg BID, 120 mg BID, 180 mg BID and 240 mg BID with dose escalation predicated on 
PK, safety, and tolerability of the preceding dose.  HD subjects remained at each dose level 
for 2-3 days for a minimum of 4-5 consecutive doses.  Healthy subjects remained at each 
dose level for 3-4 days for a minimum of 5 consecutive doses.   
Study subjects were separated into 2 cohorts:  Of the 15 HD subjects in enrolled into 
Cohort 1, 11 were assigned to dose escalate up to 180 mg BID and 4 were assigned to dose 
escalate up to 240 mg BID.  13 subjects (11 males and 2 females) completed the study.  
One male subject discontinued secondary to non-drug related disease progression diagnosis 
of pleural effusion at the 30 mg BID dose level and a female subject discontinued 
following a Grade 3 AE of vertigo at the 240 mg BID dose level.  Cohort 2 were healthy 
subjects who were assigned to dose escalate up to 180 mg BID.  Cohort 2 consisted of 8 
healthy subjects (6 males and 2 female) who completed the study and one male subject 
who discontinued at the 120 mg BID dosing level with only Grade 1 intensity AEs.  All 
study subjects were closely monitored for AEs throughout the study.    
In healthy subjects, the dosing regimen resulted in mainly Grade 1 AEs and the dose 
escalation was tolerable in 8/9 subjects dosed.  Of the nine healthy subjects enrolled, one 
subject withdrew from the study secondary to AE Grade 1 level gastrointestinal reflux, 
nausea/vomiting and vertigo symptoms at the 120 mg BD dosing level.  The subject 
recovered from the AE following drug discontinuation.  AEs that occurred in greater than 
two subjects were somnolence (N=2), headaches (N=2), flatulence (N=2) and constipation 
(N=3).   
In the HD subjects, there were no deaths or drug-related serious AEs.  There were no dose-
limiting AEs reported as defined as two HD subjects experiencing a drug-related AE of 
Grade 3.  A total of 72 AEs were reported in the 15 HD subjects of Cohort 1.  The nervous 
and gastrointestinal organ systems had the highest incidence of AEs.  The most frequently 
occurring AEs were nausea and somnolence.  Of the 13 HD subjects who completed the 
study (10 HD patients assigned to dose up to 180 mg BID and 3 HD subjects assigned to 
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dose up to 240 mg BID), 12 subjects completed the trial per protocol and 1 subject 
completed the study but did not dose titrate beyond 120 mg BID.   
With regard to the gastrointestinal organ system, of the 14 HD subjects who completed 13 
days of dosing (1 subject at 120 mg BID and 13 subjects at 180 mg BID), 4/14 (29%) 
experienced no nausea during the study and 7/14 (50%) experienced Grade 1 intensity 
nausea that was self-limited and only occurred at the initiation dose of 30 mg.  One subject 
(1/14, 7%) experienced Grade 2 nausea starting from the 60 mg BID through the 180 mg 
BID dose.  Three subjects (3/14, 21%) only developed nausea at the 180 mg dose level.   
With regard to the nervous system AEs, of the 14 HD subjects who completed the 13 days 
of dosing, 5/14 (36%) did not experience somnolence, 4/14 (29%) experienced somnolence 
that was self-limited and only occurred at the initiation dose of 30 mg.  With regards to AE 
intensity, two subjects (2/14, 14%) experienced somnolence of Grade 2 intensity at dosing 
levels above 30 mg BID.  Only one drug-related Grade 3 AE (vertigo) was reported in one 
subject at the 240 mg dose which resolved completely following drug termination.  No 
clinically relevant findings in vital signs, blood pressure (BP), ECGs or physical 
examinations were noted during the study.  Oxygen saturation was also monitored via pulse 
oximetry as a safety precaution.  The oximetry readings were taken at regular intervals 
during the daytime and continuously monitored during the nighttime hours over the 15 
days of drug dosing and up to a maximal dose of 240 mg BID.   
In both the HD and healthy subjects, no clinically significant decrease in daytime readings 
were recorded in the oximetry readings except in the one male HD subject previously 
mentioned who discontinued from the study at the time of the development of a pleural 
effusion.  There was no clinically significant decrease in the nocturnal oxygen saturation 
level below the pre-dosing baseline nocturnal oxygen saturation level in any HD subject.  
The Investigator’s Brochure and Section 5.4.4.4; Table 21 and Section 5.4.4.2.2; Table 17 
summarizes the AE profile of the TR01 HD subjects and healthy subjects respectively. 
During the course of TR01, the 15 HD subjects that were enrolled were on multiple 
concomitant medications.  Common concomitant medications included heparin, vitamin D, 
aspirin, iron, hyperphosphatemia management with sevelamer, erythropoiesis-stimulating 
agent, secondary hyperparathyroidism management with cinacalcet, neuropathic pain 
management with gabapentin; antihypertensive medications such as amlodipine (calcium 
channel blocker), carvedilol (beta and alpha-1 blocker), metoprolol (beta blocker), 
lisinopril (ACE inhibitor); gastrointestinal medications: omeprazole, pantoprazole, 
ranitidine and renal vitamins and supplements. These medications seem to be commonly 
used by HD patients both in the US and the EU (Schmid et al 2010).  There was no 
clinically significant difference in the adverse event profile observed based on concomitant 
medication use or obvious pharmacodynamic interaction over the course of the study. 
 
Data on Itch Intensity was obtained in an unblinded fashion from the HD subjects enrolled 
in the open-label single arm Study TR01 using a 0 (none) to 10 cm (maximal possible 
intensity) itch Visual Analogue Scale (VAS) recording “worst itch” intensity.  From a 
baseline mean daytime VAS of 4.4±2.3 cm and nighttime of 2.8±2.  cm, the mean VAS 
decreased over a 13-day dosing period by -3.6±2.5 cm and by -1.8±2.1 cm, respectively. 
Please see the Investigator’s Brochure for more details on the TR01 study. 
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3.3.3 Additional Nalbuphine HCl ER Tablet Clinical Data 
In addition to the subjects in the TR01 study, a total of 331 subjects have been exposed to 
nalbuphine HCl during the course of 8 previous clinical studies. 
Four Phase 1 studies were early biopharmaceuticals studies conducted in healthy subjects 
mainly for formulation selection and as such they support the safety of the drug product.  In 
addition, two Phase 1 studies were conducted with the current clinical formulations and 
each consisted of a single dose study assessing the safety, tolerability, and PK of the 
current tablet formulations in the 30 mg -180 mg range.  
A safety and efficacy analgesic study was conducted in subjects with dental-pain following 
third molar extractions following a single dose (placebo or 60 mg or 120 mg).  The subjects 
were otherwise healthy male and female subjects.  The study also contained PK-PD 
analysis demonstrating an analgesic dose-response relationship, with clear differentiation 
between the nalbuphine dose groups and placebo group. 
Oxygen saturation was monitored via pulse oximetry as a safety precaution during Phase 1 
studies and in the single dose third molar extraction dental pain treatment study.  All 
subjects who received the drug had oxygen saturation levels within the 90%-100% range 
during the studies. 
A safety and efficacy analgesic study was conducted in a patient population experiencing 
osteoarthritic related joint pain using the current nalbuphine HCl ER 60 mg tablet.  The 
population was demographically older with the mean age of 57 years and a range extending 
from age 40-70 years.  Subjects were dosed continuously for up to 3 weeks starting at 
60 mg BID up to a dose of 180 mg BID.  Subjects who tolerated the initial dosing were 
titrated up in weekly increments of 60 mg BID to the maximal dose of 180 mg BID.  The 
AEs that developed mainly had their onset at the initiation of dosing with no new type of 
AE developing in any statistically significant incidence during the course of dose 
escalation.  
In both genders, the most frequently reported adverse events were primarily in the Central 
Nervous System and Gastrointestinal organ system categories.  A higher incidence of AEs 
was noted in females during week one of dosing with the gender asymmetry in AE 
generation lessening as a function of time.  This difference in AE incidence may be related 
to the tendency of females to have higher plasma levels than males (about 1.7 and 1.3 fold 
higher for Cmax and AUC, respectively).  Nalbuphine total systemic clearance is reported 
to decrease with age leading to a higher absolute bioavailability (~ 44%) in elderly subjects 
(older than 65 years) relative to younger adults (11%) following oral administration 
(Jaillon, 1989). 
 
In these eight clinical studies overall, the most frequently reported AEs in the single dose 
and multi-dose studies were CNS events, namely dizziness, headache, and somnolence.  
Gastrointestinal system AEs were mainly nausea and vomiting.  Most of the AEs noted in 
the clinical study program were mild to moderate in severity.   
In the case of single dose Phase 1 nalbuphine HCl ER tablet administration, there was a 
dose relationship to the incidence of AEs and there was minimal AEs observed at the 30 
mg dose compared to initiating dosing at the higher doses.  As a result, a titration to higher 
doses from a starting dose of 30 mg was selected for subsequent studies that also included 
TR01 in order to improve the tolerability of the drug. 
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Section 5 of the Investigator’s Brochure summarizes the results of the clinical development 
program in detail. 
4 STUDY OBJECTIVES 
4.1 
PRIMARY OBJECTIVE 
The primary objective of the study is: 
• To evaluate the safety and tolerability of nalbuphine HC1 ER tablets during a drug 
treatment period of up to 50 weeks. 
4.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to evaluate the effect of nalbuphine HCl ER 
tablets on: 
• To evaluate the safety of nalbuphine HCl ER by achieved maintenance dose at the 
end of Treatment Week 4  
• Assess skin lesion improvement using the metrics of the PAS  
• Change from Baseline in Patient-Reported Outcome measures Worst (i.e., most 
severe itching over the past 24 hours) itch NRS, average itch intensity NRS, VRS 
(itchy, burning and stinging), MOS Sleep-R, ItchyQoL, HADS by the final 
Treatment Period Visit 
• Change between Baseline and the final Treatment Period Visit in PBI-P 
• A description of the percentage of patients utilizing various doses of nalbuphine 
HCl ER tablets by Study Week 
• A description of the frequency and reasons for dose up and down-titration and 
treatment discontinuation during the study 
• Frequency and distribution by time on study of patients determined to meet failure-
to-improve criteria 
• Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets 
• 
Time to first use of rescue medications and the number of days of use of rescue 
medications for itching 
• 
To evaluate the daily changes in the Subjective Opiate Withdrawal Scale (SOWS) 
during the Washout Period after cessation of treatment of nalbuphine HCl ER 
tablets 
4.3 
EXPLORATORY OBJECTIVES 
• The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve 
fiber density (histology) and MOR/KOR density (histology, Western Blot) and 
Histological (H&E) changes in skin biopsies taken Baseline and the final Treatment 
Period Visit to investigate possible correlation with any clinical response and also 
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compared to biopsy material assessed during study TR03 (optional procedure at 
select sites only). 
5 STUDY ENDPOINTS 
5.1 
PRIMARY ENDPOINT 
• A description of the incidence and nature of TEAEs during Treatment Weeks 5- 
50 
5.2 
SECONDARY ENDPOINTS 
Visit 1a or 1b will serve as the baseline visit for efficacy endpoints.  Visit 1a will be 
the baseline for patients directly entering the Treatment Period as of Visit 1a.  Visit 
1b will be the baseline for patients entering the Treatment Period after participating 
in the Observation Period for any length of time. 
• Assess skin lesion improvement using the metrics of the PAS  
• Change from Baseline in Patient-Reported Outcome measures Worst itch NRS, 
average itch intensity NRS, VRS (itchy, burning and stinging), MOS Sleep-R, 
ItchyQoL, HADS) by Treatment Period study visit and Baseline NRS score  
• Change between Baseline and the final Treatment Period visit in PBI-P 
• A description of the percentage of patients utilizing various doses of nalbuphine 
HCl ER tablets by Study Week 
• A description of the frequency and reasons for dose up- and down-titration and 
treatment discontinuation during the study 
• Frequency and distribution by time on study of patients determined to meet 
failure-to-improve criteria 
• Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets 
• Time to first use of rescue medications and the number of days of use of rescue 
medications for itching 
• To evaluate the daily changes in the Subjective Opiate Withdrawal Scale 
(SOWS) during the Washout Period after cessation of treatment of nalbuphine 
HCl ER tablets. 
5.3 
EXPLORATORY ENDPOINTS 
The exploratory objectives of the study are to evaluate the effect of nalbuphine HCl ER 
tablets on: 
• The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve 
fiber density (histology) and MOR/KOR density (histology, Western Blot), as well 
as histological (H&E) changes in skin biopsies taken at Baseline and the final 
Treatment Period Visit when compared to biopsy material assessed during study 
TR03 (optional procedure at select sites only). 
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6 NUMBER OF SITES AND PATIENTS 
Up to 20 sites in the North America and Europe are planned to participate in this study.  
Eligible patients who have successfully completed the TR03 study and wish to participate 
in TR03ext may be enrolled, treated, and analyzed.  The maximum number of patients will 
not exceed the number of patients who complete the TR03 study (i.e., approximately 60 
patients). 
7 ESTIMATED STUDY DURATION 
The total study duration for any individual patient will be up to 53 weeks.  Patients will 
receive drug treatment for up to 50 weeks, followed by a two week washout period. 
8 SELECTION CRITERIA 
8.1 
STUDY POPULATION 
Patients with prurigo nodularis who completed the TR03 study and have met all Inclusion 
and Exclusion criteria for TR03ext (see Section 8.2 and Section 8.3). 
8.2 
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be eligible: 
1. Have been adequately informed of the nature and risks of the study and have given 
written informed consent at the conclusion of the TR03 Visit 6 and prior to Visit 1a. 
2. Have completed participation in the TR03 study. 
Completion of participation in the TR03 study is defined as completion of Study 
Drug treatment through TR03 Visit 5 and completion of the TR03 Visit 6.  
3. Agree to comply with the contraception requirements as below: 
Sexually active female patients of childbearing potential are required to use one 
barrier method (e.g., condom, cervical cap, or diaphragm) of contraception in 
addition to one other method (e.g., intrauterine device [IUD], hormonal 
contraception, tubal ligation, Essure procedure, or spermicide).  
For the purpose of this study, all females are considered to be of childbearing 
potential unless they are post-menopausal (i.e., at least 1 year since last menses and 
age >50 years) or surgically sterile (i.e., tubal ligation, hysterectomy and/or bilateral 
oophorectomy). 
Female patients who are abstinent may participate in the study, however; they must be 
counseled on the requirement to use appropriate contraception should they become sexually 
active.  This counseling should occur at each study visit and must be documented in source 
records. 
4. Willing and able to comply with study requirements and restrictions.  
5. Agree to the confidential use and storage of all data (including photography) and 
use of all anonymized data for publication including scientific publication. 
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8.3 
EXCLUSION CRITERIA 
If a patient meets any of the following criteria, he or she is not eligible: 
1. Patients with a history of congestive heart failure of Class 2 or higher as graded 
using the New York Heart Association scale (scale provided in Appendix 5) 
2. Patients with a history of angina pectoris grade 2 or higher as graded using the 
Canadian Cardiovascular Society grading scale (scale provided in Appendix 5)  
3. History of ventricular tachycardia, torsade de pointes, family history of sudden 
death, myocardial infarction or acute coronary syndrome within the previous 3 
months, as reported by the patient. 
4. Serum potassium below the laboratory lower limit of normality at the TR03 Visit 5.  
Note: Potassium levels below the laboratory lower limit of normal at Visit 6/Visit 
1a should be repeated and potassium supplementation provided as appropriate. 
5. QTcF interval >450ms on screening/Visit 1a ECG 
6. Heart rate <50 BPM on any screening assessment.  Patients with a resting heart rate of 
<50 bpm will have it repeated once after 5 minutes in the supine position, and if it remains 
<50 bpm during the repeat, they will be considered a screen failure 
7. Use of a medication known to be associated with risk of torsade de pointes (see 
Section 9.7.8, Safety Assessments, for hyperlink to the CredibleMeds Filtered 
QTDrug List for cardiovascular related prohibited medications with a known 
associated risk of Torsade de Pointes)  
8. History of substance abuse within the past year as determined by the Investigator 
9. Significant medical condition or other factors that in the opinion of the Investigator 
may interfere with the conduct of the study 
10. Known hypersensitivity or allergy to nalbuphine or formulation components  
11. Is a pregnant or lactating female. 
9 STUDY PLAN 
9.1 
GENERAL STUDY DESIGN 
This is an open label extension study for patients who have completed the TR03 study. 
9.2 
RATIONALE FOR STUDY DESIGN 
The primary objective of this TR03ext study is to evaluate the safety of nalbuphine HCl ER 
tablets in patients with prurigo nodularis for up to 50 weeks on drug, followed by a two 
week washout period for a total of up to 53 weeks of study duration.  The open label design 
allows all patients, who have completed the parent study TR03, an opportunity to receive 
active treatment for the assessment of the safety of nalbuphine HCl ER tablets over a 
longer term and to follow the effect of skin lesion healing in addition to reducing itch.  A 
maximum of 50 weeks on study drug was chosen as a reasonable time frame that would 
add substantially to the understanding of chronic use of nalbuphine HCl ER tablets chronic 
use in prurigo nodularis. 
 
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Metze et al (1999) reported that 9 out of 17 patients with PN who were treated with the mu 
antagonist medication naltrexone reported a decrease in pruritus intensity of at least 50%.  
Reduced scratching as well as skin lesion healing was reported over a time period of up to 
20 months on drug.  Based on these clinical observations, TR03ext was designed to be of 
sufficient duration to observe potential anti-pruritic suppressive effects of study drug on 
scratching behavior and thus potentially skin lesion healing.  Furthermore, the TR03ext 
study design anticipates potential sustained anti-pruritic effect that may outlast the actual 
dosing of study drug in TR03.  Thus an Observation Period has been incorporated to follow 
patients whose Worst Itch NRS has been significantly reduced for up to 12 weeks in order 
to measure the durability of the anti-pruritic effect and to allow patients to receive study 
drug if pruritus intensity increases within the 12 week time period. 
 
This study will also allow evaluation of a titration algorithm that mimics the manner in 
which opioid medications are often used in clinical practice (i.e., stepwise titration) to a 
tolerable dose with an improvement in worst itch intensity.  To facilitate evaluation by 
achieved dose, the dose to which the patient has been titrated at the end of Treatment Week 
4 will be maintained through Study Week 50, with the exception of two allowable down-
titrations (See Table 3 for dosing schedule).  Patients who require a third down-titration 
after Treatment Week 4 must be discontinued from the study.  
 
Patients can enroll into TR03ext and receive drug as early as approximately 2 weeks 
following their last dose of study drug in the parent study TR03.  Approximately one-third 
of patients are expected to enter the study after having received placebo in TR03.  These 
patients are expected to have a high level of pruritus intensity.  On the other hand, some 
patients who have received active treatment in TR03 may still have either reverted to their 
original pruritic conditions or may have a residual anti-pruritic effects from the drug 
treatment even following the 2-week wash out period.  To allow for various starting levels 
of pruritus intensity, patients who have Worst Itch NRS that is ≥ 5 will enter the Treatment 
Period upon completion of Visit 1a.  Patients whose Worst Itch NRS score is < 5 will be 
entered into an extended screening period, no-treatment criteria Observation Period for up 
to 12 weeks or until they develop a higher level of pruritus (i.e., Worst Itch NRS ≥ 5), at 
which point they will transition to the Treatment Period upon completion of Visit 1b.  All 
patients entering the Treatment Period, whether immediately upon study entry or following 
a period of time in the Observation Period, will initially be titrated to a dose that can be as 
high as 180 mg BID during the first 4 weeks of the Treatment Period (See Table 3 for 
dosing schedule).  Patients who continue in the Observation Period and maintain a Worst 
Itch NRS score of < 5 will be screen failed from the study at the end of the 12-week period.  
While patients remain in the Observation Period, they will not be considered as enrolled 
into the study, but as participating in an extended screening process until they are eligible 
for treatment. 
 
Patients, who fail to improve, as defined by the failure-to-improve criteria, will be taken off 
study drug treatment.  A failure-to-improve criteria is implemented beginning on TV 3 and 
at every subsequent Treatment Visit, and is described in Section 11.1.  The rationale for the 
failure-to-improve criteria is based on the following: Following a maximal titration period 
of up to 3-weeks, an approximate 2-week window on stable drug dose should be sufficient 
for the drug to start eliciting a beneficial effect.  The patient’s self-reporting of pruritus 
intensity at each visit, beginning at TV 3, will be compared to the baseline value of the 
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patient’s pruritus intensity upon entry to TR03ext.  The premise of the failure-to-improve 
criteria is that patients will not be allowed to continue to receive study drug for an extended 
period of time if there is no demonstration of diminishment in pruritus intensity.  Patients 
discontinued from treatment are to participate in the Washout and Safety Follow-up Period, 
unless consent is withdrawn.  These patients will also receive a Telephone Contact 30 days 
(+2 weeks) post the completion of study drug to collect safety information related to 
previous drug exposure. 
 
In the parent study, TR03, the two target doses (90 mg and 180 mg) of nalbuphine HCl ER 
are both within the dose range that was well tolerated in HD subjects and healthy 
volunteers subjects from study TR01 (30 mg to 240 mg BID for up to 15 days).  
Additionally, data from TR01 suggested a decrease in itching intensity in this dose range.  
Further, the safety profile of nalbuphine following injection is well documented.  Injectable 
nalbuphine has been commercially available in the United States since 1979 and there has 
been marketing experience within the European Union dating back to 1986 (See 
Nalbuphine -Medicines Evaluation Board in the Netherlands Public Assessment Report 
(2010) for a recent review). 
In order to facilitate analysis of the clinical safety data and efficacy data, patients in the 
present study will begin titration at the 30 mg QD dose and titrate to only a maintenance 
dose ranging between 30 mg BID and 180 mg BID.  The 30 mg BID and 60 mg BID doses 
are believed to be only marginally effective doses based on available TR01 data.  However 
there is a two time dose reduction permitted for all patients during Treatment Weeks 5-50 
(see Table 3) to the next lower allowed dose (e.g., a patient at the 90 mg BID maintenance 
dose will be permitted a dose reduction to 60 mg BID or subsequently to 30 mg BID and 
then be maintained at that dose level for the remainder of the study). 
The study population being evaluated is an intended target population for oral nalbuphine 
HCl ER tablets: prurigo nodularis patients. 
 
Patients will be closely monitored for safety.  All patients will be seen at the Investigator 
site (See Schedule of Events in Appendix 1).  Adverse events and vital signs will be 
recorded.  Additionally, 12-lead ECGs (locally and centrally read), physical examinations, 
and clinical laboratory testing will be conducted to monitor safety on patients receiving 
study drug.  Safety monitoring will be done to address the primary objective of evaluating 
the longer term safety of study drug exposure.  The primary endpoint is a description of 
adverse events during up to 50-weeks of treatment with nalbuphine HCl ER tablets.  An 
important secondary endpoint objective of the study is to use recorded PAS metrics to 
assess the study drug anti-pruritic suppression of the scratching behavior of the patient and 
impact on skin lesion improvement.  Changes in patient-reported outcome measures will be 
explored to include: Worst itch NRS, Average itch intensity NRS, VRS (itchy, burning and 
stinging), ItchyQoL, MOS Sleep-R, HADS and PBI-P. 
9.3 
SAFETY MONITORING PLAN 
Patients will be closely monitored for safety.  Adverse events will be continuously 
evaluated throughout the study (and in particular AEs of special interest: nausea, vomiting, 
constipation, somnolence, sedation, dizziness, and vertigo) and vital signs, locally and 
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central cardiac core laboratory read 12-lead ECGs, physical examinations, and clinical 
laboratory testing will be conducted to monitor patient safety.  
 
An independent Data Safety Monitoring Board (DSMB) will periodically review safety 
data during the time period that the blinded part of the nalbuphine HCl program remains 
ongoing.  The frequency of data review and DSMB processes are outlined in the DSMB 
charter. 
 
Patients with apparent failure-to-improve to a stable dose of study drug will be taken off 
study drug. 
 
As with all patients who are discontinued from study drug, the patient will complete a daily 
SOWS scale for the two weeks following the last dose of study drug.  The SOWS is a self-
administered scale for grading opioid withdrawal symptoms.  If the patient is experiencing 
any symptoms on the SOW scale to a moderate degree, they will be instructed to contact 
the site.  If a patient is determined to be experiencing significant subjective withdrawal 
symptoms (at the Investigator’s discretion), they will be offered treatment. 
 
As summarized in Section 6.2.7 of the Investigator’s Brochure, the CNS has been 
identified as the only target organ when nalbuphine was given to animals at high doses.  In 
addition, the most frequently reported adverse events reported in the nalbuphine HCl ER 
tablet dosing studies were primarily in the nervous system and gastrointestinal organ 
system categories.   
To mitigate opioid-related side effects, nalbuphine will be titrated over 4 weeks based on 
tolerability to a dose that is between 30 mg BID to 180 mg BID (see Table 3).  Titration is 
a clinical management strategy consistent with dosing of opioids in general (Jovey 2003).  
The titration regimen planned in this study is similar to the regimen used in study TR01, in 
which doses in the planned range were well tolerated (Section 3.3.2) except up-titration is 
not a forced titration.  This will provide flexibility for each patient to assess tolerability.  In 
this study, the combination of a low starting dosing (30 mg on the first day) followed by a 
relatively slow titration (dose escalation after a minimum of six consecutive doses over 
approximately 3 days) is expected to minimize treatment-limiting opioid adverse effects.  
See Table 3 for the drug titration scheme.  The time interval between dose escalations is 
consistent with the “three day tolerance check” suggested by the National Opioid Use 
Guideline Group of Canada (2010) for outpatient clinical practice management of opioid 
drug titration as part of monitoring patient side effects. 
Nalbuphine has µ-opioid antagonist pharmacological properties.  To minimize the 
possibility of acute opiate withdrawal occurring at drug initiation in a physically dependent 
subject, patients receiving daily doses of opiates are excluded from the study.  Patients who 
require ongoing non-daily opiates concurrently with nalbuphine should be monitored 
carefully for additive opiate effects.  If patients develop a new need for daily opiates during 
the study, the Investigator is required to contact the Medical Monitor to discuss the 
specifics of the situation. 
It is known from prior studies, that gastrointestinal opioid-like adverse effects (e.g., nausea, 
vomiting, and constipation) occur early and can be treatment-limiting.  In anticipation of 
the possible occurrence of these effects, pre-medications for nausea will be permitted and 
Investigators will be advised to use pharmacologic or non-pharmacologic means to avoid 
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constipation as clinically indicated.  In anticipation of the possible occurrence of central 
nervous system (CNS) AEs such as somnolence, patients will be instructed to be aware of 
possible CNS AEs that may occur.  The evening doses during the Titration Period should 
be taken at home.  The first dose of any new titration step will occur with an evening dose 
(see Table 3).  In order to monitor any potential CNS related side effects, a brief 
neurological assessment will be conducted at each study visit as well as a focused 
neurological medical history will be obtained at enrollment. 
Patients will be additionally instructed that if any significant CNS AEs occur, they are to 
avoid activities such as driving and operation of dangerous machinery until the effect of the 
Study Drug can be assessed by the Investigator.  Additionally, concomitant use of daily 
opioids during the course of the study, other than for short-term use, can be undertaken 
with the approval of the Medical Monitor.  Overdoses or opioid-related significant central 
nervous system adverse effects may be reversed with opioid antagonists if clinically 
indicated. 
Although psychological dependence or abuse can develop to opioid drugs when chronically 
administered, the risk for psychological dependence or abuse in this study is judged to be 
low based on previous clinical studies with nalbuphine HCl ER oral tablets.  To date, there 
have been no reported cases of psychological dependence or abuse reported following 
dosing for 3 weeks up to 180 mg BID and dosing for 15 days up to 240 mg BID.  See the 
Investigator’s Brochure for details.  Nevertheless, the nalbuphine HCl injection package 
insert for the product sold in the United States states that “individuals with a prior history 
of opioid or other substance abuse or dependence may be at greater risk for the 
development of drug abuse and dependence”. 
9.4 
RISK-BENEFITS 
The selected dose range for study in TR03ext of 30 mg BID to 180 mg BID were chosen 
given the safety profile summarized in Section 3.3.2 and discussed further in Section 9.2 as 
well as detailed in the Investigator’s Brochure.  As summarized in, Section 3.1.3.3, open 
label data from the TR01 study showed that pruritus suppression in the HD patients was 
noted with drug administration within the dose range that is planned for the current study.  
Data obtained from a previous study in osteoarthritis patients dosed up to 180 mg BID with 
nalbuphine HCl ER tablets showed that objective opioid withdrawal symptoms at the 
termination of 3 weeks of therapy were absent or mild in degree (See the Investigator’s 
Brochure Section 5.4.4.5 for details).   
It should be noted that the commercially available nalbuphine HCl for Injection product in 
the United States (Nalbuphine HCl package insert) has a usual recommended dose of 10 
mg for a 70 kg adult, administered subcutaneously, intramuscularly, or intravenously, 
which may be repeated every 3 to 6 hours as necessary (i.e., up to a daily dose of 40-80 mg 
IV); and, in non-tolerant individuals, the recommended single maximum dose is 20 mg, 
with a maximum total daily dose of 160 mg.  Exposure following IV administration is 
approximately 6-fold higher than following oral administration (estimated oral 
bioavailability of nalbuphine HCl = 16%).  Therefore, a 10-mg, 20-mg, or 160-mg IV dose 
would correspond to approximately 60 mg, 120 mg, and 960 mg oral nalbuphine, 
respectively.  The highest dose proposed in the TR03 study is 180 mg BID (360 mg daily 
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dose), and this oral dose is well below the highest recommended daily treatment of 160 mg 
IV (equivalent to 960 mg oral) for the current marketed product. 
The risk for patients participating in the study is judged to be low based on previous 
experience with nalbuphine oral tablets.  In addition, in the current study, there will be a 
low initiation dose of 30 mg, a slow dose titration rate, and careful safety monitoring of 
patients during the clinical study. 
There is no approved therapy for prurigo nodularis related pruritus in the United States or 
Europe.  Should nalbuphine prove effective, patients with prurigo nodularis could 
potentially see benefit.  
9.5 
STUDY OVERVIEW 
This is an open label safety and tolerability extension study for patients who have 
completed study TR03.  Patients will either enter directly into the drug Treatment Period 
(Worst Itch NRS greater than or equal to 5 (≥ 5)) or enter an extended screening period of a 
no-drug Observation Period (Worst Itch NRS less than 5 (<5)) based on their reported NRS 
scores on the first Visit (Visit 1a).  For up to 12 extended screening weeks, patients in the 
no-drug Observation Period may also transition into the drug Treatment Period if their 
Worst Itch NRS increases to greater than or equal to 5 (≥ 5). 
The total study duration for any individual patient will be up to 53 weeks.  For patients who 
enter directly into the Treatment Period, the total amount of time on drug will not exceed 
50 weeks.  For patients who enter the Treatment Period from the Observation Period, the 
total amount of time spent in the combined two periods of the study cannot exceed 50 
weeks.  All patients who received drug treatment will have a 2-week Washout and Safety 
Follow-up period at the end of the dosing period, unless consent is withdrawn.   
The total amount of time in the Observation Period cannot exceed 12 weeks.  After 12 
extended screening weeks, patients not eligible for the Treatment Period are screen failed 
from the study.  The study periods are summarized below in Table 2.   
 
 
 
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Table 2:  
TR03ext Study Periods 
Study Period 
Study Weeks 
Duration 
Observation Period 
Patients who do not meet the criteria to start 
Treatment are followed in Observation Period 
visits for up to 12 extended screening weeks.  
During this time, the patient may meet criteria 
and become eligible to enter the Treatment 
Period.  If the patient does not meet the criteria to 
enter the Treatment Period by the end of 12 
extended screening weeks (OV12), participation 
in the study ends and the patient is screen failed. 
Up to 12 
extended 
screening weeks 
Treatment Period 
For patient directly entering the Treatment Period 
as of Visit 1a, the Treatment Period begins with 
Study Week 1 (Visit 1a) and ends with Study 
Week 50  
For patients entering the Treatment Period after 
being followed in the Observation Period, the 
number of weeks on treatment and the end of the 
Treatment Period varies; Table 8 calculates the 
Treatment Visit assignments for any patient 
entering the Treatment Period from the 
respective Observation Period visits. 
The End of Treatment Visit will take place after 
the patient completes the last week of study drug. 
Up to   
50 weeks 
Washout and Safety 
Follow-Up Period 
The Washout and Safety Follow-up Period is two 
(2) weeks in duration.   
For patients directly entering the Treatment 
Period as of Visit 1a and completing 50 weeks of 
study drug treatment, the Washout and Safety 
Follow-up Period should take place during weeks 
51 and 52.   
For patients entering the Treatment Period after 
being followed in the Observation Period, the 
number of weeks on treatment and the end of the 
Treatment Period varies; Table 8 calculates the 
Treatment Visit assignments for any patient 
entering the Treatment Period from the 
respective Observation Period visits.  The 
Washout and Safety Follow-up Period will take 
place during the two (2) weeks after the patients 
completes the last week of study drug. 
The Washout and Safety Follow-up Period Visit 
will take place in the week following the 
completion of the two (2) week Washout and 
Safety Follow-up Period. 
2 weeks 
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9.6 
STUDY PROCEDURES 
Before the initiation of study-specific procedures the patient must be given a complete 
explanation of the purpose of the study, evaluations to be conducted, and risks/benefits for 
study participation.  Patients must understand the requirements of the study, provide 
informed consent (See Section 9.6.1 and Section 20.3), agree to the study restrictions, and 
agree to return for the required assessments.  After review of the informed consent is 
documented, the patient must give written consent.  For this study, patients will retain their 
study number from study TR03. 
 
With the exception of Visits 1a and 1b, windows for all visits will be +/-3 Days.  Please see 
the Schedule of Events in Appendix 1 for details of the Titration Period assessments and 
the Study Schematics Flow Charts in Appendix 2.  See Section 9.7.1 for details of Study 
Drug Dosing and Section 9.7.6.4 for information on the use of pre-medications with the 
Study Drug.  Visit 6 of TR03 will serve as TR03ext Visit 1a unless these visits do not 
occur on the same calendar day. 
 
Visit 1a has procedures to be done as summarized in Section 9.6.1 regardless of the 
patient’s pruritus intensity score.  Following a set of common procedures, only patients 
who qualify for the Treatment Period based on meeting the pruritus intensity criteria will 
be eligible to receive study drug; Visit 1a corresponds to TV1.  For patients who, during 
the final visit of TR03, did not meet the pruritus intensity criteria to enter the TR03ext 
Treatment Period, Visit 1a corresponds to OV1, the first visit of the Observation Period.  If 
during a subsequent observation period visit to the site, the patient meets the pruritus 
intensity criteria, then that observation visit immediately transitions into Visit 1b (it also 
corresponds to TV1 since it is now the first Treatment Period visit) – See Section 9.6.3.3 
and Section 9.6.4.  
 
For patients who transition to the Treatment Period from the Observation Period, Table 8 
provides details on the treatment visit schedule based on the study week that the patient 
transitioned from the Observation Period to the Treatment Period.  The patient will follow 
the Treatment Visit schedule outlined on the Schedule of Events (Appendix 1). 
 
For clarity, 
Patients with a Worst Itch NRS greater than 5 (≥ 5) enter the Treatment Period 
and will receive Study Drug starting with an evening 30 mg dose (to be taken at home), 
after the Visit 1a (or Visit 1b) procedures have been completed. 
 
Receipt of the first dose of study drug will define Day 1.  Visit 1a or Visit 1b for these 
patients is also Treatment Visit 1 (TV1).  Subsequent visits will be defined as TV2, 
TV3, etc. 
 
Patients with a Worst Itch NRS less than 5 (<5) enter the Observation Period and 
will not receive study drug treatment.  Visit 1a for these patients is also 
Observational Visit 1 (OV1).  Subsequent visits will be defined as OV2, OV3, etc. 
 
Patients in the observation period can be followed for up to 12 weeks.   
 
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If during the Observation Period, a patient’s Worst Itch NRS increases to greater 
than or equal to 5 (≥ 5) and the patient meets all other eligibility criteria, Visit 1b 
procedures are to be performed.  The patient’s next visit will be Treatment Visit 2 
(TV2).  Do not repeat the Worst Itch NRS during Visit 1b.    
 
If, however, at Observation Visit 12 the patient does not have a Worst Itch NRS 
greater than or equal to 5 (≥ 5), the patient will be screen failed without having 
initiated treatment with nalbuphine. 
 
Figure 2, Figure 3 and Figure 4 visually display the relationship between TR03ext study 
weeks, Treatment Period weeks and Observation Period weeks. 
9.6.1 Visit 1a (Day 1 of Study Week 1)  
See Table 4 for summary of Visit 1a procedures.  See Section 20.3 regarding the informed 
consent process that must take place prior to any study procedures.   
 
. 
 
To the extent possible, the TR03 Visit 6 and Visit 1a should be performed on the same 
calendar day.  In cases where this is not possible, the Investigator must contact the Medical 
Monitor prior to conducting Visit 1a to discuss which procedures are required to be 
repeated at the visit.  All patients must complete Visit 1a within 30 days of their last dose 
of TR03 study drug in order to be eligible for study participation. 
 
Study TR03 Visit 6 procedures in common with Study TR03 extension Visit 1a procedures 
do not have to be repeated unless the two visits do not occur on the same calendar day.  
The following procedures will be performed: 
 
• obtain informed consent  
• confirm eligibility  
• obtain vital signs 
• conduct a physical examination  
• conduct a neurological exam 
• collect central laboratory samples (hematology and chemistry) 
• collect serum pregnancy sample in women of childbearing potential (regardless of 
sexual activity) and send for processing at the central laboratory*  
• collect urine for central lab urinalysis 
• collect urine for pregnancy test (regardless of sexual activity) and confirm negative 
results prior to dispensing study drug* 
* If the urine pregnancy test result is negative and the serum pregnancy test result is 
positive, the patient is to be contacted and the following actions are to take place: 
• instruct the patient to immediately discontinue taking study drug 
• schedule the patient for an unscheduled visit to collect another serum 
pregnancy test  
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment.  See Section 17.5.2.1 regarding how 
pregnancies are to be handled in this study. 
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• obtain blood for PK 
• perform skin biopsy (optional procedure at select sites only).  Obtain 3 samples (i.e., 
H&E, nerve fiber density (histology) and MOR/KOR density (histology, Western 
Blot)); see the Lab and Study Reference Manuals for details 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins; also collect the TR03 rescue medication log 
• retrieve any remaining study drug from the parent study TR03 
• administer the Worst itch NRS (paper version) and review score for eligibility to 
either enter the Treatment Period or to continue in screening under the 
Observation Period 
a) If the Worst Itch NRS score is < 5, start the Observation Period.  Do 
NOT initiate study drug treatment at this visit  
b) If Worst Itch NRS score is ≥ 5, confirm eligibility and start the 
Treatment Period (see below, ‘For patients qualifying for drug 
Treatment Period only’). 
The Worst Itch NRS (paper version) must be administered at the study site under 
the supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual) 
For patients qualifying for the drug Treatment Period only (Visit 1a is also study visit 
TV1): 
• complete PAS 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
o PBI-P 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual) 
• perform skin biopsy (optional procedure at select sites only).  Obtain 3 samples (i.e., 
H&E, nerve fiber density (histology) and MOR/KOR density (histology, Western 
Blot)); see the Lab and Study Reference Manuals for details 
• 
dispense enough Study Drug to the patient for required dosing until their return at 
Treatment Visit 2, TV2 
• dispense the Dosing Diary and instruct the patient on how to complete it 
• dispense the TR03ext Rescue Medication Log and instruct the patient on how to 
complete it 
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• instruct patients to self-administer the first dose on the evening of Visit 1a at home  
• instruct patients to notify the Investigator if any significant CNS AEs occur, and not 
to drive or operate dangerous machinery until the effect of the Study Drug can be 
assessed by the Investigator, see Section 9.3 
• instruct the patient to take the Study Drug twice daily at approximately the same 
times of day.  All patients should be instructed to titrate to their most tolerated dose.  
See Table 3 Drug Dosing Schedule for more information.  Here is the recommended 
Week 1 titration schedule for patients who tolerate study drug: 
 
                     Day 1 (the first day that the patient receives a study drug dose): No dose in the 
AM and 30 mg in the PM 
                     Day 2: No dose in the AM and 30 mg in the PM  
                     Day 3: 30 mg in the AM and 30 mg in the PM 
                     Day 4: 30 mg in the AM and 30 mg in the PM 
                     Day 5: 30 mg in the AM and 60 mg in the PM 
                     Day 6: 60 mg in the AM and 60 mg in the PM 
                     Day 7: 60 mg in the AM and 60 mg in the PM 
• instruct patients to bring all remaining Study Drug to the Investigator site for each 
study visit 
• If a patient misses 3 or more consecutive doses, contact the Medical Monitor. 
 
For patients starting the Treatment Period, the next visit will be TV2, Treatment Week 3.  
 
For patients not qualifying for the drug Treatment Period only (Visit 1a is also study 
visit OV1), the patient will enter the Observation Period and the next visit will be OV2, 
Extending Screening Week 4.  See Section 9.6.3, Observation Period (Extended Screening 
Weeks 1-12). 
9.6.2 Treatment Period (Treatment Weeks 1-50) 
Patients who enter the Treatment Period on Visit 1a will be in the Treatment Period for up 
to 50 weeks and thus are eligible to receive study drug for up to 50 weeks.   
Patients entering the Treatment Period after being followed in the Observation Period will 
have a variable number of weeks on treatment depending on how many weeks they were in 
the Observation Period.  The total amount of time spent in the combined two periods of the 
study (Observation and Treatment) cannot exceed 50 weeks.  The maximum number of 
weeks that a patient entering the Treatment Period from the Observation Period will be on 
study drug (Treatment Period) is 46 weeks.  Patients enter the Treatment Period from an 
Observation Visit (OV) when their Worst itch NRS is greater than or equal to 5 (≥ 5). 
Regardless of how many treatment weeks the patient was on study drug, all patients who 
enter the Treatment Period will complete End of Treatment Visit TV14 (unless consent is 
withdrawn).  Since all patients must titrate to their maintenance dose over the first four 
weeks of the Treatment Period, Visits 1a/Visits 1b (TV 1) and TV 2 over the first four 
weeks of the Treatment Period will be common to all patients in TR03ext regardless of 
when they enter into the Treatment Period.  Patients who transition from the Observation 
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Period to the Treatment Period at a respective Observation Visit will follow the Treatment 
Visit schedule outlined in Table 8.   
9.6.2.1  Treatment Period Weeks 2-4 (Titration Phase of Study Drug) 
The first week in the Titration phase is initiated as part of Visit 1a/1b (Day 1 Treatment 
Week 1, see Section 9.6.1 and Section 9.6.4).  Subsequently, the following events TC1, 
TV2 and TC2 will be conducted during the remainder of the titration phase.  See Table 5 
for the Schedule of Events during the titration phase. 
9.6.2.1.1 Telephone Contact Number 1 (TC1, Treatment Week 2) 
The patient is to be contacted by phone and the following are to take place: 
• record AEs  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• confirm that patient has titrated drug in accordance with the dosing schedule on 
Table 3 
• document tolerability/intolerability to study drug and decision to continue dose 
titration/maintenance following the dosing schedule of Table 3 
• discontinue study medication in patients who do not tolerate 30 mg BID dose and 
complete the End of Treatment Visit, TV14 (See Section 9.6.2.2.12 and Section 11) 
9.6.2.1.2 TV 2 (Treatment Week 3) 
The following procedures are to take place at this visit: 
• complete PAS 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity and confirm negative 
status prior to dispensing additional study drug 
• collect blood for PK 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• perform brief neurological assessment 
• administer PRO measurements (paper versions):  
o Worst itch NRS 
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS. 
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The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual). 
• record AEs (including tolerability to study drug) 
• review concomitant medications, including over-the-counter medications, nutritional 
supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required study 
related procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform Study Drug accountability, retrieve previously dispensed Study Drug  
• dispense enough Study Drug to the patient for required dosing until their return at 
TV3 (Treatment Week 5) 
• document tolerability/intolerability to study drug and titration decision based on 
Table 3 
• discontinue study medication in patients who do not tolerate 30 mg BID dose and 
complete the End of Treatment Visit, TV14 (See Section 9.6.2.2.12 and Section 11) 
9.6.2.1.3 Telephone Contact Number 2 (TC2, Treatment Week 4) 
The patient is to be contacted by phone and the following are to take place: 
• record AEs 
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• instruct the patient on dose titration/maintenance based on Table 3  
• patients reporting intolerable side effects at their current dose should titrate down to 
a tolerable preceding dose and this should be record as the patient’s maintenance dose 
• patients at any dose who reported intolerable AEs for the previous week (Week 3 
on drug) and continue to report intolerable AEs on this visit, should be discontinued 
from study drug and scheduled for the End of Treatment Visit, TV14 (See Section 
9.6.2.2.12 and Section 11) 
9.6.2.2 Treatment Period Weeks 5-50  
During this period of the study, the patient continues on the maintenance dose established 
by the end of Treatment Week 4 for the remainder of the study with the exception of two 
allowable dose reductions permitted during Treatment Weeks 5 – 50 (e.g., a patient at 90 
mg BID can be reduced to 60 mg BID and then subsequently to 30 mg BID).  If a third 
dose reduction is needed, the patient should be discontinued from the study (See Table 3, 
Section 9.6.2.2.12 and Section 11).  Patients who are on the 30 mg BID dose will be 
discontinued if a dose reduction is required. 
 
See Table 6 for the Schedule of Events for Treatment Weeks 5-50. 
 
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9.6.2.2.1 
TV 3 (Treatment Week 5) 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve criteria, perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug 
• collect blood for PK 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• perform brief neurological assessment 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and record patient’s compliance with dosing and all other required study 
procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing  until their next 
Treatment Visit  
 
9.6.2.2.2 
TV 4 (Treatment Week 9) 
The following procedures are to take place at this visit: 
• complete PAS 
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• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug 
• collect blood for PK 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• perform brief neurological assessment 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed Study Drug  
• dispense enough study drug for required dosing until the patient returns for their 
next Treatment Visit  
  
9.6.2.2.3 
TV 5 (Treatment Week 13) 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
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o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug 
• collect blood for PK 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• perform brief neurological assessment 
• administer PRO measurements:  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.4 
TV 6 (Treatment Week 17) 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
 
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For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug) 
• collect blood for PK 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• perform brief neurological assessment 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
•  reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.5 
TV 7 (Treatment Week 21) 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version)and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
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• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug) 
• collect blood for PK 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• perform brief neurological assessment 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability,  
• retrieve previously dispensed Study Drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.6 TV 8 (Treatment Week 26) 
 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• perform physical examination 
• perform brief neurological assessment 
• complete the PAS 
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• perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug) 
• collect urine for urinalysis for central lab 
• collect blood for central laboratory (hematology and chemistry) and for PK 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.7 TV 9 (Treatment Week 30) 
 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DID NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug) 
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• collect blood for PK 
• perform brief neurological assessment 
• perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.8 TV 10 (Treatment Week 34) 
 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug) 
• collect blood for PK 
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• perform brief neurological assessment 
• perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins 
• reinforce compliance for dosing and all other required study procedures (i.e. 
rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
  
9.6.2.2.9 TV 11 (Treatment Week 38) 
 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug 
• collect blood for PK 
• perform brief neurological assessment 
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• perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.10 TV 12 (Treatment Week 42) 
 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual status) and confirm negative 
status prior to dispensing study drug 
• collect blood for PK 
• perform brief neurological assessment 
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• perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.11 TV 13 (Treatment Week 46) 
 
The following procedures are to take place at this visit: 
• complete PAS 
• administer the Worst Itch NRS (paper version) and evaluate against the Failure-to-
Improve criteria (see Section 11.1) 
For patients who MEET the Failure-to Improve criteria: 
o Stop study medication 
o Perform End of Treatment Visit (TV14) procedures 
For patients who DO NOT meet Failure-to-Improve perform the following 
procedures: 
• obtain vital signs 
• collect urine for pregnancy test (regardless of sexual activity) and confirm 
negative status prior to dispensing additional study drug) 
• collect blood for PK 
• perform brief neurological assessment 
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• perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO 
Administration Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• reinforce and document patient’s compliance with dosing and all other required 
study procedures (i.e. rescue medication log, dosing diary, etc.) 
• perform study drug accountability, retrieve previously dispensed study drug  
• dispense enough study drug to the patient for required dosing until their next 
Treatment Visit  
 
9.6.2.2.12 TV 14 (End of Treatment Visit) 
 
This visit applies to all patients who completed TV13; including patients who met Failure-
to-Improve criteria at any Treatment Visit during the study (unless consent is withdrawn). 
 
For patients who DID NOT meet Failure-to-Improve criteria during the conduct of the 
study, this visit (TV14) takes place after the patient has completed dosing with study 
medication.    
• For patients who entered the Treatment Period at Visit 1a, TV14 will take place 
during week 51; four (4) weeks after TV13, as these patients should complete 50 
weeks of treatment prior to TV14   
• For patients who entered the Treatment Period at Visit 1b see Table 8 for information 
on when TV14 is to take place 
The following procedures are to take place at this visit: 
• complete PAS 
• obtain vital signs 
• perform physical examination 
• perform brief neurological assessment 
• complete the PAS 
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• perform 12-lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• collect blood for central laboratory (hematology and chemistry) and serum pregnancy 
test (regardless of sexual activity) for central laboratory 
• collect urine for urinalysis at the central laboratory 
• collect blood for PK 
• perform skin biopsy (optional procedure at select sites only).  Obtain 3 samples (i.e., 
H&E, nerve fiber density (histology) and MOR/KOR density (histology, Western 
Blot)); see the Lab and Study Reference Manuals for details 
• administer PRO measurements (paper versions):  
o Worst itch NRS 
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS 
o SOWS  
 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• perform study drug accountability, final retrieval of any previously dispensed study 
drug 
• retrieve the Dosing Diary  
• Dispense the 14 Day SOWS packet, instruct the patient on how to complete the scales 
and to complete the scales daily for 14 days 
• Schedule the patient for the Washout and Safety Follow-up Period Visit 
9.6.3 Observation Period (Extended Screening Weeks 1-12) 
Only patients with Visit 1a Worst itch NRS score of less than 5 (<5) should enter the 
Observation Period (Visit 1a for these patients is considered OV1), which includes 
subsequent study visits OV 2-4 at approximately one month intervals over the next 12 
extended screening weeks (See Table 7).  While patients remain in the Observation Period, 
they will not be considered enrolled into the study, but as participating in an extended 
screening process until they are eligible for enrollment.  Patients evaluated at OV 2-4 and 
who record Worst itch NRS greater than or equal to 5 (≥ 5), and are otherwise eligible, can 
immediately begin Visit 1b and transition into the Treatment Period. 
For these patients, the sum of time in the Observation Period and Treatment Period will not 
exceed 50 weeks.  As a result, both the Observation Period and Treatment Period will 
differ in length for different patients.  To ensure that the total number of study weeks does 
not exceed 50 weeks, that all patients complete proper titration of study drug up to the 
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assessment of TV 2 during Treatment Week 3, and that the final Treatment Period visit is 
always TV14, see Table 8 for visit details.  As such, visits during this period are not 
equivalent to Treatment Weeks.  During the Observation Period, patients are participating 
in Extended Screening Weeks. 
9.6.3.1 Observation Visit 2 at Extended Screening Week 4 and Observation Visit 3 at 
Extended Screening Week 8 
The following procedures are to take place at this visit: 
• administer the Worst itch NRS (paper version)  
o If the Worst Itch NRS is less than 5 (<5), perform the following Observation 
Visit procedures at any time during the visit   
 obtain vital signs 
 record AEs 
 record concomitant medications 
o If the Worst Itch NRS is greater than or equal to 5 (≥5), transition the patient 
to the Treatment Period and conduct Visit 1b procedures (described in Section 
9.6.4) on the same day as this visit.  See Table 8 for a summary related to 
future Treatment Period Visits. 
9.6.3.2 Observation Visit 4 at Extended Screening Week 12 
The following procedures are to take place at this visit: 
• administer the Worst itch NRS (paper version) 
o If Worst Itch NRS is less than 5 (<5), perform the following Observation 
Visit procedures at any time during the visit   
 obtain vital signs 
 administer the  PRO measurements (paper versions): 
• Average itch intensity NRS 
• VRS 
• ItchyQoL 
• MOS Sleep-R  
• HADS 
 record AEs 
 record concomitant medications 
o If the Worst Itch NRS is greater than or equal to 5 (≥5), transition the patient 
to the Treatment Period and conduct Visit 1b procedures (described in Section 
9.6.4) on the same day as this visit.  See Table 8 for a summary related to 
future Treatment Period Visits. 
Patients whose Worst Itch NRS is less than 5 (<5) at the OV4 should be screen failed from 
the study.  No Washout/Safety follow-up visit is to take place. 
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9.6.3.3 Transitioning from the Observation Period to the Treatment Period  
• For patients who have a Worst NRS score that is greater than or equal to 5 (≥5) at 
Observation Visit 2, 3, or 4, complete Visit 1b procedures (see Section 9.6.4).     
• These patients will receive up to 46 weeks of study medication treatment. 
• See Table 8 for the Treatment Period Visits to be completed post Visit 1b, as well as 
the number of weeks of study drug to dispense at each Treatment Visit and when to 
schedule the End of Treatment Visit 14 (TV14) to take place. 
• See Section 9.6.2 and the Schedule of Events (Appendix 1) for procedures to be 
performed at each applicable Treatment Visit. 
 
9.6.4 Transition to Treatment Period (Visit 1b) 
Confirm each patient’s eligibility (see Sections 8.2 and 8.3) prior to performing any Visit 
1b procedures.  If the patient does not meet eligibility requirements, do not perform any 
Visit 1b procedures; the patient is to be screen failed. 
See Table 4 for summary of Visit 1b procedures. 
Patients evaluated at OV 2-4 who record a Worst itch NRS greater than or equal to 5 (≥ 5) 
and, are otherwise eligible, can immediately begin Visit 1b and transition into the 
Treatment Period.  The following procedures are to take place at this visit: 
• obtain vital signs 
• conduct a physical examination  
• collect central laboratory samples (hematology and chemistry) 
• collect serum pregnancy test sample in women of childbearing potential (regardless 
of sexual activity) and send for processing at the central laboratory*  
• collect urine for central lab urinalysis 
• urine for pregnancy test (regardless of sexual activity) and confirm negative status 
prior to dispensing study drug* 
* If the urine pregnancy test result is negative and the serum pregnancy test result is 
positive, the patient is to be contacted and the following actions are to take place: 
• instruct the patient to immediately discontinue taking study drug 
• schedule the patient for an unscheduled visit to collect another serum 
pregnancy test  
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment.  See Section 17.5.2.1 regarding how 
pregnancies are to be handled in this study. 
• obtain blood for PK 
• Perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• administer PRO measurements (paper versions):  
o Average itch intensity NRS 
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o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
o PBI-P 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• complete the PAS 
• dispense enough Study Drug to the patient for required dosing until their return at 
Treatment Visit 2 (TV2) 
• instruct patients to self-administer the first dose on the evening of Visit 1b at home  
• instruct patients to notify the Investigator if any significant CNS AEs occur, and not 
to drive or operate dangerous machinery until the effect of the Study Drug can be 
assessed by the Investigator, see Section 9.3 
• all patients should be instructed to titrate to their most tolerated dose.  See Table 3 
Drug Dosing Schedule for more information.  Here is the recommended Week 1 
titration schedule for patients who tolerate study drug: 
                 Day 1(the first day that study drug is dispensed to a patient on treatment): No 
dose in the AM and 30 mg in the PM 
                 Day 2: No dose in the AM and 30 mg in the PM  
                 Day 3: 30 mg in the AM and 30 mg in the PM 
                 Day 4: 30 mg in the AM and 30 mg in the PM 
                 Day 5: 30 mg in the AM and 60 mg in the PM 
                 Day 6: 60 mg in the AM and 60 mg in the PM 
                 Day 7: 60 mg in the AM and 60 mg in the PM 
 
• Instruct patients to bring all remaining Study Drug to the dialysis unit for each 
subsequent treatment period study visits. 
• If a patient misses 3 or more consecutive doses, contact the Medical Monitor. 
The next study visit will be Treatment Visit 2 (TV2).  However, to ensure that the total 
number of study weeks does not exceed 50 weeks, that all patients complete proper 
titration of study drug, and that the End of Treatment Visit is always TV14, see Table 8 for 
more information. 
 
The next visit will be Treatment Visit 2 (Section 9.6.2.1.2).  See Appendix 1, Schedule of 
Event and Table 8 for the Treatment Visit Schedule for Patients Entering Treatment via 
Visit 1b.  
 
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9.6.5 Washout and Safety Follow-Up Period  
All patients who received Treatment, but did not withdraw consent, will have a 2-week 
Washout and Safety Follow-Up Period following TV14.  During this visit, the PRO 
questionnaires (paper versions) must be administered at the study site under the supervision 
of and by trained study staff, strictly adhering to PRO Administration Instructions (see 
Study Reference Manual).  Please see the Schedule of Events in Appendix 1 for details of 
the Washout and Safety Follow-Up Period assessments.  Additional information for this 
visit is provided below. 
 
For patients who entered the Treatment Period at Visit 1a, the Washout and Safety Follow-
Up Period Visit would take place during week 53, post TV14.  However, for a patient who 
enters the Treatment Period at Visit 1b, the Washout and Safety Follow-up Period Visit 
will take place 14 days (plus the visit window) post TV14.   
 
For patients who met Failure-to-Improve criteria or who discontinue treatment for other 
reasons (see Section 11.1), this visit is to take place 14 days (+ 7 days) after TV14. 
The following procedures are to take place at this visit: 
• obtain vital signs 
• perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• perform brief neurological assessment 
• collect blood for central laboratory measurements and PK 
• administer PRO measurements (paper versions):  
o Worst itch NRS 
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual). 
• AEs and concomitant medications (including rescue medications) will be recorded 
• collect the Rescue Medication Log from the patient at this visit 
• retrieve any remaining study drug not previously returned by the patient 
• retrieve the 14 day SOWS packet 
 
For patients who prematurely discontinued study medication for reasons other than 
withdrawal of consent, schedule the Premature Discontinuation of Study Drug Follow-up 
Telephone Contact visit.   
9.6.6 Premature Discontinuation of Study Drug Follow-up Telephone 
Contact Visit 
Patients who prematurely discontinued study drug during the study, for reasons other than 
withdrawal of consent, will have completed TV14 and the Washout and Follow-up Safety 
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Period Visit.  These patients are to be contacted by telephone 30 days (+ 2 weeks) after the 
visit that the patient met the Failure-to-Improve criteria and stopped study drug.   
During this Telephone Contact, record AEs and changes in concomitant medications since 
the completion of the Washout and Follow-up Safety Period Visit. 
Document any additional efforts that take place to reach a patient who is non-responsive to 
telephone contact.   
9.6.7 Early Termination Visit for Patients who Withdraw Consent 
Patients may withdraw consent from the study at any time.  However, if feasible, the 
patient should return for an Early Termination Visit.  The Early Termination Visit will be 
conducted as soon as practical after the Study Drug treatment is discontinued but no later 
than 2 weeks following the last dose of study drug.  The following procedures should take 
place as part of an Early Termination Visit: 
• obtain vital signs 
• perform physical examination 
• complete the PAS 
• perform brief neurological assessment 
• collect blood for central laboratory (hematology and chemistry) and serum pregnancy 
test at the central laboratory 
• collect blood for PK 
• Perform 12-Lead ECG after at least 5 minutes in a supine position (See the Study 
Reference Manual for ECG procedures, Section 17.4 Electrocardiograms for the 
handling of Cardiovascular adverse events) 
• collect urine for urinalysis at central lab 
• administer PRO measurements (paper versions):  
o Worst itch NRS 
o Average itch intensity NRS 
o VRS 
o ItchyQoL 
o MOS Sleep-R  
o HADS  
o SOWS 
o PBI-P 
The PRO questionnaires must be administered at the study site under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual). 
• record AEs  
• review of concomitant medications, including over-the-counter medications, 
nutritional supplements, and vitamins  
• perform study drug accountability, final retrieval of any dispensed study drug 
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9.6.8 Unscheduled Visits 
If a patient needs to be evaluated in relation to the study on a day other than one of the 
study visit days, that day will be considered an Unscheduled Visit.  The reason for each 
unscheduled visit will be recorded and the following procedures will be performed: vital 
signs (BP, HR, RR, temperature), assessment for AEs, review of concomitant medications 
(including rescue medications), and Study Drug accountability.  Additional procedures 
such as central or local laboratory sample collection may also take place, if clinically 
indicated.  See Section 17.5.2.1 in regards to the handling of positive pregnancy test 
results.  All unscheduled visits will be recorded on the Unscheduled Visit CRF.   
9.6.9 Schedule of Events 
The Schedule of Events is shown in Appendix 1 and is described in Section 9.6. 
9.7 
STUDY DRUG TREATMENT AND DRUG ACCOUNTABILITY 
Please see the Study Reference Manual for additional information on Study Drug supplies, 
packaging, storage, dispensation, and accountability. 
9.7.1 Study Drug Dosing 
Following enrollment, the patient will receive 30 mg open-label tablets.  At each visit at 
which study drug is to be dispensed, enough study drug should be supplied to ensure a 
sufficient number of tablets are available for dosing until the next visit; plus an additional 8 
tablets to allow for visit windows and/or possibility of a missed visit.  Bottles can be re-
dispensed, as appropriate. 
Study drug can be taken with or without food.  Patients will be instructed to take the AM 
and PM Study Drug tablets at the same times of the day, approximately 12 hours apart, 
preferably with 240 mL (approximately 8 ounces) of water.  If the patient does not take a 
particular dose at the planned time he or she may take it up to 2 hours later.  For example, 
if a patient is taking the Study Drug at 9 AM and 9 PM but forgets to take the 9 AM dose, 
he may take the 9 AM dose as late as 11 AM.  After that time, the patient should skip the 9 
AM dose and, instead, take the regularly scheduled next dose at 9 PM.   
The first dosing day will be on either Visit 1a or Visit 1b.  Titration will be based on 
tolerability.  If the patient is experiencing a study-drug related AE or an AE that may be 
aggravated by study drug up-titration, the study drug dose should not be increased, 
regardless of the NRS score.  
The Study Drug will be titrated during the Treatment Weeks 1 - 4, according to the 
schedule in Table 3 to a final dose of 30 mg BID up to 180 mg BID.  The dosing for 
Treatment Week 1 is further described in Section 9.6.1 (Visit 1a) and Section 9.6.4 (Visit 
1b).  Patients should only ever be dispensed a single strength of the study drug (e.g. 30mg 
bottle(s) or 60mg bottle(s) at a visit. 
Patients will titrate to tolerability beginning with a 30 mg dose on Day 1 (Visit 1a or Visit 
1b) with a dose increase of 30 mg BID not more often than every 3 to 4 days in order to 
attain steady-state plasma concentrations of nalbuphine at each dose.   
 
Patients should be instructed to up-titrate beginning with a single 30 mg dose in the 
evening (PM) and then begin dosing with an increased 30 mg BID dose the following day.  
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Dose titrations should be maintained for 3-4 days before further up-titration of the patient’s 
dose is attempted.   
 
For example, a patient starting at 30 mg BID during Week 1, and titrating to 60 mg BID, 
would dose as follows: 
 
Day 1 30 mg (evening dose only) 
Day 2 30 mg (evening dose only) 
Day 3 30 mg BID 
Day 4 30 mg BID 
Day 5 30 mg in AM and 60 mg in PM 
Day 6 60 mg BID 
Day 7  60 mg BID 
 
The maximum dose the patient should reach at the end of Week 1 is 60 mg BID.  If this 
dose is tolerated (as determined by the TC1 assessment), an additional up-titration may be 
attempted during Week 2.  An example of a possible titration schedule would be as 
follows:   
 
Day 1 60 mg BID 
(Perform TC1 to assess tolerability) 
Day 2 60 mg in AM and 90 mg in PM 
Day 3 90 mg BID 
Day 4  90 mg BID 
Day 5  90 mg in AM and 120 mg in PM 
Day 6 120 mg BID 
Day 7 120 mg BID 
 
The maximum dose the patient should reach at the end of Week 2 is 120 mg BID.  If this 
dose is tolerated (as determined by the TC2 assessment), an additional up-titration may be 
attempted during Week 3.  An example of a possible titration would be as follows:   
 
Day 1 120 mg BID  (Perform TC2 to assess tolerability) 
Day 2  120 mg in AM and 180 mg in PM 
Day 3 120 mg in AM and 180 mg in PM 
Day 4  180 mg BID 
Day 5 180 mg BID 
Day 6 180 mg BID 
Day 7  180 mg BID 
 
The maximum dose the patient should reach at the end of Week 3 is 180 mg BID.  If this 
dose is tolerated, it should be maintained throughout Week 4. 
 
The dose achieved as of the end of Treatment Week 4 will be maintained throughout the 
rest of the Treatment Period.  This dose will be defined as the patient’s “maintenance 
dose”.      
 
 
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During Treatment Weeks 1-4, the decision to up-titrate the patient’s dose should be made 
based on tolerance to study drug.  If the tolerance level becomes unacceptable to either the 
patient or the Investigator, the dose should be reduced incrementally until tolerance is 
stabilized (reduce dose by 30 mg BID if at the 30 mg, 60 mg, 90 mg, or 120 mg dose level 
and reduce dose by 60 mg BID if patient is at the 180 mg dose level).  Patients who do not 
tolerate the 180 mg BID should be down titrated to the 120 mg BID dose level and 
maintained there if stabilized. 
 
Two single dose reductions or dose holds per patient are permitted during Treatment Period 
at the Investigator’s discretion.  If subsequent dose reductions or dose interruptions are 
needed, the Medical Monitor must be contacted.  The duration of any dose hold must be 
discussed with the Medical Monitor.   
 
 
 
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Table 3: 
 Dosing Schedule for TR03ext 
Week of 
Treatment 
Period1 
(TV or TC) 
 
Day 
Drug Tolerance 
Discontinuation  
Acceptable 
Unacceptable3 
Week 1 
(TV1/Visit1a
/1b) 
 
 
1 
30 mg (PM dose) 
-- 
 
2 
0 mg (AM dose) 
30 mg (PM dose)  
-- 
 
3-4 
30 mg BID 
 
 
5-7 
Titrate patients to tolerability with 
dose increases of 30 mg BID   
 
Maintain dose for at least 3 to 4 
days up to next dose level 
Reduce dose 
incrementally by 30 
mg  BID 
NA 
The highest possible titration dose by the end of Treatment Week 1 is 60 mg BID 
Week 22 
TC#1  
1-7 
Continue incremental increase in 
dose and maintaining at each dosed 
level for 3 to 4 days 
Reduce dose 
incrementally by 30 
mg BID 
If 30 mg BID is not 
tolerated within 
one week, 
discontinue patient 
The highest possible titration dose by the end of Treatment Week 2 is 120 mg BID 
Week 32 
 
1-7 
Continue dose increase 
Reduce dose by 30 mg 
BID and maintain  
If 30 mg BID is not 
tolerated within 
one week, 
discontinue patient 
The highest possible titration dose by the end of Treatment Week 3 is 180 mg BID 
Week 42 
(TC#2) 
1-7 
Maintain dose at highest dose level 
reached on Week 3 Day 7 
Reduce dose reached on 
Week 3 Day 7 so that 
subject is now in 
maintenance dosing at 
one of the following: 30 
mg BID, 60 mg BID, 90 
mg BID, 120 mg BID 
or 180 mg BID 
NA 
Treatment 
Week 54 up 
to Treatment 
Week 50 
(TV3-TV 14) 
1-7 
Maintain dose from Week 4  
through TV145,6 
Patient may down 
titrate twice over 
remaining duration of 
study  
Patient 
discontinued if a 
3rd time down-
titration is needed. 
1The decision to enter the patient into the Titration Period is based on Worst Itch NRS score NRS ≥ 5 obtained from the patient on 
Visit 1a or 1b 
2The titration decision will be made based on tolerance to study drug 
3Tolerance level is unacceptable to either the patient and/or investigator 
4 The number of Treatment Weeks prior to TV 14 will vary for patients previously in the Observation Period depending upon the 
number of weeks spent in the Observation Period.  See Table 8 
5The achieved dose attained as of the end of Treatment Week 4 will be maintained throughout the rest of the Treatment Period.  
This dose will be defined as the patient’s “maintenance dose”.  Two dose reductions to the next lower allowed dose are permitted 
during Treatment Weeks 5 – 50 (e.g., a patient at 90 mg BID can be reduced to 60 mg BID).  If a third dose reduction is needed, 
the patient should be discontinued from the study. 
6Beginning on TV 3 and at every subsequent Treatment Visit, patients with a Worst itch NRS ≥ the Worst itch NRS at Visit 1a (or 
at Visit 1b in the case of patient who require the OV period) will be discontinued from study drug, complete the End of Treatment 
Visit 14, the Washout and Safety Follow-up Period and Visit, and a Telephone Contact Visit 30 days after the last dose of study 
drug (unless consent is withdrawn). 
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9.7.2 Down-Titration 
Down-titration is not permitted except as discussed in Section 9.7.1. 
9.7.3 Multiple Missed Doses 
If a patient misses multiple doses of the Study Drug, please follow the procedures below.  
In no case should patients take additional doses of Study Drug to make up for missed 
doses.  If Study Drug is re-started after missed doses, the patient should be instructed to 
take Study Drug from the tablets designated for the visit during which Study Drug is being 
re-started rather than from the visits during which Study Drug doses were missed. 
 
• During the Titration Period 
 
If a patient misses 3 (or more) consecutive doses, please contact the study Medical 
Monitor.  
 
• During the Stable Dose Period 
 
If a patient misses 6 (or more) consecutive doses, please contact the study Medical 
Monitor.  If authorized by the Medical Monitor, patients who miss more than 6 consecutive 
doses may be allowed to continue on study.  In such situations, patients should receive the 
Study Drug only once daily (i.e., the AM or PM dose only) for the first 3 days before 
returning to the full (BID) target dose. 
9.7.4 Overdose  
The effects of nalbuphine may be reversed with opioid antagonists such as naloxone.  
Please see Guidance to the Investigator section of the Investigator’s Brochure for additional 
information. 
9.7.5 Treatment Compliance 
Returned study drug tablets will be used to assess compliance at each visit.  Medication 
compliance will be recorded on the CRF for each designated visit (See Appendix 1).  
Patient compliance with the study dosing schedule will be assessed as part of the planned 
study analyses. 
9.7.6 Rescue Medications, Concomitant Medications, Prohibited 
Medications, and Pre-Medications 
9.7.6.1 Rescue Medications 
A secondary objective of the study is to quantitate the number of days of rescue medication 
used for itching during the course of nalbuphine HCl ER treatment.  Rescue medications 
will be defined as those drugs, when used for the purpose of treating itch, that were 
required to be washed out prior to entry into TR03 (See Table 9).  For the purposes of this 
study, any UV light treatment received will also be defined as a rescue medication. 
If a medication is prescribed for chronic anti-pruritic use of greater than 2 weeks, the 
patient should be discontinued (see Section 11.2). 
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9.7.6.2 Concomitant Medications 
Any medication taken by a patient following the signing of informed consent during the 
course of the study, and the reason for use of the medication, will be recorded on the case 
report form (CRF).  Each patient will be instructed to report the use of all medication to the 
Investigator, including over-the-counter [OTC] medications, herbal medications, vitamins, 
and nutritional supplements.  Patients will also be instructed about the importance of not 
taking any new medications during the study (including OTC medications) without 
consulting the Investigator.   
9.7.6.3 Prohibited Medications 
Initiating use of opiate medications during the study should be done with caution with 
assessment of the patient for potential additive opiate AEs.  If an enrolled patient requires 
daily treatment with opioid medications during the study (e.g., for post-surgical pain), 
please contact the Medical Monitor.  Use of acetaminophen, non-steroidal anti-
inflammatory medications, and aspirin is permitted.  If an opioid medication is introduced 
in anticipation for chronic use of greater than 2 weeks, the patient should be discontinued. 
Concomitant use of opioid antagonists (e.g. naloxone, naltrexone) is also prohibited during 
the study, unless required for urgent reversal of opioid adverse effects or opioid overdose.  
Use of all other investigational drugs is prohibited during the study.  A patient who initiates 
an investigational drug during the study should be discontinued. 
 
If the patient is prescribed a medication(s) included on the list of those with a known risk 
of Torsade de Pointes (see Section 9.7.8, Safety Assessments, for hyperlink to the 
CredibleMeds Filtered QTDrug List for cardiovascular related prohibited medications with 
a known associated risk of Torsade de Pointes), contact the Medical Monitor. 
9.7.6.4 Pre-Medications 
Nalbuphine use may be associated with nausea, vomiting, and/or constipation, particularly 
as the dose is escalated or upon initiation of treatment.  At the Investigator’s discretion, 
anti-emetics may be administered prophylactically, prior to taking the Study Drug or, as 
needed, for treatment.  Dietary and other prophylactic measures to avoid constipation 
should also be considered as clinically indicated Please see Section 9.7.8, Safety 
Assessments, for the hyperlink to the CredibleMeds Filtered QTDrug List for 
cardiovascular related prohibited medications with a known associated risk of Torsade de 
Pointes. 
9.7.7 Efficacy Assessments 
The below PRO instruments (paper versions) will be administered at the site and under the 
supervision of and by trained study staff, strictly adhering to PRO Administration 
Instructions (see Study Reference Manual) according the Schedule of Events  (see 
Appendix 1). 
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9.7.7.1 Numerical Rating Scale (NRS)  
The NRS is a patient-reported outcome instrument, designed to quantify the intensity of 
worst itching experienced during a 24-hour period.  The scale is a set of boxes, one for 
each number, from 0 (no itching) to 10 (worst possible itching).  The NRS is a widely used 
instrument recommended by IFSI for quantifying itch intensity as well as a useful 
instrument for grouping patients into categories of itch intensity described as mild, 
moderate or severe (Stander et al 2013).  The itch NRS has been investigated in patients 
with chronic pruritus of a variety of origins and has a high reliability and concurrent 
validity was found (Phan et al 2012).  
In this study, patients will be asked to record two NRS values:  
• rate itching on average over the past 24 hours 
• rate worst itching over the past 24 hours 
This instrument can be found in Appendix 4. 
9.7.7.2 Verbal Rating Scale (VRS) 
The VRS scale to be used in this study has three dimensions, each dimension is coded with 
graduated adjectives (from 0 = none; to 5 = very severe) for the skin sensations of itchy, 
burning and stinging.  
 
In this study, patients will be asked to record the VRS value: 
• 
How is your skin sensation today?   
 
This instrument can be found in the Appendix 4. 
9.7.7.3 Hospital Anxiety and Depression Scale (HADS) 
The HADS instrument includes 14 multiple-choice questions, each with 4 possible choices, 
scored between 0 and 3.  This instrument can be found in Appendix 4.    
9.7.7.4 ItchyQoLTM 
The ItchyQoLTM consists of 22 pruritus-specific items measuring how pruritus affects 
patients’ QOL in the area of symptoms related to the itch condition (6 questions), 
functional limitations (7 questions), and emotions (9 questions).  The patient scores each 
question never =1, rarely=2, sometimes=3, often=4, all the time=5.  The instrument can be 
found in Appendix 4.  
9.7.7.5 Medical Outcomes Sleep Scale –Revised (MOS Sleep-R) 
MOS Sleep Scale-R measure is a 12-item self-report sleep measure that was developed to 
assess sleep quality and quantity.  It is a multi-dimensional assessment of sleep parameters 
with scoring results in six subscales or domains: sleep disturbance (4 items), snoring (1 item), 
awaken short of breath or with headache (1 item), quantity of sleep (1 item), optimal sleep 
(1 item), sleep adequacy (2 items), and daytime somnolence (3 items).  
 
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Additionally, a 9-item Sleep Problems Index (“Sleep Problem Index I”) can be generated 
which assesses overall sleep problems that includes the 4 sleep disturbance and the 2 sleep 
adequacy items, 2 of the somnolence items, and awakening short of breath/headache; 
higher scores indicate greater sleep impairment, and this index is often used in clinical 
trials as an indication of sleep quality.  The instrument can be found in Appendix 4.   
9.7.7.6 Patient Benefit Index (PBI-P) 
The PBI-P questionnaire assesses the importance of treatment objectives to the individual.  
Before, and at the end of drug treatment in this study, the patient completes the same 
questionnaire and rates the extent to which the treatment objectives have been achieved.  
The instrument consists of 27 multiple choice questions that can be answered “not at all”, 
“somewhat”, “moderately”, “quite” and “very”.  The instrument can be found in 
Appendix 4. 
9.7.7.7 Prurigo Activity Score (PAS)  
The PAS consists of 7 qualitative and quantitative measurements related to the examination 
of the skin.  Type, number, distribution, affected body parts, and quantitative number of 
lesions in a representative body part are documented.  The biggest lesion and the most 
representative lesion are monitored with documentation of height and area measurements. 
Prurigo lesion activity is recorded as a percentages based on their stage (0-4).   
 
Photographs of the body are obtained with monitored lesions marked.  For consistency, the 
same lesion(s) documented at Visit 1a are to be documented for the duration of the study.  
Photographs should be obtained in the same manner at all visits regardless of healing status 
(i.e. if the previously affected area has healed continue to photograph this area for study 
purposes).   
 
The PAS instrument can be found in Appendix 4.  Please see the Study Reference Manual 
for instructions for obtaining and storing photographs collected in conjunction with the 
PAS. 
9.7.7.8 Exploratory Histological Endpoints (optional) 
Punch biopsy skin material for measurement of routine histology (H&E), nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot) analysis was obtained 
during TR03 (optional procedure at select sites only).  Punch biopsy may be obtained 
(optional at select sites) at Visit 1a/1b and End of Treatment Visit of TR03ext for a 
comparative analysis with the results of the histological results of pre-dosing TR03 and end 
of study TR03 results. 
 
9.7.7.8.1 MOR/KOR density and Nerve Fiber Density  
The potential of nalbuphine HCl ER tablets to impact the Measurement of nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot) in skin biopsies taken 
at Baseline visit and the Evaluation visit will be investigated at select sites. 
In addition to skin biopsy tissue obtained prior to drug treatment for H&E and analysis by a 
central reading dermatopathologist, at select sites, additional skin biopsy material may be 
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obtained before and at the end of drug treatment.  These biopsies will be compared to 
investigate, in an exploratory manner, any evidence of change in expression of MOR and 
KOR and nerve fiber density in relation to any noted changes in clinical study endpoints.  
 
Bigliardi et al (2007) reports that in normal skin, keratinocytes express high amounts of 
MOR and it is therefore concluded that endogenous ligands are bound primarily to opioid 
receptors on keratinocytes and thus the endogenous opiate ligands are not binding to opioid 
receptors located on nerve endings –the net result is at most a weak itch signal to the 
central nervous system in the normal state.  In chronic pruritic skin disorders, most opioid 
receptors on keratinocytes are reported as internalized; therefore there are many opioid 
ligands available to bind to opioid receptors on sensory nerve endings.  This state leads, 
together with the changed morphology of the epidermal nerve endings, to a strong itch 
signal to the CNS.  The authors reported that topical administration of the opioid mu 
receptor antagonist naltrexone in subjects with atopic dermatitis, lichen simplex chronicus 
or prurigo simplex showed an antipruritic effect.  In addition, there was also an 
upregulation of epidermal MOR expression following two weeks of treatment, but no 
MOR upregulation in subjects who did not experience an antipruritic response.  Bigiliardi 
and Bigliardi-Qi (2004`) reported that in PN human skin tissue samples there was a down 
regulation of the mu-opiate receptor (MOR) expression in the epidermis compared to 
normal skin.   
 
Bigliardi-Qi et al (2009) reports that while it is widely accepted that KOR signaling 
suppresses itch, there is currently no animal, behavioral or human data relating the 
regulation of skin KOR expression to pruritus.  Salemi et al 2007 however reported high 
upregulation of KOR in the skin of fibromyalgia subjects that was thought to correlate with 
reported complaints of pain symptoms. 
 
With regard to peripheral sensory nerve fiber density in the skin, Bigliardi et al (2009, 
2007) report that epidermal nerve endings of pruritic skin in prurigo are thinner when 
compared to normal skin.  In addition, the nerve fibers have a different morphology which 
may relate to initiating the sensation of pruritus because of the altered anatomical 
relationship to the various cellular elements of the skin.   
 
9.7.7.8.2 
Routine histology (H&E) and immunohistochemical examination of 
inflammatory cells and pro-inflammatory mediators 
Weigelt et al (2010) summarized the characteristic histological pattern in PN that include 
the presence of thick compact orthohyperkeratosis; folliculosebaceous units in nonvolar 
skin in conjunction with a thick and compact cornified layer; irregular epidermal 
hyperplasia or pseudoepitheliomatous hyperplasia; focal parakeratosis; hypergranulosis; 
fibrosis of the papillary dermis with vertically arranged collagen fibers; increased number 
of fibroblasts and capillaries; a superficial, perivascular and/or interstitial inflammatory 
infiltrate of lymphocytes, macrophages and, to a lesser extent, eosinophils and neutrophils. 
While the skin biopsy from PN patients is reported to show a composite pattern of 
dermatopathologic findings, the condition is not defined internationally by a Dermpath 
expert board.  Thus the biopsy obtained at the Baseline Visit and Evaluation Visit will be 
analyzed as an exploratory endpoint by a central dermatopathologist for histological review 
investigating possible correlation of pre-existing histopathological findings (i.e., level of 
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inflammation, etc.) with any subsequent clinical response noted on drug 
9.7.8   Safety Assessments 
As summarized in Section 6.2.7 of the Investigator’s Brochure, the CNS has been 
identified as the only target organ when nalbuphine was given to animals at high doses.  In 
addition, the most frequently reported adverse events reported in the nalbuphine HCl ER 
tablet dosing studies were primarily in the nervous system and gastrointestinal organ 
system categories.  In order to monitor any potential CNS related side effects, a brief 
neurological assessment will be conducted at each study visit as well as a focused 
neurological medical history will be obtained at screening. 
Safety will be determined by evaluation of the following: 
• AEs 
• Vital signs including weight, BP, heart rate (HR), respiratory rate (RR), and body 
temperature 
• Physical examination  
• Clinical laboratory data  (see Appendix 3 for list of analytes) 
• Investigator reviewed ECG and central cardiac core laboratory read 12 Lead-ECG, 
cardiovascular grading, and/or cardiovascular related prohibited medications 
• Subjective Opiate Withdrawal Scale (SOWS) 
 
The SOWS is a self-administered scale for grading opioid withdrawal symptoms.  It 
contains 16 symptoms whose intensity the patient rates on a scale of 0 (“not at all”) to 4 
(“extremely”).  The instrument can be found in Appendix 4.  In this study, patients will 
complete SOWS daily, starting at TV14, End of Treatment Visit through to the 
Washout and Safety Follow-up Period Visit.  The SOWS will also be completed at the 
Premature Discontinue of Study Drug Treatment Visit.  As with all patients who are 
discontinued from study drug, the patient will complete a daily SOWS scale for the two 
weeks following the last dose of study drug (unless consent is withdrawn).  The SOWS 
is a self-administered scale for grading opioid withdrawal symptoms.  If the patient is 
experiencing any symptoms on the SOW scale to a moderate degree, they will be 
instructed to contact the site.  If a patient is determined to be experiencing significant 
subjective withdrawal symptoms (at the Investigator’s discretion), they will be offered 
treatment. 
 
The following will be used to assess patient eligibility to continue participation if the 
patient experiences CHF, angina pectoris and/or other cardiovascular exclusion criteria 
(see Section 8.3 for the Exclusion Criteria and Appendix 5 for the grading scales) 
• The Canadian Cardiovascular Society grading of angina pectoris assessment:  
The Canadian Cardiovascular Society grading of angina pectoris (sometimes 
referred to as the CCS Angina Grading Scale or the CCS Functional 
Classification of Angina) is commonly used for the classification of severity of 
angina 
• The New York Heart Association (NYHA) Functional Classification:  The New 
York Heart Association Function Classification provides a simple way of 
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classifying the extent of heart failure by placing patients in one of four 
categories based on how much they are limited during physical activity; the 
limitations/symptoms are in regard to normal breathing and varying degrees in 
shortness of breath and/or angina pain. 
 
CredibleMeds Filtered QTDrug [List: Known Risk of TdP]:  Cardiovascular related 
prohibited medications are provided on the CredibleMeds Filtered QTDrug List.  
Drugs are placed into one of four risk categories based on their relative potential to 
alter the electrocardiogram (QT prolongation) and/or cause life-threatening ventricular 
arrhythmias.  See the following link to the CredibleMeds Filtered QTDrug List for 
cardiovascular related prohibited medications with a known associated risk of Torsade 
de Pointes:  https://www.crediblemeds.org/  Users of the CredibleMeds website will 
be required to complete a short (one-time) registration process in order to access the 
QTDrug listing. 
10 STUDY DRUG 
Please see the Study Reference Manual for additional information on Study Drug supplies, 
packaging, storage, dispensation, and accountability. 
10.1 FORMULATION, PACKAGING AND LABELING 
The Study Drug in this trial is nalbuphine HCl ER tablets.  Nalbuphine HCl ER tablets are 
white to off white film-coated round tablet containing either 30 mg or 60 mg nalbuphine 
HCl.   
All study medication will be supplied by the Sponsor.  Following confirmation of 
eligibility to start the Treatment Period, the patient will receive bottles of study drug tablets 
containing 60 tablets each.  Bottles will be labeled with at minimum: contents, storage 
conditions, expiration date, clinical trial statement, and the name and lot number of the 
study drug Sponsor (Trevi Therapeutics). 
10.2 SHIPPING, STORAGE AND HANDLING 
The Investigator will ensure that the Study Drug is stored and dispensed in accordance with 
ICH QE6(R1) (Guideline for Good Clinical Practice) and EU Clinical Trial Directive and 
Annex13 regulations concerning the storage and administration of investigational drugs.   
Nalbuphine HCl ER tablets and placebo tablets should be stored at 20°C-25°C (68°F-77°F) 
with excursions permitted between 15°C and 30°C (59° to 86°F).  The storage conditions 
were established following ICH Q1A(R2) (Stability testing of new drug substances and 
drug product) and the CHMP Guideline CPMP/QWP/122/02, rev 1 corr CHMP Guideline 
(Stability Testing of existing active substances and related Finished products)  for 
assessment and provision of appropriate labelling and storage conditions. 
The Study Drug will be stored away from any extreme conditions of temperature, light, or 
humidity as an additional precaution 
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In the EU, the investigational medicinal products will remain under the control of the 
Sponsor until after completion of a two-step procedure: certification by the Qualified 
Person; and release by the Sponsor for use in a clinical trial following fulfillment of the 
requirements of Article 9 (Commencement of a clinical trial) of Directive 2001/20/EC.  
Both steps will be recorded and retained in the relevant trial files held by or on behalf of 
the Sponsor. 
10.3 UNBLINDING 
Not applicable.  This is an open-label study. 
10.4 DRUG ACCOUNTABILITY 
The Investigator must ensure that all drug supplies are kept in a secure locked area with 
access limited to those authorized by the Investigator.  The Investigator must maintain 
accurate records of the receipt of all Study Drug shipped by the Sponsor or the Sponsor’s 
representative, including but not limited to the date received, lot number, expiration date, 
amount received, and the disposition of all Study Drug.  Current dispensing records will 
also be maintained including the date and amount of drug dispensed and the patient 
receiving the drug.  All remaining drug not required by regulations to be held by the 
clinical facility will be returned to the depot for destruction at the end of the study. 
11 PREMATURE DISCONTINUATION OF STUDY DRUG 
TREATMENT 
Patients who complete Study Drug treatment through the End of Treatment Visit (TV14) 
are considered to have completed Study Drug treatment (even if some doses have been 
missed).  Patients who discontinue Study Drug treatment, for reasons other than 
withdrawal of consent, prior to the End of Treatment visit (TV14) will be considered to 
have prematurely discontinued Study Drug treatment and will be asked to complete the 
following visits: 
• End of Treatment Visit (TV14) *regardless of where they are in the study visit 
schedule 
• Washout and Safety Follow-up Period Visit 
• Premature Discontinuation of Study Drug Telephone Contact Visit 
11.1 PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT ASSOCIATED WITH 
FAILURE-TO-IMPROVE CRITERIA 
Patients, who meet failure-to-improve criteria during the conduct of the study, will stop 
taking study medication.  The Failure-to-Improve criteria are as follows:  
Beginning on TV 3, and at every subsequent Treatment Visit, patients with a Worst 
itch NRS equal to or greater than (≥) the Worst Itch NRS at Visit 1a (or at Visit 1b 
in the case of patients who require the Observation Visit period) will be 
discontinued from study drug.  Patients discontinued from study drug are to 
undergo the End of Treatment Visit (TV14), the Washout/Safety Follow-up Period 
assessment in two weeks, and receive a follow-up Telephone Contact 30 days 
following end of study drug dosing for final safety assessment. 
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Below are examples of the assessment of Failure to Improve Criteria: 
 
Examples 
Visit 
Worst 
Itch NRS 
Worst Itch NRS 
Lower/Higher or 
no change from 
V1a/1b 
Failure-to-
improve met for 
that visit? 
Next Steps 
Visit 1a (or Visit 1b) 
5 
-- 
-- 
-- 
Ex #1 
TV3 
5 
No Change 
Yes 
Discontinue 
study drug 
Ex #2 
TV3 
4 
Lower 
No 
Maintain 
patient on 
treatment 
Ex #3 
TV3 
6 
Higher 
Yes 
Discontinue 
study drug 
 
11.2 PREMATURE DISCONTINUATION OF STUDY DRUG TREATMENT FOR REASONS 
OTHER THAN FAILURE-TO-IMPROVE 
Patients who complete Study Drug treatment (as defined in Section 11) are considered to 
have completed Study Drug treatment including those that were followed in the 
Observation Period prior to receiving Study Drug treatment.  Patients discontinuing Study 
Drug treatment prior to the maximum allowable number of Treatment Weeks (based on 
their entry into the study at either Visit 1a or Visit 1b) will also be considered to have 
prematurely discontinued Study Drug treatment.  Patients removed from the study after 
enrollment and who have received a dose of study drug will not be replaced. 
Some reasons for premature discontinuation of Study Drug treatment include: 
• Intercurrent Illness 
• Any intolerable AE that cannot be ameliorated or safely managed with 
medical intervention or one that poses undue risk to the patient if Study 
Drug treatment were continued in the opinion of the Medical Monitor or 
Investigator. 
• ECG changes as summarized in Section 17.4 
• Opioid medication is introduced in anticipation for chronic use of greater 
than 2 weeks (see Section 9.7.8) 
• Any medication prescribed for chronic anti-pruritic use of greater than 2 
weeks (see Section 9.7.6.1)  
• Development of substance abuse as determined by the Investigator  
12 PREMATURE WITHDRAWAL OF PATIENTS FROM THE 
STUDY 
All patients who receive study treatment should remain in the study whenever possible.  
Reasons for withdrawal of the patient from the study, not just discontinuation of study 
drug, include: 
• Withdrawal of consent for study participation 
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• Sponsor terminates the study for any reason 
• Investigator decision 
The Investigator may withdraw any patient from the study if, in the Investigator’s 
opinion, it is not in the patient’s best interest to continue on the study. 
• Death of the patient 
Any patient whose condition significantly changes after entering the study should be 
carefully evaluated by the Investigator and discussed with the Medical Monitor.  Such 
patients should be withdrawn from the study if continuing would place them at risk or 
compromise the results of the study. 
Patients who prematurely discontinue from the study will be asked to undergo and have 
completed Early Termination visit procedures and evaluations that may be necessary to 
ensure that the patient is free of untoward effects and to seek appropriate follow-up for any 
continuing problems.  The date on which the patient is withdrawn from the study and the 
reason for discontinuation will be recorded on the CRF.  Patients who withdraw from the 
study will not be replaced. 
13 WARNINGS AND PRECAUTIONS 
Please refer to the accompanying Investigator’s Brochure for more details summarizing the 
safety data on nalbuphine HCl ER tablets.  In addition, see the Warnings and Precautions 
sections of the parenteral nalbuphine HCl package insert for safety-related information.  
The package insert is contained in the Study Reference Manual. 
14 EFFICACY EVALUATIONS 
Efficacy measurements will be evaluated as secondary endpoints in this study.  The 
measurements include: 
• Worst itch intensity NRS  
• Average itch intensity baseline. 
• VRS (itchy, burning and stinging)  
• ItchyQoL  
• MOS Sleep-R  
• HADS 
• Prurigo Activity Score (PAS)  
• Patient Benefit Index, pruritus version (PBI-P)  
• Frequency, pattern, and reasons for dose titration 
• Frequency and distribution by time on study of patients determined to meet failure-
to-improve criteria 
• Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets 
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• Time to first use of rescue medications and number of days of use of rescue 
medications for itching 
• 
To evaluate the daily changes in the Subjective Opiate Withdrawal Scale (SOWS) 
during the Washout Period after cessation of treatment of nalbuphine HCl ER 
tablets. 
14.1 EXPLORATORY 
The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot), as well as 
histological (H&E) in skin biopsies taken during TR03 and the last week on study drug 
during TR03ext  (optional procedures at select sites only). 
15 COLLECTION, HANDLING, AND ANALYSIS OF 
PHARMACOKINETIC BLOOD SAMPLES 
15.1 BLOOD SAMPLE COLLECTION 
Blood samples will be collected for safety, pharmacokinetic and CYP analysis.  At the time 
of sample collection and processing, study patient information will be anonymized.  Only 
the patient’s identification number, assigned by an IVR/IWR system, and a sample barcode 
aligned to the lab requisition form will be noted on the tube/vial.   
See the PPD Laboratory Manual for specimen collection, handling and shipping details.  
15.2 CENTRAL LABORATORY 
Blood samples, including chemistry, serum pregnancy test, hematology, and urine for 
urinalysis will be obtained for the study and analyzed at a central laboratory.  
Urine pregnancy testing will be conducted at the site. 
The serum pregnancy test result will be used to determine the patient’s eligibility to 
continue receiving study treatment should the urine and serum pregnancy test results differ.  
See Section 17.5.2.1 regarding how pregnancies are to be handled in this study. 
15.3 PHARMACOKINETIC SAMPLES 
To determine Study Drug content in plasma, blood samples will be collected at various 
time intervals over the duration of the study. 
15.4 PREPARATION, STORAGE, AND HANDLING FOR PHARMACOKINETIC SAMPLES 
Immediately after blood sample collection, the tubes will be gently inverted several times 
to mix the anticoagulant with the blood sample and placed on ice (4 to 8°C) until 
centrifuged.  
The plasma fraction will be separated by centrifugation of the collection tube.  It is 
preferable that a refrigerated (4 to 8°C) centrifuge be used.  Centrifugation will be 
conducted in a manner to yield approximately 2 x1 mL of plasma (e.g., 10 minutes at 1,500 
x g).  The plasma fraction will be withdrawn by pipette and divided into 2 evenly 
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proportioned aliquots in polypropylene freezing tubes.  All sample collection and freezing 
tubes will be clearly labeled in a fashion that identifies the patient identification number, 
the study dose, and the collection date and time. 
Labels will be fixed to freezing tubes in a manner that will prevent the label from becoming 
detached after freezing.  All plasma samples will be processed and placed into either a 
minus 70°C or minus 20°C refrigerator within 1 hour after collection.  Tube labels for PK 
samples will be provided in the central laboratory kits.  Each label will contain the study 
number, patient number, study day of sample, and time of sample.  The actual date and 
time of blood collection, as well as the processing time will be recorded in the patient’s 
source records and/or the CRF.  
All plasma samples will be stored frozen (at either -70ºC or -20°C) until they are shipped 
for storage and analysis. 
15.5 ANALYTICAL 
Plasma samples will be analyzed for Study Drug using a validated liquid chromatography 
mass spectrometry (LC-MS/MS) method developed at Tandem Lab/s-RTP, Durham, North 
Carolina.  The units for nalbuphine will be in ng/mL.  In addition, metabolite 
concentrations will be assessed in these samples using an exploratory analytical LC-
MS/MS method. 
Analysis and reporting of results will be conducted according to the current Standard 
Operating Procedures for bioanalysis at Tandem labs Durham, North Carolina. Details of 
the sample analysis, including a bioanalytical study report, will be included with the final 
clinical study report. 
16 TISSUE SAMPLES AND HISTOLOGY 
At selected sites only, up to three 3 mm punch skin biopsy samples (optional) will be 
obtained at Visit 1a/1b and the End of Treatment Visit (TV14).  
• A 3x3 mm punch skin biopsy is taken from an itchy region which will be fixed in 
formalin and then paraffin for routine histology (H&E) and immunohistochemical 
examination of inflammatory cells and pro-inflammatory mediators. 
• For the other two 3x3 mm punch skin biopsy samples taken from an itchy region,  
o One sample will be fixed in 4% paraformaldehyde for 2 h to 5 days, and 
then kept in 5% sucrose overnight, buffered in 10% and 20% sucrose and 
after 6 h stored in liquid nitrogen. This tissue will serve for the 
determination of the nerve fiber density.  
o One sample will be used for RNA and protein extraction for the 
quantification of MOR/KOR by PCR and western blot.   
Analysis will be performed at the University of Munster, Munster, Germany.  
See the Study Reference Manual and the Laboratory Manual for specimen collection, 
handling and shipping details. 
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17 SAFETY EVALUATIONS 
Safety evaluations will include physical examination findings, changes in vital signs and 
ECGs (locally and centrally read), findings from central laboratory studies and the 
incidence of AEs 
17.1 PHYSICAL EXAMINATION 
A complete physical examination will be performed at the Screening Visit and 
subsequently according to the Schedule of Events (Appendix 1).  Physical examinations 
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 treatment 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.  
17.2 VITAL SIGN MEASUREMENTS 
Blood pressure and HR will be taken while sitting or semi-recumbent/recumbent for at 
least 5 minutes.  Temperature may be taken by any standard method (e.g., oral, tympanic, 
rectal, etc.), but the method must be recorded. 
Vital signs (BP, HR, RR, body temperature, and weight will be obtained according to the 
Schedule of Events (Appendix 1).  The height, weight and BMI will be recorded only on 
Visit 1a. 
17.3 LABORATORY EVALUATIONS 
A complete series of laboratory evaluations (including hematology, serum chemistry, 
serum pregnancy and urine pregnancy (both if applicable) and urinalysis will be obtained 
according to the Schedule of Events (Appendix 1).  The required clinical laboratory tests 
are listed in Appendix 3.  
Clinically-significant worsening in laboratory findings following start of Study Drug 
treatment will be recorded as AEs and these will be repeated for verification.  Clinically-
significant findings noted prior to the start of Study Drug treatment will be recorded as 
Medical History.  The recorded AE will indicate the underlying abnormality or diagnosis as 
opposed to the observed deviation in laboratory results if the diagnosis is known (e.g. 
“acute Hepatitis A” is preferable to “ALT increased”).   
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal result or to monitor the course of an AE will be obtained when clinically 
indicated.  In particular, if a clinically significant abnormal result is observed that is not 
resolved by the final study visit, tests will be repeated to document resolution or stability of 
the abnormality. 
17.4 ELECTROCARDIOGRAM 
A standard 12-lead ECG will be obtained according to the Schedule of Events (Appendix 
1); see the Study Reference Manual for ECG procedures.  Electrocardiograms will be read 
locally by the Principal Investigator for clinical significance and centrally for ECG 
intervals (PR, RR, QRS, QT, and QTcF using nomogram table), rate, rhythm, and other 
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clinically significant abnormalities such as left ventricular hypertrophy, pathological Q-
waves, etc.  Clinically-significant worsening in ECG findings following start of Study Drug 
treatment will be recorded as AEs.  Clinically-significant findings noted prior to the start of 
Study Drug treatment will be recorded as Medical History. 
If a patient develops a QTcF >500ms, associated with an increase from baseline of >60ms, 
the ECG will be repeated at least 30min later.  If these parameters are confirmed on the 
second ECG by the Core ECG laboratory, the patient will be discontinued from the study. 
During the conduct of the trial, if a patient develops any other cardiovascular events noted 
as part of the exclusion criteria, the cardiovascular assessments in Appendix 5 are to be 
completed.  See Section 17.5 Adverse Events for the handling and follow-up of Adverse 
Events. 
17.5 ADVERSE EVENTS  
Adverse events will be recorded starting with the signing of the first informed consent.  All 
AEs will be collected through the Washout and Safety follow up visit (or Early 
Termination Visit).  Adverse events that have not been directly reported to the Investigator 
will be promptly conveyed to the Investigator by the study staff.  Investigators will 
additionally review any AE source documents and the patient’s medical records, on a 
regular basis during the course of the study; including all study visits. 
Following the Washout and Safety follow up visit (or Early Termination Visit), all 
unresolved AEs that were reported by the Investigator to be probably drug related should 
be followed by the Investigator until the events are resolved, the patient is lost to follow-
up, or the adverse event has stabilized. 
17.5.1 Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
reported on or after the first screening date.  A treatment-emergent AE (TEAE) is any 
untoward medical occurrence in a clinical investigation patient or patient administered a 
pharmaceutical product on or after the initial administration of study medication.  An AE 
does not necessarily have to have a causal relationship with the treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom whether or not related to the medicinal (investigational) product, or 
disease temporally associated with the use of a medicinal (investigational) product. 
The AE may be any of the following: 
• a new illness 
• worsening of a pre-existing condition  
• worsening of a sign or symptom of the condition under treatment or of a 
concomitant illness 
• an effect of the study medication, including comparator 
• a combination of 2 or more of these factors. 
No causal relationship with the study medication or with the clinical study itself is implied 
by the use of the term “AE.” 
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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. 
Adverse events fall into the categories “non-serious” and “serious.” 
17.5.2 Serious Adverse Events 
The reporting period for serious AEs is the same as for AEs.  Serious AEs must be 
submitted to the Sponsor within 24 hours of their discovery, even if the full information 
about the event is not yet available.  These events should also be reported to the IRB/IEC 
as needed based on local requirements.  Fax SAE forms to the following number: 
Serious AE Fax #: 888-529-3580 
Also notify the PPD Medical Monitor at (888) 483-7729. 
17.5.2.1 Serious Adverse Event Definition 
An SAE is one that, at any dose, results in any of the following: 
• Death 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect. 
A hospitalization is defined as an inpatient admission lasting 24 hours or more.  Visits to 
urgent care centers and emergency departments that do not result in admission to a hospital 
for 24 hours will not be considered hospitalizations.  Hospitalizations for elective 
procedures, defined as any procedure that was planned prior to signing of the informed 
consent will not, in and of themselves, be considered to fulfill criteria for an SAE.  For 
example, for patients on the kidney transplant waiting list prior to signing the ICF who 
subsequently are hospitalized for a transplant, the hospitalization would be considered 
elective.  
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at immediate risk of death at the time of the SAE.  It does not refer to a SAE 
that hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether other AEs, such 
as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed above.  These should also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Female patients who become pregnant should be immediately discontinued from the study 
if they have not yet received Study Drug.  If a patient is found to be pregnant after they 
have received Study Drug, she should discontinue dosing, complete all end-of-study 
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procedures, and be followed to determine the outcome of the pregnancy.  Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  While 
pregnancy itself is not considered an AE or SAE, any pregnancy complications or less than 
a healthy, normal outcome will be recorded as an AE or SAE.   
Clarification on the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  This is not the same as 
“serious,” which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
17.5.3 Non-Serious Adverse Events 
A non-serious AE is any AE not meeting the SAE criteria. 
17.5.4 Definition of Relationship to Study Medication 
Association or relatedness to the study medication will be graded as either “probably,” 
“possibly,” or “unlikely.”  Determination of relatedness includes: 
PROBABLY – The AE: 
• follows a reasonable temporal sequence from drug administration; 
• abates upon discontinuation of the drug; 
• cannot be reasonably explained by the known characteristics of the patient’s clinical 
state. 
POSSIBLY – The AE: 
• follows a reasonable temporal sequence from drug administration; 
• could have been produced by the patient’s clinical state or by other modes of therapy 
administered to the patient. 
UNLIKELY – The AE: 
• does not follow a reasonable temporal sequence from drug administration; 
• is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient. 
17.5.5 Definition of Severity 
All AEs will be graded, if possible, by the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 [http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_5x7.pdf].  This is also provided in the Study Reference Manual for 
reference purposes. 
The severity of AEs that cannot be graded by the most current version of CTCAE will be 
categorized as follows: 
• Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
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• Grade 2 – Mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required. 
• Grade 3 – Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required hospitalizations possible. 
• Grade 4 – Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required hospitalization or hospice care probable. 
• Grade 5 – Death. 
17.5.6 Definition of Unexpected Adverse Event 
Any AE, the specificity or severity of which is not consistent with the current 
Investigator’s Brochure, rather than from the perspective of such experience not being 
anticipated from the pharmacological properties of the drug. 
17.6 DATA SAFETY MONITORING BOARD 
An unblinded, independent Data Safety Monitoring Board (DSMB) will periodically 
review safety data during the time period that the blinded nalbuphine HCl program remains 
ongoing.  The frequency of data review and DSMB processes are outlined in the DSMB 
charter.  The DSMB will periodically review group-unblinded study information (on a 
treatment group level, using random letters instead of actual treatments) during the conduct 
of the study.  If necessary, un-blinding of individual subject data and treatment groups may 
be done. 
18 EMERGENCY PROCEDURES 
In case of study-related medical questions, or if a pregnancy is confirmed in a trial patient, 
the Investigator should contact the designated Medical Monitor. 
18.1 EMERGENCY SPONSOR CONTACT 
In emergency situations, the Investigator should contact the designated Sponsor 
representative at the following address: 
Thomas Sciascia, MD 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, CT 06510 USA 
Telephone:   (203) 304-2499 
Mobile:   
(617) 913-6808 
19 CONSIDERATION, ANALYSIS PLAN AND DETERMINATION 
OF SAMPLE SIZE 
19.1 GENERAL 
As a companion to this protocol and in an effort to provide a more detailed explanation of 
the statistical methodology to be used for this study, which will consist of data summaries, 
a statistical analysis plan (SAP) will be developed prior to locking the data base. 
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No formal statistical testing is planned for this study.  Data summaries will provide the 
basis for clinical interpretation of efficacy and safety outcomes 
19.2 INTERIM ANALYSES 
There is no interim analysis planned in this study. 
19.3 METHODS FOR HANDLING MISSING DATA 
No replacement or imputation of missing data will be conducted for this study.  
19.4 PATIENT DISPOSITION 
Patient disposition will be summarized, including the reasons for discontinuation.  The 
number of patients in each analysis population will be displayed and an accounting of 
exclusions from each study population will be provided. 
19.5 BASELINE CHARACTERISTICS 
Demographics, medical history, laboratory data, and physical examination findings will be 
summarized. 
19.6 CONCOMITANT MEDICATIONS 
Concomitant medications will be tabulated by Anatomic and Therapeutic Class (ATC) of 
WHO drug, preferred term, and treatment group.  A medication’s usage will be considered 
concomitant if it was used by the patient at the time of informed consent or started and/or 
continued after administration of the study medication.  If the start date is missing, it will 
be assumed that the medication was used concomitantly.  Rescue and opioid medication 
usage will be tabulated separately from all other concomitant medications. 
19.7 STUDY DRUG DOSING 
The percentage of patients reaching various achieved doses at the end of Treatment Week 4 
and through Study Week 50 will be summarized.  The mean dose during the Treatment 
Period and the dose distribution by Treatment Period Visit will be reported.  Descriptive 
statistics will be used to describe the mean daily dose by Visit. 
19.8 EFFICACY ANALYSES 
19.8.1 Efficacy Population 
The Safety population, consisting of all enrolled patients who have received a single dose 
of study medication, will be used to evaluate the efficacy endpoints defined for this study.  
Eligibility for analysis of a particular endpoint will require only that the patient have a 
baseline value and at least one post-baseline value for the endpoint of interest, so that a 
change from baseline calculation can be obtained.  All efficacy endpoints will be evaluated 
through the generation of descriptive summary statistics.  For continuous variables, the 
mean, standard deviation, median, minimum, and maximum will be presented for a 
particular visit and for the change from baseline (Visit 1a or 1b).  For categorical variables, 
the number and percentage of patients within each category of classification will be 
summarized by study visit.  No formal statistical testing will be conducted. 
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19.8.2 Premature Discontinuation Due to Lack of Efficacy or Adverse 
Events 
The distribution of patients who prematurely discontinue due to lack of efficacy or adverse 
events will be summarized.  Patients who prematurely discontinue after having been 
followed in the Observation Period only will be also be summarized.  
19.9 SAFETY ANALYSES 
19.9.1  Safety Population 
The Safety Population will consist of all patients who have received a single dose of study 
medication, i.e., this same population will be used both for the efficacy and safety 
evaluations.  The Safety Population will be used in all safety analyses. 
19.9.2  Adverse Events 
All treatment emergent AEs (TEAE) will be summarized overall and for each body system 
and preferred term by treatment group, relationship to study medication, and severity.  For 
tabulations by severity, only a patient’s most severe event within the category (e.g., overall, 
body system, or preferred term) will be counted.  Adverse events will be dichotomized into 
“related” (probably and possibly) and “unrelated” (unlikely).  “Treatment-emergent” will 
be defined as starting or worsening after the first dose of study drug.  If the start date is 
missing, the event is assumed to be treatment emergent.  All SAEs will be tabulated as 
well. 
Although nalbuphine is not a controlled substance in the United States, adverse events of 
special interest that suggest a possible addiction or abuse potential or withdrawal will be 
specifically analyzed to screen for these effects.  The list of MedDRA preferred terms for 
adverse events of special interest will be described in the Statistical Analysis Plan.  
19.9.3  Vital Signs 
Vital signs, including BP, HR, body temperature, and RR, and weight will be summarized 
by treatment group at Baseline and at each assessment time point during the post dosing 
period. 
19.9.4 Laboratory Evaluations 
Clinical safety laboratory data will be summarized descriptively by treatment group at 
baseline and at each scheduled visit.  Summaries of safety laboratory parameters will 
include the first measurement of each scheduled assessment but repeat assessments done at 
the same study time point will not be included in summary calculations.  Lab data will also 
be listed by treatment, patient, and visit.  Listings will include scheduled, unscheduled, and 
repeat evaluations.  A listing of markedly abnormal values, as defined in the Statistical 
Analysis Plan, will additionally be generated. 
19.9.5  Physical Examinations 
Abnormal physical examination findings that suggest a clinically significant worsening will 
be reported as AEs and analyzed as such.  Clinically significant findings noted prior to start 
of Study Drug treatment will be recorded as medical history and analyzed as such. 
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19.9.6  Electrocardiograms 
A standard 12-lead ECG will be obtained on Visit 1a/1b (pre-treatment) and subsequently, 
according to the Schedule of Events in Appendix 1.  Electrocardiogram intervals (PR, RR, 
and QTcF) will be summarized with descriptive statistics.  All findings, including any 
follow-up ECGs as a result of any significant abnormal results, will be listed by treatment, 
patient, and visit. 
 
ECG procedures should be automatically repeated if the following results are obtained: 
artifact, excessive noise, reversed leads, or baseline wander.  Repeating ECG procedures 
for any other reason will require prior written approval from the Sponsor. 
 
19.10 DETERMINATION OF SAMPLE SIZE 
As this is a safety extension study for which patients will be recruited from patients who 
have completed parent study TR03, the sample size cannot be predicted.  No formal sample 
size calculations have been performed and no inferential statistics are planned.  The 
maximum number of patients will not exceed the number of patients who completed TR03 
(i.e., approximately 60 patients). 
19.11 PHARMACOKINETIC AND PHARMACOKINETIC / 
PHARMACODYNAMIC ANALYSES 
The Study Drug plasma concentration data will be provided as data listings and will be 
summarized descriptively (mean, median, SD, minimum, and maximum) by collection time 
and nalbuphine dose.  Additionally, these PK data may be analyzed through population, 
nonlinear mixed effects modeling (NONMEM), using the software package NONMEM 
(Version V, Level 1.1 or higher; GloboMax LLC, Hanover, MD). 
20 ETHICS 
20.1 INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD  
Prior to initiation of the study, the Investigator will submit the study protocol, sample 
informed consent form (ICF), and any other documents that pertain to patient information, 
recruitment methods such as patient diaries, and advertisements, to the Institutional Review 
Board/Independent Ethics Committee (IRB/ IEC).  The Investigator must also submit any 
other information that may be requested to the IRB/IEC for review and approval.  The 
Investigator will request that the IRB/IEC provide written approval of the study, and will 
keep on file; records of approval of all documents pertaining to this study.  A letter 
confirming the approval must be forwarded to the Study Monitor prior to initiation of this 
study.  This letter will be forwarded to the Sponsor prior to the initiation of the study. 
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC for 
all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the IRB/IEC of deviations from the protocol or SAEs occurring at the site, as well as 
other AE reports received the Sponsor, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IRB/IEC approval or renewal 
throughout the duration of the study.   
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20.2 ETHICAL CONDUCT OF THE STUDY 
This study is to be conducted according to globally accepted standards of good clinical 
practice (as defined in the ICH E6 Guideline for Good Clinical Practice [GCP], 1 May 
1996), in agreement with the latest revision of the Declaration of Helsinki and in keeping 
with local regulations. 
The Investigator should ensure that all persons assisting with the trial are adequately 
qualified, informed about the protocol, any amendments to the protocol, the study 
treatments, and their trial-related duties and functions. 
The Investigator should maintain a list of Sub-investigators and other appropriately 
qualified persons to whom he or she has delegated significant trial-related duties.  Should 
the Investigator delegate the supervision of the investigational product administration to a 
designated person, this individual must have the appropriate medical qualifications to 
effectively conduct or supervise any potential resuscitation procedures. 
20.3 PATIENT INFORMATION AND INFORMED CONSENT 
Patients must provide written consent to participate after the nature, scope, and possible 
consequences of the clinical study have been explained in a form understandable to them. 
An ICF that includes information about the study will be prepared and given to the patient.  
This document will contain all the elements required by the ICH E6 Guideline for GCP and 
any additional elements required by local regulations.  The document must be in a language 
understandable to the patient and must specify who informed the patient.  Where required 
by local law, the person who informs the patient must be a physician. 
After reading the ICF, the patient must give consent in writing.  The patient’s consent must 
be confirmed at the time of consent by the personally dated signature of the patient and by 
the personally dated signature of the person conducting the informed consent discussions. 
A copy of the signed ICFs must be given to the patient.  The original signed ICFs will be 
retained by the Investigator.  
The Investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained.  
21 STUDY ADMINISTRATION 
21.1 CLINICAL MONITORING 
Monitoring and auditing procedures, developed or endorsed by Trevi Therapeutics will be 
followed to comply with GCP guidelines.  Access to the on-site study documentation and 
medical records will be ensured. 
The study will be monitored by Trevi Therapeutics or its designee.  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.  During the on-site visits, the CRF will be 
reviewed for completeness and adherence to the protocol.  As part of the data audit, all 
source documents in the Investigators’ possession must be made available to the Study 
Monitor for review.  The Study Monitor will also perform drug accountability checks and 
will request to perform a review of the Investigator study file to ensure completeness of 
documentation in all respects of clinical study conduct. 
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Upon completion of the study, the Study Monitor will arrange for a final review of the 
study files, after which the files should be secured for the appropriate time period.  The 
Investigator, or appointed delegate, will meet with the Study Monitor during the on-site 
visits and will cooperate in providing the documents for inspection and responding to 
inquiries.  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. 
21.2 DATA QUALITY ASSURANCE 
The Investigator, or designee, will enter study data required by the protocol into an 
electronic data capture (EDC) system.  The Study Monitor will visit each study site, at a 
frequency documented in the monitoring plan, to review the electronic CRF (eCRF) for 
completeness and accuracy.  Any discrepancies found between source documents and 
completed eCRF will be entered as a discrepancy in the EDC system by the Study Monitor.  
Appropriate study site personnel should then address those discrepancies in the EDC 
system.  Uniform procedures for eCRF correction (queries) will be discussed during the 
study site initiation visits and will be documented in the study operations manual. 
Data from eCRF and other external data sources will be entered into a clinical database as 
specified in the data management plan.  Quality control and data validation procedures will 
be applied to ensure the validity and accuracy of the clinical database.  
Computerized and manual procedures should be used to review and check data from eCRF 
and data from other external sources for omissions, apparent errors, and values that may 
require further clarification.  Data queries requiring clarification should be documented, 
and the study site should be requested to review and resolve the queries.  Only authorized 
personnel can make corrections to the clinical database, and all corrections should be 
documented in an audit trail. 
Adverse events will be coded using the most current MedDRA version.  Prior and 
concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Dictionary. 
21.3 RETENTION OF STUDY RECORDS 
The following records must be retained by the Investigator for a minimum of 2 years after 
the Sponsor has notified the FDA that investigations have been discontinued or after the 
FDA has approved the new drug application:  
• Signed ICFs for all patients 
• Patient identification code list, screening log (if applicable), and enrollment log 
• Record of all communications between the Investigator and the IRB/IEC 
• Composition of the IRB/IEC or other applicable statement  
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• Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
• List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in 
the study and their signatures 
• Copies of CRFs and of documentation of corrections for all patients  
• Drug accountability records 
• Record of any body fluids or tissue samples retained 
• All other source documents (patient records, hospital records, laboratory records, 
etc.) 
• All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
However, because of international regulatory requirements, the Sponsor may request 
retention for a longer period of time.  The Investigator must therefore obtain approval in 
writing from the Sponsor prior to destruction of any records. 
Normally, these records will be held in the Investigator's archives.  If the Investigator is 
unable to meet this obligation, he or she must ask the Sponsor for permission to make 
alternative arrangements.  Details of these arrangements should be documented. 
21.4 CONFIDENTIALITY 
Patient names will not be supplied to the Sponsor.  Only the patient number and patient 
initials will be recorded in CRF (unless not allowed by local regulations), and if the patient 
name appears on any other document (e.g., pathologist 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 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. 
The Investigator will maintain a personal patient identification list (patient numbers with 
the corresponding patient names) to enable records to be identified. 
21.5 DOCUMENTATION OF STUDY RESULTS 
As part of the responsibilities assumed by participating in the study, the Investigator or 
Sub-investigator agrees to maintain adequate case histories for the patients treated as part 
of the research under this protocol.  The Investigator or Sub-investigator agrees to maintain 
accurate eCRF and source documentation as part of the case histories.  These source 
documents may include laboratory reports and ECG recordings. 
The Investigator or designees must enter all results collected during the clinical study into 
the eCRF.  Guidelines for completion of the eCRF will be reviewed with study-site 
personnel at the site initiation visits.  There is a 2-part process to review and collect the 
eCRF data.  Study-site personnel will enter the data from each study visit.  The Investigator 
is responsible for approval of the entered/corrected data.  The eCRF responsibilities of the 
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study team members will be documented on the site delegation log, which will be collected 
at the closeout visits. 
Under special circumstances, and with prior written Sponsor approval, the Investigator can 
authorize Sub-investigators to sign and approve the eCRF if they are designated on Form 
FDA 1572 as Sub-investigators, have been trained on the EDC system, and have their own 
user name and password.  The Investigators or designees must review and approve the data 
before database lock. 
In the EU, the Investigator agrees to maintain documentation of the data generated by the 
trial so that it complies with the requirements of Directive 2001/20/EC, as amended and 
Directive 2005/28/EC as amended to incorporate recommendations on ‘The Trial Master 
File and Archiving’. 
21.6 USE OF STUDY RESULTS 
All information concerning the product, as well as any matter concerning the operation of 
Trevi Therapeutics (such as clinical indications for the drug, its formula, methods of 
manufacture, and other scientific data relating to it, that have been provided by Trevi 
Therapeutics and are unpublished) are confidential and must remain the sole property of 
Trevi Therapeutics.  The Investigator and participating vendors will agree to use the 
information only for the purposes of carrying out this study and for no other purpose unless 
prior written permission from Trevi Therapeutics is obtained.  The Sponsor has full 
ownership of the CRFs completed as part of the study. 
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. 
 
 
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79. Wolfe F, Michaud K, Li T. Sleep disturbance in patients with rheumatoid arthritis: 
evaluation by medical outcomes study and visual analog sleep scales. J Rheumatol. 
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pain. Pain. 2011 Mar;152(3 Suppl):S2-15. 
 
 
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APPENDICES 
Appendices 1 through 4 are provided on the following pages. 
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Appendix 1: Schedule of Events 
 
Table 4: Schedule of Events for Visits 1a and 1b 
(Day 1 of Week 1 of Treatment Period)  
 
 
 
 
 
 
1Visit 6/1a procedures in common do 
not have to be repeated if visits are 
performed on the same day. 
2 To be completed any time before start 
of Visit 1a procedures 
3BP and HR (sitting or semi-
recumbent), RR, temperature.  Height, 
weight, and BMI at Visit 1a only. 
4 Visit 1b is the first visit of the 
Treatment Period for patients 
transitioning from the Observation 
Period to the Treatment Period.   
5Hematology and chemistry 
6Females of Childbearing potential 
only 
7Questionnaires must be administered 
strictly adhering to instructions (see 
Study Reference Manual)  
8Includes review of patient TR03 
Rescue Medication Log 
9Study procedures only conducted if 
patient qualifies to enter the Treatment 
Period based on Worst itch NRS ≥ 5 
10Titrate study drug according to the 
schedule in Table 3;  
The first dose of study drug treatment 
will define enrollment into the study 
11 For female patients of child-bearing 
potential, a urine pregnancy test must 
be negative prior to dispensing study 
drug.  
 
12 ECGs are to be performed after the 
patient has been in the supine position 
for at least 5 minutes.  ECGs will be 
read by the Investigators for clinical 
significance and centrally by a core 
ECG laboratory for analytical and 
DSMB safety review 
 
13The first dose of study drug is to be 
taken in the evening, see Section 9.7.1 
and Section 9.3 
Visit 
1a1 
1b4 
 
Informed Consent2 
X 
 
 
Confirm Eligibility 
X 
 
 
Vital Signs3 
X 
X 
 
Physical Examination 
X 
X 
 
Neurological Exam 
X 
X 
 
Central Clinical Labs5 & serum 
PregnancyTest6 
X 
X 
 
Urinalysis 
X 
X 
 
Urine for pregnancy test11 
X 
X 
 
Blood for PK 
X 
X 
 
Perform skin biopsy (only at select sites and 
the procedure is optional)9 
X 
X 
 
12-lead ECG12 
X 
X 
 
Worst itch Numerical Rating Scale 
(NRS)7 
X 
X 
 
Average itch intensity Numerical Rating 
Scale (NRS)7 
X9 
X 
 
Verbal Rating Scale (VRS)7 
X9 
X 
 
ItchyQoL7 
X9 
X 
 
MOS Sleep-R7 
X9 
X 
 
Hospital Anxiety and Depression Scales 
(HADS)7 
X9 
X 
 
Patient Benefit Index Pruritus (PBI-P)7 
X9 
X 
 
Prurigo Activity Score (PAS) 
X9 
X 
 
Record AEs  
X 
X 
 
Review Rescue Medications and 
Concomitant Medications 
X8 
X 
 
Retrieve TR03 study drug 
X 
 
 
Dispense Study Drug for TR03ext13 
X9 
X 
 
Collect Rescue Medication Log for TR03 
X 
 
 
First dose of Study Drug for TR03ext10,13 
X9 
X 
 
Dispense Drug Dosing Instructions and 
Dosing Diary 
X 
X 
 
 
Dispense TR03ext Rescue Medication Log 
X 
X 
 
 
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Table 5:  Treatment Weeks 2-4  
 
TC 11 
TV 21 
TC 21 
Treatment Week  
2 
3 
4 
Dispense Study Drug2 
 
X 
 
Titrate Study Drug2 
X 
X 
 
Confirm Maintenance Dose 
 
 
X2 
Vital Signs3 
 
X 
 
Neurological Assessment 
 
X 
 
Urine pregnancy test5 
 
X 
 
Blood for PK 
 
X 
 
12-lead ECG6 
 
X 
 
Worst itch NRS4 
 
X 
 
Average itch intensity NRS4 
 
X 
 
VRS4 
 
X 
 
MOS Sleep-R4 
 
X 
 
HADS4 
 
X 
 
ItchyQoL4 
 
X 
 
Study Drug BID 
X 
Record AEs  
 X 
X 
X 
Record Concomitant Medications 
  
X 
 
Reinforce Compliance7 
X 
X 
X 
Study Drug Accountability  
 
X 
 
Dispense Dosing Diary 
 
X 
 
Dispense Rescue Medication Log 
 
X 
 
1 The window for TC 1-2 and TV2 is +/-3 days 
2 Instruct the patient in the dose titration/maintenance according to the schedule in Table 3 and assess 
tolerability/intolerability to study drug   
3 BP and HR (sitting or semi-recumbent), RR, temperature. 
4Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual) 
5 For female patients of child-bearing potential, a urine pregnancy test must be negative prior to dispensing 
additional study drug.   
6 ECGs are to be performed after the patient has been in the supine position for at least 5 minutes.  ECGs will be 
read by the Investigators for clinical significance and centrally by a core ECG laboratory for analytical and DSMB 
safety review 
7Includes review of Rescue Medication Log and Drug Dosing Diary for accuracy and completeness. 
 
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Table 6: Treatment Period Visits12 During Study Weeks 5-50 and Washout/Safety Follow-up Visit or Treatment Period Early 
Termination Visit 
 
TV
3 
TV
4 
TV
5 
TV
6 
TV
7 
TV
8 
TV
9 
TV
10 
TV
11 
TV
12 
TV
13 
End of 
Treatment 
Visit 
(TV14) 
Washout / 
Safety Follow-
up Period 
Premature 
Discontinuation 
of Study Drug 
Telephone 
Contact14 
ET9 
Treatment Week1,3 
5 
9 
13 
17 
21 
26 
30 
34 
38 
42 
46 
--2 
-- 
-- 
Physical Examination 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Brief Neurological Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Central Clinical Labs6 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
Serum pregnancy test to central lab11 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Urinalysis to central lab 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
PAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
PBI-P7 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
12-lead ECG13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Skin biopsy (at select sites and is an 
optional procedure) 
 
 
 
 
 
 
 
 
 
 
 
X10 
 
 
X 
Blood for PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Failure-to-Improve Evaluation17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Dispense Study Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Urine pregnancy test5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Worst itch NRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Average itch intensity NRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ItchyQoL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
VRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
MOS Sleep-R7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
HADS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
SOWS7 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Dispense 14 day SOWS packet15 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Retrieve 14 day SOWS packet15 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record  Concomitant Medications16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reinforce Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Drug Accountability  
X 
X 
X 
X 
X 
X8 
X 
X 
X 
X 
X 
X 
 
 
X8 
Study Drug BID 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
1Patients who were previously in the Observation Period should start the Treatment Period at Visit 1b and continue in the study for 38-46 weeks; the total number of weeks in the 
combined Observation and Treatment Periods is no more than 50 weeks. The last scheduled visit on study drug for patients previously in the Observation Period should be TV 14 
regardless of the study week. 
2 The number of Treatment Weeks prior to TV 14 will vary for patients who prematurely discontinue study drug for reasons other than withdrawal of consent see Section 11. 
3Two allowable dose reductions are permitted during Treatment Weeks 5 – 50 (a patient can be reduced to 30 mg BID). If a third dose reduction is needed, the patient should be 
discontinued from the study. 
4 BP and HR (sitting or semi-recumbent), RR, temperature 
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5For female patients of child-bearing potential, a urine pregnancy test must be negative prior to dispensing additional study drug. 
6 Hematology and chemistry. 
7Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual) 
8 Retrieve remaining study drug at TV 14 or ET Visit 
9 ET Visit is conducted within 2 weeks of study drug termination, see Section 12 
10 Skin biopsy material for nerve fiber density, histology (H&E) and MOR/KOR density to be performed, only at select sites (optional procedure)  
11Females of Childbearing potential only 
12 Visit windows will be +/-3 Days 
13 ECGs are to be performed after the patient has been in the supine position for at least 5 minutes.  ECGs will be read by the Investigators for clinical significance and centrally by a core 
ECG laboratory for analytical and DSMB safety review 
14The Premature Study Drug Discontinuation Telephone Contact is to take place for all patients who prematurely discontinue study drug for reasons noted in Section 11.  This telephone 
contact takes place 30 days (+2 weeks) from the last dose of study drug. 
15The 14 Day SOW packet is to be completed at home by the patient.  A SOWS is to be completed each day starting at TV14.  The packet is to be retrieved at the Washout and Safety 
Follow-up Period Visit 
16Includes review of Rescue Medication Log and Drug Dosing Diary for accuracy and completeness 
17See Section 11.1 for the Failure-to-Improve criteria; perform End of Treatment Visit (TV14) procedures for patients that meet the Failure-to-Improve criteria 
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Version 2.0, 11 MARCH 2015 
  
Page 105 of 126 
 
 
 
Table 7:  
Observation Period Visits5 
 
Observation Visit 
OV 
2 
OV 
3 
OV 
4 
Observation Study Week 
4 
8 
121 
Check Worst itch NRS2: If ≥ 5 , patient must undergo Visit 1b  
X4 
X4 
X4 
Vital Signs3 
X 
X 
X 
Average itch intensity NRS2 
 
 
X 
VRS2 
 
 
X 
MOS Sleep-R2 
 
 
X 
HADS2 
 
 
X 
ItchyQoL2 
 
 
X 
Record AEs  
 X 
X 
 X 
Record concomitant medications 
X 
X 
X 
1Patients whose NRS is <5 at OV 4 are to be screen failed from the study  
2 Questionnaires must be administered strictly adhering to instructions (see Study Reference Manual) 
3BP and HR (sitting or semi-recumbent), RR, temperature 
4If patient’s NRS is ≥ 5 proceed to Visit1b procedures and no need to record any further data under OV 
visit procedures 
5Visit windows will be +/-3 Days 
 
 
 
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Version 2.0, 11 MARCH 2015 
  
Page 106 of 126 
 
 
 
Table 8:  Treatment Visit Schedule for Patients Entering Treatment via Visit 1b 
Patients with a Worst Itch NRS score of greater than or equal to 5 (≥5) at an Observation Visit 
are to complete Visit 1b and transition from the Observation Period to the Treatment Period. 
If the above criteria are met, Visit 1b procedures are to be completed at the Observation Visit 
Visit of 
Transition 
OV2 
OV3 
OV4 
Treatment 
Visits to 
Complete 
Visit 1b/TV1, TV2 
through TV12, and 
TV13 
Visit 1b/TV1, TV2 
through TV11, and 
TV12 
Visit 1b/TV1, TV2 
through TV10, and 
TV11 
Last Treatment 
Visit  
TV13 
 
Dispense 1 week of 
study  drug  
 
Week 46 is last week of 
treatment for a patient 
who transitioned to the 
Treatment Period from 
OV2 
 
Conduct the End of 
Treatment Visit (TV14) 
during week 47 
TV12 
 
Dispense 1 week of 
study  drug  
 
Week 42 is last week of 
treatment for a patient 
who transitioned to the 
Treatment Period from 
OV3 
 
Conduct the End of 
Treatment Visit (TV14) 
during week 43 
TV11 
 
Dispense 1 week of 
study  drug  
 
Week 38 is last week of 
treatment for a patient 
who transitioned to the 
Treatment Period from 
OV4 
 
Conduct the End of 
Treatment Visit (TV14) 
during week 39 
Total Potential 
Weeks on 
Treatment 
46 
42 
38 
 
 
 
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Version 2.0, 11 MARCH 2015 
  
Page 107 of 126 
 
 
 
Table 9: Rescue Medications for Itching 
Rescue Medication 
Only intended for anti-
pruritic treatment 
Examples 
Opioid receptor antagonists  
 
naltrexone, naloxone 
Antihistamines   
  
topical or systemic 
Topical calcineurin inhibitors  
  
tacrolimus 
Topical antibiotics 
  
--- 
Topical steroids 
  
--- 
Topical capsaicin 
  
--- 
Anti-septic baths and anti-septic 
cleansing lotions  
  
--- 
Anti-convulsant class drugs 
  
gabapentin or pregabalin 
Systemic Steroids 
  
--- 
cyclosporin A and other 
immunosuppressants 
  
--- 
antidepressant medications  
  
paroxetine, fluvoxamine, 
amitriptyline 
Malignant tumor related active 
treatment with a systemic drug 
  
--- 
UV Therapy 
  
--- 
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Version 2.0, 11 MARCH 2015 
  
Page 108 of 126 
 
 
 
Appendix 2: Study Schematic Flow Charts  
 
Figure 2:  
Overview of TR03-EXT Study Design 
 
 
 
 
 
 
 
 
 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
 
 
 
 
 
 
Page 109 of 126 
 
 
 
Figure 3:  
Examples illustrating possible Observation and Treatment periods Scenarios in TR03-Ext 
 
 
 
 
 
 
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Figure 4:  
Dosing Schedule in TR03ext 
 
 
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Version 2.0, 11 MARCH 2015 
  
Page 111 of 126 
 
 
Appendix 3: Clinical Laboratory Tests 
 
Hematology: 
Serum Chemistry: 
 
 
Hemoglobin 
ALT 
Hematocrit 
Red Blood Cell Count 
Albumin 
Alkaline Phosphatase 
White Blood Cell Count  
Platelet Count  
White Blood Cell Differential 
AST 
Bicarbonate 
Blood Urea Nitrogen (BUN) 
 
Carbon Dioxide 
Calcium  
Urine: 
Urinalysis 
Pregnancy  
 
 
22.1.1.1.1.1 Serum Pregnancy: 
β-Human Chorionic  
Gonadotropin (HCG) (women of childbearing 
potential regardless of sexual activity  
Chloride 
Creatinine 
Gamma-glutamyl transferase 
Glucose 
LDH 
Phosphorus 
Potassium 
Sodium 
Total Bilirubin 
Total Protein 
Uric acid 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
Page 112 of 126 
 
 
Appendix 4:  Patient Reported Outcomes 
 
The Patient Reported Outcomes are provided on the subsequent pages. 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
Page 113 of 126 
 
 
 
Medical Outcomes Sleep Scale (Revised MOS Sleep-R) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
Your Sleep 
 
For each of the following questions, please mark an 
 in the one box that best describes your 
answer. 
 
1. How long did it usually take for you to fall asleep during the past 4 weeks? 
0-15 
minutes 
16-30 
minutes 
31-45 
minutes 
46-60 
minutes 
More than 60 
minutes 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
2. On the average, how many hours did you sleep each night during the past 4 
weeks? 
 
Write in number of hours per night:  
 
3. How often during the past 4 weeks did you… 
 
Copyright, 1986, RAND. 
MOS 12-Item Sleep Scale – Revised 2010 
United States (English) 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
a 
feel that your sleep was not quiet 
(moving restlessly, feeling tense, 
speaking, etc., while sleeping)? ...........
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
b 
get enough sleep to feel rested  
upon waking in the morning? .............
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
c 
awaken short of breath or with 
a headache? .................................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
d 
feel drowsy or sleepy during  
the day? ......................................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
e 
have trouble falling asleep? ................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
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Version 2.0, 11 MARCH 2015 
  
 
Page 114 of 126 
 
 
 
Medical Outcomes Sleep Scale (Revised MOS Sleep-R) (cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
How often during the past 4 weeks did you… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright, 1986, RAND. 
MOS 12-Item Sleep Scale – Revised 2010 
United States (English) 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
f 
awaken during your sleep time  
and have trouble falling asleep 
again? .........................................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
g 
have trouble staying awake  
during the day? ..............................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
h 
snore during your sleep? ................... 
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
i 
take naps (5 minutes or longer)  
during the day? ..............................
 1........... 
 2 ...........
 3........... 
 4 ...........
 5 
j 
get the amount of sleep you  
needed? ......................................
 1 ........... 
 2 ...........
 3 ........... 
 4 ...........
 5 
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Version 2.0, 11 MARCH 2015 
  
 
 
 
 
 
 
 
Page 115 of 126 
 
ItchyQoLTM 
 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
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Protocol No. TR03ext 
 
 
 
Trevi Therapeutics, Inc. 
Version 2.0, 11 MARCH 2015 
  
 
 
 
 
 
 
Page 116 of 126 
 
ItchyQoLTM (cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
 
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Protocol No. TR03ext 
 
 
 
Trevi Therapeutics, Inc. 
Version 2.0, 11 MARCH 2015 
  
 
 
 
 
 
 
Page 117 of 126 
 
ItchyQoLTM (cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
 
Page 337


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Trevi Therapeutics, Inc. 
Version 2.0, 11 MARCH 2015 
  
 
Page 118 of 126 
 
Prurigo Activity Score (PAS) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
SST-Pr-10-2007, Amendment 9, PAS, Version 0.7; 11.09.2013 
 
 
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Trevi Therapeutics, Inc. 
Version 2.0, 11 MARCH 2015 
  
 
Page 119 of 126 
 
Patient Benefit Index, Pruritus Version (PBI-P) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
PBI-Patient Benefit Index (index of benefits and needs in therapy), Augustin 2006 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
Page 120 of 126 
 
PBI-P (Cont’d) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
PBI-Patient Benefit Index (index of benefits and needs in therapy), Augustin 2006 
 
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Trevi Therapeutics, Inc. 
Version 2.0, 11 MARCH 2015 
  
 
Page 121 of 126 
 
Numerical Rating Scale (Worst Itch) 
 
How would you rate your most severe itching over the past 24 hours? 
 
 
 
 
 
Numerical Rating Scale (Average-Itch) 
 
How would you rate your itching on average over the past 24 hours? 
 
 
 
Verbal Rating Scale 
 
How is your skin sensation today?   
 
0:  
not 
present 
1:  
mild 
present 
2: 
moderately 
present 
3: 
severely 
present 
4:  
very severely 
present 
Itchy 
 
 
 
 
 
Burning 
 
 
 
 
 
Stinging 
 
 
 
 
 
 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
Page 122 of 126 
 
Hospital Anxiety and Depression Scale (HADS) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
 
 
Page 342


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Version 2.0, 11 MARCH 2015 
  
 
Page 123 of 126 
 
Subjective Opiate Withdrawal Scale (SOWS) 
Sample – actual assessment scale will be provided to the patient at appropriate visits 
 
 
 
PLEASE SCORE EACH OF THE 16 ITEMS BELOW ACCORDING TO HOW YOU FEEL 
NOW 
(CIRCLE ONE NUMBER) 
 
SYMPTOM 
NOT AT ALL 
A LITTLE 
MODERATELY 
QUITE A BIT 
EXTREMELY 
1 
I feel anxious 
0 
1 
2 
3 
4 
2 
I feel like yawning 
0 
1 
2 
3 
4 
3 
I am perspiring 
0 
1 
2 
3 
4 
4 
My eyes are teary 
0 
1 
2 
3 
4 
5 
My nose is running 
0 
1 
2 
3 
4 
6 
I have goosebumps 
0 
1 
2 
3 
4 
7 
I am shaking 
0 
1 
2 
3 
4 
8 
I have hot flushes 
0 
1 
2 
3 
4 
9 
I have cold flushes 
0 
1 
2 
3 
4 
10 
My bones and muscles 
ache 
0 
1 
2 
3 
4 
11 
I feel restless 
0 
1 
2 
3 
4 
12 
I feel nauseous 
0 
1 
2 
3 
4 
13 
I feel like vomiting 
0 
1 
2 
3 
4 
14 
My muscles twitch 
0 
1 
2 
3 
4 
15 
I have stomach 
cramps 
0 
1 
2 
3 
4 
16 
I feel like using now 
0 
1 
2 
3 
4 
 
Range 0-64. Handelsman, L., Cochrane, K. J., Aronson, M. J. et al. (1987) 
Two New Rating Scales for Opiate Withdrawal, American Journal of Alcohol Abuse, 13, 293-308. 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
Page 124 of 126 
 
APPENDIX 5:  CARDIOVASCULAR RELATED PROHIBITED MEDICATIONS AND CARDIOLOGICAL 
ASSESSMENTS   
 
The Cardiological Assessments are provided on the subsequent pages. 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
Page 125 of 126 
 
Canadian Cardiovascular Society Grading of Angina Pectoris 
Sample – actual grading scale will be completed at appropriate visits 
 
Grade 
Description 
 
Grade I 
 
Ordinary physical activity does not cause angina, such as walking 
and climbing stairs.  Angina with strenuous or rapid or prolonged 
exertion at work or recreation 
 
Grade II 
 
Slight limitation of ordinary activity. Walking or climbing stairs 
rapidly, walking uphill, walking or stair climbing after meals, or in 
cold, or in wind, or under emotional stress, or only during the few 
hours after awakening. Walking more than two blocks on the level 
and climbing more than one flight of ordinary stairs at a normal 
pace and in normal conditions 
 
Grade III 
 
Marked limitation of ordinary physical activity. Walking one or two 
blocks on the level and climbing one flight of stairs in normal 
conditions and at normal pace 
 
Grade IV 
 
Inability to carry on any physical activity without discomfort, 
anginal syndrome may be present at rest 
 
References 
Campeau Lucien. Grading of angina pectoris.  Circulation 1976;54:522­3 
 
Available on the Canadian Cardiovascular Society Website at www.ccs.ca 
 
 
 
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Version 2.0, 11 MARCH 2015 
  
 
Page 126 of 126 
 
NYHA FUNCTIONAL CLASSIFICATION 
Sample – actual grading scale will be completed at appropriate visits 
 
The NYHA classifies heart failure into classes based on functional limitations and severity. 
 
Class 
Patient Symptoms 
Class I 
(Normal) 
Few observable symptoms, no limitation in ordinary physical activity.  
 
Class II 
(Mild) 
Mild observable symptoms and slight limitation during ordinary activity. 
Comfortable at rest. 
 
Class III 
(Moderate) 
Marked limitation in physical activity due to symptoms even during less- 
than-ordinary activity. Comfortable only at rest. 
 
Class IV 
(Severe) 
End-stage heart failure. Severe limitations. Experience symptoms even 
while at rest. 
  
 
 
ACC/AHA CLASSIFICATION OF CHF 
 
The ACC/AHA created four classifications from risk for developing the disease to severe 
disability. 
 
Stage 
 
Description 
A 
(High risk for developing  CHF) 
 
Hypertension, diabetes mellitus, family history, 
coronary artery disease 
B 
(Asymptomatic HF) 
 
Previous myocardial infarction (heart attack), 
valvular disorders, left ventricular dysfunction 
C 
(Symptomatic HF) 
 
Structural heart disease, fatigue, low tolerance 
level for physical activity 
D 
(Refractory end-stage HF) 
 
Severe limitations. Experience symptoms even 
while at rest. 
 
Source:  American Heart Association 
 
Page 346

SAP_000.pdf: 
Trevi Therapeutics, Inc. 
 
Statistical Analysis Plan, Version 1.0  
Protocol TR03ext 
 
Date Issued: 03May 2017 
 
  
1 
 
 
 
 
 
 
 
 
 
 
Trevi Therapeutics, Inc. 
 
Protocol TR03ext 
 
An Open Label Extension Study of the Safety and Anti- 
Pruritic Efficacy of Nalbuphine HCl ER Tablets in 
Prurigo Nodularis Patients 
 
Statistical Analysis Plan 
 
Version 1.0 
 
03 May 2017 
 
 
 


Trevi Therapeutics, Inc. 
 
Statistical Analysis Plan, Version 1.0  
Protocol TR03ext 
 
Date Issued: 03May 2017 
 
  
2 
 
Approval Signature Page: 
 
Statistical Analysis Plan for Protocol TR03ext 
 
An Open Label Extension Study of the Safety and Anti- 
Pruritic Efficacy of Nalbuphine HCl ER Tablets in 
Prurigo Nodularis Patients 
 
Protocol Version 3.0 (Amendment 2), 02 June 2016 
 
Issued By: 
 
 
Date: 
 
Cheryl Schoen 
Lead Biostatistician, Biostatistics 
PPD, Inc. 
  
 
 
Date:  
 
Pamela Launt 
Senior Statistical Reviewer, Biostatistics 
PPD, Inc. 
  
 
Upon review of this document, including table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are 
acceptable, and the table, listing, and figure production can begin. 
 
Approved By: 
 
 
 
 
 
Date: 09 May 2017 
Howard Hait 
Biostatistician 
Edenridge Associates, LLC  
  
 
  
 
Date: 09 May 2017 
Thomas Sciascia, MD 
Chief Medical Officer 
Trevi Therapeutics, Inc. 
  
 


Trevi Therapeutics, Inc. 
 
Statistical Analysis Plan, Version 1.0  
Protocol TR03ext 
 
Date Issued: 03May 2017 
 
  
3 
 
Table of Contents 
 
List of Abbreviations ........................................................................................................................... 6 
1. 
Introduction ................................................................................................................................... 7 
2. 
Objectives ....................................................................................................................................... 7 
2.1. 
Primary Objectives ............................................................................................................................ 7 
2.2. 
Secondary Objectives ........................................................................................................................ 7 
2.3. 
Exploratory Objectives ..................................................................................................................... 8 
3. 
Investigational Plan .................................................................................................................... 8 
3.1. 
Overall Study Design and Plan ...................................................................................................... 8 
3.2. 
Premature Discontinuation of Study Drug Treatment ......................................................... 11 
3.2.1. 
Premature Discontinuation of Study Drug Treatment Associated with Failure-to-Improve 
Criterion ............................................................................................................................................................................ 11 
3.2.2. 
Premature Discontinuation of Study Drug Treatment For Reasons Other Than Failure-to-
Improve .............................................................................................................................................................................. 11 
3.3. 
Study Endpoints ............................................................................................................................... 12 
3.3.1. 
Primary Endpoint ........................................................................................................................................... 12 
3.3.2. 
Secondary Endpoints .................................................................................................................................... 12 
3.3.3. 
Exploratory Endpoints ................................................................................................................................. 12 
3.3.4. 
Safety Assessments ......................................................................................................................................... 13 
3.4. 
Treatments ........................................................................................................................................ 13 
4. 
Statistical Considerations ...................................................................................................... 14 
4.1. 
General Methodology ..................................................................................................................... 14 
4.2. 
Baseline, Study Day and Analysis Visit Windows ................................................................... 15 
4.3. 
Sample Size ........................................................................................................................................ 15 
4.4. 
Randomization, Stratification, and Blinding .......................................................................... 16 
4.5. 
Pooling of Study Sites ..................................................................................................................... 16 
4.6. 
Analysis Populations ...................................................................................................................... 16 
4.6.1. 
All Enrolled ...................................................................................................................................................... 16 
4.6.2. 
Safety .................................................................................................................................................................. 16 
4.7. 
Methods for Handling Dropouts and Missing Data ............................................................... 16 
4.8. 
Multiple Comparisons/Multiplicity Considerations .............................................................. 16 
4.9. 
Examination of Subgroups ............................................................................................................ 16 
4.10. 
Data Display Treatment and Other Descriptors .................................................................... 16 
4.11. 
Changes in the Planned Analysis ................................................................................................ 17 
5. 
Patient Disposition ................................................................................................................... 17 
5.1. 
Disposition ......................................................................................................................................... 17 
5.2. 
Protocol Deviations ......................................................................................................................... 17 
5.3. 
Eligibility Criteria ............................................................................................................................ 18 
6. 
Demographics and Baseline Characteristics ................................................................... 18 
6.1. 
Demographics ................................................................................................................................... 18 
6.2. 
Medical History ................................................................................................................................ 18 
6.2.1. 
General Medical History ............................................................................................................................. 18 
6.2.2. 
Prurigo Nodularis History .......................................................................................................................... 19 


Trevi Therapeutics, Inc. 
 
Statistical Analysis Plan, Version 1.0  
Protocol TR03ext 
 
Date Issued: 03May 2017 
 
  
4 
 
6.2.3. 
Neurological History .................................................................................................................................... 19 
7. 
Treatments and Medications ................................................................................................ 19 
7.1. 
Concomitant Medications .............................................................................................................. 19 
7.2. 
Rescue Anti-Pruritic Medications ............................................................................................... 20 
7.3. 
Study Treatments ............................................................................................................................ 22 
7.3.1. 
Study Drug Dosing ........................................................................................................................................ 22 
7.3.2. 
Extent of Exposure ......................................................................................................................................... 22 
7.3.3. 
Treatment Compliance ................................................................................................................................. 22 
8. 
Secondary Endpoint Analysis ............................................................................................... 23 
8.1. 
Change from Baseline in PRO Measures ................................................................................... 23 
8.1.1. 
Change from Baseline in Worst Itch Intensity NRS ............................................................................ 24 
8.1.2. 
Change from Baseline in Average Itch Intensity NRS ....................................................................... 24 
8.1.3. 
Change from Baseline in the VRS ............................................................................................................ 24 
8.1.4. 
Change from Baseline in the HADS ........................................................................................................ 25 
8.1.5. 
Change from Baseline in the ItchyQoL .................................................................................................. 25 
8.1.6. 
Change from Baseline in the MOS Sleep Scale-R ............................................................................... 26 
8.1.7. 
Change from Baseline in the PBI-P ......................................................................................................... 27 
8.1.8. 
Change from Baseline in PAS .................................................................................................................... 27 
8.2. 
Change during the Washout Period in PROs ........................................................................... 28 
8.3. 
Dose-Up and Down-Titration ....................................................................................................... 28 
8.4. 
Failure-to-Improve Criteria .......................................................................................................... 28 
8.5. 
Rescue Medication Use ................................................................................................................... 28 
8.6. 
Premature Discontinuation Due to Lack of Efficacy or Adverse Events .......................... 29 
9. 
Safety Analysis ........................................................................................................................... 29 
9.1. 
Adverse Events .................................................................................................................................. 29 
9.1.1. 
Incidence of Adverse Events ....................................................................................................................... 31 
9.1.2. 
Relationship of Adverse Events to Study Drug ..................................................................................... 32 
9.1.3. 
Severity of Adverse Events .......................................................................................................................... 32 
9.1.4. 
AEs Leading to Treatment Discontinuation .......................................................................................... 32 
9.1.5. 
SAEs and Deaths ............................................................................................................................................ 33 
9.1.6. 
AEs of Special Interest ................................................................................................................................. 33 
9.1.7. 
Abuse-Potential Related AEs ..................................................................................................................... 33 
9.2. 
Other Safety Assessments ............................................................................................................ 34 
9.2.1. 
SOWS ................................................................................................................................................................. 34 
9.2.2. 
Neurological Examination .......................................................................................................................... 35 
9.3. 
Clinical Laboratory Evaluations ................................................................................................ 35 
9.3.1. 
Hematology ...................................................................................................................................................... 35 
9.3.2. 
Serum Chemistry ............................................................................................................................................ 35 
9.3.3. 
Urinalysis .......................................................................................................................................................... 36 
9.3.4. 
Serum Pregnancy ........................................................................................................................................... 36 
9.4. 
Vital Sign Measurements ............................................................................................................... 36 
9.5. 
Physical Examination ..................................................................................................................... 36 
9.6. 
Electrocardiogram .......................................................................................................................... 36 
10. 
Pharmacokinetic (PK) and Pharmacokinetic (PK)/Pharmacodynamic (PD) 
Analyses ................................................................................................................................................ 37 
11. 
Interim Analyses and Data Monitoring ......................................................................... 37 


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12. 
References ............................................................................................................................... 38 
13. 
Appendices ............................................................................................................................. 39 
13.1. 
Clinical Laboratory Tests ............................................................................................................. 39 
13.2. 
List of Abuse-Potential Associated Adverse Events ............................................................ 40 


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List of Abbreviations 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomic and Therapeutic Class 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ER 
Extended release 
H&E 
Hematoxylin and eosin 
HADS 
Hospital Anxiety and Depression Score 
HCG 
Human chorionic gonadotropin 
HCl 
Hydrochloride  
HR 
Heart rate 
IFSI 
International Forum for the Study of Itch  
KOR 
Kappa opiate receptor 
LDH 
Lactate dehydrogenase 
LOV 
Last observed value 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
MOR 
Mu opiate receptor 
MOS 
Medical Outcomes Study 
NRS 
Numerical Rating Scale 
OV 
Observation Period Visit 
PAS 
Prurigo Activity Score 
PBI-P 
Patient Benefit Index, pruritus version 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PRO 
Patient-Reported Outcome 
PT 
Preferred term 
QoL 
Quality of life 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP  
Statistical analysis plan 
SAS 
SAS® statistical software 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOC 
System organ class 
SOWS 
Subjective Opiate Withdrawal Scale 
TEAE 
Treatment-emergent adverse events 
TV 
Treatment Period Visit 


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US 
United States 
UV 
Ultraviolet light 
UV-B 
Ultraviolet light – B 
VRS 
Verbal Rating Scale 
WHO 
World Health Organization 
 
1. Introduction 
Protocol TR03ext is being conducted to examine the safety and anti-pruritic efficacy of 
nalbuphine hydrochloride (HCl) extended release (ER) tablets in prurigo nodularis patients. The 
purpose of this statistical analysis plan (SAP) is to provide specific guidelines from which the 
analysis will proceed. It will describe in detail the algorithms and conventions to be used in the 
analysis and presentation of the efficacy and safety data for protocol TR03ext. Any deviations 
from these guidelines will be documented in the clinical study report (CSR). In the event where 
discrepancies in statistical analysis may be encountered between the SAP and what is described 
in the study protocol, the SAP will take precedence.  
 
2. Objectives 
2.1. Primary Objectives 
The primary objective of the study is to evaluate the safety and tolerability of nalbuphine HCl 
ER tablets during a treatment period of up to 50 weeks. 
2.2. Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety of nalbuphine by achieved maintenance dose at the end of 
Treatment Week 4, 
• To assess skin lesion improvement using the metrics of the Prurigo Activity Score 
(PAS), 
• Change from Baseline in Patient-Reported Outcome (PRO) measures Worst (i.e. 
most severe itching over the past 24 hours) itch Numerical Rating Scale (NRS), 
average itch intensity NRS, Verbal Rating Scale (VRS) (itchy, burning and 
stinging), Medical Outcomes Scale (MOS) Sleep-R, ItchyQol, and Hospital 
Anxiety and Depression Score (HADS) by the final Treatment Period Visit, 
• Change between Baseline and the final Treatment Period Visit in Patient Benefit 
Index, pruritus version (PBI-P), 
• A description of the percentage of patients utilizing various doses of nalbuphine 
HCl ER tablets by Study Week, 
• A description of the frequency and reasons for dose up-and down-titration and 
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• Frequency and distribution by time on study of patients determined to meet failure-
to-improve criteria, 
• Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets, 
• Time to first use of rescue medications and the number of days of use of rescue 
medications for itching, 
• To evaluate the daily changes in the Subjective Opiate Withdrawal Scale (SOWS) 
during the Washout Period after cessation of treatment of nalbuphine HCl ER 
tablets. 
2.3. Exploratory Objectives 
The exploratory objective of the study is to evaluate the potential of nalbuphine HCl ER tablets 
impact on the measurement of nerve fiber density (histology) and mu opiate receptor 
(MOR)/kappa opiate receptor (KOR) density (histology, Western Blot), as well as histological 
hematoxylin and eosin (H&E) changes in skin biopsies taken at Baseline and by the final 
Treatment Period Visit to investigate possible correlation with any clinical response and also 
compared to biopsy material assessed during study TR03 (optional procedures at select sites 
only). 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is an open label safety and tolerability extension study for patients who have completed the 
TR03 study. Patients will either enter directly into a drug Treatment Period (Worst Itch NRS ≥ 5) 
or enter an extended screening period of a no-drug Observation Period (Worst Itch NRS < 5) 
based on their reported NRS scores on the first Visit (Visit 1a). For up to 12 extended screening 
weeks, patients in the no-drug Observation Period may also transition into the drug Treatment 
Period if their Worst Itch NRS increases to ≥ 5. 
To allow for various starting levels of pruritus intensity, patients who have a Worst Itch NRS 
that is ≥ 5 will enter the Treatment Period upon completion of Visit 1a.  Patients whose Worst 
Itch NRS score is < 5 will be entered into an extended screening period, no-treatment criteria 
Observation Period for up to 12 weeks or until they develop a higher level of pruritus (i.e., Worst 
Itch NRS ≥ 5), at which point they will transition to the Treatment Period upon completion of 
Visit 1b.  All patients entering the Treatment Period, whether immediately upon study entry or 
following a period of time in the Observation Period, will initially be titrated to a dose that can 
be as high as 180 mg twice daily (BID) during the first 4 weeks of the Treatment Period. Patients 
who continue in the Observation Period and maintain a Worst Itch NRS score of < 5 will be 
screen failed from the study at the end of the 12-week period.  For enrolled patients whose Visit 
1a worst itch NRS score satisfies the ≥ 5 enrollment criterion and for whom treatment is 
initiated, the screening visit Visit 1a will also be designated as the baseline visit. For enrolled 
patients who must continue into the Observation Period, the first visit during that period when 
the worst itch NRS ≥ 5 criterion is satisfied will be designated as Visit 1b and that visit will serve 
as the baseline visit.     


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The total study duration for any individual patient will be up to 53 weeks. For patients who enter 
directly into the Treatment Period, the total amount of time on drug will not exceed 50 weeks. 
Patients who enter the Treatment Period from the Observation Period, the total amount of time 
spent in the combined two periods of the study cannot exceed 50 weeks. All patients who 
received drug treatment will have a 2-week Washout and Safety Follow-up period at the end of 
the dosing period, unless consent is withdrawn. 
The total amount of time in the Observation Period cannot exceed 12 weeks. After these 12 
extended screening weeks, patients not eligible for the Treatment Period are screen failed from 
the study. The study periods are summarized below. 
 
 


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Study Period 
Study Weeks 
Duration 
Observation 
Period 
Patients who do not meet the criteria to start 
Treatment are followed in Observation Period 
visits (OV) for up to 12 extended screening weeks.  
During this time, the patient may meet criteria and 
become eligible to enter the Treatment Period.  If 
the patient does not meet the criteria to enter the 
Treatment Period by the end of 12 extended 
screening weeks (OV12), participation in the study 
ends and the patient is screen failed 
Up to 12 
Extended 
Screening weeks 
Treatment 
Period 
For patients directly entering the Treatment Period 
as of Visit 1a, the Treatment Period begins with 
Study Week 1 (Visit 1a) and ends with Study Week 
50.  
For patients entering the Treatment Period after 
being followed in the Observation Period, the 
number of weeks on treatment and the end of the 
Treatment Period varies. (See Table 8 in the study 
protocol for the details of which treatment visits 
are to take place). 
The End of Treatment Visit will take place after the 
patient completes the last week of study drug. 
Up to   
50 weeks 
Washout and 
Safety Follow-
Up Period 
The Washout and Safety Follow-up Period is two 
(2) weeks in duration.   
For patients directly entering the Treatment Period 
as of Visit 1a and completing 50 weeks of study 
drug treatment, the Washout and Safety Follow-up 
Period should take place during weeks 51 and 52.   
For patients entering the Treatment Period after 
being followed in the Observation Period, the 
number of weeks on treatment and the end of the 
Treatment Period varies; Table 8 in the Study 
Protocol calculates the Treatment Visit 
assignments for any patient entering the Treatment 
Period from the respective Observation Period 
visits.  The Washout and Safety Follow-up Period 
will take place during the two (2) weeks after the 
patient completes the last week of study drug. 
The Washout and Safety Follow-up Period Visit 
will take place in the week following the 
completion of the two (2) week Washout and 
Safety Follow-up Period. 
2 weeks 


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3.2. Premature Discontinuation of Study Drug Treatment  
3.2.1. Premature Discontinuation of Study Drug Treatment Associated with Failure-to-
Improve Criterion 
Patients who meet failure-to-improve criterion during the conduct of the study, will stop taking 
study medication.  
The Failure-to-Improve criteria are as follows: Beginning on Treatment Period Visit 3 (TV3), 
and at every subsequent Treatment visit, patients with a worst itch NRS score ≥ the worst itch 
NRS score at Visit 1a (or at Visit 1b in the case of patients who require the OV period) will be 
discontinued from study drug. Patients discontinued from study drug are to undergo the End of 
Treatment Visit (TV14), the Washout/Safety Follow-up Period assessment in two weeks, and 
receive a follow-up telephone contact 30 days following end of study drug dosing for final 
safety assessment. 
3.2.2. Premature Discontinuation of Study Drug Treatment For Reasons Other Than Failure-
to-Improve 
Patients who complete Study Drug treatment through the End of Treatment Visit 14 (TV14) 
(even if some doses have been missed or if the patient was followed in the Observation Period 
before receiving study drug treatment) are considered to have completed Study Drug treatment.  
Patients discontinuing Study Drug treatment prior to the maximum allowable number of 
Treatment Weeks (based on their entry into the study at either Visit 1a or Visit 1b) will also be 
considered to have prematurely discontinued Study Drug treatment. Patients discontinuing 
Study Drug treatment prior to End of Treatment Visit 14 will be considered to have prematurely 
discontinued Study Drug treatment and will be asked to complete the End of Treatment Visit 
(TV14) regardless of where they were in the study visit schedule, the Washout and Safety 
Follow-up Period Visit and the Premature Discontinuation of Study Drug Telephone Contact 
visit.  Patients removed from the study after enrollment and who have received a dose of study 
drug will not be replaced. 
Some reasons for premature discontinuation of Study Drug treatment include: 
• Intercurrent illness 
• Any intolerable Adverse Event (AE) that cannot be ameliorated or safely 
managed with medical intervention or one that poses undue risk to the subject if 
Study Drug treatment were continued in the opinion of the Medical Monitor or 
Investigator 
• Electrocardiogram (ECG) changes summarized in protocol Section 17.4 
• Opioid medication is introduced in anticipation for chronic use of greater than 2 
weeks 
• Any medication prescribed for chronic anti-pruritic use of greater than 2 weeks 
• Development of substance abuse as determined by the Investigator. 


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3.3. Study Endpoints 
3.3.1. Primary Endpoint 
The primary endpoint is a description of the overall incidence and nature of treatment-emergent 
adverse events (TEAEs) during treatment weeks 5-50. 
3.3.2. Secondary Endpoints 
Visit 1a or Visit 1b will serve as the baseline visit for efficacy endpoints. Visit 1a will be the 
Baseline for patients directly entering the Treatment Period as of Visit 1a. Visit 1b will be the 
Baseline for patients entering the Treatment Period after participating in the Observation Period 
for any length of time.  
The secondary endpoints are: 
• Assess skin lesion improvement using the metrics of the PAS 
• Change from Baseline in PRO measures Worst itch NRS, average itch intensity NRS, 
VRS (itchy, burning and stinging), MOS-Sleep-R, ItchyQoL, HADS by Treatment Period 
study visit and Baseline NRS score 
• Change between Baseline and the final Treatment Period visit in PBI-P 
• A description of the percentage of patients utilizing various doses of nalbuphine HCl ER 
tablets by study week 
• A description of the frequency and reasons for dose up-and down-titration and treatment 
discontinuation during the study 
• Frequency and distribution by time on study of patients determined to meet failure-to-
improve criterion 
• Changes in the PRO measurements during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets 
• Time to first use of rescue medications and the number of days of use of rescue 
medications for itching 
• To evaluate the daily changes in the SOWS during the Washout Period after cessation of 
treatment of nalbuphine HCl ER tablets. 
3.3.3. Exploratory Endpoints 
The exploratory objectives of the study are to evaluate the effect of nalbuphine HCl ER tablets 
on: 
• The potential of nalbuphine HCl ER tablets to impact on the measurement of nerve fiber 
density (histology) and MOR/KOR density (histology, Western Blot), as well as 
histological (H&E) changes in skin biopsies taken at Baseline and the final TV when 
compared to biopsy material assessed during study TR03 (optional procedure at select 
sites only). 


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3.3.4. Safety Assessments 
Safety assessments include the following: 
• 
AEs 
• 
Vital signs 
o 
Weight 
o 
Systolic blood pressure (SBP) 
o 
Diastolic blood pressure (DBP) 
o 
Heart rate (HR) 
o 
Respiration rate (RR) 
o 
Body temperature 
• 
Physical examination 
o 
Clinically significant abnormalities pre-dose are reported as part of medical 
history  
o 
Clinically significant abnormalities representing a worsening from baseline, 
subsequent to dosing, are reported as AEs 
• 
Neurological examination 
• Clinical laboratory tests 
o Blood chemistry 
o Hematology 
o Urinalysis 
o Serum Pregnancy 
• 
Investigator reviewed ECG and central cardiac core laboratory read 12 Lead-ECG 
cardiovascular grading, and/or cardiovascular related prohibited medications 
• 
SOWS. 
3.4. Treatments  
Following enrollment, the patient will receive 30 mg open-label tablets.  At each visit at which 
study drug is to be dispensed, enough drug should be supplied to ensure a sufficient number of 
tablets available for dosing until the next visit plus an additional 8 tablets to allow for visit 
windows and/or possibility of a missed visit.  
Study drug can be taken with or without food.  Patients will be instructed to take the AM and PM 
Study Drug tablets at the same times of the day, approximately 12 hours apart, preferably with 
240 milliliters (mL) (approximately 8 ounces) of water.  If the patient does not take a particular 
dose at the planned time he or she may take it up to 2 hours later.  For example, if a patient is 
taking the Study Drug at 9 AM and 9 PM but forgets to take the 9 AM dose, the patient may take 
the 9 AM dose as late as 11 AM.  After that time, the patient should skip the 9 AM dose and, 
instead, take the regularly scheduled next dose at 9 PM.   
The first dosing day will be on either Visit 1a or Visit 1b.  Titration will be based on tolerability.  
If the patient is experiencing a study-drug related AE or an AE that may be aggravated by study 
drug up-titration, the study drug dose should not be increased, regardless of the NRS score.  


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The Study Drug will be titrated during the Treatment Period Weeks 1 - 4, according to the 
schedule in Table 3 in the study protocol to a final dose of 30 mg BID up to 180 mg BID.  The 
dosing for Treatment Week 1 is further described in Section 9.6.1 (Visit 1a) and Section 9.6.4 
(Visit 1b) of the study protocol. Patients should only ever be dispensed a single strength of the 
study drug (e.g. 30 mg bottle(s) or 60 mg bottle(s)) at a visit. 
Patients will titrate to tolerability beginning with a 30 mg dose on Day 1 (Visit 1a or Visit 1b) 
with a dose increase of 30 mg BID not more often than every 3 to 4 days in order to attain 
steady-state plasma concentrations of nalbuphine at each dose. 
Patients should be instructed to up-titrate beginning with a single 30 mg dose in the evening 
(PM) and then begin dosing with an increased 30 mg BID dose the following day. Dose titrations 
should be maintained for 3-4 days before further up-titration of the patient’s dose is attempted 
The maximum dose the patient should reach at the end of Week 1 is 60 mg BID. If this dose is 
tolerated (as determined by the Telephone Contact 1 (TC1) assessment), an additional up-
titration may be attempted during Week 2. 
The maximum dose the patient should reach at the end of Week 2 is 120 mg BID. If this dose is 
tolerated (as determined by the TC2 assessment), an additional up-titration may be attempted 
during Week 3. 
The maximum dose the patient should reach at the end of Week 3 is 180 mg BID. If this dose is 
tolerated, it should be maintained throughout Week 4.  
The dose achieved as of the end of Treatment Week 4 will be maintained throughout the rest of 
the Treatment Period.  This dose will be defined as the patient’s “maintenance dose”.   
During Treatment Weeks 1-4, the decision to up-titrate the patient’s dose should be made based 
on tolerance to study drug. If the tolerance level becomes unacceptable to either the patient or the 
Investigator, the dose should be reduced incrementally until tolerance is stabilized (reduce dose 
by 30 mg BID if at the 30 mg, 60 mg, 90 mg or 120 mg dose level and reduce by 60 mg BID if 
the patient is at the 180 mg dose level). Patients who do not tolerate the 180 mg BID should be 
down titrated to the 120 mg BID dose level and maintained there if stabilized. 
Two single dose reductions or dose holds per patient is permitted during Treatment Period at the 
Investigator’s discretion.  If subsequent dose reductions or dose interruptions are needed, the 
Medical Monitor must be contacted.  The duration of any dose hold must be discussed with the 
Medical Monitor.   
4. Statistical Considerations 
4.1. General Methodology  
Continuous data will be described using descriptive statistics including patient count (n), mean, 
standard deviation (SD), median, minimum, and maximum. Categorical data will be described 
using the patient count and percentage in each category. The percentage will be suppressed when 
the count is zero for a category in order to draw attention to the non-zero counts. Where specified 
on the table shells, a row denoted “Missing” is to be included in count tabulations to account for 
dropouts and missing values. The denominator for all percentages will be the number of patients 
in that treatment arm within the analysis population of interest, unless otherwise specified. 


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Patients will be identified in the listings by the patient identification number concatenated with 
the investigator/site number. Data will be displayed in all listings sorted by patient identification 
number concatenated with the investigator/site number.  Data listings, unless otherwise specified, 
will include all patients who provide consent to participate in the study.  
Unscheduled results will not be included in the summary tables except for determining Baseline 
values for efficacy and safety evaluations and the handling of laboratory data both at Baseline 
and during treatment (see Section 4.2). For patients discontinuing from the study, planned study 
visit data that are collected at the early termination visit will be included in by-visit summaries in 
the summary tables or figures (e.g. PRO questionnaires) using the serial next visit number 
associated with what would have been the patient’s next scheduled visit.  Thus, for example, a 
patient discontinuing from the study after Treatment Visit 2 would have efficacy and safety data 
obtained at the study termination visit treated as Treatment Visit 3 results. Data listings will 
include all data from scheduled, repeated, unscheduled and early termination visits. 
All p-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be 
reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as “>0.999.” Point 
estimates of the parameter of interest will be generated along with, where appropriate, 95% 
confidence intervals. 
All analyses will be conducted using SAS Version 9.2 or higher. 
4.2. Baseline, Study Day and Analysis Visit Windows  
Unless otherwise specified, “Baseline” for efficacy and safety information is defined as the last 
non-missing evaluation taken prior to the first dose of study medication during the TR03 
extension study (including repeated and unscheduled assessments).  
For variables that require the analysis of change from baseline, the post-baseline assessment 
value minus the baseline assessment value will be used to derive change from baseline value. If 
either value is missing then the change from baseline will also be missing. 
When study day is used for display or in comparisons, the following algorithm will be used: 
• Study day = date of assessment – date of first dose of study medication + 1, if the date of 
the assessment is on or after the date of first dose; 
• Study day = date of assessment – date of first dose of study medication, if the date of the 
assessment is prior to the date of first dose. 
No analysis visit windows will be defined for this study, i.e., by-visit assessments will be based 
on the designated scheduled visit number associated with the data recorded for the endpoint of 
interest. 
4.3. Sample Size 
As this is a safety extension study for which patients will be recruited from patients who have 
completed parent study TR03, the sample size cannot be predicted.  No formal sample size 


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calculations have been performed and no inferential statistics are planned.  The maximum 
number of patients will not exceed the number of patients who completed TR03. 
4.4. Randomization, Stratification, and Blinding 
Patients will not be randomized into this study.  For this study, patients will retain their study 
number from the TR03 study. 
4.5. Pooling of Study Sites  
No a priori pooling of sites is planned for this study as no formal statistical testing is planned. 
4.6. Analysis Populations 
4.6.1. All Enrolled 
An enrolled patient is one who provides consent to participate in the TR03ext study.   
4.6.2. Safety 
The Safety population will consist of all enrolled patients who have received a single dose of 
study medication in the TR03 extension study. The Safety population will be used to evaluate the 
safety and efficacy endpoints defined for this study.   
Patients will be summarized in a single nalbuphine treatment group. 
4.7. Methods for Handling Dropouts and Missing Data 
No replacement or imputation of missing data will be conducted for this study.   
4.8. Multiple Comparisons/Multiplicity Considerations 
There will be no consideration for multiple comparisons/multiplicity for this study as no 
inferential analyses will be performed.  
4.9. Examination of Subgroups 
No a priori planned subgroup analyses are specified and none will be performed.   
4.10. Data Display Treatment and Other Descriptors 
Unless otherwise noted, TR03 extension study treatments will be presented in all tables, listings 
and figures (TLFs) as: All Patients. Additionally, TR03 core study randomized treatments will be 
presented as: Nalbuphine 90 mg, Nalbuphine 180 mg, and Placebo. 
For measurements collected at multiple study visits, visit and week number will be used in all 
TLFs.  Baseline results (as described in Section 4.2) will be displayed as “Baseline.”  


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4.11. Changes in the Planned Analysis 
Section 9.7.7.5 of the protocol discusses a 9-item sleep problems index that can be generated for 
the MOS Sleep Scale-R. This, however, will not be implemented. SAP Section 8.1.6 describes 
the summaries that will be presented for the MOS Sleep Scale-R. 
Section 19.6 of the protocol states that opioid medication usage will be tabulated separately from 
all other concomitant medications. Instead, opioid medication usage will be tabulated with all 
other concomitant medications as discussed in SAP Section 7.1.  
Section 19.7 of the protocol states that mean dose during the treatment period will be 
summarized. Instead, as discussed in SAP Section 7.3.1, highest dose achieved during the 
treatment period will be summarized. 
Section 8.6 of the SAP describes the summarization and graphical presentation of premature 
discontinuation due to lack of efficacy or adverse events. This is not included in the protocol but 
is desired for reporting purposes. 
5. Patient Disposition 
5.1. Disposition 
The number of patients in the safety population will be summarized overall and percentages will 
be based on the number of enrolled patients. 
The number and percentage of patients who consented to participate (i.e. enrolled patients), 
consented to participate but were not treated, were treated, completed the study, discontinued 
from the study and the primary reason for premature study and treatment discontinuation will be 
summarized for all patients who provided consent to participate in the TR03 extension study. 
Reason for screening failure for patients who discontinued during the Observation Period are not 
collected on the electronic case report form (eCRF) so will not be summarized. The number and 
percentage of patients who met failure to improve criterion at any time during the study will also 
be summarized.  
Patient disposition will also be summarized by site. 
Patient disposition data will be presented in a data listing.  
Reason(s) for exclusion from the safety population will be presented in a data listing.  
5.2. Protocol Deviations  
Protocol deviations represent departures from protocol-specified procedures and practices. 
During the course of the study, protocol deviations will be tracked and entered into a single 
master database that captures the patient number, the type of protocol deviation, and detailed 
information surrounding the nature and/or circumstance for which the deviation may have 
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Protocol deviations will be identified and accounted for prior to database lock. The number and 
percentage of patients reporting any protocol deviations and the incidence of each deviation type 
will be summarized by treatment group and overall for the safety population and individual 
responses will be presented in a data listing for all enrolled patients. 
5.3. Eligibility Criteria  
For those patients who fail to fulfill any of the inclusion/exclusion criteria or fail to meet the 
NRS criteria, the criteria not met will be presented in a single data listing for all enrolled 
patients.  
6. Demographics and Baseline Characteristics 
6.1. Demographics 
Demographics and baseline information will be summarized overall for the safety population.  
The demographic characteristics consist of age (years), sex, race, ethnicity, and geographic 
region (United States (US) or Europe). A patient’s age in years is calculated as 
FLOOR[(informed consent date for the TR03 extension study – date of birth)/365.25] expressed 
as an integer value. The baseline characteristics consist of baseline height (cm) and baseline 
weight (kg).  
Baseline height (cm) and weight (kg) are obtained from the last non-missing evaluation taken 
prior to the first dose of study medication during the extension study. All other demographic and 
baseline characteristics (i.e. sex, race, ethnicity and geographic region) were obtained prior to 
first dose of study medication during the core TR03 study.  
Age (years), baseline height (cm) and baseline weight (kg) will be summarized using descriptive 
statistics. The number and percentage of patients by race (White, Black or African American, 
Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and Other) 
and ethnicity (Hispanic or Latino, Not Hispanic or Latino) will also be reported.  
Patient demographics and baseline characteristics will be presented in a listing for the safety 
population. 
6.2. Medical History 
6.2.1. General Medical History 
Past and present medical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA, version to be delineated in the clinical study report) and presented in a data 
listing for the safety population.  
For the patients who entered the TR03 Observation Period, medical history with an onset date on 
or after the TR03 core study randomization date will be presented in a data listing. The listing, 
thus, will include all TEAEs for the TR03 core study that were converted into medical history in 


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the TR03 extension study and the non-serious AEs that occurred in the Observation Period of 
TR03 extension study. 
6.2.2. Prurigo Nodularis History 
Prurigo nodularis history data for the subset of TR03 core study patients entering the TR03 extension 
study will be taken from the TR03 core study database as this history was not collected separately for 
the TR03 extension. 
Patients’ prurigo nodularis history, collected at the Screening visit during the TR03 core study 
and consisting of a multitude of categorical responses within various component sub-categories 
of interest, will be summarized using frequencies and percentages for the safety population. 
Responses to all questions will be presented in a data listing for the safety population. 
6.2.3. Neurological History 
Primary cause of neurological history, collected at Visit 1a/Visit 1b, will be summarized using 
frequencies and percentages for the safety population. All neurological history information and 
neurological examination details regarding abnormal findings will be presented in data listings 
for the safety population. 
7. Treatments and Medications 
7.1. Concomitant Medications 
Patients may receive all clinically indicated medications during the study with the exceptions 
noted in the study protocol.  
A medication’s usage will be considered concomitant if it was used by the patient at the time of 
informed consent or started and/or continued after administration of the study medication.  
Concomitant medications, including over-the-counter medications, nutritional supplements, and 
vitamins will be coded according to the World Health Organization (WHO) Drug Dictionary. 
For the purpose of summarizing prior and concomitant medications, incomplete medication start 
and end dates for medications which are not ongoing will be imputed as follows: 
• If the year and month are present and the day is missing, then the day is set to the first 
day of the month for the start date, and to the last day of the month for the end date. 
• If the year and day are present and the month is missing, then the month is set to January 
for the start date, and to December for the end date. 
• If the year is present and the month and day are missing, then the month and day are set 
to January 1 for the start date, and to December 31 for the end date. 
• Data listings will include the recorded and imputed (as described above) start and end 
dates for each reported medication. 
 


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If the medication start date is completely missing and the end date is after the first dose of study 
drug, then the medication will be classified as concomitant. If the end date is missing, then the 
medication will be classified as ongoing (concomitant). Medications for which the start and end 
dates are missing will be classified as concomitant. 
 
The total number of concomitant medications and the number and percentage of patients using at 
least one concomitant medication will be summarized overall for the safety population.  
The number and percentage of all concomitant medications will be summarized by Anatomic 
and Therapeutic Class (ATC) of WHO drug and preferred term overall for the safety population. 
Patients will be counted only once within a medication category.  If a patient reports taking the 
same medication more than once, as determined by WHO Drug name, then the medication will 
be counted only once for that WHO Drug name and patient. 
Concomitant medications will be presented in a data listing for the safety population. 
Opioid medication usage is summarized and listed with all other concomitant medications. 
Rescue medications, as described in Section 7.2, will be summarized and listed separately from 
concomitant medications. 
7.2. Rescue Anti-Pruritic Medications 
Rescue medications will be defined as those drugs, when used for the purpose of treating itch, 
that were required to be washed out prior to entry into TR03 as described in the protocol. For the 
purposes of this study, any ultraviolet (UV) light treatment received will also be defined as a 
rescue medication. If a medication is prescribed for chronic anti-pruritic use of greater than 2 
weeks, the patient should be discontinued as described in the protocol. 
Concomitant use of medications for pruritus is not prohibited except as described in the protocol. 
Details pertaining to the use of opiate medications are also discussed in the protocol. The list of 
protocol-defined rescue medications for itching is presented in Table 1. 
For drugs that may be used for multiple indications including pruritus, a drug is only considered 
a rescue medication if taken for pruritus. Use of rescue medications will not preclude 
continuation in the study; however, all uses of such medication along with their indication for 
use will be recorded. Patients will be provided a log on which to record use of rescue 
medications. 
 
 


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Table 1: List of Rescue Medications for Itching 
Table 1: Rescue Medications for Itching 
Rescue Medication 
Only intended for anti-
pruritic treatment 
Examples 
Opioid receptor antagonists  
 
naltrexone, naloxone 
Antihistamines   
ü  
topical or systemic 
Topical calcineurin inhibitors  
ü  
tacrolimus 
Topical antibiotics 
ü  
--- 
Topical steroids 
ü  
--- 
Topical capsaicin 
ü  
--- 
Anti-septic baths and anti-septic 
cleansing lotions  
ü  
--- 
Anti-convulsant class drugs 
ü  
gabapentin or pregabalin 
Systemic Steroids 
ü  
--- 
cyclosporin A and other 
immunosuppressants 
ü  
--- 
antidepressant medications  
ü  
paroxetine, fluvoxamine, 
amitriptyline 
Malignant tumor related active 
treatment with a systemic drug 
ü  
--- 
UV Therapy 
ü  
--- 
 
The total number of rescue medications subsequent to the first dose of treatment with study 
medication and the number and percentage of patients using at least one rescue medication 
subsequent to the first dose of treatment with study medication will be summarized overall for 
the safety population.   
Incidence of concomitant rescue medication use will be summarized for the safety population. 
For incidence of use, patients will be counted only once within a medication category.  In 
addition, for incidence of use calculations, if a patient reports taking the same medication more 
than once, as determined by WHO Drug name, then the medication will be counted only once 
(incidence of use) for that WHO Drug/medication name and patient. 
The prevalence of use of rescue medications will also be summarized for rescue medications for 
the safety population.  In this construct, multiple, distinct instances when a particular rescue 
medication was required will be counted as the number of times reported.  
Antihistamine use across ATC classifications (a list to be furnished prior to data base lock) will 
also be summarized by incidence and prevalence for the safety population. 


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Rescue medication use will be presented separately in a data listing for the safety population. 
The number and proportion of patients with rescue medication use at each visit and within ATC 
classification will be presented. This will be obtained by comparing the rescue medication onset 
date to the patient’s visit dates and slotting the rescue medication accordingly.  The number of 
days of rescue medication use will also be evaluated using descriptive statistics.  Details 
regarding the analysis of number of days of rescue medication use are presented in Section 8.5.  
7.3. Study Treatments  
7.3.1. Study Drug Dosing 
The number and percentage of patients reaching various achieved doses (30, 60, 90,120, 150, 
180 and 210 mg BID) will be summarized at each study visit beginning at the Visit 3/Week 5 
study visit for the safety population.  In addition, the number of percentage of patients will be 
presented for the highest dose achieved during the entire 50 weeks of active treatment. 
Patient study drug dispensing/return and missed doses information will be presented in data 
listings for the safety population.  
7.3.2. Extent of Exposure 
Duration of exposure is defined as the total number of days a patient is exposed to any study 
drug and will be presented as the total number of days from the first dose date to the last dose 
date: (date of last dose of study medication - the date of first dose of study medication + 1). The 
date of first dose and date of last dose are reported in the eCRF on the dosing history and study 
completion pages, respectively. If the last dose date on the study completion page is missing, or 
if a patient is lost to follow-up, the visit date at which drug was last returned will be used as the 
date of last dose.  
The duration of exposure to study drug will be summarized using descriptive statistics for the 
safety population.  
Patient exposure information will be presented in a listing for the safety population.  
It should be noted that duration of exposure calculated in this fashion does not account for 
missing individual doses or dosing interruptions as recorded in the eCRF. 
7.3.3. Treatment Compliance 
On the date of the first dose of study medication, the patient is expected to take only one dose (3 
tablets) of study medication (in the evening). For the remainder of the study, patients should take 
two doses (6 tablets) of study medication each day (one in the morning and one in the evening). 
At designated visits (i.e. Weeks 1, 3, 5, 9, 13, 17, 21, 26, 30, 34, 38, 42 and 46) patients will be 
distributed bottles containing study medication. Patients will return the bottles at a subsequent 
study visit, as instructed.  


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The number of tablets taken will be derived as: (total tablets dispensed across visits – total tablets 
returned across visits) and will be used to assess overall study compliance. 
 
The total number of tablets planned will be derived as:  
3 + (number of days between day after first dosing day and last dosing day, inclusive)*6. 
 
Patient compliance over the entire time interval from first day of treatment until the last reported 
dosing date will be derived as: (number of tablets taken/number of tablets planned) * 100%. 
Patient study compliance will be summarized using descriptive statistics overall for the safety 
population. 
Patient compliance information will be presented in a data listing for the safety population.  
8. Secondary Endpoint Analysis 
Efficacy measurements will be evaluated as secondary endpoints in this study. The safety 
population will be used to evaluate the efficacy endpoints defined for this study.  Eligibility for 
analysis of a particular endpoint will require only that the patient have a baseline value and at 
least one post-baseline value so that a change from baseline calculation can be obtained.  All 
efficacy endpoints will be evaluated through the generation of descriptive summary statistics.  
For continuous variables, the mean, standard deviation, median, minimum, and maximum will be 
presented for a particular visit and for the change from baseline (Visit 1a or 1b).  For categorical 
variables, the number and percentage of patients within each category of classification will be 
summarized by study visit.  No formal statistical testing will be conducted. 
Visit 1a or 1b will serve as the baseline visit for efficacy endpoints. Visit 1a will be the baseline 
for patients directly entering the Treatment Period as of Visit 1a and Visit 1b will be the baseline 
for patients entering the Treatment Period after participating in the Observation Period for any 
length of time. 
Last observed value (LOV) is defined as the values at the last post-baseline visit, up to and 
including the Safety and Washout Period visit.  
8.1. Change from Baseline in PRO Measures 
For the PRO measures detailed in the subsections below, change from baseline analysis will be 
performed.  
Summary statistics will be generated for each PRO measure for total patients and for patients by 
their TR03 core study treatment at Baseline, each Treatment Period study visit, the Washout and 
Safety Follow-up visit and LOV and for change from baseline in each PRO measure at each 
Treatment Period study visit, the Washout and Safety Follow-up visit and LOV.  
Means and change from baseline means for each PRO with a continuous response will be 
presented in bar charts for all patients by study visit.  
Values from all PRO measures will be presented in data listings.   


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8.1.1. Change from Baseline in Worst Itch Intensity NRS  
The NRS is a patient-reported outcome instrument, designed to quantify the intensity of worst 
itching experienced during a 24-hour period. The scale is a set of boxes, one for each number, 
from 0 (no itching) to 10 (worst possible itching). The NRS is a widely used instrument 
recommended by International Forum for the Study of Itch (IFSI) for quantifying itch intensity 
as well as a useful instrument for grouping patients into categories of itch intensity described as 
mild, moderate or severe (Stander et al 2013). The itch NRS has been investigated in patients 
with chronic pruritus of a variety of origins and has a high reliability and concurrent validity was 
found (Phan et al 2012). The patient is to check the number that best reflects the worst itching 
during the prior 24 hours. 
Summaries and bar charts of the worst itch intensity NRS scores will be presented as detailed in 
Section 8.1.   
Worst itch intensity NRS values will be presented in a data listing. 
8.1.2. Change from Baseline in Average Itch Intensity NRS 
 
In addition to worst itch intensity, the patient is also to rate average itch intensity during the prior 
24 hours. 
Summaries and bar charts of the average itch intensity NRS scores will be presented as detailed 
in Section 8.1.   
Average itch intensity NRS values will be presented in a data listing.   
8.1.3. Change from Baseline in the VRS 
 
The VRS scale to be used in this study has three dimensions, each dimension is coded with 
graduated adjectives (from 0 = none; to 5 = very severe) for the skin sensations of itchy, burning 
and stinging. Patients will be asked to record the VRS value: “How is your skin sensation 
today?”  
Summaries of each of the three skin sensations will be presented as detailed in Section 8.1. In 
addition, for each of the three skin sensations, patients’ change between baseline and LOV will 
be summarized using frequencies and percentages for the following categories: 4 grades better, 3 
grades better, 2 grades better, 1 grade better, no change (VRS change of < abs(1)), 1 grade 
worse, 2 grades worse, 3 grades worse and 4 grades worse. The summary will be presented for 
all patients, patients with at least 6 months of treatment, patients with at least 9 months of 
treatment and patients who have completed the treatment period. Patients will be counted in each 
treatment duration category whose criteria they have met (i.e. A patient who has completed the 
treatment period will be included in the denominator for all patients, patients with at least 6 
months of treatment, patients with at least 9 months of treatment and patients who have 
completed the treatment period.). 
All VRS data will be presented in a data listing for the safety population.  


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8.1.4. Change from Baseline in the HADS  
The HADS instrument includes 14 multiple-choice questions, each with 4 possible choices, 
scored between 0 and 3. 
Separate anxiety and depression subscale scores will be derived, each with a possible value of 0-
21 with higher scores indicating worse impairment. 
The HADS anxiety subscale score will be derived as the sum of the responses to the following 
items: 
• 
I feel tense or wound up 
• 
I get a sort of frightened feeling as if something bad is about to happen 
• 
Worrying thoughts go through my mind 
• 
I can sit at ease and feel relaxed 
• 
I get a sort of frightened feeling like butterflies in the stomach 
• 
I feel restless and have to be on the move 
• 
I get sudden feelings of panic. 
The HADS depression subscale score will be derived as the sum of the responses to the 
following items: 
• 
I still enjoy the things I used to enjoy 
• 
I can laugh and see the funny side of things 
• 
I feel cheerful 
• 
I feel as if I am slowed down 
• 
I have lost interest in my appearance 
• 
I look forward with enjoyment to things 
• 
I can enjoy a good book or radio or TV program. 
In the event of a single missing item from a subscale, the missing value will be derived as the 
mean of the remaining six items. If more than one item is missing, then the subscale score will 
not be derived.   
Summaries for the anxiety and depression scales will be will be presented as detailed in Section 
8.1. 
Responses to each of the 14 individual HADS items will be summarized at the baseline visit, 
Visit 14/End of Treatment visit and at the Washout and Safety Follow-up visit using descriptive 
statistics. 
Individual HADS items and anxiety and depression subscale scores will be presented in a data 
listing for the safety population. 
8.1.5. Change from Baseline in the ItchyQoL  
The ItchyQoL consists of 22 pruritus-specific items measuring how pruritus affects patients’ 
QOL in the area of symptoms related to the itch condition (6 questions), functional limitations (7 


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questions), and emotions (9 questions). The subject scores each question never =1, rarely=2, 
sometimes=3, often=4 and all the time=5. 
Individual scores for each of the 22 items will be summarized categorically using frequencies 
and percentages at each study visit. 
The ItchyQoL total score will be obtained as the sum of the 22 items. If no more than three items 
are missing, each missing item will be estimated as the mean of the remaining items. If more 
than three items are missing, the ItchyQoL total score will be set to missing. 
Summaries for ItchyQol total score will be presented as detailed in Section 8.1. In addition, 
change in ItchyQoL total score between baseline and LOV will be summarized using frequencies 
and percentages for the following categories: very good improvement, marked improvement, 
some improvement, no change, slightly worse, markedly worse and much worse. The magnitude 
of ItchyQoL change associated with each category is taken from Siebenhaar et al., 2013: Very 
good improvement: > 50% to 100% reduction; Marked improvement: > 20% to 50% reduction; 
Some improvement: > 5% to 20% reduction; No change: 5% reduction to 5% increase; Slightly 
worse: > 5% to 20% increase; Markedly worse: > 20% to 50% increase; Much worse: > 50% 
increase. The summary will be presented for all patients, patients with at least 6 months of 
treatment, patients with at least 9 months of treatment and patients who have completed the 
treatment period. Patients will be counted in each treatment duration category whose criteria they 
have met (i.e. A patient who has completed the treatment period will be included in the 
denominator for all patients, patients with at least 6 months of treatment, patients with at least 9 
months of treatment and patients who have completed the treatment period.). 
Individual ItchyQoL item scores as well as the calculated total score for each patient will be 
presented in a data listing for the safety population. 
8.1.6. Change from Baseline in the MOS Sleep Scale-R  
The MOS Sleep Scale-R measure is a 12-item self-report sleep measure that was developed to 
assess sleep quality and quantity. It is a multi-dimensional assessment of sleep parameters with 
scoring results in six subscales or domains: sleep disturbance (4 items), snoring (1 item), awaken 
short of breath or with headache (1 item), quantity of sleep (1 item), optimal sleep (1 item), sleep 
adequacy (2 items), and daytime somnolence (3 items). There are three question types with the 
third type consisting of 10 sub-questions. The first question pertains to how long it takes for a 
patient to get to sleep: 0-15 minutes, 16-30 minutes, 31-45 minutes, 46-60 minutes and >60 
minutes. The second question asks how many hours of sleep per night the patient reports getting. 
The third question (consisting of 10 sub-questions) categorically evaluates sleep quality and 
sleep disturbance. Categories of response are 1=“all of the time”, 2=”most of the time”, 3=”some 
of the time”, 4=”a little of the time”, and 5=”none of the time.” 
Question 1, having to do with sleep onset, will be summarized by creating a crosstabulation table 
of the baseline vs. post-baseline visit categorical distributions for each post-baseline visit up to 
and including the Washout and Safety Follow-up visit, and LOV. 
Question 2, number of hours per night of sleep, will be summarized as detailed in Section 8.1. 


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Individual sub-question scores for Question 3 will be summarized categorically using 
frequencies and percentages. 
 
MOS Sleep Scale-R questions will be presented in a data listing for the safety population. 
8.1.7. Change from Baseline in the PBI-P  
The PBI-P questionnaire assesses the importance of treatment objectives to the individual. 
Before, and at the end of drug treatment in this study, the patient completes the same 
questionnaire and rates the extent to which the treatment objectives have been achieved. The 
instrument consists of 27 multiple choice questions that can be answered “not at all”, 
“somewhat”, “moderately”, “quite” and “very”. 
At baseline and at the end of treatment visit, the total PBI-P summed across 27 items will be 
calculated and a mean total score will be obtained. For mean score calculation, responses of 
“does not apply” and “question unanswered” will be treated as missing values. Mean score will 
be derived as (sum of all non-missing items)/(number of non-missing items).  
PBI-P mean score and each of the 27 individual PBI-P items will be summarized as detailed in 
Section 8.1. 
Responses to each of the 27 individual PBI-P items will be summarized at baseline and the end 
of treatment visit using descriptive statistics. 
Individual PBI-P item scores will be presented in a data listing for the safety population 
8.1.8. Change from Baseline in PAS   
The PAS consists of 7 qualitative and quantitative measurements related to the examination of 
the skin. Type, number, distribution, affected body parts, and quantitative number of lesions in a 
representative body part are documented. The biggest lesion and the most representative lesion 
are monitored with documentation of height and area measurements. Prurigo lesion activity is 
recorded as a percentage based on their stage (0-4).  
Separate activity classification is provided for prurigo lesions with excoriations/crusts compared 
to all prurigo lesions and for healed prurigo lesions compared to all prurigo lesions. The 
proportion of patients with each stage of classification will be summarized at each visit for each 
of the two activity classifications (note that PAS is not completed at the Washout/Safety and 
Follow-up visit). Shift from baseline to LOV and the End of Treatment visit for all patients, 
patients with at least 6 months of treatment, patients with at least 9 months of treatment and 
patients who complete treatment will also be presented for each of the two activity 
classifications. Shift from baseline to Visit 5/Week 13, Visit 8/Week 26 and Visit 11/Week 38 
for all patients will also be presented for each of the two activity classifications. 
Classification is provided for total number of prurigo lesions (not including scars). The 
proportion of patients at each classification level (0, 1-19, 20-100 and >100) will be summarized 
at each visit (note that PAS is not completed at the Washout/Safety and Follow-up visit). Shift 
from baseline to LOV and the End of Treatment visit for all patients, patients with at least 6 


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months of treatment, patients with at least 9 months of treatment and patients who complete 
treatment will also be presented. Shift from baseline to Visit 5/Week 13, Visit 8/Week 26 and 
Visit 11/Week 38 for all patients will also be summarized. 
All PAS data obtained in the study will be presented in a data listing for the safety population 
8.2. Change during the Washout Period in PROs  
Change during the Washout Period after cessation of treatment in the following PROs will be 
summarized using simple summary statistics generated for the End of Treatment visit and the 
Washout/Safety Follow-up visit and for change from the End of Treatment visit to the 
Washout/Safety Follow-up Visit. 
• Worst itch intensity NRS 
• Average itch intensity NRS 
• VRS (itchy, burning, stinging) 
• ItchyQoL Total Score 
• MOS Sleep Scale-R Question 2 
• HADS 
No formal analysis of this presentation of data will be performed. Note that only patients who 
complete the study through the End of Treatment visit will be included in this evaluation. 
8.3. Dose-Up and Down-Titration 
The number and percentage of patients with any dosing change during the Treatment Period and 
for each Treatment Period visit will be presented by reason for dosing change.  
Reasons for dosing changes will be presented in a data listing for the safety population.  
8.4. Failure-to-Improve Criteria 
Beginning with the TV3 visit and at each subsequent treatment visit (up to and including the 
TV13 visit) the number and percentage of patients who meet failure-to-improve criteria will be 
summarized.  
The visit at which failure-to-improve criteria are met will be presented in a data listing for the 
safety population. 
8.5. Rescue Medication Use 
Details regarding the definition of and overall summary of rescue medications are presented in 
Section 7.2. 
The number of days of use of rescue medications by study period (Pre-Treatment (after the date 
of last visit during the TR03 core study and prior to first dose during the TR03 extension study) 
and Treatment Period (Visits 2-14)) and by visit for the Treatment Period will be summarized 


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using descriptive statistics for both the overall number of days of use as well as for the number of 
days of rescue medication use for the drug classes presented in Table 1.  
The number of days of rescue medication use between each visit will be presented graphically 
for overall rescue medication use as well as for each of the drug classes presented in Table 1.  
The overall number of days of rescue medication use and number of days of rescue medication 
use for each of the drug classes presented in Table 1 will be summarized using descriptive 
statistics. For patients with >=1 day of rescue medication use, percentage of total time on study 
will be derived as: [(the number of days of rescue medication use)/[days from the informed 
consent date through the fixed dose period]]*100. The mean for all patients on-study during the 
time period will be presented.  
Time to first new use of rescue medication (days) will be summarized using descriptive statistics. 
The earliest date on or after the date of first dose of study medication on which a patient begins 
new rescue medication use will be considered the date of first new use of rescue medication. 
Time to first new rescue medication use will be derived as: (date of first new use of rescue 
medication – date of first dose of study medication) + 1. For patients who have no new rescue 
medication use on or after the date of their first dose of study medication time to first new use of 
rescue medication is not calculated.    
It is recognized, however, that all of these evaluations are potentially confounded with early 
discontinuation that may or may not be observed among patients reporting use of rescue 
medications.  That is, the extent and duration of use of rescue medications may, at least in part, 
be a function of duration of participation in the study. 
8.6. Premature Discontinuation Due to Lack of Efficacy or Adverse Events 
The distribution of patients who prematurely discontinue due to lack of efficacy or adverse 
events during the Treatment Period and Washout Period will be summarized for the safety 
population across all Treatment Period visits, separately at each Treatment Period visit, and for 
the Washout Period. Date of discontinuation during the Treatment Period will be defined as the 
date of last dose of study medication. For patients who complete the Treatment Period, date of 
discontinuation during the Washout Period will be defined as the earliest non-missing of the date 
of last contact or the last observed visit date. 
9. Safety Analysis 
All analyses of safety will be conducted using the safety population.  
 
No formal statistical analysis will be performed on safety outcomes; inferences, if any, will be 
derived through clinical review and interpretation. 
9.1. Adverse Events 
Details regarding the definition and reporting of an AE or a serious adverse event (SAE) are 
provided in the study protocol. AEs will be recorded starting with the signing of the first 


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informed consent. All AEs will be collected through the Washout and Safety follow up visit (or 
Early Termination Visit). Following the Washout and Safety follow up visit (or Early 
Termination Visit), all unresolved AEs that were reported by the Investigator to be probably drug 
related should be followed by the Investigator until the events are resolved, the patient is lost to 
follow-up, or the AE has stabilized. 
Non-serious AEs that begin during the Observation Period will be captured as medical history in 
the TR03 extension study; patients who never transition from the Observation Period to the 
Treatment Period are screening failures and did not complete the early termination or end of 
study CRFs. SAEs occurring during the Observation Period will be recorded as SAEs. 
Also, AEs that were ongoing at the time of a patient’s completion of the TR03 core study are 
recorded as medical history in the TR03 extension study. 
A treatment-emergent AE (TEAE) will be defined as one starting or worsening on or after the 
first dose of study medication during the extension study.  If the start date is missing, the event is 
assumed to be treatment emergent.  
For patients who complete study treatment through the Visit 14/End of Treatment visit, Titration 
Period AEs are those with an onset date from first dose date of the extension study through (first 
dose date + 27 days). Treatment Period AEs are those with an onset date from first dose date of 
the extension study through (first dose date + 349 days). Washout and Safety Follow-up AEs are 
those with an extension study onset date of (first dose date + 350 days) through (first dose date + 
363 days). For patients who are treated and who discontinue study drug use prior to the Visit 
14/End of Treatment visit yet remain on-study, AEs with an onset date on or after the first dose 
date of the extension study will be considered Treatment Period AEs.   
For the purpose of inclusion in TEAE table summaries, incomplete AE onset and end dates will 
be imputed as described below. 
For incomplete AE onset dates: 
• If the day is missing but the month and year are known: 
o If the month and year are different from the month and year of the first dose of 
study drug, then use the first day of the month as the imputed onset date. 
o If the month and year are the same as the month and year of the first dose of study 
drug, and the end date (after any imputation) is on or after the first dose of study 
drug, then use the date of the first dose of study drug as the imputed onset date. 
o If the month and year are the same as the month and year of the first dose of study 
drug, and the end date (after any imputation) is prior to the date of the first dose of 
study drug, then use the end date as the imputed onset date. 
• If the month is missing but the year is known (day can be either missing or known):  
o If the year is different from the year of the first dose of study drug then use Jan. 
1st of the reported year as the imputed onset date. 


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o If the year is the same as the year of the first dose of study drug and the end date 
(after any imputation) is on or after the first dose of study drug then use the date 
of the first dose of study drug as the imputed onset date. 
o If the year is the same as the year of the first dose of study drug and the end date 
(after any imputation) is prior to the date of the first dose of study drug, then use 
the end date as the imputed onset date.  
• If the start date is completely missing, the event is assumed to be treatment-emergent. 
For incomplete AE end dates: 
• If the day is missing but the month and year are known then use the last day of the month 
as the imputed end date. 
• If the month is missing but the year is known (and the day is either missing or known) 
then use Dec. 31st of the year as the imputed end date. 
Adverse events will be coded according to MedDRA (version to be delineated in the clinical 
study report).  
All AE summary tables will present system organ class (SOC) and preferred term (PT), will 
include counts of patients, and will be based on TEAEs. SOC will be displayed in descending 
order of frequency overall and then alphabetically. PT will be displayed in descending order of 
frequency overall and then alphabetically within SOC. A patient with two or more AEs within 
the same level of summarization will be counted only once in that level using the most extreme 
incident. Percentages will be based on the number of patients in the safety population.   
In all AE summary tables, TEAEs will be presented in descending order of incidence from the 
SOC with the highest total incidence to the SOC with the lowest total incidence. If the total 
incidence for any two or more SOCs is equal then the SOCs will be presented in alphabetical 
order. Within each SOC, the PTs will also be presented in descending order of total incidence 
among the active treatment arms with ties at the PT level being presented in alphabetical order. 
At each level of patient summarization, a patient is counted once if the patient reported one or 
more events. Percentages will be calculated out of the number of patients in the safety 
population.  
9.1.1. Incidence of Adverse Events 
An overview summary of the number and percentage of patients with any TEAE and the total 
number of TEAEs recorded will be presented for: patients experiencing any TEAE, any 
treatment-emergent SAE, any related TEAE, any TEAE by maximum intensity, and any TEAE 
by treatment period for the Treatment Period and Washout and Safety Follow-up Period.    
The overview summary will be repeated for the Treatment Period and Washout and Safety 
Follow-up Period.  For an AE that is reported during more than one of these periods, the earliest 
period of onset will be used in the incidence calculation. Additionally, the overview summary 
will be repeated for the Titration Period. Since the Titration Period is a subset of the Treatment 
Period, AEs will be reported in both periods, where applicable. 


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Summaries of the total number of TEAEs and the number and percentage of patients with at least 
one TEAE will be provided by SOC and PT.  
A summary of the total number of AEs occurring during the Observation Period (captured in the 
TR03 extension study medical history form) and the number and percentage of patients with at 
least one AE during the Observation Period will be provided by body system and dictionary 
term. New medical history for the TR03 extension study (i.e. with an onset date on or after the 
signing of the informed consent for the TR03 extension study) is captured in the TR03 extension 
study medical history form.  
 
All AEs will be presented in a data listing for the safety population. 
9.1.2. Relationship of Adverse Events to Study Drug 
Association or relatedness to the study medication will be graded as either “probably,” 
“possibly,” or “unlikely.”  For the purpose of summarization, AEs will be dichotomized into 
“related” (probably and possibly) and “unrelated” (unlikely). 
A summary of TEAEs by relationship (“related”, “unrelated”) to study drug will be presented in 
a table by incidence of occurrence. A patient with two or more AEs within the same level of 
summarization will be counted only once in that level using the most related category. TEAEs 
that are missing a relationship will be presented in the summary table as “related” but will be 
presented in the data listing with a missing relationship.  
9.1.3. Severity of Adverse Events 
The severity of all AEs will be graded by the investigator as Grade 1, Grade 2, Grade 3, Grade 4, 
or Grade 5 according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03.  
A summary of TEAEs by severity will be presented. The severity that will be presented 
represents the most extreme severity captured on the eCRF page (Grade 1 through Grade 5 with 
Grade 5 being the most severe). A patient with two or more AEs within the same level of 
summarization will be counted only once in that level using the most severe incident. TEAEs 
that are missing severity will be presented in tables as “Severe” (i.e. Grade 3) but will be 
presented in the data listing with a missing severity. Percentages will be calculated out of the 
number of patients in the safety population. 
The summary of TEAEs by severity will be repeated for the Treatment Period and Washout and 
Safety Follow-up Period.  For an AE that is reported during more than one of these periods, the 
earliest period of onset will be used in the incidence calculation. Additionally, the summary will 
also be repeated for the Titration Period. Since the Titration Period is a subset of the Treatment 
Period, AEs will be reported in both periods, where applicable. 
9.1.4. AEs Leading to Treatment Discontinuation 
The incidence of AEs leading to study drug discontinuation will be summarized by SOC and PT 
and will be presented in a data listing. This listing will be a subset of the full listing of all AE 
information. 


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9.1.5. SAEs and Deaths  
A summary of the total number of treatment-emergent SAEs and the number and percentage of 
patients with at least one treatment-emergent SAE will be provided by SOC and PT. An 
additional summary of all SAEs will be provided, broken down by the AE severity grade and 
investigator assessment of relationship to treatment. The summaries will also be presented 
separately for the Treatment Period and the Washout and Safety Follow-up Period.  
A summary of the total number of SAEs during the Observation Period and the number and 
percentage of patients with at least one SAE during the Observation Period will be provided by 
SOC and PT. An additional summary of all SAEs during the Observation Period will be provided, 
broken down by the AE severity grade and investigator assessment of relationship to treatment. 
All SAEs and fatal AEs will be presented in data listings for the safety population. These listings 
will be subsets of the full listing of all AE information.  
9.1.6. AEs of Special Interest 
The following AEs of special interest are noted: nausea, vomiting, constipation, somnolence, 
sedation, dizziness and vertigo. For each of these AEs, summary tables of incidence and 
prevalence will be prepared that look at the number of days from the start of treatment until first 
onset and duration of the AE in days for all patients and by gender. 
The summary of TEAEs by severity will be repeated for each AE of special interest overall and 
for the Treatment Period and Washout and Safety Follow-up Period. The severity that will be 
presented represents the most extreme severity captured on the eCRF page (Grade 1 through 
Grade 5 with Grade 5 being the most severe). A patient with two or more AEs within the same 
level of summarization will be counted only once in that level using the most severe incident. 
TEAEs that are missing severity will be presented in tables as “Severe” (i.e. Grade 3) but will be 
presented in the data listing with a missing severity. Percentages will be calculated out of the 
number of patients in the safety population. For an AE that is reported during more than one of 
these periods, the earliest period of onset will be used in the incidence calculation. Additionally, 
the summary will also be repeated for the Titration Period. Since the Titration Period is a subset 
of the Treatment Period, AEs will be reported in both periods, where applicable. 
9.1.7. Abuse-Potential Related AEs 
Although nalbuphine is not a controlled substance in the US or Europe, AEs of special interest 
that suggest a possible addiction or abuse potential or withdrawal will be specifically analyzed to 
screen for these effects. These AEs, obtained from the list provided by Love et al (2013) [see 
Section 13.2] will be designated as such in the study data base.  
The overview AE summary will be repeated for abuse-potential related AEs. Summary tables of 
incidence and prevalence for these events will be prepared that look at the number of days from 
the start of treatment until first onset and duration of the AE in days for all patients and by 
gender. 
The summary of TEAEs by severity will be repeated for abuse-potential related AEs overall and 
for the Treatment Period and Washout and Safety Follow-up Period. The severity that will be 


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presented represents the most extreme severity captured on the eCRF page (Grade 1 through 
Grade 5 with Grade 5 being the most severe). A patient with two or more AEs within the same 
level of summarization will be counted only once in that level using the most severe incident. 
TEAEs that are missing severity will be presented in tables as “Severe” (i.e. Grade 3) but will be 
presented in the data listing with a missing severity. Percentages will be calculated out of the 
number of patients in the safety population. For an AE that is reported during more than one of 
these periods, the earliest period of onset will be used in the incidence calculation. Additionally, 
the summary will also be repeated for the Titration Period. Since the Titration Period is a subset 
of the Treatment Period, AEs will be reported in both periods, where applicable. 
9.2. Other Safety Assessments 
9.2.1. SOWS 
The SOWS is a self-administered scale for grading opioid withdrawal symptoms. It contains 16 
symptoms whose intensity the patient classifies as: 0=“not at all”, 1=”a little”, 2=”moderately”, 
3=”quite a bit”, and 4=“extremely”. In this study, patients will complete the SOWS daily, 
starting at the TV14, End of Treatment visit through to the Washout and Safety Follow-up Period 
visit. The SOWS will also be completed at the Premature Discontinue of Study Drug Treatment 
visit. As with all patients who are discontinued from study drug, the patient will complete a daily 
SOWS scale for the two weeks following the last dose of study drug (unless consent is 
withdrawn).  
To evaluate the daily changes in the SOWS during the Washout Period after cessation of 
treatment, each of the 16 symptom items will be summarized for each of the first 14 days 
beginning with the End of Treatment visit as frequencies and percentages of patients. No formal 
analysis will be undertaken. Additionally, the sum of all non-missing responses for the 16 items 
(SOWS total score) will be derived and similarly presented for each of those 14 days. 
The change from the End of Treatment visit (defined as the maximum SOWS total score across 
days from the End of Treatment visit date to 7 days following the End of Treatment visit date), to 
the Washout and Safety Follow-up visit (defined as the SOWS total score on the date of the 
Washout and Safety Follow-up Period or the latest date following the End of Treatment Visit and 
before the Washout and Safety Follow-up visit) will be summarized using descriptive statistics 
for each treatment group. 
A categorical summary will also be provided for the number and percentage of patients by their 
highest observed SOWS total score during the 14-day (washout) period already defined. The 
categories will be: ≤10, 11-20, 21-30, 31-40, 41-50, 51-60, >60. No formal analysis will be 
undertaken. 
Maximum SOWS symptom score (defined for each patient for each day of the Washout and 
Safety Follow-up Period as the maximum (i.e. worst) non-missing score across all 16 symptom 
items) will be summarized using descriptive statistics for each treatment group.  


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9.2.2. Neurological Examination 
A categorical summary of the number and percentage of patients by result (normal, abnormal-
NCS, abnormal-CS, not done) will be presented for each neurological condition by study visit. 
No formal analysis will be undertaken. 
9.3. Clinical Laboratory Evaluations 
A complete series of laboratory evaluations (including hematology, serum chemistry, serum 
pregnancy and urine pregnancy (both if applicable) and urinalysis will be obtained according to 
the Schedule of Events. The required clinical laboratory tests are listed in Section 13.1.  
Clinically-significant worsening in laboratory findings following start of Study Drug treatment 
will be recorded as AEs and these will be repeated for verification. Clinically-significant findings 
noted prior to the start of Study Drug treatment will be recorded as Medical History. The 
recorded AE will indicate the underlying abnormality or diagnosis as opposed to the observed 
deviation in laboratory results if the diagnosis is known (e.g. “acute Hepatitis A” is preferable to 
“ALT increased”).  
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result or to monitor the course of an AE will be obtained when clinically indicated. In 
particular, if a clinically significant abnormal result is observed that is not resolved by the final 
study visit, tests will be repeated to document resolution or stability of the abnormality. 
All summaries will be based on the conventional units of measurements.  
Clinical safety laboratory data will be summarized descriptively at baseline and all post-baseline 
visits as detailed in the Schedule of Events. Change from baseline summary statistics (n, mean, 
SD, median, minimum, maximum) will also be provided for all post-baseline visits. Summaries 
of safety laboratory parameters will include the first measurement of each scheduled assessments 
but repeat assessments (except as already described for the determination of the Baseline value 
of interest) done at the same study time point will not be included in summary calculations.   
 
Laboratory data will also be listed by patient, and visit. Listings will include scheduled, 
unscheduled, and repeat evaluations.  
 
9.3.1. Hematology 
All hematology lab tests with a numerical result will be summarized and listed as described in 
Section 9.3. 
9.3.2. Serum Chemistry 
All chemistry lab tests with a numerical result will be summarized and listed as described in 
Section 9.3.  


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9.3.3. Urinalysis 
All urinalysis lab tests with a numerical result will be summarized and listed as described in 
Section 9.3. 
9.3.4. Serum Pregnancy 
Serum pregnancy test results will be presented in a data listing. 
9.4. Vital Sign Measurements 
Blood pressure and HR will be taken while sitting or semi-recumbent for at least 5 minutes. 
Temperature may be taken by any standard method (e.g., oral, tympanic, rectal, etc.), but the 
method must be recorded. Vital signs will be obtained according to the Schedule of Events 
presented in the protocol.  
Vital signs will be summarized during the Observation Period, at Baseline and at each 
assessment time point during the post dosing periods. 
All vital sign data will be presented in a data listing.  
9.5. Physical Examination 
A complete physical examination will be performed according to the Schedule of Events as 
described in the protocol. Any clinically significant worsening after the start of Study Drug 
treatment 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. 
Physical examination details regarding abnormal findings will be summarized and listed with the 
AE and medical history information.  
9.6. Electrocardiogram 
A standard 12-lead ECG will be obtained according to the Schedule of Events as detailed in the 
protocol. ECGs will be read locally for clinical significance and centrally for ECG intervals (PR, 
RR, QRS, QT and QTcF using nomogram table), rate, rhythm, and other clinically significant 
abnormalities such as left ventricular hypertrophy, pathological Q-waves, etc. Clinically 
significant worsening in ECG findings following start of study drug treatment will be recorded as 
AEs. Clinically significant findings noted prior to the start of study drug treatment will be 
recorded as Medical History. 
 
ECG summaries and listings will be provided by a core cardiac laboratory and will be described 
further in a separate ECG analysis plan.   


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10. Pharmacokinetic (PK) and Pharmacokinetic (PK)/Pharmacodynamic 
(PD) Analyses 
All PK and PD analyses will be performed by PPD’s PK group. The PK/PD analyses will be 
described further in a separate PK/PD analysis plan.  
 
11. Interim Analyses and Data Monitoring 
No interim analyses or data monitoring committee meetings are planned for this study. 


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12. References 
1. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
[http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf]. 
2. Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, Augustin M, Szepietowski JC, 
Ständer S. Assessment of pruritus intensity: prospective study on validity and reliability of 
the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with 
chronic pruritus. Acta Derm Venereol. 2012 Sep;92(5):502-7. 
3. Siebenhaar F, Fortsch A, Krause K, Weller K, Metz M, Magerl M, Martus P, Church MK, 
Maurer M. Rupatadine improves quality of life in mastocytosis: a randomized, double-blind, 
placebo-controlled trial. Allergy 2013; 68: 949-952. 
4. Stander S, Augustin M, Reich A, Blome C, Ebata T, Phan NQ, Szepietowski JC; International 
Forum for the Study of Itch Special Interest Group Scoring Itch in Clinical Trials. Pruritus 
assessment in clinical trials: consensus recommendations from the International Forum for the 
Study of Itch (IFSI) Special Interest Group Scoring Itch in Clinical Trials. Acta Derm Venereol. 
2013 Sep 4;93(5):509-14. 
 
 
 
 
 
 
 
 
 
 
 


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13. Appendices 
 
13.1. Clinical Laboratory Tests 
 
Hematology: 
Serum Chemistry: 
Hemoglobin 
ALT 
Hematocrit 
Albumin 
Red Blood Cell Count 
Alkaline Phosphatase 
White Blood Cell Count 
AST 
Platelet Count 
Bicarbonate 
White Blood Cell Differential 
Blood Urea Nitrogen (BUN) 
 
Carbon Dioxide 
 
Calcium 
Urine: 
Chloride 
Urinalysis 
Creatinine 
Pregnancy 
Gamma-glutamyl transferase 
 
Glucose 
 
LDH 
 
Phosphorus 
 
Potassium 
 
Sodium 
 
Total Bilirubin 
Serum Pregnancy: 
Total Protein 
b-Human Chorionic  
Gonadotropin (HCG) (women of 
childbearing potential regardless of 
sexual activity) 
Uric acid 
 
 
 


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13.2. List of Abuse-Potential Associated Adverse Events 
From Love et al (2013): “Proposed Query to Capture Abuse-Associated Adverse Events,” 
College on Problems of Drug Dependence, 75th Annual Meeting, San Diego, CA 
 
******** SELECTED ABUSE-RELATED ADVERSE EVENTS ********; 
"Abnormal behaviour", "Abnormal dreams", "Abnormal sleep-related event", 
"Accidental death", "Accidental overdose", "Accidental poisoning", "Acute psychosis", "Affect 
lability", "Affective disorder", "Aggression", "Agitation", "Alice in wonderland syndrome", 
"Altered state of consciousness", "Altered visual depth perception", "Amnesia", 
"Amnestic disorder", "Amphetamines", "Amphetamines positive", "Analgesic therapy", "Anger", 
"Anhedonia", "Anterograde amnesia", "Antisocial behaviour", "Antitussive therapy", "Anxiety", 
"Anxiolytic therapy", "Apathy", "Asocial behaviour", "Asthenia", "Attention-seeking 
behaviour", "Balance disorder", "Belligerance", "Benzodiazepine drug level", "Blunted affect", 
"Bradyphenia", "Central nervous system stimulation", "Cognitive disorder", "Completed 
suicide", "Compulsions", "Confabulation", "Confusional arousal", "Confusional state", 
"Consciousness fluctuating", "Coordination abnormal", "Deja vu", "Delirium", "Delusion", 
"Delusion of grandeur", "Delusion of reference", "Delusion of replacement", "Delusional 
perception", "Delusional disorder, erotomatic type", "Delusional disorder, grandiose type", 
"Delusional disorder, jealous type", "Delusional disorder, mixed type", "Delusional disorder, 
persecutory type", "Delusional disorder, somatic type", "Delusional disorder, unspecified type", 
"Delusions, mixed", "Dependence", "Depersonalization", "Depressed level of consciousness", 
"Depressive delusion", "Derailment", "Derealisation", "Disinhibition", "Disorientation", 
"Dissociation", "Dissociative amnesia", "Dissociative identity disorder", "Disturbance in 
attention", "Disturbance in social behaviour", "Dopamine dysregulation syndrome", 
"Dopaminergic drug therapy", "Drug abuse", "Drug abuser", "Drug dependence", 
"Drug dependence, antpartum", "Drug dependence, postpartum", "Drug detoxification", "Drug 
diversion", "Drug screen positive", "Drug tolerance increased", "Dyslogia", "Dysphoria", 
"Elevated mood", "Emotional disorder", "Emotional distress", "Energy increased", "Erotomanic 
delusion", "Euphoric mood", "Executive dysfunction", "Fear", "Feeling abnormal", "Feeling 
drunk", "Feeling jittery", "Feeling of despair", "Feeling of relaxation", "Flashback", "Flat affect", 
"Flight of ideas", "Formication", "Hallucination", "Hallucination, auditory", "Hallucination, 
gustatory", "Hallucination, olfactory", "Hallucination, synaesthetic", "Hallucination, tactile", 
"Hallucination, visual", "Hallucinations, mixed", "Hangover", "Homicidal ideation", 
"Homicide", "Hostility", "Hypervigilance", "Hypnagogic hallucination", 
"Hypnopompic hallucination", "Ideas of reverence", "Illogical thinking", "Illusion", 
"Impaired driving ability", "Impaired reasoning", "Impulsive behaviour", "Inappropriate affect", 
"Incoherent", "Intentional drug misuse", "Intentional overdose", "Intentional self-injury", 
"Irritability", "Jamais vu", "Jealous delusion", "Judgement impaired", "Loose associations", 
"Magical thinking", "Mania", "Maternal use of illicit drugs", "Memory impairment", "Mental 
disability", "Mental disorder", "Mental impairment", "Mental status changes", "Miosis", "Mood 
altered", "Multiple drug overdose", "Multiple drug overdose accidental", "Multiple drug 
overdose intentional", "Muscle relaxant therapy", "Mydriasis", "Nasal necrosis", "Nasal septum 
perforation", "Nasal septum ulceration", "Needle track marks", "Neonatal complications of 
substance abuse", "Overdose", "Panic attack", "Panic reaction", "Paramnesia", 


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"Paranoia", "Parasomnia", "Paroxysmal perceptual alteration", "Persecutory delusion", 
"Personality change", "Personality disorder", "Physical assault", "Poisoning", "Polysubstance 
dependence", "Prescription form tampering", "Product tampering", "Product used for unknown 
indication", "Psychomotor hyperactivity", "Psychomotor retardation", "Psychomotor skills 
impaired", "Psychotic behaviour", "Psychotic disorder", "Reactive psychosis", "Restlessness", 
"Retrograde amnesia", "Sedation", "Self-injurious behaviour", "Self-injurious ideation", 
"Sensory disturbance", "Sensory level abnormal", "Sleep sex", "Sleep terror", "Slow speech", 
"Somatic delusion", "Somatic hallucination", "Somnolence", "Staring", "Steroid withdrawal 
syndrome", "Stupor", "Substance abuse", "Substance abuser", "Substance use", "Substance-
induced mood disorder", "Substance-induced psychotic relief", "Suicidal behaviour", 
"Suicidal ideation", "Suicide attempt", "Suspiciousness", "Tangentiality", "Thinking abnormal", 
"Thought blocking", "Thought broadcasting", "Thought insertion", "Thought withdrawal", 
"Toxicity to various agents", "Transient global amnesia", "Transient psychosis", "Treatment 
noncompliance", "Urine amphetamine", "Urine amphetamine positive", "Violence-related 
symptom"