A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period Crossover Efficacy and Safety Study of Nalbuphine ER Tablets for the Treatment of Refractory Chronic Cough
Phase: PHASE2
Conditions: Refractory Chronic Cough
Sponsor: Trevi Therapeutics

Official Title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period 
Crossover Efficacy and Safety Study of Nalbuphine ER Tablets for the Treatment of 
Refractory Chronic Cough
NCT Number: NCT05962151
Document Date: Protocol Amendment 2 : 19 June 2024

CLINICAL TRIAL PROTOCOL: NAL04-201 
Study Title: 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-
Period Crossover Efficacy and Safety Study of Nalbuphine ER Tablets 
for the Treatment of Refractory Chronic Cough 
Short Study Title 
Cough Reduction in RCC with NAL ER (RIVER) 
Study Number: 
NAL04-201 
Study Phase: 
2 
Product Name: 
Nalbuphine Extended-Release Tablets (NAL ER) 
Reference 
Number/s: 
N/A 
Indication: 
Refractory Chronic Cough 
Investigators: 
Multicenter 
Sponsor: 
Trevi Therapeutics, Inc. 
195 Church Street, 16th Floor 
New Haven, CT 06510, USA 
Sponsor Contact: 
 
Medical Monitor: 
, MD 
 
Protocol Version 
Protocol Amendment 2  19-Jun-2024 
 
Amendment Scope 
Global protocol revision including all country-specific 
amendments, and additional global changes 
 
Confidentiality Statement 
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. 
 

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Clinical Trial Protocol: NAL04-201 
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Protocol Amendment 2 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Date 
Protocol Amendment 2 
19-Jun-2024 
Protocol Amendment 1a-UK 
24-Oct-2023 
Protocol Amendment 1 
7-Aug-2023 
Original Protocol 
27-Jun-2023 
AMENDMENT 2 19-JUN-2024 
Overall Rationale for the Amendment: Protocol Amendment 2 was created to align local 
amendments into one global unified Protocol Amendment, and clarify the changes detailed 
below: 
 
SECTION # AND 
NAME 
DESCRIPTION OF CHANGE 
BRIEF RATIONALE 
Synopsis and SoE 
Align the synopsis and SoE with the body of the protocol. 
See the applicable section for details and rationale for the 
updates in the synopsis SoE. 
Administrative 
List of Abbreviations 
Added EOS, FU, IUS, PP, SoE, and TdP, corrected or 
removed abbreviations. 
Terms with © or ® are marked at important points in the 
text, and symbols removed from the rest of the text. 
Administrative 
Throughout Protocol 
Added text “End of Study” or “EOS” to reference to the 
“Safety Follow-up” or “FU” visit. 
Clarify End of Study 
(EOS) for the subject 
2.1 and 2.2 
Background on RCC 
and Nalbuphine 
Added clarifications on definition of RCC, and 
availability of NAL ER in Europe. 
Add detail for clarity 
2.4 Rationale for 
Study Design 
Added text “The use of placebo as a comparator is 
justified for this study due to 
….” 
Clarify alternative 
therapies and rationale 
for use of placebo 
2.5 Risk/Benefit and 
Ethical Assessment 
Added paragraph starting and ending with the below text: 
“The TR12 study in patients with IPF-associated chronic 
cough demonstrated 
… 
dose level, so the maximal dose in the current RIVER 
study is 108 mg BID.” 
Increase detail on the 
dose justification 
3.2 Secondary 
Objectives 
Patient and Clinical Global Assessments – 
Separated endpoint for assessment of change, as it is not 
done at baseline. 
Correct the endpoint to 
match the use of the 
tool 
4.1 Study Duration 
and Dates 
Added text “The overall end of study is defined as the last 
study visit for the last patient (LPLV)” 
Clarify EOS for the 
overall study 
4.1 Study Duration 
and Dates 
Added text “Following their participation in the study, 
subjects will return to the care of their usual physician for 
the continued management of their condition or, if needed, 
they will be referred to appropriate care.” 
Define subject return to 
routine care at the end 
of the study 
4.2 Overall Study 
Design and plan 
Removed requirement for follow up at planned end of 
study in case of early discontinuation 
Not required for Phase 
2a study 

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SECTION # AND 
NAME 
DESCRIPTION OF CHANGE 
BRIEF RATIONALE 
5.2 Inclusion Criteria 
#1 – added “Current” and “and history of chronic cough” 
#2 – added “and after onsent of chronic cough” 
#5 – corrected FEV1/FVC to the ratio 
Added detail to correct 
and clarify 
5.3 Exclusion 
Criteria 
#3 - added “or other significant respiratory disorder that 
might effect cough” 
#7 Cardiac Safety: corrected criteria to differentiate 
correctly the QRS in regular subjects vs those with RBBB 
#13 – added “as assessed by the investigator” 
#23 – added “baclofen, tricyclics” 
#24 – clarify reason for ACE inhibitor exclusion 
#25 – add example of cough suppressants 
Added detail to correct 
and clarify 
5.3 Exclusion 
Criteria 
#26 – new criteria: “Medications prescribed for asthma, 
rhinitis/upper airway cough syndrome, or 
gastroesophageal reflux disease are prohibited unless on 
a stable dose for 14-days prior to the baseline visit and 
are expected to remain at that dose for the duration of the 
study” 
Stabilize confounding 
medications that could 
impact the endpoint. 
6.5 Multiple Missed 
Doses 
Changed 6 missed doses (approx. 3 days) to 3 missed 
doses (approx. 1.5 days) as the threshold for discussion 
with the study Medical Monitor/s 
Facilitate Medical 
Monitor contact at an 
earlier timepoint 
7.2 Reporting of 
Adverse Events 
Added text “Clinically relevant findings on ECG, 
laboratory testing, or physical examination during 
Screening 
… 
the Adverse Event eCRF.” 
To replace the text “Clinically significant findings noted 
prior to the start of investigational product treatment will 
be recorded as medical history”. 
Add detail for clarity 
7.2.2 Adverse Events 
Requiring Additional 
Narratives 
Added the terms: Dissociation, Feeling drunk and 
Hallucinations (any) 
Revised the terms: Polysubstance dependence to 
Substance dependence, Intentional drug misuse to 
Intentional product misuse, Elevated Mood to Euphoric 
mood 
Revisions due to 
MedDRA updates and 
Sponsor Decision 
7.2.4 Severity 
Grading 
Updated the section title 
Add detail for clarity 
7.4 Pregnancy 
Clarified procedures in case of pregnancy, and updated 
that the outcome of the pregnancy will be followed up no 
later than 6-8 weeks following estimated due date 
Update for clarity 
8.4 Subject Symptom 
and Medication Logs 
and 
8.6 Concomitant 
Medication and 
Therapy Assessments 
Added text for Symptom Log that “new and/or changed” 
items should be recorded. 
Added text for the Medication Log that the addition, 
change, or discontinuation of “medications, therapies, 
including oxygen therapy, over-the-counter (OTC) 
medications, herbal medications, vitamins, and nutritional 
supplements will be reported” 
Added text that the logs will be “reviewed by staff and 
applicable information entered in eCRF” 
Clarify how the subject 
logs should be used 

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SECTION # AND 
NAME 
DESCRIPTION OF CHANGE 
BRIEF RATIONALE 
8.6.1 Prohibited and 
Restricted 
Medications, and 
Washout 
Including Table 7 
Clarified implications for study withdrawal of taking 
restricted medication, and defined stable dose. 
Table 7 updated table to align with the medication 
exclusion criteria, and for consistency 
Added detail for clarity, 
and update for 
consistency 
8.9 
Electrocardiogram 
(ECG) 
Added text “will be assessed by the ECG specialist vendor 
and a report sent to site within 72 hours of successful 
transmission. 
The screening ECG central read report will be used for 
the purpose of meeting the ECG study inclusion criteria” 
Added detail for clarity 
8.11 Clinical 
Laboratory Tests 
Added text “Once processed, samples will be stored for 
an interim period at the site before shipping to the 
location where the analysis will be performed. Once at the 
analysis location, after analysis, samples can be stored for 
up to 1 month, before being destroyed.” 
“at the central lab using consistent methodology and 
procedures globally at the testing locations (ICON 
Laboratories in Ireland and US)” 
Clarified that only the Urine Pregnancy Test is tested 
locally at site. 
Define the testing, 
storage time and 
location of routine lab 
samples 
8.12 Blood Sampling 
for Pharmacokinetics 
(PK) 
Added text “Once processed, samples will be stored for 
an interim period at the site, before shipping to the central 
lab for forwarding to the PK lab. Samples that are sent to 
the PK lab can be stored for up to 5 years in case of the 
need for retesting for this study before being destroyed.” 
Define the storage time 
and location of PK lab 
samples 
8.13 WOCBP 
Pregnancy test, and 
contraceptive 
counselling 
Added text “without an alternative medical or medication 
cause (e.g. hormonal treatments)” and “Permanently”, 
and expanded on definition of permanently sterile, for 
definition of non-WOCBP. 
Added text “Intrauterine hormone-releasing system 
(IUS)”, as acceptable method of birth control. 
Align with Clinical 
Trials Facilitation & 
Coordination Group 
(CTFG) Guidance 
8.15 24-hour Digital 
Cough Monitor 
Added text about the measures taken to preserve privacy: 
“The recording is encrypted on the device and transferred 
electronically to the UK via a secure web portal.” 
And “by specially trained individuals working under strict 
SOPs to ensure confidentiality 
… 
do not have access to listen to the records” 
Add detail for clarity 
8.16 Patient Reported 
Outcomes (PRO) 
Questionnaires 
Clarifications on Tools and timing of the PROs 
Add detail for clarity 
8.16.1 SOWS 
(Subjective Opiate 
Withdrawal Scale), 
and PRO SoE 
Footnotes 
Added text “Subject reported symptoms of withdrawal 
captured on the SOWS will not be reported as an Adverse 
Event unless reported verbally as part of the overall AE 
assessment at each visit”, to replace text requiring 
reporting of SOWS answers as Medical History or 
Adverse Events. 
Correct the 
documentation of 
SOWS PRO answers 
8.21 Tolerance and 
Titration Symptoms 
Management 
Added text about consultation with the medical monitor in 
case of missed doses or continued lack of tolerance. 
Increase medical 
monitor contact 
8.22 Premature 
Discontinuation 
Clarified the protocol allowed reasons for discontinuation 
from the study. 
Facilitate Medical 
Monitor real-time 

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Protocol Amendment 2 
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SECTION # AND 
NAME 
DESCRIPTION OF CHANGE 
BRIEF RATIONALE 
Added text “Subjects have the right to discontinue 
… 
discontinuation has occurred.” 
Clarified the steps to be taken if a subject permanently 
discontinues the study drug. 
Added the text that “the last study procedure or visit 
under the subject’s consent will be considered End of 
Study” 
awareness of premature 
discontinuations 
Add detail for clarity 
8.23 Appropriateness 
of Measurements 
Added detail about use of the VitaloJAK and e-diary 
Add detail for clarity 
9.5 Analysis 
Populations 
Added text “Per Protocol (PP) population: The PP 
population will consist of all subjects in the mITT 
population who have a treatment compliance >80% 
during the fixed dose period and do not have a protocol 
deviation that excludes subjects from the PP population. A 
complete list of protocol deviations that will exclude 
subjects from the PP population will be provided in the 
SAP. Subjects who are withdrawn from the study by the 
sponsor due to a deviation (see Section 10.9) will be 
excluded from the PP population” 
Increase detail on the 
per protocol population 
10.1 Quality Control 
and Assurance 
Changed “should” to “will” for Investigator 
responsibilities. 
Make investigator 
responsibility 
compulsory 
10.6 Patient 
Confidentiality and 
Data Protection 
Added text to this section: 
“(e.g., from the e-diary, cough monitor, labs)” 
“(pseudonymized)” 
“This code list will remain on site and kept in a secure 
manner with the study documentation, with access limited 
to authorized individuals.” 
“Identifiable (non- pseudonymized) personal study-
related data will be accessed by the sponsor 
… 
used in this way to participate in the study.” 
“The compliance with these requirements is confirmed 
and documented throughout 
… 
data transfer agreements and quality agreements, where 
appropriate.” 
“In case of security breach procedures for reporting and 
disclosure within the regulations and timelines of the 
applicable countries for the study will be followed.” 
The above text replaced and expanded upon the below 
deleted text: 
“The level of disclosure will be explained to the subject 
who will be required to give consent for their data to be 
used as described in the informed consent” 
Increase detail on the 
data protection 
processes 
10.9 Protocol 
Violations/Deviations 
Changed “not evaluable” to “ineligible for inclusion in 
the per protocol population” 

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SECTION # AND 
NAME 
DESCRIPTION OF CHANGE 
BRIEF RATIONALE 
10.11 Data 
Generation and 
Analysis 
Added text “The data generated to answer the objectives 
of the study are: 
… 
and no data is recorded in the eCRF directly. Data will 
be” 
And “The following data is generated by the subject or by 
a vendor, 
… 
source of the actions and results themselves will be the 
vendor database.” 
Clarify data collected, 
and the location of the 
source data 
10.12 Retention of 
Data 
Replaced text “as long as needed” with “25 years” 
Deleted “and sponsor requirements” and added “before 
destroying the data” 
Clarify data retention 
time and destruction 
10.14 Publication and 
Disclosure Policy 
Added text “The results of the study will be posted to the 
publicly accessible website ClinicalTrials.gov 
independent of the outcome of the study. 
Clarify disclosure of 
results 
11 References 
and throughout 
Added new references, and removed references no longer 
applicable. 
Corrected, added, or aligned in-text references throughout 
where required. 
Administrative 
 
AMENDMENT 1: 7-AUGUST-2023 
Overall Rationale for the Amendment: 
Protocol Amendment 1 was created to clarify exclusion criteria and restricted medications as 
follows: 
 
SECTION # 
AND NAME 
DESCRIPTION OF CHANGE 
BRIEF RATIONALE 
Synopsis 
Addition of exclusion regarding a 
IB section 6.4 “Contraindications” indicates that 
Exclusion 
subject’s hypersensitivity to 
Nalbuphine ER tablets should not be used in 
Criteria/Section 
nalbuphine or NAL ER excipients. 
subjects with a hypersensitivity to nalbuphine or 
5.3 Exclusion 
to any of the other ingredients in NAL ER 
Criteria 
tablets. 
Synopsis 
Addition of exclusion regarding 
IB section 6.7 indicates that because a formal 
Exclusion 
language defining use of Known Risk 
TQT study has not been conducted for NAL 
Criteria and 
Drugs. 
ER, concomitant use of medications classified 
Section 5.3 
as having a known risk for Torsade des Pointes 
Exclusion 
should not be used concomitantly. 
Criteria 
Section 8.6.1 
Addition of the use medication having 
known risk of Torsades de Pointe 
(categorized as KR on the Credible 
Meds® website 
Medications associated with a 
potential risk of QT prolongation, but 
not clearly associated with Torsade de 
Pointes. 
Explanation of restriction and washout period 
Table 7 
Prohibited and 
Restricted 
Medications, 
and Washout 

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Clinical Trial Protocol: NAL04-201 
Trevi Therapeutics, Inc. 
Protocol Amendment 2 
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1. PROTOCOL SYNOPSIS 
1.1. 
Synopsis 
 
Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Study Number: 
NAL04-201 
Protocol Amendment 2 
Name of Finished Product: Nalbuphine Extended-Release Tablets (NAL ER) 
Name of Active Ingredient: nalbuphine hydrochloride (HCl) 
Title of Study: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period Crossover 
Efficacy and Safety Study of Nalbuphine ER Tablets for the Treatment of Refractory Chronic Cough 
Short Study Title: Cough Reduction in RCC with NAL ER (RIVER) 
Study Phase: 
Phase 2 
Study Centers: 
Approximately 12-16 centers 
Protocol Amendment 2 
19-Jun -2024 
Planned Study Period: 
2023-2024 
Duration of Treatment per subject: 
21 Days per Treatment Period 
Duration of Study per subject: 
up to 15 Weeks 
Number of Subjects: Approximately 60 subjects diagnosed with RCC will be randomized to ensure 
evaluable data from at least 48 subjects who complete both treatment periods. 
Study Objectives and Efficacy Endpoints: 
Objective 
Endpoint 
Primary Objective 
Effect of treatment on 24-hour 
cough frequency (coughs per 
hour) after 21 days 
• Relative change from Baseline in 24-hour cough frequency 
(coughs per hour) as assessed by objective cough monitoring at 
Day 21 for NAL ER compared with placebo. 
Secondary Objectives 
Safety and tolerability of 
NAL ER for the treatment of 
Refractory Chronic Cough 
(RCC) 
• Adverse events, clinical laboratory assessments, vital signs, and 
physical examination summaries. 
• ECG summaries [ECGs will be analyzed in a separate report]. 
• Subjective Opiate Withdrawal Scale (SOWS) daily summaries for 
the 14 days following the last dose of investigational product. 
24-hour cough frequency 
(Coughs per hour) 
• Relative change from Baseline in 24-hour cough frequency 
(coughs per hour) at Days 7 and 14 for NAL ER compared with 
placebo. 
• Proportion of responders with ≥30%, ≥50% and ≥75% reduction 
in the 24-hour cough frequency at Days 7, 14, and 21 for 
NAL ER compared with placebo. 
Awake cough frequency 
(Coughs per hour) 
• Relative change from Baseline in awake cough frequency (coughs 
per hour) at Days 7, 14, and 21 for NAL ER compared with 
placebo. 
Sleep cough frequency 
(Coughs per hour) 
• Relative change from Baseline in sleep cough frequency (coughs 
per hour) at Days 7, 14, and 21 for NAL ER compared with 
placebo. 
CS-VAS (Cough Severity 
Visual Analogue Scale) 
• Change from Baseline in the Cough Severity Visual Analogue 
Scale at Days 7, 14, and 21 for NAL ER compared with placebo. 

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Clinical Trial Protocol: NAL04-201 
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Protocol Amendment 2 
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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Study Number: 
NAL04-201 
Protocol Amendment 2 
LCQ© (Leicester Cough 
Questionnaire) 
• Change from Baseline in the LCQ total score at Day 21 for NAL 
ER compared with placebo. 
Patient-Reported Cough 
Frequency (PR-CF) 
• Change from Baseline in the PR-CF at Days 7, 14, and 21, for 
NAL ER compared with placebo. 
• Proportion of PR-CF responders, with response defined as at least 
a one category improvement at Days 7, 14, and 21 for NAL ER 
compared with placebo. 
PGI-S, PGI-C, Cough (Patient 
Global Impression of Severity 
and Change for Cough) 
• Change from Baseline in the PGI-S Cough at Days 7, 14, and 21 
for NAL ER compared with placebo. 
• PGI-C Cough score at Days 7, 14, and 21 for NAL ER compared 
with placebo. 
CGI-S, CGI-C, Cough 
(Clinical Global Impression of 
Severity and Change for 
Cough) 
• Change from Baseline in the CGI-S Cough at Day 21 for NAL 
ER compared with placebo. 
• CGI-C Cough score at Day 21 for NAL ER compared with 
placebo. 
Pharmacokinetics: Nalbuphine (and/or metabolites) plasma concentration will be measured for each 
treatment group at all visits where subject is on treatment. A PK sample will be drawn and correlated with 
the time of IP intake as reported by the subject. 
Study Design: 
A double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of cough in 
subjects with Refractory Chronic Cough. 
Based on the screening cough monitor results, the study will enroll subjects in a 1:1 ratio to subgroups of 
10-19 coughs/hour and ≥20 coughs/hour. 
After meeting eligibility during the screening period, subjects will be randomly assigned (1:1) to one of the 
following sequences: 
• 
NAL ER in Treatment Period 1, followed by Placebo (PBO) in Treatment Period 2 
OR 
• 
PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2 
The 21-day treatment periods are separated by a 21-day washout period. NAL ER will be titrated according 
to the Table: Dosing Scheme. 
Study visits in each treatment period will be at Day -1 for Baseline cough assessments, and at Days 6, 13, 
and 20. Visits and Assessments are described in Figure: Study Schematic, and Section 1.2 Schedule of 
Events, Table 1 and Table 2. Subjects will have blood drawn for pharmacokinetic (PK) analysis of 
nalbuphine plasma concentration. Subjects will also complete questionnaires for efficacy evaluations and 
undergo safety evaluations including an electrocardiogram (ECG). 
At the Screening and Baseline visits and on Days 6, 13, and 20 during each treatment period, site staff will 
place an electronic cough monitor on the subject, which will be worn for a 24-hour recording period to 
assess cough frequency. At the end of each recording session (Days 7, 14, and 21), the monitor will be 
removed at home by the subject, and the subjects will complete Patient Reported Outcomes (PROs) 
questionnaires in the diary. The monitor will be returned to the clinical study center for processing. 
Subjects will be taken off study drug at the end of the Treatment Period 2 and followed off treatment for an 
additional 2 weeks. 

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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Study Number: 
NAL04-201 
Protocol Amendment 2 
If permanent discontinuation of investigational product occurs the discontinuation and safety follow-up 
(FU)/end of study (EOS) visits should be performed. End of Study for any participant will occur when the 
safety follow-up visit is completed,14+3 days after last dose, or withdrawal of consent. 
Figure: Study Schematic 
 
Table: NAL ER Dosing Scheme 
Grey shading indicates cough monitor application and recording period. 
VISIT 
Study Day 
(TP1 or TP2) 
NAL ER 
Dose (mg) 
PLACEBO 
(PBO) 
AM 
PM 
AM 
PM 
Baseline 
-1 
— 
— 
— 
— 
1 
— 
27 
— 
PBO 
2 
— 
27 
— 
PBO 
3 
27 
27 
PBO 
PBO 
4 
27 
27 
PBO 
PBO 
5 
27 
27 
PBO 
PBO 
Day 6 
6 
27 
27 
PBO 
PBO 
7 
27 
54 
PBO 
PBO 
8 
54 
54 
PBO 
PBO 
9 
54 
54 
PBO 
PBO 
10 
54 
54 
PBO 
PBO 
11 
54 
54 
PBO 
PBO 
12 
54 
54 
PBO 
PBO 
Day 13 
13 
54 
54 
PBO 
PBO 
14 
54 
108 
PBO 
PBO 
15 
108 
108 
PBO 
PBO 
16 
108 
108 
PBO 
PBO 
17 
108 
108 
PBO 
PBO 
18 
108 
108 
PBO 
PBO 
19 
108 
108 
PBO 
PBO 
Day 20 
20 
108 
108 
PBO 
PBO 
21 
108 
— 
PBO 
— 

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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Study Number: 
NAL04-201 
Protocol Amendment 2 
Study Population: 
Inclusion Criteria 
Subjects eligible for randomization to receive investigational product must meet all the following criteria: 
1. Current diagnosis of refractory chronic cough (RCC); and history of cough for at least one year. 
Defined in the ERS Guidelines as chronic cough that is refractory to conventional treatment of cough-
associated conditions or where no cough-associated conditions can be identified (Morice et al, 
2020). 
2. Chest radiograph or computed tomography (CT) of the thorax performed within the last 24 
months and after the onset of chronic cough or during the screening period not demonstrating any 
abnormality considered to be significantly contributing to the refractory chronic cough in the opinion 
of the Principal Investigator. 
3. Score of ≥40mm on the Cough Severity VAS at the Screening visit. 
4. 24-hour objective cough frequency ≥10 or ≥20 coughs/hour based on cough monitor recording 
performed during the Screening Period, with results reviewed prior to baseline visit. Study will enroll 
subjects in a 1:1 ratio to subgroups of 10-19 coughs/hour and ≥20 coughs/hour. 
5. FEV1 / FVC ratio ≥ 60% as determined by spirometry adhering to ATS/ERS guidelines. (Graham et 
al, 2019). 
6. Males or females ages 18 years and older at the time of consent. 
7. Willing and able to provide written informed consent, comply with study requirements and restrictions, 
and 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 are not eligible for participation in the study: 
1. Clinical diagnosis of sleep apnea and/or use of CPAP. 
2. Upper or lower respiratory tract infection or change in pulmonary status in the last 6 weeks prior to 
the baseline visit. 
3. History of bronchiectasis, chronic obstructive pulmonary disease (COPD) or idiopathic 
pulmonary fibrosis (IPF), or other significant respiratory disorder that might affect cough. 
4. History of uncontrolled asthma. 
5. Current smokers/vapers, individuals who have given up smoking ≤12 months, individuals using 
nicotine patches, gum, or any other nicotine supplements, or individuals with a smoking history of 20 
pack-years or more. 
6. Speech therapy/physiotherapy for RCC is acceptable if the subject has started the therapy at least 
4 weeks prior to the Baseline visit and continues the therapy through the Treatment Periods. It may not 
be started within 4 weeks of starting the study or for the duration of the study. 
7. Cardiac Safety: Mean QTcF value of 3 centrally read screening Electrocardiograms (ECG) calculated 
as 
a) ≥470ms if QRS <120ms or 
b) ≥500ms in the presence of either a Right Bundle Branch Block (RBBB) or QRS≥120ms 
8. Heart Rate <50 bpm or >100 bpm, as determined by vital signs pulse obtained over 30-60 seconds 
a) Subjects with a resting heart rate of <50 bpm will have it repeated once after 5 minutes in the supine 
position, and if it remains <50 bpm during the repeat, they will be considered a screen failure. 

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Protocol Amendment 2 
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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Study Number: 
NAL04-201 
Protocol Amendment 2 
b) Subjects with a rate >100 bpm should be considered a screen failure. Rescreening may be possible 
with the approval of the medical monitor, after medical or alternative management of the atrial 
fibrillation. 
9. Kidney Function: Estimated glomerular filtration rate ≤ 44 mL/min/1.73 m2 at Screening. 
10. Liver Function: Total Bilirubin >3mg/dl [>50umol/L] and Serum Albumin <2.8g/dl 
11. History of major psychiatric disorder, which in the opinion of the Investigator, could interfere with 
the assessment of anti-cough efficacy and/or safety events during the study or with the ability of the 
subject to cooperate with study requirements. 
12. History of substance abuse including excessive alcohol consumption, that in the opinion of the 
Investigator, may interfere with the conduct of the study. 
Alcohol consumption should be limited for the duration of study treatment. 
13. Significant medical condition or other factors as assessed by the investigator that may interfere with 
the subject’s ability to successfully complete the study. 
14. Pregnant or lactating female subject. Women of childbearing potential (WOCBP) must use an 
acceptable method of birth control and have a negative pregnancy test at the screening and baseline 
visits. WOCBP and acceptable methods of birth control are defined in the protocol, 
Section 8.13 Pregnancy test, and contraceptive councelling. 
15. Known intolerance (gastrointestinal, central nervous system symptoms), hypersensitivity, drug allergy 
following the use of an opioid drug. 
16. Known hypersensitivity to nalbuphine or to NAL ER excipients. 
17. Previous enrollment in a NAL ER clinical study. 
18. Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a concurrent clinical 
trial. Observational or long-term safety follow-up studies (e.g., in a vaccine study) may be allowed upon 
medical monitor approval. 
Medication-related Exclusions: 
(Refer to protocol Section 8.61 Prohibited and Restricted Medications, and Washout): 
19. Use of opiates is prohibited within 14 days prior to the baseline visit. Includes opiate-containing anti-
cough agents, and naltrexone. Subjects are prohibited from using opioids for the duration of the study. 
20. Use of benzodiazepines are prohibited within 14 days prior to the baseline visit and for the duration of 
the study. 
21. Monoamine oxidase inhibitors (MAOIs) including methylene blue (methylthioninium chloride) and 
the antibiotic linezolid are prohibited within 14 days prior to the baseline visit and for the duration of 
the study. 
22. Exposure to any investigational medication, including placebo, is prohibited within 4 weeks prior to 
the baseline visit and for the duration of the study. 
23. Use of pregabalin, gabapentin, baclofen, tricyclics, or thalidomide given for the treatment of cough 
is prohibited within 14 days of the Baseline visit, and for the duration of the study. 
Pregabalin, gabapentin, baclofen, tricyclics, or thalidomide required for other indications, is permitted 
if on a stable dose for at least 4 weeks, and still experiencing significant cough, and expected to remain 
on that dose for the duration of the study. 
24. Use of ACE inhibitors is prohibited within 12 weeks prior to the baseline visit, and for the duration of 
the study (due to potential for causing cough). 

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Study Number: 
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Protocol Amendment 2 
25. Other medications prescribed as cough suppressants (such as dextromethorphan or benzonotate) are 
prohibited unless on a stable dose 14-days prior to the baseline visit and are expected to remain on that 
dose for the duration of the study. 
26. Medications prescribed for asthma, rhinitis/upper airway cough syndrome, or gastroesophageal 
reflux disease are prohibited unless on a stable dose for 14-days prior to the baseline visit and are 
expected to remain at that dose for the duration of the study. 
27. Use of medications that affect serotonergic neurotransmission and that when used concomitantly 
with opioids can cause serotonin syndrome are prohibited unless on a stable dose for 14-days prior to 
the baseline visit and are expected to remain on that dose for the duration of the study. 
28. Strong inhibitors/inducers of the P450 Isozymes are prohibited unless on a stable dose for 14-days 
prior to baseline visit and are expected to remain on that dose for the duration of the study. 
29. Use of a medication having a “known risk” of Torsade de Pointes (TdP) (categorized as “KR” on the 
Credible Meds® website) is prohibited at entry or during the study. Medications associated with a 
potential risk of QT prolongation, but not clearly associated with TdP, 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 baseline. 
• Medication dose will not be increased after screening, or during the study, and it is anticipated that 
the subject will receive the medication for the entirety of the study. 
Statistical Methods: 
Efficacy 
The primary efficacy endpoint of relative change in 24-hour cough frequency (coughs per hour) will be 
analyzed using a mixed-effects repeated model. This model will use log-transformed relative change in 24-
hour cough frequency (log (Timepoint/ Baseline)) as the response with sequence, treatment, and time as 
fixed effects, the log-transformed baseline 24-hour cough frequency and sex as covariates, site as a random 
effect, and subject as a random repeated effect. There will be no imputation for dropouts or missing data 
for assessments not completed at study visits. In the presentation of results, log-scale fitted mean treatment 
group differences at Day 21 will be back-transformed to fitted ratios of geometric means. 
As a supplementary analysis, a negative binomial model will be fitted with the number of coughs as the 
outcome, with terms for sequence, treatment, time, baseline cough frequency with subject as a random 
effect. 
The primary efficacy analysis and secondary analyses that require comparison of placebo and NAL ER will 
be analyzed using the population of subjects for whom baseline and Day 21 measurements are non-missing 
for both periods. Summaries by treatment will consist of all subjects with a baseline and Day 21 
measurement for that treatment, unless evidence suggests a sequence effect, in which case summaries will 
be presented by treatment and sequence. 
Safety 
The incidence of adverse events will be summarized through the presentation of proportions by Medical 
Dictionary for Regulatory Activities (MedDRA) body system classification and preferred term. Vital signs 
laboratory data, physical examinations, and SOWS 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. 
Additional descriptive narratives will be collected for relevant adverse events to support an eight-factor 
analysis. 

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ECGs will be reviewed locally for safety. ECGs will be read centrally by specially trained staff and once 
the database is complete, ECG data (e.g., heart rate, PR, QTcF intervals) will be presented in listings by 
subject and summarized by collection date and time. A complete ECG assessment will be documented in 
a separate report from the central ECG specialist vendor. 
Pharmacokinetics 
Nalbuphine (parent and/or metabolites) plasma concentration data will be listed by collection time and 
nalbuphine dose where applicable. Additional PK-PD analysis may be conducted if data allows and will 
be presented in an ad-hoc report. 
Sample Size and Power 
Assuming that subjects on placebo will experience a mean 20% reduction in 24-hour cough frequency from 
baseline to Day 21 and subjects on NAL ER will experience a mean 45% reduction from baseline to Day 
21, the planned sample size of 48 subjects (24 per sequence) provides at least 80% power to detect a 
significant difference between NAL ER treatment and placebo at the 5% significance level (2-sided). This 
assumes a coefficient of variation (CV) of 1.12 in log-transformed Day 21 cough frequencies which is the 
CV estimated from Kelsall et al (2011) data on chronic cough in patients without esophageal catheterization. 
A total of approximately 60 subjects will be randomized to ensure complete data from at least 48 subjects, 
assuming a ~20% dropout rate. 

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1.2. 
Schedule of Events (SoE) 
Table 1 
Schedule of Events 
 
Screening 
Study 
Baseline 
Treatment Period 
TP1 
TP2 
Baseline 
Treatment Period 
TP2 
DC 6 
EOS/ 
FU 7 
Treatment Day 
(visit window [days]) 
Day 
-28 to -21 
Day 
-1 
Day 
2 
(±1) 
Day 
6 
(-2) 
Day 
13 
(-2) 
Day 
20 
(-2) 
Day 
-1 
(+5) 1 
Day 
2 
(±1) 
Day 
6 
(-2) 
Day 
13 
(-2) 
Day 
20 
(-2) 
Premature 
DC 
14 Days 
(+3 days) 
Informed consent 
X 
Demographics, Medical History, RCC History 
X 
Assess subject eligibility against inclusion/exclusion criteria 
X 
X 
X 
Subject Medication and Symptom Log – Dispense, Review, 
Re-dispense 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record/assess AEs, Concomitant Medications, and Therapies 
Continuous 
 
Throughout the Study 
 
Continuous Throughout the Study 
Vital signs including pulse oximetry and weight 2 
X 
X 
X 
X 
X 
21 Day Washout Period 
X 
X 
X 
X 
X 
X 
Height, BMI 
X 
Electrocardiogram (ECG) - triplicate, central over-read 2 
X 
X 
X 
X 
X 
X 
Spirometry 
X 
Chest Radiograph or Computed Tomography (CT) 4 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests 3 
X 
X 
X 
X 
X 
X 
Pharmacokinetics (PK) blood Sample 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test, and contraceptive counselling, if 
applicable 
X 
X 
X 
Urine pregnancy test (confirm result before dispensing IP), if 
applicable 
X 
X 
24 hr Cough monitor - Hook up, remove at home and return 
after 24-hrs 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e-diary – Dispense and train on use 
X 
e-diary – Review e-diary compliance and retrain as necessary 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
e-diary – PRO questionnaires, including sows 
As described in the PRO Schedule of Events 
Clinical Global Impression of Severity (CGI-S) 
X 
X 
X 
X 
X 
Clinical Global Impression of Change (CGI-C) 
X 
X 
X 
Randomization 
X 
IP - Dispense blister card, review dosing instructions 
X 
X 
X 
X 
X 
X 
IP - Review compliance 
 
X 
X 
X 
 
X 
X 
X 
IP - Review Tolerance and manage symptoms as needed 
 
X 
X 
X 
 
X 
X 
X 
Review IP Blister Card and redispense, or retrieve at DC 8 
X 
X 
X 
X 
X 
X 
X 
Retrieve e-diary, Review and retrieve IP and symptom log 
X 
AE - Adverse Event  DC - Discontinuation 
EOS - End of Study 
SOWS - Subjective Opiate Withdrawal Scale 
IP - Investigational Product 
PRO - Patient Reported Outcomes TP - Treatment Period 
FU - Follow-Up 
 Telephone Contact 

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RIVER Schedule of Events (SoE) Footnotes 
1 
Screening should be completed within 14 days, with possibility to extend to 28 days without re-screen, for scheduling or logistical reasons. 
Contact medical monitor regarding extensions beyond the 28 day screening period. 
Washout period is 21 days, with a visit window of +5 days. Please contact medical montitor regarding extensions in the washout beyond the 
+5 day window. 
2 
Vital signs after at least 5 minutes in sitting position, Triplicate ECG after at least 5 minutes in supine position. Vital signs and ECG to be 
performed before invasive procedures. 
ECG to be transmitted for central over-read, and screening central over-read reports (received within 72 hours) are used to assess eligibility. 
3 
PK sample to be drawn as soon as possible after the ECG. Labs will be drawn for clinical chemistry, hematology, urinalysis, and 
coagulation and sent to the central lab. 
4 
Chest Radiograph or CT: If the assessment has been performed within the last 24 months, a copy of the radiologist report is to be filed in 
the source as documentation of eligibility. 
If not assessed in the last 24 months, or a report is not able to be obtained for review, then the procedure will be performed at screening. 
5 
Digital cough monitor 
- Day of the Visit - hook up for 24-hour recording; monitor will be worn until the following day to obtain at least a full 24-hour recording 
period of cough frequency. 
- After 24 hours - removal and return - At the end of the recording session, the monitor will be removed at home by the subject. Subject to 
be provided with appropriate shipping material to return monitor after removal, for upload of data to Vitalograph portal. First dose of IP is 
taken after the removal of the cough monitor on Day 1. 
6 
In case of premature discontinuation of IP, the IRT/e-diary system to be updated immediately to activate the PROs (do not wait for the 
subject to come to site) 
The site should complete discontinuation procedures per the DC Visit Schedule at the current visit OR subject to return to the site for the 
premature DC visit as soon as possible, if discontinuation occurs between scheduled visits. 
7 
End of Study/ Safety Follow-up visit will occur 14+3 days after the last dose of IP (last dose can be TP2: Day 20, or earlier in case of 
premature discontinuation). 
8 
IP Blister card is to be returned to site by courier together with the cough monitor after removal at Day 21. At Discontinuation visit (if 
applicable), retrieve blister card. 

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Table 2 
Schedule of Events (SoE) for PROs 
 
Screening 
Baseline 1 
Treatment Period 2 
DC 
EOS/FU 
Day/Week: 
Day 
-28 to -2 
Day -1 
Day 7 
Day 14 
Day 21 
DC 5 
FU 
CS-VAS 
X 
X 
H 
H 
H 
H 
X 
LCQ 
X 
H 
H 
Patient-Reported Cough Frequency (PR-CF) 
X 
Daily from Day -7, and thoughout the study 
H 
X 
PGI-S, Cough 
X 
H 
H 
H 
H 
PGI-C, Cough 
H 
H 
H 
H 
SOWS Baseline 3 
X 
H 
SOWS for 14 days after last dose 4 
H 
H 
For full PRO titles, refer to the protocol 
FU - Follow-Up 
DC - Premature Study Discontinuation 
 
H 
PROs completed in the eDiary at home, on the appropriate day as presented in the e-diary. 
X 
PROs completed in the eDiary at the study site . 
1 At Baseline, all PROs will be completed during the visit, on the day of cough monitor application. 
2 At post baseline visits with a cough monitor, PROS will be completed the day after the per protocol visit date, 
regardless of when the actual visit is performed. 
3 SOWS baseline: will be completed once at Baseline and Day 7 to determine baseline status for relevant 
symptoms. 
4 SOWS: From the last day the subject took IP, regardless of when this occurs, SOWS will be completed daily 
via e-diary until 14 days after last IP dose. Site will monitor SOWS compliance to confirm subject is 
completing entries as required. 
5 In case of premature discontinuation of IP - PROs to be activated immediately via the IRT/e-diary portal (do 
not wait for the subject to come to site). 

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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL: NAL04-201 ......................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................................... 2 
DOCUMENT HISTORY ..................................................................................................... 2 
AMENDMENT 2 19-JUN-2024 .......................................................................................... 2 
AMENDMENT 1: 7-AUGUST-2023 .................................................................................. 6 
1. 
PROTOCOL SYNOPSIS ................................................................................................... 7 
1.1. 
Synopsis ................................................................................................................... 7 
1.2. 
Schedule of Events (SoE) ....................................................................................... 14 
TABLE OF CONTENTS ......................................................................................................... 17 
LIST OF ABBREVIATIONS .................................................................................................. 21 
2. 
INTRODUCTION ............................................................................................................ 24 
2.1. 
Background Information on Refractory Chronic Cough ........................................ 24 
2.2. 
Background Information on Nalbuphine ................................................................ 24 
2.3. 
Rationale for Investigation of Nalbuphine in Refractory Chronic Cough ............. 25 
2.4. 
Rationale for Study Design and Control Group ..................................................... 25 
2.5. 
Risk/Benefit and Ethical Assessment ..................................................................... 26 
3. 
STUDY OBJECTIVES .................................................................................................... 28 
3.1. 
Primary Objective .................................................................................................. 28 
3.2. 
Secondary Objectives ............................................................................................. 28 
4. 
INVESTIGATIONAL PLAN .......................................................................................... 30 
4.1. 
Study Duration and Dates ...................................................................................... 30 
4.2. 
Overall Study Design and Plan .............................................................................. 30 
4.2.1. 
Study Schematic ........................................................................................... 31 
5. 
STUDY POPULATION SELECTION ............................................................................ 32 
5.1. 
Study Population and Sites..................................................................................... 32 
5.2. 
Inclusion Criteria .................................................................................................... 32 
5.3. 
Exclusion Criteria ................................................................................................... 32 
6. 
STUDY TREATMENT ................................................................................................... 35 
6.1. 
Description of Treatment(s) ................................................................................... 35 
6.1.1. 
Study Drug ................................................................................................... 35 
6.1.2. 
Placebo ......................................................................................................... 35 
6.2. 
Treatments Administered ....................................................................................... 35 
6.2.1. 
Dosing Scheme ............................................................................................. 36 
6.3. 
Dispensing and Intake Instructions ........................................................................ 36 
6.4. 
Subject Compliance and Accountability ................................................................ 37 
6.5. 
Multiple Missed Doses ........................................................................................... 37 
6.6. 
Randomization and Blinding .................................................................................. 37 

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6.7. 
Investigational Product Supplies Management ...................................................... 38 
6.7.1. 
Packaging and Labeling ............................................................................... 38 
6.7.2. 
IP Storage ..................................................................................................... 38 
6.7.3. 
Accountability .............................................................................................. 38 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................ 39 
7.1. 
Adverse Event Definition ....................................................................................... 39 
7.2. 
Reporting of Adverse Events ................................................................................. 39 
7.2.1. 
Events Exempt from Adverse Event Reporting ........................................... 40 
7.2.2. 
Adverse Events Requiring Additional Narratives ........................................ 40 
7.2.3. 
Timing .......................................................................................................... 41 
7.2.4. 
Severity Grading .......................................................................................... 41 
7.2.5. 
Relationship to Study Drug .......................................................................... 41 
7.3. 
Serious Adverse Events .......................................................................................... 42 
7.3.1. 
Serious Adverse Event Definition ................................................................ 42 
7.3.2. 
Reporting Serious Adverse Events to the Sponsor ....................................... 43 
7.3.3. 
Regulatory Aspects of SAE Reporting ......................................................... 43 
7.4. 
Pregnancy ............................................................................................................... 44 
7.5. 
Overdose ................................................................................................................ 44 
8. 
STUDY ACTIVITIES AND PROCEDURES ................................................................. 45 
8.1. 
Informed Consent ................................................................................................... 45 
8.2. 
Demographics, Medical History, RCC History ..................................................... 45 
8.3. 
Assess subject eligibility against inclusion/exclusion criteria ................................ 45 
8.4. 
Subject Medication and Symptom Log .................................................................. 46 
8.5. 
Adverse Event Assessments ................................................................................... 46 
8.6. 
Concomitant Medication and Therapy Assessments.............................................. 46 
8.6.1. 
Prohibited and Restricted Medications, and Washout .................................. 46 
8.7. 
Vital signs, pulse oximetry, weight, height and BMI ............................................. 48 
8.8. 
Chest Radiograph or Computed Tomography (CT) ............................................... 48 
8.9. 
Electrocardiogram (ECG)....................................................................................... 48 
8.10. Physical Examination ............................................................................................. 49 
8.11. Clinical Laboratory Tests ....................................................................................... 49 
8.12. Blood Sampling for Pharmacokinetics (PK) .......................................................... 49 
8.13. WOCBP Pregnancy test, and contraceptive counselling ........................................ 50 
8.14. Spirometry .............................................................................................................. 50 
8.15. 24-Hour Digital Cough Monitor ............................................................................ 51 
8.16. Patient Reported Outcome (PRO) Questionnaires ................................................. 51 
8.16.1. 
SOWS (Subjective Opiate Withdrawal Scale) ............................................. 52 
8.17. Clinical Global Impression of Severity and Change (CGI-S, CGI-C) ................... 52 

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8.18. Randomization....................................................................................................... 52 
8.19. Telephone Contacts ............................................................................................... 53 
8.20. Study Drug Dispensing and Compliance Management......................................... 53 
8.21. Tolerance and Titration Symptoms Management ................................................. 53 
8.22. Premature Discontinuation / Removal of Subjects from the Trial or Study 
Drug ....................................................................................................................... 55 
8.23. Appropriateness of Measurements ........................................................................ 55 
9. 
PLANNED STATISTICAL METHODS ........................................................................ 57 
9.1. 
General Considerations ......................................................................................... 57 
9.2. 
Incurrent Event Handling ...................................................................................... 57 
9.3. 
Missing Data and Dropouts ................................................................................... 57 
9.4. 
Determination of Sample Size............................................................................... 57 
9.5. 
Analysis Population ............................................................................................... 57 
9.6. 
Demographics and Baseline Characteristics.......................................................... 58 
9.7. 
Subject Disposition ............................................................................................... 58 
9.8. 
Concomitant Medication ....................................................................................... 58 
9.9. 
Efficacy Analyses .................................................................................................. 58 
9.9.1. 
Primary Efficacy Endpoint .......................................................................... 58 
9.9.2. 
Secondary Efficacy Endpoint(s) .................................................................. 59 
9.10. Safety Analyses ..................................................................................................... 59 
9.10.1. 
Adverse Events ............................................................................................ 60 
9.10.2. 
Clinical Laboratory Assessments ................................................................ 60 
9.10.3. 
Vital Signs ................................................................................................... 60 
9.10.4. 
Physical Examinations ................................................................................ 60 
9.10.5. 
Subjective Opiate Withdrawal Scale (SOWS) ............................................ 60 
9.10.6. 
Electrocardiograms ...................................................................................... 61 
9.11. Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis ........................... 61 
9.12. Other Assessments or Analyses ............................................................................ 61 
9.13. Interim Analysis .................................................................................................... 61 
10. ADMINISTRATIVE CONSIDERATIONS ................................................................... 62 
10.1. Quality Control and Assurance ............................................................................. 62 
10.2. Investigators and Study Administrative Structure ................................................. 62 
10.3. Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................ 62 
10.4. Ethical Conduct of the Study ................................................................................ 62 
10.5. Patient Information and Consent ........................................................................... 63 
10.6. Patient Confidentiality and Data Protection .......................................................... 63 
10.7. Study Monitoring .................................................................................................. 63 
10.8. Case Report Forms and Study Records ................................................................. 64 

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10.9. Protocol Violations/Deviations ............................................................................... 64 
10.10. Access to Source Documentation ........................................................................... 65 
10.11. Data Generation and Analysis ................................................................................ 65 
10.12. Retention of Data ................................................................................................... 66 
10.13. Financial Disclosure ............................................................................................... 66 
10.14. Publication and Disclosure Policy .......................................................................... 66 
11. REFERENCE LIST ......................................................................................................... 67 
APPENDICES .......................................................................................................................... 71 
 
LIST OF IN-TEXT TABLES 
Table 1 
Schedule of Events ...................................................................................... 14 
Table 2 
Schedule of Events (SoE) for PROs ............................................................ 16 
Table 3. 
Dosing Scheme ............................................................................................ 36 
Table 4 
Adverse Events Requiring Additional Narratives ....................................... 40 
Table 5 
CTCAE Severity Grading ............................................................................ 41 
Table 6 
Adverse Event Relationship to Study Drug ................................................. 42 
Table 7 
Prohibited and Restricted Medications, and Washout Period ...................... 47 
Table 8 
List of Laboratory Tests ............................................................................... 49 
Table 9 
Patient Reported Outcome (PRO) Tools ...................................................... 52 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Schematic .......................................................................................... 31 
LIST OF APPENDICES 
Appendix 1 
Sponsor Signature .............................................................................. 72 
Appendix 2 
Investigator’s Signature ...................................................................... 73 

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LIST OF ABBREVIATIONS 
ACE 
Angiotensin converting enzyme 
AE 
adverse event 
AR 
Autoregressive 
ATC 
Anatomical and Therapeutic Class 
ATS/ERS 
American Thoracic Society / European Respiratory Society 
BID 
twice daily 
BMI 
body mass index 
bpm 
beats per minute 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CPAP 
Continuous Positive Airway Pressure 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CS-VAS 
Cough Severity Visual Analog Scale 
CT 
Computed Tomography 
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trials Facilitation and Coordination Group 
CV 
coefficient of variation 
DCF 
Data Clarification Form 
dl 
deciliter 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ESR 
Expedited Safety Report 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 second 
FU 
Follow-up 
FVC 
Forced Vital Capacity 
g 
gram 
GCP 
Good Clinical Practice 
g/dl 
grams per deciliter 
HCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HT 
Hydroxytryptamine 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational Product (Study Drug) 

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IPF 
Idiopathic Pulmonary Fibrosis 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology for IP management 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LCQ© 
Leicester Cough Questionnaire 
m2 
square meter 
MAOIs 
monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
mITT 
modified intent-to-treat 
ml 
milliliter 
mm 
millimeter 
ms 
millisecond 
NA 
Not Applicable 
NAL ER 
Nalbuphine Extended-Release tablets 
OTC 
over the counter 
PBO 
Placebo 
PD 
pharmacodynamics 
PGI-C 
Patient Global Impression of Change 
PID 
Patient Identification Number 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetics 
PP 
Per Protocol 
PR 
interval that extends from P wave onset until start of QRS complex 
PR-CF 
Patient Reported Cough Frequency 
PRO 
Patient Reported Outcome 
QD 
once a day 
QoL 
Quality of Life 
QRS 
complex representing depolarization of ventricles 
QT 
interval between the start of the Q wave and the end of the T wave 
QTcF 
the corrected QT interval by Fridericia 
RBBB 
Right Bundle Branch Block 
RCC 
Refractory Chronic Cough 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SNRI 
serotonin and norepinephrine reuptake inhibitor 
SoE 
Schedule of Events 
SOP 
standard operating procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
SSRI 
serotonin reuptake inhibitor 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCA 
tricyclic antidepressant 
TdP 
Torsade de Pointes 

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TEAE 
Treatment Emergent Adverse Event 
TP1 
Treatment Period 1 
TP2 
Treatment Period 2 
UK 
United Kingdom 
umol/l 
micromoles per liter 
US 
United States 
USUBJID 
Unique Subject ID 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 

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2. INTRODUCTION 
2.1. 
Background Information on Refractory Chronic Cough 
The European Respiratory Society Task Force Report guidelines on the diagnosis and 
treatment of chronic cough (Morice et al 2020) used the term Refractory Chronic Cough to 
indicate that the cough is refractory to conventional treatment of cough-associated conditions 
or traits. The terminology of Refractory Chronic Cough (RCC) is a cough that persists despite 
optimal treatment for the presumed associated clinical condition or in cases where no cough-
associated condition is found despite adequate investigation, according to published best 
practice guidelines in an adherent patient (McGarvery et al, 2019). 
Chronic cough accounts for 10-38% of patients attending specialist cough clinics in the United 
Kingdom (UK) and the United States (US), and most commonly occurs in the fifth through 
seventh decade of life (Gibson and Vertigan, 2015). Females compose 66% of the patient 
population and the median duration of chronic cough was 6.5 years. Referrals of patients with 
persistently troublesome chronic cough have been shown to account for up to 38% of a US 
pulmonologist's outpatient practice (French et al 1998). 
It is reported that 50% of women in cough clinic report incontinence related to coughing and 
80% of patients stated interference with lifestyle and leisure was the commonest complaint in 
relation to coughing (Young and Smith, 2010). 
2.2. 
Background Information on Nalbuphine 
The Sponsor is developing an oral pharmaceutical nalbuphine extended-release (ER) tablet 
product. 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 US as 
Nubain®, on which the presently sold generic injectable formulations are based. Approved 
indications in the US include the management of pain severe enough to require an opioid 
analgesic and for which alternative treatments are inadequate, as a supplement to balanced 
anesthesia, pre-operative and post-operative analgesia, and obstetrical analgesia during labor 
and delivery (Nubain US Prescribing Information, 2023). Nalbuphine remains an unscheduled 
drug in the US (US Drug Enforcement Agency, Jan 2023; US Dept of Justice List of Scheduling 
for Controlled Substances, 2023). 
Commercial availability in the European Union (EU) of the parenteral formulation of 
nalbuphine dates to 1986 (Medicines Evaluation Board in the Netherlands, 2010) when the 
originator product, Nubain 10 mg/ml solution for injection, was registered in the Netherlands 
by Bristol-Myers Squibb. In 2020, an application from Altamedics GmbH for Nubain 10 
mg/ml Injektionslösung was approved in Germany, Austria, and the Netherlands for the for 
short-term relief of moderate to severe pain and for pre- and post-operative analgesia (Nubain 
Public Assessment Report, 2020). Nalbuphine is not listed in the List of Narcotic Drugs Under 
International Control in accordance with the United Nations Single Convention on Narcotic 
Drugs of 1961 as amended by the 1972 Protocol (List of Psychotropic Substances Under 
International Control, 2022). 
Nalbuphine is a member of the opioid agonist-antagonist class of drugs with agonistic action 
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(Yaksh and Wallace 2011). In addition to a prior phase 2 study in IPF related cough (Clinical 
Study TR12), the clinical development program of NAL ER tablets has included 
investigational studies for the treatment of prurigo nodularis related pruritus, uremic pruritus 
in hemodialysis patients as well as safety and efficacy analgesic studies. Additional 
information can be found in the Investigator’s Brochure (IB). 
2.3. 
Rationale for Investigation of Nalbuphine in Refractory Chronic Cough 
There is medical literature reporting that the opioid drug class may be effective antitussives. 
In chronic cough subjects, morphine may be effective treatment (Morice et al, 2007; Morice et 
al, 2020). Nalbuphine has been shown in human studies to have preventative antitussive effect 
on acute cough during anesthesia induction (Wang et al, 2020). Other mixed agonist-
antagonist pharmacologic class of drugs have also been shown to be effective in managing the 
adverse effect of acute cough during anesthesia induction (Ai et al, 2010; Cheng et al, 2016). 
The mixed agonist-antagonist butorphanol has been approved as an animal anti-tussive 
(Torbutrol® US Package Insert, 2013). 
Integration of cough reflex behavior that occurs at brainstem level (Canning et al, 2014) may 
be modulated by nalbuphine pharmacologic action given the high density of opiate receptors 
(Volkow and McLellan, 2016) Opiate receptors in the cerebrum may also potentially be 
modulated by nalbuphine pharmacologic action where cortical mediated control of cough is an 
important regulator of the cough reflex set point (Mazzone et al, 2009). 
Since  opiate  receptors  are  also  located  at  the  peripheral  nerve  level 
(Volkow and McLellan, 2016), this is an additional potential site of pharmacologic action of 
nalbuphine that may be important given the “cough hypersensitivity syndrome” hypothesis 
that inflammation-induced effects (“neuro-inflammation”) in the neural pathways between the 
airway tissue and the brain may lead to refractory cough (Morice et al, 2014; McGarvey and 
Gibson, 2019). 
2.4. 
Rationale for Study Design and Control Group 
The purpose of the NAL04-201 study is to evaluate the safety and efficacy of NAL ER titrated 
to 108 mg BID compared to placebo (PBO) in RCC patients. 
The primary study endpoint, change in 24-hour cough frequency (coughs per hour), will be 
analyzed by use of an objective digital recording device, as consistent with the 
recommendations of Boulet et al who summarized the CHEST Expert Panel recommendations 
regarding tools to be used in clinical trials assessing cough (Boulet et al, 2015). The Panel 
recommended that acoustic cough counting to assess cough frequency should be done through 
objective means. Secondary endpoints include PRO measures that have been studied in RCC 
programs. 
The TR12 study in chronic cough in IPF successfully utilized the same study design planned 
for the NAL04-201 study. TR12 was a randomized, double-blind, placebo (controlled, 
crossover trial with two 22-day treatment periods (1: NAL ER-PBO; 2: PBO-NAL ER) 
separated by a 2-week washout using an objective digital monitor (VitaloJAK®). Subjects 
treated with doses escalating to 162mg BID of NAL ER showed a 76.1% improvement (95% 
CI, −83.1 to −69.1) in the geometric mean percent change in objective cough frequency 
compared with 25.3% (95% CI, −43.9 to −6.7) in placebo-treated subjects, with a 50.8% 
placebo-adjusted change (P<0.0001). 

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The purpose of this present study is to evaluate the safety and efficacy of NAL ER titrated to 
108 mg BID compared to placebo in RCC patients. 
Centrally active drugs are typically titrated in order to minimize the incidence and severity of 
AEs that can occur with drug initiation; thus, NAL ER is titrated to the target dose of the 
respective randomized study arm (see Table 3 Dosing Scheme). The AEs most commonly 
associated with titration involve the central nervous system (CNS) (nausea, headache and 
dizziness)  and  gastrointestinal  (nausea  and  vomiting)  organ  systems  (see 
Section 8.21 Tolerance and Titration Symptoms Management). A similar titration rate of NAL 
ER has been safely used in the IPF TR12 study and in other study populations (see IB for 
details) and the titration rate is consistent with opioid class guidelines such as the “three-day 
tolerance check” (National Opioid Use Guideline Group Canada, 2010) and “five ½ life” rule 
(CDC Guideline for Prescribing Opioids for Chronic Pain, 2016). In the TR12 trial subjects 
were escalated from 27 mg QD to 54 mg, to 108 mg and then 162 mg BID dose levels on Days 
5, 9 and 16. In the present study, subjects will be escalated from 27 mg QD to 54 mg BID and 
then to 108 mg BID on Days 7 and 14. 
The study staff, subjects, and Sponsor/clinical research organization (CRO) clinical staff will 
all be blinded to treatment assignment/sequence to avoid potential bias. This study will be 
conducted in compliance with the protocol and with the International Conference on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP). 
The use of placebo as a comparator is justified for this study due to: 
• The study assessing NAL ER in addition to treatments for underlying conditions 
(participants should continue their therapies for underlying etiologies) 
• The negative consequences of not receiving treatment are low (not a life-threatening 
disease) 
• Need to maintain the study blinding, allowing for an unbiased assessment of efficacy 
and safety. 
2.5. 
Risk/Benefit and Ethical Assessment 
Nalbuphine is currently in medical use as a parenteral formulation (Nalpain UK package insert, 
2011; Nubain US Prescribing Informationt, 2023) indicated for analgesia management as well 
as in the US as a supplement to anesthesia. The highest dose proposed in the current clinical 
study is 108 mg BID (216 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. 
Opiate drug class-related concerns such as the potential for physical dependence, linked to 
long-term use of opiates, is acknowledged. A requirement for completion of a 2-week safety 
observation period with daily Subjective Opiate Withdrawal Scale (SOWS) reporting has been 
incorporated into the study. 
The TR12 study in patients with IPF-associated chronic cough demonstrated that subjects 
treated with doses escalating to 162 mg BID of NAL ER showed a 76.1% improvement (95% 
CI, −83.1 to −69.1) in the geometric mean percent change in objective cough frequency 
compared with 25.3% (95% CI, −43.9 to −6.7) in placebo-treated subjects, with a 50.8% 

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placebo-adjusted change (P<0.0001). In TR12, cough PRO measurements, including daily 
EXACT2 Cough Frequency Scores and the CS-NRS measure of cough severity, revealed large 
cough effect size reductions at end of treatment, with near maximal effects on cough PROs 
seen at Day 8/9 when subjects were taking the 54 mg BID dose of NAL ER. The 108 mg BID 
dose of NAL ER in TR12 produced similar effects on cough PROs to those of the 162 mg BID 
dose level, so the maximal dose in the current RIVER study is 108 mg BID. 
The prescribing information for parenterally administered nalbuphine states that the drug may 
produce the same degree of respiratory depression as an equianalgesic dose of morphine; it 
also states that the drug exhibits a ceiling effect such that increases in dose greater than 30 mg 
nalbuphine HCl salt (27 mg free base) do not produce further respiratory depression in the 
absence of other CNS active medications affecting respiration. (Nubain US Prescribing 
Information, 2023). Route of administration is also likely to affect the risk for respiratory 
depression. Based on the safety data obtained to date in the study populations investigated with 
oral NAL ER, no safety signals related to respiratory function impairment have been identified. 
This includes the TR12 study in idiopathic pulmonary fibrosis (IPF) patients studied with doses 
of up to 162 mg BID of NAL ER, compared to the maximal dose of 108 mg BID of NAL ER 
planned for this study. 
Because of the rare but potentially life-threatening condition of serotonin syndrome that can 
result from the concomitant administration of serotonergic drugs, subjects should be on a stable 
dose of any medications that may induce serotonin syndrome during the study. Subjects will 
be informed of the symptoms of serotonin syndrome of which to be aware. 
Because NAL ER is metabolized through the cytochrome (CYP) pathway, use of strong 
inhibitors or inducers of the P450 isozymes is prohibited unless subjects are on a stable dose 
before and during the course of the study. 
In summary, there is evidence for potential benefit of NAL ER treatment in RCC, including 
improvement in objective cough frequency and patient reported outcomes for patients with 
chronic cough, based on results of a recently completed Phase 2a study of NAL ER in IPF-
associated cough (TR12). The risk for subjects participating in this current study is judged to 
be low based on previous experience with oral administration of NAL ER, including the TR12 
study in IPF patients studied with doses of up to 162 mg BID of NAL ER. The current study 
in RCC patients will utilize a low initiation dose of 27 mg QD and a gradual dose titration 
schedule up to a maximal dose of 108 mg BID. Careful safety monitoring of subjects will be 
performed during the clinical study. Investigators will be educated regarding the symptoms of 
rare but significant AEs that are linked to the opiate class. 

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3. STUDY OBJECTIVES 
3.1. 
Primary Objective: 
 
Objective 
Endpoint 
Effect of treatment on 24-
hour cough frequency 
(coughs per hour) after 21 
days 
• Relative change from Baseline in 24-hour cough frequency 
(coughs per hour) as assessed by objective cough 
monitoring at Day 21 for NAL ER compared with placebo. 
3.2. 
Secondary Objectives: 
 
Objective 
Endpoint 
Safety and tolerability of 
NAL-ER for the treatment 
of Refractory Chronic 
Cough (RCC) 
• Adverse events, clinical laboratory assessments, vital signs, 
and physical examination summaries. 
• ECG summaries [ECGs will be analyzed in a separate 
report]. 
• Subjective Opiate Withdrawal Scale (SOWS) daily 
summaries for the 14 days following the last dose of 
investigational product. 
24-hour cough frequency 
(Coughs per hour) 
• Relative change from Baseline in 24-hour cough frequency 
(coughs per hour) at Days 7 and 14 for NAL ER compared 
with placebo. 
• Proportion of responders with ≥30%, ≥50% and ≥75% 
reduction in the 24-hour cough frequency at Days 7, 14, and 
21 for NAL ER compared with placebo. 
Awake cough frequency 
(Coughs per hour) 
• Relative change from Baseline in awake cough frequency 
(coughs per hour) at Days 7, 14, and 21 for NAL ER 
compared with placebo. 
Sleep cough frequency 
(Coughs per hour) 
• Relative change from Baseline in sleep cough frequency 
(coughs per hour) at Days 7, 14, and 21 for NAL ER 
compared with placebo. 
CS-VAS (Cough Severity 
Visual Analogue Scale) 
• Change from Baseline in the Cough Severity Visual 
Analogue Scale at Days 7, 14, and 21 for NAL ER 
compared with placebo. 
LCQ© (Leicester Cough 
Questionnaire) 
• Change from Baseline in the LCQ total score at Day 21 for 
NAL ER compared with placebo. 
Patient-Reported Cough 
Frequency (PR-CF) 
• Change from Baseline in the PR-CF at Days 7, 14, and 21, 
for NAL ER compared with placebo. 
• Proportion of PR-CF responders, with response defined as at 
least a one category improvement at Days 7, 14, and 21 for 
NAL ER compared with placebo. 

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PGI-S, PGI-C, Cough 
(Patient Global Impression 
of Severity and Change for 
Cough) 
• Change from Baseline in the PGI-S Cough at Days 7, 14, 
and 21 for NAL ER compared with placebo. 
• PGI-C Cough score at Days 7, 14, and 21 for NAL ER compared 
with placebo. 
CGI-S, CGI-C, Cough 
(Clinical Global Impression 
of Severity and Change for 
Cough) 
• Change from Baseline in the CGI-S Cough at Day 21 for 
NAL ER compared with placebo. 
• CGI-C Cough score at Day 21 for NAL ER compared with 
placebo. 
Pharmacokinetics: Nalbuphine (and/or metabolites) plasma concentration will be measured 
for each treatment group at all visits where subject is on treatment. A PK sample will be drawn 
and correlated with the time of IP intake as reported by the subject. 

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4. INVESTIGATIONAL PLAN 
4.1. 
Study Duration and Dates 
The planned study period is from 
• Estimated first subject randomized in Q3 2023, until 
• Estimated last subject completed in 2024. 
which includes an approximately 12-month recruitment period, and 3-month study period, 
including screening and safety follow-up (FU)/end of study (EOS). The overall end of study is 
defined as the last study visit for the last patient (LPLV). 
The duration of participation for each subject will be up to 15 weeks and includes the 
following: 
• Screening Period: Day -28 to Day -2. Screening should be completed within 14 days, 
with the possibility to extend to 28 days without re-screen for scheduling or logistical 
reasons. 
• Treatment Period 1: 21 Days (-2 days visit window at each visit) 
• Washout: 21 Days (+5 days) 
• Treatment Period 2: 21 Days (-2 days visit window at each visit) 
• Safety Follow-up: 14 (+3 days) days after the last study treatment administration. 
Actual overall study duration and/or recruitment period may vary. Following their participation 
in the study, subjects will return to the care of their usual physician for the continued 
management of their condition or, if needed, they will be referred to appropriate care. 
4.2. 
Overall Study Design and Plan 
A double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of 
cough in subjects with Refractory Chronic Cough. 
Based on the screening cough monitor results, the study will enroll subjects in a 1:1 ratio to 
subgroups of 10-19 coughs/hour and ≥20 coughs/hour. 
After meeting eligibility during the screening period, subjects will be randomly assigned (1:1) 
to one of the following sequences: 
• NAL ER in Treatment Period 1, followed by PBO in Treatment Period 2 
OR 
• PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2 
The 21-day treatment periods are separated by a 21-day washout period. NAL ER will be 
titrated according to the Table 3 Dosing Scheme. 
Study visits in each treatment period will be at Day -1 for Baseline cough assessments, and at 
Days 6, 13, and 20. Visits and Assessments are described in Figure 1 Study Schematic, and 
Section 1.2 Schedule of Events, Table 1 and Table 2. Subjects will have blood drawn for 
pharmacokinetic (PK) analysis of nalbuphine plasma concentration.  Subjects will also 

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complete questionnaires for efficacy evaluations and undergo safety evaluations including an 
electrocardiogram (ECG). 
At the Screening and Baseline visits and on Days 6, 13, and 20 during each treatment period, 
site staff will place an electronic cough monitor on the subject, which will be worn for a 24-
hour recording period to assess cough frequency. At the end of each recording session (Days 
7, 14, and 21), the monitor will be removed at home by the subject, and the subjects will 
complete Patient Reported Outcomes (PROs) questionnaires in the diary. The monitor will be 
returned to the clinical study center for processing. 
Subjects will be taken off study drug at the end of the Treatment Period 2 and followed off 
treatment for an additional 2 weeks. 
If permanent discontinuation of investigational product occurs, the discontinuation and safety 
follow-up/EOS visits should be performed. End of Study for any participant will occur when 
the safety follow-up visit is completed,14+3 days after last dose, or withdrawal of consent. 
4.2.1. Study Schematic 
Figure 1    Study Schematic 
 
 
 
 
 

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5. STUDY POPULATION SELECTION 
5.1. 
Study Population and Sites 
Approximately 60 subjects with diagnosed Refractory Chronic Cough will be randomized, 
across approximately 12-16 centers. 
Subjects will be enrolled in a 1:1 ratio to subgroups of 10-19 coughs/hour and ≥20 
coughs/hour. 
5.2. 
Inclusion Criteria 
Subjects eligible for randomization to receive investigational product must meet all the 
following criteria: 
1. Current diagnosis of refractory chronic cough (RCC), and history of cough for at least 
one year. 
Defined in the ERS Guidelines as chronic cough that is refractory to conventional treatment 
of cough-associated conditions or where no cough-associated conditions can be identified 
(Morice et al, 2020). 
2. Chest radiograph or computed tomography (CT) of the thorax performed within the 
last 24 months and after the onset of chronic cough or during the screening period not 
demonstrating any abnormality considered to be significantly contributing to the refractory 
chronic cough in the opinion of the Principal Investigator. 
3. Score of ≥40mm on the Cough Severity VAS at the Screening visit. 
4. 24-hour objective cough frequency ≥10 or ≥20 coughs/hour based on cough monitor 
recording performed during the Screening Period, with results reviewed prior to baseline 
visit. Study will enroll subjects in a 1:1 ratio to subgroups of 10-19 coughs/hour and ≥20 
coughs/hour. 
5. FEV1 / FVC ratio ≥ 60% as determined by spirometry adhering to ATS/ERS guidelines. 
(Graham et al, 2019). 
6. Males or females ages 18 years and older at the time of consent. 
7. Willing and able to provide written informed consent, comply with study requirements and 
restrictions, and agree to the confidential use and storage of all data and use of all 
anonymized data for publication including scientific publication. 
5.3. 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for participation in the study: 
1. Clinical diagnosis of sleep apnea and/or use of CPAP. 
2. Upper or lower respiratory tract infection or change in pulmonary status in the last 6 
weeks prior to the baseline visit. 
3. History of bronchiectasis, chronic obstructive pulmonary disease (COPD) or 
idiopathic pulmonary fibrosis (IPF) or other significant respiratory disorder that might 
effect cough. 
4. History of uncontrolled asthma. 

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5. Current smokers/vapers, individuals who have given up smoking ≤12 months, individuals 
using nicotine patches, gum, or any other nicotine supplements, or individuals with a 
smoking history of 20 pack-years or more. 
6. Speech therapy/physiotherapy for RCC is acceptable if the subject has started the 
therapy at least 4 weeks prior to the Baseline visit and continues the therapy through the 
Treatment Periods. It may not be started within 4 weeks of starting the study or for the 
duration of the study. 
7. Cardiac Safety: Mean QTcF value of 3 centrally read screening Electrocardiograms 
(ECG) calculated as 
a) ≥470ms if QRS <120ms or 
b) ≥500ms in the presence of either a Right Bundle Branch Block (RBBB) or QRS≥120ms 
8. Heart Rate <50 bpm or >100 bpm, as determined by vital signs pulse obtained over 30-
60 seconds 
a) Subjects with a resting heart rate of <50 bpm will have it repeated once after 5 minutes 
in the supine position, and if it remains <50 bpm during the repeat, they will be 
considered a screen failure. 
b) Subjects with a rate >100 bpm should be considered a screen failure. Rescreening may 
be possible with the approval of the medical monitor, after medical or alternative 
management of the atrial fibrillation. 
9. Kidney Function: Estimated glomerular filtration rate ≤ 44 mL/min/1.73 m2 at Screening. 
10. Liver Function: Total Bilirubin >3mg/dl [>50umol/L] and Serum Albumin <2.8g/dl 
11. History of major psychiatric disorder, which in the opinion of the Investigator, could 
interfere with the assessment of anti-cough efficacy and/or safety events during the study 
or with the ability of the subject to cooperate with study requirements. 
12. History of substance abuse including excessive alcohol consumption, that in the opinion 
of the Investigator, may interfere with the conduct of the study. 
Alcohol consumption should be limited for the duration of study treatment. 
13. Significant medical condition or other factors as assessed by the investigator that may 
interfere with the subject’s ability to successfully complete the study. 
14. Pregnant or lactating female subject. Women of childbearing potential (WOCBP) must 
use an acceptable method of birth control and have a negative pregnancy test at the 
screening and baseline visits. WOCBP and acceptable methods of birth control are defined 
in the protocol, 
Section 8.13 WOCBP Pregnancy test, and contraceptive counselling. 
15. Known intolerance (gastrointestinal, central nervous system symptoms), hypersensitivity, 
drug allergy following the use of an opioid drug. 
16. Known hypersensitivity to nalbuphine or to NAL ER excipients. 
17. Previous enrollment in a NAL ER clinical study. 
18. Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a 
concurrent clinical trial. Observational or long-term safety follow-up studies (e.g., in a 
vaccine study) may be allowed upon medical monitor approval. 

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Medication-related Exclusions: 
(Refer to protocol Section 8.6.1 Prohibited and Restricted Medications, and Washout): 
19. Use of opiates is prohibited within 14 days prior to the baseline visit. Includes opiate-
containing anti-cough agents, and naltrexone. Subjects are prohibited from using opioids 
for the duration of the study. 
20. Use of benzodiazepines are prohibited within 14 days prior to the baseline visit and for 
the duration of the study. 
21. Monoamine oxidase inhibitors (MAOIs) including methylene blue (methylthioninium 
chloride) and the antibiotic linezolid are prohibited within 14 days prior to the baseline 
visit and for the duration of the study. 
22. Exposure to any investigational medication, including placebo, is prohibited within 4 
weeks prior to the baseline visit and for the duration of the study. 
23. Use of pregabalin, gabapentin, baclofen, tricyclics, or thalidomide given for the 
treatment of cough is prohibited within 14 days of the Baseline visit, and for the duration 
of the study. 
Pregabalin, gabapentin, baclofen, tricyclics, or thalidomide required for other indications, 
is permitted if on a stable dose for at least 4 weeks, and still experiencing significant cough, 
and expected to remain on that dose for the duration of the study. 
24. Use of ACE inhibitors is prohibited within 12 weeks prior to the baseline visit, and for 
the duration of the study (due to potential for causing cough). 
25. Other medications prescribed as cough suppressants (such as dextromethorphan or 
benzonotate) are prohibited unless on a stable dose 14-days prior to the baseline visit and 
are expected to remain on that dose for the duration of the study. 
26. Medications prescribed for asthma, rhinitis/upper airway cough syndrome, or 
gastroesophageal reflux disease are prohibited unless on a stable dose for 14-days prior 
to the baseline visit and are expected to remain at that dose for the duration of the study. 
27. Use of medications that affect serotonergic neurotransmission and that when used 
concomitantly with opioids can cause serotonin syndrome are prohibited unless on a stable 
dose for 14-days prior to the baseline visit and are expected to remain on that dose for the 
duration of the study. 
28. Strong inhibitors/inducers of the P450 Isozymes are prohibited unless on a stable dose 
for 14-days prior to baseline visit and are expected to remain on that dose for the duration 
of the study. 
29. Use of a medication having a “known risk” of Torsade de Pointes (TdP) (categorized as 
“KR” on the Credible Meds® website) is prohibited at entry or during the study. 
Medications associated with a potential risk of QT prolongation, but not clearly 
associated with TdP, 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 baseline. 
• Medication dose will not be increased after screening, or during the study, and it is 
anticipated that the subject will receive the medication for the entirety of the study. 

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6. STUDY TREATMENT 
6.1. 
Description of Treatment(s) 
6.1.1. Study Drug 
The investigational product (IP) in this trial is nalbuphine ER tablets (NAL ER). The NAL ER 
tablets are round, white to off-white, film-coated tablets containing either 27 or 54 mg of 
nalbuphine (equivalent to 30 or 60 mg nalbuphine HCl); the 27 or 54 mg NAL ER round tablets 
are identical in appearance. The NAL ER tablets will be provided by the Sponsor. 
6.1.2. Placebo 
The matching placebo tablet supplied is identical in appearance to the 27 and 54 mg tablets 
respectively and will be packaged identically to the IP. 
6.2. 
Treatments Administered 
Administration of the investigational product will be according to the dosing scheme in 
Table 3 Dosing Scheme. Dosing will consist of 2 tablets for the AM dose and 2 tablets for the 
PM dose. 
For subjects assigned to one of the NAL ER arms, the dose will be titrated from a starting dose 
of 27 mg QD to 108 mg BID over the treatment period. 

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6.2.1. Dosing Scheme 
Table 3. 
Dosing Scheme 
Grey shading indicates cough monitor application and recording period. 
VISIT 
Study Day 
(TP1 or TP2) 
NAL ER 
Dose (mg) 
PLACEBO 
(PBO) 
AM 
PM 
AM 
PM 
Baseline 
-1 
— 
— 
— 
— 
1 
— 
27 
— 
PBO 
2 
— 
27 
— 
PBO 
3 
27 
27 
PBO 
PBO 
4 
27 
27 
PBO 
PBO 
5 
27 
27 
PBO 
PBO 
Day 6 
6 
27 
27 
PBO 
PBO 
7 
27 
54 
PBO 
PBO 
8 
54 
54 
PBO 
PBO 
9 
54 
54 
PBO 
PBO 
10 
54 
54 
PBO 
PBO 
11 
54 
54 
PBO 
PBO 
12 
54 
54 
PBO 
PBO 
Day 13 
13 
54 
54 
PBO 
PBO 
14 
54 
108 
PBO 
PBO 
15 
108 
108 
PBO 
PBO 
16 
108 
108 
PBO 
PBO 
17 
108 
108 
PBO 
PBO 
18 
108 
108 
PBO 
PBO 
19 
108 
108 
PBO 
PBO 
Day 20 
20 
108 
108 
PBO 
PBO 
21 
108 
— 
PBO 
— 
6.3. 
Dispensing and Intake Instructions 
The blinded IP kit number will be dispensed using the Interactive Response Technology (IRT) 
system, and the corresponding kit will be dispensed to the subject. The Study staff will review 
the dosing instructions with the subject, including counselling on the options for management 
of possible symptoms during titration. 
Investigational product is taken orally and must be swallowed whole without crushing or 
chewing. Subjects will be instructed to take the investigational product tablets twice per day 
(BID) with a glass of water, and preferably with food. 
If a dose is missed and there are less than 8 hours until the next planned dose, the subject should 
skip the dose. 
Subjects will be informed 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, and to limit alcohol consumption for the duration of study treatment. 

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6.4. 
Subject Compliance and Accountability 
Subject Compliance and Accountability are assessed through the drug accountability records. 
Subjects will be instructed to retain the blister cards and return them at the next visit, even if 
they are partially or completely empty. 
Accountability will be determined through an accurate and current documentation of the IP 
dispensed and returned for each subject, recorded on the appropriate investigational product 
accountability forms and in the IRT system by a member of the study site staff. 
Compliance is defined as the amount of investigational product that should have been taken 
by a subject based on the dosing instructions provided during a period, compared to what 
they actually took, based on the number of tablets returned. This is typically expressed as 
percent (%) compliance. 
Compliance will be monitored: 
• after each investigational product return, based on the information on the 
investigational product accountability forms, 
• between visits, via subject contact - if the subject is not able to take their medication 
as scheduled at any time, they should contact the site, and site should support them 
in maintaining full compliance where possible. 
• Plasma samples taken for PK will be blinded during the study, and nalbuphine 
plasma concentrations will verify compliance for the purposes of analysis. 
Dosing and/or compliance discrepancies (above or below 100%), will be noted in the eCRF 
for the applicable subject visit. 
For compliance over 100% and the definition of overdose, refer to Section 7.5 Overdose. 
6.5. 
Multiple Missed Doses 
If the subject misses 3 or more consecutive doses (equivalent to approximately 1.5 days), 
contact the study Medical Monitor to discuss the situation and, if needed, dosing instructions 
(See  also  Section 8.21 Tolerance  and  Titration  Symptoms  Management  and 
Section 8.22 Premature Discontinuation / Removal of Subjects from the Trial or Study Drug). 
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, 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. 
6.6. 
Randomization and Blinding 
Randomization will be performed, and blinding maintained, via IRT. Upon confirmation of 
eligibility by the study site and completion of all scheduled procedures at the 
Baseline (Day -1) visit, subjects will be randomized in a 1:1 ratio to either the NAL ER-PBO 
or PBO-NAL ER arm. The study will enroll subjects in an approximate 1:1 ratio based on 
objective cough/hour to a 10-19 cough/hour subgroup and a ≥20 coughs/hour subgroup. As 
recruitment is predicted to be quicker for the 10-19 cough/hour subgroup when the 10-19 
cough/hour subgroup has reached its target of approximately 30 subjects randomized, 
recruitment will be stopped for that subgroup. 

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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 IRT. 
Reasons for unblinding, date, and identity of the person responsible for breaking the blind will 
be documented in the eCRF. 
Randomization will be stratified by baseline 24-hour cough frequency (10-19 cough/hour vs 
>20 cough/hour) and sex. 
6.7. 
Investigational Product Supplies Management 
Please see the pharmacy manual for additional information on investigational product supplies, 
packaging, storage, dispensation, and accountability. 
6.7.1. Packaging and Labeling 
IP will be packaged in blister cards, which will be labeled with, at minimum: contents, storage 
conditions, expiration date, clinical trial statement, and the name of the sponsor (Trevi 
Therapeutics, Inc). 
6.7.2. IP Storage 
Store NAL ER tablets and placebo tablets below 25°C (77°F), do not refrigerate, and do not 
freeze. The investigational product should be stored away from any extreme conditions of 
temperature, light, or humidity as an additional precaution. 
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. 
6.7.3. Accountability 
The Investigator must maintain accurate records in the study documents and IRT system, of 
the receipt, dispensation and return of all investigational product shipped by the Sponsor or the 
Sponsor’s representative, including but not limited to date, lot number, expiration date, and 
amount. 

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7. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Subjects will be closely monitored for safety throughout the study. In addition to adverse 
events, vital signs including pulse oximetry, ECGs reviewed by the Investigator, physical 
examinations, and clinical laboratory testing will be conducted to monitor subject safety. To 
monitor for possible withdrawal symptoms, subjects will complete the SOWS daily for 14 days 
following each treatment period. Details of assessments are provided in Section 8 Study 
Activities and Procedures. 
7.1. 
Adverse Event Definition 
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical 
investigation subject reported on or after the first screening date. A Treatment Emergent 
Adverse Event (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 and which does not necessarily have a causal relationship with 
treatment. The Investigator is responsible for ensuring that any AEs observed by the 
investigator or reported by the subject are recorded in the subject’s medical record. 
The AE may be any of the following: 
• 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 
• 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 two 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 but rather 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. 
7.2. 
Reporting of Adverse Events 
All AEs occurring during the study will be collected on the AE eCRF. 
Clinically relevant findings on ECG, laboratory testing, or physical examination during 
Screening (i.e., after the signing of the informed consent form and prior to the first dose of IP) 
should be recorded on the Medical History eCRF unless considered to be acute or caused by a 
study procedure in which case they are to be recorded on the Adverse Event eCRF. 
All serious adverse events and non-serious adverse events other than those described above 
with an onset during Screening should be recorded on the Adverse Event eCRF. All Adverse 
Events with onset after exposure to any amount of study drug are to be recorded on the Adverse 
Event eCRF. 

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Starting from the point when the subject signs the Informed Consent Form (ICF), and 
continuing for the duration of the study, subjects must be instructed to record any new AEs on 
the study specific symptom log. Subjects should bring the log to every clinic visit, where it 
will be retrieved for review by study staff prior to re-dispensing it (or issuing a new log) to the 
subject. 
During visits, phone calls, or other study contacts, study staff will solicit information using 
open ended questions, and document volunteered information regarding adverse events. 
AEs 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 study. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate AE on the eCRF. 
Laboratory abnormalities will be recorded as adverse events 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 adverse event will indicate the 
underlying abnormality or diagnosis as opposed to the observed deviation in laboratory results 
if the diagnosis is known. 
7.2.1. Events Exempt from Adverse Event Reporting 
As cough is an endpoint in this study, it will NOT be reported as an adverse event. Refer to 
Section 8.15 24-Hour Digital Cough Monitor and Section 8.16 Patient Reported Outcome 
(PRO) Questionnaires for additional details regarding data collection for cough. 
7.2.2. Adverse Events Requiring Additional Narratives 
As part of the formal investigation of a drug that is classified as CNS active opioid, certain 
adverse events will be documented in more detail to support an eight-factor analysis. The 
following AE preferred terms will require an additional narrative in the eCRF: 
Table 4 
Adverse Events Requiring Additional Narratives 
Behavioral addiction 
Feeling drunk 
Dependence 
Hallucinations (any) 
Dissociation 
Intentional product misuse 
Drug abuser 
Overdose (see also Section 7.5 Overdose) 
Drug dependence 
Prescription form tampering 
Drug detoxification 
Product tampering 
Drug diversion 
Substance abuse 
Drug use disorder 
Substance dependence 
Drug withdrawal convulsions 
Substance use disorder 
Drug withdrawal syndrome 
Withdrawal syndrome 
Euphoric mood 

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7.2.3. Timing 
Adverse events experienced by a subject starting from signing of informed consent until the 
last safety follow-up/EOS, will be recorded in the Adverse Event or Medical History eCRF 
as appropriate. 
Any clinically significant abnormal findings identified during the screening period (e.g., 
laboratory, physical exam) will be documented in the medical history (see 
Section 8.2 Demographics, Medical History, RCC History). 
Any (S)AE still unresolved at the safety follow-up/EOS or premature discontinuation visit will 
be followed by the Investigator for at least 30 days from the last dose of investigational product. 
All unresolved AEs 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. 
7.2.4. Severity Grading 
All AEs will be reported and graded, if possible, using the current version of Common 
Terminology Criteria for Adverse Events (CTCAE). 
The AE terms that are not found in the most current version of CTCAE will be graded 
according to the general guideline in Table 5 CTCAE Severity Grading: 
Table 5 
CTCAE Severity Grading 
 
Grade 
Comment 
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 
Every effort will be made to obtain an adequate evaluation of the severity of an AE. An AE 
that is assessed as severe should not be confused with a serious adverse event (SAE). Severity 
is a category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. An event is described as ‘serious’ when it meets one of the pre-defined 
outcomes as described in Section 7.3.1 Serious Adverse Event Definition. 
7.2.5. Relationship to Study Drug 
The investigator will assess the relationship of any AE to the study drug (NAL ER or 
placebo) using the guidelines presented in Table 6 Adverse Event Relationship to Study Drug. 

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Table 6 
Adverse Event Relationship to Study Drug 
 
Relationship 
to Drug 
Comment 
Definitely 
related 
• 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 
• 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 
• 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 
• 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 
• Clearly not related to the investigational product and another cause of 
the event is most plausible 
• A clinically plausible temporal sequence is inconsistent with the onset 
of the event 
7.3. 
Serious Adverse Events 
7.3.1. Serious Adverse Event Definition 
A serious adverse event (SAE) is defined by regulation as any AE occurring at any dose that 
results in any of the following outcomes: 
• death, 
• life-threatening AE, 
• hospitalization or prolongation of existing hospitalization, 
• a persistent or significant disability/incapacity, 
• a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. These should also be considered to be SAEs. 

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A hospitalization is defined as an inpatient admission lasting 24 hours or more. Visits to urgent 
care centers and emergency departments that do not result in admission to a hospital lasting 
for at least 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. 
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. 
7.3.2. Reporting Serious Adverse Events to the Sponsor 
The study site will report any SAE to the Sponsor or their designee, without regard to causality, 
within 24 hours after becoming aware of its occurrence. 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, 
that AE should be reported to the Sponsor as a new SAE within 24 hours. 
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the study drugs. 
Information not available at the time of the initial report (e.g., an end date for the SAE, 
laboratory values received after the report, or hospital discharge summary) must be 
documented. All follow-up information must be reported as soon as the relevant info is 
available. 
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 and the EDC must be updated with the information on the paper report as soon as the 
EDC is available. 
Paper reports must be emailed to the following address within 24 hours: 
Follow-up information on SAEs must also be reported by the Investigator within the same time 
frames. 
7.3.3. Regulatory Aspects of SAE Reporting 
The Investigator will promptly report all SAEs to the Sponsor or their designee within the 
timeframe specified in Section 7.3.2 Reporting Serious Adverse Events to the Sponsor. Prompt 
notification of SAEs by the Investigator is essential so that the Sponsor can meet legal 
obligations and fulfill ethical responsibilities towards the safety of all subjects participating in 
their sponsored investigational trials. 
The Investigator will comply with the applicable local regulatory requirements related to 
reporting of SAEs to his or her Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). 
A given SAE may qualify for submission to applicable regulatory authorities (e.g., submission 
of SUSARs to EudraVigilance in the EU) as an Expedited Safety Report (ESR) if the SAE is 
both attributable to study drug and unexpected. In this case, all Investigators participating in 
a NAL ER study will receive a copy of the ESR. 

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Assessment for expectedness for SAEs will be determined by the Sponsor using reference 
safety information specified in the current IB or relevant local label, as applicable. 
The ESRs are prepared according to the Sponsor’s policy and are forwarded to the Investigator, 
as necessary. The purpose of the ESR is to fulfill specific regulatory and Good Clinical 
Practice (GCP) requirements regarding the product under investigation. When a study site 
receives from the Sponsor an Initial or Follow-Up ESR or other safety information (e.g., a 
revised Investigator’s Brochure), the Investigator is required to promptly notify his or her IRB 
or IEC. 
7.4. 
Pregnancy 
Female subjects who become pregnant should be immediately discontinued from study drug if 
applicable, and she should complete the discontinuation and safety follow-up visits, and be 
followed to determine the outcome of the pregnancy. Generally, follow-up will be completed 
no later than 6 to 8 weeks following the estimated delivery date. 
Pregnancy itself is not considered an adverse event or SAE, however pregnancy information 
on  female  subjects  will  be  collected  with  the  same  process  as  for  an  SAE 
(see Section 7.3 Serious Adverse Events). Any pregnancy complications or less than a healthy, 
normal outcome will be recorded as an adverse event or SAE. 
7.5. 
Overdose 
Overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labeling (as it applies to the daily dose of the subject in 
question). 
In cases of a discrepancy in drug accountability, overdose will be established only when it is 
clear that the subject has taken the excess dose(s). Overdose cannot be established when the 
subject cannot account for the discrepancy except in cases in which the Investigator has reason 
to suspect that the subject has taken the additional dose(s). 
Overdose is one of the AEs which require an additional narrative in the eCRF (see 
Section 7.2.2 Adverse Events Requiring Additional Narratives). 
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 the IB for additional information. 

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8. STUDY ACTIVITIES AND PROCEDURES 
The study activities are described in detail in Section 1.2 Schedule of Events, Table 1 and 
Table 2. This table is the definitive source of the schedule for visits and procedures 
throughout the study. 
8.1. 
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. The Investigator will not undertake any measures specifically required only for the 
clinical study until valid consent has been obtained. 
An Informed Consent Form (ICF) will be prepared that includes information about the study 
for the subject, and documentation of subject informed consent in writing. 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 will be in a language understandable to the subject 
and will specify who informed the potential subject. Where required by local law, the person 
who informs the potential subject must be a physician. 
The ICF will be given to the subject to read, and the study will be explained by a qualified 
member of the study staff. 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. 
The informed consent form will be performed on paper. A copy or second original of the 
signed ICF must be given to the subject to keep. One original signed ICF will be retained by 
the Investigator. 
8.2. 
Demographics, Medical History, RCC History 
The subject’s demographics and medical history will be documented, including age, sex, body 
weight, height and body mass index (BMI). Race and/or ethnicity will be collected where 
possible in accordance with local regulations. 
Clinically significant abnormal findings identified during the screening period for the first time 
but indicative of existing condition (e.g. laboratory, physical exam) will be documented in the 
medical history. 
RCC history will include history of smoking, speech therapy/physiotherapy for RCC, and other 
cough treatments. 
8.3. 
Assess subject eligibility against inclusion/exclusion criteria 
The investigator will assess the eligibility of the subject during the screening period and will 
confirm their eligibility prior to randomizing. At the point that the subject is found not eligible, 
further screening procedures are not required, and can be documented as not done. For unique 
circumstances that may justify rescreening, Investigators may contact the Medical Monitor to 
discuss and obtain approval for rescreening. 

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8.4. 
Subject Medication and Symptom Log 
Subject Medication and Symptom Logs will be provided to fill in at home by the subjects in 
between visits. 
• On the Subject Symptom Log any new and/or changed symptoms or side effects that 
bother the subject will be reported during the study. 
The symptom log will be reviewed by staff and applicable AEs reported and entered 
in eCRF. 
• On Subject Medication Log the addition of new, changes in the dose, or 
discontinuation of any non-study medications including oxygen therapy, speech 
therapy/physiotherapy for RCC, over-the-counter (OTC) medications, herbal 
medications, vitamins, and nutritional supplements will be reported. 
The medication log will be reviewed by staff and applicable information entered in 
eCRF. 
Subjects should be instructed to bring the logs to every visit and have them ready during the 
check-in phone calls. The logs should be reviewed and re-dispensed, if applicable. The logs 
are to be retrieved once full or at the end of the study, and filed in the subject file. 
8.5. 
Adverse Event Assessments 
Refer to Section 7 Adverse Events and Serious Adverse Events for full details on safety 
management and recording of adverse events. 
8.6. 
Concomitant Medication and Therapy Assessments 
Subjects may receive all clinically indicated medications and therapies during the study with 
the exceptions noted in Table 7. 
Any medication or therapy including oxygen therapy, speech therapy/physiotherapy for RCC, 
over-the-counter (OTC) medications, herbal medications, vitamins, and nutritional 
supplements taken and their reason for use will be recorded in the Concomitant Medication 
eCRF from 14 days prior to the first day of the screening until the last safety follow-up. 
Each subject will be instructed to report the use of all new and/or changed medications on the 
study specific medication log, and to bring the log to each study visit for review (See 
Section 8.4 Subject Medication and Symptom Log). Subjects will also be instructed about the 
importance of not taking any new medications during the study (including OTC medications) 
without consulting the Investigator. 
If the subject begins taking or requires changes to dosage regimen of a prohibited or restricted 
medication after screening, it will be determined if the subject may continue in the study upon 
consultation with the sponsor. Such medications or dosage changes are to be collected and 
recorded in the Concomitant Medication eCRF. 
Concomitant procedures and surgeries, will be collected in the Procedures and Surgeries eCRF. 
8.6.1. Prohibited and Restricted Medications, and Washout 
The medications described in Table 7 are prohibited or restricted during the study: If clinically 
necessary changes to medications that should be stable, or a prohibited medication is taken, 
the subject does not need to be automatically withdrawn from the study, unless there is a safety 

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issue (e.g. MAOIs, Benzodiazepines, and sedative hypnotics). The Investigator should 
continue the subject in the study and contact the medical monitor for instructions. 
For the purposes of this table, stable dose is defined as maintenance of a similar dose, 
frequency, and formulation for a particular drug for the specified period, including as needed 
dosing (PRN). 
Table 7 
Prohibited and Restricted Medications, and Washout Period 
 
Medication 
Restriction 
Washout Period 
Opioid Medications, including opiate 
containing cough suppressants 
Prohibited throughout the 
study 
14 days prior to the 
baseline visit 
Opioid antagonists 
(e.g., naloxone, naltrexone) 
Prohibited throughout the 
study unless required for 
urgent reversal of opioid 
adverse effects or clinical 
opioid overdose 
14 days prior to the 
baseline visit 
Benzodiazepines and sedative hypnotics 
Prohibited throughout the 
study 
14 days prior to the 
baseline visit 
Monoamine oxidase inhibitors (MAOIs) 
Prohibited throughout the 
study 
14 days prior to the 
baseline visit 
Any other investigational Product, 
including placebo 
Prohibited throughout the 
study 
4 weeks prior to the 
baseline visit 
Pregabalin, gabapentin, baclofen, 
tricyclics, or thalidomide 
Prohibited throughout the 
study for cough indications. 
OR Stable Dose throughout 
the study for other (non-
cough) indications 
For cough: 14 days 
prior to the baseline 
visit 
For non-cough Stable 
dose for at least 4 
weeks, and still meet 
cough inclusion criteria 
ACE inhibitors 
Prohibited throughout the 
study 
12 weeks prior to the 
baseline visit 
Use of a medication having a “known 
risk” of TdP (categorized as “KR” on the 
Credible Meds® website.) 
Prohibited throughout the 
study 
4 weeks prior to the 
baseline visit 
Medications associated with a potential 
risk of QT prolongation, but not clearly 
associated with TdP 
Stable dose throughout the 
study 
Stable dose from 4 
weeks prior to the 
baseline visit 
Medications prescribed as cough 
suppressants (non-opioid) e.g. 
dextromethorphan or benzonotate 
Stable Dose throughout the 
study 
Stable dose from 14 
days prior to the 
baseline visit 
Medications prescribed for asthma, 
rhinitis/upper airway cough syndrome, or 
gastroesophageal reflux 
Stable Dose throughout the 
study 
Stable dose from 14 
days prior to the 
baseline visit 
Serotonergic drugs 
• serotonin reuptake inhibitors (SSRIs), 
• serotonin and norepinephrine reuptake 
inhibitors (SNRIs), 
• tricyclic antidepressants (TCAs), triptans, 
• 5-HT3 receptor antagonists, 
• tetracyclic antidepressants, 
Stable Dose throughout the 
study, where possible 
Subjects will be informed 
of the risk of serotonin 
syndrome and the potential 
side effects they should be 
alert for, in the ICF 
Stable dose from 14 
days prior to the 
baseline visit 

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• 5-HT2 antagonists 
Strong inhibitors/inducers of the P450 
Isozymes as per the current FDA Drug 
Interactions list* 
Stable Dose throughout the 
study, where possible 
Stable dose from 14 
days prior to the 
baseline visit 
Alcohol 
Limit use during the study 
NA 
*www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers 
8.7. 
Vital signs, pulse oximetry, weight, height and BMI 
The following will be recorded, prior to blood sampling wherever possible. 
Vitals should be recorded with the subject in a sitting position for at least 5 minutes (except 
weight and height). 
• Blood pressure: measured with a standard mercury sphygmomanometer, or an 
automated oscillometric blood pressure monitor. 
• Pulse oximetry: Pulse Oximetry will be recorded with finger pulse oximeter device. 
• Heart rate 
• Respiratory rate 
• Body temperature 
• Weight 
• Height: recorded at screening only, to allow the calculation of BMI. 
8.8. 
Chest Radiograph or Computed Tomography (CT) 
Chest radiograph or computed tomography (CT) of the thorax will be assessed for inclusion. 
If the assessment has been performed within the last 24 months, a copy of the radiologist report 
is to be filed in the source as documentation of eligibility. 
If not assessed in the last 24 months, or a report is not able to be obtained for review, then the 
procedure will be performed at screening. 
8.9. 
Electrocardiogram (ECG) 
Triplicate standard ECGs will be obtained according to the SoE. ECGs are to be performed in 
triplicate after the subject has been in the supine position for at least 5 minutes with all 3 
tracings obtained within a period of 3-10 minutes. Whenever possible, ECG testing should be 
performed prior to the collection of vital signs and blood samples (clinical laboratory and PK 
samples). 
ECGs will be reviewed locally for safety by the Investigator and/or their designee. 
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) 
will be assessed by the ECG specialist vendor and a report sent to site within 72 hours of 
successful transmission. 
The screening ECG central read report will be used for the purpose of meeting the ECG study 
inclusion criteria. 

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8.10. Physical Examination 
A physical examination will be performed according to the SoE. This evaluation will include 
examination of the following body systems: general appearance, eyes, ears, nose, throat, head 
and neck, chest and lungs, cardiovascular, abdomen, musculoskeletal, lymphatic, 
dermatological, neurological, and extremities. 
8.11. Clinical Laboratory Tests 
Clinical laboratory tests will be performed by a qualified central laboratory. Whenever 
possible, blood samples are to be obtained after the collection of vital signs and ECG 
recordings at designated visits. Fasting is not required for routine lab tests. If medically 
indicated for follow-up of a certain condition or event, fasting labs can be performed. 
Blood and urine samples will be collected and processed as indicated in the central laboratory 
manual. All blood and urine laboratory tests, except for urine pregnancy test, will be performed 
at the central lab. Once processed, samples will be stored for an interim period at the site 
before shipping to the location where the analysis will be performed. Once at the analysis 
location, after analysis, samples can be stored for up to 1 month, before being destroyed. 
The clinical laboratory analytes described in Table 8 will be measured at the central laboratory 
using consistent methodology and procedures globally at the testing locations (ICON 
Laboratories in Ireland and US): 
Table 8 
List of Laboratory Tests 
 
Hematology: 
Hematocrit, hemoglobin, red blood cell count, white blood cell count, 
differentials (neutrophils, 
eosinophils, basophils, lymphocytes, and 
monocytes), platelet count, and reticulocytes 
Serum chemistry: 
Albumin, 
alkaline 
phosphatase 
and 
isoenzyme 
subtypes, 
alanine 
aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
calcium, chloride, carbon dioxide, creatinine, total bilirubin, gamma-
glutamyl transferase, glucose, lactic dehydrogenase, 
Magnesium, 
phosphorus,  potassium,  sodium,  total  cholesterol,  LDL  and  HDL 
cholesterol, total protein, and uric acid 
Urinalysis: 
Color, specific gravity, pH, glucose, ketones, protein, bilirubin, 
urobilinogen, blood. Microscopy will be performed on urine samples with 
abnormal urinalysis results. 
Coagulation: 
Prothrombin time, international normalized ratio, and activated partial 
thromboplastin time 
For WOCBP: 
Serum pregnancy test: betaHCG 
Urine pregnancy test: betaHCG (tested locally at site) 
 
8.12. Blood Sampling for Pharmacokinetics (PK) 
Blood samples will be collected to determine the plasma concentrations of nalbuphine and its 
metabolites, Samples will be collected at the site with safety labs, according to the SoE. Further 
details of PK sample collection and processing will be provided in the laboratory manual. Once 
processed, samples will be stored for an interim period at the site, before shipping to the central 

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lab for forwarding to the PK lab. Samples that are sent to the PK lab can be stored for up to 5 
years in case of the need for retesting for this study before being destroyed. 
Plasma samples will be analyzed for nalbuphine and its metabolites using a validated liquid 
chromatography mass spectrometry, and reporting of concentration results will be conducted 
according to the current Standard Operating Procedures (SOP) at Labcorp Laboratory, Inc., 
Madison, Wisconsin. A bioanalytical study report will be included with the final clinical study 
report. 
8.13. WOCBP Pregnancy test, and contraceptive counselling 
For the purpose of this study, all biological females are considered to be Women of 
childbearing potential (WOCBP) unless they are: 
• Postmenopausal; i.e., 1 year since last menses without an alternative medical or 
medication cause (e.g. hormonal treatments) 
• Permanently sterile; i.e., Hysterectomy, Bilateral Salpingectomy, Bilateral 
Oophorectomy. 
Women not of childbearing potential (non-WOCBP) may participate in the study without 
pregnancy tests and contraception requirements. 
WOCBP will have urine and serum pregnancy tests as specified in the SoE regardless of sexual 
activity status or method of contraception. The subject must have a confirmed negative urine 
test prior to randomization. 
WOCBP must use at least one acceptable method of birth control (if sexually active) until at 
least 14 days after the last dose of IP. Acceptable methods of birth control are defined in the 
recommendations of the Clinical Trials Facilitation and Coordination Group (CTFG 
Recommendations related to contraception and pregnancy testing in clinical trials, 2020), and 
for the purposes of this study are: 
• Hormonal birth control for at least 3 months prior to baseline – oral, intravaginal, 
transdermal, injectable, or implantable, 
• Intrauterine device (IUD) or or Intrauterine hormone-releasing system (IUS) in place 
for at least 1 month prior to baseline visit, 
• Bilateral tubal occlusion (e.g. via clipping, ligation, or hysteroscopic occlusion 
following confirmation of full occlusion), 
• Vasectomized partner, 
• Barrier method – male or female condom without spermicide; cap, diaphragm or 
sponge with spermicide, 
• Sexual abstinence - Subjects 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. 
There are no contraceptive requirements for males. 
8.14. Spirometry 
Spirometry will be performed locally at site with a locally provided device, to assess FEV1 
and FVC. Performance of spirometry should adhere to ATS/ERS guidelines (Graham et al, 
2019). 

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8.15. 24-Hour Digital Cough Monitor 
Measurement of cough frequency will be done using objective digital cough monitoring, the 
VitaloJAK®. The digital cough monitor consists of a portable sound recording device, which 
is worn in a pouch or pocket. The small microphone is clipped onto the subject’s collar or 
lapel, as close as possible to the anterior neck, and a sensor is attached to the chest. The device 
has the capability to make a continuous sound recording of up to 36 hours. The device will be 
programed to stop recording automatically after 24-hrs. The recording is encrypted on the 
device and transferred electronically to the UK via a secure web portal. The digital recording 
is then processed through accompanying computer software, which automatically registers 
sound patterns typical for cough, and provides a compressed file for further analysis. 
Software output provides the total number of cough events over the entire time period of 
recording and average hourly cough frequency and determines awake and sleep times based 
on the recording. The output is reviewed and analyzed by specialist analysts at the vendor. In 
case of poor quality, or other analyst findings, a full 24-hour manual count may be performed 
by specially trained individuals working under strict SOPs to ensure confidentiality of the data. 
Under the basis of legal obligation, sounds that may contain information that could indicate 
the possibility of direct harm to the participant or others may be disclosed to the principal 
investigator for further management under local disclosure laws. The site personnel, including 
the study doctor do not have access to listen to the records. 10% of readings will be reanalyzed 
for quality control, and variances are to be within defined limits. 
At the timepoints defined in the SoE, site staff will place the digital cough monitor on the 
subject prior to their departure from the clinic. The monitor will be worn until the following 
day to obtain at least a full 24-hour recording period of cough frequency. At the end of each 
recording session, the monitor will be removed at home by the subject. The monitor will be 
returned to the site for upload of data to the vendor portal. 
During the Screening Period, the cough monitor will be performed at least 10 days before the 
planned baseline, to allow for the analysis and results to be available prior to baseline, for 
inclusion in the study. 
On Day 1 of the study, the monitor will be removed prior to taking the first dose of 
investigational product. 
8.16. Patient Reported Outcome (PRO) Questionnaires 
Refer to Section 1.2 Schedule of Events, Table 2 for the overall frequency of PRO 
questionnaires. The questionnaires will be presented to the subject at the appropriate time as a 
task within the ediary provided for the purpose of the study. The details on the PROs selected 
are provided in Table 9. 

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Table 9 
Patient Reported Outcome (PRO) Tools 
 
PRO 
Abbreviation 
PRO Full Title 
Nr of 
Qs 
Recall Period 
CS-VAS 
Cough Severity Visual Analog Scale 
1 
24 hr 
LCQ© 
Leicester Cough Questionnaire 
19 
2 weeks 
PR-CF 
Patient Reported Cough Frequency 
1 
24 hr 
PGI-S Cough 
Patient Global Impression of Severity – Cough 
1 
7 Days 
PGI-C Cough 
Patient Global Impression of Change – Cough 
1 
7 Days 
SOWS 
Subjective Opiate Withdrawal Scale 
(See Section 8.16.1) 
16 
24 hr 
The recall period is the period the patient considers when responding to the questions in a PRO 
tool (e.g., over the last 24hr, over the last week, or since baseline). 
At Baseline, PROs will be completed prior to the intake of the first dose of IP. During the 
study, the Patient-Reported Cough Frequency (PR-CF) will be completed daily. Other PROs 
will be completed at post-baseline timepoints the day after the per protocol visit date, 
regardless of when the actual visit is performed. 
In case of premature discontinuation of IP, the IRT/e-diary system is to be updated 
immediately, to activate the discontinuation PROs (do not wait for the subject to come to site). 
At each study visit, the PRO compliance is to be reviewed via the e-diary portal and discussed 
with the subject. 
8.16.1. 
SOWS (Subjective Opiate Withdrawal Scale) 
The SOWS is a self-administered scale for grading opioid withdrawal symptoms and will be 
collected via the e-diary. Subjects will complete the SOWS daily for 14 days, starting on (or 
as close as possible to) the day of stopping investigational product, whether this is at the 
planned end of each treatment period, or due to IP discontinuation. 
Baseline SOWS will be completed to determine baseline status for relevant symptoms. 
Subject reported symptoms of withdrawal captured on the SOWS will not be reported as an 
AE unless reported verbally as part of the overall AE assessment at each visit. 
8.17. Clinical Global Impression of Severity and Change (CGI-S, CGI-C) 
The CGI-S and CGI-C will be performed by the investigator. 
The CGI-S is a one-item measure evaluating severity of the condition. 
The CGI-C is a one-item measure evaluating change from the initiation of treatment on a 
seven-point scale. After a clinical evaluation, the CGI-C form can be completed in less than a 
minute by an experienced rater. In practice, the CGI-C captures clinical impressions that 
transcend symptom checklists. The CGI-C can track clinical progress across time. 
8.18. 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 randomized in the IRT, and a blinded IP kit number will be allocated. 

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8.19. Telephone Contacts 
At timepoints specified in the SoE, the site staff will contact the subject to support the subject 
with the goal of subject comfort and reducing the discontinuation rate. Activities during the 
phone visit include: 
• Open ended questions about 
o changes to Concomitant Medication and Therapies 
(See Section 8.6 Concomitant Medication and Therapy Assessments) 
o changes to, or new Adverse Events 
(See Section 7 Adverse Events and Serious Adverse Events) 
• Open ended questions about wellbeing, and a discussion on managing any concerns 
around titration symptoms 
(See Section 8.21 Tolerance and Titration Symptoms Management) 
• Confirm IP intake and compliance 
(see Section 6.4 Subject Compliance and Accountability) 
• Discussion on e-diary and PRO completion compliance, after review of the portal, as 
needed (see Section 8.16 Patient Reported Outcome (PRO) Questionnaires. 
Notes on the phone call will be detailed in the source documents, and relevant information will 
be entered in the eCRF. 
8.20. Study Drug Dispensing and Compliance Management 
Refer to Section 6 Study Treatment, and the pharmacy manual for details on the investigational 
product and its management for the study. 
8.21. Tolerance and Titration Symptoms Management 
Systematic reviews of the literature found about 22% of patients with non-cancer pain 
management discontinue opioid therapy because of side effects (McNichol, 2007). A similar 
AE-related discontinuation rate for NAL ER was observed in clinical study TR12 in 
participants with IPF. The most frequent titration period related AEs reported with NAL ER 
are nausea, headache, and dizziness. 
NAL ER tablets will be initiated with a titration schedule. The first dose of any new titration 
step will occur with an evening dose. Subjects will be educated about possible CNS AEs that 
may occur. If the subject misses dose/s due to titration symptoms, the Medical Monitor should 
be consulted to ensure all protocol allowed opportunities are used to support the participant 
and potentially prevent premature treatment discontinuation of the subject (see Section 6.5 
Multiple Missed Doses for additional details). 
Summarized below are the recommended options for management of side effects in those 
subjects that experience them. The goal is to support the subject’s comfort and wellbeing 
through the titration period and reduce the discontinuation rate. 
1. Education and expectations – balanced information about titration side effects should 
be provided. Patient material is provided to support with educating about starting NAL 
ER. Key points for education are: 
• There is a chance that they will experience the side effects, but also a chance they 
may not have any side effects during titration. 
• If they do experience side effects, there may be ways to manage these. 

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• For many individuals, the side effects are transient in nature. 
2. Non-medical management of Titration Symptoms – A description of the non-medical 
options to manage side effects is provided in the patient material and includes 
recommendations like taking the medication together with a meal or snack, ginger, 
peppermint, and/or travel sickness acupressure bands. 
3. Medications to manage titration symptoms –The management options in common 
opioid-induced adverse effects have been reviewed (Swegle and Logemann, 2006). One 
source noted that nausea was the most common opioid-related AE that patients want to 
avoid (Rogers et al, 2013). The prophylactic treatment and management of established 
opioid-induced nausea and vomiting has also been reviewed. (Smith et al, 2012). 
If subjects experience nausea and/or dizziness, Investigators are allowed to prescribe 
medications to manage the symptoms, as indicated for a particular subject. Subjects 
should be educated to start on medication in consultation with the study staff if they 
experience side effects. Suggested medical strategies for managing titration symptoms 
are: 
Nausea: 
• Prokinetic antiemetic: e.g., metoclopramide/Reglan® (metoclopramide - 
consider limiting dose/ frequency due to potential side effects such as 
dystonic reactions; avoid in any subject on concomitant SSRIs as 
metoclopramide can potentiate serotonin syndrome in this setting) 
• Antihistamines 
Dizziness (and associated nausea if applicable): 
• Antihistamines 
• Antimuscarinics 
Medications that should NOT be used: serotonin 5-HT3 receptor antagonist 
(ondansetron/Zofran®) - association with serotonin syndrome. 
4. Step down to QD dosing: Up to and including Day 16 of either Treatment Period, if the 
subject is experiencing intolerable titration side effects, the subject may switch to QD 
dosing (i.e., skip the morning dose, and take the nighttime dose only) for 1-3 days. After 
the symptoms have subsided, or at the latest after 3 days, the subject is to restart BID 
dosing for at least 2 days. The subject can repeat the step down up to 3 times in total if 
symptoms return. After Day 16, the subject should have resumed consistent BID dosing, 
unless discussed with the Medical Monitor. 
If the above steps have been tried and intolerable symptoms continue, Investigators are 
strongly encouraged to contact the Medical Monitor for further discussion prior to prematurely 
discontinuing treatment (see Section 8.22 Premature Discontinuation / Removal of Subjects 
from the Trial or Study Drug for additional details). In all cases, the Medical Monitor must be 
notified within 24 hours of premature discontinuation of treatment. 

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8.22. Premature Discontinuation / Removal of Subjects from the Trial or Study 
Drug 
The investigator may withdraw a subject from the study for any of the following reasons: 
• A significant protocol violation occurs that may adversely affect the subject’s ability 
to remain safely in the study, 
• A serious or intolerable adverse event occurs, 
• A clinically significant change in a laboratory parameter occurs that may make it 
unsafe for the subject to continue in the study, 
• The sponsor or investigator terminates the study, or 
• The subject requests to be discontinued from the study. 
Subjects have the right to discontinue taking study drug or withdraw from the study at any time 
for any reason, without prejudice to their medical care. Investigators are strongly encouraged 
to contact the Medical Monitor to review the reasons for a subject’s discontinuation of study 
drug or withdrawal from the study as soon as this action is being considered by either the 
subject or the Investigator and before the subject stops taking study drug whenever possible, 
unless precluded by medical urgency. In all cases, the Medical Monitor must be notified within 
24 hours after study drug or study discontinuation has occurred. 
If a subject permanently discontinues the study drug for whatever reason prior to the end of 
the study, the following steps should be taken. 
• The IRT/e-diary system is to be updated immediately, to activate the relevant PROs, 
especially SOWS, which should be completed from the last day of IP intake. 
• Complete discontinuation procedures per the discontinuation visit schedule at the 
current visit OR subject to return to the site as soon as possible for the 
discontinuation visit, if discontinuation occurs between visits. 
• The subject will be asked to return to the site for the safety follow-up visit 2 weeks 
after the last dose of IP. 
• Ongoing SAEs will be followed until resolved, stable, or 30 days after last dose of 
IP, unless otherwise indicated. 
If the subject withdraws consent for further study related activities at any time, then no further 
assessments will be performed, and the last study procedure or visit under the subject’s consent 
will be considered End of Study. Every effort should be made to retrieve the investigational 
product and e-diary. 
If a subject develops an acute upper respiratory tract infection (URTI) during the 21-Day 
Washout Period, the investigator may treat the subject as appropriate to ensure all symptoms 
resolve prior to the subject entering into Treatment Period 2. If necessary, the investigator 
should consult with the Medical Monitor prior to extending the Washout Period. 
8.23. Appropriateness of Measurements 
The primary efficacy and safety assessments selected are standard for clinical research in this 
subject population. 
Boulet et al summarized the CHEST Expert Panel recommendations regarding tools to be used 
in clinical trials assessing cough (Boulet et al, 2015). The Panel recommended acoustic cough 
counting to assess cough frequency through objective means. The VitaloJAK has consistently 

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been used as the cough recorder for primary endpoint capture in trials of RCC (McGarvey et 
al, 2022; McGarvey et al, 2023; Dicpinigaitis et al, 2023). 
The digital cough monitor selected is the VitaloJAK which consists of a portable sound 
recording device, worn in a pouch or pocket. 24-hour cough recordings are currently 
recognized as the standard measure of efficacy in cough studies. VitaloJAK is 510k approved 
in the US and has a CE Mark for EU for cough monitoring. The cough monitor is considered 
appropriate, as it is an objective measurement of cough frequency. 
PROs were selected based on the established use in clinical trials of cough, and to cover the 
applicable domains of cough, breathlessness, and QOL. PROs will be performed on an 
electronic device (e-diary) with a CE Mark for EU. 
The CGI-C was initially developed for use to provide a brief, stand-alone assessment of the 
clinician's view of the patient's global functioning after initiating a study medication 
(Guy 1976) and is now widely used as an instrument in clinical trials with CNS acting 
medications (Busner & Targum 2007). The CGI-C provides an overall clinician-determined 
summary measure that takes into account all available information, including knowledge of 
the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the patient's ability to function. 
Selection of safety assessments were typical of conventional medical management by 
pulmonologists managing this subject population, safety laboratory assessments and ECG. 

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9. PLANNED STATISTICAL METHODS 
9.1. 
General Considerations 
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 continuous variables directly related to cough frequency (24-
hour cough frequency, sleeping cough frequency, awake cough frequency), geometric mean 
and geometric coefficient of variation (CV) will also be presented. 
In the case that cough-frequency data are not skewed, the primary and key secondary analyses 
may be replicated with data that are not log-transformed. The statistical analysis plan (SAP) 
will contain more information on this possibility if necessary. 
9.2. 
Incurrent Event Handling 
All intercurrent events will be handled according to a “treatment policy” strategy; the collected 
data will be analyzed as-is. Intercurrent events may be summarized (e.g. counts of subjects 
who discontinue treatment) but there will be no modifications to the data or analysis based on 
their occurrence. 
9.3. 
Missing Data and Dropouts 
Missing data will not be imputed. Only subjects with baseline and necessary timepoint period 
from a given period will be eligible for summary and/or analysis for that period, and only 
subjects with baseline and endpoint data from both periods will be eligible for analyses that 
involve comparisons between treatments. 
9.4. 
Determination of Sample Size 
Assuming that subjects on placebo will experience a mean 20% reduction in 24-hour cough 
frequency from baseline to Day 21 and subjects on NAL ER will experience a mean 45% 
reduction from baseline to Day 21, the planned sample size of 48 subjects (24 per sequence) 
provides at least 80% power to detect a significant difference between NAL ER treatment and 
placebo at the 5% significance level (2-sided). This assumes a coefficient of variation (CV) of 
1.12 in log-transformed Day 21 cough frequencies, which is the CV estimated from 
Kelsall et al, 2011 data on chronic cough in patients without esophageal catheterization. 
A total of approximately 60 subjects will be randomized to ensure complete data from at 
least 48 subjects, assuming a 20% dropout rate. 
9.5. 
Analysis Population 
At a minimum, the following populations will be defined: 
• Modified Intent-to-Treat (mITT) population: The mITT population will consist of all 
subjects who have received at least one dose of study drug or placebo. mITT population 
analyses will analyze subjects according to the treatment arm of randomization. This 
population will be used for non-comparative summaries of efficacy endpoints. 
• Completer population: The Completer population will consist of all subjects who received 
at least one dose of each study drug, and for whom there is a non-missing baseline and Day 
21 primary endpoint measurement in both periods. The Completer population will be used 

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for the primary efficacy analysis and comparative secondary efficacy analyses. (For 
secondary efficacy analyses, a subset of the Completer population where the appropriate 
endpoints for the analysis are non-missing in both periods will be used.) 
• Safety population: The Safety population will consist of all subjects who have received at 
least one dose of study drug or placebo. Safety subjects will be analyzed according to the 
treatment taken; if multiple are taken, Safety subjects will be analyzed according to the 
highest dosage of study drug taken. This population will be used for, at minimum, analyses 
and summaries of adverse events, vital signs, and laboratory results. 
• Pharmacokinetic (PK) population: The PK population will consist of all subjects with at 
least one evaluable pharmacokinetic sample. This population will be used for any 
summaries and analyses of PK data. 
• Per Protocol (PP) population: The PP population will consist of all subjects in the mITT 
population who have a treatment compliance >80% and do not have a protocol deviation 
that excludes them from the per protocol population. A complete list of major protocol 
deviations that will exclude subjects from the PP population will be provided in the SAP. 
Subjects who are withdrawn from the study by the sponsor due to a deviation (see 
Section 10.9 Protocol Violations/Deviations) will be excluded from the PP population. 
9.6. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics, e-diary data, medical history, laboratory data, and 
physical examination findings will be summarized descriptively by treatment arm. 
9.7. 
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. 
9.8. 
Concomitant Medication 
Concomitant medications will be tabulated by Anatomical and Therapeutic Class (ATC) of 
World Health Organization (WHO) drug, preferred term, and treatment period. A medication’s 
usage will be considered concomitant if it was started or continued after first administration of 
the study medication. Concomitant medications taken during the wash-out period between 
treatments will be summarized according to the treatment of the first period. 
9.9. 
Efficacy Analyses 
9.9.1. Primary Efficacy Endpoint 
The primary efficacy endpoint of relative change in 24-hour cough frequency (coughs per 
hour) will be analyzed using a mixed-effects repeated model. This model will use log-
transformed relative change in 24-hour cough frequency (log (Timepoint/ Baseline)) as the 
response, sequence, treatment, and time as fixed effects, the log-transformed baseline 24-hour 
cough frequency and sex as covariates, site as a random effect, and subject as a random 
repeated effect. Repeated values for subjects will be modeled using an autoregressive(1) 
(AR(1)) covariance. Site will attempt to be modeled using a compound symmetric covariance; 
however, it is expected that due to ratio of sites to subjects, this may not converge, in which 
case a variance components covariance structure will be used instead. In the case that a 

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variance components covariance structure also cannot converge, the site random effect will be 
removed from the model. 
As a supplementary analysis, a negative binomial model will be fitted with the number of 
coughs as the outcome, with terms for sequence, treatment, time, and baseline cough 
frequency, with subject as a random effect with AR(1) covariance. As with the primary 
analysis, site will be treated as a random effect with compound symmetry covariance, followed 
by variance components covariance, followed by removing site as a random effect if 
convergence cannot be achieved. 
As a further supplementary analysis, the primary efficacy model will be re-run separately for 
subjects whose baseline objective cough frequency was 10-19 coughs/hour and those whose 
baseline objective cough frequency was ≥20 coughs/hour. 
Summaries of objective cough frequency, including change and relative change from baseline, 
will be provided by treatment arm. These summaries will be presented for subjects of all 
baseline objective cough frequencies, and also will be presented for the 10-19 coughs/hour and 
≥20 coughs/hour subgroups separately. 
9.9.2. Secondary Efficacy Endpoint(s) 
Secondary endpoints relating to relative change from baseline to 24-hour, awake, or sleep 
cough frequency will be analyzed with the same mixed-effect model as for the primary 
endpoint, with the response and baseline covariates adjusted accordingly. 
Comparisons of proportions of responders will be analyzed using a mixed-effect logistic model 
with the same fixed and random effects as the primary analysis. Responders will be defined as 
those with ≥30%, ≥50%, or ≥75% reduction in 24-hour cough frequency from baseline at Days 
7, 14, or 21. 
Comparisons between NAL ER and placebo for secondary efficacy endpoints that are not 
objective cough frequencies (CS-VAS, LCQ, PR-CF, PGI and CGI scales), summaries will be 
provided for Days 7, 14, and 21 as appropriate. Paired t-tests will be used for comparing mean 
change from baseline at each timepoint, and McNemar’s test will be used for comparing binary 
responder proportions between NAL ER and placebo at each timepoint. 
As a further supplementary analysis, the secondary efficacy endpoints will be re-run separately 
for subjects whose baseline objective cough frequency was 10-19 coughs/hour and those 
whose baseline objective cough frequency was ≥20 coughs/hour. 
Secondary endpoints will not be adjusted for multiplicity and results will be taken as 
exploratory. 
9.10. 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 an ECG specialist vendor. The totality of these data addresses the secondary 
objective of characterizing the overall safety and tolerability of NAL ER in subjects with RCC. 
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). 

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No formal statistical analysis will be performed on safety outcomes; inferences, if any, will be 
derived through clinical review and interpretation. 
9.10.1. 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. TEAEs that take place 
prior to the first dose of the second treatment in the sequence will be summarized under the 
first treatment in the sequence, even if they occur during the washout period. 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. 
As part of a formal investigation of a drug that is classified as CNS active drug within the 
opioid drug class, certain adverse events will be documented in more detail to support an eight-
factor analysis. See Section 7.2.2 Adverse Events Requiring Additional Narratives for the list 
of applicable adverse events. 
As cough is an endpoint in this study, it will not be reported nor analyzed as an adverse event. 
See Section 9.9 Efficacy Analyses. 
9.10.2. 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. 
9.10.3. 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. 
9.10.4. 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. 
9.10.5. Subjective Opiate Withdrawal Scale (SOWS) 
SOWS scores will be summarized by days post-treatment and treatment group. Maximal 
SOWS score (≤ 10, 11-20, 21-30, or > 30) and time off drug (0-1, 2, 3, 4, 5, 6, 7, or ≥ 8 days, 
calculated based on SOWS and last dose dates) will be summarized by treatment arm. 

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9.10.6. 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 report by an ECG specialist vendor. 
9.11. Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis 
The study drug plasma concentration data will be provided as data listings and will also be 
summarized descriptively (mean, median, SD, minimum, and maximum) by nalbuphine dose/ 
treatment and visit. 
Post-hoc pharmacokinetic analyses may be conducted through population, nonlinear mixed 
effects modeling; if so, this will be detailed in the SAP or in a separate post-hoc 
pharmacokinetic SAP. 
In addition, PK-PD analyses may be conducted based on exploration of exposure-response 
relationships between nalbuphine plasma concentrations and efficacy parameters. These PK-
PD analyses will be provided in separate ad-hoc reports if so. 
Additional PK-PD analyses may be conducted to include safety and/or tolerability parameters, 
as appropriate. 
Further details, including PK-PD modeling, will be detailed in the SAP or in a separate post-
hoc pharmacokinetic SAP prior to being performed. 
9.12. Other Assessments or Analyses 
Additional exploratory analyses, such as examinations of the primary and some key secondary 
endpoints for specified subgroups, will be outlined in the SAP. 
9.13. Interim Analysis 
No interim statistical analyses are planned for this study. 

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10. ADMINISTRATIVE CONSIDERATIONS 
10.1. Quality Control and Assurance 
The Sponsor shall implement and maintain quality control and quality assurance procedures 
with written Standard Operating Procedures (SOP) to ensure that the study is conducted, and 
data are generated, documented, and reported in compliance with the protocol, E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1), 2018, CTR EU 536/2014, and 
applicable regulatory requirements. 
The Investigator will 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 will maintain a list of sub-Investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties. 
10.2. Investigators and Study Administrative Structure 
The following will be maintained in the TMF: 
• List of the CRO, laboratories, medical or technical vendors 
• Coordinating Investigator details, as required by local regulations, and defined in the 
clinical trial application (CTA). 
• List of Principal Investigators, clinical study sites, and the relevant departments. 
The subject’s primary care physician will be notified of the subject’s participation in the study 
if they give permission. 
10.3. Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
Prior to initiation of the study, the Investigator will submit the study protocol, sample informed 
consent form (ICF), and other documents that pertain to subject information, recruitment 
methods such as subject diaries, and advertisements, according to the IRB/IEC requirements. 
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 provided to the Sponsor/CRO prior to 
initiation of this 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 adverse 
event reports received by 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. 
10.4. Ethical Conduct of the Study 
This study is to be conducted according to globally accepted standards of GCP (E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1), 2018), in agreement with the latest 
revision of the Declaration of Helsinki, and in keeping with local regulations. 

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10.5. Patient Information and Consent 
Refer to Section 8.1 Informed Consent for details on informed consent requirements and 
process. 
10.6. Patient Confidentiality and Data Protection 
Subjects will be assigned a unique identifier by the sponsor, referred to as the Participant 
Identification Number (PID), or unique subject ID (USUBJID). Any participant records (e.g., 
from the e-diary, cough monitor, labs) or datasets that are transferred to the sponsor will 
contain the identifier only (pseudonymized); participant names or any information which 
would make the participant identifiable will not be transferred. The Investigator is responsible 
for keeping a code list to link the subject’s assigned number with identifying information. This 
code list will remain on site and kept in a secure manner with the study documentation, with 
access limited to authorized individuals. 
Identifiable (non- pseudonymized) personal study-related data will be accessed by the sponsor 
or delegates in accordance with local data protection law. and as described in 
Section 10.7 Study Monitoring and Section 10.10 Access to Source Documentation. 
Pseudonymized data will be maintained and analyzed (see Section 10.10 Access to Source 
Documentation). Data for scientific publication will be fully anonymized 
The participant will be informed in the ICF about the level of disclosure of identifiable data, 
including their medical records, pseudonymized, and anonymized data. The participant must 
be willing and able to give consent for their data to be used in this way to participate in the 
study. 
The contract between sponsor and study sites specifies responsibilities of the parties related 
data protection, including handling of data security breaches and respective communication 
and cooperation of the parties. The compliance with these requirements is confirmed and 
documented throughout the study, starting at the initiation visit prior to the start of enrollment 
at any given site. 
Delegated vendors (data processors) are qualified prior to use for the clinical study, via audit 
or other assessment, to determine the adequacy of their procedures and processes. Vendors 
must comply with the legal and contractual requirements, including data transfer agreements 
and quality agreements, where appropriate. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data against 
accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
In case of security breach, procedures for reporting and disclosure within the regulations and 
timelines of the applicable countries for the study will be followed. 
10.7. 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 clinical research associates (CRA) will make frequent contact with the Investigator. 

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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 CRA for review. The CRA will also perform 
investigational product drug 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. 
Upon completion of the study, the CRA 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 CRA during the on-site visits and will cooperate in 
providing the documents for inspection and responding to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of the 
Sponsor or 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. 
10.8. Case Report Forms and Study Records 
The Investigator, or designee, will enter study data required by the protocol into an electronic 
data capture (EDC) system. The CRA 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 the completed eCRF will be entered as a discrepancy in 
the EDC system by the CRA. Appropriate study site personnel should then address those 
discrepancies in the EDC system. Uniform procedures for eCRF correction (queries) will be 
discussed during the study site initiation visits and will be documented in the study operations 
manual. 
Data from eCRF and other external data sources will be entered into a clinical database as 
specified in the data management plan. Quality control and data validation procedures will be 
applied to ensure the validity and accuracy of the clinical database. 
Computerized and manual procedures should be used to review and check data from eCRF and 
data from other external sources for omissions, apparent errors, and values that may require 
further clarification. Data queries requiring clarification should be documented, and the study 
site should be requested to review and resolve the queries. Only authorized personnel can 
make corrections to the clinical database, and all corrections should be documented in an audit 
trail. 
Adverse events will be coded using the most current MedDRA version. Prior and concomitant 
medications will be coded according to the WHO Drug Dictionary. 
10.9. Protocol Violations/Deviations 
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. Deviations may or may not result in the sponsor making a 
decision to have the subject withdrawn from the study and/or render that subject ineligible for 
inclusion in the Per Protocol population. The Investigator should notify the IRB/IEC of 
deviations from the protocol in accordance with local procedures. 

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10.10. Access to Source Documentation 
The study may be subject to audit by the Sponsor, its designee, or by regulatory authorities. If 
such an audit occurs, the Investigator must agree to allow access to required subject records. 
The Investigator should notify the Sponsor promptly of regulatory authority audits that are 
scheduled and must forward copies of any findings or audit reports to the Sponsor promptly. 
Examples of such documents are outlined below but are not an exhaustive list: 
• Signed ICFs for all subjects 
• Subject identification code list, screening log (if applicable), and enrollment log 
• Record of all communications between the Investigator and the IRB/IEC 
• Composition of the IRB/IEC or other applicable statement 
• Record of all communications between the Investigator and Sponsor (or CRO) 
• List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study and their signatures 
• Copies of eCRFs and of documentation of corrections for all subjects 
• Drug accountability records 
• 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 - Essential Documents for the 
Conduct of a Clinical Trial, E6(R2) Good Clinical Practice: Integrated Addendum to 
ICH E6(R1), 2018. 
By signing this protocol, the Investigator grants permission to personnel from the Sponsor, its 
representatives, and appropriate regulatory authorities for on-site monitoring and review of all 
appropriate study documentation, as well as on-site review of the procedures employed in data 
collection, where clinically appropriate. 
10.11. Data Generation and Analysis 
The data generated to answer the objectives of the study are: 
• Objective digital cough monitor (VitaloJAK) 
• Patient Reported Outcome (PRO) questionnaires 
• Clinical Global Impression assessments 
• Nalbuphine plasma concentrations 
• For safety the objective: adverse events, clinical lab tests, vital signs, pulse oximetry, 
and physical examinations. 
All participant data generated on site for the study will be documented in source records 
maintained by the site, and then entered into the CRF. Data will not be recorded directly on 
eCRFs. The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the eCRF. 
Guidance on completion of eCRFs and data clarification forms (DCFs) will be provided in the 
eCRF Completion Guidelines. 
The following data are generated by the participant or by a vendor, and the vendor database is 
considered the source. These data will be transmitted to the sponsor or designee electronically 
according to Data Transfer Agreements: 

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• PRO questionnaires and Clinical Global Impression assessments entered directly into 
the e-diary interface and secure website portal; 
• Cough Monitor recordings generated electronically on the device and transmitted to 
the Cough Monitor vendor; 
• ECG recordings generated electronically on the device and transmitted to the ECG 
specialized vendor; 
• Randomization and IP management performed directly in the IRT system. 
• Laboratory samples, sent to the analyzing laboratory. 
Vendor systems will generate confirmation or results reports available to site. These reports 
will become source data, but the source of the actions and results themselves will be the vendor 
database. 
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
10.12. Retention of Data 
When the study is completed, the Investigator must retain the essential documents for 25 years 
to comply with regulatory guidelines before destroying the data. The Investigator will notify 
the Sponsor prior to moving or destroying any of the study documents. It is the responsibility 
of the Sponsor to inform the Investigator/Institution as to when these documents no longer 
need to be retained. The Investigator should take measures to prevent any accidental or 
premature destruction of these documents. 
10.13. Financial Disclosure 
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. The initial 
financial disclosure information must be provided before the site doses the first subject. 
Investigators are responsible for providing information on financial interests during the study 
and for 1 year after completion of the study. 
10.14. Publication and Disclosure Policy 
The Sponsor will retain ownership of all data. When the study is complete, the Sponsor will 
arrange the analysis and tabulation of data. A clinical study report will then be prepared, which 
may be used for publication, presentation at scientific meetings, or submission to regulatory 
authorities. The results of the study will be posted to the publicly available website 
ClinicalTrials.gov independent of the outcome of the study. All proposed publications based 
on this study will be subject to the Sponsor’s approval requirements. 

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Advances in Respiratory Disease, 4(1), 49-55. doi:10.1177/1753465809358249 

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Clinical Trial Protocol: NAL04-201 
Trevi Therapeutics, Inc. 
Protocol Amendment 2 
Confidential 
Page 71 of 73 
 
 
APPENDICES 
 
 
LIST OF APPENDICES 
Appendix 1 
Sponsor Signature .............................................................................. 72 
Appendix 2 
Investigator’s Signature ...................................................................... 73 

Nalbuphine ER 
Clinical Trial Protocol: NAL04-201 
Trevi Therapeutics, Inc. 
Protocol Amendment 2 
Confidential 
Page 72 of 73 
 
 
Appendix 1 
Sponsor Signature 
Study Title: 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period 
Crossover Efficacy and Safety Study of Nalbuphine ER Tablets for the 
Treatment of Refractory Chronic Cough 
Short Study Title 
Cough Reduction in RCC with NAL ER (RIVER) 
Study Number: 
NAL04-201 
Protocol Version 
Protocol Amendment 2  19-Jun -2024 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. 
 
 
 
 
 
 
 
 
 MD 
Trevi Therapeutics 
Signature and Date: 

Nalbuphine ER 
Clinical Trial Protocol: NAL04-201 
Trevi Therapeutics, Inc. 
Protocol Amendment 2 
Confidential 
Page 73 of 73 
 
 
Appendix 2 
Investigator’s Signature 
Study Title: 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period 
Crossover Efficacy and Safety Study of Nalbuphine ER Tablets for the 
Treatment of Refractory Chronic Cough 
Short Study Title 
Cough Reduction in RCC with NAL ER (RIVER) 
Study Number: 
NAL04-201 
Protocol Version 
Protocol Amendment 2  19-Jun -2024 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol, and according to ICH guidelines on 
GCP and with applicable regulatory requirements. All information pertaining to the study 
shall be treated in a confidential manner. 
 
 
Name and Credentials 
 
 
Job Title 
 
Affiliation 
 
 
 
 
Signature and Date