Conditions: Prurigo Nodularis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 353
Healthy volunteers: no

Brief summary:
To investigate the anti-pruritic efficacy and safety of Nalbuphine Extended Release (ER) (NAL ER) tablets in Prurigo Nodularis. Participants were randomized to NAL ER (or matching placebo) with the primary endpoint evaluation at Week 14. During the open label extension, participants who received NAL ER were continued on NAL ER and participants who received placebo would then shift to NALER.

Detailed description:

Arms:
arm 1: During the double-blind (DB) period, participants were titrated over 2 weeks to NAL ER 162 mg, orally, twice daily (BID), followed by 162 mg, orally, BID, for 12 weeks. During the open label extension (OLE) period, participants perceived a titration period of 2 weeks, and continued to receive NAL ER 162 mg, orally, BID, for 38 weeks in total. arm 2: During the DB period, participants perceived a titration period of 2 weeks during which they received placebo to match the active titration period, followed by placebo, orally, BID, for 12 weeks. During the OLE period, participants were titrated over 2 weeks to NAL ER 162 mg, orally, BID, which they received for 38 weeks (including titration).

Interventions: intervention 1: Nalbuphine ER Tablets intervention 2: Placebo Tablets
Intervention descriptions: intervention 1: Active Nalbuphine ER Tablets intervention 2: Placebo matching NAL ER with no active substance

Protocol document:
Prot_000.pdf: 
Official Title: A Phase 2b/3, Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy 
and Safety Study in Prurigo Nodularis (PN) With Nalbuphine ER Tablets for Pruritus Relief 
Through Itch Scratch Modulation (PRISM Study)  
NCT Number: NCT03497975 
Document Date: Protocol Version 7.0 (Amendment 6) : 21 July 2021


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 1 of 176 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A Phase 2b/3, Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy, and Safety 
Study in Prurigo Nodularis with Nalbuphine ER Tablets for Pruritus Relief Through Itch 
Scratch Modulation (PRISM Study) 
 
Protocol No.: TR11 
IND No.: 
113770 EudraCT No.:  2018-001219-53 
Test Product: 
Nalbuphine ER Tablets (NAL ER) 
Indication: 
Itch associated with Prurigo Nodularis 
Sponsor: 
Trevi Therapeutics, Inc. 
Development Phase: 
2b/3 
Sponsor Medical Expert/Signatory: 
 MD 
Sponsor Contact: 
 
Date of the Protocol: 
21 July 2021 
Version of the Protocol: 
Version 7.0 (Amendment 6) 
 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee and/or Institutional Review Board. 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) 
 
 


Trevi Therapeutics, Inc. 
Protocol TRI I 
2 SIGNATURE PAGE 
CONFIDENTIAL 
21 July 2021 
SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: A Phase 2b/3, Randomized, Double-Blind, Placebo-Controlled, 
2-Arm, Efficacy, and Safety Study in Prurigo Nodularis with Nalbuphine ER Tablets 
for fruritus Relief Through !tch ~cratch Modulation (PRISM Study) 
• 
PROTOCOL NUMBER: TRI I 
Trevi Therapeutics, Inc. 
 MD 
Date (day/month/year) 
Version 7.0 
Page 2 of 176 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
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3 GENERAL INFORMATION 
A Phase 2b/3, Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy, and Safety 
Study in Prurigo Nodularis with Nalbuphine ER Tablets for Pruritus Relief Through Itch 
Scratch Modulation (PRISM Study) 
Protocol No.: 
TR11 
Date and number of the Protocol: 
21 July 2021 (Amendment 6, Version 7) 
Date and Number of prior Protocol Versions: 
08 May 2018 (Original) 
09 October 2018 (Amendment 1, Version 2) 
14 March 2019 (Amendment 2, Version 3.1) 
22 January 2020 (Amendment 3, Version 4) 
04 August 2020 (Amendment 4, Version 5) 
05 March 2021 (Amendment 5, Version 6) 
Sponsor: 
Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor New Haven, CT 06510 
USA 
Clinical Research Organization: 
ICON Clinical Research Ltd. South County Business Park 
Leopardstown 
Dublin 18 D18 X5R3 
Ireland 
Sponsor Medical Expert/Signatory: 
 MD 
195 Church Street 14th Floor 
New Haven, CT 06510 USA 
Tel No.: 
 
Fax No.: 
 
Sponsor Contact: 
 
195 Church Street 14th Floor 
New Haven, CT 06510 USA 
Tel No.: 
 
Fax No.: 
 
 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
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4 STUDY SYNOPSIS 
 
Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine extended release 
(NAL ER) tablets 
Name of Active Ingredient: 
Nalbuphine hydrochloride (HCl) 
Title of Study: 
A Phase 2b/3, Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy, and Safety Study in Prurigo 
Nodularis with Nalbuphine ER Tablets for Pruritus Relief Through Itch Scratch Modulation (PRISM Study) 
Study Center(s): 
Approximately 70 centers will be initiated for this study in 5 countries. 
Publication(s): 
None 
Planned Study Period Following Sample Size Re- 
Estimation: 
May 2018 to June 2022 
(Primary Week 14 endpoint Dec 2021) 
Development Phase: 
Phase 2b/3 
Objectives: 
Primary Objective: 
• 
To evaluate the effect of NAL ER on itch as assessed by the percentage of Responders (‘response’ is 
defined as a ≥ 4-point reduction in the 7-day average Worst Itch – Numerical Rating Scale [WI-NRS]) 
Secondary Objectives: 
Key secondary objectives are as follows: 
• 
To evaluate the effect of NAL ER on itch-related quality of life as assessed by the ItchyQoL™ total score 
• 
To evaluate the effect of NAL ER on Prurigo Nodularis (PN) skin lesions as assessed by the Prurigo 
Activity Score (PAS) Question 5a 
• 
To evaluate the effect of NAL ER on sleep as assessed by the PROMIS Sleep Disturbance Short Form 8a 
Other secondary objectives are as follows: 
• 
To evaluate the effect of NAL ER on itch as assessed by the mean change in WI-NRS 
• 
To evaluate the benefit to subjects of NAL ER using the Patient Benefit Index, pruritus version (PBI-P) 
• 
To characterize the safety and tolerability of NAL ER 
• 
To assess the pharmacokinetics (PK) of nalbuphine and its metabolites 
Methodology: 
This is a randomized, double-blinded, placebo-controlled, 2-arm study, with an open-label extension period 
following double-blind treatment. The study will investigate the anti-pruritic efficacy and safety of NAL ER when 
used for the treatment of itch in PN. 
Subjects will be randomized to NAL ER (2-week titration followed by 162 mg twice daily [BID] for 12 weeks) or 
matching placebo (14 weeks duration), with the primary endpoint evaluation at Week 14. If permanent 
discontinuation of investigational product occurs anytime between Day 1 and the Week 14 visit, the subject will 
be asked to complete the Off-Treatment Visit, the Last Visit, and the End of Study telephone call, and to return to 
the clinic for the Week 14 visit (unless consent is withdrawn). During the open-label extension, subjects who 
received NAL ER will continue on NAL ER for a total of 38 additional weeks (total treatment duration 52 weeks 
including titration) and subjects who received placebo will crossover to NAL ER for a total of 38 weeks (including 
titration). Upon discontinuation of investigational product, all subjects will complete a 2-week off-treatment safety 
follow-up period, regardless of when and why the subject discontinued study treatment; unless they withdraw 
consent. In addition, a final follow-up itch and safety assessment will be made via telephone call (‘End of Study 
telephone call’) 4 weeks after the last dose of investigational product. The total planned study duration from 
randomization through to the last telephone contact is 56 weeks. 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 5 of 176 
 
Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine extended release 
(NAL ER) tablets 
Name of Active Ingredient: 
Nalbuphine hydrochloride (HCl) 
Subjects with diagnosed PN will be randomized (1:1) to 1 of the following treatment arms: 
Arm 1: Blinded active titration over 2 weeks (to achieve a final NAL ER dose of 162 mg) followed by 162 mg BID 
for 12 weeks with continuation into the extension titration period (blinded), and the open-label fixed-dose period, 
followed by a 2-week off-treatment safety follow-up period and a final telephone contact, for itch and safety 
assessment, 4 weeks after investigational product discontinuation. 
Arm 2: Placebo “titration” over 2 weeks followed by placebo BID for 12 weeks with continuation into 
the extension titration period (blinded; to achieve a final NAL ER dose of 162 mg BID) and the open-label 
fixed-dose period (NAL ER 162 mg BID), followed by a 2-week off-treatment safety follow-up period and a final 
telephone contact, for itch and safety assessment, 4 weeks after investigational product discontinuation. 
Number of Subjects: 
Approximately 360 subjects with diagnosed PN will be randomized. This amendment increases the original sample 
size from 240 to 360 randomized. The increase results from the interim sample size re-estimation (SSRE) which 
was introduced in Amendment 2, Protocol 3.1. The results of the interim analysis provided a conditional power in 
the pre-specified “promising zone”, therefore the study Data Safety Monitoring Board (DSMB) recommended that 
the sample size should be increased to 360 randomized. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
Subjects eligible for randomization to receive investigational product must meet all of the following criteria: 
1. Individuals diagnosed with generalized PN, defined as the presence of ≥ 10 pruriginous nodules, involving 
at least 2 distinct anatomical areas: for example, either 2 limbs; or a single limb and some axial portion of 
the body. Individuals with only axial lesions but involving 2 distinct anatomical areas that have no 
peripheral nervous system overlap are also eligible: for example, lesions involving a portion of the cranium 
and a portion of the trunk of the body. For purposes of this study, the axial portion will be defined as any 
non-appendicular portion of the body. 
2. If there is any history of a primary pruritic skin condition other than PN, that condition must have been 
inactive for at least 6 months prior to screening. 
3. Subjects with a history of acute secondary dermatoses within the preceding 6 months may enroll only if 
the dermatosis has resolved completely as follows per medical history or patient self-report and current 
clinical assessment: (a) Localized contact dermatitis, environmental exposures, superficial burns, or viral 
exanthems must have been resolved for at least 4 weeks prior to screening. (b) Skin or environmental 
infestations, such as scabies, lice, or bed bugs, must have been resolved for at least 8 weeks prior to 
screening. 
4. Any identified systemic, non-dermatologic disease that could be a potential cause of concomitant pruritus 
(e.g., thyroid disease, celiac disease, hepatitis C virus [HCV]) must either have resolved, been successfully 
treated (i.e., HCV RNA negative), or must be successfully managed with stable, optimized treatment 
(e.g., thyroid replacement, dietary management with resolution of symptoms, respectively) for at least 
3 months prior to screening. 
5. WI-NRS score, recorded daily over the 7 contiguous days prior to and including the day of the baseline 
visit via electronic diary, must have at least 5 measurements recorded and all individual measurements 
must be ≥ 6. The arithmetic mean value of the measurements must be ≥ 7 as confirmed by the Trialogics 
Eligibility Check report immediately prior to randomization. The last WI-NRS value used in the 
calculation should be recorded on the day of the baseline visit and prior to dosing. 
6. Subjects using antidepressants must be on a stable dose for a minimum of 4 weeks prior to screening and 
must be willing to remain on their stable dose for the entire duration of the study. 
7. Subjects who are human immunodeficiency virus (HIV) positive may enroll if they meet the following 
criteria: (a) currently on a stable (> 6 months stable use) and well tolerated highly active antiretroviral 
therapy regimen; (b) CD4 count > 500 cells/mL; and (c) HIV ribonucleic acid (RNA) < 50 copies/mL 
documented for at least 6 months prior to enrollment. If enrolled, these subjects should continue to have 
their CD4 and HIV RNA monitored by their HIV provider per their standard of care for the duration of 


Trevi Therapeutics, Inc. 
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21 July 2021 
Protocol TR11 
 
 
 
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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine extended release 
(NAL ER) tablets 
Name of Active Ingredient: 
Nalbuphine hydrochloride (HCl) 
the TR11 study, and the data should be reported and documented at the next study visit. 
8. Females of childbearing potential must be using an acceptable method of birth control (if sexually active) 
for 14 days prior to randomization and throughout the study. All females of childbearing potential must 
have a negative pregnancy test at the screening and baseline visits. 
For the purpose of this study, all females are considered to be of childbearing potential unless they are 
postmenopausal (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). 
Sexually active female subjects of childbearing potential are required to use 1 barrier method 
(e.g., condom, cervical cap, or diaphragm) of contraception in addition to 1 other method (e.g., intrauterine 
device in place at least 1 month, stable hormonal contraception for at least 3 months, or Essure procedure, 
or spermicide). 
Female subjects 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. 
9. Age 18 years and older at the time of consent, and a life expectancy of at least 18 months. 
10. Willing and able to understand and provide written informed consent. 
11. Willing and able to comply with study requirements and restrictions. 
12. Agree to the confidential use and storage of all data and use of all anonymized data for publication 
including scientific publication. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Pruritus due to localized PN (only 1 body part affected, for example only 1 arm). 
2. Active, uncontrolled, pruritic dermatoses in need of treatment (such as atopic dermatitis or bullous 
pemphigoid for example). 
3. Prurigo Nodularis associated with a history of atopic dermatitis is excluded if acute eczematous lesions 
are present, as characterized by erythematous, active predominant lichenified plaques with oozing and 
crusting. 
4. History of a major psychiatric disorder such as bipolar disorder or schizophrenia is excluded. Subjects 
with a history of isolated major depression > 3 years previously may be eligible for enrollment if they 
have access to appropriate psychiatric care. An ‘isolated major depression’ is defined as a single event of 
depression that includes recurrent thoughts of death, recurrent suicidal ideation with or without a specific 
plan, or any history of a suicide attempt. Enrollment must be approved by the Medical Monitor. Subjects 
with general depression who are considered stable may be enrolled. 
5. Serum bilirubin > 1.5 × upper limit of normal range at screening unless explained by a clinical diagnosis 
of Gilbert’s Syndrome. 
6. Serum hepatic alanine aminotransferase or aspartate aminotransferase enzymes > 100 U/L at screening. 
7. Estimated glomerular filtration rate ≤ 44 mL/min/1.73 m2 at screening. 
8. Significant medical condition, occupational restrictions (see Section 9.3), and/or other factors that in the 
opinion of the Investigator may interfere with the conduct of the study. 
9. Subjects who have an active malignancy (either solid tumor or hematologic) are excluded. Subjects who 
have a past history of malignancy and who have no evidence of active disease, but who continue on therapy 
to prevent disease recurrence (i.e., tamoxifen for breast cancer, testosterone blockade for prostate cancer, 
etc.), may be eligible if approved by the Medical Monitor. 
10. History of active substance abuse within the past 3 years. 
11. Known intolerance of, or hypersensitivity or allergy to nalbuphine or vehicle components. 
12. Pregnant or lactating females. 
13. Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a concurrent clinical trial. 
Potential subjects who are actively participating in the safety follow-up of an ongoing COVID-19 


Trevi Therapeutics, Inc. 
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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine extended release 
(NAL ER) tablets 
Name of Active Ingredient: 
Nalbuphine hydrochloride (HCl) 
vaccination trial may enroll in this study if they meet the following criteria: 
a. 
the vaccine under study has already been approved under an Emergency Use Authorization or 
via an equivalent regulatory review by the Health Authority in the country where they are 
enrolling; 
b. they have completed the full vaccination series and are participating in a safety observation 
period without anticipation of any further vaccine trial intervention; 
c. 
the COVID-19 trial permits co-enrollment. 
Medication-Related Exclusions: 
14. Known intolerance (gastrointestinal, central nervous system symptoms) or hypersensitivity/drug allergy 
to opioids. 
15. Potential subjects taking monoamine oxidase inhibitors are excluded, as concomitant opiate use may 
increase the risk for serotonin syndrome. 
16. Potential subjects taking cyclosporin A are excluded unless they undergo a 6-week washout. Subjects are 
prohibited from using cyclosporin during the study. Please refer to Table-3 (including footnote 3) and 
Section 9.1.3.1. 
17. Potential subjects taking non-insulin biologics (including monoclonal antibodies), which modify the 
immune system, are excluded unless they undergo a 3-month washout. Please refer to Table-3 (including 
footnote 3) and Section 9.1.3.1. 
18. Prior Exclusion criterion 18 is not applicable to subjects enrolling under Protocol V6 and later. 
19. Exposure to any investigational medication, including placebo requires a 4-week washout (3 months for 
noninsulin biologics [e.g., monoclonal antibodies]). Please refer to Table-3 and Section 9.1.3.1. 
20. Potential subjects receiving UV-therapy (PUVA, UVA, UVB, Excimer) requires a 4-week washout. 
Subjects are prohibited from using UV-therapy for the duration of the study. Please refer to Table-3 and 
Section 9.1.3.1. 
21. Potential subjects who are taking opiates require a 14 –day washout. Subjects are prohibited from using 
opioids, including naltrexone, for the duration of the study. Please refer to Table-3 and Section 9.1.3.1. 
22. Potential subjects receiving gabapentin, pregabalin, calcineurin inhibitors, cannabinoid agonists, 
capsaicin, cryosurgery, topical doxepin, thalidomide or methotrexate, topical antihistamines, and topical 
corticosteroids require a 14-day washout. These medications are prohibited for the duration of the study. 
Use of systemic antihistamines are not permitted unless the subject has been on a stable dose for at 
least 4 weeks prior to screening and there are no plans to change the dose during the study. Please refer 
to Table-3 and Section 9.1.3.1. 
23. Potential subjects who have received systemic corticosteroids or local steroid injections of the PN lesions 
require a 4-week washout. These medications are prohibited for the duration of the study. Please refer to 
Table-3 and Section 9.1.3.1. 
24. Potential subjects are excluded if they have had any addition or discontinuation of their regularly used 
prescription drugs, or any changes in the doses of their regularly used prescription drugs in the 14 days 
prior to the screening period e-diary WI-NRS collection. 
25. Potential subjects taking central nervous system suppressants, such as barbiturates, benzodiazepines 
(with the exception of short-acting benzodiazepines specifically used on an intermittent and as needed 
basis), anxiolytics other than benzodiazepines, neuroleptics, and clonidine are  excluded. These 
medications are prohibited for the duration of the study (see Section 10.6.2, footnotes 1 and 2 to Table-3 
for definitions of ‘short-acting benzodiazepines’). 
Cardiac-related Exclusions: 
26. Subjects with a history of congestive heart failure of Class 2 or higher as graded using the New York Heart 
Association scale. (see Appendix 9) 
27. Subjects with a history of angina pectoris Grade 2 or higher as graded using the Canadian Cardiovascular 
Society grading scale. (see Appendix 8) 
28. History of ventricular tachycardia, Torsade de Pointes, or family history of sudden death. 


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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine extended release 
(NAL ER) tablets 
Name of Active Ingredient: 
Nalbuphine hydrochloride (HCl) 
29. Myocardial infarction or acute coronary syndrome within the previous 3 months, as reported by the 
subject. 
30. Serum potassium below the laboratory lower limit of normal. Note: If the initial screening value is low, 
but not considered clinically significant in relation to cardiac risk, then potassium supplementation may 
be prescribed and the serum potassium level repeated once at least 2 weeks later, during the screening 
period. If the repeat potassium remains < LLN, then the subject must be screen-failed. 
31. QTcF interval > 450 ms (mean of 3 screening ECG QTcF values) if QRS <120 ms (mean of 3 screening 
ECG QRS values); QTcF interval >480 ms in the presence of Right Bundle Branch Block (RBBB) 
and/or QRS ≥ 120 ms.  
32. Heart rate < 45 bpm on any screening measurement either in the clinic or on the central ECG readings. 
33. Use of a medication having a “known risk” of Torsade de Pointes (categorized as “KR” on the Credible 
Meds® website; see Appendix 10) is not permitted unless the subject has been on a stable dose for at 
least 4 weeks prior to screening and there are no plans to change the dose during the study. 
34. Prior Exclusion 34 criterion is not applicable for subjects enrolling in Protocol V7 and later.  
Test Product, Dose and Mode of Administration: 
NAL ER tablets, 162 mg BID, orally administered 
Reference Therapy, Dose and Duration of Administration: 
Matching placebo, orally administered 
Duration of Treatment: 
Up to 52 weeks 
Assessments: 
Efficacy: 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the difference between the percent “Responders” at Week 14 for the NAL ER 
treatment arm versus the placebo arm. A “Responder” is defined as a subject with a ≥ 4-point decrease in the 7-day 
average WI-NRS from baseline to Week 14. 
Secondary Efficacy Endpoints 
Key secondary efficacy endpoints include the following: 
• 
The mean change in ItchyQoL from baseline to Week 14 for the NAL ER treatment arm versus the placebo 
arm 
• 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to Week 14 for the 
NAL ER treatment arm versus the placebo arm 
• 
The mean change in sleep disturbance (PROMIS Sleep Disturbance Short Form 8a) from baseline to 
Week 14 for the NAL ER treatment arm versus the placebo arm 
Other secondary efficacy endpoints include the following: 
• 
The mean change in 7-day average WI-NRS from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm 
• 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of healed lesions (item 5b) from baseline to Week 14 for the NAL ER treatment arm versus 
the placebo arm 
• 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage number of lesions (item 2) from baseline to Week 14 for the NAL ER treatment arm versus 
the placebo arm 
• 
Change in Investigator Global Assessment-Prurigo Nodularis (IGA-PN) as assessed by the percentage of 
subjects having a 1-category improvement in activity 
• 
Change in IGA-PN as assessed by the percentage of subjects having a 1-category improvement in stage 


Trevi Therapeutics, Inc. 
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21 July 2021 
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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine extended release 
(NAL ER) tablets 
Name of Active Ingredient: 
Nalbuphine hydrochloride (HCl) 
• 
The proportion of subjects having a PBI-P score of ≥ 1 at Week 14 for the NAL ER treatment arm versus 
the placebo arm 
Safety: All on-treatment safety data will be assessed descriptively based on the number and rates of adverse events 
(AEs), Serious AEs (SAEs), clinical laboratory measurements, central cardiac core laboratory read 12-lead ECGs, 
vital signs, and physical examinations. Subjects will also complete the Subjective Opiate Withdrawal Scale 
(SOWS) on a daily basis for the 2 weeks following the last dose of investigational product, whenever that occurs 
and regardless of the reason (unless consent is withdrawn). The totality of these data addresses the secondary 
objective of characterizing the overall safety and tolerability of NAL ER in subjects with PN. 
An independent Data Safety Monitoring Board will periodically review safety data. 
Pharmacokinetics: Nalbuphine plasma concentration and its metabolites. 
 
Statistical Methods: 
Sample Size and Power 
The original planned sample size of approximately 240 subjects (120 per group) was based on assumed responder 
percentages for placebo and NAL ER of 25% and 45%, respectively. These responder percentages represent 
estimates based on the Week 10 data from the TR03 study; taking into account the longer blinded treatment period 
in this study, and the range of placebo responses observed in the literature for studies using patient reported outcome 
scales in related fields such as pain and neuropsychiatric diseases. Power is set at 90% with a 2-sided significance 
level of 0.05. 
To address the concern of the reliability of the estimates of treatment effectiveness from the TR03 study, an adaptive 
mid-course Sample Size Re-Estimation (SSRE) procedure was introduced in Amendment 2, Protocol v3.1, when 
less than 10 subjects had been randomized. The analysis was to be performed after 50% of subjects (N=120) had 
either completed the Week 14 primary endpoint assessment or terminated the study early. Due to COVID 19- 
related delays, and because the key boundary for the lower margin of the SSRE did not differ if conducted at 45% 
of subjects, the SSRE was performed based on the Week 14 data for 109 subjects (including pre-Week 14 
discontinuations). The analysis was performed as planned by a single, external, unblinded statistician, and was 
presented and discussed at a closed session of the study DSMB (July 9, 2020). Based on the DSMB’s 
recommendation, the sample size for this study is being increased to 360 subjects since the SSRE conditional power 
fell within the ‘promising zone’ as defined by Mehta and Pocock.33 
Efficacy 
The proportions of NAL ER and placebo subjects that meet the primary endpoint definition of Responder (a 
≥ 4-point reduction of the 7-day average WI-NRS from baseline to Week 14) will be analyzed using a mixed- 
effects logistic regression model which will include the baseline WI-NRS score as a covariate. Study sites (pooled) 
will be treated as a random effect to account for possible correlation between subjects within a site. The analysis 
will be based on the modified intent-to-treat (MITT) population. The primary endpoint will also be analyzed using 
the per-protocol population as a sensitivity analysis to assess the impact of protocol deviations such as selected pre- 
specified concomitant medications that might affect the primary endpoint outcome. Subjects with missing data at 
Week 14 will be imputed to have non-responder status in the primary mixed-effects model. Strategies to address 
missing data will include multiple imputation and a completers analysis, which will be used as sensitivity analyses. 
Details will be described in the statistical analysis plan. 
For all open-label visits, descriptive statistics will be displayed by treatment. 
All secondary endpoints will be analyzed using the MITT population. The change from baseline in continuous 
endpoints (WI-NRS, ItchyQoL, PROMIS Sleep Disturbance Short Form 8a) up to Week 14 will be analyzed based 
on a mixed model for repeated measures analysis that includes the fixed effects of treatment, visit, treatment by 
visit interaction, and baseline value. The main treatment comparison of interest is at Week 14. For PAS, individual 
items will be presented with counts and percentages for categories by treatment group and visit; for 
excoriations/crusts, a logistic regression analysis will be performed for data at Week 14, with responders defined 
as subjects who had a ≥ 1-category improvement from baseline. For IGA-PN, individual items (PN Activity and 
PN Stage) will be presented with counts and percentages for categories by treatment group and visit; a logistic 
regression analysis will be performed for PN Activity at Week 14, with responders defined as subjects who had a 


Trevi Therapeutics, Inc. 
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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine extended release 
(NAL ER) tablets 
Name of Active Ingredient: 
Nalbuphine hydrochloride (HCl) 
≥ 1-category improvement from baseline. For PBI-P, the count and percentage of responders (defined as those 
with a PBI-P score of ≥ 1 at Week 14) will be presented by treatment group. For extension period visits, descriptive 
statistics will be displayed by treatment for all secondary variables. 
Safety 
The incidence of AEs will be summarized through the presentation of proportions by Medical Dictionary for 
Regulatory Activities (MedDRA) body system classification and preferred term. Vital signs and laboratory data 
will be summarized using descriptive statistics. The extent and duration of use of prohibited or restricted 
medications will be similarly summarized using descriptive statistics. No formal statistical analysis will be 
performed on safety outcomes; inferences, if any, will be derived through clinical review and interpretation. 
AEs of special interest that code to the most relevant abuse-related MedDRA preferred terms will be tabulated and 
brief descriptions will be written. Additional AEs that are considered “possibly related to abuse potential” will be 
tabulated separately. 
Electrocardiograms will be read centrally by specially trained staff at ERT® Clinical, with real-time feedback to 
clinical sites regarding any findings relevant to safety. Once the database is complete, ECG data (e.g., heart rate, 
PR, QTcF intervals etc.) will be presented in listings by subject and collection date/time. A complete ECG 
assessment will be documented in a separate ECG report from ERT Clinical. 
Pharmacokinetics 
Investigational product plasma concentration data (nalbuphine and metabolites) will be listed by collection time, 
as applicable. 
Two additional sets of analyses will be conducted and provided in separate reports: 1) Analysis and reporting of 
concentration results by Covance Laboratory; and 2) pharmacokinetic–pharmacodynamic (PK-PD) analyses to 
describe the exposure-response relationships between nalbuphine plasma concentrations and efficacy parameters. 
Additional PK-PD analyses may be conducted to include safety and/or tolerability parameters, as appropriate. 
Date of the Protocol: 21 July, 2021 (Version 7, Amendment 6) 


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5 TABLE OF CONTENTS 
Description 
Page 
Table of Contents 
Description 
Page 
1 
TITLE PAGE ......................................................................................................... 1 
2 
SIGNATURE PAGE ............................................................................................. 2 
3 
GENERAL INFORMATION .............................................................................. 3 
4 
STUDY SYNOPSIS ............................................................................................... 4 
5 
TABLE OF CONTENTS ................................................................................... 11 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................. 17 
7 
INTRODUCTION ............................................................................................... 20 
7.1 
General Information on Prurigo Nodularis .................................................... 20 
7.2 
Nalbuphine ........................................................................................................... 20 
7.2.1 
Preclinical Animal Data ...................................................................................... 21 
7.2.2 
Drug Metabolism and Pharmacokinetics of Nalbuphine in 
Humans ................................................................................................................. 22 
7.2.3 
NAL ER Clinical Safety Data ............................................................................ 23 
7.2.4 
Overview of NAL ER Efficacy........................................................................... 24 
7.3 
Rationale ............................................................................................................... 24 
8 
STUDY OBJECTIVES ....................................................................................... 25 
8.1 
Primary Objective ............................................................................................... 25 
8.2 
Secondary Objectives ......................................................................................... 25 
9 
INVESTIGATIONAL PLAN ............................................................................ 25 
9.1 
Overall Study Design and Plan ......................................................................... 25 
9.1.1 
Description ............................................................................................................ 25 
9.1.2 
Schedule of Assessments ..................................................................................... 27 
9.1.3 
Study Procedures and Assessments .................................................................. 36 
9.1.3.1 
Medication Washout and Screening Period (Week -6 through 
Week -1) ................................................................................................................ 36 
9.1.3.2 
Double-blind Titration Period (Weeks 1 and 2) ............................................. 37 
9.1.3.3 
Double-blind Fixed-dose Period (Weeks 3 to 14) ............................................ 39 
9.1.3.4 
Extension Titration Period (Weeks 15 and 16) ............................................... 41 


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9.1.3.5 
Open-label Fixed-dose Period (Weeks 17 to 52) ............................................. 42 
9.1.3.6 
Washout and Safety Follow-up Period and Last Contact ............................. 47 
9.2 
Rationale for Study Design ................................................................................ 49 
9.3 
Safety Monitoring ............................................................................................... 51 
9.4 
Risk/Benefit and Ethical Assessment ............................................................... 52 
9.5 
Selection of Study Population............................................................................ 54 
9.5.1 
Inclusion Criteria ................................................................................................. 54 
9.5.2 
Exclusion Criteria ................................................................................................ 55 
9.6 
Premature Discontinuation of Investigational Product 
Treatment ............................................................................................................. 58 
9.7 
Premature Withdrawal of Subjects from the Study ...................................... 59 
10 
TREATMENT OF SUBJECTS......................................................................... 59 
10.1 
Identity of Investigational Product ................................................................... 59 
10.1.1 
Administration of Study Treatments ............................................................... 60 
10.1.2 
Down-titration ...................................................................................................... 61 
10.1.3 
Multiple Missed Doses ........................................................................................ 61 
10.2 
Study Treatment Packaging and Labeling...................................................... 62 
10.2.1 
Labeling................................................................................................................. 62 
10.2.2 
Storage ................................................................................................................... 62 
10.2.3 
Blinding and Randomization of Study Treatments ........................................ 62 
10.3 
Procedure for Breaking the Randomization Code......................................... 62 
10.4 
Subject Compliance ............................................................................................ 62 
10.5 
Investigational Product Accountability ........................................................... 63 
10.5.1 
Special Procedures for Study Drug Delivery During Periods of 
COVID-19 Pandemic Restrictions .................................................................... 63 
10.6 
Concomitant Medications, Prohibited Medications, Pre-
Medications, Symptom Management, and Itch Intervention ...................... 64 
10.6.1 
Concomitant Medications................................................................................... 64 
10.6.2 
Prohibited Medications ....................................................................................... 64 
10.6.3 
Symptom Management during the Titration Period (Tolerability 
Intervention) ......................................................................................................... 68 
10.6.4 
Itch Intervention .................................................................................................. 68 
11 
EFFICACY AND PHARMACOKINETIC ASSESSMENTS ...................... 69 
11.1 
Endpoints.............................................................................................................. 69 


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11.1.1 
Primary Endpoint ................................................................................................ 69 
11.1.2 
Secondary Endpoints .......................................................................................... 70 
11.2 
Efficacy Assessments .......................................................................................... 71 
11.2.1 
Numerical Rating Scale for Itch........................................................................ 71 
11.2.2 
ItchyQoL ............................................................................................................... 71 
11.2.3 
Prurigo Activity Score ........................................................................................ 71 
11.2.4 
Investigator Global Assessment – Prurigo Nodularis .................................... 72 
11.2.5 
Patient Benefit Index ........................................................................................... 72 
11.2.6 
Sleep Scale............................................................................................................. 72 
11.2.7 
Photography ......................................................................................................... 72 
11.3 
Pharmacokinetic Assessments ........................................................................... 73 
12 
ASSESSMENT OF SAFETY............................................................................. 73 
12.1 
Adverse Events .................................................................................................... 74 
12.1.1 
Definitions ............................................................................................................. 74 
12.1.1.1 
Recording of Adverse Events ............................................................................. 76 
12.1.1.2 
Definition of Relationship to Investigational Product ................................... 77 
12.1.1.3 
Definition of Severity .......................................................................................... 78 
12.1.1.4 
Definition of Unexpected Adverse Event ......................................................... 78 
12.1.2 
Abnormal Laboratory Values, Vital Signs, Electrocardiograms, 
and Physical Examinations ................................................................................. 78 
12.1.3 
Deaths .................................................................................................................... 79 
12.1.4 
Overdose ............................................................................................................... 79 
12.1.5 
Pregnancy ............................................................................................................. 79 
12.1.6 
Reporting of Serious Adverse Events ............................................................... 79 
12.2 
Data Safety Monitoring Board .......................................................................... 80 
12.3 
Laboratory Assessments .................................................................................... 81 
12.4 
Electrocardiogram Assessments ....................................................................... 82 
12.5 
Physical Examination ......................................................................................... 83 
12.6 
Vital Signs............................................................................................................. 83 
12.7 
Subjective Opiate Withdrawal Scale................................................................ 83 
12.8 
Brief Neurological Assessment .......................................................................... 83 
13 
STATISTICAL EVALUATION ....................................................................... 84 
13.1 
Sample Size and Power ...................................................................................... 84 


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13.2 
Randomization .................................................................................................... 85 
13.3 
Statistical Analysis Sets ...................................................................................... 85 
13.3.1 
Modified Intent-to-treat Population ................................................................. 85 
13.3.2 
Per-protocol Population...................................................................................... 85 
13.3.3 
Safety Population ................................................................................................. 85 
13.4 
Statistical Methods .............................................................................................. 86 
13.4.1 
General Principles ............................................................................................... 86 
13.4.2 
Missing Data ......................................................................................................... 86 
13.4.3 
Demographic and Baseline Characteristics ..................................................... 86 
13.4.4 
Subject Disposition .............................................................................................. 86 
13.4.5 
Concomitant Medications................................................................................... 86 
13.4.6 
Efficacy Analyses ................................................................................................. 87 
13.4.6.1 
Analysis of Primary Endpoint ........................................................................... 87 
13.4.6.2 
Analysis of Secondary Endpoints ...................................................................... 87 
13.4.6.3 
Multiplicity Considerations................................................................................ 88 
13.4.6.4 
Interim Analysis (Adaptive Sample Size Re-estimation) ............................... 88 
13.4.7 
Safety Analyses..................................................................................................... 89 
13.4.7.1 
Adverse Events ..................................................................................................... 89 
13.4.7.2 
Vital Signs ............................................................................................................. 89 
13.4.7.3 
Clinical Laboratory Assessments ...................................................................... 90 
13.4.7.4 
Physical Examinations ........................................................................................ 90 
13.4.7.5 
Electrocardiograms ............................................................................................. 90 
13.4.8 
Pharmacokinetic Analyses ................................................................................. 90 
14 
DIRECT ACCESS TO SOURCE DATA/NOTES ......................................... 90 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .............................. 91 
15.1 
Conduct of the Study .......................................................................................... 91 
15.2 
Study Monitoring ................................................................................................ 91 
16 
ETHICS................................................................................................................. 92 
16.1 
Independent Ethics Committee/Institutional Review Board ........................ 92 
16.2 
Written Informed Consent ................................................................................ 92 
17 
DATA HANDLING AND RECORD KEEPING ........................................... 93 
17.1 
Case Report Forms/Source Data Handling ..................................................... 93 
17.2 
Retention of Essential Documents .................................................................... 93 


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18 
FINANCING AND INSURANCE .................................................................... 94 
19 
PUBLICATION POLICY .................................................................................. 94 
20 
SIGNATURE OF COORDINATING INVESTIGATOR .......................... 95 
21 
SIGNATURE OF INVESTIGATOR ............................................................. 101 
22 
REFERENCE LIST .......................................................................................... 102 
23 
APPENDICES .................................................................................................... 105 
 


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List of Tables 
Description 
Page 
Table-1. 
Schedule of Assessments – Double-blind, Placebo-controlled 
Period ............................................................................................................ 28 
Table-2. 
Schedule of Assessments – Open-label Extension Period...................... 32 
Table-3. 
Prohibited Medications and Washout Requirements ............................ 65 
Table-4. 
Clinical Laboratory Assessments .............................................................. 82 
 
List of Figures 
Description 
Page 
Figure-1. 
Study Design ................................................................................................. 27 
 
 
List of Appendices and Supplements 
APPENDIX 1 ITCHYQOLTM – ITCHING QUALITY OF LIFE SURVEY ...................... 106 
APPENDIX 2 PATIENT BENEFIT INDEX, PRURITUS VERSION ................................. 110 
APPENDIX 3 PROMIS SLEEP DISTURBANCE SHORT FORM 8A ............................... 113 
APPENDIX 4 SUBJECTIVE OPIATE WITHDRAWAL SCALE....................................... 115 
APPENDIX 5 WORST ITCH NUMERICAL RATING SCALE ......................................... 117 
APPENDIX 6 INVESTIGATOR GLOBAL ASSESSMENT – PRURIGO 
NODULARIS ..................................................................................................... 119 
APPENDIX 7 PRURIGO ACTIVITY SCORE QUESTIONNAIRE ................................... 121 
APPENDIX 8 CANADIAN CARDIOVASCULAR SOCIETY GRADING OF 
ANGINA PECTORIS ....................................................................................... 124 
APPENDIX 9 CLASSIFICATION CRITERIA FOR CONGESTIVE HEART 
FAILURE............................................................................................................ 126 
APPENDIX 10 LIST OF DRUGS THAT PROLONG QT AND/OR CAUSE 
TORSADES DE POINTES .............................................................................. 128 
APPENDIX 11 NOT APPLICABLE ......................................................................................... 129 
APPENDIX 12 SUMMARY OF CHANGES: AMENDMENTS 1, 2, 3, 4, 5, 6 ................... 130 
 
 


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6 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
BMI 
Body mass index 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
e-diary 
Electronic diary 
ER 
Extended release 
EU 
European Union 
EudraCT 
European Union Drug Regulatory Agency Clinical Trial 
FDA Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HCl 
Hydrochloride 
HCV 
Hepatitis C virus 


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HD 
Hemodialysis 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFSI 
International Forum for the Study of Itch 
IGA-PN 
Investigator Global Assessment-Prurigo Nodularis 
IgA-TTG 
Immunoglobulin A tissue transglutaminase 
IRB 
Institutional Review Board 
IND 
Investigational New Drug 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LFT 
Liver function test 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MITT 
Modified intent-to-treat 
NAL 
Nalbuphine hydrochloride 
n 
number of available observations 
NRS 
Numerical Rating Scale 
OTC 
Over-the-counter 
PAS 
Prurigo Activity Score 
PBI-P 
Patient Benefit Index, pruritus version 
PCC 
Positive comparative control 
PK 
Pharmacokinetic 


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PK-PD 
Pharmacokinetic-pharmacodynamic 
PN 
Prurigo Nodularis 
PP 
Per-protocol 
PRO 
Patient-reported outcome 
RNA 
ribonucleic acid 
QD 
Once daily 
QoL 
Quality of life 
q4wk 
every 4 weeks 
q8wk 
every 8 weeks 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SHBG 
Sex hormone binding globulin 
SOWS 
Subjective Opiate Withdrawal Scale 
SubP 
Substance-P 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UP 
Uremic Pruritus 
US(A) 
United States (of America) 
UV 
Ultraviolet 
W 
Week 
WHO 
World Health Organization 
WI-NRS 
Worst Itch Numerical Rating Scale 
WOCBP 
Woman of childbearing potential 


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7 INTRODUCTION 
7.1 
General Information on Prurigo Nodularis 
Prurigo Nodularis (PN) is an intensely pruritic dermatologic condition with the presence of 
nodular pruriginous lesions with excoriations and ulcerations, together with other types of 
pruriginous lesions such as papules and/or plaques1. While triggering pathology of varying 
etiologies may have preceded and initiated the itch-scratch cycle that leads to PN, once the 
distinct pruriginous lesions evolve, there has been a neuronal sensitization process that is now 
self-sustaining. The clinical persistence and further evolution of PN now depends on the 
sustained scratch-itch cycle. Therefore, PN can and often does exist in the absence of an 
ongoing, separate, triggering pathology. Moreover, the initial triggering etiology may never have 
been identified, and often is no longer identifiable when the subject is initially diagnosed with 
PN2,3,4. 
With regard to the types of preceding conditions that are associated with chronic pruritus and that 
have been reported as part of the clinical history of subjects with PN, pruritus secondary to multi- 
factorial etiologies (“mixed origin”) was the most common pattern identified for “trigger” events. 
The majority of the “mixed origin” subjects had a combination of dermatological and systemic 
diseases or a combination of several systemic disorders. 
There is no approved agent or treatment modality which has Health Authority labeling supporting 
its use in PN. In the literature generated by expert clinicians in this field, a variety of treatment 
options and medical interventions have been discussed, generally relying on evidence from case 
reports and treatment experience with modest case series. A review of the therapies that included 
topical, systemic, and intra-lesion steroid administration; antihistamines; anxiolytics; opiate 
receptor antagonists; thalidomide; gabapentin; capsaicin cream; topical anesthetics; occlusive 
therapies; ultraviolet (UV) light was performed, and reported that they had “mild to moderate 
success at best”5. Prurigo Nodularis has been described as a debilitating condition and a 
therapeutic challenge, for which conventional treatments with steroids, standard anti-pruritic 
agents, phototherapy and immune-suppressors often fail6. 
7.2 
Nalbuphine 
Trevi Therapeutics, Inc. is developing an oral pharmaceutical product, nalbuphine hydrochloride 
(HCl) extended release (NAL ER) tablet which is currently in development for the treatment of 
PN. Nalbuphine is currently only available as a generic medication in an injectable form; no oral 
formulation of the drug is approved for any medical indication. 
The commercially available approved drug product was first marketed in 1979 in the United States 
(US) as Nubain®, on which the presently sold generic injectable formulations are based. Approved 
indications in the US include: the relief of moderate to severe pain, as a supplement to balanced 
anesthesia, pre-operative and post-operative analgesia, and obstetrical analgesia during labor and 
delivery. Commercial availability in the European Union (EU) dates to 1986, with approved 
indications for short-term relief of moderate to severe pain and pre- and post-operative analgesia. 
The most recent renewal evaluation for the current generic parenteral product in the EU was in 
2010 by the Medicines Evaluation Board in the Netherlands7. Nalbuphine remains an unscheduled 


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drug with respect to the US Drug Enforcement Agency8 and as of 2008, was not considered a 
controlled drug in most European countries including Austria, France, Germany, and Poland9. 
The nalbuphine moiety is a derivative of 14-hydroxymorphine and is structurally related to the 
opioid μ-receptor agonist oxymorphone and the opioid μ-receptor antagonist naloxone. The 
pharmacologic mechanism of action has 2 components, with competitive antagonism of the opioid 
μ-receptor and simultaneous agonism at the opioid κ-receptor10,11,12. Imbalance of activity across 
the μ- and κ–opioid system has been associated with severe, chronic itch conditions and there is 
a substantial literature suggesting that agonism of κ–receptors may have a therapeutic benefit in 
these settings13. The κ–agonist, nalfurafine, has been approved in Japan for the treatment of itch 
associated with both Uremic Pruritus (UP)14 and chronic liver diseases including primary biliary 
cholangitis. 
7.2.1 
Preclinical Animal Data 
A preclinical investigation was undertaken to demonstrate the effects of nalbuphine HCl on 
substance-P (SubP) induced scratching behavior in the mouse, a standard animal model for itch15. 
Scratching behavior induced by peripheral stimulation with the pruritogen SubP mimics the 
characteristics of itch-related scratching in humans15,16. Significant reduction in itch (P < 0.001) 
was noted following nalbuphine subcutaneous administration with approximately 43% reduction 
in itch at a 10-mg/kg dose and 52% at a 30-mg/kg dose. 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 shown to be as effective as the positive comparative control 
(PCC), nalfurafine, at reducing SubP-induced itch, with no statistical difference between 
nalbuphine and PCC effect, regardless of the dose. 
The oral bioavailability of nalbuphine solution was low in rats and dogs (~5%), largely due to 
substantial first pass metabolism. Absorption was rapid with maximum plasma concentrations 
(Cmax) achieved in both species between 20 and 30 minutes after dosing. The mean half-life of 
nalbuphine in rats and dogs was ~1 hour. 
In vitro inhibition studies demonstrated that nalbuphine does not inhibit any of the major 
cytochrome P450 isozymes. Thus, the potential for a metabolism-based interaction of nalbuphine 
on other drugs is unlikely. 
Several oxidative and conjugated metabolites of nalbuphine were identified in all species tested, 
with no metabolites being unique to humans. The metabolites have weak to no pharmacological 
activity and are unlikely to contribute to the drug activity in vivo. 
 


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7.2.2 
Drug Metabolism and Pharmacokinetics of Nalbuphine in Humans 
Nalbuphine is well absorbed in humans following oral administration of NAL ER tablets. 
Following single and multiple oral doses, exposure was dose-dependent and increased with 
increasing dose in a near dose proportional manner. Median Cmax occurred between 3 and 6 hours 
postdose, with mean half-life varying between 6.6 and 9.6 hours which supports twice daily (BID) 
dosing. Steady state exposure is achieved within 2 to 3 days following repeat-dosing with a stable 
regimen. In common with high clearance drugs in general and opioids in particular, the absolute 
bioavailability following administration of an oral solution was low and highly variable17. The 
low oral bioavailability is likely due to extensive first pass metabolism and is similar across all 
species studied (see Section 7.2.1). The inter-subject variability of nalbuphine pharmacokinetic 
(PK) parameters (area under the curve and Cmax) was high, with lower intra-subject variability, 
which is consistent with extensive hepatic metabolism. 
Nalbuphine elimination is consistently reported to be slower following oral compared to 
intravenous (IV) administration. The prolonged elimination half-life of nalbuphine associated 
with oral administration is most likely due to enterohepatic circulation. 
Several clinical single- and multiple-dose PK studies and clinical efficacy itch studies of 2 to 12-
month duration have been conducted with a range of NAL ER doses (27 to 162 mg BID). 
Clinical data in itch and pharmacokinetic-pharmacodynamic (PK-PD) modelling both support the 
decision to take the 162 mg BID dose forward into future studies in itch, given the benefit-risk 
profile as observed to date. 
The 162 mg BID dose selection was further corroborated by the exposure-response model for itch 
intensity (Worst Itch – Numerical Rating Scale [WI-NRS] using the Study TR03 PN dataset) and 
PK-PD simulations over dosing regimens of 81 to 216 mg BID. The exposure- response modelling 
provided evidence that nalbuphine exposures were associated with improved itch score responses 
and that a dose of 162 mg BID was the most optimal for achieving maximal efficacy reductions in 
Numerical Rating Scale (NRS) for itch from baseline. Doses higher than 162 mg were predicted 
to contribute minimal additional efficacy. 
The safety profile of the NAL ER 162 mg BID dose was comparable to the 81 mg BID dose, and 
there was no obvious indication of either a dose-associated increase in adverse events (AEs) or in 
discontinuations due to AEs, beyond the titration period. Consequently, given its better efficacy 
profile, the NAL ER 162 mg BID dose (with appropriate titration to that dose) was considered a 
better candidate for future study. 
Based on previous clinical observations in itch and the convergence of the PK-PD simulations, the 
selected dose of 162 mg of NAL ER is expected to show a significant improvement in 
PN-associated pruritus in this study. Lower doses are not expected to provide meaningful relief 
from itch in a significant number of subjects. 
 


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7.2.3 
NAL ER Clinical Safety Data 
The most frequently reported AEs in clinical trials to date have been central nervous system (CNS) 
and gastrointestinal (GI) symptoms. Specifically, the following events are considered potentially 
drug related: nausea, only in a minority of cases associated with vomiting; dizziness; somnolence, 
and headaches. Distinct from the opiate class in general, constipation has not been observed as a 
frequent or clinically troublesome AE in PN clinical trials with NAL ER. Thus, the overall safety 
profile observed with NAL ER is consistent with that typically associated with the mixed agonist- 
antagonist opioid class drugs10. Most of the AEs noted in the study program have been mild to 
moderate in severity, and tended to occur within the first weeks of dosing. It is thought that a slow 
initial titration to the target therapeutic dose may help induce tolerance, thereby minimizing the 
frequency and severity of these CNS and GI side effects (as the nausea may in part be mediated 
through CNS mechanisms). Therefore, in clinical trials with NAL ER in adults with PN, dosing 
begins with 27 mg taken once at bedtime and progresses over a 2-week titration period to the full 
dose of 162 mg BID. 
The above summary provides the key clinical safety observations that have been observed to date 
in studies of NAL ER. In the TR11 study, 2 organ systems - endocrine and cardiac - are being 
further evaluated. Thyroid stimulating hormone (TSH) and testosterone levels (men only), and 
electrocardiogram (ECG) monitoring are performed at specified intervals. The background and 
rationale for these 2 organ system evaluations are provided below: 
• Case reports and small prospective datasets for several orally administered opiates used in 
chronic disease management have shown evidence for associated endocrine alterations in 
humans. In the US, these data have resulted in mandatory class labeling but this class warning 
does not appear in EU labeling at the current time. The US warning addresses: (1) the potential 
for serotonin syndrome when opiates are used concomitantly with certain antidepressants (this 
study excludes monoamine oxidase inhibitors); (2) rare cases of adrenal insufficiency; and (3) 
a risk for lowered sex hormone levels. For nalbuphine, standard animal toxicology studies did 
not show any signal for endocrine toxicity based on the gross and microscopic findings in 
endocrine organs. To date, no cases of serotonin syndrome have been observed, and no cases 
of adrenal insufficiency, or abnormal endocrine levels have been attributed to nalbuphine use 
in NAL ER studies. 
Definitive data on NAL ER’s effect on cardiac conduction is not yet available from a thorough 
QT study. In this setting, the ECG procedures and enrollment criteria are a standard precaution 
appropriate for long-term studies. In previous clinical efficacy studies conducted by the sponsor 
(TR02 and TR02EXT in UP, and TR03 and TR03EXT in PN), independent reviews of ECG data 
were performed by a blinded reviewer. These reviews found no evidence that nalbuphine 
meaningfully prolongs cardiac repolarization. Heart rate changes were overall small and did not 
suggest an effect by nalbuphine at any of the studied doses. The benign ECG observations from 
these prior clinical studies are supported by the preclinical in vitro study in the human ether-à-go-
go-related gene assay, in which nalbuphine exhibited an inhibitory effect at concentrations that far 
exceed the nalbuphine plasma Cmax by approximately 200-fold. 


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In summary, there are no nonclinical or clinical data suggesting that either of these endocrine and 
cardiac concerns is of specific relevance to NAL ER. 
7.2.4 
Overview of NAL ER Efficacy 
The Phase 2 Study TR02 evaluated 2 doses (54 mg and 108 mg) of NAL ER versus placebo for 
the treatment of moderate to severe UP in 371 subjects on chronic hemodialysis (HD). The blinded 
treatment duration was 8 weeks, and results demonstrated both a dose response across the 2 NAL 
ER groups, and a significant difference in the change from baseline in the mean NRS values for 
the NAL ER 108 mg BID dose group versus placebo (difference of -0.73; P value 0.017). For the 
subset of subjects with severe UP (NRS ≥ 7) at baseline, the treatment difference was larger 
(difference of -1.39; P value 0.007). 
The Phase 2 Study TR03 evaluated 2 doses of NAL ER versus placebo for the treatment of 
moderate to severe itch in the setting of established PN. This randomized, double-blind study 
evaluated 2 doses of NAL ER (81 mg and 162 mg BID) versus placebo across a total of 62 treated 
subjects with moderate to severe itch (WI-NRS ≥ 5). The total treatment duration was 10 weeks, 
including an initial 2-week titration period. The primary endpoint was the proportion of subjects 
with a reduction in the 7-day WI-NRS from baseline to the Week 10 assessment interval of ≥ 30%. 
Although the primary endpoint was not met (NAL ER 162 mg: 44% responders versus placebo 
36%; P = 0.323), a secondary analysis of the completers subset did differentiate NAL ER 162 mg 
versus placebo (67% versus 40% [P = 0.063]). Assessing “responders” as those with a 50% 
reduction in WI-NRS from baseline showed greater discrimination, with 33% responders for NAL 
ER 162 mg versus 18% for placebo (P = 0.083) in the modified intent-to-treat (MITT) analysis 
and rates of 50% for NAL ER 162 mg versus 20% for placebo (P = 0.028) in a completers analysis. 
Subjects who completed TR03 had the option to rollover into a separate open-label study, TR03 
Extension, which provided a single arm experience using NAL ER with flexible dosing based on 
tolerability, and a total duration that could be as long as 1 year depending on when the subject 
moved from the qualification period into the active treatment period. Thirty-six subjects received 
treatment in this rollover study; 21 and 16 subjects completed 6 months and 1 year of treatment, 
respectively, though not all had complete data at both time points. Results across serial Prurigo 
Activity Score (PAS) assessments of the prurigo lesions showed that 10/18 subjects at 6 months 
and 9/15 subjects at 1 year had a ≥ 1 category improvement in excoriations/crusts. Similarly, 11/18 
and 7/15 subjects had a ≥ 1 category improvement in lesion healing at 6 months and 1 year, 
respectively. 
7.3 
Rationale 
In summary, Trevi has selected PN as the focus of the clinical development plan for NAL ER 
because the neuro-pharmacology of nalbuphine appears to be particularly well suited to address 
the pathophysiology of PN. In this chronic disease, the itch-scratch cycle, once established, 
results in a self-perpetuating neurologic pattern involving not just the skin itself, but importantly 
the signal processing from skin to spinal cord, spinal cord to brain, and back again. Moreover, 
the totality of the clinical efficacy data in subjects across 2 severe itch conditions provides a 
strong empiric rationale to further investigate the effects of NAL ER in subjects with PN. 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 25 of 176 
 
This study will be conducted in compliance with the protocol and with the International 
Conference on Harmonisation (ICH) guidelines on GCP. 
8 STUDY OBJECTIVES 
8.1 
Primary Objective 
• To evaluate the effect of NAL ER on itch as assessed by the percentage of Responders 
(‘response’ is defined as a ≥ 4-point reduction in the 7-day average WI-NRS) 
8.2 
Secondary Objectives 
Key secondary objectives are as follows: 
• To evaluate the effect of NAL ER on itch-related quality of life as assessed by the ItchyQoL 
total score 
• To evaluate the effect of NAL ER on PN skin lesions as assessed by the PAS Question 5a 
• To evaluate the effect of NAL ER on sleep as assessed by the PROMIS Sleep Disturbance 
Short Form 8a 
Other secondary objectives are as follows: 
• To evaluate the effect of NAL ER on itch as assessed by the mean change in WI-NRS 
• To evaluate the benefit to subjects of NAL ER using the Patient Benefit Index, pruritus version 
(PBI-P) 
• To characterize the safety and tolerability of NAL ER 
• To assess the PK of nalbuphine and its metabolites 
9 INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This is a randomized, double-blinded, placebo-controlled, 2-arm study, with an open-label 
extension period following double-blind treatment, to investigate the anti-pruritic efficacy and 
safety of NAL ER tablets. Eligible subjects will be randomized to NAL ER (2-week titration 
followed by 162 mg BID for 12 weeks) or matching placebo (14 weeks duration), with the 
primary endpoint evaluation at Week 14. If permanent discontinuation of investigational product 
occurs anytime between Day 1 and the Week 14 visit, the subject must be asked to complete the 
Off-Treatment visit, the Last Visit, the End of Study telephone call, and to return to the clinic for 
the study planned Week 14 visit (unless consent is withdrawn). During the open-label extension, 
subjects who received NAL ER will continue on NAL ER for a total of 38 additional weeks 
(total treatment duration 52 weeks including titration) and subjects who received placebo will 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 26 of 176 
 
crossover to NAL ER for a total of 38 weeks (including titration). Upon discontinuation of 
investigational product, all subjects will complete the 2-week off-treatment and safety follow-up 
period, regardless of when and why the subject discontinued study treatment, unless they 
withdraw consent. In addition, a final follow-up itch and safety assessment will be made via the 
End of Study telephone call 4 weeks after the last dose of investigational product. The total 
planned study duration from randomization through to the last telephone contact is 56 weeks. 
Approximately 360 subjects with diagnosed PN will be randomized (1:1) to one of the following 
treatment arms: 
Arm 1: Blinded active titration over 2 weeks (to achieve a final NAL ER dose of 162 
mg) followed by 162 mg BID for 12 weeks with continuation into the extension titration 
period (blinded), and the open-label fixed-dose period, followed by a 2-week off-
treatment safety follow-up period and a final telephone contact, for itch and safety 
assessment, 4 weeks after investigational product discontinuation. 
Arm 2: Placebo “titration” over 2 weeks followed by placebo BID for 12 weeks with 
continuation into the extension titration period (blinded; to achieve a final NAL ER 
dose of 162 mg) and the open-label fixed-dose period (NAL ER 162 mg), followed by a 
2-week off-treatment safety follow-up period and a final telephone contact, for itch and 
safety assessment, 4 weeks after investigational product discontinuation. 
At the regularly scheduled study visits for Week 28, Week 32, and Week 36, an elective dose 
reduction to a 108 mg NAL ER BID dose may be considered for subjects who achieve a confirmed 
WI-NRS ≤ 3 and visible lesion healing as assessed by an improvement of at least 1 category in 
the PAS Item 5b lesion healing activity score (e.g. if “0-24%” of PN lesions at baseline were 
assessed as ‘healed’, then a 1-category change means that “25-50%” of current Week 28 PN 
lesions are now healed). The decision to reduce dose is at the discretion of the Investigator and 
with the agreement of the subject. Dose reduction is not permitted prior to Week 28 or after Week 
36 and once this dosing has started, no re-escalation will be permitted. 
The study design schematic is presented in Figure-1. 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 27 of 176 
 
 
Figure-1. 
Study Design 
BID: twice daily; D: day; NAL ER: Nalbuphine 162 mg extended release; WI-NRS: Worst Itch – Numerical Rating 
Scale; W =week. 
 
9.1.2 
Schedule of Assessments 
The schedule of assessments is presented in Table 1 and Table 2. 
 
Randomization 
00 
C: 
Primary Efficacy Endpoint 
' 
NALER 162*81D 
C: 
0 
:.:; ,,,_ 
C: 
* ::: 180 mg Nalbuphin~ HCI 
... "t, 
cu 
I- "t, 
... C: 
cu= 
> .0 
Wk-6 
CV 
!!! 
u 
V) 
t 
t 
01 
Wk2 
.2-
0 a: 
t 
Wk14 
Final WI-NRS ' 
32 
36 
44 
Wk28 
Wk56 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 28 of 176 
 
Table-1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening and 
Washout1,2 
Double-blind Titration 
Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titratio n 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
 
 
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611 
Weeks 17 to 52 
Study Day (±2 days*; Day 
14 and Day 112: 
-2 days ONLY)14 
Up to Day -1 
1 
3 
7 
14 * 
15 
21 
42 
70 
98 
101 
105 
112 * 
Days 113 to 
364 
Informed consent13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Refer to Table-2 
for schedule of 
open-label 
extension period 
Medical, neurological, and 
Prurigo Nodularis history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Brief neurological 
assessment 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Vital signs3 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Height, weight, and 
BMI15 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Central ECG4 
(triplicate) 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
Clinical Laboratory 
assessments5 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Tolerability 
Intervention 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy5 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Inclusion/exclusion criteria1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization via IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood for PK assessment 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Record and assess 
AEs/AESIs, concomitant 
medications, and therapies 
(including restricted and 
prohibited medications) 6 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 29 of 176 
 
Table-1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening and 
Washout1,2 
Double-blind Titration 
Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titratio n 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
 
 
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611 
Weeks 17 to 52 
Study Day (±2 days*; Day 
14 and Day 112: 
-2 days ONLY)14 
Up to Day -1 
1 
3 
7 
14 * 
15 
21 
42 
70 
98 
101 
105 
112 * 
Days 113 to 
364 
e-diary7 – Dispense and 
train/review use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
e-diary – retrieve and 
review use and entry 
compliance7 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Dispense Subject 
Medication Log and 
Subject Symptom Log6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Retrieve/review/re- 
dispense Subject 
Medication Log and 
Subject Symptom Log6 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
ItchyQoL7 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
PAS and IGA-PN 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
PBI-P7 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Sleep Scale (PROMIS)7 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
WI-NRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Photography8 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Dispense investigational 
product 
 
Card 12 
 
 
B 
 
 
B 
B 
Car d 
 
 
B9 
Dispense Instructions for 
Taking TR11 Study 
Medication12 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Retrieve investigational 
product and containers 
 
 
 
 
 
NA9 
 
 
B + 
Card 
 
B 
 
B 
 
 
 
NA11 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 30 of 176 
 
Table-1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening and 
Washout1,2 
Double-blind Titration 
Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titratio n 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
 
 
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611 
Weeks 17 to 52 
Study Day (±2 days*; Day 
14 and Day 112: 
-2 days ONLY)14 
Up to Day -1 
1 
3 
7 
14 * 
15 
21 
42 
70 
98 
101 
105 
112 * 
Days 113 to 
364 
Investigational product 
accountability 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Investigational product 
- review dosing compliance 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
AE: adverse event; B: bottle; BMI: body mass index; Card: blister card; D: Day; ECG: electrocardiogram; e-diary: electronic diary; IGA-PN: Investigator Global Assessment-
Prurigo Nodularis; IWRS: Interactive Web Response System; LFT: liver function test; NA: not applicable; PAS: Prurigo Activity Score; PBI-P: Patient Benefit Index, pruritus 
version; PK: pharmacokinetic; PRO: patient-reported outcome; q4wk: every 4 weeks; SHBG: sex hormone binding globulin; SOWS: Subjective Opiate Withdrawal Scale; 
TSH: thyroid stimulating hormone; W: Week; WI-NRS: Worst Itch – Numerical Rating Scale; WOCBP: woman of childbearing potential; : telephone call. 
1. If clinically indicated, screening procedures may be completed over multiple visits (such as needed for washout of medications intended for anti- pruritic treatment) as long 
as they occur within the screening period. However, if the subject meets all inclusion/exclusion criteria, they should be randomized as soon as possible after meeting study 
requirements, but no later than 6 weeks after the initial screening visit. Except in cases of medication washout, the baseline (randomization) visit can take place in as little as 
7 days after all screening procedures have been performed, the required testing results have been obtained, and eligibility has been verified. 
2. If a medication washout is required, WI-NRS collection should begin following completion of the washout. 
3. Vital signs are to be obtained after the subject has been seated for at least 5 minutes. 
4. ECGs are to be performed in triplicate (3 serial ECGs at least 1 minute apart) after the subject has been in the supine position for at least 5 minutes. ECGs are to be 
transmitted to be read centrally by a core ECG laboratory. The average of the QTcF values from the triplicate ECGs wil be performed and presented in a report to be used as 
the final eligibility assessment for the subject, 
5. Laboratory Evaluations: Hematology and serum chemistry, LFTs, specified endocrine tests (at screening and Week 14 only: TSH, with reflex free T4 if above Upper Limit 
Normal (ULN) or below Lower Limit Normal (LLN), free testosterone [the fraction not bound to SHBG or albumin] and SHBG for males), and serum pregnancy test if 
WOCBP (regardless of sexual status at screening and baseline); urine pregnancy test to be performed by the local laboratory and confirmed to be negative prior to dispensing 
investigational product. TSH values above the upper limit of normal (ULN) should be repeated at the next study visit (or approximately 1 month later; whichever occurs first). 
If TSH remains above ULN, a Free T4 will be performed on the existing laboratory sample. 
6. AEs are to be continually assessed starting with the signing of the informed consent. Concomitant medications should be collected from 14 days prior to the signing of consent. 
During the screening visit, subjects must be instructed to record any new AEs or concomitant medication use on the Subject Symptom Log and Subject Medication Log and 
to bring the logs to every visit (including the telephone contacts). Site to retrieve and review these logs at each subsequent visit prior to re­dispensing them or issuing new logs 
to the subject. Events of special interest should trigger the collection of additional information using the AESI worksheet and documented under the AESI section of the 
Adverse Event eCRF. Event details and both subject and investigator narratives should be thoroughly documented in the AESI worksheet and completed under the AESI 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 31 of 176 
 
Table-1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening and 
Washout1,2 
Double-blind Titration 
Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titratio n 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
 
 
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611 
Weeks 17 to 52 
Study Day (±2 days*; Day 
14 and Day 112: 
-2 days ONLY)14 
Up to Day -1 
1 
3 
7 
14 * 
15 
21 
42 
70 
98 
101 
105 
112 * 
Days 113 to 
364 
section of the Adverse Event eCRF. Refer to section 12.1.1. Definitions. 
7. During screening, the e-diary must be dispensed to minimally allow for 7 contiguous days of WI-NRS collection prior to the baseline visit (collection during this period 
provides formal study data required for randomization). The e-diary administers the WI-NRS, medication compliance, and SOWS when applicable. Other PROs (Itchy 
QoL, PBI-P, and PROMIS sleep scale) are collected at select visits as described in Section 11.2. PROs administered during screening, but prior to Day -7, are to familiarize the 
subject to the instruments only, and not for the purpose of data collection. If multiple visits occur during the screening period, collection of these data (WI-NRS and PROs) 
should begin at the visit prior to the Week 1 baseline visit. Throughout the double-blind period, the subject is to record the WI-NRS data daily; daily WI-NRS data collection 
via the e-diary or in the Trialogics web portal ends at the Week 14 visit. 
8. Photography to be performed at selected sites only. See the Canfield Quick Reference Guide and the User Reference Manual for photography procedures as applicable. 
9. The Double-blind Titration blister card will be reviewed, but not be retrieved at this visit. See the Pharmacy Manual and Instructions for Taking TR11 Study Medication 
for additional instructions. 
10. Subjects who discontinue investigational product for any reason (other than withdrawal of consent) prior to the Week 14 visit must be asked to complete the 
Off-Treatment visit, the Last Visit, and the End of Study telephone call and to return to the site for their study schedule planned Week 14 visit at study Day 98 (see Table-2). 
11. The Open-Label Titration blister card will be reviewed, but not retrieved, at this visit. See the Pharmacy Manual and Instructions for Taking TR11 Study Medication for 
additional instructions. 
12. Site to dispense the Instructions for Taking TR11 Study Medication as applicable to the subject’s dosing period (i.e., Double-blind titration blister card or Double-blind fixed 
dose bottle). Note: Although both AM and PM doses are present on Day 1, only the PM dose will be taken (both Arms) 
13. At the time of informed consent, subjects identified as taking a concomitant short-acting benzodiazepine should be provided with the Benzodiazepine Patient 
Information Sheet, informing them of safety information and warnings regarding the use of NAL ER in combination with this class of drug. Likewise, any subject who is 
subsequently prescribed short-acting benzodiazepines during the course of the study should also be provided with this information sheet. 
14. At study Day 14 and Day 112, the titration card only contains 14 days of dosing. Subjects should be scheduled to come in on the target date or up to 2 days prior to ensure 
not to run out of investigational product. 
15. Height and BMI will be obtained at the screening visit only. Weight will be obtained at the screening visit and subsequently according to the schedule. 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 32 of 176 
 
Table-2. 
Schedule of Assessments – Open-label Extension Period 
Study Period → 
 
 
Open-label Fixed-dose Period 
Washout and Safety Follow- up 
Period 
Last Contact for 
WI-NRS 
Assessment ↓ 
Repeating visit q4wk or q8wk 
Off- 
Treatment1 
Last Visit1 
End of Study 
telephone call1 
W17 to W52 
Visit Week 
17 
17 
20 
24 
282 
322 
362 
44 
52 
54 
56 
Study Day (±2 days) 
113 
120 
140 
168 
196 
224 
252 
308 
364 
378 
392 
Physical examination 
 
 
 
 
 
 
 
 
X 
X 
 
Brief neurological 
assessment 
 
 
 
 
 
 
 
 
X 
X 
 
Vital signs3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
 
 
X 
 
 
X 
X 
X 
 
Central ECG4 
 
 
X 
 
X 
 
 
 
X 
 
 
Clinical Laboratory 
assessments5 
 
 
 
 
X 
 
 
X 
X 
X 
 
Blood for PK 
assessment 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
 
 
 
X 
 
 
 
X 
 
 
Urine pregnancy 
(WOCBP) 
 
 
X 
X 
X 
X 
X3 
X 
X 
X 
 
Record and assess 
AEs/AESIs6, 
concomitant 
medications, and 
therapies (including 
restricted and 
prohibited medications) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Tolerability 
intervention 
X 
X 
 
 
X 
 
X 
 
 
 
 
e-diary7 – 
retrieve and/or 
review entry 
compliance 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 33 of 176 
 
Table-2. 
Schedule of Assessments – Open-label Extension Period 
Study Period → 
 
 
Open-label Fixed-dose Period 
Washout and Safety Follow- up 
Period 
Last Contact for 
WI-NRS 
Assessment ↓ 
Repeating visit q4wk or q8wk 
Off- 
Treatment1 
Last Visit1 
End of Study 
telephone call1 
W17 to W52 
Visit Week 
17 
17 
20 
24 
282 
322 
362 
44 
52 
54 
56 
Study Day (±2 days) 
113 
120 
140 
168 
196 
224 
252 
308 
364 
378 
392 
Retrieve/revie
w/re- dispense 
Subject 
Medication 
Log and 
Subject 
Symptom 
Log8 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
ItchyQoL7 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
PAS and IGA-
PN 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PBI-P7 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Sleep Scale 
(PROMIS)7 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
WI-NRS7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photography8 
 
 
 
 
X 
 
 
 
X 
 
 
Administer 
14-day SOWS9 
 
 
 
 
 
 
 
 
X 
 
 
Retrieve 14-
day SOWS9 
 
 
 
 
 
 
 
 
 
X 
 
Dispense 
investigational 
product 
 
 
 
B 
 
B 
 
B 
 
B 
 
BB 
 
BB 
 
 
 
Retrieve 
investigational 
product and 
containers 
 
 
 
B + 
Card 
 
B 
 
B 
 
B 
 
B 
 
BB 
 
BB (B)10 
 
 
Investigational 
product - 
accountability 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 


Trevi Therapeutics, Inc. 
CONFIDENTIAL 
21 July 2021 
Protocol TR11 
 
 
 
Version 7.0 
 
Page 34 of 176 
 
Table-2. 
Schedule of Assessments – Open-label Extension Period 
Study Period → 
 
 
Open-label Fixed-dose Period 
Washout and Safety Follow- up 
Period 
Last Contact for 
WI-NRS 
Assessment ↓ 
Repeating visit q4wk or q8wk 
Off- 
Treatment1 
Last Visit1 
End of Study 
telephone call1 
W17 to W52 
Visit Week 
17 
17 
20 
24 
282 
322 
362 
44 
52 
54 
56 
Study Day (±2 days) 
113 
120 
140 
168 
196 
224 
252 
308 
364 
378 
392 
Investigational 
product - 
review dosing 
compliance 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
AE: adverse event; B: bottle; BID: twice daily; Card: blister card; ECG: electrocardiogram; e-diary: electronic diary; IGA-PN: Investigator Global Assessment-Prurigo 
Nodularis; LFT: liver function test; NA: not applicable; PAS: Prurigo Activity Score; PBI-P: Patient Benefit Index, pruritic versions; PK: pharmacokinetic; PRO: patient-
reported outcome; q4wk: every 4 weeks; q8wk: every 8 weeks; SHBG: sex hormone binding globulin; SOWS: Subjective Opiate Withdrawal Scale; TSH: thyroid stimulating 
hormone; W: Week; WI-NRS: Worst Itch – Numerical Rating Scale; WOCBP: woman of childbearing potential; : telephone call. 
1. 
Off-Treatment visit occurs upon stopping investigational product; regardless of reason. Subjects who elect to go off-treatment prior to 52 weeks of treatment (premature 
discontinuation of investigational product) should be asked to complete the Off-Treatment visit, the 2-week SOWS evaluation, the Last Visit (occurs 14 days after off-
treatment visit date), and the End of Study telephone call. 
2. 
Assess eligibility for down titration based on criteria of confirmed WI-NRS ≤ 3 and 1 category improvement in PAS lesion healing. If both criteria are met, may discuss 
the option for a permanent dose reduction to 108 mg BID. Note: if criteria are met, this decision is at the discretion of the Investigator and with the agreement of the 
subject, but once dose reduction has been initiated no re-escalation is permitted. 
3. 
Vital signs are to be obtained after the subject has been seated for at least 5 minutes. 
4. 
ECGs are to be performed in triplicate (3 serial ECGs at least 1 minute apart) after the subject has been in the supine position for at least 5 minutes. ECGs are to be 
transmitted to be read centrally by a core ECG laboratory. The average of the QTcF values from the triplicate ECGs wil be performed and presented in a report to be used as 
the final eligibility assessment for the subject. 
5. 
Laboratory Evaluations: Hematology and serum chemistry, LFTs, specified endocrine (TSH all subjects with reflex free T4 if above Upper Limit Normal (ULN) or below 
Lower Limit Normal (LLN), ; free testosterone [the fraction not bound to SHBG or albumin] and SHBG for males) and pregnancy if WOCBP (regardless of sexual 
status); urine pregnancy test to be performed by the local laboratory and confirmed to be negative prior to dispensing investigational product. TSH values above the upper 
limit of normal (ULN) should be repeated at the next study visit (or approximately 1 month later; whichever occurs first). If TSH remains above the ULN, a Free T4 will 
be performed on the existing laboratory sample). 
6. 
AEs are to be continually assessed starting with the signing of the informed consent. Subjects should continue to record any new AEs or concomitant medication use on the 
Subject Symptom Log and Subject Medication Log. Site staff are required to remind subjects to bring the logs to each visit (including the telephone contacts). Logs should be 
reviewed by site staff at every visit prior to re-dispensing (or issuing new logs as needed) to subjects. Final retrieval of the logs, for filing in source records, should occur at 
the last clinic visit. Events of special interest should trigger the collection of additional information using the AESI worksheet and documented under the AESI 
section of the Adverse Event eCRF. Event details and both subject and investigator narratives should be thoroughly documented in the AESI worksheet and completed 
under the AESI section of the Adverse Event eCRF. Refer to section 12.1.1. Definitions. 
7. 
PROs (Patient Reported Outcomes) are to be administered by site staff or e-diary as described in the Trialogics User Manual. WI-NRS data will also be collected from the 
subject via the Trialogics web portal at each clinic visit (beginning at Week 20). 
8. 
Photography: To be performed at certain sites only. See the Canfield Quick Reference Guide and User Reference Manual for photography procedures as applicable. 
9. 
The 14-day SOWS is to be completed, on the e-diary, at home by the subject. Site staff must change the subject’s status to “Off-treatment” on the Trialogics web portal to 


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Table-2. 
Schedule of Assessments – Open-label Extension Period 
Study Period → 
 
 
Open-label Fixed-dose Period 
Washout and Safety Follow- up 
Period 
Last Contact for 
WI-NRS 
Assessment ↓ 
Repeating visit q4wk or q8wk 
Off- 
Treatment1 
Last Visit1 
End of Study 
telephone call1 
W17 to W52 
Visit Week 
17 
17 
20 
24 
282 
322 
362 
44 
52 
54 
56 
Study Day (±2 days) 
113 
120 
140 
168 
196 
224 
252 
308 
364 
378 
392 
trigger the launch of the SOWS. Subjects must be instructed to enter SOWS data daily for the 14 days following discontinuation of investigational product regardless of when 
this occurs (i.e. Week 52 visit or Premature Discontinuation). Data should be reviewed by site staff during the 14-day collection period in order to assess the need for any 
withdrawal intervention. The e-diary is to be retrieved at the last clinic study visit. 
10. (B) Applicable if subject discontinues before Week 52. 
I 
I 
I 
I 
I 
I 
I 
I 
I 
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9.1.3 
Study Procedures and Assessments 
In the event of recurrent COVID-19 restrictions on in-person study visits, processes are in place 
to provide home delivery of study drug using an external courier service, and study visits may be 
conducted by phone or video conference. The study will permit continued study drug dosing and 
study participation with up to 2 missed laboratory and ECG assessments when those are 
scheduled less than or equal to 8 weeks apart, and up to 1 missed laboratory or ECG assessment 
when they are scheduled greater than 8 weeks apart. 
9.1.3.1 
Medication Washout and Screening Period (Week -6 through Week -1) 
Subjects are to undergo a screening visit 1 to 6 weeks prior to the planned first day of study 
treatment. Screening may occur over multiple visits within the 6-week screening period if 
clinically indicated (for example, to allow for washout of prohibited medications). However, 
subjects should be randomized as soon as it is determined they meet all study inclusion/exclusion 
criteria. 
Any required medication washout should be completed prior to initiating collection of the WI-
NRS in the e-Diary. 
Subjects whose washout equals or exceeds the 6-week screening window should complete 
laboratory and ECG screening as early as possible. This ensures that the washout period is not 
prolonged unnecessarily, and they can resume non-study treatment for their itch in the event that 
they fail laboratory or ECG criteria. Those who complete the washout and are otherwise eligible 
for study participation will be permitted to re-screen with written consent from the Medical 
Monitor. 
Subjects who fail their initial screening due to the requirement for an extended medication 
washout may be re-screened at the discretion of the Medical Monitor and with written 
permission from the Sponsor. In cases of other unique circumstances that may justify 
re-screening, Investigators must contact the Medical Monitor to discuss the specific conditions 
under which subjects may qualify for re-screening. 
Screening assessments are as follows: 
• Obtain written informed consent (must be completed first, before any screening assessments 
are performed) 
• Review eligibility criteria 
• Record medical, neurological, and PN history 
• Physical examination 
• Brief neurological assessment 
• Vital signs 
• Record height, weight, and body mass index (BMI) 
• Central ECG (triplicate) 


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• Clinical laboratory assessments 
• Urinalysis 
• Quantitative serum pregnancy tests will ONLY be conducted at the initial screening visit, and 
again at baseline, to confirm non-pregnant status prior to dispensation of investigational 
product. Once on study, subjects will be expected to adhere to protocol required birth control 
requirements and serum pregnancy testing will not be done at regularly scheduled intervals. 
• Urine pregnancy test (woman of childbearing potential [WOCBP]) 
• Record and assess AEs, concomitant medications, and therapies (including restricted and 
prohibited medications) 
• Dispense electronic diary (e-diary) at least 7 days prior to projected baseline visit, train on its 
use 
• Review ability to comply with e-diary entry use in the Trialogics portal and counsel and/or 
retrain subject as needed. 
• Dispense and train on use of the Subject Symptom Log and Subject Medication Log 
• ItchyQoL 
• PAS 
• Investigator Global Assessment-Prurigo Nodularis (IGA-PN) 
• PBI-P 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
9.1.3.2 
Double-blind Titration Period (Weeks 1 and 2) 
The subject will return for the Week 1 baseline visit, at which point it will be determined if the 
subject meets the entry criteria. If the subject meets all inclusion/exclusion criteria, the subject 
will be randomized and the titration period will begin. During the double-blind titration period, 
subjects will have 1 study site visit (baseline visit), just prior to entering Week 1 and 2 telephone 
contacts, followed by 1 end of titration visit at Week 2. 
Baseline Visit (Week 1, Day 1) 
The following procedures will be performed during this visit: 
• Confirm eligibility against inclusion/exclusion criteria (Section 9.5) and perform e-diary 
eligibility assessment 
• Brief neurological assessment 
• Vital signs and weight 
• Clinical laboratory assessments 
• Quantitative serum pregnancy tests will ONLY be conducted at the initial screening visit, and 
again at baseline, to confirm non-pregnant status prior to dispensation of investigational 


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product. Once on study, subjects will be expected to adhere to protocol required birth control 
requirements and serum pregnancy testing will not be done at regularly scheduled intervals. 
• Urinalysis 
• Urine pregnancy test (WOCBP) 
• Randomization via Interactive Web Response System (IWRS) 
• Blood sample for PK analysis 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Review e-diary entry and retrain on use or compliance as needed 
• WI-NRS (should be entered by subject via e-diary [prior to randomization] if not entered 
prior to the visit; reminder that subject should enter WI-NRS score via e-diary daily through 
the Week 14 visit) 
• ItchyQoL 
• PAS 
• IGA-PN 
• PBI-P (“Importance of Treatment Goal” questions only) 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• Photography (if applicable) 
• Dispense investigational product (Blister card) 
• Dispense Instructions for Taking TR11 Study Medication (Double-blind titration blister card) 
Telephone Contacts 1 and 2 (Week 1, Day 3 and Week 1, Day 7) 
During the telephone contact, the following will be assessed and documented: 
• Tolerability intervention (See Section 10.6.3) 
• Record and assess AEs, concomitant medications, and therapies 
• WI-NRS (reminder that subject should enter WI-NRS score via e-diary or Trialogics web 
portal daily through the Week 14 visit) 
End of Titration Visit (Week 2, Day 14) 
The following procedures will be performed during this visit: 
• Brief neurological assessment 
• Vital signs 


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• Central ECG (triplicate) 
• Clinical laboratory assessments 
• Tolerability intervention (See Section 10.6.3) 
• Urine pregnancy test (WOCBP) 
• Blood sample for PK analysis 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review compliance 
• Dispense investigational product (bottle) 
• Dispense Instructions for Taking TR11 Study Medication (Double-blind fixed dose bottle) 
• Investigational product accountability 
• Review investigational product compliance 
• WI-NRS (reminder that subject should enter WI-NRS score via e-diary or Trialogics web 
portal daily through the Week 14 visit) 
9.1.3.3 
Double-blind Fixed-dose Period (Weeks 3 to 14) 
During the 12-week double-blind fixed-dose period, there will be 2 telephone contacts 
(Telephone Contacts 3 and 4) and 3 study visits. 
Telephone Contacts 3 and 4 (Week 3, Day 15 and Week 3, Day 21) 
During the telephone contacts, the following will be assessed and documented: 
• Tolerability intervention (Week 3, Days 15 and 21 only; Day 15 is first day of 162 mg BID 
for active treatment group, see Section 10.6.3) 
• Record and assess AEs, concomitant medications, and therapies 
• WI-NRS (reminder that subject should enter WI-NRS score via e-diary or Trialogics web 
portal daily through the Week 14 visit) 
Week 6 Visit 
The following procedures will be performed during this visit: 
• Vital signs 
• Central ECG (triplicate) 
• Clinical laboratory assessments 
• Urine pregnancy test (WOCBP) 


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• Blood sample for PK analysis 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS (reminder that subject should enter WI-NRS score via e-diary or Trialogics web 
portal daily through the Week 14 visit) 
• Dispense investigational product (bottle) 
• Retrieve investigational product and containers 
• Investigational product accountability 
• Review investigational product compliance 
Week 10 Visit 
The following procedures will be performed during this visit: 
• Vital signs 
• Urine pregnancy test (WOCBP) 
• Blood sample for PK analysis 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• PAS 
• IGA-PN 
• PBI-P (“Treatment Benefit Assessment” questions only) 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS (reminder that subject should enter WI-NRS score via e-diary or Trialogics web 
portal daily through the Week 14 visit) 
• Dispense investigational product (bottle) 
• Retrieve investigational product and containers 
• Investigational product accountability 


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• Review investigational product compliance 
Week 14 Visit 
The following procedures will be performed during this visit: 
• Physical Examination 
• Vital signs 
• Central ECG (triplicate) 
• Clinical laboratory assessments 
• Urine pregnancy test (WOCBP) 
• Blood sample for PK analysis 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• PAS 
• IGA-PN 
• PBI-P (“Treatment Benefit Assessment” questions only) 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS (last daily entry) to be entered by subject via e-diary or Trialogics web portal; 
reminder that all future entries will occur during visits via the Trialogics web portal or the e-
diary. 
• Photography (if applicable) 
• Dispense investigational product (blister card) 
• Dispense Instructions for Taking TR11 Study Medication (open-label titration blister card) 
• Retrieve investigational product and containers 
• Investigational product accountability 
• Review investigational product compliance 
9.1.3.4 
Extension Titration Period (Weeks 15 and 16) 
During the 2-week extension titration period, there will be 2 telephone contacts (Telephone 
Contacts 5 and 6) and 1 end of titration study visit at Week 16. 


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Telephone Contacts 5 and 6 (Week 15, Day 101 and Week 15, Day 105) 
During the telephone contacts, the following will be assessed and documented: 
• Tolerability intervention (See Section 10.6.3) 
• Record and assess AEs, concomitant medications, and therapies 
End of Titration Visit (Week 16, Day 112) 
The following procedures will be performed during this visit: 
• Brief neurological assessment 
• Vital signs 
• Central ECG (triplicate) 
• Urine pregnancy test (WOCBP) 
• Blood sample for PK analysis 
• Record and assess AEs, concomitant medications, and therapies 
• WI-NRS to be entered by the subject via Trialogics web portal or e-diary 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• Dispense investigational product (bottle) 
• Dispense Instructions for Taking TR11 Study Medication (open-label fixed dose bottle) 
• Investigational product accountability 
• Review investigational product compliance 
9.1.3.5 
Open-label Fixed-dose Period (Weeks 17 to 52) 
During the 36-week open-label fixed-dose period, there will be 2 telephone contacts 
(Telephone Contacts 7 and 8) and study visits will occur in the clinic every 4 or 8 weeks. 
Telephone Contacts 7 and 8 (Week 17, Day 113 and Week 17, Day 120) 
During the telephone contacts, the following will be assessed and documented: 
• Tolerability intervention (See Section 10.6.3) 
• Record and assess AEs, concomitant medications, and therapies 
Week 20 Visit 
The following procedures will be performed during this visit: 


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• Vital signs 
• Central ECG (triplicate) 
• Blood sample for PK analysis 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• PAS 
• IGA-PN 
• PBI-P (“Treatment Benefit Assessment” questions only) 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS to be entered by subject via Trialogics web portal or e-diary 
• Dispense investigational product (bottle) 
• Investigational product accountability 
• Review investigational product compliance 
Week 24 Visit 
The following procedures will be performed during this visit: 
• Vital signs 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• PAS 
• IGA-PN 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS to be entered by subject via Trialogics web portal or e-diary 
• Dispense investigational product (bottle) 


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• Retrieve investigational product and containers 
• Investigational product accountability 
• Review investigational product compliance 
Week 28 Visit 
The following procedures will be performed during this visit: 
• Vital signs 
• Central ECG (triplicate) 
• Clinical laboratory assessments 
• Blood sample for PK analysis 
• Urinalysis 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Tolerability intervention (See Section 10.6.3) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• PAS 
• IGA-PN 
• PBI-P (“Treatment Benefit” questions only) 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS to be entered by subject via Trialogics web portal or e-diary 
• Photography (if applicable) 
• Assess whether subject is eligible for down titration based on criteria of confirmed WI-NRS 
≤ 3 and 1 category improvement in PAS lesion healing (PAS item 5b). For example, if 
“0-24%” of PN lesions at baseline were assessed as ‘healed’, then a 1-category change means 
that “25-50%” of current Week 28 PN lesions are now healed. If both criteria are met, the 
option for a permanent dose reduction to 108 mg BID may be discussed. Note: if criteria are 
met, this decision is at the discretion of the Investigator and with the agreement of the 
subject, but once dose reduction has been initiated no re-escalation is permitted 
• Dispense investigational product (bottle) 
• Retrieve investigational product and containers 
• Investigational product accountability 


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• Review investigational product compliance 
Week 32 Visit 
The following procedures will be performed during this visit: 
• Vital signs 
• Blood sample for PK analysis 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• PAS 
• IGA-PN 
• WI-NRS to be entered by subject via Trialogics web portal or e-diary 
• Assess whether subject is eligible for down titration based on criteria of confirmed WI-NRS 
≤ 3 and 1 category improvement in PAS lesion healing (PAS item 5b). For example, if “0-
24%” of PN lesions at baseline were assessed as ‘healed’, then a 1-category change means 
that “25-50%” of current Week 28 PN lesions are now healed. If both criteria are met, the 
option for a permanent dose reduction to 108 mg BID may be discussed. Note: if criteria are 
met, this decision is at the discretion of the Investigator and with the agreement of the 
subject, but once dose reduction has been initiated no re-escalation is permitted 
• Dispense investigational product (bottle) 
• Retrieve investigational product and containers 
• Investigational product accountability 
• Review investigational product compliance 
Week 36 Visit 
The following procedures will be performed during this visit: 
• Vital signs 
• Blood sample for PK analysis 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 


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• Tolerability intervention (See Section 10.6.3) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• PAS 
• IGA-PN 
• PBI-P (“Treatment Benefit Assessment” questions only) 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS to be entered by subject via Trialogics web portal or e-diary 
• Assess whether subject is eligible for down titration based on criteria of confirmed WINRS 
≤ 3 and 1 category improvement in PAS lesion healing (PAS item 5b). For example, if 
“0-24%” of PN lesions at baseline were assessed as ‘healed’, then a 1-category change means 
that “25-50%” of current Week 28 PN lesions are now healed. If both criteria are met, the 
option for a permanent dose reduction to 108 mg BID may be discussed. Note: if criteria are 
met, this decision is at the discretion of the Investigator and with the agreement of the 
subject, but once dose reduction has been initiated no re-escalation is permitted 
• Dispense investigational product (bottle) 
• Retrieve investigational product and containers 
• Investigational product accountability 
• Review investigational product compliance 
Week 44 Visit 
The following procedures will be performed during this visit: 
• Vital signs 
• Clinical laboratory assessments 
• Blood sample for PK analysis 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data and review entry compliance 
• ItchyQoL 
• PAS 
• IGA-PN 
• PBI-P (“Treatment Benefit Assessment” questions only) 


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• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS to be entered by subject via Trialogics web portal or e-diary 
• Dispense investigational product (bottle) 
• Retrieve investigational product and containers 
• Investigational product accountability 
• Review investigational product compliance 
9.1.3.6 
Washout and Safety Follow-up Period and Last Contact 
The washout and safety follow-up period begins after the subject discontinues investigational 
product; regardless of when this occurs. The Off-Treatment visit procedures will occur at the 
Week 52 (end of treatment) visit for subjects who complete the study or upon premature, 
permanent discontinuation of investigational product at any time during the study, regardless of 
reason (other than withdrawal of consent). 
The last clinic visit will occur at the end of the washout period; 14 days post discontinuation of 
dosing. The Last Visit should be scheduled 2 weeks after the Off-Treatment visit and the End of 
Study telephone call will occur 4 weeks after investigational product discontinuation. 
If a subject discontinues the study early, the specific instructions in Section 9.6 Premature 
Discontinuation of Investigational Product Treatment take precedence. 
Off-Treatment Visit (Week 52, Day 364 or at Premature Discontinuation) 
The following procedures will be performed during this visit: 
• Physical examination 
• Brief neurological assessment 
• Vital signs 
• Central ECG (triplicate) 
• Clinical laboratory assessments 
• Blood sample for PK analysis 
• Urinalysis 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• Review Subject Symptom Log and Subject Medication Log and re-dispense (or issue new 
logs as needed) 
• Retrieve e-diary data 
• ItchyQoL 


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• PAS 
• IGA-PN 
• PBI-P (“Treatment Benefit Assessment” questions only) 
• Sleep Scale (PROMIS Sleep Disturbance Short Form 8a) 
• WI-NRS to be entered by subject via Trialogics web portal or e-diary 
• Photography (if applicable) 
• Launch Subjective Opiate Withdrawal Scale (SOWS) via the subject status update to “Off- 
treatment/Week 52 (Activate SOWS)” in the Trialogics portal. The SOWS will be activated 
and subjects should be instructed to complete the questionnaire daily for the next 14 days. 
For subjects who discontinue study drug early (including in-between study visits), the 
change in subject status to “Off-treatment/Week 52 (Activate SOWS)” in the Trialogics 
portal should be made immediately as the site becomes aware of discontinuation; 
SOWS entries provide valid information ONLY if they are collected in the first 14 days 
off-treatment. 
• Retrieve investigational product and containers 
• Investigational product accountability 
• Review investigational product compliance 
Last Study Visit (Week 54, Day 378) 
The following procedures will be performed during this visit: 
• Physical examination 
• Brief neurological assessment 
• Vital signs 
• Clinical laboratory assessments 
• Urine pregnancy test (WOCBP) 
• Record and assess AEs, concomitant medications, and therapies 
• WI-NRS to be entered by subject via Trialogics web portal. Review Subject Symptom Log 
and Subject Medication Log and collect for filing in source records 
• Retrieve e-diary 
• Retrieve the 14-day SOWS, review data and assess need for withdrawal intervention 
End of Study Telephone Call (Telephone Contact 9; Week 56, Day 392) 
During this telephone contact, the following will be assessed and documented: 
• Record and assess AEs, concomitant medications, and therapies 


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• Ask the subject to verbally report their current WI-NRS score and site staff must enter the 
reported score into the Trialogics web portal. The recommended question text is: “On a scale 
of zero to ten, with zero being ‘no itch’ and 10 being the ‘worst imaginable itch’, how would 
you describe your worst itch experience over the last 24 hours?” 
9.2 
Rationale for Study Design 
The randomized, parallel, 2-arm design during the double-blind period of this study allows for 
comparison of the efficacy and safety of NAL ER to placebo. The open-label extension period 
provides all subjects an opportunity to receive active treatment and provides a long-term safety 
experience with NAL ER. It also provides an opportunity to document the effect of long-term 
NAL ER therapy on skin lesion healing, in the context of immediate versus delayed treatment 
groups. 
During the screening and washout period, prior to investigational product administration, 
subjects must refrain from using any potentially confounding drug therapies (as specified by the 
eligibility criteria, Sections 9.5.1 and 9.5.2) that could interfere with the baseline and subsequent 
assessments of pruritus. If the subject is being washed out from anti-pruritic therapy during the 
screening and washout period, palliative treatment is permitted with cleansing lotion or 
nonmedicated emollients (pure emollients without active substances such as menthol, urea, 
topical corticosteroids, antihistamines, etc.). 
The study staff, subjects, and Sponsor/Clinical Research Organization (CRO) clinical staff will all 
be blinded to treatment assignment to avoid potential bias. Blinding will be maintained through 
the completion of data lock for the primary endpoint at which time all subjects will either have 
completed the study or will have rolled over onto the open-label period. To maintain study 
integrity, increase the likelihood of establishing tolerance to the recognized early side effects of 
this drug class, and based on titration experience in prior studies, subjects will be titrated in a 
blinded manner up to 162 mg BID during the first 2 weeks of active treatment (i.e., in both the 
initial double-blind titration period and the extension titration period for subjects in Arm 2). Site 
staff will be educated that symptoms occurring during the titration period may be attributable 
either to a nocebo effect in susceptible subjects receiving placebo as investigational product, or 
to side effects of the active investigational product. Therefore, these observations should not be 
interpreted as a reliable sign of assignment to treatment group. To evaluate durability of the NAL 
ER effect, the 162 mg BID dose will be continued for 50 weeks for Arm 1 (i.e., the double-blind 
fixed-dose period, extension titration period, and open-label fixed-dose period), and 36 weeks for 
Arm 2 (i.e., the open-label fixed-dose period). 
The target dose of NAL ER 162 mg is within the dose range that was well tolerated in HD 
subjects and healthy volunteers from study TR01 (27 mg to 216 mg BID for up to 15 days). Data 
from TR01 suggested a decrease in itching intensity in this dose range. In addition, NAL ER has 
shown evidence for an effect on itch in 2 very different subject populations: subjects on HD with 
UP (108 mg BID, with nalbuphine exposures higher than would occur at that dose in subjects 
with normal renal function), and subjects with PN (162 mg BID). With respect to safety, limited 
1-year on treatment data are available from the TR03EXT population. 


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The most common treatment-emergent AEs (TEAEs) occurring in subjects receiving NAL ER 
are dizziness, nausea, headache, and fatigue. In the PN and UP patient populations, no new safety 
signals specific to that population were identified based on the clinical data obtained to date. The 
TEAEs associated with extended dosing of NAL ER in both the PN study TR03EXT (N = 20 
and 16 for 6 months and 1 year, respectively) and UP population (N = 55 and 19 for 4 and 
6 months, respectively) were similar to those observed in the shorter exposure duration (N = 66 
up to 10 weeks in TR03, and N = 246 for 8 weeks in TR02) and also consistent with the previously 
established safety and tolerability profile of nalbuphine18,19. There were no significant clinical 
issues related to physical dependence based upon an evaluation of the data from these studies. 
The primary endpoint, reduction in the average worst itch intensity (average assessed over 
1-week periods), is measured using an itch NRS scale. The NRS is a widely used instrument 
recommended by the International Forum for the Study of Itch (IFSI) for quantifying itch intensity 
as well as a useful instrument for grouping subjects into categories of itch intensity described as 
mild, moderate, or severe20. The itch NRS has been investigated in subjects with chronic pruritus 
of a variety of origins with high reliability and concurrent validity13. Assessing pruritus using 
“worst itch” as a key target parameter and recording once daily (QD) measurements of itch 
intensity is a widely used methodology for studying itch20. 
The ItchyQoL was the first pruritus-specific quality of life (QoL) instrument that is reliable, 
valid, and responsive21. Investigation of QoL factors22 related to chronic pruritus has found that 
itch severity significantly influences the ItchyQoL total score and all 3 subscores; the itch 
frequency significantly correlates with total ItchyQoL and all 3 ItchyQoL subscores indicate that 
symptoms, functional status, and emotional health deteriorate as chronic pruritus persists. 
The IFSI recommends a measurement scale to directly evaluate subject-relevant benefits of the 
pruritus treatment under study20. The PBI-P is an instrument that measures subject-defined 
treatment objectives and benefits acquired during the course of treatment23. The PBI-P was 
recommended by IFSI20 as a “highly valuable” measurement instrument. 
The PAS is a measurement instrument that was designed to classify, monitor and grade the 
number and physical characteristics (with excoriations/crusts and healed) of PN lesions during 
therapeutic interventions24. 
The IGA-PN is an instrument that collects an Investigator Global Assessment of the status of the 
PN skin lesions based on a 5-category scale (scoring 0 to 4) with respect to 2 aspects: the 
excoriation/crusting activity on the surface of the PN lesions, and the presence and character of 
the lesions. 
It is recognized that subjects with chronic itch may scratch in their sleep, whether or not they are 
aware of an itch sensation, and that in severe cases the itch itself may disrupt sleep. The degree 
of sleep disturbance in subjects with severe PN is not well understood, and no specific sleep 
assessment scale exists that is targeted to this population. The PROMIS Sleep Disturbance Short 
Form 8a has been developed as a general tool for assessing sleep in the context of clinical trials. 
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Subjects will receive an e-diary for daily collection of WI-NRS data and will be trained on the 
use of the e-diary during the screening period. They will also receive training on the proper 
completion of the other patient-reported outcomes (PROs) used in this study. 
9.3 
Safety Monitoring 
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. 
Subjects will be closely monitored for safety. AEs will be continuously evaluated throughout the 
study. Vital signs, central cardiac core laboratory-read 12-lead ECGs, physical examinations, and 
clinical laboratory testing will be conducted to monitor subject safety. 
Although nalbuphine is not a controlled substance in the US, AEs of special interest (AESIs) that 
code to the most relevant abuse-related Medical Dictionary for Regulatory Activities (MedDRA) 
preferred terms will be tabulated and descriptive narratives will be written. Additional AEs that 
are considered “possibly related to abuse potential” will be tabulated separately25. The list of 
MedDRA preferred terms for AESIs will be described in the statistical analysis plan (SAP; see 
Section 13.4.7) 
Subjects will complete the SOWS on a daily basis for the 2 weeks following the last dose of 
investigational product. Any subjects who are discontinued from investigational product will also 
complete the SOWS daily for the 2 weeks following the last dose of investigational product 
(unless consent is withdrawn). The SOWS is a self-administered scale for grading opioid 
withdrawal symptoms and will be collected via the study issued e-diary. 
If subjects experience significant withdrawal symptoms during the 2-week safety observation 
period, they should contact the Investigator. At the Investigator’s discretion, they will be offered 
treatment. 
The most frequently reported AEs from NAL ER Phase 1 and 2 clinical studies were primarily in 
the nervous system and GI organ system categories, consistent with other opiates. The specific 
AEs that are considered to be expected with use of NAL ER are nausea, vomiting, somnolence, 
sedation, dizziness, vertigo, and constipation. These are generally mild or moderate in severity 
and usually resolve over the titration and early dosing period. In order to monitor any potential 
CNS-related side effects, a brief neurological assessment will be conducted according to the 
schedule of events (Table-1 and Table-2), as well as a focused neurological medical history which 
will be obtained at screening. 
To mitigate opioid-related side effects, NAL ER will be initiated with a titration schedule for 
2 weeks in a double-blinded manner until the target dose is reached. Titration is a clinical 
management strategy consistent with dosing of opioids in general26. The titration regimen 
planned in this study is similar to the regimen used in Phase 2 studies in UP and PN, in which 
doses in the planned range were well tolerated. In this study, the combination of a low starting 
dosing (27 mg NAL ER on the first day) followed by a relatively slow titration is expected to 
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It is known from prior studies, that GI adverse effects (e.g., nausea and vomiting) and CNS 
adverse effects (e.g., dizziness, somnolence, and headaches) occur early and can be treatment-
limiting. In anticipation of the possible occurrence of these effects, pre-medications for these 
symptoms will be permitted. 
In anticipation of the possible occurrence of CNS AEs such as somnolence, subjects 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 “Instructions for Taking TR11 Study Medication”). Subjects will be 
instructed that the investigational product may impair mental and/or physical abilities required 
for the performance of potentially hazardous tasks such as driving a car or operating machinery, 
especially during the titration period and in combination with alcohol or tranquilizers or other 
pharmacologic CNS depressants. Subjects will be instructed not to drive or operate machinery 
unless they are tolerant to the drug and know how they will react to the medication. In discussing 
potential participation in this study with their subjects, Investigators and site staff should ensure 
that they understand the lifestyle of each individual, the nature of his or her professional 
activities, and any medication prohibitions or toxicology screening requirements that may be 
associated with his or her employment. The assessment should address the overall suitability of 
the subject for this study based on the safety considerations noted above. 
9.4 
Risk/Benefit and Ethical Assessment 
The selected dose of 162 mg BID for this study in PN was chosen in the context provided by 
safety and efficacy observations in non-clinical animal studies, the clinical efficacy and safety 
observations from the 4 Phase 2 studies evaluating the clinical response to itch in 2 distinct 
disease settings (TR02 and TR02EXT in UP; and TR03 and TR03EXT in PN), and the associated 
PK data and PK-PD modelling assessments based on these clinical trial datasets. These data have 
been summarized further in the Investigator’s Brochure27. 
With respect to potential benefit, the neurobiology of PN supports the concept that use of NAL 
ER may have therapeutic benefit in this condition, as previously discussed with respect to 
interruption of the self-perpetuating itch-scratch cycle. 
Two sets of Phase 2 data support the decision to further investigate the use of NAL ER as a 
potential therapeutic intervention in PN. In study TR02, 371 subjects on chronic HD with UP were 
randomized across 3 arms to placebo, and either of 2 doses of NAL ER for a blinded treatment 
duration of 8 weeks. Results demonstrated a dose response across the 2 NAL ER groups, and a 
significant difference between the higher dose group (NAL ER 108 mg BID) and placebo for the 
change in the mean NRS through Week 8 (difference of -0.73; P = 0.017). In those with severe 
UP (NRS ≥ 7) at baseline, the treatment difference was larger (difference of -1.39; P = 0.007). 
The smaller TR03 study (63 subjects across 3 arms), in moderate to severe itch due to PN, did 
not meet its primary endpoint based on a responder criterion. However, a distinct signal for 
efficacy was observed, with the mean reduction (baseline to last observation at Week 10) in 
WI-NRS of -1.11 points (P = 0.083), with a completers analysis showing a wider spread 
(reduction of -1.57 points, P = 0.025). Importantly, 36 subjects rolled over into the open-label, 
single arm extension study, in which favorable category shifts were observed in the PAS skin 


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exam for the activity of the prurigo lesions among those who completed 6 and 12 months of 
treatment. Specifically, a ≥ 1 category improvement in excoriations/crusts was documented in 
10/18 and 9/15 subjects, and for healed lesions in 11/18 and 7/15 subjects, each at 26 and 
50 weeks, respectively. There are no approved treatments for itch in the setting of PN, and 
current treatment algorithms rely on expert clinical judgment, small case series, and individual 
case reports. The subject’s experience usually involves a long sequence of attempted therapies 
without satisfactory resolution of the symptom or skin lesions. 
Therefore, there is a strong rationale for investigating therapeutic agents that may have the 
potential to address the significant unmet need in PN. 
Nalbuphine has a long history of use in a parenteral formulation, generally for short-term, 
episodic use related to surgical interventions. The highest dose proposed in the current clinical 
study is 162 mg BID (324 mg daily dose), well below the highest recommended daily treatment 
of 144 mg IV dose (equivalent to 864-mg oral dose) for the currently available parenteral 
administered product. The high peak plasma concentrations that occur in the setting of parenteral 
use significantly exceed the peak levels observed with NAL ER oral dosing, an observation that 
is reassuring with respect to the potential for severe, acute toxicity. The slow titration dose 
escalation during the 2-week initiation of therapy period for NAL ER provides additional safety 
with respect to minimizing the potential of AEs. 
Opiate drug class-related concerns such as the potential for physical dependence or the evolution 
of endocrine abnormalities, both linked to long-term use of opiates, are acknowledged. The 
proposed study, TR11, will provide up to 52 weeks of dosing for those initially assigned to the 
NAL ER treatment arm. Therefore, limited laboratory monitoring of those endocrine parameters 
that can be reliably assessed in the course of usual study conduct, and a requirement for 
completion of a 2 week safety observation period with daily SOWs reporting have both been 
incorporated into the TR11 study. These procedures will facilitate rapid identification and 
intervention for the respective relevant risks to subjects. With respect to other rare but serious 
adverse events (SAEs) which have been linked to opiate use – including rare cases of adrenal 
insufficiency (usually with prolonged use) and serotonin syndrome – (usually in combination with 
other suspect medications, particularly antidepressants including tricyclic antidepressants and 
serotonin re-uptake inhibitors, CNS stimulants, and certain herbs), Investigators and subjects will 
be informed of the signs and symptoms that may require evaluation and possible treatment. 
In addition, labeling of opiate-class drugs includes a warning that concomitant use of an opiate 
together with a benzodiazepine-class drug can increase the risk for respiratory depression, 
including a risk for respiratory arrest. This warning is based on post-marketing real world data, 
assessing the experience with a wide range of drugs in these 2 classes and in varied settings 
including recreational as well as therapeutic usage. In TR11, concomitant use of benzodiazepines 
(with the exception of short-acting benzodiazepines specifically used on an intermittent and as 
needed basis) is prohibited. At the time of the informed consent discussion, subjects who are 
identified as taking a concomitant short-acting benzodiazepine should receive the Patient 
Information Sheet on this topic, as should any subject for whom a concomitant short-acting 
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With respect to the published literature addressing respiratory depression with nalbuphine, 
1 relevant study has been identified; which evaluated the respiratory effects of serial intravenous 
administration of nalbuphine in healthy volunteers. The results were interpreted by the authors as 
demonstrating a “ceiling” effect for respiratory depression31. In previous clinical trials with NAL 
ER, a total of 41 subjects have received concomitant benzodiazepines while receiving NAL ER, 
and none of these individuals experienced any event of respiratory depression. 
In summary, the risk for subjects participating in the TR11 study is judged to be low based on 
previous experience with oral administration of NAL ER. The current study will utilize a low 
initiation dose of 27 mg, a gradual dose titration schedule, careful safety monitoring of subjects 
during the clinical study, and appropriate education of Investigators regarding symptoms of rare 
but significant AEs linked to the opiate class. 
Finally, there is no approved therapy for PN related pruritus in the US or Europe. Should NAL 
ER prove effective, subjects with PN could potentially experience substantial benefit. Therefore, 
the overall benefit-risk assessment for the TR11 protocol is considered favorable to proceed with 
the study. 
9.5 
Selection of Study Population 
9.5.1 
Inclusion Criteria 
Subjects eligible for randomization to receive investigational product must meet all of the 
following criteria: 
1. Individuals diagnosed with generalized PN, defined as the presence of ≥ 10 pruriginous 
nodules, involving at least 2 distinct anatomical areas: for example, either 2 limbs; or a single 
limb and some axial portion of the body. Individuals with only axial lesions but involving 
2 distinct anatomical areas that have no peripheral nervous system overlap are also eligible: 
for example, lesions involving a portion of the cranium and a portion of the trunk of the body. 
For purposes of this study, the axial portion will be defined as any non-appendicular portion 
of the body. 
2. If there is any history of a primary pruritic skin condition other than PN, that condition must 
have been inactive for at least 6 months prior to screening. 
3. Subjects with a history of acute secondary dermatoses within the preceding 6 months may 
enroll only if the dermatosis has resolved completely as follows per medical history or patient 
self-report, and current clinical assessment: (a) Localized contact dermatitis, environmental 
exposures, superficial burns, or viral exanthems must have been resolved for at least 4 weeks 
prior to screening. (b) Skin or environmental infestations, such as scabies, lice, or bed bugs, 
must have been resolved for at least 8 weeks prior to screening. 
4. Any identified systemic, non-dermatologic disease that could be a potential cause of 
concomitant pruritus (e.g., thyroid disease, celiac disease, hepatitis C virus [HCV]) must 
either have resolved, been successfully treated (i.e., HCV RNA negative), or must be 
successfully managed with stable, optimized treatment (e.g., thyroid replacement, dietary 
management with resolution of symptoms, respectively) for at least 3 months prior to 
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5. WI-NRS score, recorded daily over the 7 contiguous days prior to and including the day of 
the baseline visit via electronic diary, must have at least 5 measurements recorded and all 
individual measurements must be ≥ 6. The arithmetic mean value of the measurements must 
be ≥ 7 as confirmed by the Trialogics Eligibility Check report immediately prior to 
randomization. The last WI-NRS value used in the calculation should be recorded on the day 
of the baseline visit and prior to dosing. 
6. Subjects using antidepressants must be on a stable dose for a minimum of 4 weeks prior to 
screening and must be willing to remain on their stable dose for the entire duration of the 
study. 
7. Subjects who are human immunodeficiency virus (HIV) positive may enroll if they meet the 
following criteria: (a) currently on a stable (> 6 months stable use) and well tolerated highly 
active antiretroviral therapy regimen; (b) CD4 count > 500 cells/mL; and (c) HIV ribonucleic 
acid (RNA) < 50 copies/mL documented for at least 6 months prior to enrollment. If 
enrolled, these subjects should continue to have their CD4 and HIV RNA monitored by their 
HIV provider per their standard of care for the duration of the TR11 study, and the data 
should be reported and documented at the next study visit. 
8. Females of childbearing potential must be using an acceptable method of birth control (if 
sexually active) for 14 days prior to randomization and throughout the study. All females of 
childbearing potential must have a negative pregnancy test at the screening and baseline 
visits. 
For the purpose of this study, all females are considered to be of childbearing potential unless 
they are postmenopausal (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). 
Sexually active female subjects of childbearing potential are required to use 1 barrier method 
(e.g., condom, cervical cap, or diaphragm) of contraception in addition to 1 other method (e.g., 
intrauterine device in place at least 1-month, stable hormonal contraception for at least 3 months, 
or Essure procedure, or spermicide). 
Female subjects 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. 
9. Age 18 years and older at the time of consent, and a life expectancy of at least 18 months. 
10. Willing and able to understand and provide written informed consent. 
11. Willing and able to comply with study requirements and restrictions. 
12. Agree to the confidential use and storage of all data and use of all anonymized data for 
publication including scientific publication. 
9.5.2 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Pruritus due to localized PN (only 1 body part affected, for example only 1 arm). 


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2. Active, uncontrolled, pruritic dermatoses in need of treatment (such as atopic dermatitis or 
bullous pemphigoid for example). 
3. Prurigo Nodularis associated with a history of atopic dermatitis is excluded if acute 
eczematous lesions are present, as characterized by erythematous, active predominant 
lichenified plaques with oozing and crusting. 
4. History of a major psychiatric disorder such as bipolar disorder or schizophrenia is excluded. 
Subjects with a history of isolated major depression > 3 years previously may be eligible for 
enrollment if they have access to appropriate psychiatric care. An ‘isolated major depression’ 
is defined as a single event of depression that includes recurrent thoughts of death, recurrent 
suicidal ideation with or without a specific plan, or any history of a suicide attempt. 
Enrollment must be approved by the Medical Monitor. Subjects with general depression who 
are considered stable may be enrolled. 
5. Serum bilirubin > 1.5 × upper limit of normal range at screening unless explained by a 
clinical diagnosis of Gilbert’s Syndrome. 
6. Serum hepatic alanine aminotransferase or aspartate aminotransferase enzymes > 100 U/L at 
screening. 
7. Estimated glomerular filtration rate ≤ 44 mL/min/1.73 m2 at screening. 
8. Significant medical condition, occupational restrictions (see Section 9.3), and/or other factors 
that in the opinion of the Investigator may interfere with the conduct of the study. 
9. Subjects who have an active malignancy (either solid tumor or hematologic) are excluded. 
Subjects who have a past history of malignancy and who have no evidence of active disease 
but who continue on therapy to prevent disease recurrence (i.e., tamoxifen for breast cancer, 
testosterone blockade for prostate cancer, etc.), may be eligible if approved by the Medical 
Monitor. 
10. History of active substance abuse within the past 3 years. 
11. Known intolerance of, or hypersensitivity or allergy to nalbuphine or vehicle components. 
12. Pregnant or lactating females. 
13. Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a concurrent 
clinical trial. Potential subjects who are actively participating in the safety follow-up of an 
ongoing COVID-19 vaccination trial may enroll in this study if they meet the following 
criteria: 
A. the vaccine under study has already been approved under an Emergency Use 
Authorization or via an equivalent regulatory review by the Health Authority in the 
country where they are enrolling; 
B. they have completed the full vaccination series and are participating in a safety 
observation period without anticipation of any further vaccine trial intervention. 
C. the COVID-19 trial permits co-enrollment. 
Medication-related Exclusions: 
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15. Potential subjects taking monoamine oxidase inhibitors are excluded, as concomitant opiate 
use may increase the risk for serotonin syndrome. 
16. Potential subjects taking cyclosporin A are excluded unless they undergo a 6-week washout. 
Subjects are prohibited from using cyclosporin during the study. Please refer to Table 3, 
footnote 3, and Section 9.1.3.1. 
17. Potential subjects taking non-insulin biologics (including monoclonal antibodies), which 
modify the immune system, are excluded unless they undergo a 3-month washout. Please 
refer to Table 3, footnote 3, and Section 9.1.3.1. 
18. Prior exclusion criterion 18 is not applicable to subjects enrolling in Protocol V6 and later. 
19. Exposure to any investigational medication, including placebo requires a 4-week 
washout (3 months for noninsulin biologics [e.g., monoclonal antibodies]). Please refer to 
Table 3 and Section 9.1.3.1. 
20. Potential subjects receiving UV-therapy (PUVA, UVA, UVB, Excimer) requires a 4-week 
washout. Subjects are prohibited from using UV-therapy for the duration of the study. Please 
refer to Table 3 and Section 9.1.3.1. 
21. Potential subjects who are taking opiates require a 14 –day washout. Subjects are prohibited 
from using opioids, including naltrexone, for the duration of the study. Please refer to Table 3 
and Section 9.1.3.1. 
22. Potential subjects who have received gabapentin, pregabalin, calcineurin inhibitors, 
cannabinoid agonists, capsaicin, cryosurgery, topical doxepin, thalidomide or methotrexate, 
topical antihistamines, and topical corticosteroids require a 14-day washout. These 
medications are prohibited for the duration of the study.  Use of systemic antihistamines are 
not permitted unless the subject has been on a stable dose for at least 4 weeks prior to 
screening and there are no plans to change the dose during the study. Please refer to Table 3 
and Section 9.1.3.1. 
23. Potential subjects receiving systemic corticosteroids or local steroid injections of the PN 
lesions require a 4-week washout. These medications are prohibited for the duration of the 
study. Please refer to Table 3 and Section 9.1.3.1. 
24. Potential subjects are excluded if they have had any addition or discontinuation of their 
regularly used prescription drugs, or any changes in the doses of their regularly used 
prescription drugs in the 14 days prior to the screening period e-diary WI-NRS collection. 
25. Potential subjects taking central nervous system suppressants, such as barbiturates, 
benzodiazepines (with the exception of short-acting benzodiazepines specifically used on an 
intermittent and as needed basis), anxiolytics other than benzodiazepines, neuroleptics, and 
clonidine are excluded. These medications are prohibited for the duration of the study (see 
Section 10.6.2, footnotes 1 and 2 to Table 3 for definitions of ‘short-acting 
benzodiazepines’). 
Cardiac-related Exclusions: 
26. Subjects with a history of congestive heart failure of Class 2 or higher as graded using the 
New York Heart Association scale (see Appendix 9). 


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27. Subjects with a history of angina pectoris Grade 2 or higher as graded using the 
Canadian Cardiovascular Society grading scale (see Appendix 8). 
28. History of ventricular tachycardia, Torsade de Pointes, or family history of sudden death. 
29. Myocardial infarction or acute coronary syndrome within the previous 3 months, as reported 
by the subject. 
30. Serum potassium below the laboratory lower limit of normal. Note: If the initial screening 
value is low, but not considered clinically significant in relation to cardiac risk, then 
potassium supplementation may be prescribed and the serum potassium level repeated once at 
least 2 weeks later, during the screening period. If the repeat potassium remains < LLN, then 
the subject must be a screen-fail. 
31. QTcF interval > 450 ms (mean of 3 screening ECG QTcF values) if QRS < 120 ms (mean of 
3 screening ECG QRS values); QTcF interval > 480 ms in the presence of Right Bundle 
Branch Block (RBBB) and/or QRS ≥ 120 ms.  
32. Heart rate < 45 bpm on any screening measurement either in the clinic or on the central ECG 
readings. 
33. Use of a medication having a “known risk” of Torsade de Pointes (categorized as “KR” on 
the Credible Meds website; see Appendix 10) is not permitted unless the subject has been on 
a stable dose for at least 4 weeks prior to screening and there are no plans to change the dose 
during the study. 
34. Prior Exclusion criterion 34 is not applicable to subjects enrolling in Protocol V7 and later.  
9.6 
Premature Discontinuation of Investigational Product Treatment 
Subjects who complete investigational product treatment through the full study treatment course 
are considered to have completed treatment with the investigational product (even if some doses 
have been missed). Subjects who discontinue investigational product, prior to 52 weeks of 
treatment will be considered to have prematurely discontinued and will be asked to complete the 
following visits (unless consent is withdrawn): 
• If the decision to discontinue treatment is made during an onsite study visit (scheduled or 
unscheduled), perform the procedures and assessments outlined in the Off-Treatment visit, 
regardless of where they are in the study visit schedule. 
• If the decision to discontinue treatment is made while the subject is not at a study visit, 
schedule a visit as soon as logistically possible, but no later than 2 weeks later, to perform the 
procedures and assessments described in the Off-Treatment visit. Upon notification that the 
subject has permanently stopped dosing, the site should immediately update the subject’s 
status on the Trialogics web portal, in order to launch the SOWS, and instruct the subject to 
begin entering their SOWS data daily via the e-diary for the next 14 days. 
• Schedule the subject to return to the clinic 2 weeks after completion of the Off-Treatment 
visit and perform the procedures and assessments outlined in the Last Visit, regardless of 
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• Schedule the End of Study telephone call with the subject 4 weeks after completion of the 
Off- Treatment visit and perform the procedures and assessments outlined in the schedule of 
events for this visit, regardless of where they are in the study visit schedule. 
• If discontinuation of investigational product occurs any time between Day 1 and the Week 14 
visit, the subject will be asked to complete the Off-Treatment visit, the Last Visit, and the End 
of Study visit telephone call, and to return to the clinic for the study schedule planned Week 14 
visit. 
9.7 
Premature Withdrawal of Subjects from the Study 
All subjects who receive study treatment should remain in the study whenever possible. If 
possible and appropriate, subjects for whom withdrawal is considered for the reasons identified 
with an asterisk below should discontinue investigational product, but are asked to provide 
complete data as per Section 9.6. Reasons for withdrawal of the subject from the study, not just 
discontinuation of investigational product, include: 
• Withdrawal of consent for study participation 
• Sponsor terminates the study for any reason 
• Investigator decision * 
• The Investigator may withdraw any subject from the study if, in the Investigator’s opinion, it 
is not in the subject’s best interest to continue on the study * 
• Develops a QTcF > 500 ms (mean of 3 ECG QTcF values) in subjects who were randomized 
without ECG findings of RBBB and/or QRS ≥ 120 ms. 
• Develops QTcF > 530 ms (mean of 3 ECG QTcF values) in subjects who were randomized 
with ECG findings of RBBB and/or QRS ≥ 120 ms. 
• Increase from QTcF baseline of >60 ms (mean determination from 3 ECG values). 
• Death of the subject 
Subjects who prematurely discontinue from the study will be asked: (1) to undergo and complete 
procedures and evaluations that may be necessary to ensure that the subject is free of untoward 
effects; and (2) to seek appropriate follow-up for any continuing problems. The date on which 
the subject is withdrawn from the study and the reason for discontinuation will be recorded on 
the electronic case report form (eCRF). Subjects who withdraw from the study will not be 
replaced. 
10 TREATMENT OF SUBJECTS 
10.1 Identity of Investigational Product 
The investigational product in this trial is NAL ER tablets or matching placebo tablets. The NAL 
ER tablets are either round, white to off-white, film-coated tablets containing either 27 or 54 mg 
of nalbuphine (equivalent to approximately 30 or 60 mg nalbuphine HCl); or oval, white to off-
white, film-coated tablets containing 162 mg of nalbuphine (equivalent to approximately 180 mg 


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nalbuphine HCl). The 27 and 54 mg NAL ER round tablets are identical in appearance. 
Matching placebo tablets will be used for both tablet shapes (round tablets to represent the 27 
and 54 mg tablets, and oval shaped tablets to represent the 162 mg tablets). 
All investigational product will be supplied by the Sponsor. 
10.1.1 Administration of Study Treatments 
Double-blind Treatment 
Following randomization, the subject will be dispensed a 2-week blister card for the double-blind 
titration period. Dosing will consist of 3 tablets for the AM dose and 3 tablets for the PM dose. 
Arm 1 will consist of a combination of 27 mg/54 mg/placebo tablets, and Arm 2 will consist of 
placebo tablets only. Note: Although both AM and PM doses are present on Day 1, only the PM 
dose will be taken (both Arms). 
At the Week 2 end of titration visit, subjects in Arm 1 will be given one 70 count bottle of NAL 
ER 162 mg tablets and subject in Arm 2 will be given one 70 count bottle of placebo tablets. 
Additional bottles will be dispensed at subsequent study visits. At each visit at which 
investigational product is to be dispensed, enough investigational product should be supplied to 
ensure that a sufficient number of tablets are available for dosing until the next visit, allowing for 
visit windows and/or the possibility of a late visit. 
Subject dosing information for the double-blind treatment will be available in the Pharmacy 
Manual provided to the site. Additionally, all subjects are to be provided with the “Instructions 
for Taking TR11 Study Medication” which outlines dosing instructions for this treatment period. 
Open-label Treatment 
Subjects will be dispensed a 2-week blister card for the extension titration period. Dosing will 
consist of 3 tablets for the AM dose (starting on Day 2) and 3 tablets for the PM dose. (Note: 
There will not be any tablets to take on Day 1 AM for both Arms 1 and 2). For subjects 
previously assigned to Arm 2 of the double-blind treatment, the titration card will consist of 
combinations of either 27 mg/54 mg/placebo tablets to crossover to NAL ER. To maintain the 
blind, subjects previously assigned to Arm 1 will be given a card containing 3 active 54 mg NAL 
ER tablets for the AM dose and 3 active 54 mg NAL ER tablets for the PM dose. 
At the Week 16 end of titration visit, all subjects will be given 1 x 70-count bottle for the start of 
the open-label fixed-dose period containing 162 mg NAL ER tablets. Additional bottles will be 
dispensed at subsequent study visits and subjects should again be dispensed enough 
investigational product to ensure that a sufficient number of tablets are available for dosing until 
the next visit, allowing for visit windows and/or the possibility of a late visit. 
Subject dosing information for the open-label treatment will be available in the Pharmacy 
Manual provided to the site. Additionally, all subjects are to be provided with the “Instructions 
for Taking TR11 Study Medication” which outlines the dosing instructions for this treatment 
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Investigational product can be taken with or without food, as whole tablets (without crushing or 
chewing). Subjects will be instructed to take the AM and PM investigational product tablets at 
the same times of the day, 12 hours apart (± 2 hours), preferably with 240 mL (approximately 
8 ounces) of water. For example, if a subject is taking the investigational product at 9:00 AM and 
9:00 PM but forgets to take the 9:00 AM dose, he may take the 9:00 AM dose as late as 11:00 AM. 
After that time, the subject should skip the 9:00 AM dose and, instead, take the regularly 
scheduled next dose at 9:00 PM. 
Subjects will confirm (in the e-diary) whether or not they took their dose(s) and the dosing time 
for both the AM and the PM dose. Any discrepancies between the dosing records in the e-diary 
and the number of actual versus expected tablets (based on the e-diary reporting) returned to the 
site, should be documented at the actual visit in which investigational product is returned. This 
should occur at every visit during the investigational product drug accountability and 
investigational product compliance assessments. 
10.1.2 Down-titration 
At the regularly scheduled study visits for Week 28, Week 32, and Week 36, an elective dose 
reduction to a 108 mg NAL ER BID dose may be considered for subjects who achieve a 
confirmed WI-NRS ≤ 3 and visible lesion healing as assessed by an improvement of at least 
1 category in the PAS healing activity score, Item 5b. For example, if “0-24%” of PN lesions at 
baseline were assessed as ‘healed’, then a 1-category change means that “25-50%” of current 
Week 28 PN lesions are now evaluated as ‘healed’. The WI-NRS scores at and after Week 24 will 
be available to site staff via the Trialogics portal in order to assess eligibility for this down-
titration. The decision to dose reduce is at the discretion of the Investigator and with the 
agreement of the subject, but once this dosing has started, no re-escalation is permitted. Dose 
reduction is not permitted prior to Study Week 28 or after Study Week 36. 
10.1.3 Multiple Missed Doses 
If a subject misses multiple doses of the investigational product, the procedures below should be 
followed. In no case should subjects take additional doses of investigational product to make up 
for missed doses. If investigational product is being restarted after missed doses during the 
titration period, the subject should be instructed not to remove the tablets from the days and/or 
time points on which investigational product was missed; these tablets are to remain in the blister 
card. The subject is to be instructed on when to resume taking investigational product. 
During the Titration Periods 
If a subject misses 3 (or more) consecutive doses, please contact the study Medical Monitor for 
dosing instructions. 
During the Fixed-dose Periods 
If a subject misses 6 (or more) consecutive doses, please contact the study Medical Monitor. If 
authorized by the Medical Monitor, subjects who miss more than 6 consecutive doses may be 
allowed to continue on study. In such situations, subjects should receive the investigational 


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product only QD (i.e., the AM or PM dose only) for the first 3 days before returning to the full 
(BID) dose. 
10.2 Study Treatment Packaging and Labeling 
Please refer to the Pharmacy Manual for additional information on investigational product 
supplies, packaging, storage, dispensation, and accountability. 
10.2.1 Labeling 
Blister cards and bottles will be labeled with at minimum: contents, storage conditions, clinical 
trial statement, and the name of the Sponsor (Trevi Therapeutics). 
10.2.2 Storage 
NAL ER tablets and placebo tablets should be stored at 20°C to 25°C (68°F to 77°F) with 
excursions permitted between 15°C and 30°C (59°F to 86°F) or per country-specific criteria. The 
investigational product will be stored away from any extreme conditions of temperature, light, or 
humidity as an additional precaution. 
10.2.3 Blinding and Randomization of Study Treatments 
Randomization will be performed by IWRS. Upon confirmation of eligibility by the study site, 
subjects will be randomized in a 1:1 ratio to either Arm 1 or Arm 2. 
10.3 Procedure for Breaking the Randomization Code 
Under normal circumstances, the blind will not be broken. In the event of a medical emergency, 
when management of a subject’s condition requires knowledge of the treatment assignment, the 
blind may be broken via the IWRS. Investigators contemplating unblinding a subject should 
make every effort to contact the Medical Monitor prior to unblinding. 
Reasons for unblinding will be documented in the eCRF. The date and the identity of the person 
responsible for breaking the blind must be also documented. 
10.4 Subject Compliance 
Drug compliance is a critical data observation in all clinical trials, and is assessed through the 
drug accountability records. Returned blister cards and bottles will be compared to subject 
entries in the e-diary to assess compliance at each study visit. An accurate and current accounting 
of the dispensing and return of investigational product for each subject will be maintained on an 
ongoing basis by a member of the study site staff. The amount of investigational product 
dispensed and returned by the subject will be recorded on the appropriate Investigational Product 
Drug Accountability forms at each visit. 
Compliance is defined as the amount of investigational product that should have been taken by a 
subject based on the dosing instructions provided during the period for which investigational 
product was dispensed. This is typically expressed as percent (%) compliance, and is calculated 


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based on the number of tablets actually taken in a particular time interval divided by the number 
of tablets that should have been taken or prescribed for that time interval. Compliance will be 
documented after each investigational product return, based on the information on the Drug 
Accountability forms. 
Ideally, subject compliance should be 100%. Any observation of a missed or extra dose taken 
should trigger a discussion/re-education with the subject about the compliance expectations of 
this study, with the focus on ensuring maximum efficacy and minimum AEs. These discussions 
should be recorded at the time of the visit in source documents. 
Additional eCRF questions to query the subject will be completed in situations in which there 
were missing tablets (e.g., fewer tablets returned than expected) to document an explanation for 
missing investigational product. 
Any dosing and/or compliance discrepancies will be noted in source documents for the 
applicable subject visit. 
10.5 Investigational Product Accountability 
The Investigator must ensure that all investigational product supplies are kept in a secure locked 
area, under controlled temperature, with access limited to those authorized by the Investigator. 
The Investigator must maintain accurate records of the receipt of all investigational product 
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 investigational 
product. 
Current dispensing records will also be maintained including the date and amount of 
investigational product dispensed and the subject receiving the investigational product. 
Additional eCRF questions to query the subject will be completed in situations in which there 
were missing tablets (e.g., fewer tablets returned than expected) to document an explanation for 
missing investigational product. All remaining investigational product 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. 
10.5.1 Special Procedures for Study Drug Delivery During Periods of COVID-19 
Pandemic Restrictions 
A special courier service will pick up study drug at the site and deliver to the subject’s home 
address as needed. All subject-related identifying information will be communicated by site staff 
to the courier without any Sponsor involvement. This courier will also safely transport drug, in 
the possession of the patient from a previous visit, back to the site for proper accountability. 


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10.6 Concomitant Medications, Prohibited Medications, Pre-Medications, 
Symptom Management, and Itch Intervention 
10.6.1 Concomitant Medications 
Subjects may receive all clinically indicated medications during the study with the exceptions 
noted in Section 10.6.2 and Appendix 10. 
Any medication taken by a subject within the 14 days prior to the screening period, and during 
the course of the study, will be recorded on the eCRF along with the reason for use. During the 
study, each subject will be instructed to report the use of all medication, including over-the-
counter (OTC) medications, herbal medications, vitamins, and nutritional supplements on the 
study specific Subject Medication Log. Sites should instruct subjects to bring the log to each 
study visit for review (including referring to it during telephone contacts, as applicable). Subjects 
will also be instructed about the importance of not taking any new medications during the study 
(including OTC medications) without consulting the Investigator. After screening, if the subject 
begins taking prohibited or restricted medications, they are to be recorded on the corresponding 
Concomitant Medication eCRF (see Section 10.6.3). 
10.6.2 Prohibited Medications 
Prohibited medications are summarized in Table 3. Subjects receiving opiate drugs during the 14 
days prior to the screening period are excluded from the study if unable to washout (see also 
Section 9.1.3.1). 
Initiating use of opiate medications during the study should be done with caution with 
assessment of the subject for potential additive opiate AEs. If an enrolled subject requires daily 
treatment with opioid medications for greater than 7 days during the study, please contact the 
Medical Monitor. Use of acetaminophen, non-steroidal anti-inflammatory medications, and 
aspirin is permitted. If opioid medication is introduced in anticipation of chronic use, the subject 
is to 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. 
The following classes of drugs are prohibited during participation in this study due to the risk 
that they may cause increased respiratory depression, which could become life threatening with 
excess use: 
• Central nervous system suppressants, such as barbiturates, benzodiazepines (with the 
exception of short-acting benzodiazepines specifically used on an intermittent and as needed 
basis), anxiolytics other than benzodiazepines, neuroleptics, and clonidine. 
The phrase ‘short-acting benzodiazepines’ refers specifically to the following: triazolam, 
temazepam, brotizolam (available in EU only), zolpidem, and zaleplon. These drugs should be 
prescribed at the lowest effective doses and for the shortest period of time that is clinically 


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indicated during the conduct of the study. Subjects receiving these agents must be provided the 
patient information sheet as noted in Table-1 and Table-2 and in Section 9.4. 
Use of all other investigational products is prohibited during the study. A subject who initiates an 
investigational product during the study should be discontinued. 
Subject are not to receive a medication that is classified as having a known risk for Torsade de 
Pointes (see Appendix 10, for cardiovascular related prohibited medications with a known risk of 
Torsade de Pointes, classified as “KR”) unless the subject has been on a stable dose for at least 4 
weeks prior to screening and there are no plans to change the dose during the study. 
Subjects are to be washed out of any medications meeting the exclusion criteria (Section 9.5.2) 
for at least the minimal time periods summarized in Table-3. This will allow the subject to be 
adequately washed out for any medications that could potentially confound investigational 
product effect28. 
Table-3. 
Prohibited Medications and Washout Requirements 
Concomitant Medication 
Study Entry (see Section 9.5) 
During Study 
μ-opioid receptor agonists 
(e.g., codeine, oxycodone, 
hydromorphone, oxymorphone, 
morphine, fentanyl, tramadol, 
butorphanol, pentazocine, 
meperidine, methadone) 
Excluded within 14 days  
(e.g. 14-day washout) prior to 
the start of the screening e- 
diary WI-NRS collection 
Opioid medication introduced in 
anticipation for chronic use is 
prohibited 
Opioid receptor antagonists (e.g., 
naltrexone, naloxone) 
Excluded within 14 days 
(e.g. 14-day washout) prior to 
the start of the screening e- 
diary WI-NRS collection 
Prohibited except for urgent 
reversal of opioid adverse events 
or opioid overdose 
Antihistamines (systemic or topical) 
(e.g., diphenhydramine, loratadine, 
cetirizine, chlorpheniramine, 
clemastine, fexofenadine) 
Topical antihistamines:  
Excluded within 14 days 
(e.g. 14-day washout) prior to 
the start of the screening e- 
diary WI-NRS collection  
Systemic antihistamines: Not 
permitted unless the subject has 
been on a stable dose for at 
least 4 weeks prior to the start 
of screening. 
Topical antihistamines: 
Prohibited (except topicals for 
limited ‘Itch Intervention’ as in 
Section 10.6.4)  
 
Systemic antihistamines:  There 
must be no plans to change the 
dose during the study. 
Non-antihistamine class drugs that 
have well-established primary or 
secondary pharmacologic 
antihistaminic effects mediated via 
the H1 receptor (e.g., doxepin –see 
below for topical doxepin specifics) 
Not permitted unless the subject 
has been on a stable dose for at 
least 4 weeks prior to the start 
of screening.  
There must be no plans to change 
the dose during the study.  


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Table-3. 
Prohibited Medications and Washout Requirements 
Concomitant Medication 
Study Entry (see Section 9.5) 
During Study 
Topical calcineurin inhibitors (e.g., 
tacrolimus) 
Excluded within 14 days  
(e.g. 14-day washout) prior to 
the start of the screening e-diary 
WI-NRS collection 
Prohibited 
Topical corticosteroids 
Excluded within 14 days  
(e.g. 14-day washout) prior to 
the start of the screening e-diary 
WI-NRS collection 
Prohibited (except topicals for 
limited ‘Itch Intervention’ as in 
Section 10.6.4) 
Systemic corticosteroids 
Excluded within 4 weeks 
(e.g. 4-week washout) prior to 
the start of the screening e-diary 
WI-NRS collection. 
Prohibited 
Topical capsaicin 
Excluded within 14 days 
(e.g. 14-day washout) prior to 
the start of the screening e-diary 
WI-NRS collection 
Prohibited (except for limited 
‘Itch Intervention’ as in  
Section 10.6.4) 
Anti-convulsant class drugs (e.g., 
gabapentin or pregabalin) 
Excluded within 14 days 
(e.g. 14-day washout) prior to 
the start of the screening e-diary 
WI-NRS collection 
Prohibited 
Medications with anti-itch activity 
as documented in published 
literature even if this effect is not 
addressed in drug labelling or 
chronic itch guidelines. 
Consult with the Medical 
Monitor for assessment of 
washout duration 
Prohibited 
Cannabinoid agonists 
Excluded within 14 days 
(e.g. 14-day washout) prior to 
the start of the screening e-diary 
WI-NRS collection 
Prohibited 
Topical doxepin 
Excluded within 14 days 
(e.g. 14-day washout) prior to 
the start of the screening e-diary 
WI-NRS collection 
Prohibited (except for limited 
‘Itch Intervention’ as in Section 
10.6.4) 
Thalidomide or methotrexate 
Excluded within 14 days 
(e.g. 14-day washout) prior to 
the start of the screening e-diary 
WI-NRS collection 
Prohibited 
Cyclosporin A3 
Excluded within 6-weeks 
(e.g. 6-week washout) prior to 
the start of the screening 
e-diary WI-NRS collection 
Prohibited 


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Table-3. 
Prohibited Medications and Washout Requirements 
Concomitant Medication 
Study Entry (see Section 9.5) 
During Study 
Non-insulin biologics (including 
monoclonal antibodies) that modify 
the immune system3 
Excluded within 3-months 
(e.g. -month/12-week washout) 
prior to the start of the 
screening e-diary WI-NRS 
collection 
Prohibited 
Investigational drug products 
Excluded within 4 weeks (e.g. 
4-week washout) prior to the 
start of the screening e-diary 
WI-NRS collection 
Investigational monoclonal 
antibodies are excluded within 
3months (e.g. 3-month/12-week 
washout) prior to the start of the 
screening e-diary WI-NRS 
collection3 
Prohibited 
Cryosurgery 
Excluded within 14 days (e.g. 
14-day washout) prior to the 
start of the screening e- diary 
WI-NRS collection 
Prohibited 
UV-therapy (PUVA, UVA, UVB, 
Excimer) 
Excluded within 4 weeks 
(e.g.4-week washout) prior to 
the start of the screening e- 
diary WI-NRS collection 
Prohibited 
Medication known to be clearly 
associated with Torsade de Pointes 
(ie Credible Meds “KR- Known 
Risk” category 
(see Appendix 10) 
Not permitted unless the subject 
has been on a stable dose for at 
least 4 weeks prior to the start of 
screening.  
There must be no plans to change 
the dose during the study.  
Central nervous system 
suppressants, such as barbiturates, 
benzodiazepines (with the 
exception of short-acting 
benzodiazepines2 specifically used 
on an intermittent and as needed 
basis), anxiolytics other than 
benzodiazepines, neuroleptics, and 
clonidine 
Not permitted at study entry. 
Consult with Medical Monitor 
for appropriate washout period 
based on the specific 
medication. 
Prohibited. 


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Table-3. 
Prohibited Medications and Washout Requirements 
Concomitant Medication 
Study Entry (see Section 9.5) 
During Study 
1 = Footnote no longer applicable. 
2 = The phrase ‘short-acting benzodiazepines’ refers specifically to the following: triazolam, temazepam, 
brotizolam (available in EU only), zolpidem, and zaleplon. These drugs should be prescribed at the 
lowest effective doses and for the shortest period of time that is clinically indicated during the 
conduct of the study. Subjects receiving these agents must be provided the patient information sheet 
as noted in Table-1 and Table-2 and in Section 9.4. 
3 = Subjects whose washout equals or exceeds the 6-week equals or exceeds the 6-week screening 
window should complete laboratory and electrocardiogram (ECG) screening as early as possible. 
This ensures that the washout period is not prolonged unnecessarily and they can resume non-study 
treatment for their itch in the event that they fail laboratory or ECG criteria. Those who complete the 
washout and are otherwise eligible for study participation will be permitted to re-screen with written 
consent from the Medical Monitor. 
 
10.6.3 Symptom Management during the Titration Period (Tolerability Intervention) 
Nalbuphine use may be associated with nausea, vomiting, headache, and dizziness upon 
initiation of treatment and during the titration periods. Tolerability should be assessed throughout 
the study (clinic visits and telephone contacts) with particular attention given to the double-blind 
and open-label titration periods when subjects are more likely to experience symptoms due to the 
initiation of active treatment or to increasing dose(s). At the Investigator’s discretion, anti-
emetics that are NOT classified as having a known risk for Torsade de Pointes (see Appendix 10, 
for cardiovascular related prohibited medications with a known risk of Torsade de Pointes 
classified as “KR”) may be prescribed at the baseline or subsequent visits, in which case the 
subject should be educated on the appropriate, “as needed use” for early treatment of symptoms. 
Subjects may also benefit from education surrounding dosing with food and/or taking 
investigational product with 240 mL of water. The literature on managing opiate initiation 
generally recommends against prophylactic use, as only about 1 in 5 subjects will experience 
nausea. Headache, dizziness, nausea and vomiting can also be treated with agents that are 
commonly prescribed for these symptoms (e.g., acetaminophen for headache and scopolamine 
patch for dizziness, or ondansetron oral tablet for nausea or vomiting) during the titration period, 
but these symptoms are less frequent and do not warrant prophylaxis. Dietary and other 
prophylactic measures to avoid constipation may also be considered as clinically indicated based 
on subject history, but constipation has been limited with NAL ER in studies to date. 
10.6.4 Itch Intervention 
Baseline Through Week 14 
There is no protocol-specified rescue medication for intolerable itch in this study. Once the study 
treatment has been initiated, every effort should be made to support the subject through the full 
14-week blinded treatment period without the use of any prohibited medication for itch, 
including topical therapies. 
I 
I 
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During the screening and washout period, non-medicated topical emollients should be used to 
manage any worsening itch related to the discontinuation of a prior treatment. This may be 
continued throughout the study, and may be particularly important during the first 4 to 6 weeks. 
Observations from the TR03 study indicated that the mean WI-NRS value showed a modest 
decline in both placebo and NAL ER treatment groups over the initial weeks after starting 
investigational product, consistent with the placebo effect that is well recognized in studies of 
itch. The mean improvement in itch that has been associated with NAL ER in TR03 
differentiated from placebo between 4 and 6 weeks, with on-going differentiation thereafter. 
During these initial 4 to 6 weeks, discomfort due to ongoing itch can be addressed with 
continued nonmedicated topical emollients, and/or oral acetaminophen, as the latter is used 
broadly for pain and discomfort and may have some dulling effect on the burning and stinging 
component of the itch. All efforts should be made to provide emotional support to subjects 
through these first weeks. 
If at any point during the first 10 weeks of the double-blind period, debilitating itch cannot be 
managed with the conservative measures recommended above, then an “itch intervention” may 
be considered using one of the following topical therapies on the most symptomatic area or areas: 
topical corticosteroids, topical antihistamines (including topical doxepin), or topical capsaicin. 
Topical calcineurin inhibitors should not be used for this “itch intervention”. The “itch 
intervention” should not be 1) continued for more than 10 consecutive days; 2) used more 
than once per subject; or 3) used after the start of Week 10. Use in any of these 3 ways 
constitutes use of a prohibited medication. 
Week 14 Through Week 52 
Debilitating itch exacerbations that occur after Week 14 should be approached using the same 
sequence of management strategies recommended above. During this study period, any 
consideration of either extending a “itch intervention” beyond 10 days, or of repeating such an 
intervention should be discussed with the Medical Monitor. Use of prohibited medications or 
interventions (including cryotherapy and UV light therapy) other than topical corticosteroids and 
topical antihistamines is not permitted. If these are initiated, then the subject should be 
discontinued from study treatment and should complete the Off-Treatment visit, followed by the 
2-week off-treatment safety follow-up period (including SOWS reporting). In addition, a final 
follow-up itch and safety assessment will be made via telephone call 4 weeks after last dose of 
investigational product. 
11 EFFICACY AND PHARMACOKINETIC ASSESSMENTS 
11.1 Endpoints 
11.1.1 Primary Endpoint 
The primary efficacy endpoint is the difference between the percent “Responders” at Week 14 
for the NAL ER treatment arm versus the placebo arm. A “Responder” is defined as a subject 
with a ≥ 4- point decrease in the 7-day average WI-NRS from baseline to Week 14. 


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11.1.2 Secondary Endpoints 
Key secondary efficacy endpoints include the following: 
• The mean change in ItchyQoL from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm 
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in 
the percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to Week 
14 for the NAL ER treatment arm versus the placebo arm 
• The mean change in sleep disturbance (PROMIS Sleep Disturbance Short Form 8a) from 
baseline to Week 14 for the NAL ER treatment arm versus the placebo arm 
Other secondary efficacy endpoints include the following: 
• The mean change in 7-day average WI-NRS from baseline to Week 14 for the NAL ER 
treatment arm versus the placebo arm 
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in 
the percentage of healed lesions (item 5b) from baseline to Week 14 for the NAL ER 
treatment arm versus the placebo arm 
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in 
the percentage number of lesions (item 2) from baseline to Week 14 for the NAL ER 
treatment arm versus the placebo arm 
• Change in IGA-PN as assessed by the percentage of subjects having a 1-category 
improvement in activity 
• Change in IGA-PN as assessed by the percentage of subjects having a 1-category 
improvement in stage 
• The proportion of subjects having a PBI-P score of ≥ 1 at Week 14 for the NAL ER treatment 
arm versus the placebo arm 
Secondary Safety Endpoints 
The totality of the safety data will address the secondary endpoint of characterizing the overall 
safety and tolerability of NAL ER in subjects with PN. Key parameters within the overall 
descriptive assessment of safety and tolerability are considered to be the rate of subjects having 
an SAE (Safety) and the rate of subjects discontinuing due to AEs (Tolerability). 
Pharmacokinetics 
Nalbuphine plasma concentration (and metabolites as needed). 


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11.2 Efficacy Assessments 
11.2.1 Numerical Rating Scale for Itch 
The NRS is a PRO instrument, designed to quantify the intensity of worst itching experienced 
during a 24-hour period, and can be applied and validated either with reference to the average itch 
or to the absolute worst itch (WI-NRS) over that 24-hour period. Only the WI-NRS is being 
evaluated in this study. The scale is a set of boxes, one for each number, from 0 (no itching) to 10 
(worst possible itching). The WI-NRS is a widely used instrument recommended by the IFSI for 
quantifying itch intensity as well as a useful instrument for grouping subjects into categories of 
itch intensity described as mild, moderate, or severe20. The WI-NRS has been investigated in 
subjects with chronic pruritus of a variety of origins and a high reliability and concurrent validity 
was found13. 
In this study, subjects will be asked to record the WI-NRS value daily in the e-diary during the 
double- blind treatment period, at approximately the same time each day usually in the late 
afternoon or early evening. If the subject cannot access the e-diary (for any reason) during the 
double-blind period, the Trialogics web portal may be used as a backup for entering daily study 
information. Daily recording of WI-NRS score via the e-diary will end at the Week 14 visit. 
In the open-label extension period, WI-NRS data will be collected from the subject via the 
Trialogics web portal or e-diary at the regularly scheduled clinic visits. Note: after the week 14 
visit and only if instructed by the site and due to the necessity of a remote/phone visit, subjects 
may use the e-diary for recording the WI-NRS at the time of the phone visit. At the End of Study 
telephone call, site staff are to ask the subject to verbally report their current WI-NRS score and 
site staff must enter the reported score into the Trialogics web portal. The recommended question 
text is: “On a scale of zero to ten, with zero being ‘no itch’ and 10 being the ‘worst imaginable 
itch’, how would you describe your worst itch experience over the last 24 hours?”. This 
instrument can be found in Appendix 5. WI-NRS information should be collected per the 
instructions provided in the Trialogics User Manual. 
11.2.2 ItchyQoL 
The ItchyQoL consists of 22 pruritus-specific items measuring how pruritus affects subjects’ 
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 1. The 
ItchyQoL should be administered at the site or e-diary. 
11.2.3 Prurigo Activity Score 
The PAS consists of 5 quantitative and qualitative measurements related to the examination of 
the skin. The instrument can be found in Appendix 7. Type, number, distribution, quantitative 
number of lesions in a representative body part, and activity are documented. Prurigo lesion 
activity is recorded as a stage (0 to 4), based on the percentage of overall lesions with the relevant 
characteristic. A representative area, including the exact number of lesions present in the area, 
will be designated during the baseline assessment (screening visit; Question 4, Form 


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Version 1.0a), and will be re- evaluated during subsequent study visits; it should remain 
consistent throughout study visit assessments. The screening PAS Form Version 1.0a is to be 
used at screening only; the PAS Form Version 1.0b is to be completed for all other visits. All 
efforts should be made to ensure the same Investigator who performs the Baseline assessment 
performs the subsequent PAS assessments throughout the study. 
11.2.4 Investigator Global Assessment – Prurigo Nodularis 
The IGA-PN collects an Investigator Global Assessment of the status of the PN skin lesions. The 
instrument can be found in Appendix 6. The IGA-PN uses a 5-category scale (scoring 0 to 4) to 
describe the status of 2 aspects of PN lesions: the excoriation/crusting activity on the surface 
(PN-Activity), and the presence and character of the lesions (PN Stage). All efforts should be 
made to ensure the same Investigator who performs the Baseline assessment performs the 
subsequent IGA- PN assessments throughout the study. 
11.2.5 Patient Benefit Index 
Before therapy, the subject fills in the PBI-P pre-therapy Importance of Treatment Goals 
questionnaire to document their personal assessment regarding the importance of each individual 
treatment objective specified in the questionnaire. During and after therapy, the subject 
completes a matched “on-treatment” Treatment Benefits 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”, “very” and “did 
not apply to me”. The instrument can be found in Appendix 2. The PBI-P will be administered 
according to the schedule of events (Table-1 and Table-2), and should be administered at the site 
or e-diary. As the overall visual appearance of the pre- and on-treatment questionnaires is very 
similar, site administrators must ensure that the appropriate form is used at the appropriate visit. 
11.2.6 Sleep Scale 
There is no assessment scale that is targeted specifically to evaluate sleep in the PN population. 
The PROMIS Sleep Disturbance Short Form 8a questionnaire has been developed as a general 
tool for assessing sleep in the context of clinical trials. It consists of 8 open-ended statements 
about the subject’s sleep over the past 7 days, with 5 options for completing the statement. There 
is 1 broad sleep quality question with options for completing with: “very poor”, “poor”, “fair”, 
“good”, and “very good”. The remaining 7 questions can be answered with: “not at all”, “a little 
bit”, “somewhat”, “quite a bit”, and “very much”. The instrument can be found in Appendix 3. 
The PROMIS Sleep Disturbance Short Form 8a should be administered at the site or e-diary. 
11.2.7 Photography 
Only a limited number of selected sites will participate in the photographic documentation for 
this study. For those sites participating in the photography component of the study, chosen body 
areas will be monitored by photography over time. For participating subjects, 1 full truncal 
image (front or back), 1 full extremity image (arm or leg, front or back), and 1 reference lesion 
will be selected. Each of the selected areas will be followed with serial photographs over time for 
a total of 4 images at each selected location as specified in the Canfield Quick Reference Guide 


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and the User Reference Manual. Photographs will be stored on-site and in a 21 CFR Part 11 
compliant centralized study repository. Please see the Canfield User Reference Manual for 
instructions for selecting the chosen body areas, obtaining and storing photographs collected, and 
provisions for re-shooting photographs that do not meet quality standards for evaluation. 
Photographs of the body are conducted with monitored lesions marked. 
11.3 Pharmacokinetic Assessments 
To determine the plasma concentration of nalbuphine and metabolites, PK blood samples will be 
collected at the site with safety labs, according to the schedule of events (Table-1 and Table-2). 
Further details of PK sample collection and processing will be provided to the site in the 
laboratory manual. 
Plasma samples will be analyzed for nalbuphine and its metabolites using a validated liquid 
chromatography mass spectrometry method developed at Covance Laboratory, Inc., Madison, 
Wisconsin. 
Analysis and reporting of concentration results will be conducted according to the current 
Standard Operating Procedures for bioanalysis at Covance Laboratory, Inc., Madison, 
Wisconsin. Details of the sample analysis, including a bioanalytical study report, will be 
included with the final clinical study report. 
12 ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in Section 9.1.3. Safety will be 
determined by evaluation of the following: 
• AEs 
• Vital signs including blood pressure, heart rate, respiratory rate, and body temperature 
• Physical examination 
• Clinical laboratory data 
• Investigator reviewed ECG and central cardiac core laboratory-read-12-Lead-ECG, 
cardiovascular grading, and/or cardiovascular related prohibited medications 
• SOWS 
• Brief neurological assessment 
Post-treatment Safety: 
When a subject reaches their Week 52 visit, or discontinues from investigational product 
(whichever occurs first), their study status should be updated to “Off-Treatment” in the 
Trialogics web portal. A change in subject status to “Off-Treatment” will trigger the launch of the 
SOWS scale on the subject’s e-diary. Any subject who completes the open-label extension period, 
or discontinues from investigational product at any time, is expected to complete the daily 
SOWS for 14 days following the last dose of investigational product (unless consent is 


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withdrawn). The SOWS must be administered per the instructions found in section 12.7 and in 
the Trialogics manual. 
If subjects experience significant withdrawal symptoms during the 2-week (14 days) safety 
observation period, they should contact the Investigator. At the Investigator’s discretion, they 
may be offered treatment. 
12.1 Adverse Events 
12.1.1 Definitions 
The definitions for AEs and SAEs are given below. It is of the utmost importance that all staff 
involved in the study are familiar with the content of this section. The Investigator is responsible 
for ensuring this. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a clinical investigation subject reported 
on or after the first screening date. A TEAE is any untoward medical occurrence in a clinical 
investigation subject or subject administered a pharmaceutical product on or after the initial 
administration of investigational product at baseline. 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 investigational product, including comparator 
• A combination of 2 or more of these factors 
No causal relationship with the investigational product 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. 
AEs fall into the categories “non-serious” and “serious.” 
Serious Adverse Event 
An SAE is defined as one that, at any dose, results in any of the following: 


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• Death 
• A life-threatening adverse drug experience 
• In-patient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
A hospitalization is defined as an in-patient 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 subjects scheduled for 
cholecystectomy prior to signing the informed consent form (ICF) who subsequently are 
hospitalized for the procedure, the hospitalization would be considered elective. 
The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE. It does not refer to an 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 subject or may require intervention to prevent one of the 
other outcomes listed above, are 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. 
Adverse Event of Special Interest 
If a subject spontaneously reports an event, a symptom or a subjective experience that fits any of 
the 4 categories of AEs described below, that event should be probed with open-ended questions, 
such as “Can you tell me more about that?” or “Have you ever experienced that kind of feeling 
before?”. The goal is to better understand the context and the potential clinical significance of the 
event or subjective experience. Importantly, this probing and additional dialogue should take 
place ONLY if the subject spontaneously reports such an event or experience. Pro-active or 
suggestive questioning is not recommended, since the objective is to understand what the 
subjects themselves identify as new and different. 
Specifically, terms that relate to the following types of events should trigger the collection of 
additional information using the AESI worksheet and under the AESI section of the Adverse 
Event eCRF: 
Categories of Special Interest: 
• Experiences or events suggestive of euphoria, such as elation, exhilaration, feeling a sense of 
exaggerated well-being, or feeling intoxicated 


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• Experiences or events suggestive of mood changes or effects, such as reports of sedation, 
stimulation, or impaired attention/cognition. For example, descriptions of: somnolence, 
sedation, lethargy; or agitation, anxiety, restlessness; or abnormal behaviors, labile affect, 
and depressed mood; or poor attention, and mental or memory impairment. 
• Events or descriptions that suggest dissociative or psychotic experiences, such as reports of 
disorientation, abnormal thoughts, hallucinations, illusions or delusions 
• Observations that suggest events of drug abuse, misuse, dependence or withdrawal. These 
experiences or observations may be reported by the subject spontaneously (such as reports of 
feeling addicted, craving study drug, or complaints of withdrawal after stopping the study 
drug). The AE may also be based on direct observations made by the Clinician and/or study 
staff that suggest inappropriate use of the drug, drug tampering or drug diversion. For 
example, repetitive or significant single-time events of missing tablets in drug accountability 
assessments 
The AESI worksheet and section of the AE eCRF provides for recording the following details 
about any events meeting the characteristics described above: 
• A description of the AE event in the subject’s own words 
• The estimated time between the subject’s most recent dose prior to the AE, and the onset 
time of that AE (e.g., X minutes or Y hours between preceding dose and AE onset) 
• Any prior history of the same, similar or related symptoms or events, and any relevant prior 
diagnoses, treatments or additional details from the subject (if a subject reports dizziness, do 
they have a history of dizziness, vertigo or any past diagnosis of Meniere’s disease?) 
• Investigator full description based on subject's narrative, comments, and/or assessment 
Finally, the development of a confirmed pattern of behavior that results in a new diagnosis of 
drug dependency or drug abuse should be reported as an SAE. 
12.1.1.1 
Recording of Adverse Events 
AEs will be recorded starting with the signing of the informed consent. All AEs will be collected 
through the End of Study telephone call. 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 subject’s medical records, on a 
regular basis during the course of the study. 
Beginning at the screening visit, and continuing for the duration of the study, subjects must be 
instructed to record any new AEs on the Subject Symptom Log. Subjects should bring the log to 
every clinic visit and refer to it during telephone contacts. The Subject Symptom Log should be 
retrieved for review by study staff at each visit prior to re-dispensing it (or issuing a new log) to 
the subject. 
Following the End of Study telephone call, all unresolved AEs should be followed by the 
Investigator for at least 30 days from the last dose of investigational product. All unresolved AEs 


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that were reported by the Investigator to be probably drug related should be followed until the 
events are resolved/stabilized, the subject is lost to follow-up, or the AE is deemed irreversible. 
The reporting period for SAEs 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 Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) as needed based on local requirements. 
12.1.1.2 
Definition of Relationship to Investigational Product 
Association or relatedness to the investigational product will be graded as either “definitely 
related,” “probably related,” “possibly related,” “unlikely related,” or “not related.” 
Determination of relatedness includes: 
DEFINITELY RELATED – The AE: 
• follows a reasonable temporal sequence from administration of the study intervention 
• follows a known or expected response pattern to the suspected intervention, that is confirmed 
by improvement on stopping 
• reappearance of the event on repeated exposure that could not be reasonably explained by 
the known characteristics of the subject’s clinical state 
PROBABLY RELATED – The AE: 
• follows a reasonable temporal sequence from investigational product administration 
• abates upon discontinuation of the investigational product 
• cannot be reasonably explained by the known characteristics of the subject’s clinical state 
POSSIBLY RELATED – The AE: 
• follows a reasonable temporal sequence from investigational product administration 
• could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
UNLIKELY RELATED – The AE: 
• does not follow a reasonable temporal sequence from investigational product administration 
• is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
NOT RELATED – The AE: 
• clearly not related to the investigational product and another cause of the event is most 
plausible 


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• a clinically plausible temporal sequence is inconsistent with the onset of the event 
• study intervention and/or causal relationship is considered biologically implausible 
12.1.1.3 
Definition of Severity 
All AEs will be graded, if possible, by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 which can be found at the following website: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Re
ference_5x7.pdf 
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 
12.1.1.4 
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 investigational product, is defined as an unexpected AE. 
12.1.2 Abnormal Laboratory Values, Vital Signs, Electrocardiograms, and Physical 
Examinations 
To confirm study eligibility and assess safety throughout the study, all laboratory and ECG 
results should be reviewed and assessed for clinical significance within 5 days of report 
availability. Laboratory abnormalities will be recorded as AEs only if they are associated with 
clinical symptoms/events and they worsen following the start of investigational product 
treatment. Clinically significant findings noted prior to the start of investigational product 
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 “alanine aminotransferase 
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Clinically significant worsening in physical examination, vital sign, and ECG findings following 
start of investigational treatment will be recorded as AEs. Clinically significant findings noted 
prior to the start of investigational product treatment will be recorded as medical history. 
12.1.3 Deaths 
Should a death occur within the study period or within 60 days after the last administration of 
investigational product an AE form and an SAE form should be completed, detailing the AE that 
resulted in the death (Note: death is an outcome, not an event). The SAE must be reported to the 
ICON Medical Monitor within 24 hours of the Investigator becoming aware of the event. The 
report should contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death. 
12.1.4 Overdose 
For the purpose of study monitoring and AE reporting, a study specific definition of “overdose” 
of blinded Investigational Product is defined here. Intake of > 1 dose taken within 4 hours, or 
> 2 doses taken within a day, as reported by the patient will be considered an “overdose”. This 
should be reported as an AESI, with commentary about the details of the event. Of note, this 
definition of “overdose” is intended to provide a study-specific definition of the term ‘overdose’ 
based on the selected dosing regimen, but is not inherently expected to be associated with 
clinical ‘overdose’ symptoms unless dramatically exceeded. 
In the event of clinical overdose, the effects of nalbuphine may be reversed with opioid 
antagonists such as naloxone. Such events require urgent medical attention and sustained 
observation over several hours. Please see Section 6.4.7 of the Investigator’s Brochure for 
additional information. 
12.1.5 Pregnancy 
Female subjects who become pregnant should be immediately discontinued from the study if 
they have not yet received investigational product. If a subject is found to be pregnant after they 
have received investigational product, 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. 
12.1.6 Reporting of Serious Adverse Events 
Investigators and other site personnel must inform appropriate ICON representatives of any SAE 
that occurs (whether or not attributable to the investigational product) in the course of the study 
within 24 hours of when he or she becomes aware of it. 
All SAEs must be reported via the electronic data capture (EDC) system within 24 hours of 
Investigator’s knowledge of the event. If the EDC is not available, paper reports should be used 


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and the EDC must be updated with the information on the paper report as soon as the EDC is 
available. 
Paper reports must be faxed to the following number within 24 hours: 
ICON DRUG SAFETY (Pharmacovigilance Department) 
The preferred method of reporting on paper is via email: 
E-mail: 
mailto:
 (for Americas) 
mailto:
 (for Rest of World) 
Fax No.: 
 
Tel No.: SAE hotline number 
 or 
 (within US and outside of 
US). 
The ICON representative will work with the Investigator to compile all the necessary 
information and ensure that the appropriate Sponsor representative receives a report within 1 day 
(24 hours) for any and all SAEs. 
Follow-up information on SAEs must also be reported by the Investigator within the same time 
frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to ICON within 1 day as described above. 
The following variables will be recorded for each AE: verbatim/AE description, time and date 
for AE start and stop, maximum intensity, seriousness, causality rating, whether or not the AE 
caused the subject to discontinue, and the outcome. 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product or to the study procedure(s). All SAEs will be recorded in the eCRF. The Investigator is 
responsible for informing the Ethics Committee of the SAE as per local requirements. The 
Investigator should report to ICON, who will forward the report to the appropriate Sponsor 
representative. 
12.2 Data Safety Monitoring Board 
An unblinded, independent 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. 


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12.3 Laboratory Assessments 
A complete series of laboratory evaluations (including hematology, serum chemistry, liver 
function tests [LFTs], thyroid evaluations, free testosterone and sex hormone binding globulin 
[SHBG for biological males only], urine/serum pregnancy, HCV antibody and reflex HCV RNA 
if positive, Immunoglobulin A tissue transglutaminase [IgA-TTG], and urinalysis) will be 
obtained during screening and subsequently according to the schedule of events (Table-1 and 
Table-2). A positive IgA-TTG result for this test, will require a full review of celiac-related 
gastrointestinal symptoms (such a diarrhea, bloating, chronic unexplained abdominal pain), and 
other risk factors for celiac disease should be verified. These risk factors include: a family 
history of celiac disease, a personal history of Dermatitis Herpetiformis; Type 1 diabetes; 
impaired bone mineralization; malabsorption of micronutrients such as fat-soluble vitamins, iron, 
and potentially B12 and folic acid. Subjects previously enrolled prior to the addition of HCV or 
IgA-TTG testing in Amendment 2, will be asked if they are willing to have blood drawn for 
these specific tests. They may choose to refuse either or both of these additional tests and will be 
able to continue participation in the study regardless of either their refusal of consent or the 
results of the tests should they consent (the results will be used to support data analyses when the 
study is complete). 
Quantitative serum pregnancy tests will ONLY be conducted at the initial screening visit, and 
again at baseline, to confirm non-pregnant status prior to dispensation of investigational product. 
Once on study, subjects will be expected to adhere to protocol required birth control 
requirements and serum pregnancy testing will not be done at regularly scheduled intervals. A 
serum pregnancy test will be ordered/performed as follow-up to any positive and/or inconclusive 
urine test results (using unscheduled kit). The required clinical laboratory tests are listed in 
Table-4. Pregnancy test results must be confirmed as negative prior to dispensing investigational 
product. 
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. 
Specifically defined reflex testing, which will be performed for abnormal results, include: 
• On-study TSH values above or below the upper or lower limit of normal (ULN or LLN), will 
result in reflex testing for Free T4 from the existing laboratory sample (when sample is 
insufficient, a re-draw is necessary). 
• A positive HCV antibody will have HCV RNA processed from the existing laboratory 
sample, if possible (or on a re-draw if the original sample has insufficient material). The 
subject may not be enrolled if the HCV RNA result is detectable. Referral to a hepatologist or 
infectious disease specialist is recommended for consideration of antiviral treatment. Subject 
may be reconsidered, as appropriate, after treatment. 


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Table-4. 
Clinical Laboratory Assessments 
Serum Chemistry/Serology/Other 
Hematology 
Urine 
• 
Alanine aminotransferase 
• 
Albumin 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Calcium (screening) 
• 
Chloride 
• 
Creatinine 
• 
Direct bilirubin 
• 
Estimated glomerular filtration rate 
• 
Gamma-glutamyl transferase 
• 
Glucose (random) 
• 
Indirect bilirubin 
• 
Lactate dehydrogenase 
• 
Potassium 
• 
Phosphate 
• 
Pregnancy 
• 
Sex hormone binding globulin (for 
biological males) 
• 
Sodium 
• 
Free testosterone (for biological males 
only) 
• 
Thyroid stimulating hormone (with reflex 
Free T4 if > ULN or 
• 
< LLN) 
• 
Total bilirubin 
• 
Total protein 
• 
Uric acid 
• 
HCV antibody (if positive, then reflex HCV 
RNA; at screening only) 
• 
IgA-TTG (at screening only) 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count 
• 
White blood cell differential 
• 
Urinalysis 
• 
Pregnancy 
HCV = hepatitis C virus; IgA-TTG = Immunoglobulin A tissue transglutaminase. 
 
12.4 Electrocardiogram Assessments 
A standard 12-lead ECG will be obtained in triplicate (3 serial ECGs at least 1 minute apart, after 
the subject has been supine 5 minutes) according to the schedule of events (Table-1 and Table-2); 
see the ERT Study Manual for ECG procedures. Electrocardiograms will be reviewed locally 


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for safety by the Investigator and/or their designee.  The ECGs will be read centrally for the 
purpose of meeting the ECG study inclusion criteria, study withdrawal criteria and ECG intervals 
(PR, RR, QRS, QT, and QTcF using nomogram table), rate rhythm, and other clinically 
significant abnormalities (e.g., left ventricular hypertrophy, pathological Q-waves).  
During the conduct of the trial, if a subject develops any other cardiovascular events noted as 
part of the exclusion criteria, the cardiovascular assessments in Appendix 8 and Appendix 9 are 
to be completed. 
12.5 Physical Examination 
A complete physical examination will be performed at the screening visit and subsequently 
according to the schedule of events (Table-1 and Table-2). 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. 
12.6 Vital Signs 
Blood pressure and heart rate will be taken while seated for at least 5 minutes. Temperature may 
be taken by any standard method (e.g., oral, tympanic, rectal, etc.). 
Vital signs (blood pressure, heart rate, respiration rate, body temperature, and weight) will be 
obtained at the screening visit and subsequently according to the schedule of events. The height, 
weight, and BMI will be recorded only at screening. Weight will be obtained at the screening 
visit and subsequently according to the schedule of events (Table-1 and Table-2). 
12.7 Subjective Opiate Withdrawal Scale 
The SOWS is a self-administered scale for grading opioid withdrawal symptoms. It contains 16 
symptoms whose intensity the subject rates on a scale of 0 (“not at all”) to 4 (“extremely”). The 
instrument can be found in Appendix 4. In this study, subjects will complete SOWS daily for 14 
days, starting at the Off-Treatment visit and continuing through the washout and safety follow-up 
period to the Last Visit on the study. For subjects who discontinue study drug early 
(including in-between study visits), the change in subject status to “Off-treatment” in the 
Trialogics portal should be made immediately as the site becomes aware of discontinuation; 
SOWS entries provide valid information ONLY if they are collected in the first 14 days off-
treatment. 
12.8 Brief Neurological Assessment 
In order to monitor any potential CNS related side effects, a brief neurological assessment will 
be conducted according to the schedule of events (Table-1 and Table-2), as well as a focused 
neurological medical history which will be obtained at screening. Minimally, the following 
neurological criteria should be assessed: mental status, motor exam, sensory exam, coordination, 
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13 STATISTICAL EVALUATION 
As a companion to this protocol and to provide a more detailed explanation of the statistical 
methodology to be used for this study, a SAP will be developed prior to locking the database and 
before unblinding the randomization. 
13.1 Sample Size and Power 
The original planned sample size of approximately 240 subjects (120 per group) is based on 
assumed responder percentages for placebo and NAL ER of 25% and 45%, respectively. These 
responder percentages represent estimates based on the Week 10 data from the TR03 study. The 
power for the sample size estimate is set at 90% with a 2-sided significance level of 0.05. 
In the TR03 study, all those who achieved a 50% reduction in WI-NRS itch also achieved at least 
a 4-point reduction in itch from baseline, matching the responder definition for the current study. 
Results for all treated subjects showed a response rate for the 50% reduction criterion of 6 of 18 
(33.3%) for the NAL ER 162 mg treatment group versus 4 of 22 (18.2%) for placebo (for those 
who completed the 10-week study, results were 6 of 12 [50.0%] and 4 of 20 [20.0%]). Of note, 
the placebo response in TR03 falls on the lower end of the expected range for endpoints that 
reflect PRO endpoints in neurologically-mediated diseases such as pain or psychiatric disease. 
Studies in these areas frequently show placebo responses in the 20% to 30% range and 
sometimes as high as 40%29. The role of placebo response in dermatology has been increasingly 
documented and recognized in recent years30. Given the small size of the TR03 dataset, and the 
variability of placebo response in comparable disease states, the estimate of placebo response for 
TR11 was set at 25%. 
The NAL ER 162 mg responder rate is estimated at 45% for TR11, versus the 33.3% observed in 
TR03, for the following reasons: firstly, the TR03 endpoint was set at Week 10, and it is 
expected that the additional 4 weeks of active therapy will likely increase the response rate in 
this treatment arm. Secondly, experience from the TR03 study indicated that with close follow-
up and guidance during the titration period, subject drop-out due to early symptoms associated 
with opiate initiation can be decreased, although not eliminated. Given that the completer’s 
analysis in TR03 demonstrated a response rate of 50% (again acknowledging the small size of 
the cohort), increasing the number of subjects completing the study is expected to result in a 
somewhat higher all-treated response rate in the active arm than was seen in TR03. 
To address the concern of the reliability of the estimates of treatment effectiveness from the 
TR03 study, an adaptive mid-course Sample Size Re-Estimation (SSRE) procedure was 
introduced in Amendment 2, Protocol v3.1, when less than 10 subjects had been randomized. 
The analysis was to be performed after 50% of subjects (N=120) had either completed the 
Week 14 primary endpoint assessment or terminated the study early. Due to COVID 19-related 
delays, and because the key boundary for the lower margin of the SSRE did not differ if 
conducted at 45% of subjects, the SSRE was performed based on the Week 14 data for 
109 subjects (including pre-Week 14 discontinuations). The analysis was performed as planned 
by a single, external, unblinded statistician, and was presented and discussed at a closed session 
of the study DSMB. Based on the DSMB recommendation, the sample size for this study is 


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being increased to 360 subjects based on the SSRE conditional power which fell within the 
‘promising zone’ as defined by Mehta and Pocock. (see Section 13.4.6.4 for details). 
13.2 Randomization 
A randomization schedule will be computer-generated before the start of the study. After all 
screening procedures are performed and results of screening tests are available, eligible subjects 
will be activated in the IWRS, and assigned randomly on a 1:1 basis to the following treatment 
groups: 
• Arm A: 162 mg NAL ER 
• Arm B: Placebo 
Randomization will be performed by the IWRS. Subjects will be stratified by site. 
13.3 Statistical Analysis Sets 
13.3.1 Modified Intent-to-treat Population 
The MITT population will consist of all randomized subjects who have received at least a single 
dose of investigational product. The MITT population will be used for all efficacy analyses. In 
the event of a discrepancy between the randomized treatment and the actual treatment received, 
subjects will be analyzed for efficacy according to their randomized treatment assignment. 
13.3.2 Per-protocol Population 
The per-protocol (PP) population will include all subjects in the MITT population without any 
major protocol deviations that could have influenced the validity of the data for the primary 
efficacy variable. The deviations can include, but are not limited to: 
• Key inclusion/exclusion criteria not satisfied 
• Use of prohibited concomitant medications (this category includes those with anti-itch 
activity, see Section 10.6.4) 
• Inadequate investigational product compliance, which will be determined before breaking the 
blind 
The subjects to be excluded from the PP population will be identified in a blinded fashion and 
documented in a memo prior to the database lock and unblinding. 
13.3.3 Safety Population 
The safety population will consist of all randomized subjects who have received at least a single 
dose of investigational product. The safety population will be used in all safety analyses. In the 
event of a discrepancy between the randomized treatment and the actual treatment received, 
subjects will be analyzed according to the treatment they actually received. 


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13.4 Statistical Methods 
13.4.1 General Principles 
Summary statistics will be presented by treatment group. For continuous variables, unless 
otherwise stated, the number of available observations (n), mean, standard deviation, median, and 
range will be provided. For categorical variables, the number and percentage in each category 
will be displayed. 
For the open-label extension period, summary statistics will be presented by treatment group (as 
per the double-blind period) and overall as a single group. Only descriptive statistics will be 
displayed for open-label extension period. 
Assessments of change from baseline to post-baseline will include only those subjects with both 
baseline and post-baseline measurements. Baseline for WI-NRS is derived as the average of the 
responses on the 7 days prior to the first dose of investigational product. For other variables, the 
last value of a variable taken before the first dose of investigational product will be used as the 
baseline value. 
A more detailed description of study analyses will be presented in the SAP. 
13.4.2 Missing Data 
Unless otherwise specified, missing or dropout data will not be imputed for the purpose of data 
analysis. For the primary and secondary endpoint analyses, multiple imputation will be utilized 
to estimate missing data; details are discussed in Section 13.4.6 and will be elaborated upon in 
the SAP. 
13.4.3 Demographic and Baseline Characteristics 
Demographics and baseline disease characteristics, medical history, laboratory data, and physical 
examination findings will be summarized descriptively by treatment group. 
13.4.4 Subject Disposition 
Subject disposition will be summarized, including the reasons for discontinuation. The number 
of subjects in each analysis population will be displayed and an accounting of exclusions from 
each study population will be provided. 
13.4.5 Concomitant Medications 
Concomitant medications will be tabulated by Anatomic and Therapeutic Class of World Health 
Organization (WHO) drug, preferred term, and treatment group. For the purposes of data 
collection, a medication’s usage will be considered concomitant if it was started within 14 days 
prior to Informed Consent and continued after administration of the investigational product. If 
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Concomitant medications should be collected from 14 days prior to the signing of consent. 
Beginning at the screening visit, and continuing for the duration of the study, subjects must be 
instructed to record any new concomitant medication use on the Subject Medication Log. 
Subjects should bring the log to every clinic visit and refer to it during telephone contacts. The 
Subject Medication Log should be retrieved for review by study staff at each visit prior to 
re-dispensing it (or issuing a new log) to the subject. 
13.4.6 Efficacy Analyses 
13.4.6.1 
Analysis of Primary Endpoint 
The proportions of NAL ER and placebo subjects who meet the primary endpoint definition of 
response (a ≥ 4-point reduction of the 7-day average WI-NRS from baseline to Week 14) will be 
compared using a logistic regression model, with baseline WI-NRS as a covariate and the pooled 
site as a random effect. Subjects with missing Week 14 WI-NRS data and/or who withdraw 
prematurely prior to Week 14 will be imputed to have non-responder status in the primary 
mixed-effects model. The baseline covariate was selected because it is a clinically meaningful 
factor related to response to treatment. Study sites, pooled where appropriate, will be treated as a 
random effect to account for possible correlation between subjects within a site. Sites will be 
evaluated to ensure that both treatment groups are reasonably represented prior to inclusion in 
the analysis. Smaller sites will be combined regionally for Europe and the USA, with conditions 
for pooling described in the SAP. 
To assess the impact of the above “treatment failure” rule, the missing data strategy will employ 
the multiple imputation (MI) procedure, as well as the completers case (i.e., omitting subjects 
with missing outcomes) analysis. Multiple imputation was chosen because single imputation 
cannot reflect the sampling variability under one model or the uncertainty for the correct model. 
For sensitivity analyses, the above logistic regression model will be re-analyzed using MI to 
impute missing data, followed by the completers case analysis. 
The analysis will be based on the MITT population. Details will be described in the SAP. For all 
open-label visits, descriptive statistics will be displayed by treatment. 
In addition, the primary endpoint will be analyzed using the PP population. 
13.4.6.2 
Analysis of Secondary Endpoints 
All secondary endpoints will be analyzed using the MITT population. The change from baseline 
in continuous endpoints (WI-NRS, ItchyQoL, PROMIS Sleep Disturbance Short Form 8a) up to 
Week 14 will be analyzed based on a mixed model for repeated measures analysis that includes 
the fixed effects of treatment, visit, treatment by visit interaction, and baseline value. The main 
treatment comparison of interest is at Week 14. For PAS, individual items will be presented with 
counts and percentages for categories by treatment group and visit; for excoriations/crusts, a 
logistic regression analysis will be performed for data at Week 14, with responders defined as 
subjects who had a ≥ 1- category improvement from baseline. For IGA-PN, individual items (PN 
Activity and PN Stage) will be presented with counts and percentages for categories by treatment 
group and visit; a logistic regression analysis will be performed for PN Activity at Week 14, with 


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responders defined as subjects who had a ≥ 1-category improvement from baseline. For PBI-P, 
the count and percentage of responders (defined as those with a PBI-score of ≥ 1 at Week 14) 
will be presented by treatment group. For open-label extension period visits, descriptive statistics 
will be displayed by treatment for all secondary variables. 
13.4.6.3 
Multiplicity Considerations 
To control for Type I error, a fixed sequence testing procedure will be used on the primary 
endpoint and 3 key secondary endpoints. All endpoints will be tested at the 0.05 level of 
significance, following a pre-specified order. As soon as one endpoint assessment is found to be 
non-significant, subsequent endpoints will not be assessed; in other words, a given endpoint can 
only achieve significance if the prior endpoint is significant. The order of testing is as follows: 
(1) responders based on a ≥ 4-point decrease in the average WI-NRS from baseline to Week 14 
(i.e., the primary endpoint), (2) the mean change in ItchyQoL from baseline to Week 14, 
(3) responders based on a 1- category improvement in the percentage of prurigenous lesions with 
excoriations/crusts (PAS item 5a) from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm; and (4) the mean change in sleep disturbance (PROMIS Sleep 
Disturbance Short Form 8a) from baseline to Week 14 for the NAL ER treatment arm versus the 
placebo arm. 
13.4.6.4 
Interim Analysis (Adaptive Sample Size Re-estimation) 
As described below, an adaptive mid-course Sample Size Re-Estimation (SSRE) procedure was 
introduced in Amendment 2, Protocol v3.1, when less than 10 subjects had been randomized. 
The analysis was to be performed after 50% of subjects (N=120) had either completed the Week 
14 primary endpoint assessment or terminated the study early. Due to COVID 19-related delays, 
and because the key boundary for the lower margin of the SSRE did not differ if conducted at 
45% of subjects, the SSRE was performed based on the Week 14 data for 109 subjects (including 
pre-Week 14 discontinuations). The analysis was performed as planned by a single, external, 
unblinded statistician, and was presented and discussed at a closed session of the study DSMB 
(July 9, 2020). Based on the DSMB’s recommendation, the sample size for this study is being 
increased to 360 subjects since the SSRE conditional power fell within the ‘promising zone’ as 
defined by Mehta and Pocock.33 
Description of Pre-specified SSRE Procedures: The sample size re-estimation will be performed 
by one unblinded study statistician, who does not have a decision-making role in the trial; no one 
else, including Sponsor or clinical team members, had access or saw the unblinded data in the 
Data Monitoring Committee (DMC). The communication plan from the DMC is to report one of 
the following statements based on the conditional power results: 1) “carry on”; 2) “increase 
sample size to XXX”; or 3) “stop the study due to unfavorable safety and/or efficacy concern.” 
Details about the DMC and the data monitoring procedures are specified in the DMC charter. 
When 50% of the subjects have provided the Week 14 primary endpoint data or have terminated 
the study and the data are considered “lockable” by data management, the data file will be 
provided with limited access to the unblinded statistician in the DMC; the proportion of 
responders will be estimated; and the conditional power (CP) will be calculated. Given that the 
interim analysis is to be performed at 50% of the initial sample size (120 subjects), the targeted 
power is 90%, and the maximum allowable sample size is set at 1.5 times the initial sample size 


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(360 subjects), the conditional power cut-off value (CPmin) is 41%34. If the CP is between 41% 
and 90%, the number of subjects per treatment arm will be increased, up to the maximum 
allowable sample size for this study (120 × 1.5 = 180 each group), to recover the targeted power 
of 90%. 
Since sample size re-estimation occurs only when the interim conditional power falls in the pre- 
specified “promising” range. The study will not stop for efficacy regardless of the conditional 
power; the overall alpha will be protected; and the final analysis will be carried out using 
conventional tests, without the need for weighing the stage 1 and 2 results or adjusting the alpha 
value. 
13.4.7 Safety Analyses 
All on-treatment safety data will be assessed descriptively for AEs, SAEs, clinical laboratory 
measurements, vital signs, physical examinations and SOWS. ECG data will be analyzed in a 
separate report by ERT Clinical. The totality of these data addresses the secondary objective of 
characterizing the overall safety and tolerability of NAL ER in subjects with PN. Key parameters 
within the overall descriptive assessment of safety and tolerability are considered to be the rate 
of subjects having an SAE (Safety) and the rate of subjects discontinuing due to AEs 
(Tolerability). 
No formal statistical analysis will be performed on safety outcomes; inferences, if any, will be 
derived through clinical review and interpretation. 
13.4.7.1 
Adverse Events 
All TEAEs will be summarized overall and for each body system and preferred term by 
treatment group, relationship to investigational product, and severity. For tabulations by severity, 
only a subject’s most severe event within the category (e.g., overall, body system, or preferred 
term) will be counted. AEs will be dichotomized into “related” (definitely, probably, and 
possibly) and “unrelated” (unlikely and not related). “Treatment-emergent” will be defined as 
starting or worsening after the first dose of investigational product. 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 US, AESIs that code to the most 
relevant abuse related MedDRA preferred terms, will be tabulated and descriptive narratives will 
be written. Additional AEs that are considered “possibly related to abuse potential” will be 
tabulated separately25. The list of MedDRA preferred terms for AESIs will be described in the 
SAP. 
13.4.7.2 
Vital Signs 
Vital signs, including blood pressure, heart rate, body temperature, respiration rate, and weight 
will be summarized by treatment group at baseline and at each scheduled visit. 


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13.4.7.3 
Clinical Laboratory Assessments 
Clinical safety laboratory data will be summarized descriptively by treatment group at baseline 
and at subsequent scheduled visits. 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. Laboratory data will also be listed by 
treatment, subject, and visit. Listings will include scheduled, unscheduled, and repeat 
evaluations. A listing of markedly abnormal values, as defined in the SAP, will additionally be 
generated. 
13.4.7.4 
Physical Examinations 
Abnormal physical examination findings that suggest a clinically significant worsening from 
baseline will be reported as AEs and analyzed as such. Clinically significant findings noted prior 
to start of investigational product treatment will be recorded as medical history and analyzed as 
such. 
13.4.7.5 
Electrocardiograms 
Electrocardiogram data (e.g., heart rate, PR, QTcF intervals) will be presented in listings by 
subject and collection date/time. A complete ECG assessment will be analyzed and reported in a 
separate ECG report from ERT Clinical. 
13.4.8 Pharmacokinetic Analyses 
Investigational product plasma concentration data (nalbuphine and metabolites) will be listed by 
collection time, as applicable. 
Two additional sets of analyses will be conducted and provided in separate reports: 1) Analysis 
and reporting of concentration results by Covance Laboratory; and 2) PK-PD analyses to 
describe the exposure-response relationships between nalbuphine plasma concentrations and 
efficacy parameters. Additional PK-PD analyses may be conducted to include safety and/or 
tolerability parameters, as appropriate. 
14 DIRECT ACCESS TO SOURCE DATA/NOTES 
Domestic and foreign regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, eCRFs, 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 subject names are 
obliterated on the copies to ensure confidentiality. 


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15 QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 Conduct of the Study 
Trevi/ICON shall implement and maintain quality control and quality assurance procedures with 
written Standard Operating Procedures to ensure that the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, ICH GCP and applicable 
regulatory requirements. 
This study is to be conducted according to globally accepted standards of GCP (as defined in the 
ICH E6 Guideline for GCP, 01 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. 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IEC/IRB, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study. Any deviations may result in the subject having to be 
withdrawn from the study and render that subject nonevaluable. 
15.2 Study Monitoring 
Monitoring and auditing procedures, developed or endorsed by the Sponsor 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 the Sponsor 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 eCRF will be reviewed for completeness and 
adherence to the protocol. As part of the data monitoring, source documents must be made 
available to the Study Monitor for review. The Study Monitor will also perform investigational 
product accountability and subject compliance 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 and safety oversight. 
Due to unforeseen circumstances such as a pandemic which restrict monitors from performing an 
on- site visit, remote monitoring visits are allowed. 
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 


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Investigator will permit inspection of the study files by authorized representatives of the Sponsor 
or the regulatory agencies. 
During the course of the study, certain sites may be chosen and scheduled for a routine audit by 
the Sponsor or its designee as part of the Sponsor’s normal processes. 
16 ETHICS 
16.1 Independent Ethics Committee/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 subject information, recruitment methods such as subject 
diaries, and advertisements, to the 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. 
16.2 Written Informed Consent 
Potential subjects 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 subject. 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 subject and must specify who informed the potential subject. Where 
required by local law, the person who informs the potential subject must be a physician. 
After reading the ICF, the potential subject must give consent in writing. The subject’s consent 
must be confirmed at the time of consent by the personally dated signature of the subject 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 subject. 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. 


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17 DATA HANDLING AND RECORD KEEPING 
17.1 Case Report Forms/Source Data Handling 
The Investigator, or designee, will enter study data required by the protocol into an EDC system. 
Clinical research associates will visit each study site, at a frequency documented in the 
monitoring plan, to review the 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. 
AEs will be coded using the most current MedDRA version. Prior and concomitant medications 
will be coded according to the WHO Drug Dictionary. 
17.2 Retention of Essential Documents 
The following records must be retained by the Investigator for a minimum of 2 years after the 
Sponsor has notified the Food and Drug Administration (FDA) that investigations have been 
discontinued, or after the FDA has approved the new drug application: 
• Signed ICFs for all subjects 
• Subject identification code list, screening log (if applicable), enrollment log, and any 
other relevant administrative log (e.g., training logs, site visit logs) 
• 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 CRO) 
• List of Sub-investigators and other appropriately qualified persons to whom the Investigator 
has delegated significant trial-related duties (Delegation of Authority log), together with their 
roles in the study and their signatures 
• Copies of eCRFs and of documentation of corrections for all subjects 
• Drug accountability records including individual dispensing logs, overall site dispensing 
logs, room temperature logs, and drug transit logs 


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• Record of any body fluids or tissue samples retained 
• All other source documents (subject 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, due to 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 in writing and kept in the 
Investigator study file. 
18 FINANCING AND INSURANCE 
Financing and insurance are addressed in a separate agreement. 
19 PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data. When the study is complete the Sponsor shall 
arrange the analysis and tabulation of data. A clinical study report shall then be prepared, which 
may be used for publication, presentation at scientific meetings or submission to regulatory 
authorities. All proposed publications based on this study must be subject to the Sponsor’s 
approval requirements. 


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20 SIGNATURE OF COORDINATING INVESTIGATOR 
21 July 2021 
I agree to conduct the study outlined above in accordance with the terms and conditions of the 
protocol, !CH guidelines on GCP and with applicable regulatory requirements. All information 
pertaining to the study shall be treated in a confidential manner. 
DR.
, 
University of Miinster 
Version 7.0 
Date (day/month/year) 
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21 SIGNATURE OF INVESTIGATOR 
I agree to conduct the study outlined above in accordance with the terms and conditions of the 
protocol, ICH guidelines on GCP and with applicable regulatory requirements. All information 
pertaining to the study shall be treated in a confidential manner. 
 
 
 
 
Signed 
Date (day/month/year) 
 
 
Print name 
Job Title 
 


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20. Ständer S, Augustin M, Reich A, et al. International Forum for the Study of Itch Special 
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201393(5):509-14. 
21. Desai NS, Poindexter GB, Monthrope YM, et al. A pilot quality-of-life instrument for 
pruritus. J Am Acad Dermatol. 2008;59(2):234-44. 
22. Carr CW, Veledar E, Chen SC. Factors mediating the impact of chronic pruritus on quality 
of life. JAMA Dermatol. 2014;150(6):613-20. 
23. Blome C, Augustin M, Siepmann D, et al. Measuring patient-relevant benefits in pruritus 
treatment: development and validation of a specific outcomes tool. Br J Dermatol. 
2009;161(5):1143-8. 
24. Schedel F, Schurmann C, Augustin M, et al. 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. 
25. U.S. Department of Health and Human Services, Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Assessment of Abuse Potential of Drugs - 
Guidance for Industry. January 2017. 


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26. Jovey RD, Ennis J, Gardner-Nix J, et al; Canadian Pain Society. Use of opioid analgesics 
for the treatment of chronic noncancer pain--a consensus statement and guidelines from the 
Canadian Pain Society, 2002. Pain Res Manag. 2003;8 Suppl A:3A-28A. 
27. Investigator’s Brochure Nalbuphine Hydrochloride Extended-Release Tablets. 
April 29, 2020. 
28. Sher LG, Chang J, Patel IB, Balkrishnan R, Fleischer AB Jr. Relieving the pruritus of atopic 
dermatitis: a meta-analysis. Acta Derm Venereol. 2012;92(5):455-61. 
29. Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial 
outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur 
Neuropsychopharmacol. 2009;19(1):34-40. 
30. Evers AW. Using the placebo effect: how expectations and learned immune function can 
optimize dermatological treatments. Exp Dermatol. 2017;26(1):18-21. 
31. Gal TJ, DiFazio CA, Moscicki J. Analgesic and respiratory depressant activity of 
nalbuphine: a comparison with morphine. Anesthesiol. 1982;57:367-374. 
32. Chen YH, DeMets DL, Lann KK. Increasing the sample size when the unblinded interim 
result is promising. Statistics in Medicine 2004; 23:1023-1038. 
33. Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: 
a practical guide with examples. Statistics in Medicine 2011; 30(28):3267-84. 
 


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23 APPENDICES 
Appendices 1 – 5 provide the Patient Reported Outcomes (PRO) questionnaires and scales 
that are used in this study. 
Patient Reported Outcomes: 
Appendix 1 
ItchyQoLTM – Itching Quality of Life Survey 
Appendix 2 
Patient Benefit Index, Pruritus Version 
Appendix 3 
PROMIS Sleep Disturbance Short Form 8a 
Appendix 4 
Subjective Opiate Withdrawal Scale 
Appendix 5 
Worst Itch – Numerical Rating Scale 
Appendices 6 and 7 provide the Investigator Assessment tools that are used in this study. 
Investigator Assessments: 
Appendix 6 
Investigator Global Assessment – Prurigo Nodularis 
Appendix 7 
Prurigo Activity Score Questionnaire 
Appendices 8 and 9 provide Grading or Classification Criteria to be used during the Screening 
Period in the assessment of Subject eligibility for this study. 
Appendix 10 provides the link to the CredibleMeds website to be used for assessing whether 
subject concomitant medications include any with a known risk for Torsade des Pointes. 
Cardiac Classification Criteria: 
Appendix 8 
Canadian Cardiovascular Society Grading of Angina Pectoris 
Appendix 9 
Classification Criteria for Congestive Heart Failure 
Appendix 10 List of Drugs That Prolong QT and/or Cause Torsades de Pointes 
Appendix 11 Not applicable 
Appendix 12 Summary of Changes 
 


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APPENDIX 1 ITCHYQOLTM – ITCHING QUALITY OF LIFE SURVEY 
 
 


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Site number: ______ Su~ectinitials: ______ Su~ectnumber: _____ Visit date (dd/mmm/yyyy): ______ _ 
ltchyOoL™ 
y':;\ 
\/-) 
{>--
4w 
' 
ITCHING QUALITY OF LIFE SURVEY 
The following questions concern your feelings about your itchy skin 
How often during the past week do these 
condition. Please check the answer that best describes your experience. 
statements apply to you? 
ALL THE 
NEVER 
RARELY 
SOMETIMES 
OFTEN 
TIME 
1. My itchy skin condition bleeds. 
D 1 
D 2 
D i 
D 4 
D s 
2. My skin hurts because ofmy itchy skin condition. 
D 1 
D 2 
D i 
D 4 
D s 
3. My itchy skin condition burns or stings. 
D 1 
D 2 
D i 
D 4 
D s 
4. I get scars from my itchy skin condition. 
D 1 
D 2 
D i 
D 4 
D s 
5. I need to scratch my itchy skin condition. 
D 1 
D 2 
D i 
D 4 
D i 
6. Temperature or seasonal changes aggravate my itchy skin condition. 
D 1 
D 2 
D i 
D 4 
D s 
7. I spend a lot of money treating my itchy skin condition. 
D 1 
D 2 
D i 
D 4 
D s 
8. My itchy skin condition makes it hard to work or do what I enjoy. 
D 1 
D 2 
D i 
D 4 
D i 
9. My itchy skin condition affects my interaction with others. (For example: family, friends, close 
D 1 
D 2 
D i 
D 4 
D s 
relationships, etc.) 
© 2004, 2012 Emory University. All rights reserved. 
Page 1/3 


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The following questions concern your feelings about your itchy skin 
condition. Please check the answer that best 
describes your experience. 
10. My itchy skin condition affects how well I sleep. 
11. My itchy skin condition often makes it difficult to concentrate. 
12. My itchy skin condition limits the types of clothes I can wear. 
13. My itchy skin condition forces me to buy special soaps, detergents, and lotions. 
14. I am frustrated by my itchy skin condition. 
15. I am embarrassed by my itchy skin condition. 
© 2004, 2012 Emory University. All rights reserved. 
Page 213 
How often during the past week do these 
statements apply to you? 
NEVER 
RARELY 
SOMETIMES 
OFTEN 
ALL lHE 
TIME 
D
1 
D
2 
D
1 
D
1 
D
1 
D
I 
D
1 


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16. My itchy skin condition drives me crazy/nuts. 
17. My itchy skin condition makes me angry or irritable. 
18. My itchy skin condition makes me feel depressed or sad. 
19. I worry about what other people think about me because of my itchy skin condition. 
20. I worry that the itching will last forever. 
21. I feel self-conscious because of my itchy skin condition. 
22. My personality has changed because ofmy itchy skin condition. 
SuQj ect signature 
© 2004, 2012 Emory University. All rights reserved. 
Page 3/3 
Date 
How...ll!lw during the past week do these 
statements apply to you? 
ALL lHE 
NEVER 
RARELY 
SOMETIMES 
OFTEN 
TIME 


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APPENDIX 2 PATIENT BENEFIT INDEX, PRURITUS VERSION 
 
 


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PBI-P - Patient Benefit Index, pruritus version 
Importance of Treatment Goals 
With the help of the following questions, we'd like to know how important the goals mentioned below are 
to you personally in the current treatment of your skin disease. 
For each of the following statements, please mark how important this treatment goal is to you. 
If a statement does not apply to you, for example because you are not experiencing pain, please mark 
"does not apply to me". 
As a result of therapy, how important is it for you to ... 
1 ... be free of pain 
2 ... be free of itching 
3 ... no longer have burning sensations on your skin 
4 ... be healed of all skin defects 
5 ... concentrate better 
6 ... be less nervous 
7 ... be able to wear all types of clothing 
8 ... be able to bathe and shower normally 
9 ... sleep better 
10 .. .feel less depressed 
11 ... experience greater enjoyment of life 
12 ... have no fear that the disease will get worse 
13 ... lead a normal everyday life 
14 ... be more productive in everyday life 
15 ... be less of a burden to relatives and friends 
16 ... engage in normal leisure activities 
17 ... be able to lead a normal 'M?rking life 
18 ... be able to have more contact with other people 
19 .. . be more comfortable showing yourself in public 
20 ... be less burdened in your partnership 
21 ... be able to have a normal sex life 
22 ... be less dependent on doctor and clinic visits 
23 ... need less time for daily treatment 
24 ... have fewer out-of-pocket treatment expenses 
25 ... have fewer side effects 
26 ... find a clear diagnosis and therapy 
27 ... have confidence in the therapy 
iii 
ro 
0 
C: 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
ro 
j 
Cl) 
E 
0 
"' 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Please recheck your answers to make sure your have clearly marked each statement with an "x". 
Thank you very much for your cooperation! 
PBI-Patient Benefit Index (index of benefits and needs in therapy}, Augustin 2006 
(I) 
E: 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 


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PBI-P - Patient Benefit Index, pruritus version 
Treatment Benefits 
When the treatment began, you indicated in a questionnaire how important various goals were in the 
treatment of your skin disease. 
Please mark each of the following statements according to the extent to which those treatment goals 
were achieved, indicating if the treatment has benefited you. If a statement did not apply to you, for 
example because you did not experience any pain, please mark "did not apply to me". 
>, 
iv 
ai 
The current treatment has helped me to ... 
iij 
.c 
iv 
iv 
== 
... 
a, 
a, 
2 
E 
iJ 
>, 
0 
0 
·s 
... 
0 
E 
a, 
C: 
II) 
C" 
> 
1 ... be free of pain 
0 
0 
0 
0 
0 
2 ... be free of itching 
0 
0 
0 
0 
0 
3 ... no longer have burning sensations on my skin 
0 
0 
0 
0 
0 
4 ... be healed of all skin defects 
0 
0 
0 
0 
0 
5 ... concentrate better 
0 
0 
0 
0 
0 
6 ... be less nervous 
0 
0 
0 
0 
0 
7 ... be able to wear all types of clothing 
0 
0 
0 
0 
0 
8 ... be able to bathe and shower normally 
0 
0 
0 
0 
0 
9 ... sleep better 
0 
0 
0 
0 
0 
10 .. .feel less depressed 
0 
0 
0 
0 
0 
11 ... experience greater enjoyment of life 
0 
0 
0 
0 
0 
12 ... have no fear that the disease will get worse 
0 
0 
0 
0 
0 
13 ... lead a normal everyday life 
0 
0 
0 
0 
0 
14 ... be more productive in everyday life 
0 
0 
0 
0 
0 
15 ... be less of a burden to relatives and friends 
0 
0 
0 
0 
0 
16 ... engage in normal leisure activities 
0 
0 
0 
0 
0 
17 ... be able to lead a normal 'M:lrking life 
0 
0 
0 
0 
0 
18 ... be able to have more contact with other people 
0 
0 
0 
0 
0 
19 ... be more comfortable showing myself in public 
0 
0 
0 
0 
0 
20 ... be less burdened in my partnership 
0 
0 
0 
0 
0 
21 ... be able to have a normal sex life 
0 
0 
0 
0 
0 
22 .. . be less dependent on doctor and clinic visits 
0 
0 
0 
0 
0 
23 ... need less time for daily treatment 
0 
0 
0 
0 
0 
24 ... have fewer out-of-pocket treatment expenses 
0 
0 
0 
0 
0 
25 ... have fewer side effects 
0 
0 
0 
0 
0 
26 ... find a clear diagnosis and therapy 
0 
0 
0 
0 
0 
27 ... have confidence in the therapy 
0 
0 
0 
0 
0 
<I) 
E: 
.E 
<' & 
(lJ 
0 
C: 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Please recheck your answers to make sure your have clearly marked each statement with an "x". 
Thank you very much for your cooperation! 
PBI-Patient Benefit Index (index of benefits and needs in therapy}, Augustin 2006 


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APPENDIX 3 PROMIS SLEEP DISTURBANCE SHORT FORM 8A 
 


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PROMIS Item Bank v!0 - Sleep Disturbance - Short Form 8a 
Sleep Disturbance - Short Form 8a 
Please respond to each question or statement by marking one box per row. 
In the past 7 days ... 
Very poor 
Poor 
Fair 
Good 
Very good 
SleBp10Q 
My sleep quality was .................................. 
4 
In the past 7 days ... 
Not at all 
A little bit 
Somewhat 
Quite a bit Very much 
Sleep116 
My sleep was refreshing ............................. 
4 
Sleep20 
I had a problem with my sleep .................. 
4 
Sleep44 
I had difficulty falling asleep .................... 
4 
Sleep108 
My sleep was restless ................................ 
4 
Slesp72 
I tried hard to get to sleep ........................... 
4 
Sleep67 
I worried about not being able to fall 
asleep ................ ......................................... 
4 
SleBp115 
I was satisfied with my sleep ...................... 
4 
2 June 2016 
© 2008-2016 PROMIS Health Organization and PROMIS Cooperative Group 
Page I of I 


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APPENDIX 4 SUBJECTIVE OPIATE WITHDRAWAL SCALE 
 


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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 
0 
1 
2 
3 
4 
muscles ache 
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 !'Mich 
0 
1 
2 
3 
4 
15 
I have stomach 
0 
1 
2 
3 
4 
cramps 
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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APPENDIX 5 WORST ITCH NUMERICAL RATING SCALE 
 


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Numerical Rating Scale (Worst Itch) 
Sample – actual assessment scale will be on e-diary 
 
How would you rate your most severe itching over the past 24 hours? 
Numerica l Rating Sca le 
No Itch 
Worst Imaginable Itch 


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APPENDIX 6 INVESTIGATOR GLOBAL ASSESSMENT – PRURIGO 
NODULARIS 
 


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Investigator’s Global Assessment - Prurigo Nodularis 
 
 
 
IGA I: PN Activity. Considers excoriations 
and crusts on the top of PN lesions (first 
sign of pruritus improvement) 
 
Score 
Category 
Description: Activity 
0 
Clear 
No nodules have excoriations or crusts 
1 
Almost 
Clear 
Small number of nodules have excoriations or crusts 
2 
Mild 
Minority of nodules have excoriations or crusts 
3 
Moderate 
Most nodules have excoriations or crusts 
4 
Severe 
Vast majority of nodules have excoriations or crusts 
 
 
 
 
IGA II: PN Stage. Considers the nodules themselves (long-term sign of 
improvement) 
 
Score 
Category 
Description: Presence 
0 
Clear 
No nodules (0 nodules) 
1 
Almost 
Clear 
Rare, flattened lesions, with no more than single 
dome- shaped palpable nodules (1-5 nodules) 
2 
Mild 
Few, mostly flattened lesions, with small number of 
dome- shaped palpable nodules (6-19 nodules) 
3 
Moderate 
Many lesions, partially flattened and dome-shaped 
palpable nodules (20-100 nodules) 
4 
Severe 
Abundant lesions, majority are dome-shaped 
palpable nodules (over 100 nodules) 


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APPENDIX 7 PRURIGO ACTIVITY SCORE QUESTIONNAIRE 
 


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P/lS, Version 1 .Da (Baseline) 18.08.2017 
Prurigo Activity Score (PAS) 
Name: -------
1 a. T)lp e af Pru rlgo: W hie h efflorescences do you see? 1 Mult1p1, answ,,, ~s, bk!! 1 
D-typo-/1-typerpigmented maculae 
Papules 
Plaques 
Ulcers 
1b. J)lpe af Prurlgo: Which type of prurlgo Is predominant? 1s,"lli. arr;w,r ont,,1 
Completely healed (except scars) 
Prurigo papul ar type 
D Prurigo nodular type 
D Prurigo plaquestype 
D Prurigo ulcerated type 
Z. flilUDbi:.ti How many prurlgo lesions do you see? 1s,"ll1, arr;w.ront,,1 
Pl,;ase note 
1-19 
EHimate; don ot mu nt! 
20-100 
Don ot consider scars. 
> 100 
3 lllUtlbl.Blao· Please mark the affected areafs) (Mult,pke sale!<t"" =,b1,1 
Affected 
Area 
[Please mark as 
Code for Item 4 
appropriate) 
Left forearm 
I ) 
(1) 
Right forearm 
I ) 
(2) 
Upper left arm 
I ) 
(3) 
Upper right arm 
I ) 
(4) 
Lower left leg 
I ) 
(S) 
Lower right leg 
I ) 
(6) 
Upper left leg 
I ) 
(7) 
Upper right leg 
I ) 
(8) 
Ventral trunk fsee Fill. 1 l 
f 
l 
191 
Dorsal trunk [see Fig. 1) 
I ) 
(10) 
Ca pi 11 iti um 
I ) 
(11) 
Face 
I ) 
(12) 
4. Represent at ille Area: 
Date: -------
IDD/MP,\l'l'Y'IYI 
.. 
" 
l) (~ 
~\1i~ ~-i) 
Fig. 1 
Please choose a representative area which will be re-examined during each visit. During the study the 
area must be always the same, please count In that area! 
Representative area [.see Cade fram item 3): 
---
Exact number of pru riginous lesions in representative area (exd uding scars): ---
5 .e.a~n~· 
[Di}[k lb~ [~D~Cli~~ g~[C~D!ili:~ iD cgmg~[i~go Jg ~11 D[Ll[ii:iogu~ l~igo~ 
1s1ngle answ,, on t,,I 
a) Prurlglnous l,;slons with 
0% 
1- 25 % 
26- so% 
S 1 - 75 % 
76-100% 
,;:i«:0rlatlons/crusts: 
b) fiealed prurlgo l,;slons: 
100% 
75-99 % 
so- 74 % 
25 -49 % 
0- 24% 


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P/lS, Version 1 .Db (FollowUp) 18 .08.2017 
Prurigo Activity Score (PAS) 
Name: -------
1 a. T)lp e af Pru rlgo: W hie h efflorescences do v ou see? 1 Mult1p1, answ,,, ~s, bk!! 1 
D-typo-/1-typerpigmented maculae 
Papules 
Plaques 
Ulcers 
1b. J)lpe af Prurlgo: Which type of prurlgo Is predominant? 1s,"lli. arr;w,r ont,,1 
Completely healed (except scars) 
Prurigo papul ar type 
D Prurigo nodular type 
D Prurigo plaquestype 
D Prurigo ulcerated type 
Z. flilUDbi:.ti How manv prurlgo lesions do vou see? 1s,"ll1, arr;w.ront,,1 
Pl-,ase note 
1-19 
EHimate; don ot mu nt! 
20-100 
Don ot consider scars. 
> 100 
3 lllUtlbl.BlaD· Please mark the affected areafs) (Mult,pke sale!<t"" =,b1,1 
Affected 
Area 
[Please mark as 
Code for Item 4 
appropriate) 
Left forearm 
I ) 
(1) 
Right forearm 
I ) 
(2) 
Upper left arm 
I ) 
(3) 
Upper right arm 
I ) 
(4) 
Lower left leg 
I ) 
(S) 
Lower right leg 
I ) 
(6) 
Upper left leg 
I ) 
(7) 
Upper right leg 
I ) 
(8) 
Ventral trunk fsee Fill. l l 
f 
l 
191 
Dorsal trunk [see Fig. 1) 
I ) 
(10) 
Ca pi 11 iti um 
I ) 
(11) 
Face 
I ) 
(12 ) 
4. Represent at ille Area: 
Date: -------
IDD/MP,\l'l'Y'IYI 
.. 
" ) c~ 
~\1i~i ~-i) 
Fig. 1 
Please look for the representative area defined at baseline. During the study, the area must remain the 
same, please count In that area! 
Representative area [see Cade fram item 3): 
---
Exact number of pru tiginous lesions in representative area (exd uding scars): ---
5. Actillit:it: Please mark the respective percent5!£e In comparison to all prurlglnous I es Ions. 
1s1ngl<!:! ans-.w.?, on fyl 
a) Prurlglnous lesions with 
0% 
1- 25 % 
26- so % 
51 - 75 % 
76-100% 
1'.>J«:Or la tlons/crusts: 
bl f4ealed prurlgo 1-,slons: 
100% 
7 5-99 % 
so- 74 % 
25 -49 % 
0- 24% 


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APPENDIX 8 CANADIAN CARDIOVASCULAR SOCIETY GRADING OF 
ANGINA PECTORIS 
 


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Canadian Cardiovascular Society Grading of Angina Pectoris 
 
Grade 
Description 
Grade 1 
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 
Reference 
Campeau Lucien. Grading of angina pectoris. Circulation 1976;54:522-3 


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APPENDIX 9 CLASSIFICATION CRITERIA FOR CONGESTIVE HEART 
FAILURE 
 


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NYHA FUNCTIONAL CLASSIFICATION OF HEART 
FAILURE 
 
Classification is based on functional limitations and severity. 
 
 
Class Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure 
at rest. 
If any physical activity is undertaken, discomfort increases. 
 
1 Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York 
Heart Association. Criteria Committee. Nomenclature and criteria for diagnosis of 
diseases of the heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and 
Wilkins; March 1, 1994. 


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APPENDIX 10 
LIST OF DRUGS THAT PROLONG QT AND/OR CAUSE 
TORSADES DE POINTES 
 
 
A list of drugs that prolong QT and/or cause Torsades de Pointes is available at 
www.crediblemeds.org. All concomitant medications taken by a subject should be verified on the 
Credible Meds website to confirm they DO NOT have a Known Risk (i.e. KR category) for 
Torsade de Pointes. 
 


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APPENDIX 11 
NOT APPLICABLE 
Appendix 11 is not applicable effective with protocol V7.   


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APPENDIX 12 
SUMMARY OF CHANGES: AMENDMENTS 1, 2, 3, 4, 5, 6 
Amendment 6: 
Clinical Research Protocol TR11 V7.0 (21 July 2021) was produced for the following purposes: 
• To update the inclusion criteria 6 to remove “non-sedating” so that it is consistent 
with the change allowing sedating antidepressants.  Duration at stable dose also 
changes to coincide with allowed changes for sedating antidepressants. 
• To update the exclusion criteria to eliminate systemic antihistamines as excluded and 
add that the subject must be on a stable dose. 
• To update the exclusion criteria to eliminate sedating antidepressants as excluded. 
• To update Table 3 to revise exclusion information for systemic antihistamines, 
sedating antidepressants, and for medicines with a known risk for Torsade de Pointes. 
• To provide clarification on the QTcF values to prevent exclusion of subjects who 
present with Right Bundle Branch block 
• To allow drugs previously not allowed due to known risk for Torsade de Pointes as 
long as the subject has been on a stable dose for at least 4 weeks prior to screening.  
Elimination of exclusion criteria #34 as it is no longer required. 
 


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Study Modifications: 
 
 
Subjects using non-sedating 
antidepressants must be on a stable dose 
for a minimum of 8 4 weeks prior to 
signing consent screening and must be 
willing to remain on their stable dose for 
the entire duration of the study 
 
Synopsis Inclusion 
Criteria #6 and 
Section 9.5.2 
Inclusion Criteria #6 
To update the inclusion criteria 6 to remove non-sedating so that 
it is consistent with the change allowing sedating 
antidepressants.  Duration at stable dose also changes to 
coincide with allowed changes for sedating antidepressants. 
Potential subjects who have received 
gabapentin, pregabalin, calcineurin 
inhibitors, cannabinoid agonists, capsaicin, 
cryosurgery, topical doxepin, thalidomide 
or methotrexate, topical antihistamines 
(systemic or topical), or drugs of other 
classes (such as oral doxepin) which have 
significant anti-histaminic activity and 
topical corticosteroids require a 14-day 
washout.  These medications are 
prohibited for the duration of the study.  
Use of systemic antihistamines are not 
permitted unless the subject has been on a 
stable dose for at least 4 weeks prior to 
screening and there are no plans to change 
the dose during the study. Please refer to 
Table 3 and Section 9.1.3.1. 
 
Synopsis Exclusion 
Criteria #22) and 
Section 9.5.2 
(Exclusion Criteria 
#22) 
Elimination of the exclusion of antihistamines (systemic and 
topical) based on the evolving recognition that long term use of 
antihistamines does not meaningfully address the itch of prurigo 
nodularis (PN).  Use of stable dose antihistamines in patients 
that present with severe pruritus will not interfere with the 
efficacy assessments of this protocol. 
 


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Potential subjects taking central nervous 
system suppressants, such as sedative 
antidepressants, barbiturates, 
benzodiazepines (with the exception of 
short-acting benzodiazepines specifically 
used on an intermittent and as needed 
basis), anxiolytics other than 
benzodiazepines, neuroleptics, and 
clonidine are excluded.  These medications 
are prohibited for the duration of the study.  
These medications are prohibited for the 
duration of the study (see Section 10.6.2, 
footnotes 1 and 2 to Table 3 for definitions 
of ‘sedative antidepressants’ and ‘short-
acting benzodiazepines’). 
 
Synopsis Exclusion 
Criteria #25 and 
Section 9.5.2 
(Exclusion Criteria 
#25) 
Lower and delayed Cmax Following Oral ER Nalbuphine: 
• The oral BA of a nalbuphine solution was low 
(approximately 5%) in both rats and dogs (Studies NAL78 
and NAL79) suggesting ~ 20-fold lower Cmax after oral 
Nalbuphine ER administration (Ref: IB). In humans, the 
mean nalbuphine plasma concentration five minutes after 
10 mg intravenously was 53 ng/mL (Lo et al, 1987).  As the 
doses for injectable nalbuphine range from 10 mg to 20 mg, 
the maximal concentrations will range from 53 to 106 ng/mL 
Following a single oral 162-mg nalbuphine ER dose, the 
mean Cmax was 21.6 ng/mL (Ref: IB).  As expected of an ER 
formulation, peak concentrations were blunted and rate of 
absorption delayed. Thus, Cmax after administration of 
162 mg oral nalbuphine ER formulation are ~2.5-5 fold 
lower than the intravenous formulation. 
No Drug-Drug interaction Potential of Oral Nalbuphine ER 
and tricyclic antidepressants, SSRI, SNRI: 
• In vitro inhibition studies demonstrated that nalbuphine does 
not inhibit any of the major CYP isozymes.  Thus, the 
potential for a metabolism-based interaction of nalbuphine 
on other drugs is unlikely. Most of the tricyclic anti-
depressants are metabolized by CYPs 3A4, 2D6, 1A2, 2C9 
and 2B6 (Saraghi et al, 2018).  As nalbupine does not inhibit 
these enzyme systems at the suggested concentrations, there 
is negligible likelihood of a drug-drug interactions between 
nalbuphine and tricyclic antidepressants.  Also, having a 
lower and blunted Cmax will reduce the potential for any drug 
-drug interaction.  
• SSRI and SNRI may inhibit CYP 2D6 (Saraghi et al, 2018).  


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Nalbuphine is metabolized by a number of cytochrome P450 
isozymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) 
and is potentially conjugated by UGT2B7 (Ref: IB).  Thus, 
inhibition of one of the CYPs alone will not impact the 
concentration of Nalbuphine.  Hence, the potential for DDI 
of nalbuphine with SSRIs and SNRIs is also low.  
No Pharmacodynamic Drug-Drug interaction Potential 
• Even though package insert of injectable nalbuphine 
suggests that that the concomitant use of opioids with other 
drugs that affect the serotonergic neurotransmitter system, 
such as SSRIs, SNRIs, TCAs, drugs has resulted in serotonin 
syndrome and if concomitant use is warranted, carefully 
observe the patient, particularly during treatment initiation 
and dose adjustment;  it should be noted that the risk of this 
effect is for those opioids demonstrate their effects not only  
via the three major opioid receptors – µ , ∂, κ but also have 
actions on other targets, for example blocking serotonin and 
noradrenaline reuptake and N-methyl-aspartate (NMDA) 
receptors. The contraindication of coadministration of 
injectable nalbuphine and sedating antidepressants is based 
on general contra-indication of opioids and not based on 
specific data for nalbuphine. 
• Thus, opioids such as morphine, codeine, buprenorphine, 
oxymorphone, hydromorphone, oxycodone have low risk for 
serotonin effect; fentanyl, tapentadol, methadone have 
medium risk; and tramadol, pethidine and dextromethorphan 
have high risk for serotonin syndrome.   
• Even in the case of occasional case reports of serotonin 
toxicity with low-risk opioid and antidepressant 


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combinations, such as oxycodone and 
buprenorphine/naloxone (Suboxone) with other serotonergic 
medicines can usually be explained by very obvious 
alternative medical explanations for all the signs of the 
alleged severe serotonin toxicity.  
• Furthermore, based on the abuse liability screen for 
nalbuphine and its metabolites that included 44 targets 
(receptors, transporters, on gated-channel systems) related to 
the dopamine, norepinephrine, serotonin, gamma-
aminobutyric acid (GABA), acetylcholine, N methyl-D-
aspartate (NMDA) cannabinoid, and opioid neurotransmitter 
systems, nalbuphine, M1, M3, M4, and M5 have no affinity 
to any of the non-opioid CNS receptors and nalbuphine 
showed significant binding to only µ -, κ-opioid receptors 
(95% to 100% inhibition).   
• Hence nalbuphine does appear to have a potential risk for 
serotonin syndrome when co administered with sedating 
antidepressants. 
Different Risk/Benefit for Formulation/Indication:  
Anesthesia for injectable Nalbuphine vs. PN for Oral-ER 
nalbuphine with dose titration:  
• In Study TR 11, up to 162 mg of Nalbuphine as an extended-
release oral formulation is administered for potential use in 
PN population.  In contrast intravenous nalbupine is used as 
a supplement to balanced anesthesia, for preoperative and 
postoperative analgesia, and for obstetrical analgesia and 
thus concomitant use with sedating anti-depressants could be 
of clinical consequence (Ref: Nubain Package Insert).  
However, in the case of oral nalbupine ER that is dose 


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titrated for use in PN the risk of using sedating anti-
depressants may be lower. 
 
Thus, as nalbuphine oral extended release (ER) 
formulation/tablet is dose titrated and has lower, delayed and 
blunted maximal exposure (Cmax) as compared to intravenous 
nalbuphine, with no potential for either pharmacokinetic 
and/or pharmacodynamic based drug-drug interaction with 
sedating antidepressants, the concomitant use of sedating anti-
depressants in a non-anesthetic setting such as PN is 
acceptable. 
 
QTcF interval > 450 ms (mean of 3 
screening ECG QTcF values) if QRS <120 
ms (mean of 3 screening ECG QRS 
values); QTcF interval >480 ms in the 
presence of Right Bundle Branch Block 
(RBBB) and/or QRS ≥ 120 ms on any 
screening ECG tracing (triplicate). 
 
Synopsis: Exclusion 
Criteria (#31) and 
Section 9.5.2 
(Exclusion Criteria # 
31) 
To more accurately capture the electrophysiological criteria that 
can be identified by ECG that will be the basis for excluding 
subjects who would be at potential risk for developing a 
clinically significant cardiac arrhythmia. 
In the presence of RBBB measured on ECG, the QRS is at least 
30 ms wider than would otherwise be recorded in subjects with 
normal QRS duration.  The QT interval will therefore be at least 
30 ms longer in duration. 
In the absence of RBBB, prolonged QRS complexes are 
commonly noted in pulmonary disease patients, so the increase 
in QT due to a wide QRS may be observed in patients who do 
not have typical RBBB, but instead have a nonspecific 
intraventricular conduction defect (IVCD). 
 
Use of a medication having a “known risk” 
of Torsade de Pointes (categorized as 
“KR” on the Credible Meds website; see 
Appendix 10) is not permitted unless the 
Synopsis: Exclusion 
Criteria # 33 and 
Section 9.5.2 
(Exclusion Criteria 
Based ICH Guidance E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic Drugs — Questions and Answers (R3) Guidance 
for Industry, 2017 states that “Concentration-response analysis, 


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subject has been on a stable dose for at 
least 4 weeks prior to screening and there 
are no plans to change the dose at entry or 
during the study (See Appendix 10). 
 
 
Prior exclusion criterion 34 is not 
applicable to subjects enrolling in Protocol 
V7 and later. 
Medications associated with a potential 
risk of QT prolongation, but not clearly 
associated with Torsade de Pointes (i.e. 
CredibleMeds categories of Possible Risk 
[PR] or Conditional Risk [KR] presuming 
the concomitant risk ‘conditions’ 
referenced are not present at baseline), are 
permitted at study entry if the following 
criteria are met: 
- 
subject has been given medication 
at stable doses for a full 4 weeks prior to 
screening 
- 
medication dose will not be 
increased after screening, or during the 
study, and it is anticipated that they will 
receive the medication for the entirety of 
the study 
- 
QTcF at screening is £ 450 ms on 
centrally read screening ECGs. 
 
33) 
 
 
 
 
 
 
Synopsis: Exclusion 
Criteria # 34 and 
Section 9.5.2 
(Exclusion Criteria 
34) 
in which all available data across all doses are used to 
characterize the potential for a drug to influence QTc, can serve 
as an alternative to the by-timepoint analysis or intersection-
union test as the primary basis for decisions to classify the risk 
of a drug.” 
Concentration-QT (QTCF) analysis conducted to -date provides 
reasonable information that there is no potential QTc 
prolongation risk akin to what may have been provided by a 
TQT study and hence it is reasonable to make the revisions to 
exclusion criteria 33 and 34 to reflect that subjects are allowed 
this medication if they are on a stable dose for at least one month 
at the time of screening. 
Please note that the concentration and ECG/QT monitoring will 
still be part of the Protocol 
It was decided that exclusion criteria 34 information was 
covered in exclusion criteria 33 and therefore no longer 
required. 


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If the subject develops a QTcF > 500 ms or 
a confirmed increase from baseline of > 60 
ms based on the average QTcF of the 3 
ECGs obtained at the indicated on-
treatment visit, versus the average at 
baseline. 
Develops a QTcF > 500 ms (mean of 3 
ECG QTcF values) in subjects who were 
randomized without ECG findings of 
RBBB and/or QRS ≥ 120 ms.  
Develops QTcF > 530 ms (mean of 3 ECG 
QTcF values) in subjects who were 
randomized with ECG findings of RBBB 
and/or QRS ≥ 120 ms. 
Increase from QTcF baseline of > 60 ms 
(mean determination from 3 ECG values) 
 
Section 9.7: 
Premature 
Withdrawal of 
Subjects from the 
Study 
To accurately reflect an electrophysiologically meaningful 
change on ECG parameters that would indicate a potential 
cardiac arrhythmia risk to a subject if they continued in the 
study. 
To update Table 3 to revise exclusion 
information for systemic antihistamines 
and drugs of other classes (such as oral 
doxepin) that have significant 
antihistaminic activity, sedating 
antidepressants, and for medicines with a 
known risk for Torsade de Pointes. 
 
Section 10.6.2, 
Table 3 
To be consistent with the changes to Exclusion criteria 22, 25, 
33 and 34. 


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Headache, and dizziness, nausea and 
vomiting can also be treated with agents 
that are commonly prescribed for these 
symptoms (e.g., acetaminophen for 
headache and scopolamine for dizziness 
and ondansetron for nausea and vomiting) 
during the titration period, but these 
symptoms are less frequent and do not 
warrant prophylaxis. 
 
Section 10.6.3 
Addition of another drug considered for symptom management 
during the titration period.   
Electrocardiograms will be reviewed 
locally for safety by the Investigator and/or 
their designee. The ECGs will be read 
centrally for the purpose of meeting the 
ECG study inclusion criteria, study 
withdrawal criteria and ECG intervals (PR, 
RR, QRS, QT, and QTcF using nomogram 
table), rate, rhythm, and other clinically 
significant abnormalities (e.g., left 
ventricular hypertrophy, pathological Q-
waves) 
Electrocardiograms will be read centrally 
for clinical significance and 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. In cases of Left or Right 
Bundle Branch Block (LBBB and RBBB, 
respectively) together with a QRS duration 
> 110 ms, a QTcF adjusted for the widened 
Section 12.4 
Electrocardiogram 
Assessments 
To clarify Local ECG read is for safety purposes and central 
ECG read is related to subject inclusion/withdrawal. 


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QRS duration can be used to assess if a 
patient meets criteria for protocol 
exclusion, drug hold, or discontinuation 
using the below formula (See Appendix 
10): 
  
“Adjusted QTcF” = measured 
QTcF - [measured QRS - 90 ms]. 
If a subject develops a QTcF > 500 ms or 
presents with an increase from baseline > 
60 ms, the ECG will be repeated at least 30 
minutes later and the subject should be 
discontinued from the study. 
 
 


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Amendment 5 Rationale: 
Clinical research Protocol TR11 V6.0 (5 March 2021) was produced for the following purposes: 
• To delete exclusion criterion #18 to permit enrollment of subjects who have had prior 
exposure to dupilumab or nemolizumab. As per Exclusion Criterion #17, eligibility still 
requires a minimal period of 3 months with no exposure to either dupilumab or nemolizumab 
immediately prior to enrollment in TR11. 
• To enable co-enrollment in TR11 for potential subjects who may also be participating in the 
long-term safety follow-up period of a COVID-19 vaccine study so long as: 1) they have 
completed the full vaccine series; 2) that specific vaccine has been approved via an 
Emergency Use Authorization or comparable relevant Health Authority assessment in the 
country where enrollment takes place; and 3) the concomitant vaccine safety follow-up study 
permits co-enrollment. 
• The additional text updates are all considered to be Operational clarifications in response to 
key questions from site staff and are described in the table below. 
• To correct a typographic error in the body of the protocol for inclusion criterion #5. In the V5 
version of the protocol the Synopsis text was updated correctly, but that update was 
accidentally omitted in Section 9.5.1 in the body of the protocol. The current change provides 
internal consistency between the Synopsis and Section 9.5.1. 
• Addition of clarifications regarding the eligibility check prior to randomization, and the 
specific instruction that the final WINRS score entry for confirming eligibility should be 
performed on the day of the baseline visit and prior to dosing. 
• To clarify the specific ‘lesion healing’ criterion to be used for assessing whether a subject is 
eligible to consider dose reduction at Weeks 28, 32 and 36 by specifically referencing the 
Prurigo Activity Score Item 5b. 
 


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Study Modifications: 
Removal of Exclusion Criterion 18 
Note: In order to maintain proper 
tracking across protocol versions, this 
deletion will not translate to a change 
in numbering of the subsequent 
Exclusion Criteria. 
Synopsis 
Section 9.5.2 
(Exclusion Criteria) 
On-going study experience shows that sites are 
requesting enrollment consideration for real 
numbers of potential patients who have now 
had off-label prior treatment with dupilumab or 
nemolizumab but who experience on-going 
active PN with severe itch. In response to this 
observation and in consultation with the 
Coordinating Investigator, 
 Dr. 
 
, it has been agreed that this exclusion 
criterion may be removed. Broadening this 
enrollment criterion will help to bring 
enrollment to closure and will more 
appropriately reflect the evolving clinical 
practice environment with respect to PN 
management. 
Note: any potential subjects who are 
eligible under this modification must still 
comply with Exclusion Criterion 17 which 
requires a 3-month washout for 
any immunologically-mediated biologic. 


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Modification of Exclusion Criterion 
13 to enable co-enrollment in TR11 
for potential subjects who may also be 
participating in the long-term safety 
follow-up period of a COVID-19 
vaccine study so long as: 1) they have 
completed the full vaccine series; 2) 
that specific vaccine has been 
approved via an Emergency Use 
Authorization or comparable relevant 
Health Authority assessment in the 
country where enrollment takes place; 
and 3) the concomitant vaccine safety 
follow-up study permits co- 
enrollment. 
Synopsis 
Section 9.5.2 (Exclusion 
Criteria) 
As the protocol permits on-study vaccination 
with either of the 2 currently approved COVID-
19 vaccines in the course of routine medical 
care, it was inconsistent to prohibit new 
enrollment of those who had received the same 
vaccines in a prior study environment so long 
as their continued participation in any vaccine 
safety follow-up study is not jeopardized. The 
text is written to accommodate future potential 
COVID-19 vaccine approvals. 
Trialogics Eligibility Check report 
immediately prior to randomization. If 
necessary, tThe last WI-NRS value used 
in the calculation may should be 
recorded on the day of the baseline visit 
and prior to dosing.” 
 
 


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Operational clarification text was added 
to Inclusion Criterion 3 as follows: 
“Subjects with a history of acute 
secondary dermatoses within the 
preceding 6 months may enroll only if 
the dermatosis has resolved completely 
as follows per medical history or 
patient self-report and current clinical 
assessment 
Synopsis 
Section 9.5.1 (Inclusion 
Criteria) 
This text confirms that the ‘medical history’ 
requirement was not intended to be restricted 
to medical record documentation when not 
available. Therefore, references to ‘patient 
self-report’ and the Investigator’s ‘current 
clinical assessment’ were added. 
Operational clarification text was 
added to specify the intended 
meaning of the 2nd criterion for 
down-titration eligibility at the Week 
28, Week 32, and Week 36 visits. 
“(as assessed by an improvement of at 
least 1 category in the PAS healing 
activity score, Item 5b). For example, if 
“0-24%” of PN lesions at baseline 
were assessed as ‘healed’, 
then a 1-category change means that 
“25-50%” of current Week 28 PN 
lesions are now 
evaluated as ‘healed’." 
Section 9.1.3.5 – see Weeks 
28, 32, 
and 36 
The original text referenced the PAS skin 
healing assessment and was thought to be 
self-evident as the PAS only includes one 
reference to ‘healed prurigo lesions.’ 
However, it became clear that in practice a 
more specific reference and case example 
would be helpful to site staff. 


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Amendment 4 Rationale: 
Clinical research Protocol TR11 v5.0 (4 August, 2020) was produced for the following 
purposes: 
• To update the target enrolment of study subjects from 240 to 360, based on the DSMB 
recommendations after reviewing results from the pre-specified Sample Size Re-
Estimation (SSRE). In that analysis, the Conditional Power fell within the ‘promising 
zone’ as defined in the reference Mehta and Pocock33 publication; the increase required in 
the ‘promising zone’ was pre-specified as 360. 
• To refine the exclusion criteria related to the ECG assessments of the QTcF based on 
advice from the consultant Cardiologist who is a recognized arrythmia expert. 
• To clarify text that washout during screening should be completed prior to the start of the 
WI- NRS collection. This has been the requirement throughout prior study conduct but 
the specific language has been confusing to sites. This confusion was primarily introduced 
by textual changes that inadvertently dropped the phrase ‘WI-NRS collection’ from the 
longer ‘screening period WI-NRS collection” in earlier protocol revisions. 
• To clarify study procedures, and ambiguities noted across previous protocol versions, 
including ambiguity regarding the specifications for medication washout periods in 
relationship to the screening period and or the screening WI-NRS collection. 
• To formalize and integrate into the Study Protocol document the actual changes in the 
Operational implementation of the study that occurred due to the initial imposition of 
COVID- 19 Pandemic-related limitations on in-person study visits. These were previously 
documented and submitted to Health Authorities in real time as “COVID-19 
Administrative Memorandum” numbers 1 and 2, dated April 1, 2020 and April 23, 2020, 
respectively. 


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Study Modifications: 
Incorporation of the increased Sample Size 
of 360 subjects (versus initial plan for 240) 
based on the protocol-specified Sample Size 
Re-Estimation (SSRE) procedure that was 
introduced in Amendment 2, Protocol 
Version 3.1. 
Synopsis (subsections ‘Number 
of Subjects’; ‘Statistical 
Methods’) 
Sections 9.1.1, 13.1, 13.4.6.4 
The SSRE procedure showed that the interim 
Conditional Power of the study fell in the ‘Promising 
Zone’ as defined by in the paper by Pocock and 
Mehta33. This resulted in a DSMB recommendation 
to continue the study and to increase the sample size 
(ie number randomized) to 360. 
“QTcF interval > 450 ms on any single 
screening electrocardiogram ECG, based on 
the central reading.” was changed to “QTcF 
interval > 450 ms based on the central ERT 
calculation of the mean value from the 3 
sequential screening ECGs” 
Synopsis (Exclusion 31) 
Section 9.5.2 
The consulting cardiologist expert in drug-associated 
Torsade de Pointes, proposed this change based on 
the standard approach he recommends in the pre- 
market screening of investigational drugs for their 
potential to extend the QTcF interval. This criterion 
will be built into the formal core ECG lab reports for 
both screening eligibility and on-study monitoring of 
the QTcF change from baseline. (Note: the historical 
use of the injectable nalbuphine formulation has not 
suggested that this drug poses a QT risk but may not 
be applicable to the oral formulation, for which a 
formal TQT study has not yet been conducted). 
New text added: “In cases of Left or Right 
Bundle Branch Block (LBBB and RBBB, 
respectively) together with a QRS duration 
> 110 ms, a QTcF adjusted for the widened 
QRS duration can be used as follows: 
measured QTcF - [measured QRS - 90 ms]” 
Section 12.4 Electrocardiogram 
Assessments 
Appendix 11 
The consulting cardiologist expert in drug-associated 
Torsade de Pointes, proposed this change based on 
the fact that extension of the QRS period of 
depolarization does not affect the duration of 
repolarization, which is the key concern for the 
induction of Torsade de Pointes. 


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Operational/Executional Modifications and Clarifications: 
Change 
Location of Text that Changes 
Rationale 
Multiple statements in the study eligibility 
criteria that relate to medication-specific 
washout periods required additional 
clarification. These changes now provide 
unambiguous guidance that is aligned with 
the original design principle articulated in 
Protocol V1 (18 May, 2018): ‘the washout 
is required prior to the collection of the 
screening WI-NRS, irrespective of when it 
(sic ‘washout’) occurs within or prior to the 
screening period.’ 
Synopsis: Subsection titled 
‘Diagnosis and Main Criteria for 
Inclusion’ 
Section 9.5.2: Exclusion Criteria 
(subsection with the header: 
‘Medication-related ‘Exclusions’) 
Section 10.6.2 Prohibited 
Medications (see also Table 3: 
Prohibited medications and 
Washout requirements) 
These changes represent logical Operational 
modifications that clarify executional details and 
result from 1) the extension of the study screening 
period (Amendment 3) and 2) inadvertent text 
deletions made in prior Amendments that resulted in 
references to washout “prior to screening” rather 
than “prior to the screening WI-NRS collection. 
Operational execution has been based on ‘prior to 
screening WI-NRS’. 
Added instructions for site to consult with 
Medical Monitor regarding concomitant use 
of medications with anti-itch activity as 
documented in published literature, even if 
this effect is not addressed in drug labelling 
or chronic itch guidelines. 
Section 10.6.2, Table 3 - 
Prohibited Medications 
The intention of the study is to exclude concomitant 
medications with anti-itch activity; despite the 
exclusion of multiple medications, sites have raised 
appropriate questions about a broader range of 
medications than was anticipated. Therefore, the need 
for a more general statement regarding any agent 
with perceived anti-itch activity is needed, and 
guidance from the medical monitor should be 
obtained on a case by case basis. 


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Rationale 
In the event that pandemic COVID-19 
conditions recur in in the geographies where 
TR11 study sites are located, Operational 
procedures provide for the possibility of 
phone or videoconference visits with 
subjects according to the protocol-specified 
schedule. These provide for a review and 
documentation of the patient’s general 
health status, any adverse events 
experienced, and any study-related concerns 
or questions. 
Section 9.1.3, ‘Study Procedures 
and Assessments’ 
In light of the uncertainty as to whether COVID- 
related limitations on travel and in-person attendance 
at clinic-based study visits will recur, the protocol 
now includes text regarding the potential use of 
modified processes and procedures should they again 
become necessary during the remainder of the study 
execution. These reflect the Changes that were 
implemented via the Administrative Memorandum of 
23 April, 2020 (the second COVID-19 Related 
Administrative memo titled “COVID-19 Related 
Follow-on Actions in Response to Evolving 
Country/Site-Specific Conditions”) 
Phone or videoconference visits are only permitted in 
the setting of COVID-19 restrictions or with specific 
approval of the study Medical Monitor and are not to 
be used under routine conditions. 


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In the event that pandemic COVID-19 
conditions recur in the geographies where 
TR11 study sites are located, Operational 
procedures enabling direct delivery of study 
drug supplies to patients at their home 
remain available if needed. A special 
courier service that will pick up study drug 
at the site and deliver to the subject’s home 
address. All subject-related identifying 
information will be communicated by site 
staff to the courier without any Sponsor 
involvement. This courier will also safely 
transport drug, in the possession of the 
patient from a previous visit, back to the site 
for proper accountability. 
Section 10.5.1: Special 
Procedures for Study Drug 
Delivery During Periods of 
COVID-19 Pandemic 
Restrictions 
In light of the uncertainty as to whether COVID- 
related limitations on travel and in-person attendance 
at clinic-based study visits will recur, the protocol 
now includes text regarding the potential use of 
modified processes and procedures should they again 
become necessary during the remainder of the study 
execution. This reflects the Changes that were 
implemented via the Administrative Memorandum of 
23 April, 2020. This was the second COVID-19 
Related Administrative memo titled COVID-19 
Related Follow-on Actions in Response to Evolving 
Country/Site-Specific Conditions”. 
Revision of the TSH reflex testing 
requirements to accurately reflect revised 
testing practices which have been 
implemented in the interval since the prior 
version of the protocol document: “On- 
study TSH values above or below the upper 
or lower limit of normal (ULN or LLN), 
will result in reflex testing for Free T4 from 
the existing laboratory sample.” 
Section 12.3 Laboratory 
Assessments 
The process described in the prior protocol versions 
required re-testing at the next visit to confirm an 
abnormal TSH and resulted in delayed access to real- 
time information regarding the full status of the 
subject’s thyroid function. 


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Revision of text regarding the reflex testing 
for HCV RNA if the HCV antibody result is 
positive. The text now clarifies that the 
HCV RNA test will provide a quantitative 
value rather than a qualitative statement of 
‘detectable’ or ‘not detected’. 
Section 12.3 Laboratory 
Assessments 
This provides more useful information for the patient 
and patient’s physician and is medically appropriate 
in the setting of a positive HCV antibody when that 
reflects active infection rather than resolved or 
successfully treated infection. 
Analytic Clarifications/Revisions: No changes have been made with respect to analytic clarifications or revisions (Section 13: 
Statistical Evaluation” and its subsections) except as noted above that the sample size was increased in accordance with results of the 
Sample Size Re-Estimation Procedure specified in Amendment 2 to the protocol. 


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Amendment 3 Rationale: 
Clinical research Protocol TR11 v4 (22 January 2020) was produced for the following purposes: 
• To incorporate Administrative Clarification Memo dated 16 July, 2019 
• To incorporate Administrative Clarification Memo dated 7 November, 2019 
• To clarify the intention and/or execution of various study procedures. 
• To clarify procedural ambiguities in the previous version. 
 


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Incorporation of Interval Administrative Memos from 16 July, 2019 and 7 November, 2019 
Exclusion Criterion #30: “Serum potassium 
below the laboratory lower limit of normal.” to 
add to: “Note: If the initial screening value is 
low, but not considered clinically significant in 
relation to cardiac risk, then potassium 
supplementation may be prescribed and the 
serum potassium level repeated once at least 2 
weeks later, during the screening period. If the 
repeat potassium remains 
< LLN, then the subject must be screen-failed.” 
Study Synopsis 
Protocol Section 
9.5.2 
To bring the current protocol text into 
alignment with Administrative Clarification of 
16 July, 2019. 
Inclusion Criterion #5: Correction of an 
inadvertent typographical error in Protocol 
Section 9.5.1. 
Inclusion Criterion # 5 was accurately 
represented in the Synopsis but when repeated 
in Section 9.5.1, the “≥” sign was inadvertently 
replaced by the “>” sign. 
Protocol Section 9.5.1 
To bring the current protocol text into 
alignment with Administrative Clarification of 
7 November, 2019. 
To clarify the intention and/or execution of various study requirements and/or procedures 
Study Centers: Increased centers 
from approximately 40 to 65. 
Study Synopsis 
Study Center(s): 
To align the current number of participating 
centers 
Planned Study Period: updated to extend 
study period to January 2022 
Study Synopsis 
Planned Study Period 
To align the planned study period with the 
updated study timeline 


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Inclusion Criterion #8: modified the previous 
text to add the following italicized phrase: 
“Females of childbearing potential must be 
using an acceptable method of birth control (if 
sexually active) for 14 days prior to 
randomization and throughout the study. As a 
consequence, the previous sentence stating “For 
female subjects using a barrier method plus 
spermicide, that method must be used for at 
least 14 days prior to screening.” was also 
deleted. 
Study Synopsis 
Protocol Section 
9.5.1 
Clarification to the requirement for use of 
appropriate birth control for the 14 days prior to 
randomization, regardless of the method of use 
and ensures that consent has been obtained prior 
to the start of a study-specific requirement. 
Exclusion Criterion #4: modified to clarify the 
meaning of the phrase “major depression” to 
add “An ‘isolated major depression’ is defined 
as a single event of depression that includes 
recurrent thoughts of death, recurrent suicidal 
ideation with or without a specific plan, or any 
history of a suicide attempt.”. 
Clarification 
language of “Subjects with general depression 
who are considered stable may be enrolled.”. 
Study Synopsis 
Protocol Section 
9.5.2 
Modified to provide a definition of “major 
depression” (based on DSM 5, consistent with 
the original design intention) in response to 
multiple queries from site Investigators/staff 
requesting guidance on assessing for ‘major’ 
depression. 
Exclusion Criterion #22: added “or drugs of 
other classes (such as oral doxepin) which have 
significant anti-histaminic activity”. 
Study Synopsis 
Protocol Section 
9.5.2 
To include clarifying language for excluding 
other drugs with significant antihistaminic 
activity. 
Exclusion Criteria #31: procedural clarification 
to add “on any single” and “based on the central 
reading.”. 
Study Synopsis 
Protocol Section 
9.5.2 
Procedural clarification in order that the QTcF 
interval assessment must be based on the value 
reported in the formal EGC report from the 
Central ECG reader and (i.e. not based on a site 
staff reading of the paper ECG print-out which 
is for record documentation only) to ensure that 
the appropriate expert judgment is used to 
establish the ECG exclusionary findings; this 
ensures subject safety. 


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Exclusion Criteria #34: procedural clarification 
to add “on centrally read screening 
electrocardiograms (ECGs).”. 
Study Synopsis 
Protocol Section 
9.5.2 
Procedural clarification to ensure that the 
appropriate expert judgement is used to 
establish exclusionary findings. 
Medication Washout and Screening Period: 
changed the screening period from 4 to 6 
weeks. Updated “Subjects meeting certain 
criteria” to “Subjects who fail their initial 
screening due to the requirement for an 
extended medication washout”. Added “In cases 
of other unique circumstances that may justify 
rescreening”. 
Section 9.1.3.1 
Screening period modification to allow time for 
completion of treatment washout and/or 
completion and reporting of any needed reflex 
testing . 
Open-label Fixed-dose Period (Weeks 17 to 
52): updated “at the discretion of the 
Investigator and subject” to “at the discretion of 
the Investigator and with the agreement of the 
subject”. 
Protocol Section 9.1.3.5 
Protocol Section 
10.1.2 
Clarification to the text describing the optional 
dose reduction at Weeks 28, 32 or 36 for 
subjects meeting specified criteria to more 
appropriately reflect the decision making roles 
of the Investigator and the subject. 
Washout and Safety Follow-up Period and Last 
Contact: added “If a subject discontinues the 
study early, the specific instructions in Section 
9.6 Premature Discontinuation of 
Investigational Product Treatment take 
precedence.” 
Protocol Section 
9.1.3.6 
Clarification on prioritization of assessments for 
subjects who discontinue early 


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Off Treatment Visit: added to SOWS 
assessment “via the subject status update to 
“Off-treatment” in the Trialogics portal. The 
SOWs will be activated and subjects should be 
instructed to complete the questionnaire” and 
“For subjects who discontinue study drug 
early (including in-between study visits), the 
change in subject status to “Off- treatment” 
in the Trialogics portal should be made 
immediately as the site becomes aware of 
discontinuation; SOWS entries provide valid 
information ONLY if they are collected in the 
first 14 days off-treatment.”. 
Protocol Section 
9.1.3.6 
Clarification to SOWS assessment instruction in 
the Trialogics portal and for subjects who 
discontinue early. 
End of Study Telephone Call: updated “Obtain 
WI- NRS score” to “Ask the subject to verbally 
report their current WI-NRS score and site staff 
must enter the reported score into the Trialogics 
web portal. The recommended question text is: 
“On a scale of zero to ten, with zero being ‘no 
itch’ and 10 being the ‘worst imaginable itch’, 
how would you describe your worst itch 
experience over the last 24 hours?”. 
Protocol Section 
9.1.3.6 
Clarification to the WI-NRS assessment 
instruction for the End of Study Telephone Call 
Down Titration: added “The WI-NRS scores at 
and after Week 24 will be available to site staff 
via the Trialogics portal in order to assess 
eligibility for this down-titration.”. 
Protocol Section 
10.1.2 
Clarification to the WI-NRS score availability 
after Week 24 to assess eligibility for down-
titration. 
Table 3. Prohibited Medications: updated and 
added “Non-antihistamine class drugs” and 
updated concomitant medications. Updated 
washout requirements 
Protocol Section 
10.6.2 
Clarification to prohibited medications and 
washout requirements. 


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Numerical Rating Scale for Itch: added “At the 
End of Study telephone call, site staff are to ask 
the subject to verbally report their current WI-
NRS score and site staff must enter the reported 
score into the Trialogics web portal. The 
recommended question text is: “On a scale of 
zero to ten, with zero being ‘no itch’ and 10 
being the ‘worst imaginable itch’, how would 
you describe your worst itch experience over 
the last 24 hours?”. This instrument can be 
found in Appendix 5. WI-NRS information 
should be collected per the instructions provided 
in the Trialogics User Manual.” and removed 
“This instrument can be found in Appendix 5. 
WI-NRS information should be collected per 
the instructions provided in the Study Reference 
Manual.”. 
Protocol Section 
11.2.1 
Clarification to the WI-NRS assessment 
instruction for the End of Study Telephone Call 
Adverse Events of Special Interest: added 
“using the AESI worksheet and” 
Protocol Section 
12.1.1 
Modification to include AESI worksheet 
Adverse Events of Special Interest: added “full 
description based on subject’s narrative,” 
Protocol Section 
12.1.1 
Modification to include investigator instruction 
on AESI collection 
Definition of Severity: updated “4.03 or later.” 
With “5.0 which can be found at the following 
website: 
https://ctep.cancer.gov/protocoldevelopment/ele
ctr 
onic_applications/docs/CTCAE_v5_Quick_Refe
re nce_5x7.pdf 
Protocol Section 
12.1.1.3 
Modification to the latest CTCAE version. 


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Abnormal Laboratory Values, Vital Sign, 
Electrocardiograms, and Physical Examination: 
added “To confirm study eligibility and assess 
safety throughout the study, all laboratory and 
ECG results should be reviewed and assessed for 
clinical significance within 5 days of report 
availability.” 
Protocol Section 
12.1.4 
Modification to include definition and site 
requirements. 
Overdose: added “For the purpose of study 
monitoring and AE reporting, a study specific 
definition of “overdose” of blinded 
Investigational Product is defined here. Intake of 
>1 dose taken within 4 hours, or >2 doses taken 
within a day, as reported by the patient will be 
considered an “overdose”. This should be 
reported as an AESI, with commentary about 
the details of the event. Of note, this definition 
of “overdose” is intended to provide a study-
specific definition of the term ‘overdose’ based 
on the selected dosing regimen, but is not 
inherently expected to be associated with 
clinical ‘overdose’ symptoms unless 
dramatically exceeded.”, “In the event of 
clinical overdose, the”, and “Such events 
require urgent medical attention and sustained 
observation over several hours.”. Removed 
“Guidance to the Investigator” 
Protocol Section 
12.1.4 
Modification to include definition and site 
requirements. 


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Laboratory Assessments: added “A positive 
IgA- TTG result for this test, will require a full 
review of celiac-related gastrointestinal 
symptoms (such as diarrhea, bloating, chronic 
unexplained abdominal pain), and other risk 
factors for celiac disease should be verified. 
These risk factors include: a family history of 
celiac disease, a personal history of Dermatitis 
Herpetiformis; Type 1 diabetes; impaired bone 
mineralization; malabsorption of micronutrients 
such as fat-soluble vitamins, iron, and 
potentially B12 and folic acid.”, “A positive 
HCV antibody will have a HCV RNA 
processed from the existing laboratory sample, 
if possible (or an a re-draw if the original 
sample has insufficient material). The subject 
may not be enrolled if the HCV RNA result is 
detectable. Referral to a hepatologist or 
infectious disease specialist is recommended for 
consideration of antiviral treatment. Subject 
may be reconsidered, as appropriate, after 
treatment.”, and removed visit timepoints listed 
in table 4. 
Protocol Section 
12.3 
Clarification to IgA-TTG and HCV RNA test 
assessment requirements during screening. 


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Laboratory Assessments: added “Subjects 
previously enrolled prior to the addition of 
HCV or IgA-TTG testing in Amendment 2, will 
be asked if they are willing to have blood drawn 
for these specific tests. They may choose to 
refuse either or both of these additional tests 
and will be able to continue participation in the 
study regardless of either their refusal of 
consent or the results of the tests should they 
consent (the results will be used to support data 
analyses when the study is complete).” 
Protocol Section 
12.3 
Modification to include HCV and IgA-TTG test 
assessment option for subjects previously 
enrolled prior to the addition of HCV or IgA-
TTG testing in Amendment 2. 
Operational/Administrative Clarifications: 
Removed IVRS (Interactive Voice Response 
System) 
List of Abbreviations 
Schedule of 
Assessments Protocol 
Section 9.1.3 
Protocol Section 10.2.3 
Protocol Section 10.3 
13.2 
IVRS function is not used in the study. 
Added LLN (Lower Limit of Normal) 
Study Synopsis 
List of 
Abbreviations 
Protocol Section 
9.5.2 
Inclusion of LLN added to Exclusion Criteria 
#30 
Added “Eligible” to 
Protocol Section 
9.1.1 
Clarification that only eligible subjects will be 
randomized to NAL ER or matching placebo. 
Added “Day 14 and Day 112: -2 days ONLY” 
to Study Day window 
Schedule of 
Assessments 
Clarification that Days 14 and 112 will only allow 
a 
-2 day window due to investigational product 
supply quantity provided during the titration 
periods. 


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Weight assessment added beyond the 
screening visit. 
Added “Weight will be obtained at the 
screening visit and subsequently according to 
the schedule of events (Table 1 and Table 2).”. 
Schedule of 
Assessments Protocol 
Section 9.1.3 
Protocol Section 
12.6 Protocol 
Section 
Modification to align weight with lab visits to 
ensure the current weight is applied for 
estimated glomerular filtration rate calculation. 
Added “and perform e-diary eligibility 
assessment”. 
Protocol Section 
9.1.3 
Clarification to site instruction on the e-diary 
eligibility assessment 
Added “or Trialogics web portal” and “to be 
entered by the subject via Trialogics web 
portal” 
Protocol Section 
9.1.3 
Clarification to site instruction on assessment 
completion in the Trialogics web portal 
Updated “last study visit will” to “Last Visit 
should” and added “scheduled 2 weeks after” 
and “Off-Treatment Visit and” 
Protocol Section 
9.1.3.6 
Clarification to the visit weeks from the Off- 
Treatment to the Last Visit and the End of 
Study telephone call. 
Double-blind Treatment: Added “Although both 
AM and PM doses are present on” 
Protocol Section 
10.1.1 
Clarification to sites that subjects should skip 
the AM dose on Day 1 
Study Treatment Packaging and Labeling: 
updated “see” to “refer to” and “Study 
Reference” to “Pharmacy” 
Protocol Section 
10.2 
Modification that treatment packaging and 
labeling information is located in the Pharmacy 
Manual 
ItchyQoL: updated “Study Reference Manual” 
to “Investigator Site File”. 
Protocol Section 
11.2.2 
Modification that the questionnaire instructions 
are located in the Investigator Site File. 
Prurigo Activity Score: added “All efforts 
should be made to ensure the same Investigator 
who performs the Baseline assessment performs 
the subsequent PAS assessments throughout the 
study.”. 
Protocol Section 
11.2.3 
Clarification to that effort should be made to 
use the same investigator throughout the study. 


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Investigator Global Assessment-Prurigo 
Nodularis: added “All efforts should be made to 
ensure the same Investigator who performs the 
Baseline assessment performs the subsequent 
IGA-PN assessments throughout the study.”. 
Protocol Section 
11.2.4 
Clarification to that effort should be made to 
use the same investigator throughout the study. 
Patient Benefit Index: added “pre-therapy 
Importance of Treatment Goals”, “Treatment 
Benefits”, “did not apply to me”, and “As the 
overall visual appearance of the pre- and on- 
treatment questionnaires is very similar, site 
administrators must ensure that the appropriate 
form is used at the appropriate visit.”. Removed 
“per the instructions found in the Study 
Reference Manual.” 
Protocol Section 
11.2.5 
Clarification to the questionnaires that should 
be used for the pre-therapy and on-treatment 
visits. 
Pharmacokinetic Assessments: added “PK”, “at 
the site with safety labs” and “Further details of 
PK sample collection and processing will be 
provided to the site in the laboratory manual.” 
Protocol Section 
11.3 
Clarification to PK sample collection and 
reference to the laboratory manual for further 
details on collection and processing. 


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Post-treatment Safety: moved “The SOWS is a 
self- administered scale for grading opioid 
withdrawal symptoms. It contains 16 symptoms 
whose intensity the subject rates on a scale of 0 
(“not at all”) to 4 (“extremely”). The instrument 
can be found in Appendix 4. In this study, 
subjects will complete SOWS daily for 14 days, 
starting at the Off- Treatment visit and 
continuing through the washout and safety 
follow-up period to the Last Visit on the study. 
For subjects who discontinue study drug 
early (including in-between study visits), the 
change in subject status to “Off-treatment” 
in the Trialogics portal should be made 
immediately as the site becomes aware of 
discontinuation; SOWS entries provide valid 
information ONLY if they are collected in the 
first 14 days off-treatment.” to new section 12.7 
Subjective Opiate Withdrawal Scale. 
Protocol Section 12 
Protocol Section 
12.7 
Modification to include SOWS description and 
instruction as a distinct sub-section, as for other 
study instruments. 
Electrocaridogram Assessments: added “in 
triplicate (3 serial ECGs at least 1 minute apart, 
after the subject has been supine 5 minutes)” 
and removed “Reference” from “Study 
Reference Manual” 
Protocol Section 
12.4 
Clarification to ECG collection and update on 
the manual of ECG procedures 
Appendix 6 Investigator Global Assessment– 
Prurigo Nodularis (IGA-PN): master 
questionnaire included with footer. 
Protocol Section 23 
Updated to include full version of the 
questionnaire with the version date of 
02Sep2018 in the footer 
Appendix 7 Prurigo Activity Score 
Questionnaire (PAS) 
Protocol Section 23 
Added the original source date to the title area 
that was inadvertently dropped in Amendment 1 
for 1a and 1b. Content of the PAS remains 
stable. 


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Appendix 9: American College of 
Cardiology/American Heart Association 
Classification of Heart Failure removed 
Protocol Section 23 
Removed American College of 
Cardiology/American Heart Association 
Classification of Heart Failure as it is not 
required to support study execution (see protocol 
exclusion criterion 26 which uses NYHA 
criteria). 
Appendix 10: List of Drugs That Prolong QT 
and/or Cause Torsades de Pointes: added “All 
concomitant medications taken by a subject 
should be verified on the Credible Meds 
website to confirm they DO NOT have a 
Known Risk (i.e. KR category) for Torsade de 
Pointes.” 
Protocol Section 23 
Clarification to sites to verify all concomitant 
medications on the provided website. 


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Amendment 2 Rationale: 
Clinical research Protocol TR11 v3.1 (14 March 2019) was produced for the following 
purposes: 
• To address comments by Ethics Committees in Austria and Germany which proposed 
modification to the concomitant medication guidance for the study. 
• To incorporate suggestions from Investigators based on their experiences with practical 
implementation of the protocol. 
• To clarify study procedures. 
• To clarify ambiguities in the previous version. 
• To incorporate revised statistical methodology for consistency with statistical analysis plan 
in development based on additional statistical consultation. 
 
 


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Rationale 
Design Clarifications/Modifications: 
Secondary study objectives were 
divided into “key secondary objectives” 
and “other secondary objectives” to 
align with specification of “key 
secondary endpoints” and “other 
secondary endpoints.” 
Synopsis Section 8.2 
Secondary objectives were organized into 
categories of “key” and “other” to align with 
specification of “key secondary endpoints” and 
“other efficacy endpoints.” The order was 
adjusted in recognition of recent Health Authority 
comments. 
Inclusion Criterion 1: Combined first two 
inclusion criteria into one and changed 
definition of generalized PN from 
“presence of ≥ 20 pruriginous nodules” to 
“presence of 
≥ 10 pruriginous nodules.” 
Synopsis Section 9.5.1 
Discussion with Investigators indicated that 
combining criteria provides greater clarity for 
patient selection; change in number of pruriginous 
nodules from 20 to 10 is a response to feasibility 
considerations and was approved by key PN 
experts. 
Inclusion Criterion 2: Added 
clarification that any history of a 
primary pruritic skin condition other 
than PN must have been inactive for at 
least 6 months prior to screening. 
Synopsis  
Section 9.5.1 
Additional text clarifies inclusion requirement 
for subjects with a history of a primary pruritic 
skin condition other than PN and addresses 
Health Authority comments. 
Inclusion Criterion 3: Added criterion to 
allow subjects with a history of acute 
secondary dermatoses if the dermatosis 
has resolved completely as specified. 
Synopsis  
Section 9.5.1 
Addition of this inclusion criterion clarifies 
conditions under which subjects with a 
history of acute secondary dermatoses may be 
enrolled. 
Inclusion Criterion 4: Added criterion 
to specify that any identified systemic, 
non-dermatologic disease that could be a 
potential cause of concomitant pruritus 
must either have resolved, been 
successfully treated, or must be 
successfully managed with stable, 
optimized treatment for at least 3 months 
prior to screening. 
Synopsis  
Section 9.5.1 
Addition of this inclusion criterion ensures that 
the study enrolls subjects in whom PN is the 
cause of their ongoing itch and addresses 
Health Authority comments. 


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Inclusion Criterion 5: Corrected 
criterion that the arithmetic mean of 
the 7-day daily WI-NRS scores prior 
to the baseline visit must be ≥ 7. 
Section 9.5.1 
Criterion in Section 9.5.1 incorrectly used the 
> symbol instead of the ≥ symbol; the criterion 
listed in the Synopsis was correctly stated. 
Correction to the criterion in Section 9.5.1 to 
align with the inclusion criterion in the 
Synopsis. 
Inclusion Criterion 6: Clarified that 
subjects using non-sedating 
antidepressants must be on a stable 
dose for a minimum of 8 weeks prior 
to signing consent; deleted allowance 
for subjects on neuroleptic 
medications. 
Synopsis  
Section 9.5.1 
Sedative antidepressants and neuroleptic 
medications are not permitted at study entry or 
through the duration of the study, per Exclusion 
Criterion 25. 
Inclusion Criterion 8: Clarified that 
contraceptive requirement applies 
only to women of childbearing 
potential. 
Synopsis  
Section 9.5.1 
Current text was ambiguous in that it could 
have been interpreted to mean that males, non-
fecund females, and females of childbearing 
potential must have been using an acceptable 
method of birth control. New text clarifies that 
the contraceptive requirement applies only to 
females of childbearing potential. 
Exclusion Criterion 4: Clarified types 
of psychiatric disorders that are 
excluded (major disorders such as 
bipolar disorder and schizophrenia) 
and removed condition of “in the 
opinion of the Investigator.” 
Specified that subjects with a history 
of isolated major depression for 
longer than 3 years may be eligible 
for enrollment if they have access to 
appropriate psychiatric care. 
Synopsis  
Section 9.5.2 
This exclusion criterion was refined to offer a 
more standardized method for excluding major 
psychiatric disorders and specifies the restricted 
conditions under which cases of isolated major 
depression may be enrolled. 


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Exclusion Criterion 5: Changed 
exclusion criterion on entry serum 
bilirubin level from 
> 2.5 ×ULN to > 1.5 ×ULN unless 
explained by a clinical diagnosis of 
Gilbert’s Syndrome. 
Synopsis  
Section 9.5.2 
A more conservative approach was taken with 
respect to entry hepatic laboratory values given 
that data from a full hepatic impairment study 
are not available. 
Exclusion Criterion 8: Added 
occupational restrictions (with a 
cross-reference to Section 9.3) as an 
eligibility consideration. Added text 
to Section 9.3 Safety Monitoring to 
highlight responsibility of the 
Investigator to understand the 
lifestyle of each individual, the nature 
of his or her professional activities, 
and any medication prohibitions or 
toxicology screening requirements 
that may be associated with his or her 
employment as safety considerations 
when assessing the overall suitability 
of the subject for the study. 
Synopsis 
Section 9.3 
Section 9.5.2 
In response to an Ethics Committee question 
regarding the enrollment of professional groups 
with occupational requirements related to 
driving or operating heavy machinery, and 
given the risk for impaired attention/alertness 
for drugs with CNS activity and in the opiate 
class, occupational restrictions were added as 
an eligibility consideration. Text was added to 
reinforce the importance of the Investigator’s 
evaluation of safety considerations when 
assessing the overall suitability of subjects for 
the study. 
Exclusion Criterion 10: Clarified that 
a history of active substance abuse 
within the past 3 years was excluded 
and removed condition of “in the 
opinion of the Investigator.” 
Synopsis 
Section 9.5.2 
This exclusion criterion was refined to offer a 
more standardized method for excluding 
substance abuse. 
Exclusion Criteria 17 and 19: 
Clarified that restrictions on 
concomitant biologics apply to non-
insulin biologics (e.g., monoclonal 
antibodies). 
Synopsis 
Section 9.5.2 
Clarification on biologics restriction; insulin 
allowed. 


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Exclusion Criterion 25: Added 
prohibition of central nervous system 
suppressants, such as sedative 
antidepressants, barbiturates, 
benzodiazepines (with the exception 
of short-acting benzodiazepines 
specifically used on an intermittent 
and as needed basis), anxiolytics 
other than benzodiazepines, 
neuroleptics, and clonidine at 
screening and throughout 
participation in the study. Included 
definitions of sedative 
antidepressants and short-acting 
benzodiazepines. 
Synopsis 
Section 9.4 
Section 9.5.2 
Section 10.6.2 
Table 1 
Schedule of 
Assessments 
Table 3 
Prohibited 
Medications 
In response to an Ethics Committee comment 
on the risk of respiratory depression with 
concomitant use of sedative medications 
together with drugs in the opiate class, a more 
conservative approach was adopted in 
prohibiting certain nervous system suppressants 
during participation in the study. Short-acting 
benzodiazepines specifically used on an 
intermittent and as needed basis are allowed. 
Operational/Administrative Clarifications: 
Changed abbreviation for Worst Itch 
Numerical Rating Scale from 
WINRS to WI-NRS. 
Throughout 
Correction to standard abbreviation for 
assessment tool. 
Added WI-NRS to Schedule of 
Assessments. Clarified that recording 
of WI-NRS score is done daily 
throughout the double-blind period 
via e-diary (ending at the Week 14 
visit) and via Trialogics web portal at 
subsequent study visits thereafter. 
Table 1 
Schedule of 
Assessments 
Table 2 
Schedule of 
Assessments 
Section 9.1.3.2 
Section 9.1.3.3 
Section 9.1.3.4 
Section 9.1.3.5 
Section 9.1.3.6 
Section 11.2.1 
Clarification on frequency of WI-NRS data 
collection. 


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Added clarification that, except in 
cases of medication washout, the 
baseline (randomization) visit can 
take place approximately 8 days after 
screening as long as all screening 
procedures have been performed and 
required test results have been 
obtained by the site. 
Table 1 
Schedule of 
Assessments 
Clarification on timing of baseline visit relative 
to screening visit. 
Added clarification that 
randomization can take place even if 
screening laboratory results for non-
thyroid endocrine parameters are not 
yet available at the baseline visit. 
Table 1 
Schedule of 
Assessments 
Clarification that site staff do not need to wait 
for results from screening non-thyroid 
endocrine laboratory tests before randomizing 
subjects as there are no inclusion/exclusion 
criteria related to these results. 
Added clarification regarding which 
part of PBI-P (“Treatment Benefit 
Assessment” questions only) should 
be administered at Week 10. 
Section 9.1.3.2 
Clarification on PBI-P administration at 
Week 10. 
Corrected unit on TSH from 
microIU/mL to milliIU/mL in 
criterion for reflex testing; that is, 
TSH < 0.05 milliIU/mL will have a 
Free T4 processed from the existing 
laboratory sample, if possible. 
Table 1 
Schedule of 
Assessments 
Table 2 
Schedule of 
Assessments 
Section 12.3 
Correction. 
Specified that the time frame of 
3 months at screening for prohibited 
investigational products applies to 
non-insulin biologics. 
Table 3 
Prohibited 
Medications 
Correction/clarification. 


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Changed QTcF reason for withdrawal, 
from QTcF > 500 ms associated with a 
confirmed increase from baseline of 
> 60 ms, to QTcF 
> 500 ms or a confirmed increase 
from baseline of > 60 ms. 
Section 9.7 
Either QTcF > 500 ms or an increase from 
baseline of > 60 ms is a reason for withdrawal 
of the subject from the study, as stated in 
Section 12.4; the statement was corrected. 
Added text that the Trialogics web 
portal can be used for data entry if 
subjects cannot access the e-diary. 
Section 11.2.1 
Provision of another option for data entry if e-
diary cannot be accessed. 
Specified that the screening PAS 
Form Version 1.0a is to be used at 
screening only and the PAS Form 
Version 1.0b is to be completed for 
all other visits. Emphasized that the 
representative area chosen at 
screening should not be changed at 
subsequent visits. 
Section 11.2.3 
Clarification on PAS Forms and procedures. 
Added screening laboratory 
assessments for HCV antibody (if 
positive, then reflex HCV RNA) and 
IgA-TTG. 
Section 12.3 
Table 4 Clinical 
Laboratory Assessments 
Screening laboratory tests (HCV antibody 
and IgA-TTG) were added to identify 
systemic, 
non-dermatologic disease that could be a 
potential cause of concomitant pruritus (i.e., 
HCV, celiac disease) and align with Inclusion 
Criterion 4. 
In list of References, deleted version 
number on reference for Investigator 
Brochure for Nalbuphine and added 
two new references for updated 
statistical methodology information. 
Section 22 
Updates to list of references. 
Analytic Clarifications/Revisions: 
Moved the mean change in 7-day 
average WI-NRS from baseline to 
Synopsis 
Section 11.1.2 
Alignment of the “key secondary efficacy 
endpoints” with the “key secondary study 


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Week 14 from a key secondary 
efficacy endpoint to another 
secondary efficacy endpoint; moved 
the mean change in sleep disturbance 
(PROMIS Sleep Disturbance Short 
Form 8a) from baseline to Week 14 
from another secondary efficacy 
endpoint to a key secondary efficacy 
endpoint; and adjusted the 
description of the fixed sequence 
testing procedure for the primary 
efficacy endpoint and 3 key secondary 
efficacy endpoints accordingly. 
Section 13.4.6.3 
objectives” and the “other secondary efficacy 
endpoints” with the “other secondary study 
objectives” to address Health Authority 
comments. 
Added an interim analysis for 
adaptive sample size re-estimation 
when 50% of the subjects have either 
completed the Week 14 primary 
endpoint assessment or terminated 
the study early. 
Synopsis 
Section 13.1 
Section 13.4.6.4 
An adaptive mid-course sample size re-
estimation procedure was added to address the 
concern of the reliability of the estimates of 
treatment effectiveness from the TR03 study. 
Specified that multiple imputations 
will be used to deal with missing data. 
Synopsis 
Section 13.4.2 
Section 13.4.6.1 
Clarification of imputation method for handling 
missing data; refinement of pre-specified 
statistical methodology information and 
alignment of protocol with statistical analysis 
plan in development. 
Specified that a mixed-effects logistic 
regression model will be used for 
analysis of the primary efficacy 
endpoint instead of the Cochran-
Mantel-Haenszel test. 
Synopsis 
Section 13.4.6.1 
Clarification of method for analysis of primary 
efficacy endpoint; refinement of pre-specified 
statistical methodology information and 
alignment of protocol with statistical analysis 
plan in development. 


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Clarified and adjusted statistical 
methodology for analysis of 
secondary efficacy endpoints. 
Synopsis 
Section 13.4.6.2 
Clarification of method for analysis of 
secondary efficacy endpoints; refinement of 
pre-specified statistical methodology 
information in response to Health Authority 
feedback, and alignment of protocol with 
statistical analysis plan in development. 
Modified PBI-P endpoint and 
analysis methodology. 
Synopsis 
Section 11.1.2 
Section 13.4.6.2 
Modified PBI-P endpoint to be consistent with 
the analytic approach developed by the 
originator of the PBI-P instrument. 
Modified language related to use of 
the logistic regression model. 
Synopsis 
Section 13.4.6.1 
Section 13.4.6.2 
Prior text was internally inconsistent regarding 
the approach to sensitivity analysis testing for 
the primary endpoint. 


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Amendment 1 Rationale: 
Clinical research Protocol TR11 v2.0 (09 October 2018) was produced for the following 
purposes: 
• To address comments by Health Authority reviewers which identified items requiring 
further clarification or precision. 
• To incorporate suggestions from Investigators based on their experiences with practical 
implementation of the protocol. 
• To clarify study procedures. 
• To clarify ambiguities in the previous version. 
• To address ambiguities regarding safety procedures and safety assessments by clarifying 
the relevant safety definitions and assessments. 
 


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Design Clarifications/Modifications: 
Inclusion Criterion 1: Remove requirement 
to get written or verbal confirmation that 
pruriginous nodules “have been actively 
present and documented for at least 6 
weeks prior to signing consent.” 
Synopsis 
Table 1 Schedule of Assessments 
Section 9.5.1 
Discussion with PN experts and Study Investigators 
confirmed that if a potential subject has ≥ 20 
pruriginous nodules (part 1 of Inclusion Criterion 
1), then 100% will inherently have a history of PN 
lasting ≥ 6 weeks (i.e., this requirement is 
redundant). 
Exclusion Criterion 16: Clarify the 
relevant “biologics” which require 
washout. 
Synopsis 
Section 9.5.2 
The current text was not sufficiently clear in 
referencing ‘biologics’ (i.e., long-acting insulin 
technically meets the broad definition of a 
‘biologic’). The new text clarifies the original 
intention and medical concern around biologics that 
affect the immune system and may have prolonged 
biological effects. 
Exclusion Criteria 22 and 23: addition of 
appropriate restriction around prior 
thalidomide and systemic corticosteroid 
use. 
Synopsis 
Section 9.5.2 
Investigators indicated that prior/on-going 
thalidomide use may occur in potential subjects and 
requested washout clarification. Text regarding 
systemic corticosteroid use was inadvertently 
omitted. Because the exclusion period for systemic 
steroids exceeds that for items in Criterion 22, a 
separate Criterion was added. 
Clarification of End of Study Definition: 
provide consistent language throughout the 
protocol with respect to the definition of the 
“End of the Study.” This was always 
considered by the Sponsor to be the “End of 
Study Phone Call” which is scheduled to 
occur at Week 56 (2 weeks after the last 
subject visit to the study site) since this is the 
last study contact with the subject. 
Synopsis 
Sections 9.1.1 and 9.1.2 
Section 9.1.3.6 
Section 9.6 
Section 12.1.1 
Section 13.4.7 
The purpose of this change is to provide consistent 
language recognizing the final study telephone call 
as the “end of the Study.” 


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Design Clarifications/Modifications: 
Clarification of Follow-Up for Early 
Discontinuations: If permanent 
discontinuation of investigational product 
occurs anytime between Day 1 and the 
Week 14 visit, the subject will be asked to 
complete the off-treatment visit, the last 
visit, and the end of study telephone call, 
and to return to the clinic for the Week 14 
visit (unless consent is withdrawn). 
Synopsis 
Section 9.1.2 and Table 1 
Section 9.6 
The original protocol text specified that subjects 
who discontinue study prematurely but who do not 
withdraw consent should return for all subsequent 
study assessments as per the study schedule of 
visits with the objective to avoid missing data on 
these subjects. However, given the TR11 standard 
off-treatment procedures, if a subject discontinues 
during the double-blind period and were to attempt 
to complete both off-treatment visits and the 
as-intended on-treatment visit schedule, there 
arises an irrational overlap of visits. Therefore, this 
simplified set of visits was specified in order to 
maximize subject participation in the desired 
follow-up. 
Clarification of Intention regarding Safety 
Assessment Objective and Endpoint: For 
consistency with the original protocol 
intention, the Study Objective with respect 
to safety has been changed to 
“characterize the safety and tolerability of 
NAL ER” rather than to “analyze …”, 
which implies a more formal comparison 
across the 2 treatment arms. In line with 
this objective, text has been added in 
Section 11.1.2 that describes key 
descriptive safety parameters. 
Synopsis – Objectives 
Section 8.2 
Section 11.1.2 
Section 13.4.7 
A question was raised regarding the consistency 
between the study Objectives and the study 
Endpoints with respect to Safety. This was 
appreciated and appropriate changes made to 
reflect the original design intentions. 


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Design Clarifications/Modifications: 
Modification: On treatment ECG 
observations: change the original ECG 
parameters that trigger study drug 
discontinuation (both a QTcF > 500 ms 
together with an increase from baseline of > 
60 ms) to the more conservative approach 
that either of these conditions should result 
in discontinuation of study drug. 
Section 12.4 
Change was suggested by a Health Authority 
reviewer and accepted by the Sponsor. 
Modification: Safety Procedures: The Week 
40 home urine pregnancy testing and 
associated telephone call check-in from site 
staff were removed. 
Table 2 
Section 9.1.2 
Section 9.1.3.5 
Upon clinical and operational review, this testing 
was assessed as being of minimal value and placing 
undue procedural burden on subjects. 
Analytic Clarifications: 
Clarification - Inclusion Criterion 3: Re- 
written text clarifies the precise collection 
criteria, numeric requirements, and the 
basic calculation method (arithmetic 
mean) for the qualifying Worst Itch 
Numeric Rating Scale (WI-NRS) value 
(i.e., baseline value) 
Synopsis Section 9.5.1 
Investigators communicated that they were 
uncertain about whether a WI-NRS value on the 
Day of the randomization visit could contribute to 
the eligibility evaluation (collection criteria) so this 
was clarified. 
Also, although the Investigator does not calculate 
the baseline average score for eligibility (this 
calculation is pre-programmed into the e-diary 
site- based functions), it was considered important 
to clarify that this is an arithmetic mean. 


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Design Clarifications/Modifications: 
The safety relatedness scale was expanded 
from 3 to 5 items with the new categories 
“definitely related” (symptoms follow a 
known, expected response pattern, 
disappear after stop of study medication 
and reappear after reintroduction) and “not 
related” (plausible other cause, no 
clinically plausible temporal sequence 
leading to onset of AE, biologically 
implausible causal relationship). 
Section 12.1.1.2 
Increase precision of clinical assessment of 
possible causal relationship. 
Clarification of the time-window for dose 
reduction now specifies that this can occur 
only at Visits at Weeks 28, 32 and 36. 
Sections 9.1.1 and 10.1.2 
Original wording was ambiguous as to a time 
limit after Week 28 when dose reduction could be 
implemented. 
AEs will be dichotomized into “related” 
(definitely, probably and possibly) and 
“unrelated” (unlikely and not related) in 
descriptive safety tables. 
Section 13.4.7.1 
Text added for analytic clarification 
Clarification of analysis groups (safety as 
treated, modified intention-to treat as 
randomized, per-protocol as identified 
before unblinding). 
Sections 13.3.1 to 13.3.3 
Analytic Clarifications 
Safety analysis: All on-treatment safety data 
will be assessed descriptively based on the 
number and rates of adverse events (AEs), 
serious AEs (SAEs), clinical laboratory 
measurements, central cardiac core 
laboratory read-12-lead ECG, vital signs, 
and physical examinations. 
Synopsis Section 13.4.7 
Alignment of text in synopsis and statistical 
Section 13.4.7. 


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Design Clarifications/Modifications: 
To clarify that the safety objective for this 
study is a descriptive rather than a 
statistical comparison, and that the totality 
of the safety data will address this 
secondary objective regarding the overall 
safety and tolerability of NAL ER in 
subjects with PN. Key parameters are 
considered to be the rate of subjects with 
SAEs (Safety) and the rate of subjects 
discontinuing due to AEs (Tolerability). 
Sections 11.1.2 and 13.4.7 
Specification of safety endpoints was requested by 
a Health Authority Reviewer. 
Operational/Executional Clarifications: 
Corrected the references to the vendor 
who will perform the analysis of the ECG 
data and who will generate a separate ECG 
report for inclusion as an appendix to the 
TR11 CSR. (The previous TR03 protocol 
used iCardiac for these vendor activities; 
that company has since been acquired by 
ERT Clinical.) 
Synopsis – Safety 
Section 13.4.7.5 Safety Analyses 
– Electrocardiograms 
Changed iCardiac to ERT Clinical since ERT holds 
the contract for TR11 (note that in the interval since 
the prior Trevi PN study TR03, iCardiac was 
acquired by and integrated into ERT) 
Multiple clarifications to the use of e- 
diary, Subject Symptom Log and Subject 
Medication Log (concomitant medication) 
were added. This concerns especially the 
e-diary to assess WI-NRS, medication 
compliance and SOWS and other PROs. 
Table 1 
Table 2 
Section 9.1.3.1 
Section 9.1.3.2 
Section 9.1.3.3 
Section 9.1.3.5 
Section 10.6.1 
Section 10.6.3 
Sections 11.2.1 to 11.2.6 
Section 13.4.5 
The importance of the use of the e-diary in the 
assessment of PROs as well as Subject Symptom 
Log and Subject Medication Log makes it 
necessary to make instructions as clear as possible. 


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Design Clarifications/Modifications: 
Updated Prohibited/Rescue medication: 
changed the word ‘biologics’ to the phrase 
“biologics (including monoclonal 
antibodies) that modify the immune 
system”. 
Section 10.6.2 
Alignment with updates of Exclusion Criteria 22 
and 23. 
Clarifications regarding the use of 
Trialogics web portal to assess SOW and 
other PROs. 
Table 2 
Section 9.3 
Section 9.6, 
Operational/Executional Clarification 
Clarification for the selection of areas to be 
photographed as well as involved 
procedures according to the Canfield 
Quick Reference Guide and the User 
Reference Manual were added. 
Table 1 
Table 2 
Section 11.2.3 
Section 11.2.7 
The technical aspects of photography require clear 
instructions. 
Specification of procedures to retest 
abnormal TSH values. 
Table 1 
Table 2 
Section 12.3 
Clinical relevance of TSH abnormal values 
requires clarifications of follow-up procedures to 
ensure safety. 
Clarification of the use Titration Blister 
card for consistency with the Pharmacy 
Manual and Instructions for Taking TR11 
Study Medication; additional instructions 
regarding confirmation of dose 
administration in the e-diary. Added text 
clarifies that the assessment of compliance 
will be based on comparison of returned 
blister cards and e-diary entries. 
Table 1 
Section 9.1.3.2 
Section 10.1.1 
Section 10.4 
Operational/Executional Clarifications 
Introduction of re-screening option: 
Subjects may be re-screened at the 
discretion of the Medical Monitor after 
discussion with Investigator and with 
written permission from the Sponsor. 
Section 9.1.3.1 
Operational clarity. 


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Design Clarifications/Modifications: 
Various clarifications to provide aligned 
wording regarding study procedures in 
Table 1 and later Sections describing visit- 
by-visit procedures. 
Table 1 
Section 9.1.3.2 
Section 9.1.3.4 
Operational clarity. 
Clarification that dose reduction may only 
occur only at the Week 28, 32, or 36 visits. 
Table 2 
Section 9.1.3.2 
Operational clarification of the specific visits at 
which dose reduction may be implemented during 
the Open-Label Period. 
Risk/benefit assessment was expanded by 
adding a discussion of the opiate class 
warning regarding combined usage with a 
concomitant benzodiazepine and the 
increased the risk for respiratory 
depression in this setting. Added text 
references the need to ensure subjects 
receive the Patient Information Sheet on 
this topic if they are taking or prescribed a 
new benzodiazepine during the study. 
Table 1 
Section 9.4 
Section 22 
Operational clarification to ensure safety, to 
augment the existing safety information, and to 
ensure that subjects for whom this risk is relevant 
receive the relevant Safety Information Sheet to 
complement the information in the ICF. 
Clarification that tolerability assessment 
should be especially vigilant during the 
two dose titration periods. 
Section 10.6.3 
Operational/Executional Clarifications and to 
ensure safety. 
Clarification of adverse events of special 
interest regarding the use of nalbuphine 
(as opioid). These are now explicitly 
stated (signs of Euphoria, Mood Changes, 
Dissociative or Psychotic experience, drug 
abuse, misuse, dependence or withdrawal). 
Section 12.1.1 
Operational/Executional Clarifications and to 
ensure safety. 
Website for CTCAE version 4.03 added for 
site access and investigator reference 
during assessment of adverse events. 
Section 12.1.1.3 
Operational/Executional Clarifications and to 
ensure safety. 


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Design Clarifications/Modifications: 
Clarifications that physical examinations 
are only to be performed by appropriately 
licensed and credentialed health 
professional. 
Section 12.5 
Operational/Executional Clarifications and to 
ensure safety. 
Specification of brief neurological 
assessment to include mental status, motor 
exam, sensory exam, coordination, and 
gait. 
Section 12.7 
Operational/Executional Clarifications and to 
ensure safety. 
Changes to ensure Consistency of Terminology: 
General replacement of Numerical rating 
scale (NRS) by Worst Itch Numerical 
Rating Scale (WI-NRS) in Exclusion 
Criteria 16, 17, 19 and 20, as well as in the 
description of Study Design. 
Synopsis: Exclusion Criteria 16, 
17, 19 and 20 
Section 9.5.1 
Figure 1 
Table 2 
Section 9.1.3 
Section 9.2 
Table 4 
Section 10.6.2 
Section 11.2.1 
The prior protocol document used the 2 acronyms 
- “WI-NRS” (Worst Itch Numerical Rating Scale) 
and “NRS” (Numerical Rating Scale”) – 
interchangeably. However, the only Numerical 
Rating Scale to be used in the protocol is the 
Worst Itch Numerical Rating Scale (with 24 hour 
recall). It was recognized that the use of 2 
acronyms for a single patient reported outcome 
could be confusing. Therefore the acronym for the 
more specific terminology of “Worst Itch 
Numerical Rating Scale” or “WI-NRS” was 
applied throughout the protocol except in 
instances where historical studies and associated 
NRS measurements are referenced. 
Text Clarifications: 
Renaming end of Screening and Washout 
Period from Week 0 to Week 1 and Day 0 to 
Day 1, respectively. Accordingly 
randomization should not take place later 
than 4 weeks after initial screening. 
Section 9.1.1 
Table 1 
Study start should be named Day 1 in Week 1. 


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Rationale 
Design Clarifications/Modifications: 
A section of text was removed whose 
original intention was to ensure the safety 
of subjects whose medical condition 
(unrelated to the Prurigo Nodularis) 
worsened during the course of the study. It 
was recognized that this language could be 
misinterpreted to support the inappropriate 
early discontinuation of subjects, and that 
it therefore presented a risk to the integrity 
of study data. 
Section 9.7 
A Health Authority reviewer noted the potential for 
the unintended interpretation. The Sponsor 
reviewed the pros and cons of a revision versus a 
deletion and concluded that standard safety 
monitoring practices are well established and 
sufficient to protect subject safety with respect to 
on-study worsening of the subject’s medical 
condition unrelated to Prurigo Nodularis. 
Therefore a full deletion rather than a textual 
modification was implemented 
Itch intervention replaces rescue 
intervention. 
Section 10.6.2 
Section 10.6.4 
Section 13.3.2 
More appropriate term, and for alignment with 
Section 10.6.2. 
 

SAP_001.pdf: 
Official Title: A Phase 2b/3, Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy and 
Safety Study in Prurigo Nodularis (PN) With Nalbuphine ER Tablets for Pruritus Relief Through 
Itch Scratch Modulation (PRISM Study)
NCT Number: NCT03497975
Document Date: Statistical Analysis Plan (FINAL Version 2.1) : 1 June 2022 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.0 Date: 25 April 2022 
Page 1 of 80 
DocUUID : 7e92afa8-f525-4d40-81e8-2b78d5ce783b 
Confidentiality statement: 
The information provided in this document is strictly confidential. 
The recipients of the SAP must not disclose the confidential information contained 
within this document or any related information to other persons without the sponsor’s 
permission. In addition, the recipients of the SAP must keep this confidential 
document in a controlled environment which prevents unauthorized access to the 
document. 
Protocol Title: 
A Phase 2b/3, Randomized, Double-Blind, Placebo- 
Controlled, 2-Arm, Efficacy, and Safety Study in Prurigo 
Nodularis with Nalbuphine ER Tablets for Pruritus Relief 
Through Itch Scratch Modulation (PRISM Study) 
Protocol Number: 
TR11 
Protocol Version, Date 
Version 7.0, 21 July 2021 
ICON ID: 
4318/0001 
Document Version, Date:   FINAL Version 2.1, 1 June 2022 
Prepared by: 
ICON Clinical Research Services 
On behalf of: 
Trevi Therapeutics, Inc. 




Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
Page 3 of 80 
DocUUID : 7e92afa8-f525-4d40-81e8-2b78d5ce783b 
 
 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ....................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................. 3 
LIST OF ABBREVIATIONS .......................................................................................................... 5 
I. INTRODUCTION ..................................................................................................................... 7 
II. STUDY OBJECTIVES .............................................................................................................. 8 
A. 
Primary objective .................................................................................................. 8 
B. 
Secondary objectives............................................................................................. 8 
III. STUDY DESIGN ...................................................................................................................... 8 
A. 
General study design ............................................................................................. 8 
B. 
Randomization and blinding ............................................................................... 10 
C. 
Study treatments and assessments ....................................................................... 10 
IV. STUDY ENDPOINTS ............................................................................................................. 27 
A. 
Primary Efficacy Endpoint ................................................................................. 27 
B. 
Secondary Efficacy Endpoints ............................................................................ 27 
C. 
Pharmacokinetics Endpoint ................................................................................ 28 
D. 
Safety Endpoints ................................................................................................. 28 
5. SAMPLE SIZE AND POWER .................................................................................................. 29 
5.1 Responder percentage assumptions........................................................................... 29 
5.2 Calculations ............................................................................................................... 29 
6. ANALYSIS POPULATIONS .................................................................................................. 31 
6.1. Modified Intention-To-Treat population (mITT) ..................................................... 31 
6.2. 
Safety population (Safety) .................................................................................. 31 
6.3. 
Per-Protocol population (PP) .............................................................................. 31 
7. Statistical Considerations and analysis .................................................................................... 32 
7.2. 
Derived Variables ............................................................................................... 32 
7.2.1. Baseline ............................................................................................................... 32 
7.2.2. Changes from Baseline ....................................................................................... 32 
7.2.3. Date of First Dose of Study Drug ....................................................................... 32 
7.2.4. Date of Last Administration of Study Drug ........................................................ 32 
7.2.5. Study Day ........................................................................................................... 33 
7.2.6. Exposure and Compliance .................................................................................. 33 
7.2.7. Visit Window Definitions ................................................................................... 34 
7.3. 
Efficacy Derived Variables ................................................................................. 36 
7.3.1. WI-NRS .............................................................................................................. 36 
7.3.2. ItchyQoL Total Score (ItchyQoL) ...................................................................... 37 
7.3.3. PBI-P ................................................................................................................... 37 
7.3.4. Prurigo Activity Score (PAS) ............................................................................. 39 
7.3.6.  Sleep Scale .......................................................................................................... 40 
7.4. 
Handling of missing data and outliers ................................................................. 40 
7.4.1. Missing data analysis methods ............................................................................ 40 
7.4.2. Handling of missing or incomplete dates ............................................................ 41 
Concomitant Medications Start/End Date....................................................................... 41 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
Page 4 of 80 
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8. STATISTICAL METHODS AND ANALYSI8 ....................................................................... 43 
8.1 
General Statistical Conventions .......................................................................... 43 
8.2 Subject disposition .................................................................................................... 43 
Protocol deviations .......................................................................................................... 44 
8.3 
Demographics and baseline characteristics ......................................................... 44 
8.3.1 Demographics ..................................................................................................... 44 
8.3.2 Baseline and disease characteristics (Prurigo Nodularis History) ...................... 44 
8.3.3 Neurological history............................................................................................ 46 
8.3.4 Medical history ................................................................................................... 46 
8.3.5 Prior and concomitant medications ..................................................................... 46 
8.4 
Extent of exposure .............................................................................................. 47 
8.4.1 Treatment duration .............................................................................................. 47 
8.4.2 Treatment compliance ......................................................................................... 47 
8.4.3 Treatment dose reduction .................................................................................... 48 
8.5 
Efficacy analyses ................................................................................................ 48 
8.5.1 Analysis methods ................................................................................................... 48 
8.6. Multiplicity .............................................................................................................. 49 
8.6 
Analysis of Primary EfficacyEendpoint .............................................................. 50 
8.6.1.1 Control Based Imputation ................................................................................... 51 
8.6.1.3. Sensitivity Analysis for Subjects who take Prohibited Medications .................. 53 
8.6.3 Analysis of secondary efficacy endpoints .............................................................. 54 
8.7 
Safety analyses .................................................................................................... 57 
8.7.1 Adverse events .................................................................................................... 57 
8.7.2 Clinical laboratory evaluations ........................................................................... 60 
8.7.3 Vital signs ........................................................................................................... 61 
8.7.4 Brief Neurological Assessment ........................................................................... 61 
8.7.5 Physical examinations ......................................................................................... 61 
8.7.6 Electrocardiograms ............................................................................................. 61 
8.7.7 SOWS ................................................................................................................. 61 
8.7.8 Pharmacokinetic analysis .................................................................................... 62 
8.8 
Primary analysis .................................................................................................. 62 
8.8.1 Interim analysis (Adaptive Sample Size Re-estimation) .................................... 62 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ............................... 64 
10 REFERENCES ........................................................................................................................ 65 
11 VERSION HISTORY .............................................................................................................. 66 
12 Appendix .................................................................................................................................. 67 
12.3 
Programming Guidance Document for Multiple Imputation, Control – 
based Imputation & Tipping Point Analysis ................................................................... 67 
12.4 
Sleep Disturbance Conversion Table .................................................................. 78 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
Page 5 of 80 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
or 
special term 
Explanation 
ADaM 
Analysis Dataset Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CP 
Conditional Power 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DBL 
Database Lock 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
ICE 
Intercurrent Events 
IGA-PN 
Investigator Global Assessment-Prurigo Nodularis 
IRT 
Interactive Response Technology 
ItchyQoL 
Itchy Quality of Life 
ITT 
Intent To Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measurements 
MVN 
Multivariate Normal 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
Page 6 of 80 
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OC 
Observed Cases 
OR 
Odds Ratio 
PAS 
Prurigo Activity Score 
PBI-P 
Patient Benefit Index, Pruritus 
PCS 
Potentially Clinically Significant 
PMH 
Past Medical History 
PNQ 
Patients Need Questionnaire 
PN 
Prurigo Nodularis 
PP 
Per Protocol 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
Preferred Term 
Q1 
Lower Quartile 
Q3 
Upper Quartile 
QLS 
Quality of Life Scale 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
SSP 
Study Specific Procedure 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
ULN 
Upper Limit of Normal 
WI-NRS 
Worst Itch Numerical Rating Scale 
WOCF 
Worst Observation Carried Forward 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
Page 7 of 80 
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I. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations, and data displays for study protocol TR11 “A Phase 2b/3, 
Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy, and Safety Study in Prurigo 
Nodularis with Nalbuphine ER Tablets for Pruritus Relief Through Itch Scratch Modulation 
(PRISM Study)” dated 14 March 2019 for final analysis. The table of contents and templates for 
the TFLs will be produced in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on International Conference on Harmonization (ICH) 
E9 and ICH E91 guidelines. 
All data analyses and generation of TFLs will be performed using SAS 9.4® or higher. 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
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II. 
STUDY OBJECTIVES 
 
 
A. 
Primary objective 
To evaluate the effect of Nalbuphine Extended-Release tablets (NAL ER) on itch as assessed by 
the percentage of Responders (‘response’ is defined as a ≥ 4-point reduction in the 7-day average 
Worst Itch Numerical Rating Scale [WI-NRS]). 
 
B. 
Secondary objectives 
The secondary objectives of this study are designed to establish proof of principle and are as 
follows: 
Key secondary objectives: 
• 
To evaluate the effect of NAL ER on itch-related quality of life as assessed by the 
ItchyQoL total score. 
• 
To evaluate the effect of NAL ER on Prurigo Nodularis (PN) skin lesions as assessed by 
the Prurigo Activity Score (PAS) Question 5a. 
• 
To evaluate the effect of NAL ER on sleep as assessed by the PROMIS Sleep Disturbance 
Short Form 8a. 
Other secondary objectives: 
• 
To evaluate the effect of NAL ER on itch as assessed by the mean change in WI-NRS. 
• 
To evaluate the benefit to subjects of NAL ER using the Patient Benefit Index, pruritus 
version (PBI-P). 
• 
To evaluate the safety and tolerability of NAL ER. 
• 
To assess the PK of nalbuphine and its metabolites. 
 
 
III. 
STUDY DESIGN 
 
A. General study design 
 
This is a randomized, double-blind, placebo-controlled, 2-arm study, with an open-label extension 
period following double-blind treatment, to investigate NAL ER tablets' anti-pruritic efficacy and 


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Protocol Number: TR11 
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safety. Subjects will be randomized to NAL ER (2-week titration followed by 162-mg BID for 12 
weeks) or matching placebo (14 weeks duration), with the primary endpoint evaluation at Week 14. 
If permanent discontinuation of investigational product occurs anytime between Day 1 and the 
Week 14 visit, the subject must complete the off-treatment visit and procedures, and must return to 
the clinic for ALL remaining study evaluation visits up to and including the Week 14 visit. During 
the open-label extension, subjects who received NAL ER will continue on NAL ER for a total of 
38 additional weeks (total treatment duration 52 weeks including titration) and subjects who 
received placebo will crossover to NAL ER for a total of 38 weeks (including titration). Upon 
discontinuation of investigational product, all subjects will complete a 2-week off-treatment safety 
follow-up period, regardless of when and why the subject discontinued study treatment unless they 
withdraw consent. In addition, a final follow-up itch and safety assessment will be made via phone 
call 4 weeks after the last dose of investigational product. The total planned study duration from 
randomization through the last phone contact is 56 weeks. 
Approximately 240 subjects with diagnosed PN will be randomized (1:1) to one of the following 
treatment arms: 
Arm 1: Blinded active titration over 2 weeks (to achieve a final NAL ER dose of 162 mg) followed 
by 162-mg BID for 12 weeks with continuation into the extension titration period (blinded), and the 
open-label fixed-dose period, followed by a 2-week off-treatment safety follow-up period and a 
final phone contact, for itch and safety assessment, 4 weeks after investigational product 
discontinuation. 
Arm 2: Placebo “titration” over 2 weeks followed by placebo BID for 12 weeks with continuation 
into the extension titration period (blinded; to achieve a final NAL ER dose of 162 mg) and the 
open-label fixed-dose period (NAL ER 162 mg), followed by a 2-week off-treatment safety follow- 
up period and a final phone contact, for itch and safety assessment, 4 weeks after investigational 
product discontinuation. 
An interim sample size re-estimation will occur once 50% (120) of the subjects have either 
completed the Week 14 primary endpoint assessment or terminated the study early. A maximum of 
360 subjects total may be enrolled, dependent upon the results of the re-estimation. 
After Study Week 28, an elective dose reduction to NAL ER 108 mg BID may be considered for 
subjects who achieve a confirmed WI-NRS ≤ 3 and visible lesion healing (as assessed by an 
improvement of at least 1 category in the PAS lesion healing activity score). The decision to dose 
reduce is at the discretion of the Investigator and the subject, but once this dosing has started, no re- 
escalation will be permitted. 


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Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
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The study design schematic is presented in Figure 1. 
Figure 1 
Study Design 
 
BID: twice daily; D = day; NAL ER: Nalbuphine 162-mg extended release; WI- 
NRS: Worst Itch Numerical Rating Scale; W =week. 
 
B. Randomization and blinding 
 
Randomization will be performed by an IVRS/IWRS. Upon confirmation of eligibility by the 
study site, subjects will be randomized in a 1:1 ratio to either Arm 1 or Arm 2. 
 
C. 
Study treatments and assessments 
Double-blind Treatment Period 
Following randomization, the subject will receive a 2-week blister card for the titration segment of 
the double-blind period. Each card will contain 3 tablets for the AM dose and 3 tablets for the PM 
dose. The tablets will be combinations of either 27 mg/54 mg/placebo tablets, or placebo tablets 
only, depending on the arm assigned. At the end of titration visit, subjects will be given one 70 
count bottle for the start of the fixed-dose segment of the double-blind period containing either 
placebo tablets or 162-mg NAL ER tablets, depending on the arm assigned. Further bottles will be 
dispensed at subsequent study visits. At each visit at which investigational product is to be 
dispensed, enough investigational product should be supplied to ensure that a sufficient number of 
tablets are available for dosing until the next visit, allowing for visit windows and/or the possibility 
of a missed visit. 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date: 01 June 2022 
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Open-Label Period 
Subjects will receive a 2-week blister card for the titration segment of the open-label period. Each 
card will contain 3 tablets for the AM dose and 3 tablets for the PM dose except for the first day 
(only PM dose is included). The tablets will be combinations of either 27 mg/54 mg/placebo tablets 
for subjects in Arm 2 who received placebo during double-blind treatment and are crossing over to 
NAL ER, or a card containing 3 active 54-mg NAL ER tablets for the AM dose and three 54-mg 
NAL ER tablets for the PM dose for subjects in Arm 1 who are continuing with NAL ER. At the 
end of titration visit, subjects will be given one 70-count bottle for the start of the open-label fixed- 
dose period containing 162-mg NAL ER tablets. Further bottles will be dispensed at subsequent 
study visits. At each visit at which investigational product is to be dispensed, enough 
investigational product should be supplied to ensure that a sufficient number of tablets are available 
for dosing until the next visit, allowing for visit windows and/or the possibility of a missed visit. 
Down-titration: At the regularly scheduled study visits for Week 28, Week 32, and Week 36, an 
elective dose reduction to a 108 mg NAL ER BID dose may be considered for subjects who 
achieve a confirmed WI-NRS ≤ 3 and visible lesion healing as assessed by an improvement of at 
least 1 category in the PAS healing activity score, Item 5b. For example, if “0-24%” of PN lesions 
at baseline were assessed as ‘healed’, then a 1-category change means that “25-50%” of current 
Week 28 PN lesions are now evaluated as ‘healed’. The WI-NRS scores at and after Week 24 will 
be available to site staff via the Trialogics portal in order to assess eligibility for this down titration. 
The decision to dose reduce is at the discretion of the Investigator and with the agreement of the 
subject, but once this dosing has started, no re-escalation is permitted. Dose reduction is not 
permitted prior to Study Week 28 or after Study Week 36. 
The schedule of assessments is presented in Table 1 and Table 2. 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Informed consent13 
X 
Refer to Table 2 
for schedule of 
open-label 
extension period 
Medical, neurological, 
and Prurigo Nodularis 
history 
X 
Physical examination 
X 
X 
Brief neurological 
assessment 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
Height, weight, and 
BMI 
X 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date 01 June 2022: 
Page 13 of 80 
1 apr2022 
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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Central ECG4 
(triplicate) 
X 
X 
X 
X 
X 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1 Date 01 June 2022: 
Page 14 of 80 
1 apr2022 
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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Clinical Laboratory 
assessments5 
X 
X 
X 
X 
X 
Tolerability 
Intervention 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
Urine pregnancy5 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion 
criteria1 
X 
X 
Randomization via 
IVRS/IWRS 
X 


Statistical Analysis Plan (SAP) 
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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Blood for PK 
assessment 
X 
X 
X 
X 
X 
X 


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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Record and assess AEs, 
concomitant 
medications, and 
therapies (including 
restricted and prohibited 
medications) 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e-diary7 – Dispense and 
train/review use 
X 
e-diary – retrieve and 
review use and entry 
compliance7 
X 
X 
X 
X 
X 
X 
X 
Dispense Subject 
X 


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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Medication Log and 
Subject Symptom Log6 


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Statistical Analysis Plan 
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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Retrieve/review/re- 
dispense Subject 
Medication Log and 
Subject Symptom Log6 
X 
X 
X 
X 
X 
X 
ItchyQoL7 
X 
X 
X 
X 
X 
PAS and IGA-PN 
X 
X 
X 
X 
PBI-P7 
X 
X 
X 
X 
Sleep Scale (PROMIS)7 
X 
X 
X 
X 
X 
WI-NRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photography8 
X 
X 


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Statistical Analysis Plan 
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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Dispense 
investigational product 
Card12 
B 
B 
B 
Card 
B9 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
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Table 1. 
Schedule of Assessments – Double-blind, Placebo-controlled Period 
Study Period → 
Screening 
and 
Washout1,2 
Double-blind Titration Period10 
Double-blind Fixed-dose 
Period10 
Extension Titration 
Period 
Open-label 
Fixed-dose 
Period 
Assessment ↓ 
Screening 
and Washout 
Baseline1 
  
End of 
Titration 
W3D1 to W14D7 
Transition to 
Open-label 
W17, D1 to 
W52, D7 
  
Repeating visit 
q4wk 
  
End of 
Titration 
Repeating 
extension visits 
Visit Week 
-6 to -1 
1 
1 
1 
29 
3 
3 
6 
10 
14 
15 
15 
1611, 
Weeks 17 to 52 
Study Day 
(±2 days*; Day 14 and 
Day 
112 
-2 
days 
only)14 
Up to Day -1 
1 
3 
7 
14* 
15 
21 
42 
70 
98 
101 
105 
112 
Days 113 to 364 
Dispense Instructions 
for Taking TR11 Study 
Medication12 
X 
X 
X 
X 
Retrieve investigational 
product and containers 
NA9 
B + 
Card 
B 
B 
NA11 
Investigational product 
accountability 
X 
X 
X 
X 
X 
Investigational product 
- review dosing 
compliance 
X 
X 
X 
X 
X 


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Statistical Analysis Plan 
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AE: adverse event; B: bottle; BMI: body mass index; Card: blister card; D: Day; ECG: electrocardiogram; e-diary: electronic diary; IGA-PN: Investigator Global Assessment-Prurigo 
Nodularis; IWRS: Interactive Web Response System; LFT: liver function test; NA: not applicable; PAS: Prurigo Activity Score; PBI-P: Patient Benefit Index, pruritus version; PK: 
pharmacokinetic; PRO: patient-reported outcome; q4wk: every 4 weeks; SHBG: sex hormone---binding globulin; SOWS: Subjective Opiate Withdrawal Scale; TSH: thyroid stimulating 
hormone; W: Week; WI-NRS: Worst Itch – Numerical Rating Scale; WOCBP: woman of childbearing potential; : telephone call. 
1. If clinically indicated, screening procedures may be completed over multiple visits (such as needed for washout of medications intended for anti- pruritic treatment) as long as they 
occur within the screening period. However, if the subject meets all inclusion/exclusion criteria, they should be randomized as soon as possible after meeting study requirements, but no 
later than 6 weeks after the initial screening visit. Except in cases of medication washout, the baseline (randomization) visit can take place in as little as 7 days after all screening 
procedures have been performed, the required testing results have been obtained, and eligibility has been verified. 
2. If a medication washout is required, WI-NRS collection should begin following completion of the washout. 
3. Vital signs are to be obtained after the subject has been seated for at least 5 minutes. 
4. ECGs are to be performed in triplicate (3 serial ECGs at least 1 minute apart) after the subject has been in the supine position for at least 5 minutes. ECGs are to be transmitted to be 
read centrally by a core ECG laboratory. The average of the QTcF values from the triplicate ECGs will be performed and presented in a report to be used as the final eligibility 
assessment for the subject. 
5. Laboratory Evaluations: Hematology and serum chemistry, LFTs, specified endocrine tests (at screening and Week 14 only: TSH, with reflex free T4 if above Upper Limit Normal 
(ULN) or below Lower Limit Normal (LLN), free testosterone [the fraction not bound to SHBG or albumin] and SHBG for males), and serum pregnancy test if WOCBP (regardless of 
sexual status at screening and baseline); urine pregnancy test to be performed by the local laboratory and confirmed to be negative prior to dispensing investigational product. TSH values 
above the upper limit of normal (ULN) should be repeated at the next study visit (or approximately 1 month later; whichever occurs first). If TSH remains above ULN, a Free T4 will be 
performed on the existing laboratory sample. 
6. AEs are to be continually assessed starting with the signing of the informed consent. Concomitant medications should be collected from 14 days priorto the signing of consent. During 
the screening visit, subjects must be instructed to record any new AEs or concomitant medication use on the Subject Symptom Log and Subject Medication Log and to bring the logs 
to every visit (including the telephone contacts). Site to retrieve and review these logs at each subsequent visit prior to re-dispensing them or issuing new logs to the subject. Events of 
special interest should trigger the collection of additional information using the AESI worksheet and documented under the AESI section of the Adverse Event eCRF. Event details 
and both subject and investigator narratives should be thoroughly documented in the AESI worksheet and completed under the AESI section of the Adverse Event eCRF. 
7. During screening, the e-diary must be dispensed to minimally allow for 7 contiguous days of WI-NRS collection prior to the baseline visit (collection during this period provides formal 
study data required for randomization). The e-diary administers the WI-NRS, medication compliance, and SOWS when applicable. Other PROs (Itchy QoL, PBI-P, and PROMIS 
sleep scale) are collected at select visits as described in. PROs administered during screening, but prior to Day -7, are to familiarize the subject to the instruments only, and not for the 
purpose of data collection. If multiple visits occur during the screening period, collection of these data (WI-NRS and PROs) should begin at the visit prior to the Week 1 baseline visit. 
Throughout the double-blind period, the subject is to record the WI-NRS data daily; daily WI-NRS data collection via the e-diary or in the Trialogics web portal ends at the Week 14 visit. 
8. Photography to be performed at selected sites only. See the Canfield Quick Reference Guide and the User Reference Manual for photography procedures as applicable. 
9. The Double-blind Titration blister card will be reviewed, but not be retrieved at this visit. See the Pharmacy Manual and Instructions for TakingTR11 Study Medication for 
additional instructions. 
10. Subjects who discontinue investigational product for any reason (other than withdrawal of consent) prior to the Week 14 visit must be asked to complete the 
Off-Treatment visit, the Last Visit, and the End of Study telephone call and to return to the site for their study schedule planned Week 14 visit at study Day 98 (see Table 2) 
 


Statistical Analysis Plan (SAP) 
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11. The Open-Label Titration blister card will be reviewed, but not retrieved, at this visit. See the Pharmacy Manual and Instructions for Taking TR11 Study Medication for additional 
instructions. 
12. Site to dispense the Instructions for Taking TR11 Study Medication as applicable to the subject’s dosing period (i.e., Double-blind titration blister card or Double-blind fixed dose bottle). 
Note: Although both AM and PM doses are present on Day 1, only the PM dose will be taken (both Arms). 
13. At the time of informed consent, subjects identified as taking a concomitant short-acting benzodiazepine should be provided with the Benzodiazepine Patient Information 
Sheet, informing them of safety information and warnings regarding the use of NAL ER in combination with this class of drug. Likewise, any subject who is subsequently prescribed 
short-acting benzodiazepines during the course of the study should also be provided with this information sheet. 
14. At study Day 14 and Day 112, the titration card only contains 14 days of dosing. Subjects should be scheduled to come in on the target date or up to 2 days prior to ensure not to run 
out of investigational product. 
15. Height and BMI will be obtained at the screening visit only. Weight will be obtained at the screening visit and subsequently according to the schedule. 


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Table 2 
Schedule of Assessments – Open-label Extension Period 
Study Period → 
 
 
Open-label Fixed-dose Period 
Washout and Safety Follow-up 
Period 
Last Contact for 
WI-NRS 
Assessment ↓ 
Repeating visit q4wk or q8wk 
Off-treatment1 
Last Visit1 
End of Study 
Phone call1 
W17 to W52 
Visit Week 
17 
17 
20 
24 
282 
322 
362, 
44 
52 
54 
56 
Study Day (±2 days) 
113 
120 
140 
168 
196 
224 
252 
308 
364 
378 
392 
Physical examination 
X 
X 
Brief neurological 
assessment 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
Central ECG4 
X 
X 
X 
Clinical Laboratory 
assessments 5 
X 
X 
X 
X 
Blood for PK 
assessment 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
Urine pregnancy 
(WOCBP) 
X 
X 
X 
X 
X3 
X 
X 
X 


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Table 2 
Schedule of Assessments – Open-label Extension Period 
Study Period → 
 
 
Open-label Fixed-dose Period 
Washout and Safety Follow-up 
Period 
Last Contact for 
WI-NRS 
Assessment ↓ 
Repeating visit q4wk or q8wk 
Off-treatment1 
Last Visit1 
End of Study 
Phone call1 
W17 to W52 
Visit Week 
17 
17 
20 
24 
282 
322 
362, 
44 
52 
54 
56 
Study Day (±2 days) 
113 
120 
140 
168 
196 
224 
252 
308 
364 
378 
392 
Record and assess 
AEs6, concomitant 
medications, and 
therapies (including 
restricted and prohibited 
medications) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability intervention 
X 
X 
X 
X 
e-diary7 – retrieve 
and/or review entry 
compliance 
X 
X 
X 
X 
X 
X 
X 
X 
Retrieve/review/re- 
dispense Subject 
Medication Log and 
Subject Symptom Log8 
X 
X 
X 
X 
X 
X 
X 
X 
ItchyQoL7 
X 
X 
X 
X 
X 
X 
PAS and IGA-PN 
X 
X 
X 
X 
X 
X 
X 
PBI-P7 
X 
X 
X 
X 
X 


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Table 2 
Schedule of Assessments – Open-label Extension Period 
Study Period → 
 
 
Open-label Fixed-dose Period 
Washout and Safety Follow-up 
Period 
Last Contact for 
WI-NRS 
Assessment ↓ 
Repeating visit q4wk or q8wk 
Off-treatment1 
Last Visit1 
End of Study 
Phone call1 
W17 to W52 
Visit Week 
17 
17 
20 
24 
282 
322 
362, 
44 
52 
54 
56 
Study Day (±2 days) 
113 
120 
140 
168 
196 
224 
252 
308 
364 
378 
392 
Sleep Scale (PROMIS)7 
X 
X 
X 
X 
X 
X 
WI-NRS7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photography8 
X 
X 
Administer 14-day 
SOWS9 
X 
Retrieve 14-day SOWS9 
X 
Dispense investigational 
product 
B 
B 
B 
B 
BB 
BB 
Retrieve investigational 
product and containers 
B + 
Card 
BB 
B 
B 
B 
BB 
BB (B)10 
Investigational product 
- accountability 
X 
X 
X 
X 
X 
X 
X 
Investigational product 
- review dosing 
compliance 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
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AE: adverse event; B: bottle; BID: twice daily; Card: blister card; ECG: electrocardiogram; e-diary: electronic diary; IGA-PN: Investigator Global Assessment-Prurigo AE: 
adverse event; B: bottle; BID: twice daily; Card: blister card; ECG: electrocardiogram; e-diary: electronic diary; IGA-PN: Investigator Global Assessment-Prurigo Nodularis; 
LFT: liver function test; NA: not applicable; PAS: Prurigo Activity Score; PBI-P: Patient Benefit Index, pruritic versions; PK: pharmacokinetic; PRO: patient-reported 
outcome; q4wk: every 4 weeks; q8wk: every 8 weeks; SHBG: sex hormone-binding globulin; SOWS: Subjective Opiate Withdrawal Scale; TSH: thyroid stimulating 
hormone; W: Week; WI-NRS: Worst Itch – Numerical Rating Scale; WOCBP: woman of childbearing potential; : telephone call. 
1. 
Off-Treatment visit occurs upon stopping investigational product; regardless of reason. Subjects who elect to go off-treatment prior to 52 weeks of treatment (premature 
discontinuation of investigational product) should be asked to complete the Off-Treatment visit, the 2-week SOWS evaluation, the Last Visit (occurs 14 days after off-treatment visit 
date), and the End of Study telephone call. 
2. 
Assess eligibility for down titration based on criteria of confirmed WI-NRS ≤ 3 and 1 category improvement in PAS lesion healing. If both criteria are met, may discuss the option for 
a permanent dose reduction to 108 mg BID. Note: if criteria are met, this decision is at the discretion of the Investigator and with the agreement of the subject, but once dose reduction 
has been initiated no re-escalation is permitted. 
3. 
Vital signs are to be obtained after the subject has been seated for at least 5 minutes. 
4. 
ECGs are to be performed in triplicate (3 serial ECGs at least 1 minute apart) after the subject has been in the supine position for at least 5 minutes. ECGs are to be transmitted to be read 
centrally by a core ECG laboratory. The average of the QTcF values from the triplicate ECGs will be performed and presented in a report to be used as the final eligibility assessment for 
the subject. 
5. 
Laboratory Evaluations: Hematology and serum chemistry, LFTs, specified endocrine (TSH all subjects with reflex free T4 if above Upper Limit Normal (ULN) or below Lower Limit 
Normal (LLN), free testosterone [the fraction not bound to SHBG or albumin] and SHBG for males) and pregnancy if WOCBP (regardless of sexual status); urine pregnancy test to 
be performed by the local laboratory and confirmed to be negative prior to dispensing investigational product. TSH values above the upper limit of normal (ULN) should be repeated at 
the next study visit (or approximately 1 month later; whichever occurs first). If TSH remains above the ULN, a Free T4 will be performed on the existing laboratory sample). 
6. 
AEs are to be continually assessed starting with the signing of the informed consent. Subjects should continue to record any new AEs or concomitant medication use on the Subject 
Symptom Log and Subject Medication Log. Site staff are required to remind subjects to bring the logs to each visit (including the telephone contacts). Logs should be reviewed by site staff 
at every visit prior to re-dispensing (or issuing new logs as needed) to subjects. Final retrieval of the logs, for filing in source records, should occur at the last clinic visit. Events of 
special interest should trigger the collection of additional information using the AESI worksheet and documented under the AESI section of the Adverse Event eCRF. Event 
details and both subject and investigator narratives should be thoroughly documented in the AESI worksheet and completed under the AESI section of the Adverse Event eCRF. 
7. 
PROs (Patient Reported Outcomes) are to be administered by site staff or e-diary as described in the Trialogics User Manual. WI-NRS data will also be collected from the subject via 
the Trialogics web portal at each clinic visit (beginning at Week 20). 
8. 
Photography: To be performed at certain sites only. See the Canfield Quick Reference Guide and User Reference Manual for photography procedures as applicable. 
9. 
The 14-day SOWS is to be completed, on the e-diary, at home by the subject. Site staff must change the subject’s status to “Off-treatment” on the Trialogics web portal to trigger the 
launch of the SOWS. Subjects must be instructed to enter SOWS data daily for the 14 days following discontinuation of investigational product regardless of when this occurs (i.e. Week 52 
visit or Premature Discontinuation). Data should be reviewed by site staff during the 14-day collection period in order to assess the need for any withdrawal intervention. The e-diary is to 
be retrieved at the last clinic study visit. 
 
 


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IV. 


Statistical Analysis Plan (SAP) 
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V. 
STUDY ENDPOINTS 
 
A. Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the difference between the percentage of “Responders” at 
Week 14 for the NAL ER treatment arm versus the placebo arm. A “Responder” is defined as a 
subject with a ≥ 4-point decrease in the 7-day average WI-NRS from baseline to Week 14. 
 
B. Secondary Efficacy Endpoints 
 
Key secondary efficacy endpoints include the following: 
• 
The mean change in ItchyQoL from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm. 
• 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in 
the percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to 
Week 14 for the NAL ER treatment arm versus the placebo arm. 
• 
The mean change in sleep disturbance (PROMIS Sleep Disturbance Short Form 8a) from 
baseline to Week 14 for the NAL ER treatment arm versus the placebo arm. 
Other secondary efficacy endpoints include the following: 
• 
The mean change in 7-day average WI-NRS from baseline to Week 14 for the NAL ER 
treatment arm versus the placebo arm. 
• 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in 
the percentage of healed lesions (item 5b) from baseline to Week 14 for the NAL ER 
treatment arm versus the placebo arm. 
• 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in 
the percentage number of lesions (item 2) from baseline to Week 14 for the NAL ER 
treatment arm versus the placebo arm. 
• 
Change in IGA-PN as assessed by the percentage of subjects having a 1-category 
improvement in activity for the NAL ER treatment arm versus the placebo arm. 
• 
Change in IGA-PN as assessed by the percentage of subjects having a 1-category 
improvement in stage for the NAL ER treatment arm versus the placebo arm. 
• 
The proportion of subjects having a PBI-P score of  1 at Week 14 for the NAL ER 
treatment arm versus the placebo arm. 


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C. Pharmacokinetics Endpoint 
 
Nalbuphine plasma concentration (and metabolites as needed). 
 
 
D. Safety Endpoints 
Safety will be assessed based on adverse events (AEs), clinical laboratory measurements, central 
cardiac core laboratory read-12-lead ECG, vital signs, brief neurological assessments, and 
physical examinations. 
Subjects will also complete the Subjective Opiate Withdrawal Scale (SOWS) on a daily basis for 
the 2 weeks following the last dose of investigational product, whenever that occurs and 
regardless of the reason (unless consent is withdrawn). 
An independent Data Safety Monitoring Board will periodically review safety data. 


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5. SAMPLE SIZE AND POWER 
The planned sample size of approximately 240 subjects (120 per group) is based on assumed 
responder percentages for placebo and NAL ER of 25% and 45%, respectively. These responder 
percentages represent estimates based on the Week 10 data from the TR03 study. Power is set at 
90% with a 2-sided significance level of 0.05. 
 
 
5.1 Responder percentage assumptions 
In the TR03 study, all those who achieved a 50% reduction in WI-NRS itch also achieved at least 
a 4-point reduction in itch from baseline, matching the responder definition for the current study. 
Results showed a response rate of 6 of 18 (33.3%) for the NAL ER 162 mg treatment group versus 
4 of 22 (18.2%) for placebo. Of note, the placebo response in TR03 falls on the lower end of the 
expected range for endpoints that reflect PRO endpoints in neurologically-mediated diseases such 
as pain or psychiatric disease. Studies in these areas frequently show placebo responses in the 
20% to 30% range and sometimes as high as 40%. The role of placebo response in dermatology 
has been increasingly documented and recognized in recent years. Given the small size of the 
TR03 dataset, and the variability of placebo response in comparable disease states, the estimate of 
placebo response for TR11 was set at 25%. 
 
The NAL ER 162 mg responder rate is estimated at 45% for TR11, versus the 33.3% observed in 
TR03 for the following reasons: First, the TR03 endpoint was set at Week 10, and it is expected 
that the additional 4 weeks of active therapy will likely increase the response rate in this treatment 
arm. Second, experience from the TR03 study indicated that with close follow-up and guidance 
during the titration period, subject drop-out due to early symptoms associated with opiate 
initiation can be decreased, although not eliminated. Given that the completer’s analysis in TR03 
demonstrated a response rate of 50% (again acknowledging the small size of the cohort), 
increasing the number of subjects completing the study is expected to result in a somewhat higher 
all-treated response rate in the active arm than was seen in TR03. 
5.2 Calculations 
Approximately 30 - 45 sites are expected to participate in the current study. In SAS PROC 
POWER, the LOGISTIC setting was used to approximate the power for a chi-square test 
comparing the 2 treatment groups with respect to response, without site in the model, and a CMH 


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test comparing the 2 treatment groups with respect to response, with site in the model. In a model 
without site, the sample size was n=234 (117 per treatment group). The model with sites included 
was originally considered with the following assumptions: 30 sites of varying sizes (6 sites with 
1% of the total sample each, 6 with 2%, 6 with 3%, 6 with 4%, 3 with 5%, 1 with 6%, 1 with 8% 
and 1 with 11%); and varying responder rates among sites (one fixed as having the lowest, and the 
next lowest having an odds ratio of 1.05 compared to the lowest and so on, until the one with the 
highest, which has an odds ratio of [1.05]29 ≈ 4.12 compared to the lowest; this variation among 
sites is perhaps larger variation among sites than one would expect). In the PROC POWER runs, 
this site effect was specified in fixed order, and the site size was randomly scrambled. In 10 runs, 
the sample size needed for 90% power ranged from 239 to 242, averaging 240.7. Hence, the final 
target sample size is taken to be 240. With a sample size of 240, the study will have 80% power 
to detect a difference if the NAL ER 162 mg responder rate is as low as 41.8%. 
To address the concern of the reliability of the estimates of treatment effectiveness from the 
previous studies, an adaptive mid-course sample size re-estimation procedure will be performed 
when 50% of the subjects have either completed the Week 14 primary endpoint assessment or 
terminated from the study early. The data for the re-estimation of sample size will be unblinded to 
an independent statistician and the sample size may be increased up to the predefined maximum 
allowable sample size if the conditional power is within the promising zone; therefore, this re- 
estimation will not inflate the type I error. 
 
Given that the interim analysis is to be performed at 50% of the initial sample size (120 subjects), 
the targeted power is 90%, and the maximum allowable sample size is set at 1.5 times the initial 
sample size (360 subjects), the conditional power cut-off value (CPmin) is 41%2. If the CP is 
between 41% and 90%, the number of subjects per treatment arm will be increased, up to the 
maximum allowable sample size for this study (360), to recover the targeted power of 90%. 
Since sample size re-estimation occurs only when the interim conditional power falls in the pre- 
specified “promising” range, and the study will not stop for efficacy regardless of the conditional 
power, the overall alpha will be protected, and the final analysis will be carried out using 
conventional tests, without the need for weighing the stage 1 and 2 results or adjusting the alpha 
value 2 


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6. ANALYSIS POPULATIONS 
 
 
6.1. Modified Intention-To-Treat population (mITT) 
The mITT population will consist of all randomized subjects who have received at least a single 
dose of the investigational product. The mITT population will be used for all efficacy analyses. In 
the event of a discrepancy between the randomized treatment and the actual treatment received, 
subjects will be analysed according to the randomization treatment. 
 
 
6.2. Safety population (Safety) 
The safety population will consist of all randomized subjects who have received at least a single 
dose of the investigational product. The safety population will be used in all safety analyses. In the 
event of a discrepancy between the randomized treatment and the actual treatment received, 
subjects will be analyzed according to the treatment they actually received. 
 
6.3. Per-Protocol population (PP) 
The per-protocol (PP) population will include all subjects in the mITT population without any 
major protocol deviations that could have influenced the validity of the data for the primary 
efficacy variable. 
The deviations can include, but are not limited to: e.g. inclusion criteria 1-6 and exclusion criteria 
1-3, 16, 17, and 19-25 must have been satisfied. 
• Key inclusion/exclusion criteria not satisfied. 
• Use of prohibited concomitant medications. 
• Inadequate investigational product compliance (<50% compliant), which will be 
determined before breaking the blind. 
The subjects to be excluded from the PP population will be identified in a blinded fashion and 
documented in a memo prior to the database lock and unblinding. 


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7. STATISTICAL CONSIDERATIONS AND ANALYSIS 
 
 
7.2. Derived Variables 
7.2.1. Baseline 
The baseline WI-NRS value is calculated as the arithmetic mean of the WI-NRS values (minimum 
of 5 required) taken for eligibility review by site at the time of randomization. The Trialogics 
original average of the WI-NRS will be used as the baseline for all analysis. For all other efficacy 
and safety variables, baseline is defined as the last non-missing evaluation (including repeated and 
unscheduled assessments) taken prior to or on the first dose of study medication. 
7.2.2. Changes from Baseline 
For WI-NRS, the change from baseline during the double-blind period is described in Section 
7.3.1. For quantitative measurements other than WI-NRS, change from baseline will be calculated 
as: 
Change from baseline = Test Value at Visit X – Baseline Value 
If either value is missing, then the change from baseline will also be missing. 
 
 
7.2.3. Date of First Dose of Study Drug 
The date of randomization will be utilized for the date of first study drug dose, and will be referred 
to as the start date of study drug. 
 
For the analysis referring to the open-label period, the date of the first administration of the 
extension titration medication will be considered as the start of this period. 
 
7.2.4. Date of Last Administration of Study Drug 
The date of last administration of the study drug in the double-blind period is derived as the last 
date when a dose of study drug was administered and recorded on the eCRF page of “Exposure 
(EX)” in that period. 
The date of last administration of the study drug in the open-label period is derived as the last date 
when a dose of study drug was administered and recorded on the eCRF page of “Exposure (EX)” 
in that period. 


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The date of the last administration of the study drug for the study is derived as the last date when a 
dose of the study drug was administered and recorded on the eCRF page of “Exposure (EX)” 
whenever that occurs. 
 
7.2.5. 
Study Day 
The study day (e.g. adverse event onset, laboratory abnormality occurrence, vital sign 
measurement, dose interruption, etc.) will be calculated using the start date the of double-blind 
study drug (Study Day 1) as the origin. Subsequent study days will be calculated as (date of 
assessment) – (start date of study drug) + 1. 
 
For visits (or events) that occur prior to study day 1, the study day is defined as (date of visit (or 
events) – date of study day 1). There is no study day 0. Therefore, the study day displayed on the 
listing will be negative. 
 
7.2.6. 
Exposure and Compliance 
Duration of exposure (days) = (Date of last administration of study drug - Date of first 
administration of study drug) +1. 
 
Compliance (%) = Number of tablets subject actually took/ Number of tablets subject was 
expected to take multiplied by 100. 
 
Duration and compliance will be calculated for the double-blind and open-label periods, 
separately. 


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7.2.7. Visit Window Definitions 
Windowing is applicable to efficacy and safety endpoints, except for WI-NRS and SOWS for reporting purposes. 
 
BL* 
Week 
2 
Week 
6 
Week 
10 
Week 14 ** 
Week 16 
Week 20 
Week 
24 
Week 28 
Week 
32 
Week 
36 
Week 
44 
Week 
52 
Week 
54 
Week 
56 
Scheduled 
Day 
1 
14 
42 
70 
98 
112 
140 
168 
196 
224 
252 
308 
364 
378 
ItchyQoL 
Day 1 
22 to 
56 
57 to 
84 
85 to (titration 
start day-1) 
titration 
start day to 
154 
155 to 
182 
183 to 
224 
225 to 
280 
281 to 
336 
>=337 
PAS and 
IGA-PN 
Day 1 
29 to 
84 
85 to (titration 
start day-1) 
titration 
start day to 
154 
155 to 
182 
183 to 
210 
211 to 
238 
239 to 
280 
281 to 
336 
>=337 
PBI-P 
Day 1 
29 to 
84 
85 to (titration 
start day-1) 
titration 
start day to 
168 
169 to 
210 
211 to 
238 
239 to 
280 
281 to 
336 
>=337 
Sleep Scale 
Day 1 
22 to 
56 
57 to 
84 
85 to (titration 
start day-1) 
titration 
start day to 
154 
155 to 
182 
183 to 
224 
225 to 
280 
281 to 
336 
>=337 
Vital Signs 
Day 1 
8 to 
28 
29 to 
56 
57 to 
84 
85 to (titration 
start day-1) 
titration 
start day 
to 126 
127 to 154 
155 to 
182 
183 to 
210 
211 to 
238 
239 to 
280 
281 to 
336 
337 to 
371 
>=372 
Clinical lab 
Day 1 
8 to 
28 
29 to 
70 
71 to (titration 
start day-1) 
106 to 
252 
253 to 
336 
337 to 
371 
>=372 
Urinalysis 
Day 1 
99 to 280 
>=281 
* If a Day 1 value is missing, then the last screening value is used as the baseline value. 
** In the Week 14 column, the end of the window applies to subjects who go on to enter the open-label period. For subjects who don’t enter the open-label period, the end of 
the window is 14 days later than that displayed in the column. 


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Note: ECG windowing will be established by ERT, who will perform ECG analyses. 
 
If two or more observations fall into the same window, the observation closest to the scheduled day will be used in the analysis. If there is a tie, the later 
observation will be used. 


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7.3. 
Efficacy Derived Variables 
7.3.1. WI-NRS 
The WI-NRS is a PRO 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 the IFSI for quantifying itch 
intensity as well as a useful instrument for grouping subjects into categories of itch intensity described as 
mild, moderate, or severe3: The itch NRS has been investigated in subjects with chronic pruritus of a 
variety of origins, and a high reliability and concurrent validity was found3,4. 
 
In this study, during the double-blind period, subjects will be asked to record the WI-NRS value daily, at 
approximately the same time each day, usually in the late afternoon or early evening. All WI-NRS 
information will be entered into the e-diary. During the open-label period, only a single value will be 
collected for the WI-NRS at each study visit. This will be collected using the same electronic diary format 
via web portal. 
 
The primary endpoint depends on the change from baseline to Week 14. The calculation of the Week 14 
value is described below. 
 
For the 2-, 6- and 10-week visits, the WI-NRS will be calculated as the arithmetic means of the WI-NRS 
values on Study Days 8 through 14 (Week 2), 36 through 42 (Week 6), and 64 through 70 (Week 10), 
respectively, regardless of when the Weeks 2, 6 and 10 visits actually occur. 
 
The Week 14 WI-NRS is calculated as follows: 
• 
Case 1: Subject’s Week 14 visit is on or after Study Day 98 (target day) 
o Use all values in the period Study Day 92 through Study Day 98 
▪ 
If there are ≥ 5 values, calculate the arithmetic mean of them 
▪ 
If there are < 5 values, calculate an arithmetic mean based on all of them plus any 
available values in the range from Study Day 99 till titration begins that will bring the 
total to 5 values, but do not use any values collected after titration begins. If this range has 
more values than necessary to bring the total to 5 values, use values closest to Study Day 
 
98. If there are still less than 5 values, continue to use any available values in the first 3 


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days before Day 92 that will bring the total to 5 values. If this range has more values than 
necessary to bring the total to 5 values, use values closest to Study Day 92 
• 
Case 2: Subject’s Week 14 visit is before Study Day 98 
o Use all values from Study Day 92 to the Study Day of the Week 14 visit 
▪ 
If there are ≥ 5 values, calculate the arithmetic mean of them 
▪ 
If there are < 5 values, calculate an arithmetic mean based on all of them plus any 
available values in the first 3 days before Day 92 that will bring the total to 5 values. If 
this range has more values than necessary to bring the total to 5 values, use values closest 
to Study Day 92 
 
A “Responder” is defined as a subject with a ≥ 4-point decrease in the 7-day average WI-NRS from 
baseline to Week 14. Baseline is as described in Section 7.2.1. 
 
7.3.2. 
ItchyQoL Total Score (ItchyQoL) 
The ItchyQoL consists of 22 pruritus-specific items measuring how pruritus affects subjects’ 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 ItchyQoL must be administered at the site under supervision by trained and 
authorized study staff, strictly adhering to administration instructions. 
 
The ItchyQoL total score will be obtained as the sum of the 22 items. For each subscale (symptoms, 
functional limitations, emotions) of ItchyQoL, if one item within a subscale is missing, the median of 
remaining items within that subscale will be used to impute the missing value. If more than 1 item within 
a subscale is missing, that subscale and the ItchyQoL total score will be set to missing. 
 
7.3.3. 
PBI-P 
Before therapy, the subject fills in the PBI-P questionnaire as to the individual importance of treatment 
objectives. During and after therapy, the subject completes a matched “on-treatment” 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 PBI-P must be administered at the site under supervision by trained and authorized study 
staff, strictly adhering to administration instructions4. 


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Part 1: Patient Needs Questionnaire (PNQ). The PNQ consists of the “treatment goal” items. Each item 
has 5 categories: not at all (0), somewhat (1), moderately (2), quite (3), and very (4). PNQ is analysed 
descriptively. The analysis consists of the following: 
▪ 
means and standard deviations of all items (“does not apply to me” is coded as 0 for this single- 
item analysis of the PNQ) 
▪ 
for each item the percentage of the response “does not apply to me” 
▪ 
for each item the percentage of responses with high agreement (quite or very) 
▪ 
percentage of missing values 
 
 
Part 2: Patient Benefit Questionnaire (PBQ). The PBQ consists of the “benefit” items measuring the 
extent to which the treatment goals have been achieved. It is analysed descriptively. The analysis consists 
of the following: 
▪ 
means and standard deviations of all items ((“did not apply to me”) is treated as missing here) 
▪ 
for each item the percentage of the response “did not apply to me” 
▪ 
for each item the percentage of responses with high agreement (quite or very) 
▪ 
percentage of missing values 
 
The PBI-P global score may only be computed if the subject has provided valid data on importance 
(PNQ) and benefit (PBQ) for at least 75% of the respective treatment goals, that is, for at least 21 of the 
27 items. The responses “does/did not apply” and “question answered” are considered valid values 
when counting the number of non-missing responses. 
 
The PBI-P global score is computed for each subject according to the following algorithm. 
Identify the subjects who have 21/27 needs answered at baseline & 21/27 of the benefits questions 
answered at each visit. For this assessment 0 & 5 are considered non-missing. 
PBI-P Global Score: 
Individual PNQ (‘Patient Needs’ or ‘Importance’) scores are in the SDTM data set QS. 
(QS.QSTESTCD.PBIP101 to QS.QSTESTCD.PBIP127). 
Individual PBQ (‘Patient Benefit’ or ‘Benefit’) scores are in the SDTM data set QS. 
(QS.QSTESTCD.PBIP201 to QS. QSTESTCD.PBIP227). 
1. Determine individual baseline PNQ scores. 


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2. Count PNQ scores, where individual score is from 1 to 4, as PNQ count. 
3. Sum PNQ scores, where individual score is from 1 to 4, as PNQ sum. 
4. Merge PBQ score at visit with corresponding baseline PNQ scores, creating item 
pairs. (e.g., merge PBIP101 with PBIP201) by subject-visit. 
5. For each item pair, if both PNQ and PBQ score is 1 to 4, multiply PNQ*PBQ as 
calculated raw score. 
6. Sum calculated raw scores as PBQ sum. 
7. If PNQ count >= 21, calculate and output PBI-P Global Score as (PBQ sum/PNQ sum). 
 
However, for the score calculation, both “does/did not apply” and “question unanswered” will be treated 
as missing values. The global score will be calculated using only those items pairs (i.e., importance item 
and benefit item) for which the subject has given a response other than “does/did not apply” in both PNQ 
and PBQ. That is, importance items for which the corresponding benefit item has been rated as “does/did 
not apply” or “not at all” (or vice versa) will not be included in the sum of needs (i.e., the denominator in 
the algorithm). 
The interpretation of data includes the distribution characteristics of PBI-P (e.g., mean and standard 
deviation) and the proportion of subjects with PBI-P ≥ 1, PBI-P ≥ 2, PBI-P ≥ 3. Subjects with PBI-P ≥ 1 
are considered as having at least minimum patient-relevant treatment benefit (based on pilot studies). 
7.3.4. 
Prurigo Activity Score (PAS) 
The PAS consists of 5 quantitative and qualitative measurements related to the examination of the skin: 
Type; number; distribution; quantitative number of lesions in a representative body part; and activity. 
Prurigo lesion activity is recorded as a stage (0 to 4), based on the percentage of overall lesions with the 
relevant characteristic. 
Three types of PAS responders are defined, one for each of the following items: Prurigenous lesions with 
excoriations/crusts (item 5a); Healed lesions (item 5b); Number of lesions (item 2). For each of these, a 
responder is defined as a subject who has at least 1-category improvement in the relevant item from 
baseline to Week 14. For all three, a patient who does not have Week 14 measurement is a non-responder. 


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7.3.5. Investigator Global Assessment – Prurigo Nodularis (IGA-PN). 
The IGA-PN collects an Investigator Global Assessment of the status of the PN skin lesions. The IGA-PN 
uses a 5-category scale (scoring 0 to 4) for assessing the status of 2 aspects of the disease: The Activity 
(amount of excoriation and crusting associated with the prurigo lesions), and the Stage (the quantitative 
presence and proportion of flattening of the lesions). An IGA-PN responder for Activity or Stage is 
defined as a subject who has at a least 1-category improvement in the respective score from baseline to 
Week 14. 
7.3.6. Sleep Scale 
There is no assessment scale that is targeted specifically to evaluate sleep in the PN population. The 
Patient Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Short Form 
8a questionnaire has been developed as a general tool for assessing sleep in the context of clinical trials. 
It consists of 8 open-ended statements about the subject’s sleep over the past 7 days, with 5 options for 
completing the statement. There is 1 broad sleep quality question with options for completing with: “very 
poor”, “poor”, “fair”, “good”, and “very good”. The remaining 7 questions can be answered with: “not at 
all”, “a little bit”, “somewhat”, “quite a bit”, and “very much”. The sleep scale score is estimated per 
algorithm below. 
Each question usually has five response options ranging in value from one to five. To find the total raw 
score for a short form with all questions answered, sum the values of the response to each question and 
use Table 1 in the Appendix to translate the total raw score into a T-score for each participant. The 95% 
confidence interval around the observed score is estimated as (T-score +/- (1.96*SE). 
 
7.4. Handling of missing data and outliers 
 
 
7.4.1. Missing data analysis methods 
For the primary efficacy endpoint, missing values at week 14 will be set to missing. The data will be 
analysed using the mixed model technique. The analysis assumes that the missing data is missing at 
random (MAR). Thus, it provides an unbiased estimate of the treatment effect that would have been 
observed had all subjects continued on treatment until Week 14. It therefore assumes that the response for 
withdrawn subjects will follow the trajectory of the respective treatment after discontinuation. In order to 
assess the robustness of the results to the MAR assumption, a sensitivity analysis will be conducted under 


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the assumption that the data is missing not at random (MNAR). The details of this analysis are described 
in 
For the change from baseline in ItchyQoL and PROMIS, all observed data up to and including Week 14 
will be used without using imputation methods for missing data. However, in sensitivity analyses, two 
multiple imputation (MI) methods will be used: Control based multiple Imputation and Tipping Point 
Analysis approaches 
 
7.4.2. Handling of missing or incomplete dates 
Unless otherwise stated, other than for partial dates, missing dates will not be imputed and will be treated 
as missing, as specified below. The imputed date will be included in the analysis datasets, but not 
displayed in the listings. 
Concomitant Medications Start/End Date 
Partial missing start/end date to concomitant medications will be imputed as follows: 
Start date of concomitant medications 
• If only the day of the month is missing, use the first day of the month to replace the missing part; 
• If both the day and the month are missing, January 1st will be used to replace the missing part; 
• If day, month and year are all missing, use a date one day before the first date of study drug. 
End date of concomitant medications 
• If only day is missing, use the last day of the month 
• If both day and month are missing, use the last day of the year 
• If day, month and year are all missing, assign ‘continuing’ status to stop date 
Adverse Events Start/End Date 
Missing or partial missing date to the onset date of AE will be imputed as below: 
• 
If the AE onset date is completely missing, the AE start date will be imputed as the first date of 
study drug; 
• 
If the AE onset date is partially missing, then 
o If both the year and the month are available, and they correspond to the year and month of 
the first dosing date, then the AE start date will be imputed as the first dosing date; 
o If both the year and the month are available, and they do not correspond to the year and 
month of the first dosing date, then the AE start date will be imputed as the 1st day of the 
month; 


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o If only the year is available, and it corresponds to the year of the first dosing date, then 
the AE start date will be imputed as the first dosing date; 
o If only the year is available, and it does not correspond to the year of the first date of 
study drug, then the AE start date will be imputed as the January 1st of the year. 
Adverse event end date will be imputed as below for the partial date only. 
• 
If both the year and the month are available, AE end date will be imputed as the last day of the month; 
• 
If only the year is available, AE end date will be imputed as the December 31st of the year. 
If the imputed AE end date is after the death date, then the date of the death will be imputed as the AE 
end date. 


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8. STATISTICAL METHODS AND ANALYSI8 
 
 
8.1 
General Statistical Conventions 
All statistical procedures will be completed using SAS 9.4® or higher. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a significance 
(alpha) level of 0.05, and two-sided 95% confidence intervals (CI) will be provided when relevant. 
Continuous variables will be summarized using descriptive statistics, including number of subjects (n), 
mean, median, standard deviation (SD), minimum and maximum. For efficacy variables with subscales, 
the total score and subscales will be summarized. 
For categorical variables, summaries will include counts of subjects and percentages. Percentages will be 
rounded to one decimal place. 
Unless otherwise stated all summaries will be presented by treatment group. 
All subject data, including those derived, will be presented in individual subject data listings. Unless 
otherwise stated, unscheduled visit results will be included in date/time chronological order, within 
subject listings only. All listings will be sorted by treatment group, subject ID, date/time and visit/study 
day. Subject’s sex and age will be stated on each listing. Unless otherwise stated, data listings will be 
based on All Subjects Randomized Set. 
 
8.2 Subject disposition 
Subject disposition information will be tabulated for all screened subjects, including rows for all screened 
subjects, randomized subjects (total and by whether or not treated), and screen failures (total and by 
reason). 
A separate table will describe disposition for all randomized subjects, by treatment group and overall. The 
table will provide rows for the number of randomized subjects and the number of treated subjects (i.e., the 
mITT population), as well as the numbers and percentages (based on the mITT population) of subjects 
who completed the double-blind period, who entered the open-label period, who completed the entire 
study, and who withdrew early (by period). The primary reason for early withdrawal will also be 
tabulated. 
The number and percentage (using the mITT population as the denominator) of subjects in each analysis 
set will also be tabulated. 
By-subject disposition listings will be provided separately for screened subjects who were not in the ITT 
population and for subjects in the mITT population. 


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Treatment Misallocations: 
If a subject was randomized but took incorrect treatment throughout the double-blind period, they will be 
reported under the randomized treatment group for all efficacy analysis, but will be reported under the 
treatment they actually received for all safety analysis. However, if a subject took the incorrect treatment 
for only part of the time during the double-blind period, they will be reported under the randomized 
treatment group for all efficacy and safety analysis. The subjects who took incorrect treatment 
intermittently will be identified, and Ad Hoc analyses may be performed. 
 
Protocol deviations 
All key protocol deviations (categorized) will be summarized by treatment group and overall, using the 
mITT population. Subjects excluded from the mITT population to yield the Per-Protocol population will 
be listed, with reason for exclusion, treatment group, age, sex and race. A by-subject listing will include 
the inclusion/exclusion criteria violated at Screening and at Baseline Visits as well as other protocol 
deviations identified, based on data recorded on the eCRF and/or protocol deviation logs from ICON 
Medical (on Randomized subjects). 
 
8.3 Demographics and baseline characteristics 
8.3.1 
Demographics 
Age, height, weight, BMI and other continuous demographic variables at baseline will be summarized 
descriptively using the mITT population. Sex, race, ethnicity and other categorical variables will be 
summarized using frequency counts and percentage for the mITT Population. By-subject listings will also 
be provided. 
8.3.2 
Baseline and disease characteristics (Prurigo Nodularis History) 
The following categorical disease baseline characteristics will be summarized using frequency counts and 
percentages for the mITT population: 
• 
When did the subject’s Prurigo Nodularis start? 
• 
If less than 3 months, did it start greater than 6 weeks ago? 
• 
The quality of the itch 
• 
What increases the itching? 
• 
Scratching Behavior 1 
• 
Scratching Behavior 2 


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• 
How does the subject perform the scratching? 
• 
Previous treatments for Prurigo Nodularis 
 
 
Data in Part 2 of the Prurigo Nodularis History represent Past Medical History (PMH) that may represent 
a risk factor for subsequent evolution of PN. Analyses of key efficacy endpoints will be performed for 
subgroups of sufficient size (See Section 8.6.2). These subgroups will combine subjects with relevant past 
medical histories based on the general understanding of the mechanism that may drive the association 
with itch. The following broad subgroups are anticipated, although the final grouping will be established 
based on the actual PMH data available prior to unblinding. Of note, the immune system may contribute 
to the itch component across these various categories and diseases, and if the understanding of PN itch 
evolves during the timeframe of the TR11 trial, these categories may shift. 
• 
Subjects with a past history of dermatologic diseases associated with itch (atopic dermatitis, 
nummular or discoid eczema, venous stasis skin disorder, Epidermolysis Bullosa Acquisita, or 
other skin disease depending on type); 
• 
Subjects with a past history of metabolic diseases associated with itch, or with other primary 
diseases thought for which itch induction is thought to act through a metabolic pathway, such as 
hepatic impairment (Diabetes, Diabetic or Non-Diabetic Kidney Disease, Chronic Anemia, Hypo- 
or Hyperthyroidism, Hepatitis B or C presumably mediated via hepatic dysfunction); 
• 
Subjects with a non-dermatologic history of atopic disease (gluten enteropathy/Celiac disease, 
food allergy, environmental allergy, malabsorption/nutritional deficiencies); 
• 
Subjects with a past history of neurological disease (peripheral neuropathy of hands/feet; other 
peripheral neuropathy; radiculopathy/sciatica; degenerative disc disease; degenerative vertebral 
bony disease; notalgia paresthetica; brachioradial neuropathy; trigeminal neuropathy; history of 
herpes simplex [severe] or herpes zoster infection); 
• 
Other: subjects with a past history of various miscellaneous diseases expected to be of lower 
frequency (gastric ulcer disease, HIV infection, Haematologic malignancy, solid organ 
malignancy). 
 
These conditions will be summarized using frequency counts and percentages using the mITT population, 
with the following categories for each condition: Yes, resolved; Yes, not resolved; No. Depending on 


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the completeness of the dates of onset and resolution, durations may be summarized with 
descriptive statistics. 
By-subject listings will also be provided. 
 
 
8.3.3 
Neurological history 
Neurological history will be summarized using frequency counts and percentages for the mITT population. 
By-subject listings will also be provided. 
 
8.3.4 
Medical history 
A summary of medical history will be presented by system organ class (SOC) and preferred term (PT) 
using Medical Dictionary for Regulatory Affairs® (MedDRA) Version 21.1 or higher. By-subject listings 
will also be provided. 
 
8.3.5 
Prior and concomitant medications 
Medications used in this study will be coded using the latest available version of the World Health 
Organization Drug Dictionary Enhanced (WHODDE). 
Prior medications: those medications taken (i.e., dosing documented) during the last 14 days prior to the 
first dose of study drug. 
Concomitant medications (double-blind period): those medications taken (i.e., dosing documented) at 
any time from the first dose of study medication date through the end of the subject’s double-blind 
participation. 
Concomitant medications (open-label period): those medications taken (i.e., dosing documented) at any 
time from the start of the open label titration period (i.e., day of first dose of open label titration study 
drug supplies) through the date of the last dose of study medication. 
Prior medications and concomitant medications will be summarized descriptively using frequency tables 
by Anatomical Therapeutic Chemical’ (ATC) class and generic name by treatment group for the mITT 
population and presented separately for the following groups: 
• Prior medications; 
• Concomitant medications taken during the double-blind treatment period; 
• Concomitant medications taken during the open-label period; 
• Medications taken during the first 14 days after the date of the last dose of study medication. 


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Details for imputing missing or partial start and/or stop dates of medication are described in 
 
 
8.4 Extent of exposure 
 
 
8.4.1 Treatment duration 
The duration of double-blind period study drug (in days) will be calculated as: last dose date in the 
double-blind period – first dose date in the double-blind period + 1 day, regardless of study drug 
interruption. 
The duration of the open-label period study drug (in days) will be calculated as: last dose date in the open- 
label period – first dose date in the extension titration period + 1 day, regardless of study drug 
interruption. 
Duration of overall study drug (in days) will be calculated as: last dose date – first dose date + 1 day, 
regardless of study drug interruption. 
Study drug exposure will be summarised by treatment group for the safety population using descriptive 
statistics. By-subject listings will also be provided. 
 
8.4.2 
Treatment compliance 
Compliance in the double-blind period (%) = Number of double-blind period tablets subject actually took/ 
Number of double-blind period tablets subject was expected to take*100. In the double-blind titration 
period, a subject is expected to take 3 tablets in the AM and 3 tablets in PM for two weeks, with the 
exception of Day 1, on which they take only the PM dose. In the double-blind fixed-dose period, a 
subject is expected to take 1 tablet each in the AM and PM. The number of double-blind period tablets a 
subject was expected to take is the sum of {6 x [last dose date of double-blind titration – first dose date of 
double-blind titration +1] – 3} and {2 x [last dose date of double-blind fixed-dose – first dose date of 
double-blind fixed-dose +1]}. The number of double-blind period tablets a subject actually took will come 
from the pill counts from the eCRF, i.e., the number of tablets dispensed - the number of tablets returned 
from the blister cards and bottles for the double-blind period. 
Compliance in the open-label period (%) = Number of tablets subject actually took during open-label 
period/ Number of tablets subject was expected to take during open-label period*100. The compliance is 
calculated similarly to the double-blind period. The number of tablets a subject was expected to take is the 
sum of {6 x [last dose date of extension titration – first dose date of extension titration +1] – 3} and {2 x 
[last dose date of open-label fixed-dose period – first dose date of open-label fixed-dose period +1]}. 


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Number of tablets a subject actually took during open-label period is calculated by the number of tablets 
dispensed - the number of tablets returned from the blister cards and bottles for the open-label period. 
Study drug compliance will be summarized by treatment group, with the number of subjects (n), mean, 
standard deviation, standard error, median, minimum, and maximum. They will also be summarized in 
categories “< 50% compliant” and “≥ 50% compliant” using frequency tables. Also, the categories of “< 
60% compliant” and “≥60% compliant” will be provided by count and percentage. By-subject listings 
will also be provided. 
Study drug compliance summaries will be based on the Safety Population. 
 
8.4.3 
Treatment dose reduction 
The count and percentage of subjects who reduced their dose per protocol (at weeks 28, 32 or 36) will be 
summarised by prior treatment group on the Safety Population. 
 
8.5 Efficacy analyses 
 
 
8.5.1 Analysis methods 
 
8.5.1.1. Logistic Regression Analysis 
The primary efficacy endpoint (and other binary efficacy endpoints) “responder type” efficacy endpoints 
will be analyzed with a logistic regression model with baseline score as a covariate and site ( USA versus 
other) as a fixed effect. The logistic regression model will provide estimated response rates, standard 
error, odds ratio (OR), two-sided 95% confidence interval for OR, and p-values at Week 14. 
8.5.1.2 Mixed model repeated measures analysis 
A mixed model repeated measures analysis using ‘direct likelihood’ will be performed for continuous 
efficacy outcomes. The SAS procedure PROC MIXED will be used. The preferred model will include the 
fixed effects of treatment, visit, treatment-by-visit interaction, and the baseline value of the endpoint 
variable as a covariate. An unstructured matrix for the variance-covariance will be used. The denominator 
degrees of freedom will be calculated according to the Kenward-Roger method. 
In case of non-convergence of the preferred model or memory issues, the following back-up models are 
defined: 
1. The same as the preferred model, but the Kenward-Roger method will be replaced by Satterthwaite 
approximation. 


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2. The same as the preferred model, but with handling of the selection of the covariance structure for 
the final model in a hierarchical fashion, with the order being Toeplitz, AR (1), and compound 
symmetry, respectively. 
The second back-up model will only be used if the first back-up model does not converge or has memory 
issues. 
The model will provide least-squares mean estimates, standard errors, two-sided 95% confidence intervals 
and p-values (where applicable) for mean change at all visits between treatments (NAL ER vs. placebo). 
 
 
8.6. Multiplicity 
In order to control for Type, I error (0.05), a fixed sequence testing procedure will be used on the primary 
and 3 key secondary endpoints. All endpoints will be tested (NAL ER treatment arm versus the placebo 
arm) at the 0.05 level of significance, following a pre-specified order. As soon as one endpoint assessment 
is found to be non-significant, subsequent endpoints will not be assessed. The rank order of testing is 
specified below. 
- 
Time to onset of effect on pruritus as measured by proportion of participants with an 
improvement (reduction) in WI-NRS by ≥4 from baseline during the 14-week treatment period. 
- 
Change in Investigator Global Assessment-Prurigo Nodularis (IGA-PN) as assessed by the 
percentage of subjects having a 1-category improvement in activity. 
- 
The mean change in 7-day average WI-NRS from baseline to Week 14 for the NAL ER treatment 
arm versus the placebo arm. 
- 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to Week 14 for 
the NAL ER treatment arm versus the placebo arm. 
- 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of healed lesions (item 5b) from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm. 
- 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage number of lesions (item 2) from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm. 
- 
The mean change in ItchyQoL from baseline to Week 14 for the NAL ER treatment arm versus 
the placebo arm. 


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- 
The mean change in sleep disturbance (PROMIS Sleep Disturbance Short Form 8a) from baseline 
to Week 14 for the NAL ER treatment arm versus the placebo arm. 
- 
The proportion of subjects having a PBI-P score of ≥ 1 at Week 14 for the NAL ER treatment arm 
versus the placebo arm. 
8.6 Analysis of Primary Efficacy Endpoint 
Hypothesis: 
The null hypothesis is that there is no treatment group difference (NAL ER vs. placebo) for the primary 
efficacy endpoint and the alternative hypothesis is that a treatment group difference exists. 
Statistical Decision Rules 
Unless otherwise indicated, all tests will be 2-sided, and differences resulting in a p-value <0.05 will be 
considered statistically significant. 
The primary efficacy endpoint is the difference between the percent responders at Week 14 for the NAL 
ER treatment arm versus the placebo arm. 
A responder is defined as a subject with a ≥ 4-point decrease in the 7-day average WI-NRS from baseline 
to Week 14. 
The proportions of responders in NAL ER and placebo will be compared using a logistic regression 
model, with baseline WI-NRS as a covariate and country as fixed effect, as described below. Missing 
Week 14 WI-NRS data will be set to missing. 
Sample SAS code: 
proc genmod data=winrsa descending; where avisitn ge 3; 
class usubjid avisitn trt posite ; 
model resp = trt avisitn avisitn*trt posite base 
/ dist=binomial; 
repeated subject=usubjid / withinsubject=avisitn 
type=un; 
lsmeans trt*avisitn /cl ilink diff oddsratio; 
Ods output diffs=diff lsmeans=lsm ; 
run; 
* Estimate Response rate and SE; 
Recoding the resp to a new resp variable 
data winrsa; set winrsa; 
if resp = 0 then respnw = 2; 
else if resp= 1 then respnw = 1; 
run; 


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Using proc freq to create the binomial dataset; 
 
proc sort data = winrsa; by avisitn trt; 
proc freq data = winrsa; by avisitn trt; 
tables respnw/ out = FreqCount binomial ; 
exact binomial; 
ods output binomial=bin; 
run; 
The variable _bin_ is the response rate for resp = 1; 
The variable for SE is E_bin 


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* Estimate Odds ratio and CI; 
These are provided in the diff dataset and can be output directly. 
run; 
Sensitivity analysis 
To assess the impact of the above “treatment failure” rule, the missing data strategy will employ the 
control-based multiple imputation (MI) procedure and delta-based multiple imputation (or tipping point 
analysis) to assess the sensitivity of the study conclusions to the missing response data. Multiple 
imputation provides a better estimate of the effect of missing data on the variance of the estimates and is 
therefore less likely to result in false positive inferences. Control based imputation restricts imputing 
responses for the active arm participants to responses in the control arm. This process will be done 
sequentially for each time point with missing responses. The process is described by Ratitch & O’Kelly 
(2011)6 and summarized below. These methods will be implemented in SAS9.4® using PROC MI and 
PROC MIANALYZE and are based on pattern mixture models that assume monotone drop out. 
In order to meet the monotone assumption, if there are intermittent missing data points, these will be first 
imputed using a Monte Carlo Markov Chain Method (MCMC). Please refer to Appendix. 
Intermittent missing data is typically a very small percentage of overall missing and is not expected to 
affect or bias inference. The MI procedure will be used for subjects with missing Week 14 WI-NRS data 
and/or who withdraw prematurely prior to Week 14. 
8.6.1.1 Control Based Imputation. 
The monotone missing data is sequentially imputed using the responses of the control group only. This is 
done sequentially for each time point. In order to ensure that only the control group data is used for active 
arm subjects with responses missing starting at time t1, the data set is subset to include all control subjects 
and only those active arm subjects who have missing values at time t. This is repeated for each time point 
going forward – please refer to Appendix for details. 
 
PROC MI is then used to impute all missing values for t1 in the treatment arm using the standard PMM 
imputation approach. Please refer to Appendix for details. 
The data set is combined with the rest of the data and a new subset is created for active arm recipients 
with responses missing for time t2. This is repeated for each subsequent time point. 


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Finally, each fully imputed data set is analyzed using the appropriate procedure, e.g., Proc Mixed, and 
then the results are collated using PROC MIANALYZE. 
After imputing the missing values, logistic regression will be performed 50 times using imputed datasets. 
The estimates will be combined using PROC MIANALYZE procedure. 
8.6.1.2. Tipping point analysis. 
The tipping point analyses is to assess how much the missing data would have to differ from the imputed 
data that is based on a MAR assumption in order to reverse the conclusions of the trials. This can be done 
using PROC MIANALYZE. Tipping point analyses are typically used to ensure that missing data 
imputation does not create false positive inferences. 
this time, we do not know if the current study will result in an inference that suggests treatment benefits. 
The TPA description below describes the derivation for treatment benefit and absence of treatment benefit. 
The primary decision to be made in the tipping point analysis is determining the value of delta). In this 
case, we have used the standard deviation of the efficacy measure of the subjects in the treatment group 
who completed all visits. 
 
Non-monotonic data will be imputed as above. The Monotonic missing data will be the result of subjects 
dropping out of the study. For the primary endpoint, we are only concerned with responders (decrease ≥ 4 
points in the WINRS scale) and non-responders at week 14. So in this case we will be looking at the 
dropouts in the stable double-blind phase. 
Determining the delta for the tipping point analysis would follow the following steps. Impute missing 
values one visit at a time as above for control subjects; Please refer to the Appendix for details. 
1. Estimate the mean scores and standard deviations (SD) in those who completed all visits; 
2. 
Use the standard deviation of the completers as the initial delta value for the dropouts; 
3. If the week 2 value is missing in the original data, then in the TPA, the imputed value for week 2 
will be modified by adding the SD of the completer’s week 2 value to the imputed value. 
Assuming that the scores in completers indicate better outcomes than dropouts, i.e. mean score in 
completers < mean score in dropouts, the TPA score will first assume worse outcomes in dropouts. 
The delta value will therefore be added to the mean score of completers to impute missing scores 
for the dropouts. Since the data set has been converted to monotonic missing data, if week 2 
values are missing, week 4, week 6, week 10 & week 14 will also be missing & have been 
imputed assuming MAR. Therefore, each of these values will be increased by the SD of the 
corresponding week for the completers. This will be repeated for each set of missing values, i.e., 


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if the week of dropout is week 4, then week 4, week6, week 10 & week 14 imputed values will be 
modified. 
4. After we run the models adding the SD to the imputed values, we will also subtract the delta value 
to assess how inference might change if dropouts had better outcomes than completers and the 
delta values will be subtracted from the mean scores of completers to impute values for the 
dropouts. 
8.6.1.3. Sensitivity Analysis for Subjects who take Prohibited Medications 
This analysis is to assess the impact of concomitant medications that might affect the primary endpoint. 
The medications listed below are considered inter-current events (ICEs) confounding with the efficacy 
outcomes. 
• 
μ-opioid receptor agonists (e.g., codeine, oxycodone, hydromorphone, oxymorphone, morphine, 
fentanyl, tramadol, butorphanol, pentazocine, meperidine, methadone) 
• 
Opioid receptor antagonists naltrexone and nalmefene 
• 
Antihistamines (topical or systemic) 
• 
Topical calcineurin inhibitors 
• 
Topical corticosteroids 
• 
Topical capsaicin 
• 
Anti-convulsant class drugs 
• 
Cannabinoid agonists 
• 
Topical doxepin 
• 
Thalidomide or methotrexate 
• 
Cyclosporin A 
• 
Biologics with an immune suppressive effect* 
• 
Investigational drug products* 
• 
Cryosurgery 
• 
UV-therapy 
 
Efficacy data on subjects who experience an ICE will be set to missing at the designated time points after 
the start of such events. The analysis will provide an answer to the question that is crucial to individual 
subjects; “If I take this study medication as part of my treatment regimen, without adding any further 
medications that may impact the underlying disease, what response (response is defined as a ≥ 4-point 
reduction in the 7-day average WI-NRS) might be anticipated after 14 weeks?” 
Sensitivity analysis using missing data handling approaches will also be performed as outlined in the 
Appendix. 


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In addition, the primary endpoint will be analyzed using the PP population. 
 
 
8.6.2. Subgroup analyses 
Additional subgroup summaries will be performed for the primary endpoint to determine whether 
differences exist in primary endpoint results between subgroups. These subgroup summaries will be 
carried out using the subjects from the mITT. 
The list of potential subgroups (with applicable definitions in parentheses) includes, but is not necessarily 
limited to, the following: 
• Age (18-39, 40-64, 65+ years) 
• Sex (Female vs. Male) 
• History of diseases associated with, or risk factors for, prurigo nodularis, as described in 
o Dermatologic diseases; 
o Conditions associated with metabolic itch (e.g., liver, renal or endocrine); 
o Atopy (including atopic dermatitis alone, if the numbers are large enough); 
o Neurologic conditions associated with itch; 
o Other. 
These medical history subgroup analyses will be performed if the smaller of the 2 groups (with or without 
the condition) has at least 30 subjects. Additional post-hoc subgroup evaluations may be performed if the 
initial observations warrant it. 
For each subgroup variable, the frequency and percentage of responders for each category will be 
displayed by treatment group. The difference in response rate between the treatment groups and 95% CI 
will also be presented. These subgroup analyses will be considered exploratory, as they do not control 
for multiplicity. 
 
8.6.3 Analysis of secondary efficacy endpoints 
All secondary endpoints will be analyzed using the mITT population. 
 
 
MMRM without imputation for missing data: 
The following secondary efficacy endpoints will be analyzed using a mixed model for repeated measures 
(MMRM): 


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• The mean change in 7-day average WINRS from baseline to Week 14 for the NAL ER treatment 
arm versus the placebo arm; 
• The mean change in ItchyQoL from baseline to Week 14 for the NAL ER treatment arm versus 
the placebo arm; 
• The mean change in sleep disturbance (PROMIS Sleep Disturbance Short Form 8a) from baseline 
to Week 14 for the NAL ER treatment arm versus the placebo Arm. 
 
The analysis of change from baseline to week 14 will be performed utilizing all observed data for visits up 
to and including Week 14, without imputation for missing data. The model used for this analysis will 
include the fixed effects of treatment, visit, treatment-by-visit interaction, and baseline value. An 
unstructured variance-covariance matrix will be used in the analyses. The comparison of interest is the 
treatment difference at Week 14. The model will provide least-squares mean estimates, standard errors, 
two-sided 95% confidence intervals and p-values for mean change at all time points between treatments 
(NAL ER vs. placebo) for ItchyQoL (total score and subscales: symptoms, functional limitations, 
emotions) and PROMIS. The same statistics will be provided for WI-NRS, except for the p-values. 
Sample SAS code: 
PROC MIXED data=xxxx; 
CLASS visit treatment subjid; 
MODEL CHG = treatment visit treatment*visit baseline/solution DDFM=KENWARDROGER; 
REPEATED visit / type=un subject=subjid; 
LSMEANS treatment*visit / pdiff CL; 
ODS output Diffs=outdata1 LSMeans=outdata2; 
RUN; 
 
Sensitivity analyses: MMRM with imputation for missing data 
We will use the imputation methods described above for the primary efficacy endpoints to assess the 
sensitivity of missing data on inference regarding the secondary endpoints. Since these are continuous 
measures, we will use the delta methods described above. 
 
Summary for Categorical Endpoints: 
The count and percentage will be provided for the following endpoints: 
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to Week 14 for the 
NAL ER treatment arm versus the placebo arm; 


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• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of healed lesions (item 5b) from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm; 
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage number of lesions (item 2) from baseline to Week 14 for the NAL ER treatment arm 
versus the placebo arm; 
• Change in IGA-PN as assessed by the percentage of subjects having a 1-category improvement in 
activity from baseline to Week 14 for the NAL ER treatment arm versus the placebo arm; 
• Change in IGA-PN as assessed by the percentage of subjects having a 1-category improvement in 
stage from baseline to Week 14 for the NAL ER treatment arm versus the placebo arm; 
• The proportion of subjects with PBI-P ≥ 1 at Week 14 for the NAL ER treatment arm versus the 
placebo arm; 
• The proportion of subjects with PBI-P ≥ 2 at Week 14 for the NAL ER treatment arm versus the 
placebo arm; 
• The proportion of subjects with PBI-P ≥ 3 at Week 14 for the NAL ER treatment arm versus the 
placebo arm. 
In addition, shift tables from baseline for improved ≥ 1, no change, worsened ≥ 1, and discontinued at 
Week 14 will be presented for PAS (item 5a), PAS (item 5b), PAS (item 2), IGA-PN for Activity, and 
IGA-PN for Stage. 
 
Logistic Regression for Categorical Endpoints 
The logistic regression model used for the primary endpoint will also be used for several secondary 
efficacy endpoints. Subjects with missing Week 14 measurement are treated as non-responders. Response 
rate, standard error, OR between the treatment groups, 95% confidence interval and p-values will be 
provided. The endpoints are: 
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to Week 14 for the 
NAL ER treatment arm versus the placebo arm; 
• Change in IGA-PN as assessed by the percentage of subjects having a 1-category improvement in 
activity from baseline to Week 14 for the NAL ER treatment arm versus the placebo arm (95% CI 
only, with no p-value). 


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Sensitivity analysis for PAS (item 5a) 
The sensitivity analysis to assess the impact of concomitant medications use for the primary endpoint will 
also be used for PAS (item 5a). 
For open-label period visits, descriptive statistics will be displayed by treatment and overall for all 
secondary variables. 
 
8.7 
Safety analyses 
Safety summaries will be conducted on the safety population (treated subjects) and will be performed for 
all safety variables specified below: 
• 
Adverse events; 
• 
Laboratory tests; 
• 
Vital signs; 
• 
Central Electrocardiograms (ECG); 
• 
Brief neurological assessments; 
• 
Physical Examinations; 
• 
SOWS. 
 
 
All safety data will be summarized by treatment group. 
The safety summaries of changes from baseline to a specific time point in safety variables (e.g., laboratory 
parameters, vital signs, and ECG) will only include subjects from the safety population who have data 
available for both the baseline and the time point under consideration unless otherwise specified. No 
statistical tests will be performed. 
 
8.7.1 
Adverse events 
All adverse events (AEs) will be classified by SOC and PT according to the MedDRA Version 21.0 or 
higher. 
In summaries by SOC and PT, adverse events will be sorted by decreasing frequency within each SOC 
and PT according to the total group. In summaries by PT, AEs will be sorted by decreasing frequency 
according to the total group. 


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Treatment-emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or 
after the first double-blind dose of study medication. 
Double-blind period treatment-emergent adverse events (TEAEs) are defined as AEs that started or 
worsened in severity on or after the first double-blind dose of study medication and prior to the first 
extension titration dose of study medication in the open-label period. 
Open-label period treatment-emergent adverse events (TEAEs) are defined as AEs that started or 
worsened in severity on or after the first extension titration dose of the study medication. 
All TEAEs will be summarized by period (double-blind period and open-label period) and treatment 
group, presenting the number and percentage of subjects having at least one TEAE and the number of 
TEAEs occurring in each SOC and PT. A subject with multiple occurrences of an AE will be counted 
only once in the corresponding AE category. 
 
The following AE summaries will be performed by period: 
• An overall summary of the number and percentage of subjects with the specified AEs, the number 
of episodes in each TEAE category will be presented; 
• Exposure-adjusted AE incidence rate (per 100 subject-years) for TEAEs, regardless of study drug 
relationship by SOC and PT; 
• Number and percentage of subjects with TEAEs, regardless of study drug relationship by SOC 
and PT; 
• Number and percentage of subjects with TEAEs suspected to be drug-related by SOC and PT; 
• Number and percentage of subjects with CTC grade 3 or higher TEAEs, regardless of study drug 
relationship by SOC and PT; 
• Number and percentage of subjects with CTC grade 3 or higher TEAEs suspected to be drug- 
related by SOC and PT; 
 
TEAEs starting after the first dose of study medication with a missing severity will be classified as severe. 
If a subject reports a TEAE more than once within that System Organ Class (SOC)/ Preferred Term (PT), 
the AE with the highest severity will be used in the corresponding severity summaries. 
 
Relationship, as indicated by the Investigator, is classified as “Not related”, “Unlikely related”, “Possibly 
related”, “Probably related” and “Definitely related” (increasing strength of relationship). TEAEs with a 


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missing relationship to study medication will be regarded as “Probably related” to study medication. If a 
subject reports the same AE more than once within that SOC/PT, the AE with the strongest relationship to 
study medication will be used in the corresponding relationship summaries. Relationship will be 
summarized as “Related” and “Unrelated”. Adverse events with investigator indicated drug-event 
relationship of “Not related” and “Unlikely related” are classified as “Unrelated” with the study 
medication, while adverse events with drug-event relationship documented as “Possibly related”, 
“Probably Related” and “Definitely related” are considered as “Related” with the study Medication. 
 
Deaths, Serious and Other Significant Adverse Events 
TEAEs leading to Death are those events with an “Outcome” recorded as “Fatal” on the Adverse Events 
page of the eCRF. The number of subjects with TEAEs leading to death will be summarized by SOC and 
PT. A listing of all TEAEs leading to death will be provided. 
Serious adverse events (SAEs) are those events with a response of “Yes” for the item “Was AE Serious” 
on the AE eCRF form. Summaries of incidence rates (frequencies and percentages) of SAEs by SOC and 
PT will be prepared. A by-subject data listing of all SAEs will be provided. 
Actions taken with study drug are dose discontinuation and interruption from the eCRF page of Adverse 
Events. TEAEs leading to drug adjustment will be summarized by SOC and PT for study treatment 
discontinuation and interruptions. 
The following summaries of TEAEs will be provided: 
• TEAEs leading to deaths, by SOC and PT; 
• Serious TEAEs, regardless of study drug relationship, by SOC and PT; 
• Serious TEAEs suspected to be drug-related, by SOC and PT; 
• TEAEs leading to drug interruption by SOC and PT; 
• TEAEs leading to study drug discontinuation by SOC and PT. 
Listings to be provided are: 
• AEs leading to Deaths (CRF Adverse Event page: AE outcome is Fatal.); 
• Serious AEs; 
• AEs leading to dose interruption and discontinuation, respectively; 
• All deaths with date of event, study day, AEs reported around the time of death etc. 


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8.7.2 
Clinical laboratory evaluations 
All laboratory data will be summarized in the International System of Units (SI) and conventional units, 
respectively. Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X 
for the purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the 
listings. All laboratory assessments will be listed. 
Descriptive statistics of absolute value and change from baseline (mean, SD, median, minimum, and 
maximum) for continuous assessments will be presented by windowed visits. 
 
Laboratory Reference Ranges High/Low Criteria and Investigator’s Assessment 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in 
SI units and categorized as: 
• Low: Below the lower limit of the laboratory reference range; 
• Normal: Within the laboratory reference range (upper and lower limit included); 
• High: Above the upper limit of the laboratory reference range. 
Shift tables (Low, Normal, High) from baseline to worst post-baseline in lab parameters for each 
treatment group in the double-blind treatment period will be displayed. 
Values outside the normal range will be flagged in the listings of individual subject data. Unscheduled 
visits will not be included in the analysis but will be listed. 
 
Hepatobiliary Laboratory Abnormalities 
Treatment emergent hepatobiliary laboratory abnormalities defined as values outside pre-specified 
thresholds will be summarized and listed by treatment and windowed visit. Treatment emergent is defined 
as any disorder/event recorded on the eCRF which started on or after the start date of treatment. 
A summary of any treatment emergent hepatobiliary laboratory abnormalities according to different pre- 
specified thresholds will be made by treatment group: 
• ALT or/and AST >3 x ULN and ≤5 x ULN; 
• ALT or/and AST >5 x ULN; 
• Total bilirubin >2 x ULN; 
• (ALT and/or AST >3 x ULN) and Bilirubin > 2 x ULN; 


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• 
Hy's law laboratory criteria: (ALT and/or AST >3 x ULN) and Bilirubin > 2 x ULN and ALP<2 x 
ULN. 
ULN = Upper limit of normal range. 
 
 
8.7.3 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The parameters 
collected are the following: systolic and diastolic blood pressure (mmHg), body temperature (°C), heart 
rate (beats/min) and respiratory rate (breaths/min). The observed values and change from baseline will be 
summarized by descriptive statistics at each windowed visit. By-subject listings will also be provided. 
8.7.4 
Brief Neurological Assessment 
All neurological assessment data and abnormalities will be listed (including pre-treatment and post- 
treatment results). The count and percentage will be provided by treatment group and visit. 
8.7.5 
Physical examinations 
All physical examination data and abnormalities will be listed (including pre-treatment and post-treatment 
results). The count and percentage of normal vs. abnormal assessments will be provided by treatment 
group and visit. 
8.7.6 
Electrocardiograms 
Electrocardiogram data (e.g., heart rate, PR, QTcF intervals, etc.) will be presented in listings by subject 
and collection date/time. A complete ECG assessment will be analyzed and reported in a separate ECG 
report from ERT. 
8.7.7 
SOWS 
The Subjective Opiate Withdrawal Scale (SOWS) is a self-administered scale for grading opioid 
withdrawal symptoms. It contains 16 symptoms whose intensity the subject rates on a scale of 0 (“not at 
all”) to 4 (“extremely”). In this study, subjects will complete SOWS daily for 14 days, starting at the off- 
treatment visit through the washout and safety follow-up period visit to the last visit on the study. Any 
subjects who are discontinued from investigational product will complete the SOWS daily for the 14 days 
following the last dose of investigational product (unless consent is withdrawn). 
 
SOWS total scores and the individual item scores will be summarized descriptively by day (there are 14 
days of SOWS) and treatment. 


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Categories of SOWS total score (mild: ≤10; moderate: 11 – 20; and severe: 21 – 30; and > 30) will be 
provided by count and percentage by day and treatment. 
 
By-subject listings will also be provided. 
 
 
8.7.8 
Pharmacokinetic analysis 
Investigational product plasma concentration data (nalbuphine and metabolites) will be listed by 
collection time, as applicable. Details will be summarized in a bioanalytical report generated by Covance 
Labs and appended to the CSR. Additional PK/PD analyses may be performed and presented in a 
separate document and may be appended to the CSR. 
 
8.8 Primary analysis 
The primary study analyses will be performed when the last subject has completed the double-blind 
treatment period. This will be documented in a full clinical study report. Final analyses and an addendum 
clinical study report will be performed when the last subject has completed the Week 56 phone call. 
 
8.8.1 
Interim analysis (Adaptive Sample Size Re-estimation) 
The sample size re-estimation will be performed by one unblinded study statistician, who will not have a 
decision-making role in the trial; no one else, including Sponsor or clinical team members, will see the 
data presented in the Data Monitoring Committee (DMC). The communication plan from the DMC is to 
report one of the following statements based on the conditional power results: 1) “carry on”; 2) “increase 
sample size to XXX”; or 3) “stop the study due to unfavorable safety and/or efficacy concern.” Details 
about the DMC and the data monitoring procedures are specified in the DMC charter. When 50% of the 
subjects have provided the Week 14 primary endpoint data or have terminated the study and the data are 
considered “lockable” by data management, the data file will be provided with access limited to the 
specified unblinded statistician in the DMC; the proportion of responders will be estimated; and the 
conditional power (CP) will be calculated. Given that the interim analysis is to be performed at 50% of 
the initial sample size (120 subjects), the targeted power is 90%, and the maximum allowable sample size 
is set at 1.5 times the initial sample size (360 subjects), the conditional power cut-off value (CPmin) is 
41%8. If the CP is between 41% and 90%, the number of subjects per treatment arm will be increased, up 


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to the maximum allowable sample size for this study (120 × 1.5 = 180 each group), to recover the targeted 
power of 90%. 
Since sample size re-estimation occurs only when the interim conditional power falls in the pre-specified 
“promising” range. The study will not stop for efficacy regardless of the conditional power; the overall 
alpha will be protected; and the final analysis will be carried out using conventional tests, without the 
need for weighing the stage 1 and 2 results or adjusting the alpha value. 


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9 
CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL 
 
 
The following changes were agreed upon 
1. Sites were changed from random effects to region (US or Europe) which is being treated as a 
fixed effect. 
2. LOCF was excluded from imputation methods. 
3. The ranked outcome for adjustment for multiplicity was changed. The ItchyQoL measure & the 
PROMIS scale were excluded from the ranking and replaced with PAS (5a) 
4. The analyses for prohibited medication were changed to set all efficacy outcomes to missing 
from the date of ingestion of the prohibited medication. Previously, missing outcomes were set 
= non-responders. 
5. A new set of simple multiple imputation models were added to assess the impact of missing 
efficacy measures due to the use of prohibited medications. 


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10 REFERENCES 
 
 
1. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted March 
1998). 
2. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Statistics in Medicine 2011; 30(28):3267-84. 
3. 
Miriam Kimel, Phd; Claudia Xeidler, MD; Paul Kwon, MD; et al (2020), Validation of 
psychometric properties of the itch numeric rating scale for pruritus associated with prurigo 
nodularis. 
4. 
Blome C, Augustin M, Siepmann D, et al. Measuring patient-relevant benefits in pruritus 
treatment: development and validation of a specific outcomes tool. Br J Dermatol. 2009 Nov; 
161(5):1143-8. 
5. 
Ratitch & O’Kelly (2011), Implementation of Pattern Mixture Models Using SAS/STA 
Procedures. 


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11 VERSION HISTORY 
 
 
Version 
Date 
Notes 
Draft 1.0 
27Aug2018 
First draft base on Protocol V1.0 
Draft 2.0 
10Oct2018 
Stable version after addressing Trevi review comments and 
incorporating changes in Protocol Amendment 1 (Protocol 
V2.0) 
Final 1.0 
15Mar2019 
Final version after incorporating changes in Protocol 
Amendment 2 (Protocol V3.1) 
Draft V1.4 
19Feb 
2022 
Version above modified after several meetings with TREVI in 
2021 & 2022 as clarified in comments above. 
Draft V1.5 
9Mar2022 
Version above modified after several meetings with TREVI in 
2021 & 2022 as clarified in comments above. V1.5 had 
modified section of TPA. The analysis has been refined here & 
an updated Guidance document added to the Appendix. 
Draft V1.6 
23Mar 
2022 
Version above modified after several meetings with TREVI in 
2021 & 2022 as clarified in comments above. V1.5 had 
modified section of TPA. The analysis has been refined here & 
an updated Guidance document added to the Appendix. Proc 
GENMOD has been modified as well. 
Final 2.0 
25th March 
2022 
Modified rank order of the outcomes to address issues of 
multiplicity & efficacy outcomes for subjects who took 
Prohibited Medications 
Final 2.1 
01 
June 
2022 
Changed Compliance cut off to 50%. Changed Efficacy 
Analysis from Proc Glimmix to Proc Genmod because of 
convergence issues. Reduced number of imputations from 
1000 to 50 to increase efficiency. 


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12 
APPENDIX 
 
 
12.3 
Programming Guidance Document for Multiple Imputation, Control –based 
Imputation & Tipping Point Analysis 
 
Introduction. 
This appendix describes three approaches to multiple imputation. 
1. Simple Multiple Imputation; 
2. Control- based Imputation; 
3. Tipping Point Analysis. 
All of these are being implemented in data sets that have repeated measures data collected from subjects 
at multiple time points. 
The primary efficacy endpoint is defined as the difference between the percentage of “Responders” at 
Week 14 for the NAL ER treatment arm versus the placebo arm. A “Responder” is defined as a subject 
with a ≥ 4-point decrease in the 7-day average WI-NRS from baseline to Week 14.” 
Secondary endpoints are: 
• 
The mean change in ItchyQoL from baseline to Week 14 for the NAL ER treatment arm versus 
the placebo arm; 
• 
Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the 
percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to Week 14 for the 
NAL ER treatment arm versus the placebo arm; 
• 
The mean change in sleep disturbance (PROMIS Sleep Disturbance Short Form 8a) from baseline 
to Week 14 for the NAL ER treatment arm versus the placebo arm. 
 
Multiple imputation is a missing data approach that assumes that the missing data is missing at random 
(MAR), i.e., that the probability of missing is not a function of the values that are missing but only depend 
on the observed responses. 
The advantage of MI over single imputation is that it allows one to adjust the variance to account for the 
imputation of the missing data. 
All of the data sets on which imputation is applied are longitudinal data sets, specifically the following 
ADaM datasets: ADEFF and ADQS. Please note: ADEFF will use 4 visits (AVISITN 2-5/ Week 2, 6, 10, 
14) 
ADQS will use 3 visits (AVISITN 3-5/Week 6, 10, 14). 
The following is an explanation of the process. 
This is a guidance document. It does not provide the exact code to be implemented but describes the 
processes & principles that need to be followed in order to implement these analyses. 


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There are five steps in simple MI process. 
1. Check missing data patterns; 
2. Impute non-monotonic / intermittent data – leaving only monotone missing data; 
3. Use monotone regression to impute monotone missing data & create multiply imputed data sets; 
4. Run the efficacy analyses (PROC GENMOD, PROC MIXED) on the multiply imputed data sets; 
5. Use PROC MIANALYZE to combine the efficacy output to get a single estimate from all the 
imputed data sets. 
 
 
Step 1. Checking missing data patterns 
For this study, the missing data patterns will be checked by treatment and visits 3 to 5. 
There are 3 steps to this process: 
Create dataset for efficacy measure including visits from baseline to week 14 
data mi_chk1; set datax; 
where param="" and paramcd="" and dtype="" and 3 <= visit <=5; 
run; 
Transpose dataset to display each visit as one column: 
proc sort data = mi_chk1; by treatment id; 
proc transpose data=mi_chk1 out=mi_chk2 prefix=’’; 
by treatment id; 
id avisitn; 
var aval; 
run; 
Use PROC MI with the NIMPUTE=0 option to create the "Missing Data Patterns" table for 
the specified variables: 
ods output MissPattern=missp; 
proc mi data=mi_chk2 NIMPUTE=0; 
by treatment; 
var visit3 – visit5; 
run; 
/*Add baseline to estimate change from baseline*/ 
 
proc sort data = mi_chk1; by id; data base; set mi_chk1 (Keep = id base country); by id; if first.id; 
run; 
proc sort data = mi_chk2; by id; 
proc sort data = base; by id; 
data mi_chk2; merge mi_chk2 base; by id; 
run; 


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Step 2: Impute non-monotonic / intermittent data – leaving only monotone missing data. 
Fill in the intermittent missing data using the following code. 
proc sort data = mi_chk2; by treatment; 
proc mi data=mi_chk2 seed=12345 NIMPUTE=50 out=MI; 
by trt01pn; 
mcmc impute=monotone; 
var Visit3 – Visit5; 
run; 
Step 3. Use monotone regression to impute monotone missing data & create multiply imputed data 
sets. 
Here the non-missing values for subjects in the control group are used to impute values for the subjects 
with missing values in the control group and similarly for the subjects in the active treatment group. 
Visit 3 values are imputed using baseline value and treatment; 
visit 4 values are imputed using baseline, treatment and visit 3 & so on. 
 
proc sort data = mi; by _Imputation_; 
proc mi data=mi out=mi_reg seed=54321 nimpute=1; 
by _Imputation_; 
var trt01pn base v3 v4 v5; 
class trt01pn; 
monotone regression; 
run; 
Convert the data set from a horizontal dataset, i.e. one row per subject to a vertical data set, 
i.e., multiple rows per subject. 
Data mi_reg1; set mi_reg; 
Visit = 1; WINRSA=base; output; 
Visit = 2; WINRSA=v3; output; 
visit = 3; WINRSA=v4; output; 
visit = 4; WINRSA=v5; output; 
drop v3 v4 v5; 
run; 
Step 4. Run the efficacy analyses (PROC GENMOD, PROC MIXED) on the multiply imputed data 
sets. 
Create variables needed for the 50 data sets, e.g. RESP, Pooled Site, treatment coded as (0- 
Placebo,1-Treatment) etc. 
1. Fit the models on the 50 imputed data sets by _Imputation_. 
proc sort data = mi_reg1; 
by _imputation_ visit trt; 


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ods select none; /*suppress printing the output*/ 
proc genmod data=winrsa descending; where avisitn ge 3; 
class usubjid avisitn trt posite ; 
model resp = trt avisitn avisitn*trt posite base 
/ dist=binomial; 
repeated subject=usubjid / withinsubject=avisitn 
type=un; 
lsmeans trt*avisitn /cl ilink diff oddsratio; 
Ods output diffs=diff lsmeans=lsm ; 
run; 
Step 5. Combine estimates of the 50 GENMOD models to create an overall estimate and a relative 
efficacy score. 
Due to the finicky nature of PROC MIANALYZE, the suggestion is to produce output to one 
effect at a time. This can be programmed in a macro. 
 
Run three separate instances of GENMOD to get the effect for the interaction first, then the treatment & 
then visits 
MIANALYZE cannot handle too many effects and too many variables in the input data sets, so 
subset to the needed effects. For the interaction, choose the estimate for the same visit but 
different treatments. That is what the next two statements do. 
 
data diff_mi_nw; set diff_mi; where visit = _visit and trt ne _ 
trt;run; 
data diff_mi_nw2; set diff_mi_nw (keep = _imputation_ estimate stderr effect); run; 
The data set diff_mi_nw2 is then fed into the Proc MIANALYZE: 
proc mianalyze parms=diff_mi_nw2; /*where _imputation_ le 4; 
modeleffects treatment*visit ; 
run; 
Since this is GENMOD the results should be presented as odds ratios (ORs). The final estimate & the SEs 
should be exponentiated to create the ORs. 
Also fit the continuous ITCH score using Proc Mixed. 
ods select none; 
proc mixed data = mi_reg1; by _Imputation_ ; 
class variables; 
Model (Continuous endpoint) = Treatment, Baseline Vars, Time, Treatment * Time/solution 
covb; 
repeated ID/ type = cs subject = ID(treatment) 
lsmeans Interaction Term/diff cl; 


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ods output Diffs=diff_mi LSMEANS=lsm_mi; 
run; 
ods select all; 
Subset the data set to be input into MIANALYZE. 
data diff_mi_nw; set diff_mi (keep = _imputation_ 
estimate stderr effect probt); 
run; 
proc mianalyze parms=diff_mi_nw; 
modeleffects effect of interest (e.g., treatment, Visit or interaction but to be done one at a time); 
run; 


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Control-Based Imputation. 
STEPS 1-4 ARE EXACTLY AS DESCRIBED ABOVE. 
The imputation of missing values is done one visit at a time. 
The difference between this process and the simple multiple imputation above is primarily in the 
data management step where a dataset is created with all control subjects and only those trt = 
NALER subjects who have missing values for visit, one visit at a time. 
Below is the suggested approach. 
In this case use v3, v4 & v5. After the intermittent missing data is filled in, one would expect all v3 to be 
filled in & only v4 & v5 to be missing. 
This is also a way to check & make sure that the data is behaving as expected. 
Step 1. Create two separate data sets, i.e., one with just control subjects and one with just NALER 
subjects; 
Step 2. Create a subset NALER data to include only those who have missing values for visit 4; 
Step 3. Set the Control data set and the dataset with V4 missing by _Imputation & usubjid. 
 
Now, the dataset has all of the control subjects and only the NALER subjects with v4 missing in 
this data set. 
 
Sample Program: 
data control_mi; set mi; where trt = 0; run; 
data trt_mi; set mi; where trt = 1; 
data v4_trt_mi; set trt_mi; where v4 = .; run; 
proc sort data = control_mi; by _imputation_ usubjid; 
proc sort data = v4_trt_mi; by _imputation_ usubjid; 
data mi_v4; set v4_trt_mi control_mi; by _imputation_ usubjid; 
run; 
Then use monotone regression to impute the v4 values. 
proc sort data = mi_v4; by _Imputation_; 
proc mi data=mi_v4 out=mi_reg_v4 seed=54321 nimpute=1; 
by _Imputation_; 
var base v3 v4 
monotone regression (v4); 
run; 
 
Repeat for v5. 
 
Then merge the data set back to include the full treatment = NALER data set with the non-missing & 
imputed values together. Set the Trt = 1 & trt = 0 data sets by _Imputation_ & usubjid 
 
2. Convert the data set from a horizontal dataset, i.e. one row per subject to a vertical data set, 
i.e., multiple rows per subject. 
Data mi_reg1; set mi_reg; 
Visit = 1; WINRSA=base; output; 


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Visit = 2; WINRSA=v3; output; 
visit = 3; WINRSA=v4; output; 
visit = 4; WINRSA=v5; output; 
drop v3 v4 v5; 
run; 
Create required variables needed in these 50 data sets, e.g. RESP, Pooled Site, treatment coded as (0,1) 
etc. 
Run Proc GENMOD or Proc Mixed 
Run Proc MIANALYZE 


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Tipping Point Analysis. 
In this analyses, the concept is to assess the level of bias introduced by the missing at random assumption 
in the first simple MI performed above. In this approach, subtract a pre-determined value from the 
imputed values for the actively treated group. this approach uses the standard deviation of the scores for 
the completers in the treated group. It could be a %change in the mean or a variety of other values 
depending on the expected effect. The suggested approach is below. 
data mi_chk1; set adeff; 
where param="WINRS Average" and paramcd="WINRSA" and dtype="" and 2 <=avisitn<=5; 
run; 
data mi_chk1; set mi_chk1; 
if trt01pn = 1 then trt = 1; 
else if trt01pn = 2 then trt = 0; 
run; 
proc sort data = mi_chk1; by trt usubjid; 
proc transpose data=mi_chk1 out=mi_chk2 prefix=v; 
by trt usubjid; 
id avisitn; 
var aval; 
run; 
by trt ; 
var v2-v5; 
run; 
Next estimate the standard deviation of the WINRS score in the control group and active treatment group 
by visit among those subjects who completed all visits. 
 
Then merge a data set with the delta value to the data set where values will be imputed. 
 
Use proc univariate to obtain the mean values, stddev, range for the completers in the treated group in 
order to identify a delta value (SD in this case. Other approaches could use the median, or percentiles). 
 
Suggested code is below. 
proc sort data = mi_chk1; by usubjid; 
data base; set mi_chk1 ( Keep = usubjid base country complfl); by usubjid; if first.usubjid;run; 
proc sort data = mi_chk2; by usubjid; 
proc sort data = base; by usubjid; 
data mi_chk2; merge mi_chk2 base; by usubjid; 
run; 
proc univariate data = mi_chk2; where complfl = 'Y'; by trt; 
var v2 v3 v5 v5; 
output out=WINRSCOMP_uni mean=Meanv2 Meanv3 meanv4 meanv5 
std=stdv2 stdv3 stdv4 stdv5 
range=range_v2 range_v3 range_v4 range_v5; 
run; 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1: 01 June 2022 
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proc sort data = WINRSCOMP_UNI; by trt; 
data mi_chk3; merge mi_chk2 winrscomp_uni; by trt; 
run; 
Fill in the intermittent missing data using the following code. 
proc sort data = mi_chk3; by treatment; 
proc mi data=mi_chk3 seed=12345 NIMPUTE=50 out=MI; 
by trt01pn; 
mcmc impute=monotone; 
var Visit2 – Visit5; 
run; 
Create an id variable to identify which visits were imputed in the active treatment group. 
 
data control_mi; set mi; where trt = 0; run; 
data NALER_mi; set mi; where trt = 1; 
Data NALER_MI; Set NALER_MI; 
if V2 = . then Imp_v2 = 1; else IMP_V2 = 0; 
if V3 = . then Imp_v3 = 1; else Imp_v3 = 0; 
if v4 = . then Imp_v4 = 1; else Imp_v4 = 0; 
if v5 = . then Imp_v5 = 1; else Imp_v5 = 0; 
run; 
proc sort data = control_mi; by trt _imputation_ usubjid; 
proc sort data = NALER_mi; by trt _imputation_ usubjid; 
data mi; set NALER_mi control_mi; by trt _imputation_ usubjid; 
run; 
Imputing values in the monotone missing data using regression. 
Visit 3 values are imputed using baseline value and treatment; 
Visit 4 values are imputed using baseline, treatment and visit 3 & so on. 
 
proc sort data = mi; by _Imputation_; 
proc mi data=mi out=mi_reg seed=54321 nimpute=1; 
by _Imputation_; 
var trt01pn base v3 v4 v5; 
class trt01pn; 
monotone regression; 
run; 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1: 01 June 2022 
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1. Tipping Point Analysis – Starts here: 
Take each group of dropouts – those who dropped out at v3 & subtracting (or adding) the SD of the 
completers group for that visit from the imputed value. 
Then merge it to the original data set. 
Then go to the next set of dropouts. 
data mi_reg2_Impv3; set mi_reg2; 
if Imp_v3 = 1 
then do; 
/*Create a macro where this value is replaced by the following: (-.25SD, -0.5SD, - 
0.75stdev, -SD, 0.25SD, 0.5SD, 0.75SD, SD), thus reducing the imputed values by a 
quarter, a half, three-quarter and a whole SD. Then, on the other side add 0.25SD, 0.5SD, 
0.75SD*/ 
 
v3 = v3-stdv3; 
v4 = v4-stdv4; 
v5_= v5-stdv5; (each of these is done only for visits that were imputed in the previous step) 
end; 
run; 
proc sort data = mi_reg2; by _Imputation_ usubjid; 
proc sort data = mi_reg2_impv3; by _Imputation_ usubjid; 
data mi_reg4; merge mi_reg2 mi_reg2_impv3; by _Imputation_ usubjid; 
run; 
 
data mi_reg4_Impv4; set mi_reg4; 
if Imp_v4 = 1 
then do; 
v4 = v4-stdv4; 
v5 = v5-stdv5; 
end; 
run; 
proc sort data = mi_reg4; by _Imputation_ usubjid; 
proc sort data = mi_reg4_impv4; by _Imputation_ usubjid; 
data mi_reg5; merge mi_reg4 mi_reg4_impv4; by _Imputation_ usubjid; 
run; 
data mi_reg5_Impv5; set mi_reg5; 
if Imp_v5 = 1 
then do; 
v5 = v5-stdv5; 
end; 
run; 
proc sort data = mi_reg5; by _Imputation_ usubjid; 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1: 01 June 2022 
Page 79 of 80 
DocUUID : 7e92afa8-f525-4d40-81e8-2b78d5ce783b 
 
 
 
 
proc sort data = mi_reg5_impv5; by _Imputation_ usubjid; 
data mi_reg6; merge mi_reg5 mi_reg5_impv5; by _Imputation_ usubjid; 
run; 
The result of the above steps is a modified horizontal data set with the modified imputed values. 
Now, proceed as before by converting this to a vertical data set & fitting GENMOD or MIXED. 
2. Convert the data set from a horizontal dataset, i.e. one row per subject to a vertical data set, 
i.e., multiple rows per subject. 
Data mi_reg1; set mi_reg; 
Visit = 1; WINRSA=base; output; 
Visit = 2; WINRSA=v3; output; 
visit = 3; WINRSA=v4; output; 
visit = 4; WINRSA=v5; output; 
drop v3 v4 v5; 
run; 
3. Create required variables in these 50 data sets, e.g. RESP, Pooled Site, treatment coded as 
(0,1) etc. 
4. Fit the models on the 50 imputed data sets by _Imputation_. 
 
PROC GENMOD data=mi method= QUAD; by _imputation_; 
Class trt visit posite usubjid; 
Model Resp (descending) = trt visit trt*visit posite base/ dist=binary 
link=logit /*ddfm = KR*/ s ; 
random intercept / subject = usubjid(trt) type = un g s; 
lsmeans trt/cl ilink diff oddsratio; 
Ods output diffs=diff_mi lsmeans=lsm_mi parameterestimates=parms1 ; 
run; 
Combine estimates of the 50 GENMOD models to create an overall estimate and a relative 
efficacy score. Use PROC MIANALYZE as above. Also follow guidance re ORs provided 
earlier. 


Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: TR11 
Version: Final 2.1: 01 June 2022 
Page 80 of 80 
DocUUID : 7e92afa8-f525-4d40-81e8-2b78d5ce783b 
 
 
 
 
12.4 
Sleep Disturbance Conversion Table. 
 
 
Sleep Disturbance 8a 
Raw Score 
T_Score 
SE 
8 
28.9 
4.8 
9 
33.1 
3.7 
10 
35.9 
3.3 
11 
38 
3 
12 
39.8 
2.9 
13 
41.4 
2.8 
14 
42.9 
2.7 
15 
44.2 
2.7 
16 
45.5 
2.6 
17 
46.7 
2.6 
18 
47.9 
2.6 
19 
49 
2.6 
20 
51.2 
2.5 
21 
52.2 
2.5 
22 
52.2 
2.5 
23 
53.3 
2.5 
24 
54.3 
2.5 
25 
55.3 
2.5 
26 
56.3 
2.5 
27 
57.3 
2.5 
28 
58.3 
2.5 
29 
59.4 
2.5 
30 
60.4 
2.5 
31 
61.5 
2.5 
32 
62.6 
2.5 
33 
63.7 
2.6 
34 
64.8 
2.6 
35 
66.1 
2.7 
36 
67.5 
2.8 
37 
69 
3 
38 
70.8 
3.2 
39 
73 
3.5 
40 
76.6 
4.4