Clinical trial NCT04030026
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Nalbuphine Cough Idiopathic Pulmonary Fibrosis Pharmacokinetics
Sponsor: Trevi Therapeutics
Start date: 2019-10-29; Completion date: 2022-05-27
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To evaluate the safety and tolerability of nalbuphine ER tablets in the study population and to evaluate the effect of NAL ER tablets on the mean daytime cough frequency (coughs per hour) at Day 22 (dose 162 mg BID) as compared to placebo tablets.

Detailed description:

Arms: arm 1: Participants received NAL ER in treatment period 1 at dose 27 mg once daily (QD) to 54 mg twice daily (BID) over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days, followed by placebo matching NAL ER for 3 weeks in treatment period 2. Both the treatment periods were separated by 2 weeks of washout period. arm 2: Participants received placebo matching NAL ER for 3 weeks in treatment period 1 followed by NAL ER in treatment period 2 at dose 27 mg QD to 54 mg BID over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days. Both the treatment periods were separated by 2 weeks of washout period.
Interventions: intervention 1: NAL ER intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received NAL ER 27 mg QD, 27 mg BID, 54 mg BID, 108 mg BID, 162 mg BID. intervention 2: Participants received Placebo tablet (matching NAL ER ).

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Treatment, 
Two-Period Crossover Efficacy and Safety Study in Idiopathic Pulmonary Fibrosis with 
Nalbuphine ER Tablets for the Treatment of Cough 
NCT Number: NCT04030026
Document Date: Protocol Version 7.0: 14 December 2021


Trevi_Nalbuphine_Protocol_TR12_60287
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Confidential 
Trevi Therapeutics, Inc. 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Treatment, 
Two-Period Crossover Efficacy and Safety Study in Idiopathic Pulmonary 
Fibrosis with Nalbuphine ER Tablets for the Treatment of Cough 
Protocol Number: 
TR12 
Investigational Product: 
Nalbuphine Extended-Release Tablets (NAL ER) 
EudraCT Number: 
2018-004744-31 
Development Phase: 
2 
Sponsor Name and Address: Trevi Therapeutics, Inc. 
195 Church Street, 14th Floor 
New Haven, CT 06510 
USA 
Responsible Medical Officer: 
 MD 
Sponsor Contact: 
 
Version: 
Version 7.0 
Protocol Date: 
14 December 2021 
CONFIDENTIALITY STATEMENT 
The information in this document contains commercial information and trade secrets that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations.  In any 
event, persons to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them.  These restrictions on disclosure will apply equally to all 
future information supplied to you that is indicated as privileged or confidential. 


Trevi Therapeutics, Inc. 
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2021 
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1 PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
Title of Study: 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Treatment, Two-Period Crossover 
Efficacy and Safety Study in Idiopathic Pulmonary Fibrosis with Nalbuphine ER Tablets for the Treatment 
of Cough 
Study Centers: 
Up to 15 centers 
Publication(s): 
None 
Planned Study Period: 
May 2019 to March 2022 
Development Phase: 
Phase 2 
Objectives: 
Primary Objectives: 
•
To evaluate the safety and tolerability of nalbuphine extended-release (NAL ER) tablets in the
study population.
•
To evaluate the effect of NAL ER tablets on the mean daytime cough frequency (coughs per hour)
at Day 22 (dose 162 mg twice daily [BID]) as compared to placebo.  Assessment is done using
objective digital cough monitoring.  Daytime is defined as the time the subject is awake in the 24
hours after the digital cough monitor is applied for use.
Secondary Objectives: 
•
To evaluate the effect of NAL ER tablets on the mean relative change from baseline in 24-hour
(combined daytime and nighttime) cough frequency (coughs per hour) at Day 22 (dose: 162 mg
BID).
•
To evaluate the effect of NAL ER tablets on the mean relative change from baseline in nighttime
cough frequency (coughs per hour) at, and Day 22 (dose: 162 mg BID).
•
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline
on the Evaluating Respiratory Symptoms (E-RS™) diary cough scale (E-RS diary question
number 2) by treatment at Days 9, 16, and 22.
•
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline
in the Cough Severity Numerical Rating Scale by treatment at Days 8, 15, and 21.
•
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline
in the E-RS diary breathlessness scale (E-RS diary questions 7, 8, 9, 10, and 11) by treatment at
Days 9, 16, and 22.
•
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline
in the 14-item the EXAcerbation of Chronic pulmonary disease Tool (EXACT®) version 1.1 e-
diary tool total score by treatment at Days 9, 16, and 22.
•
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline
in the Patient Reported Outcomes Measurement Information System (PROMIS®) Item Bank v1.0
Fatigue Short Form 7a scale by treatment at Day 21.


Trevi Therapeutics, Inc. 
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NAL ER Tablets 
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Confidential 
Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
• 
To evaluate the change in the Clinical Global Impression of Change (CGI-C) over time by 
treatment measured at Day 21. 
Methodology: 
This is a double-blind, randomized, placebo-controlled, 2-treatment, 2-period crossover efficacy and 
safety study in IPF subjects with NAL ER tablets for the treatment of cough.  The study consists of 2 
treatment periods of 3 weeks, each followed by a washout period of 2 weeks.     
During Treatment Period 1, eligible subjects will be randomized (1:1) to one of the following treatment 
arms: 
• 
Arm 1: Active NAL ER tablets followed by crossover Placebo tablets in Treatment Period 2 
• 
Arm 2: Placebo tablets followed by crossover NAL ER tablets in Treatment Period 2 
Following 3 weeks of dosing in Treatment Period 1, subjects will complete a 2-week washout period 
before entering Treatment Period 2.  Subjects assigned to Arm 1 will receive placebo tablets and subjects 
assigned to Arm 2 will receive NAL ER tablets during Treatment Period 2.  A final 2-week washout period 
will occur at the completion of Treatment Period 2. 
NAL ER Dosing 
Subjects on NAL ER tablets will have the dose titrated from 27 mg once daily (QD) to 54 mg BID over a 
5-day period and then maintained at 54 mg BID for approximately 4 days.  Doses will be subsequently 
escalated and maintained at 108 mg BID over 1 week and then to 162 mg BID over 6 days. 
Study Visits 
Study visits will include screening to determine eligibility, and for each treatment period: visits at Day -1 
for baseline assessments, at Days 8, 15, and 21 during treatment, and a follow-up at the end of the 2-week 
washout period.  At study screening and the Day 21 visits, during each treatment period, subjects will 
have blood drawn for safety analysis.  Pharmacokinetic (PK) analysis of nalbuphine plasma concentration 
will also be done at Day 21.  Subjects will complete questionnaires for efficacy evaluations and undergo 
safety evaluations including an ECG.  At the baseline and Day 21 visits, during each treatment period, 
site staff will place an electronic cough monitor on the subject, which will be worn until the evening of 
the following day in order 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 prior to bedtime. 
Subjects will complete a daily e-diary twice per day. 
Subjects who discontinue investigational product, for reasons other than withdrawal of consent, will be 
considered to have prematurely discontinued treatment and will be asked to complete the premature 
discontinuation and 2-week off-treatment safety follow-up evaluations. 
 
 
 
 
 
 
  


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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
Figure: Study Schematic  
 
 
Screening Period 
N=30 Nalbuphine 
Placebo 
Predose 
27 mg QD 27 mg BID 54 mg BID 
Randomization 
N=30 
108 mg BID 162 mg BID 
Predose 
Placebo 
14-day washout 
Day -1 
D1 pm & D2 pm D3 am – D5 am D5 pm – D9 am D9 pm – D16 
am 
D16 pm – D22 
am 
Double-blind treatment period 
Visits on 
Days: 
-1 
8 
15 
21 


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Table:  Dosing Scheme 
 Treatment 
Period 
Visit 
No. 
Treatment 
Day 
Dose (mg) 
Arm 1 
Arm 2 
AM 
PM 
AM 
PM 
 
Treatment 
Period 1 
2 
-1 
— 
— 
— 
— 
 
  
1 
— 
27 
— 
Placebo 
 
  
2 
— 
27 
— 
Placebo 
 
  
3 
27 
27 
Placebo 
Placebo 
 
  
4 
27 
27 
Placebo 
Placebo 
 
  
5 
27 
54 
Placebo 
Placebo 
 
  
6 
54 
54 
Placebo 
Placebo 
 
7 
54 
54 
Placebo 
Placebo 
 
3 
8 
54 
54 
Placebo 
Placebo 
 
  
9 
54 
108 
Placebo 
Placebo 
 
  
10 
108 
108 
Placebo 
Placebo 
 
  
11 
108 
108 
Placebo 
Placebo 
 
  
12 
108 
108 
Placebo 
Placebo 
 
  
13 
108 
108 
Placebo 
Placebo 
 
14 
108 
108 
Placebo 
Placebo 
 
4 
15 
108 
108 
Placebo 
Placebo 
 
  
16 
108 
162 
Placebo 
Placebo 
 
  
17 
162 
162 
Placebo 
Placebo 
 
  
18 
162 
162 
Placebo 
Placebo 
 
  
19 
162 
162 
Placebo 
Placebo 
 
  
20 
162 
162 
Placebo 
Placebo 
 
5 
21 
162 
162 
Placebo 
Placebo 
 
  
22 
162 
— 
Placebo 
— 
 
2-Week Washout 
 
Treatment 
Period 2 
6 
-1 
— 
— 
— 
— 
 
  
1 
— 
Placebo 
— 
27 
 
  
2 
— 
Placebo 
— 
27 
 
  
3 
Placebo 
Placebo 
27 
27 
 
  
4 
Placebo 
Placebo 
27 
27 
 
  
5 
Placebo 
Placebo 
27 
54 
 
  
6 
Placebo 
Placebo 
54 
54 
 
7 
Placebo 
Placebo 
54 
54 
 
7 
8 
Placebo 
Placebo 
54 
54 
 
  
9 
Placebo 
Placebo 
54 
108 
 
  
10 
Placebo 
Placebo 
108 
108 
 
  
11 
Placebo 
Placebo 
108 
108 
 
  
12 
Placebo 
Placebo 
108 
108 
 
  
13 
Placebo 
Placebo 
108 
108 
 
14 
Placebo 
Placebo 
108 
108 
 
8 
15 
Placebo 
Placebo 
108 
108 
 
  
16 
Placebo 
Placebo 
108 
162 
 
  
17 
Placebo 
Placebo 
162 
162 
 
  
18 
Placebo 
Placebo 
162 
162 
 
  
19 
Placebo 
Placebo 
162 
162 
 
  
20 
Placebo 
Placebo 
162 
162 
 
9 
21 
Placebo 
Placebo 
162 
162 
 
  
22 
Placebo 
— 
162 
— 
 
2-Week Washout 
 
 


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Confidential 
Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
Number of Subjects: 
Approximately 60 subjects with diagnosed IPF will be randomized to ensure evaluable data from at least 
44 subjects who complete both treatment periods. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
Subjects eligible for randomization to receive investigational product must meet all the following criteria: 
1.
Diagnosis of “definite” or “probable” IPF based on ATS/ERS/JRS/ALAT criteria (see Raghu et al
2018 in Appendix 6).
2.
Forced vital capacity (FVC) > 40% predicted of normal.
3.
Diffusing capacity of the lung for carbon monoxide corrected for hemoglobin [DLCO] > 25% predicted
of normal within the past 6 months.  Subjects who have not had DLco testing may be enrolled with
medical monitor approval.
4.
Chronic cough > 8 weeks.
5.
Adequate swallow reflex as assessed by the ability to sip 3 fluid oz (or 89 ml) of water without
coughing or choking.
6.
Daytime cough severity score ≥ 4 on Cough Severity Numerical Rating Scale at screening.
7.
Males or females age 18 years and older at the time of consent.
8.
Females of childbearing potential must use an acceptable method of birth control (if sexually active).
All females of childbearing potential must have a negative pregnancy test at the screening and baseline 
visits.
For the purpose of this study, all females are considered to be of childbearing potential unless they
are postmenopausal (i.e., at least 1 year since last menses and age > 50 years) or surgically sterile
(i.e., tubal ligation, hysterectomy, and/or bilateral oophorectomy).
Sexually active female subjects of childbearing potential are required to use 1 barrier method
(e.g., condom, cervical cap, or diaphragm) of contraception in addition to 1 other method
(e.g., intrauterine device in place for at least 1-month, stable hormonal contraception for at least
3 months, Essure procedure, or spermicide).  For female subjects using a barrier method plus
spermicide, that method must be used for at least 14 days prior to Screening.
Female subjects who are abstinent may participate in the study; however, they must be counseled on
the requirement to use appropriate contraception should they become sexually active.  This counseling
should occur at each study visit and must be documented in source records.
9.
Willing and able to understand and provide written informed consent.
10. Willing and able to comply with study requirements and restrictions.
11. 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.
The following conditions are excluded:
a)
Interstitial lung disease (ILD) known to be caused by domestic and occupational environmental
exposures.
b) Interstitial lung disease (ILD) known to be caused by connective tissue disease.
c)
Interstitial lung disease (ILD) known to be caused by drug related toxicity.


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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
2.
Currently on continuous oxygen therapy for longer than 16 hours at any level or delivered by any
modality.  Intermittent oxygen use of any duration over any given 24-hour period is allowed.
3.
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.
4.
Serum bilirubin > 1.5 × upper limit of normal range at screening unless explained by a clinical
diagnosis of Gilbert’s syndrome.
5.
Serum hepatic alanine aminotransferase or aspartate aminotransferase enzymes > 100 U/L at
screening.
6.
Estimated glomerular filtration rate ≤ 44 mL/min/1.73 m2 at screening.
7.
Upper or lower respiratory tract infection within 4 weeks of screening.
8.
Significant medical condition or other factors that may interfere with the subject’s ability to
successfully complete the study.
9.
History of substance abuse that, as determined by the Investigator, may interfere with the conduct of
the study.
10. Known intolerance or hypersensitivity/drug allergy to nalbuphine or vehicle components.
11. Pregnant or lactating female subject.
12. Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a concurrent clinical
trial.
13. Clinical diagnosis of sleep apnea and/or use of continuous positive airway pressure (CPAP).
14. History of clinically significant head injury in past 1 month.
15. Clinical diagnosis of aspiration pneumonitis.
16. Clinical history of opiate withdrawal symptoms following use of opiates.
17. Documented or clinically suspected hypercapnia (pCO2 >6.0kPa).
Medication-related Exclusions: 
18. Known intolerance (gastrointestinal, central nervous system symptoms) or hypersensitivity/drug
allergy to opioids.
19. Exposure to any investigational medication, including placebo, within 4 weeks.
20. Potential subjects cannot have received opiates, including opiate-containing anti-cough agents, within
14 days prior to the screening period.  Subjects are prohibited from using opioids, including
naltrexone, for the duration of the study.
21. Potential subjects cannot currently be receiving benzodiazepines or other CNS Depressant Class
Drugs that when used concomitantly with opioids are known to have the potential to cause added
pharmacologic effects of depressing CNS activity (See Section 9.6.2.2 (“Benzodiazepines and Other
CNS Depressant Class Drugs”).
22. Potential subjects cannot currently be receiving medications that affect serotonergic
neurotransmission and that when used concomitantly with opioids can cause serotonin syndrome (See
Section 9.6.2.3 (“Serotonergic Class Drugs”).
23. Alcohol consumption should be limited for the duration of study treatment (due to the potential cause
of added pharmacologic effects of CNS depression when used concomitantly with opioids.
24. Change of IPF-related drug treatment regimen within 8 weeks of screening.


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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
Cardiac-related Exclusions: 
25. Subjects with a history of congestive heart failure of Class 2 or higher as graded using the New York
Heart Association (NYHA) classification (Appendix 8).
26. Subjects with a history of angina pectoris Grade 2 or higher as graded using the Canadian
Cardiovascular Society (CCS) grading scale (Appendix 7).
27. History of ventricular tachycardia, Torsade de Pointes, or family history of sudden death.
28. Myocardial infarction or acute coronary syndrome within the previous 3 months, as reported by the
subject.
29. Serum potassium below the laboratory lower limit of normal.
30. QTcF interval >450 ms (mean of 3 screening ECG QTcF values) if QRS <120 ms (mean of 3 screening 
ECG QRS values); QTcF interval >480 ms in the presence of Right Bundle Branch Block (RBBB)
and/or QRS ≥ 120 ms
31. Heart rate < 45 bpm on any screening measurement.  Subjects with a resting heart rate of < 45 bpm
will have it repeated once after 5 minutes in the supine position, and if it remains < 45 bpm during the
repeat, they will be considered a screen failure.
32. Use of a medication having a “known risk” of Torsade de Pointes (categorized as “KR” on the
Credible Meds® website) is not permitted at entry or during the study (See Appendix 9).
Medications associated with a potential risk of QT prolongation, but not clearly associated with
Torsade de Pointes, are permitted at study entry if the following criteria are met:
•
Subject has been given medication at stable doses for a full 4 weeks prior to screening.
•
Medication dose will not be increased after screening, or during the study, and it is anticipated
that the subject will receive the medication for the entirety of the study.
Test Product, Dose and Mode of Administration: 
NAL ER tablets, 27 mg, 54 mg, and placebo tablets BID, orally administered 
Reference Therapy, Dose and Duration of Administration: 
Matching placebo tablets, orally administered 
Duration of Treatment: 
Up to 11 weeks 
Variables: 
Efficacy:  
Primary Efficacy Endpoint 
•
Mean change in daytime cough frequency (coughs per hour) from baseline as assessed by objective
digital cough monitoring at Day 22 by treatment.  Daytime is defined as the time the subject is awake
in the 24 hours after the digital cough monitor is applied for use.
Secondary Efficacy Endpoints 
•
Relative change in daytime cough frequency (coughs per hour) from baseline at Day 22 (dose: 162
mg BID) by treatment.
•
Relative change in 24-hour (combined daytime and nighttime) cough frequency (coughs per hour)
from baseline at Day 22 (dose: 162 mg BID) by treatment.


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Confidential 
Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
•
Relative change in nighttime cough frequency (coughs per hour) from baseline at Day 22 (dose: 162
mg BID) by treatment.
•
Mean change in the E-RS diary cough subscale (E-RS diary question number 2) from baseline at Days
9, 16, and 22 by treatment.
•
Mean change in the Cough Severity Numerical Rating Scale at Days 8, 15, and 21 by treatment.
•
Mean change in the E-RS diary breathlessness subscale (E-RS diary questions 7, 8, 9, 10, and 11)
from baseline at Days 9, 16, and 22 by treatment.
•
Mean change in the 14-item EXACT v1.1 e-diary tool total score from baseline at Days 9, 16, and 22
by treatment.
•
Mean change in the PROMIS Item Bank v1.0 Fatigue Short Form 7a scale from baseline at Day 21
by treatment.
•
Mean change in the CGI-C over time measured at Day 21 by treatment.
Safety:  Safety will be assessed based on adverse events, clinical laboratory measurements, locally 
reviewed and central cardiac core laboratory read ECGs, vital signs, spirometry and physical 
examinations. 
Subjects will also complete the Subjective Opiate Withdrawal Scale (SOWS) on a daily basis via e-diary 
for 14 days following the last dose of investigational product, whenever that occurs and regardless of the 
reason (unless consent is withdrawn). 
An independent Data Safety Monitoring Board (DSMB) will periodically review safety data. 
Pharmacokinetics:  Nalbuphine (and/or metabolites) plasma concentration will be measured at Day 21 
by treatment group. 
Statistical Methods: 
Efficacy 
The primary efficacy endpoint of percent change in daytime cough frequency (coughs per hour) will be 
analyzed using a mixed-effects model with sequence, treatment, and time (Day 22) as fixed effects, the 
baseline value as a covariate, 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.  A log 
transformation will be applied to daytime cough frequency; in the presentation of results, log-scale fitted 
mean treatment group differences at Day 22 will be back-transformed to fitted ratios of geometric means. 
As a sensitivity analysis, a negative binomial model will be fitted with the number of coughs at Day 22 as 
the outcome, with terms for sequence, treatment, and time, as well as baseline cough frequency and 
subject, and duration of daytime (in hours) as an offset.  An autoregressive covariance structure will be 
assumed for study visits, and the site random effect will use an unstructured covariance matrix. 
Secondary efficacy endpoints will be summarized using descriptive statistics.  For continuous endpoints 
(e.g., change from baseline), summaries will include mean, median, standard deviation, minimum, and 
maximum.  For discrete variables (e.g., frequency), summaries will include number of instances and 
percentage of total instances for that category or time period. 
Safety 


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Name of Sponsor/Company: 
Trevi Therapeutics, Inc. 
Name of Product: 
Nalbuphine Extended-Release 
Tablets 
Name of Active Ingredient: 
Nalbuphine HCl 
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 and laboratory data will be summarized using descriptive statistics.  The extent and duration of use 
of prohibited or restricted medications will be similarly summarized using descriptive statistics.  No 
formal statistical analysis will be performed on safety outcomes; inferences, if any, will be derived through 
clinical review and interpretation. 
Adverse events of special interest (AESI) that code to the most relevant abuse-related MedDRA preferred 
terms will be tabulated and descriptive narratives will be written.  Additional adverse events that are 
considered “possibly related to abuse potential” will be tabulated separately. 
Electrocardiograms will be reviewed locally and read centrally by specially trained staff, with real-time 
feedback to clinical sites regarding any findings relevant to safety.  Once the database is complete, ECG 
data (e.g., heart rate, PR, QTcF intervals) 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 laboratory. 
Pharmacokinetics 
Nalbuphine (parent and/or metabolites) plasma concentration data will be listed by collection time and 
nalbuphine dose where applicable.  Further PK analyses may be conducted if data allow. 
Sample Size and Power 
The planned sample size of 44 subjects for the final analysis (22 per sequence) provides at least 80% 
power to detect a 40% reduction in Day 22 daytime cough frequency (coughs per hour) with NAL ER 
tablet treatment compared to placebo tablets at the 5% significance level (2-sided).  This assumes a 
coefficient of variation (CV) of 1.00 in log-transformed Day 22 cough frequencies.  The CV estimated 
from Kelsall et al (2011) data on chronic cough in patients without esophageal catheterization is 1.12; 
because Kelsall et al data was on 24-hour cough (including nighttime cough, a period of lower coughing 
rate) and were not taken in a sample of IPF patients only, it is believed that the CV will be lower than in 
Kelsall et al data. 
If the CV is larger than planned at 1.25, this sample size provides > 80% power to detect a 50% reduction 
from placebo to NAL ER.  Alternatively, if the CV is 0.75, this sample size provides > 80% power to 
detect a 34% reduction from placebo to NAL ER. 
Efficacy analyses will be based primarily on the completers population, which consists of all subjects who 
received both study treatments and completed both treatment periods in the study. However, methods of 
adjustment for missing or otherwise incomplete data (e.g., failure to complete both treatment periods) will 
be considered after assessing the extent that such conditions exist at the time of data base lock. 
A total of approximately 60 subjects will be randomized to ensure complete data from at least 44 subjects, 
assuming up to a potential 26% dropout rate. 
A statistical update on this Proof-of-Concept (POC) study may be conducted when a minimum of 12 
subjects have completed both study periods for the purposes of determining whether POC can be 
established prior to complete enrollment of the study.  
Date of the Protocol: 
14 December 2021 


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Table of Contents 
Description 
Page 
1 PROTOCOL SYNOPSIS ........................................................................................................2 
2 SIGNATURE PAGE ..............................................................................................................15 
3 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................16 
4 INTRODUCTION..................................................................................................................18 
4.1 
Background Information on Idiopathic Pulmonary Fibrosis ............................................18 
4.2 
Background Information on Nalbuphine ..........................................................................19 
4.3 
Rationale for Investigation of Nalbuphine in Cough and Dyspnea Related 
to Idiopathic Pulmonary Fibrosis ......................................................................................19 
5 STUDY OBJECTIVES ..........................................................................................................21 
5.1 
Primary Objectives ............................................................................................................21 
5.2 
Secondary Objectives ........................................................................................................21 
6 INVESTIGATIONAL PLAN ...............................................................................................22 
6.1 
Study Design .....................................................................................................................22 
6.2 
Study Schedule ..................................................................................................................23 
6.3 
Study Visits and Procedures .............................................................................................29 
6.3.1 
Treatment Period 1....................................................................................................29 
6.3.2 
Treatment Period 2....................................................................................................32 
6.3.3 
Premature Discontinuation Visit ...............................................................................34 
6.3.4 
Unscheduled Visits ...................................................................................................34 
6.4 
Rationale for Study Design and Dose Selection ...............................................................34 
6.5 
Safety Monitoring .............................................................................................................35 
6.6 
Risk/Benefit and Ethical Assessment ...............................................................................37 
7 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ........................................38 
7.1 
Number of Subjects ...........................................................................................................38 
7.2 
Inclusion Criteria ..............................................................................................................38 
7.3 
Exclusion Criteria .............................................................................................................39 
7.4 
Withdrawal Criteria ..........................................................................................................41 
7.5 
Premature Discontinuation of Investigational Product Treatment ....................................41 
8 STUDY ASSESSMENTS AND PROCEDURES ................................................................42 
8.1 
Efficacy Endpoints ............................................................................................................42 
8.1.1 
Primary Efficacy Endpoint .......................................................................................42 


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8.1.2 
Secondary Efficacy Endpoints ..................................................................................42 
8.2 
Efficacy Assessments ........................................................................................................42 
8.2.1 
Digital Cough Monitor..............................................................................................42 
8.2.2 
Subject e-Diary .........................................................................................................43 
8.2.3 
EXACT 14-item e-Diary Tool and E-RS Diary Cough and 
Breathlessness Scales ................................................................................................43 
8.2.4 
Cough Severity Numerical Rating Scale ..................................................................44 
8.2.5 
PROMIS Item Bank v1.0 Fatigue Short Form 7a Scale ...........................................44 
8.2.6 
Clinical Global Impression of Change Scale ............................................................44 
8.3 
Pharmacokinetic Assessments ..........................................................................................45 
8.4 
Safety Assessments ...........................................................................................................45 
8.4.1 
Adverse Events .........................................................................................................45 
8.4.2 
Clinical Laboratory Tests..........................................................................................45 
8.4.3 
Pregnancy Tests ........................................................................................................46 
8.4.4 
Vital Signs.................................................................................................................46 
8.4.5 
Physical Examination ...............................................................................................46 
8.4.6 
Electrocardiogram Assessments ...............................................................................46 
8.4.7 
Spirometry ................................................................................................................47 
8.4.8 
DLco .........................................................................................................................47 
8.4.9 
Swallow Test.............................................................................................................47 
8.4.10 Subjective Opiate Withdrawal Scale ........................................................................47 
9 STUDY CONDUCT ...............................................................................................................48 
9.1 
Treatments Administered ..................................................................................................48 
9.2 
Study Treatment Packaging and Labeling ........................................................................50 
9.2.1 
Labeling ....................................................................................................................50 
9.2.2 
Storage ......................................................................................................................50 
9.2.3 
Blinding and Randomization of Study Treatments...................................................50 
9.3 
Procedure for Breaking the Randomization Code ............................................................51 
9.4 
Subject Compliance ..........................................................................................................51 
9.5 
Investigational Product Accountability .............................................................................51 
9.6 
Concomitant and Prohibited Medications .........................................................................51 
9.6.1 
Concomitant Medications .........................................................................................51 
9.6.2 
Prohibited Medications .............................................................................................52 


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9.6.2.1 Use of Other Opioid Medications .....................................................................52 
9.6.2.2 Benzodiazepines and Other CNS Depressant Class Drugs ...............................52 
9.6.2.3 Serotonergic Class Drugs ..................................................................................52 
9.6.2.4 Prohibited Medications Related to Risk of Torsades de Pointes ......................53 
9.6.3 
Symptom Management .............................................................................................53 
9.7 
Termination of the Study ..................................................................................................53 
10 ASSESSMENT OF SAFETY ................................................................................................54 
10.1 Adverse Event Definition .................................................................................................54 
10.2 Reporting of Adverse Events ............................................................................................54 
10.2.1 Severity of Adverse Events.......................................................................................55 
10.2.2 Relationship to Investigational Product ....................................................................55 
10.2.3 Adverse Event of Special Interest .............................................................................56 
10.3 Abnormal Laboratory Values/Vital Signs/Electrocardiograms/Physical 
Examinations .....................................................................................................................57 
10.4 Deaths ...............................................................................................................................57 
10.5 Overdose ...........................................................................................................................58 
10.6 Pregnancy ..........................................................................................................................58 
10.7 Serious Adverse Events ....................................................................................................58 
10.8 Reporting Serious Adverse Events ...................................................................................59 
11 STATISTICAL EVALUATION...........................................................................................60 
11.1 Sample Size and Power .....................................................................................................60 
11.2 Statistical Analysis Sets ....................................................................................................60 
11.2.1 Safety Population ......................................................................................................60 
11.2.2 Completers Population ..............................................................................................60 
11.3 Statistical Methods ............................................................................................................61 
11.3.1 General Principles .....................................................................................................61 
11.3.2 Missing Data .............................................................................................................61 
11.4 Demographic and Baseline Characteristics ......................................................................61 
11.5 Subject Disposition ...........................................................................................................61 
11.6 Concomitant Medications .................................................................................................61 
11.7 Analysis of Efficacy Data .................................................................................................61 
11.8 Analysis of Safety Data ....................................................................................................62 
11.8.1 Adverse Events .........................................................................................................62 


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11.8.2 Vital Signs.................................................................................................................62 
11.8.3 Clinical Laboratory Assessments..............................................................................62 
11.8.4 Physical Examinations ..............................................................................................62 
11.8.5 Electrocardiograms ...................................................................................................63 
11.8.6 Spirometry ................................................................................................................63 
11.9 Pharmacokinetics Analysis ...............................................................................................63 
12 QUALITY CONTROL AND QUALITY ASSURANCE ...................................................64 
12.1 Conduct of the Study ........................................................................................................64 
12.2 Study Monitoring ..............................................................................................................64 
13 ETHICS ..................................................................................................................................65 
13.1 Independent Ethics Committee/Institutional Review Board .............................................65 
13.2 Written Informed Consent ................................................................................................65 
14 DATA HANDLING AND RECORD KEEPING ................................................................66 
14.1 Case Report Forms/Source Data Handling .......................................................................66 
14.2 Retention of Essential Documents ....................................................................................66 
14.2.1 Access to Records .....................................................................................................66 
14.2.2 Retention of Records ................................................................................................67 
15 PUBLICATION POLICY .....................................................................................................68 
16 REFERENCES .......................................................................................................................69 
APPENDICES ..............................................................................................................................72 
List of Figures 
Description 
Page 
Figure 1: 
Study Schematic ...................................................................................................23 
List of Tables 
Description 
Page 
Table 1: 
Schedule of Events – Screening and Treatment Period 1 ................................24 
Table 2: 
Schedule of Events – Treatment Period 2 ..........................................................27 
Table 3: 
Dosing Scheme ......................................................................................................49 


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2 SIGNATURE PAGE 
SPONSOR SIGNATURE PAGE 
 
PROTOCOL TITLE: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-
Treatment, Two-Period Crossover Efficacy and Safety Study in Idiopathic Pulmonary 
Fibrosis with Nalbuphine ER Tablets for the Treatment of Cough 
PROTOCOL NUMBER:  TR12 
 
Trevi Therapeutics, Inc. 
 
 
 
 
 
 
 
 MD 
 
 
 
 
 
Date (day/month/year) 
 
 
 
 
 
 
 
 
 
 
 


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3 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
AE-IPF 
acute exacerbations of idiopathic pulmonary fibrosis 
AESI 
adverse event of special interest 
ALAT 
Latin American Thoracic Association 
ATS 
American Thoracic Society 
ATC 
anatomical therapeutic class 
BID 
twice daily 
BMI 
body mass index 
CGI-C 
Clinical Global Impression of Change 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CP 
conditional power 
CPAP 
continuous positive airway pressure 
CRA 
clinical research associate 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
D 
Day 
DLco 
diffusing capacity of the lung for carbon monoxide 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ER 
extended release 
ERS 
European Respiratory Society 
E-RS 
Evaluating Respiratory Symptoms Scale 
EU 
European Union 
EXACT 
EXAcerbation of Chronic pulmonary disease Tool 
FDA 
Food and Drug Administration of the United States 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
JRS 
Japanese Respiratory Society 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
independent ethics committee 


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ILD 
interstitial lung disease 
IPF 
idiopathic pulmonary fibrosis 
IRB 
institutional review board 
IUD 
intrauterine contraceptive device 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
KR 
Known Risk 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIH 
National Institutes of Health (US) 
NRS 
Numerical Rating Scale 
OTC 
over-the-counter 
PK 
Pharmacokinetic 
POC 
proof-of-concept 
PPI 
proton pump inhibitor 
PRO 
patient-reported outcomes 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QD 
RBBB             
once daily 
Right Bundle Branch Block 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
TEAE 
treatment emergent adverse event 
TdP 
Torsade de Pointes 
UIP 
usual interstitial pneumonia 
US 
United States 
WHO 
World Health Organization 


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4 INTRODUCTION 
4.1 
Background Information on Idiopathic Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is described in an official endorsed ATS/ERS/JRS/ALAT 
Clinical Practice Guideline (Raghu et al, 2018) as a specific form of chronic, progressive fibrosing 
interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, 
and is defined by the histopathological and/or radiologic pattern of usual interstitial pneumonia 
(UIP). 
Cough and dyspnea are common symptoms of IPF patients with 81% and 90%, respectively, of 
patients reporting these symptoms at the time of diagnosis.  Swigris et al (2011) report fatigue as 
a common, underappreciated, and bothersome symptom of IPF that impacts quality of life but is 
rarely quantitatively assessed in clinical studies.   
Patients participating in the FDA’s “The Voice of the Patient” stated that cough, shortness of 
breath, and fatigue had the greatest impact on their daily life.  In addition to describing the common 
day-to-day triggers to their coughing and the impact of coughing on daily living, patients described 
coughing episodes leading to shortness of breath and exhaustion.  Shortness of breath impacted 
physical activity even after minimal exertion.  Fatigue was associated with coughing and also as a 
result of shortness of breath (“The Voice of the Patient” series report on Idiopathic Pulmonary 
Fibrosis; page 5-7; March 2015). 
Yorke et al (2014) state that regardless of which health-related quality-of-life instrument has been 
used in clinical research of IPF patients, the responses are driven by the symptoms of cough, 
dyspnea, and fatigue, in particular by dyspnea-imposed limitations on physical activities.  Swigris 
et al (2005) state that IPF patients report fatigue is as bothersome as breathlessness. 
As to the natural history of the disease, while there may be some inter-patient variability as to the 
rate of disease progression (Raghu et al, 2011), IPF has a poor prognosis with median survival of 
3.8 years for adults age 65 (Leder and Martinez, 2018).  Death in the IPF patient is frequently 
precipitated by an acute respiratory worsening, including the development of “acute exacerbations 
of IPF” (AE-IPF).  The AE-IPF phase is defined as acute worsening of dyspnea and lung function 
of unknown etiology.  It has an annual incidence of up to 20% and is typically associated with 
median survival of less than 3 months (Ryerson et al, 2015). 
On physical examination, patients have inspiratory crackles, acrocyanosis, and clubbing.  On 
laboratory workup, most patients have a restrictive pattern on pulmonary function testing, 
exercise-induced oxygen desaturation, and a chest radiograph with non-specific changes or 
bilateral reticular abnormalities (Bjoraker et al, 1998; Leder and Martinez, 2018).  The UIP is 
characterized by chest computed tomography radiologic findings of bilateral reticulation and 
honey-combing that is predominately peripheral and in the lower lobes and is diagnostic of IPF in 
the proper clinical setting (Leder and Martinez, 2018). 
Common comorbidities found in IPF patients include pulmonary hypertension, obstructive sleep 
apnea, lung cancer, chronic obstructive pulmonary disease (COPD)/emphysema, ischemic heart 
disease and gastroesophageal reflux disease (GERD) (Raghu and Richeldi, 2017).  Raghu and 


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Richeldi (2017) stated that palliative care be offered to IPF patients at all stages of disease 
management.  Lewis and Scullion (2012) report that IPF palliative care includes symptom-centered 
management that encompasses the treatment of cough, dyspnea, and fatigue/deconditioning. 
4.2 
Background Information on Nalbuphine 
Trevi Therapeutics, Inc. (Trevi) has in-licensed 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 United States 
(US) as Nubain®, on which the presently sold generic injectable formulations are based.  Approved 
indications in the US include the relief of moderate to severe pain, as a supplement to balanced 
anesthesia, pre-operative and post-operative analgesia, and obstetrical analgesia during labor and 
delivery (US Nalbuphine Package Insert, December 2016).  Nalbuphine remains an unscheduled 
drug in the US (Drug Enforcement Agency, 2013). 
Commercial availability in the European Union (EU) of the parenteral formulation of nalbuphine 
dates to 1986 (Medicines Evaluation Board in the Netherlands, 2010) with approved indications 
for short-term relief of moderate to severe pain and pre- and post-operative analgesia (UK Nalpain 
SmPC, January 2011).  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 
(2010)). 
Nalbuphine is a member of the “opioid agonist-antagonist” class of drugs with agonistic action at 
kappa opioid receptors and antagonistic activity at mu opioid receptors (Yaksh and Wallace 2011).  
The clinical development program of NAL ER tablets has included prior investigational studies 
for the treatment of prurigo nodularis related pruritus, uremic pruritus in hemodialysis patients as 
well as safety and efficacy analgesic studies.  This study protocol is to investigate NAL ER tablets 
as a treatment for cough related to IPF.  Additional information can be found in the Investigator 
Brochure. 
4.3 
Rationale for Investigation of Nalbuphine in Cough and Dyspnea Related to 
Idiopathic Pulmonary Fibrosis 
A detailed briefing document on the rationale for investigating NAL ER tablets in IPF related 
cough and dyspnea is found in Appendix 10.  A brief summary is provided below. 
There is medical literature reporting that the opioid drug class may be effective antitussives. 
Morice et al (2007) report in chronic cough subjects that morphine is effective treatment.  The 
mixed agonist-antagonist pharmacologic class of drugs has been shown in human studies to have 
antitussive effect on 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 (US 
Torbutrol® Package Insert, 2013). 


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As it relates to dyspnea from various medical diagnoses, Jennings et al (2002) summarized the 
medical literature on the use of mu agonist opioids in the treatment of dyspnea and supported their 
continued use in patients with advanced underlying disease, as did Mahler (2013). 
The brainstem cough reflex (Canning 2014) may be impacted by nalbuphine pharmacological 
action by lessening the nerve tissue irritability peripherally at the level of the afferent limb of the 
cough reflex arc by acting directly on receptors on nerve terminals, acting directly at the level of 
lung tissue where endogenous opioid ligands are likely produced by immune system cells in the 
parenchymal mileu during the inflammatory and fibrotic processes, or through other 
pharmacologic actions that reduce peripheral sensitization phenomena in the local inflammatory 
mileu.  In a different disease paradigm, opioid class drugs are known to reduce pain that is 
mediated via peripheral sensitization induced neuronal signaling. 
The physiological phenomena of central sensitization of cough may be occurring in IPF as an 
explanation of the chronic nature of the cough (Hope-Gill 2003).  Nalbuphine may be able to act 
centrally at the brainstem level to desensitize the cough reflex arc and lessen the efferent reflex arc 
outflow, with the net result that coughing will be lessened or terminated. 
Given the density of mu and kappa opiate receptors in the cortex and the anatomical and 
physiological understanding of the role of cortical activity in dyspnea (Mahler and O'Donnell 
2015) and cough (Mazzone et al 2009), cortical directed pharmacologic action of nalbuphine may 
also positively impact cough and dyspnea and then lead to less sensation of fatigue.  As it relates 
to dyspnea, nalbuphine pharmacology may act at the perceptual level of modifying the experience 
of dyspnea that adversely impacts quality of life, as well as pharmacologically modulating central 
command drives controlling breathing to bring the central nervous system (CNS) respiratory 
control drives more in balance with the mechanical capacity of ventilator apparatus of the 
pulmonary organ.  Cortical mediated control of cough may be an important regulator of the cough 
reflex set point that drives frequency and intensity of this reflex action. 
 


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5 STUDY OBJECTIVES 
5.1 
Primary Objectives 
The primary objectives of this study are as follows: 
• 
To evaluate the safety and tolerability of NAL ER tablets in the study population. 
• 
To evaluate the effect of NAL ER tablets on the mean daytime cough frequency (coughs per 
hour) at Day 22 (dose 162 mg BID) as compared to placebo.  Assessment is done using 
objective digital cough monitoring.  Daytime is defined as the time the subject is awake in the 
24 hours after the digital cough monitor is applied for use.  
5.2 
Secondary Objectives 
The secondary objectives of this study are as follows: 
• 
To evaluate the effect of NAL ER tablets on the mean relative change from baseline in daytime 
cough frequency (coughs per hour) at Day 22 (dose: 162 mg BID). 
• 
To evaluate the effect of NAL ER tablets on the mean relative change from baseline in 24-hour 
(combined daytime and nighttime) cough frequency (coughs per hour) at Day 22 (dose: 162 
mg BID). 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean relative change from 
baseline in nighttime cough frequency (coughs per hour) at and Day 22 (dose: 162 mg BID). 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline 
on the Evaluating Respiratory Symptoms (E-RS™) diary cough scale (E-RS diary question 
number 2) by treatment at Days 9, 16, and 22. 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline 
in the Cough Severity Numerical Rating Scale by treatment at Days 8, 15, and 21.    
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline 
in the E-RS diary breathlessness scale (E-RS diary questions 7, 8, 9, 10, and 11) by treatment 
at Days 9, 16, and 22.    
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline 
in the 14-item the EXAcerbation of Chronic pulmonary disease Tool (EXACT®) version 1.1 
e-diary tool total score by treatment at Days 9, 16, and 22. 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from baseline 
in the Patient Reported Outcomes Measurement Information System (PROMIS®) Item Bank 
v1.0 Fatigue Short Form 7a scale by treatment at Day 21. 
• 
To evaluate the change in the CGI-C over time by treatment measured at Day21. 


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6 INVESTIGATIONAL PLAN 
6.1 
Study Design 
This is a double-blind, randomized, placebo-controlled, 2-treatment, 2-period crossover efficacy 
and safety study in IPF subjects with NAL ER tablets for the treatment of cough.  The study 
consists of 2 treatment periods of 3 weeks, each followed by a washout period of 2 weeks.     
Treatment Period 1: 
During Treatment Period 1, eligible subjects will be randomized (1:1) to one of the following 
treatment arms: 
• Arm 1: Active NAL ER tablets followed by crossover Placebo tablets in Treatment 
Period 2 
• Arm 2: Placebo tablets followed by crossover NAL ER tablets in Treatment Period 2 
Following 3 weeks of dosing in Treatment Period 1, subjects will complete a 2-week washout 
period before entering Treatment Period 2.  Subjects assigned to Arm 1 will receive placebo tablets 
and subjects assigned to Arm 2 will receive NAL ER tablets during Treatment Period 2.  A final 
2-week washout period will occur at the completion of Treatment Period 2. 
NAL ER Dosing 
Subjects on NAL ER tablets will have the dose titrated from 27 mg once daily (QD) to 54 mg BID 
over a 5-day period and then maintained at 54 mg BID for approximately 4 days.  Doses will be 
subsequently escalated and maintained at 108 mg BID over 1 week and then to 162 mg BID over 
6 days. 
Study Visits: 
Study visits will include screening to determine eligibility, and for each treatment period: visits at 
Day -1 for baseline assessments, at Days 8, 15, and 21 during treatment, and a follow-up at the 
end of the 2-week washout period.  At study screening and the Day 21 visits, during each treatment 
period, subjects will have blood drawn for safety analysis.  Pharmacokinetic (PK) analysis of 
nalbuphine plasma concentration will also be done at Day 21.  Subjects will complete 
questionnaires for efficacy evaluations and undergo safety evaluations including an ECG.  At the 
baseline and Day 21 visits, during each treatment period, site staff will place an electronic cough 
monitor on the subject, which will be worn until the evening of the following day in order 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 prior to bedtime.  Subjects will complete a 
daily e-diary twice per day. 
Subjects who discontinue investigational product, for reasons other than withdrawal of consent, 
will be considered to have prematurely discontinued treatment and will be asked to complete the 
premature discontinuation and 2-week off-treatment safety follow-up evaluations. 
The schematic of the study design is provided in Figure 1. 


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Figure 1: 
Study Schematic 
 
D = Day. 
6.2 
Study Schedule 
The schedule of assessments is provided in Table 1 and Table 2. 
 
Screening Period 
N=30 Nalbuphine 
Placebo 
Predose 
27 mg QD 27 mg BID 54 mg BID 
Randomization 
N=30 
108 mg BID 162 mg BID 
Predose 
Placebo 
14-day washout 
Day -1 
D1 pm & D2 pm D3 am – D5 am D5 pm – D9 am D9 pm – D16 
am 
D16 pm – D22 
am 
Double-blind treatment period 
Visits on 
Days: 
-1 
8 
15 
21 


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Table 1:  
Schedule of Events – Screening and Treatment Period 1 
 
 
  
 
Treatment Period 11 
Premature 
Discontinuation 
 
  
Screening 
Baseline 
Treatment 
Follow-up2 
 
 
Visit: 
1 
2 
 
3 
4 
5 
 
6 
 
 
 
 On-Site Visit On-Site Visit 
 
Phone Visit 
Phone Visit 
On-Site Visit 
 
On-Site Visit 
On-Site Visit 
 
 
Treatment Day: 
-45 to -2 
-1 
13 
8 
(+/-1 day) 
15 
(+/-1day) 
21 
224 
36  
(+/-2days) 
 
 
 Informed consent 
X 
 
 
 
 
 
 
 
 
 
 Demographics 
X 
 
 
 
 
 
 
 
 
 
 Medical history 
X 
 
 
 
 
 
 
 
 
 
 Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
 Electrocardiogram (triplicate)5 
X 
 
 
 
 
 
 
X18 
X 
 
 Vital signs6   
X 
 
 
 
 
 
 
X 
X 
 
 Spirometry7 
X 
 
 
 
 
X 
 
 
 
 
 DLco measurement20 
X 
 
 
 
 
 
 
 
 
 
 Swallow test 
X 
 
 
 
 
 
 
 
 
 
 Physical examination 
X 
 
 
 
 
 
 
X18 
X 
 
 Urine pregnancy test 
X 
X8 
 
 
 
 
 
X 
X 
 
 Serum pregnancy test 
X 
 
 
 
 
 
 
 
X 
 
 Clinical laboratory tests9 
X 
 
 
 
 
X 
 
 
X 
 
 PK blood sampling 
 
 
 
 
 
X 
 
 
 
 
 Randomization 
 
X 
 
 
 
 
 
 
 
 
 Cough monitor – Dispense/train on use 
 
X10,11 
 
 
 
X11 
 
 
 
 
 Cough monitor – Removal/return for 
downloading of data  
 
 
X12 
 
 
 
X12 
 
 
 
 Cough frequency (via cough monitor) 
 
X 
X12 
 
 
X 
X12 
 
  
 
 Cough Severity Numerical Rating Scale 
X13 
X 
 
X 
X 
X 
 
 
X 
 
 Fatigue Scale (Short Form 7a) 
 
X 
 
 
 
X 
 
 
X 
 
 Clinical Global Impression of Change 
 
 
 
 
 
X 
 
 
 
 
 e-diary – Dispense and train on use 
 
X 
 
 
 
 
 
 
 
 
 e-diary – Review compliance19 
 
 
 
X 
X 
X 
 
 
 
 
 EXACT version 1.1 e-diary tool14 
 
<----- Recorded throughout -----> 
 
X 
 
 Subjective Opiate Withdrawal Scale 
e-diary 
 
 
 
 
 
X15 
 
 
X15 
 
 Contraceptive counseling (if applicable) 
X 
X 
 
X 
X 
X 
 
 
 
 
 Dispense Subject Medication and 
Symptom Log 
X 
 
 
 
 
 
 
 
 
 


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Treatment Period 11 
Premature 
Discontinuation 
 
  
Screening 
Baseline 
Treatment 
Follow-up2 
 
 
Visit: 
1 
2 
 
3 
4 
5 
 
6 
 
 
 
 On-Site Visit On-Site Visit 
 
Phone Visit 
Phone Visit 
On-Site Visit 
 
On-Site Visit 
On-Site Visit 
 
 
Treatment Day: 
-45 to -2 
-1 
13 
8 
(+/-1 day) 
15 
(+/-1day) 
21 
224 
36  
(+/-2days) 
 
 
 Subject Medication and Symptom Log – 
Retrieve/review/re-dispense 
 
X 
 
X 
X 
X 
 
 
 
 
 Record/assess AEs, conmeds, and 
therapies (including restricted/prohibited 
medications)16 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 Dispense Investigational Product blister 
card/dosing instructions 
 
X 
 
 
 
 
 
 
 
 
 Review Investigational Product 
compliance 
 
 
 
X 
X 
 
 
 
 
 
 Retrieve Investigational Product blister 
card/review compliance/re-dispense  
 
 
 
 
 
X 
 
X17 
X17 
 
 Retrieval of e-diary, medication and 
symptom log 
 
 
 
 
 
 
 
X 
X 
 
 
BMI = body mass index; PK = pharmacokinetic; AE = adverse event; conmeds = concomitant medications 
 
 
1 
= 
Investigational product administration in each treatment period will be separated by a washout interval of 2 weeks between dosing. 
 
2 
= 
Follow-up will occur 14±2 days after the last administration of investigational product. 
 
3 
= 
First dose of investigational product for Treatment Period 1 is taken the evening of Day 1 after removal of the cough monitor. 
 
4 
= 
Last dose of investigational product for Treatment Period 1 is the morning dose of Day 22. 
 
5 
= 
Electrocardiogram (ECG) to be recorded prior to blood sampling when possible at scheduled visits where PK and/or clinical labs are obtained.  Subjects should be in the 
supine position for at least 5 minutes prior to obtaining ECGs with all 3 tracings captured within a 3-5 minute window. 
 
6 
= 
Includes heart rate, blood pressure, respiratory rate, body temperature, and pulse oximetry.  Vital signs should be taken prior to blood sampling and measured after the 
subject has been seated for at least 5 minutes. 
 
7 
= 
Performance of spirometry should adhere to ATS/ERS guidelines; required as part of meeting inclusion criterion #2.  
 
8 
= 
A negative urine pregnancy test will be confirmed prior to randomizing any female subjects of childbearing potential. 
 
9 
= 
Blood and urine samples for clinical laboratory testing should be obtained after 8 hours of fasting whenever possible.  Clinical chemistry, hematology, urinalysis, and 
coagulation will be assessed.  
 
10 
= 
Baseline values for the purposes of the statistical analysis of treatment effect on daytime cough frequency during that crossover period.  First dose of investigational product 
on Treatment Day 1 will be taken after removal of the cough monitor. 
 
11 
= 
Monitor will be placed on the subject by site staff at the end of the visit.  
 
12 
= 
Digital cough monitor hookup (24-hour recording); monitor will be worn until the evening of the following day in order 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 prior to bedtime.  On Treatment Day 1, the monitor will be 
removed prior to taking the first dose of investigational product. Subject to be provided with appropriate shipping material to return monitor for downloading of cough data 
(after removal).  
 
13 
= 
Administered on paper for screening; required as part of meeting inclusion criterion #6. 
 


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14 
= 
E-RS consists of item numbers 1-11 on the 14-item EXACT version 1.1 e-diary tool.  E-diary tool will be completed each evening by the subject prior to bedtime.  Subject 
will be reminded to complete this daily at each appropriate study visit. 
 
15 
= 
Subjective Opiate Withdrawal Scale will be completed daily via e-diary for 14 days following discontinuation of investigational product regardless of when this occurs (i.e. 
Day 23 or premature discontinuation).  Site will log into the e-diary portal to confirm subject is completing entries as required during the washout period. 
 
16 
= 
Spontaneous AE reporting will be continuous throughout the study; however, AE assessments will be performed at each visit using non-leading questions. 
 
17 
= 
Retrieve/review compliance at these visits; investigational product and packet will not be re-dispensed. 
 
18 
= 
ECG and physical exam do not need to be repeated at Visit 6 if previously performed for Premature Discontinuation Visit.  A brief physical exam may be performed at Visit 
6 to document any changes from the previous exam. 
 
19 
20 
 
= 
During all visits (including those conducted by telephone), site will review e-diary entries for compliance.  Site will also retrain the subject on use of e-diary if needed. 
Subjects without DLco testing in the previous 6 months may be enrolled with medical monitor approval. 
 
 
 
 
 
 
 


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 Table 2: 
Schedule of Events – Treatment Period 2 
 
 
  
Treatment Period 21 
Premature 
Discontinuation 
 
  
Baseline 
Treatment 
Follow-up2 
 
 
Visit: 
6 
 
7 
8 
9 
 
10 
 
 
 
 On-Site Visit 
 
Phone Visit 
Phone Visit 
On-site Visit 
 
On-Site Visit 
 
 
 
Treatment Day: 
-1 
13 
8  
(+/-1day)  
15  
(+/-1 day) 
21  
224 
36  
(+/-2days) 
 
 
 Electrocardiogram (triplicate)5 
 
 
 
 
 
 
X17 
X 
 
 Vital signs6 
 
 
 
 
 
 
X 
X 
 
 Spirometry7 
 
 
 
 
X 
 
 
 
 
 Physical examination 
 
 
 
 
 
 
X17 
X 
 
 Urine pregnancy test 
 
 
 
 
 
 
X 
X 
 
 Serum pregnancy test 
X 
 
 
 
 
 
 
X 
 
 Clinical laboratory tests9 
X 
 
 
 
X 
 
 
X 
 
 PK blood sampling 
 
 
 
 
X 
 
 
 
 
 Cough monitor – Dispense/train on use 
X10,11 
 
 
 
X11 
 
 
 
 
 Cough monitor – Removal/return for downloading of 
data 
 
X12 
 
 
 
X12 
 
 
 
 Cough frequency (via cough monitor) 
X 
X12 
 
 
X 
X12 
 
  
 
 Cough Severity Numerical Rating Scale 
X 
 
X 
X 
X 
 
 
X 
 
 Fatigue Scale (Short Form 7a) 
X 
 
 
 
X 
 
 
X 
 
 Clinical Global Impression of Change 
 
 
 
 
X 
 
 
 
 
 e-diary – Re-train on use 
X 
 
 
 
 
 
 
 
 
 e-diary – Review compliance18 
X 
 
X 
X 
X 
 
 
 
 
 EXACT version 1.1 e-diary tool13 
<----- Recorded throughout -----> 
 
X 
 
 Subjective Opiate Withdrawal Scale e-diary 
 
 
 
 
X14 
 
 
X14 
 
 Contraceptive counseling (if applicable) 
X 
 
X 
X 
X 
 
 
 
 
 Dispense Subject Medication Symptom Log 
X 
 
 
 
 
 
 
 
 
 Subject Medication and Symptom Log – 
retrieve/review/re-dispense 
 
 
X 
X 
X 
 
 
 
 
 Record/assess AEs, conmeds, and therapies (including 
restricted/prohibited medications)15 
X 
 
X 
X 
X 
 
X 
X 
 
 Dispense Investigational Product blister card/dosing 
instructions 
X8 
 
 
 
 
 
 
 
 
 Review Investigational Product compliance 
 
 
X 
X 
 
 
 
 
 
 Retrieve Investigational Product blister card/ review 
compliance/re-dispense  
 
 
 
 
X 
 
X16 
X16 
 
 Final retrieval of e-diary, medication and symptom log 
 
 
 
 
 
 
X 
X 
 


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PK = pharmacokinetic; AE = adverse event; conmeds = concomitant medications 
 
1 
= 
Investigational product administration in each treatment period will be separated by a washout interval of 2 weeks between dosing. 
 
2 
= 
Follow-up will occur 14±2 days after the last administration of investigational product. 
 
3 
= 
First dose of investigational product for Treatment Period 2 is taken the evening of Day 1 after removal of the cough monitor. 
 
4 
= 
Last dose of investigational product for Treatment Period 2 is the morning dose of Day 22. 
 
5 
= 
 Electrocardiogram (ECG) to be recorded prior to blood sampling when possible at scheduled visits where PK and/or clinical labs are obtained.  Subjects should be in the 
supine position for at least 5 minutes prior to obtaining ECGs with all 3 tracings captured within a 3-5 minute window. 
 
6 
= 
Includes heart rate, blood pressure, respiratory rate, body temperature, and pulse oximetry.  Vital signs should be taken prior to blood sampling and measured after the 
subject has been seated for at least 5 minutes. 
 
7 
= 
Performance of spirometry should adhere to ATS/ERS guidelines.  
 
8 
= 
A negative urine pregnancy test will be confirmed prior to randomizing any female subjects of childbearing potential. 
 
9 
= 
Blood and urine samples for clinical laboratory testing should be obtained after 8 hours of fasting whenever possible.  Clinical chemistry, hematology, urinalysis, and 
coagulation will be assessed.  
 
10 
= 
Baseline values for the purposes of the statistical analysis of treatment effect on daytime cough frequency during that crossover period.  First dose of investigational 
product on Treatment Day 1 will be taken after removal of the cough monitor. 
 
11 
= 
Monitor will be placed on the subject by site staff at the end of the visit.  
 
12 
= 
Digital cough monitor hookup (24-hour recording); monitor will be worn until the evening of the following day in order 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 prior to bedtime.  On Treatment Day 1, the monitor will be 
removed prior to taking the first dose of investigational product.  Subject to be provided with appropriate shipping material to return monitor for downloading of cough 
data (after removal).   
 
13 
= 
E-RS consists of item numbers 1-11 on the 14-item EXACT version 1.1 e-diary tool.  E-diary tool will be completed each evening by the subject prior to bedtime.  
Subject will be reminded to complete this daily at each appropriate study visit. 
 
14 
= 
Subjective Opiate Withdrawal Scale will be completed daily via e-diary for 14 days following discontinuation of investigational product regardless of when this occurs 
(i.e. Day 23 or premature discontinuation).  Site will log into the e-diary portal to confirm subject is completing entries as required during the washout period. 
 
15 
= 
Spontaneous AE reporting will be continuous throughout the study; however, AE assessments will be performed at each visit using non-leading questions. 
 
16 
= 
Retrieve/review compliance at these visits; investigational product and packet will not be re-dispensed. 
 
17 
= 
ECG and physical exam do not need to be repeated at Visit 10 if previously performed for Premature Discontinuation Visit.  A brief physical exam may be performed at 
Visit 10.  
 
18 
= 
During all visits (including those conducted by telephone), site will review e-diary entries for compliance.  Site will also retrain the subject on use of e-diary if needed. 
 


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6.3 
Study Visits and Procedures 
For each subject, approximately 10 visits will be performed: screening visit, baseline visits for 
each treatment period, 2 weekly phone visits plus a Day 21 clinic visit during each treatment 
period, and an off-treatment safety follow-up visit after each treatment period.  The subject will 
undergo assessments for Follow-Up Visit of Treatment Period 1 and the Baseline Visit for 
Treatment Period 2 on the same calendar day.  The procedures and assessments to be performed 
during each period/time point are indicated in the Schedule of Events (Table 1 and Table 2).  
Further relevant details of the evaluations to be performed at each visit are described below. 
6.3.1 
Treatment Period 1 
Screening Visit 1 (Day -45 to Day -2) 
Up to 44 days prior to randomization, subjects will participate in a screening visit to determine 
eligibility to proceed in the study.   
Subjects may be re-screened at the discretion of the Medical Monitor and with written permission 
from the Sponsor. In cases of other unique circumstances that may justify re-screening, 
Investigators must contact the Medical Monitor to discuss the specific conditions under which 
subjects may qualify for re-screening. 
 
During screening, subjects will provide informed consent and undergo the following assessments 
and procedures: 
• 
Review of eligibility/inclusion and exclusion criteria 
• 
Demographics and medical history 
• 
Physical examination 
• 
Height, weight, and body mass index 
• 
ECG (triplicate) 
• 
Measurement of vital signs (blood pressure, heart rate, and respiratory rate), body temperature 
and pulse oximetry 
• 
Spirometry 
• 
DLco measurement (within the previous 6 months or approval of medical monitor) 
• 
Swallow test 
• 
Cough Severity Numerical Rating Scale (administered on paper at screening) 
• 
Clinical laboratory testing (chemistry, hematology, urinalysis, and coagulation) 
• 
Serum and urine pregnancy testing (females of childbearing potential) 
• 
Contraceptive counseling (if applicable) 
• 
Dispense Subject Medication and Symptom Log 


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• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
Baseline Visit 2 (Day -1) 
Subjects will return for the baseline visit, at which point it will be determined if they meet all study 
entry criteria prior to being randomized.  Subjects will undergo the following assessments during 
this visit: 
• 
Confirm eligibility against inclusion/exclusion criteria 
• 
Urine pregnancy tests (females of childbearing potential) 
• 
Contraceptive counseling (if applicable) 
• 
Cough Severity Numerical Rating Scale 
• 
Fatigue Scale (Short Form 7a)  
• 
Review and re-dispense Subject Medication and Symptom Log  
• 
Randomization via Interactive Voice/Web Response System (IVRS/IWRS) 
• 
Dispense investigational product blister card 
• 
Provide subject with dosing instructions including instructions for recording daily dosing 
• 
Dispense e-diary and train on its use 
• 
Provide instructions for completing the EXACT version 1.1 e-diary tool  
• 
Dispense cough monitor, train subject on use and provide instruction for removing the device 
prior to bedtime and prior to taking the first dose of investigational product the next day 
(Day 1)  
• 
Provide packing and shipping materials for return of cough monitor to Vitalograph® after 
removal 
• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
Telephone Visit 3 and 4 (Day 8 and 15) 
Visit 3 (Day 8) and Visit 4 (day 15) will be performed via a telephone call to the Subject.  During 
these visits, subjects will undergo the following assessments: 
• 
Contraceptive counseling (if applicable) 
• 
Cough Severity Numerical Rating Scale 
• 
Review e-diary entries with subjects for compliance, and re-train on use of e-diary if needed 
• 
EXACT version 1.1 e-diary tool and reminder to complete it daily until the next visit 
• 
Review Subject Medication and Symptom Log with subject 
• 
Review blister card accountability/compliance with subject  
• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 


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Treatment Visit 5 (Day 21) 
During this visit, subjects will undergo the following assessments: 
• 
Spirometry 
• 
Clinical laboratory testing (chemistry, hematology, urinalysis, and coagulation) 
• 
PK blood sampling  
• 
Contraceptive counseling (if applicable) 
• 
Cough Severity Numerical Rating Scale 
• 
Fatigue Scale (Short Form 7a) 
• 
CGI-C 
• 
Review e-diary entries for compliance, and re-train on use of e-diary if needed 
• 
EXACT version 1.1 e-diary tool and reminder to complete it daily until end of treatment 
• 
Dispense cough monitor, train subject on use and provide instruction for removing the device 
prior to bedtime the next day (Day 22) 
• 
Provide packing and shipping materials for return of cough monitor to Vitalograph® after 
removal 
• 
Retrieve, review and re-dispense Subject Medication and Symptom Log 
• 
Collect the investigational product blister card, assess accountability/compliance and return 
investigational product blister card to subject 
• 
Reminder to take the final dose of investigational product on the morning of the next day 
(Day 22) 
• 
Instructions for completing the Subjective Opiate Withdrawal Scale (SOWS) daily by e-diary 
for 14 days (beginning Day 23). 
• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
Follow-up Visit 6 (Day 36) 
Subjects will return for Follow-up Visit 6 (Day 36) 14 days (+/- 2 days) after the last day of dosing 
in Treatment Period 1.  Subjects will undergo the following assessments: 
• 
Brief physical examination 
• 
ECG (triplicate) 
• 
Measurement of vital signs (blood pressure, heart rate, and respiratory rate), body temperature, 
and pulse oximetry 
• 
Urine pregnancy test (females of childbearing potential) 
• 
Collect the investigational product blister card and assess accountability/compliance  
• 
Retrieve e-diary 
• 
Retrieve and review Subject Medication and Symptom Log 


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• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
Before proceeding to Treatment Period 2, females of childbearing potential should have a 
confirmed negative urine pregnancy test administered by study staff.  In most instances, the 
Baseline visit for Treatment Period 2 will occur on the same calendar day as the Follow-up Visit 
6. 
6.3.2 
Treatment Period 2  
Baseline Visit 6 (Day -1) 
The Baseline visit for Treatment Period 2 will be completed prior to Day 1 dose administration.  
Subjects will undergo the following assessments: 
• 
Clinical laboratory testing (chemistry, hematology, urinalysis, and coagulation) 
• 
Serum pregnancy test (females of childbearing potential) 
• 
Contraceptive counseling (if applicable) 
• 
Cough Severity Numerical Rating Scale 
• 
Fatigue Scale (Short Form 7a) 
• 
Re-distribute e-diary to subject, review entries for compliance, and re-train on use 
• 
EXACT version 1.1 e-diary tool and reminder to complete it daily until the next visit 
• 
Dispense cough monitor, re-train subject on use and provide instruction for removing the 
device prior to bedtime and prior to taking the first dose of investigational product the next day 
(Day 1)  
• 
Provide packing and shipping materials for return of cough monitor to Vitalograph® after 
removal 
• 
Dispense investigational product as per IVRS/IWRS 
• 
Provide subject with dosing instructions  
• 
Dispense Subject Medication and Symptom Log 
• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
Telephone Visit 7 and 8 (Day 8 and 15) 
Visit 7 and 8 (Day 8 and 18) will be performed via a telephone call to subjects.  During these 
visits, subjects will undergo the following assessments: 
• 
Contraceptive counseling (if applicable) 
• 
Cough Severity Numerical Rating Scale 
• 
Review e-diary entries with subject for compliance, and re-train on use of e-diary if needed 
• 
EXACT version 1.1 e-diary tool and reminder to complete it daily until the next visit 


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• 
Review Subject Medication and Symptom Log with subject  
• 
Review investigational product accountability/compliance with subject  
• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
Treatment Visit 9 (Day 21) 
During this visit, subjects will undergo the following assessments: 
• 
Spirometry 
• 
Clinical laboratory testing (chemistry, hematology, urinalysis, and coagulation) 
• 
PK blood sampling  
• 
Contraceptive counseling (if applicable) 
• 
Cough Severity Numerical Rating Scale 
• 
Fatigue Scale (Short Form 7a) 
• 
CGI-C 
• 
Review e-diary entries for compliance, and re-train on use of e-diary if needed 
• 
EXACT version 1.1 e-diary tool and reminder to complete it daily until end of treatment 
• 
Dispense cough monitor, train subject on use and provide instruction for removing the device 
prior to bedtime the next day (Day 22) 
• 
Provide packing and shipping materials for return of cough monitor to Vitalograph® after 
removal 
• 
Review and re-dispense Subject Medication and Symptom Log  
• 
Collect investigational product blister card, assess accountability/compliance and return 
investigational product blister card to subject   
• 
Reminder to take the final dose of investigational product on the morning of the next day 
(Day 22) 
• 
Instructions for completing the SOWS daily by e-diary for 14 days (beginning Day 23). 
• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
Follow-up Visit 10 (Day 36) 
Subjects will return for Follow-up Visit 10 (Day 36) 14 days (+/- 2 days) after the last day of 
dosing in Treatment Period 2.  Subjects will undergo the following assessments: 
• 
Brief physical examination 
• 
ECG (triplicate) 
• 
Measurement of vital signs (blood pressure, heart rate, and respiratory rate), body temperature, 
and pulse oximetry 


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• 
Urine pregnancy test (females of childbearing potential) 
• 
Collect 
investigational 
product 
blister 
card 
and 
assess 
investigational 
product 
accountability/compliance. 
• 
Retrieve e-diary 
• 
Retrieve and review Subject Medication and Symptom Log 
• 
Record and assess adverse events, concomitant medications, and therapies (including restricted 
and prohibited medications) 
6.3.3 
Premature Discontinuation Visit 
Subjects who complete investigational product treatment through the full study treatment course 
are considered to have completed treatment (even if some doses have been missed).  Subjects who 
discontinue investigational product prior to Treatment Period 2 (Visit 10) will be considered to 
have prematurely discontinued and will be asked to complete the following visits (unless consent 
is withdrawn): 
• If the decision to discontinue treatment is made during an onsite study visit (scheduled or 
unscheduled), perform the procedures and assessments outlined in the Premature 
Discontinuation Visit, regardless of where they are in the study visit schedule.   
• If the decision to discontinue treatment is made while the subject is not at a study visit, schedule 
a visit as soon as possible, but no later than 2 weeks later, to perform the procedures and 
assessments described in the Premature Discontinuation Visit.  Upon notification that the 
subject has permanently stopped dosing, the site should instruct the subject to begin entering 
their SOWS data daily via the e-diary. 
• The subject should be scheduled to return to the clinic 2 weeks after completion of the 
Premature Discontinuation Visit for procedures and assessments outlined in the Follow-up 
Visit (Visit 6 if in Treatment Period 1 and Visit 10 if in Treatment Period 2). 
6.3.4 
Unscheduled Visits 
Should there be a need for an unscheduled visit or assessment (e.g., to manage or follow any 
unresolved adverse events), the Investigator should use his/her judgment and perform an adequate 
evaluation of the subject.  Vital signs, physical examination, clinical laboratory tests, or any other 
evaluations required to assess the subject’s status should be performed as clinically necessary with 
data recorded in the Unscheduled Visit section of the electronic Case Report Form (eCRF). 
6.4 
Rationale for Study Design and Dose Selection 
This study has been designed as a Phase 2, double-blind, randomized, placebo-controlled, 
2 treatment, 2-period crossover study of NAL ER tablets for the treatment of cough in subjects 
with IPF.  Subjects will receive investigational product for 22 days duration during each period of 
the crossover.  The 2 crossover treatment periods will be separated by a 2-week washout period.  
The published medical literature including the work of Bacci et al (2018) concluded that reduction 


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in daytime cough frequency may be the most relevant clinical endpoint for assessing the efficacy 
of drug effect in IPF-related cough.  Daytime cough is defined as cough that occurs between the 
time that the subject wakes up and the time that the subject goes to bed. 
The primary study endpoint, mean change in daytime 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 (2015) who summarized the CHEST Expert Panel recommendations regarding tools 
to be used in clinical trials assessing cough.  The Panel recommended that acoustic cough counting 
to assess cough frequency should be done through objective means.  Secondarily, as supported by 
the development work of Bacci et al (2018), the E-RS daily diary will be used as a validated 
patient-reported outcomes (PRO) instrument in assessing NAL ER tablets efficacy in reducing 
IPF-related cough.   
The patients participating in the FDA’s “The Voice of the Patient” (2015) reported that in addition 
to cough, the symptoms of shortness of breath and fatigue had the greatest impact on their daily 
life.  Based on this information, and mechanism of action of NAL ER tablets, these additional 
symptoms may be amenable to treatment and will be investigated with secondary endpoint metrics.  
The FDA’s “The Voice of the Patient” (2015) mentions that dyspnea is an interchangeable clinical 
term with breathlessness and describe patients’ experience of breathlessness as a symptom, with 
no distinction in the descriptions being made as to the occurrence of breathlessness with physical 
activity or breathlessness occurring at rest.  The Bacci et al online supplement (2018) reports 
dyspnea in terms of severity of breathlessness with activity and the E-RS breathlessness subscale 
will be used to analyze whether the concepts of breathlessness associated with or without physical 
activity can be both or separately affected by NAL ER treatment.  The PROMIS fatigue instrument 
will be used as an additional metric in assessing investigational product efficacy in reducing this 
burdensome symptom of IPF.  There will be an overall clinical assessment of the subject's 
condition using the Clinical Global Impression of Change instrument. 
The study staff, subjects, and Sponsor/clinical research organization (CRO) clinical staff will all 
be blinded to treatment assignment/sequence to avoid potential bias.  Based on titration experience 
in prior studies in the development program, subjects will have their dose of NAL ER tablets 
titrated in a blinded manner starting with 27 mg QD up to the target dose of 162 mg BID during 
the first 2 weeks of active treatment.  This titration scheme will increase the likelihood of 
establishing tolerance to the recognized early side effects of this drug class, mainly in the CNS 
(dizziness, headache, and somnolence) and gastrointestinal (nausea and vomiting) organ system 
categories.  The target dose of 162 mg BID is within the dose range that was well tolerated in 
earlier clinical studies of NAL ER tablets. 
This study will be conducted in compliance with the protocol and with the International 
Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP). 
6.5 
Safety Monitoring 
An independent Data Safety Monitoring Board (DSMB) will periodically review safety data.  The 
frequency of data review and DSMB processes are outlined in the DSMB charter. 


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Subjects will be closely monitored for safety.  AEs will be continuously evaluated throughout the 
study.  Vital signs, locally reviewed and central cardiac core laboratory-read ECGs, physical 
examinations, spirometry, clinical laboratory testing will be conducted to monitor subject safety. 
Although nalbuphine is not a controlled substance in the US or the UK, AEs of special interest 
(AESIs) that code to the most relevant abuse-related Medical Dictionary for Regulatory Activities 
(MedDRA) preferred terms will be tabulated and descriptive narratives will be written.  Additional 
AEs that are considered “possibly related to abuse potential” will be tabulated separately (the 
FDA’s “Assessment of Abuse Potential of Drugs: Guidance for Industry” [2017]).  The list of 
MedDRA preferred terms for AESIs will be described in the statistical analysis plan (SAP). 
Subjects will complete the SOWS on a daily basis for 14 days following the last dose of 
investigational product.  Any subjects who are prematurely discontinued from investigational 
product will also complete the SOWS daily for the 14 days following the last dose of 
investigational product (unless consent is withdrawn).  The SOWS is a self-administered scale for 
grading opioid withdrawal symptoms and will be collected via the study issued e-diary. 
If subjects experience significant withdrawal symptoms during the 2-week safety observation 
period, they should contact the Investigator.  At the Investigator’s discretion, they will be offered 
treatment.   
The most frequently reported AEs from NAL ER Phase 1 and 2 clinical studies were primarily in 
the nervous system and GI organ system categories, consistent with other opiates.  The specific 
AEs that are considered to be expected with use of NAL ER are nausea, vomiting, somnolence, 
sedation, dizziness, vertigo, and constipation.  These are generally mild or moderate in severity 
and usually resolve over the titration and early dosing period. 
To mitigate opioid-related side effects, NAL ER tablets will be initiated with a titration schedule.  
Titration is a clinical management strategy consistent with dosing of opioids in general (Jovey et 
al 2003).  In this study, the combination of a low starting dosing (27 mg NAL ER on the first day) 
followed by a relatively slow titration is expected to minimize treatment-limiting opioid adverse 
effects. 
It is known from prior studies, that GI adverse effects (e.g., nausea and vomiting) and CNS adverse 
effects (e.g., dizziness, somnolence, and headaches) occur early and can be treatment-limiting.  In 
anticipation of the possible occurrence of these effects, pre-medications for these symptoms will 
be permitted.   
In anticipation of the possible occurrence of CNS AEs such as somnolence, subjects will be 
instructed to be aware of possible CNS AEs that may occur.  The evening doses during the titration 
period should be taken at home.  The first dose of any new titration step will occur with an evening 
dose (see instructions for taking study medication).  Subjects will be instructed that the 
investigational product may impair mental and/or physical abilities required for the performance 
of potentially hazardous tasks such as driving a car or operating machinery, especially during the 
titration period and in combination with alcohol or tranquilizers or other pharmacologic CNS 
depressants.  Subjects will be instructed not to drive or operate machinery unless they are tolerant 
to the drug and know how they will react to the medication. 


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6.6 
Risk/Benefit and Ethical Assessment 
Nalbuphine has a long history of use in a parenteral formulation, generally for short-term, episodic 
use related to surgical interventions.  The highest dose proposed in the current clinical study is 
162 mg BID (324 mg daily dose), well below the highest recommended daily treatment of 144 mg 
IV dose (equivalent to 864 mg oral dose) for the currently available parenteral administered 
product.  The high peak plasma concentrations that occur in the setting of parenteral use 
significantly exceed the peak levels observed with NAL ER oral dosing, an observation that is 
reassuring with respect to the potential for severe, acute toxicity.  
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 SOWS reporting has been incorporated into the TR12 study.  This 
will facilitate rapid identification and intervention for the respective relevant risks to subjects. 
In addition, labeling of opiate-class drugs includes a warning that concomitant use of an opiate 
together with a benzodiazepine-class drug can increase the risk for respiratory depression, 
including a risk for respiratory arrest.  This warning is based on post-marketing real world data, 
assessing the experience with a wide range of drugs in these 2 classes and in varied settings 
including recreational as well as therapeutic usage.  In TR12, concomitant benzodiazepine use is 
not prohibited, and all subjects are informed of this risk through the study Informed Consent Form.  
At the time of that consent discussion, subjects who are identified as taking a concomitant 
benzodiazepine should receive the Patient Information Sheet on this topic, as should any subject 
for whom a concomitant benzodiazepine is subsequently prescribed. 
With respect to the published literature addressing respiratory depression with nalbuphine, one 
relevant study has been identified; which evaluated the respiratory effects of serial intravenous 
administration of nalbuphine in healthy volunteers.  The results were interpreted by the authors as 
demonstrating a “ceiling” effect for respiratory depression (Gal et al 1982).  In previous clinical 
trials with NAL ER, a total of 41 subjects have received concomitant benzodiazepines while 
receiving NAL ER, and none of these individuals experienced any event of respiratory depression. 
In summary, the risk for subjects participating in the TR12 study is judged to be low based on 
previous experience with oral administration of NAL ER.  The current study will utilize a low 
initiation dose of 27 mg, a gradual dose titration schedule, careful safety monitoring of subjects 
during the clinical study, and appropriate education of Investigators regarding symptoms of rare 
but significant AEs linked to the opiate class.  


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7 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
7.1 
Number of Subjects 
Approximately 60 subjects with diagnosed IPF will be enrolled in the study to ensure evaluable 
data from at least 44 subjects who complete both treatment periods. 
7.2 
Inclusion Criteria 
Subjects eligible for randomization to receive investigational product must meet all the following 
criteria: 
1. Diagnosis of “definite” or “probable” IPF based on ATS/ERS/JRS/ALAT criteria (see Raghu 
et al 2018 in Appendix 6). 
2. FVC > 40% predicted of normal. 
3. Diffusing capacity of the lung for carbon monoxide corrected for hemoglobin [DLCO] > 25% 
predicted of normal within the past 6 months.  Subjects who have not had DLco testing may 
be enrolled with medical monitor approval. 
4. Chronic cough > 8 weeks. 
5. Adequate swallow reflex as assessed by the ability to sip 3 fluid oz (or 89 ml) of water without 
coughing or choking. 
6. Daytime cough severity score ≥ 4 on Cough Severity Numerical Rating Scale at Screening. 
7. Males or females age 18 years and older at the time of consent. 
8. Females of childbearing potential must use an acceptable method of birth control (if sexually 
active).  All females of childbearing potential must have a negative pregnancy test at the 
screening and baseline visits. 
For the purpose of this study, all females are considered to be of childbearing potential unless 
they are postmenopausal (i.e., at least 1 year since last menses and age > 50 years) or surgically 
sterile (i.e., tubal ligation, hysterectomy, and/or bilateral oophorectomy). 
Sexually active female subjects of childbearing potential are required to use 1 barrier method 
(e.g., condom, cervical cap, or diaphragm) of contraception in addition to 1 other method 
(e.g., intrauterine device in place for at least 1-month, stable hormonal contraception for at 
least 3 months, Essure procedure, or spermicide).  For female subjects using a barrier method 
plus spermicide, that method must be used for at least 14 days prior to Screening. 
Female subjects who are abstinent may participate in the study; however, they must be 
counseled on the requirement to use appropriate contraception should they become sexually 
active.  This counseling should occur at each study visit and must be documented in source 
records. 
9. Willing and able to understand and provide written informed consent. 
10. Willing and able to comply with study requirements and restrictions. 
11. Agree to the confidential use and storage of all data and use of all anonymized data for 
publication including scientific publication. 


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7.3 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for participation in the study: 
1. The following conditions are excluded: 
a) Interstitial lung disease (ILD) known to be caused by domestic and occupational 
environmental exposures. 
b) Interstitial lung disease (ILD) known to be caused by connective tissue disease. 
c) Interstitial lung disease (ILD) known to be caused by drug related toxicity. 
2. Currently on continuous oxygen therapy for longer than 16 hours at any level or delivered by 
any modality. Intermittent oxygen use of any duration over any given 24-hr period is allowed. 
3. 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. 
4. Serum bilirubin > 1.5 × upper limit of normal range at screening unless explained by a clinical 
diagnosis of Gilbert’s syndrome. 
5. Serum hepatic alanine aminotransferase or aspartate aminotransferase enzymes > 100 U/L at 
Screening. 
6. Estimated glomerular filtration rate ≤ 44 mL/min/1.73 m2 at Screening. 
7. Upper or lower respiratory tract infection within 4 weeks of Screening. 
8. Significant medical condition or other factors that may interfere with the subject’s ability to 
successfully complete the study. 
9. History of substance abuse that, as determined by the Investigator, may interfere with the 
conduct of the study. 
10. Known intolerance or hypersensitivity/drug allergy to nalbuphine or vehicle components. 
11. Pregnant or lactating female subject. 
12. Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a concurrent 
clinical trial. 
13. Clinical diagnosis of sleep apnea and/or use of CPAP. 
14. History of clinically significant head injury in past 1 month. 
15. Clinical diagnosis of aspiration pneumonitis. 
16. Clinical history of opiate withdrawal symptoms following use of opiates. 
17. Documented or clinically suspected hypercapnia (pCO2 > 6.0kPa). 
Medication-related Exclusions: 
18. Known intolerance (gastrointestinal, central nervous system symptoms) or hypersensitivity/ 
drug allergy to opioids. 


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19. Exposure to any investigational medication, including placebo, within 4 weeks. 
20. Potential subjects cannot have received opiates, including opiate-containing anti-cough agents, 
within 14 days prior to the screening period.  Subjects are prohibited from using opioids, 
including naltrexone, for the duration of the study. 
21. Potential subjects cannot currently be receiving benzodiazepines or other CNS Depressant 
Class Drugs that when used concomitantly with opioids are known to have the potential to 
cause added pharmacologic effects of depressing CNS activity (See Section 9.6.2.2 
(“Benzodiazepines and Other CNS Depressant Class Drugs”). 
22. Potential subjects cannot currently be receiving medications that affect serotonergic 
neurotransmission and that when used concomitantly with opioids can cause serotonin 
syndrome (See Section 9.6.2.3 (“Serotonergic Class Drugs”). 
23. Alcohol consumption should be limited for the duration of study treatment (due to the potential 
cause of added pharmacologic effects of CNS depression when used concomitantly with 
opioids. 
24. Change of IPF-related drug treatment regimen within 8 weeks of Screening. 
Cardiac-related Exclusions: 
25. Subjects with a history of congestive heart failure of Class 2 or higher as graded using the New 
York Heart Association classification (Appendix 8). 
26. Subjects with a history of angina pectoris Grade 2 or higher as graded using the Canadian 
Cardiovascular Society grading scale (Appendix 7). 
27. History of ventricular tachycardia, Torsade de Pointes, or family history of sudden death. 
28. Myocardial infarction or acute coronary syndrome within the previous 3 months, as reported 
by the subject. 
29. Serum potassium below the laboratory lower limit of normal. 
30. QTcF interval >450 ms (mean of 3 screening ECG QTcF values) if QRS <120 ms (mean of 3 screening 
ECG QRS values); QTcF interval >480 ms in the presence of Right Bundle Branch Block (RBBB) 
and/or QRS ≥ 120 ms 
31. Heart rate < 45 bpm on any screening measurement.  Subjects with a resting heart rate of 
< 45 bpm will have it repeated once after 5 minutes in the supine position, and if it remains 
< 45 bpm during the repeat, they will be considered a screen failure. 
32. Use of a medication having a “known risk” of Torsade de Pointes (categorized as “KR” on the 
Credible Meds® website) is not permitted at entry or during the study (See Appendix 9). 
Medications associated with a potential risk of QT prolongation, but not clearly associated 
with Torsade de Pointes, are permitted at study entry if the following criteria are met: 
• 
Subject has been given medication at stable doses for a full 4 weeks prior to Screening. 
• 
Medication dose will not be increased after screening, or during the study, and it is 
anticipated that the subject will receive the medication for the entirety of the study. 


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7.4 
Withdrawal Criteria 
Subjects have the right to withdraw from the study at any time for any reason, without prejudice.  
At any point, the Investigator may discontinue the subject’s study participation at his/her discretion 
and ensure the subject receives appropriate medical care.  The Investigator may consult the 
Medical Monitor to discuss out-of-range test results.  The subject may also be withdrawn at the 
request of the Sponsor.  Additionally, although the Sponsor has every intention of completing the 
study, the Sponsor reserves the right to discontinue the study at any time and for any reason. 
Subjects will be withdrawn from the study for any of the following reasons: 
• 
There is deterioration in the subject’s signs and symptoms and/or the subject develops a disease 
or condition that, in the opinion of the Investigator, would compromise the subject’s safety by 
continuing in the study. 
• 
In the Investigator’s judgment, it is in the best interest of the subject. 
• 
There is a violation of the protocol inclusion and/or exclusion criteria, as deemed relevant by 
the Investigator and discussed with the Medical Monitor. 
• 
The subject withdraws consent for study participation.  
• 
Sponsor terminates the study for any reason.  
• 
Develops a QTcF > 500 ms (mean of 3 ECG QTcF values) in subjects who were randomized 
without ECG findings of RBBB and/or QRS ≥ 120 ms.  
• 
Develops QTcF > 530 ms (mean of 3 ECG QTcF values) in subjects who were randomized 
with ECG findings of RBBB and/or QRS ≥ 120 ms. 
• 
Increase from QTcF baseline of > 60 ms (mean determination from 3 ECG values) 
• 
Death of the subject. 
If a subject withdraws prematurely from the study during a treatment period due to any of the 
above criteria or any other reason (unless consent is withdrawn), study staff should make every 
effort (at withdrawal) to have the subject complete as many of the safety assessments including 
the SOWS, if possible.  The reason for subject withdrawal must be documented in the eCRF.  
Subjects who withdraw from the study will not be replaced. 
If a subject is lost to follow-up, attempts to contact the subject must be made and documented in 
the subject’s eCRF. 
If the Sponsor decides to terminate the study, the reason(s) for termination will be documented in 
the source documents and eCRFs. 
7.5 
Premature Discontinuation of Investigational Product Treatment 
Subjects who discontinue investigational product, for reasons other than withdrawal of consent, 
will be considered to have prematurely discontinued treatment and will be asked to complete the 
premature discontinuation and 2-week off-treatment safety follow-up evaluations. 


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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Efficacy Endpoints 
8.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change in daytime cough frequency (coughs per hour) 
from baseline as assessed by objective digital cough monitoring at Day 22 by treatment.  Daytime 
is defined as the time the subject is awake in the 24 hours after the digital cough monitor is applied 
for use.  
8.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Relative change in daytime cough frequency (coughs per hour) from baseline at   Day 22 (dose: 
162 mg BID) by treatment. 
• Relative change in 24-hour (combined daytime and nighttime) cough frequency (coughs per 
hour) from baseline at Day 22 (dose: 162 mg BID) by treatment. 
• Relative change in nighttime cough frequency (coughs per hour) from baseline at Day 22 
(dose: 162 mg BID) by treatment. 
• Mean change in the E-RS diary cough subscale (E-RS diary question number 2) from baseline, 
at Days 9, 16, and 22 by treatment. 
• Mean change in the Cough Severity Numerical Rating Scale at Days 8, 15, and 21 by treatment. 
• Mean change in the E-RS diary breathlessness subscale (E-RS diary questions 7, 8, 9, 10, and 
11) from baseline at Days 9, 16, and 22 by treatment. 
• Mean change in the 14-item EXACT v1.1 e-diary tool total score from baseline at Days 9, 16, 
and 22 by treatment. 
• Mean change in the PROMIS Item Bank v1.0 Fatigue Short Form 7a scale from baseline at 
Day 21 by treatment. 
• Mean change in the CGI-C over time measured at Day21 by treatment. 
8.2 
Efficacy Assessments 
Efficacy assessments during each of the 2 treatment periods will include 24-hour digital cough 
monitoring of cough frequency, a daily e-diary tool, and instruments of patient-reported outcomes. 
8.2.1 
Digital Cough Monitor 
Boulet et al (2015) summarized the CHEST Expert Panel recommendations regarding tools to be 
used in clinical trials assessing cough.  The Panel recommended acoustic cough counting to assess 
cough frequency should be done through objective means.  


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Measurement of cough frequency will be done using objective digital cough monitoring.  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.  A continuous sound recording is made for up to 36 hours.  The digital recording 
is then processed through accompanying computer software, which automatically registers sound 
patterns typical for cough.  Software output provides the total number of cough events over the 
entire time period of recording and average hourly cough frequency. 
At the baseline visit for each treatment period (the day prior to investigational product initiation), 
and at subsequent treatment visits, 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 evening of the following 
day in order 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 prior to bedtime.  On 
Day 1 of each treatment period, the monitor will be removed prior to taking the first dose of 
investigational product. 
8.2.2 
Subject e-Diary 
All subjects randomized into the study will be provided with a device with an application for a 
subject e-diary, along with instructions for its use.  The device will be password protected.  
Subjects will complete daily e-diaries, including compliance with investigational product dosing, 
and answer study specific questionnaires throughout the duration of the study.  
Queries will be handled by the vendor managing the e-diary data through the clinical site.  The e-
diary data will be reviewed by the study staff.  The subject will return the e-diary to the site at the 
follow-up visit of Treatment Period 2 or discontinuation visit.  
8.2.3 
EXACT 14-item e-Diary Tool and E-RS Diary Cough and Breathlessness Scales 
The EXACT is a 14-item daily diary tool PRO instrument that was originally developed to quantify 
and measure exacerbations of COPD. The E-RS daily diary is a derivative instrument of the 
EXACT that consists of the 11 respiratory symptoms items contained within the 14-item  EXACT 
that measures the effect of treatment on the severity of respiratory symptoms.  Since the E-RS is 
not administered separately from the EXACT, both a total 14--item EXACT total score will be 
computed as a secondary efficacy endpoint and a separate analysis of the E-RS 11-items will be 
done based on the methodology reported in Bacci et al (2018).  
Bacci et al (2018) reported on the use of the E-RS daily diary specifically in IPF patients.  The 
authors concluded that analyzing the E-RS daily diary instrument into four separate respiratory 
symptom domain scales  (with no total E-RS score computed) is a valid, reliable and sensitive 
measure of four distinct respiratory symptoms. 
The four domain scales are breathlessness (E-RS items 7, 8, 9, 10, and 11; score range, 0-23), 
cough (E-RS item 2; score range 0-4), sputum (E-RS items 3 and 4; score range, 0-8), and chest 
symptoms (E-RS items 1, 5, and 6; score range 0-12).  A higher score on the scale indicates a more 
severe grade to the symptom.  The cough and breathlessness symptom domain scale scores  will 
each be studied as secondary efficacy endpoints in this study. 


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A copy of the daily diary tool EXACT version 1.1 is provided in Appendix 1.  Subjects will 
complete the EXACT scale via the study specific e-diary. 
8.2.4 
Cough Severity Numerical Rating Scale 
The Cough Severity Numerical Rating Scale instrument (Boulet et al 2015) is a single-dimension 
11-point Likert scale ranging from zero (“no cough”) to 10 (“worst possible cough”).  In addition 
to its use as a screening instrument, change in the Cough Severity Numerical Rating Scale over 
the conduct of the study will be monitored as a secondary efficacy endpoint. 
A copy of the Cough Severity Numerical Rating Scale is provided in Appendix 2.  The scale will 
be administered on paper during the Screening Visit.  Once a subject is randomized, the scale will 
be administered via the study specific e-diary. 
8.2.5 
PROMIS Item Bank v1.0 Fatigue Short Form 7a Scale 
The Patient-Reported Outcomes Measurement Information System (PROMIS) is a US National 
Institutes of Health (NIH) funded initiative to develop and validate patient reported outcomes 
(PROs) for clinical research and practice. 
The PROMIS fatigue scales were developed to assess a range of self-reported symptoms, from 
mild subjective feelings of tiredness to an overwhelming, debilitating and sustained sense of 
exhaustion that likely decreases one's ability to execute daily activities and function normally in 
family or social roles.  The short form versions are universal rather than disease specific (See 
PROMIS Fatigue Scoring Manual). 
The PROMIS Fatigue Short Form 7a is a self-administered Likert-type rating 5-point scale of 
7 questions that assess tiredness, exhaustion, energy, fatigue limit, tiredness to think, tiredness 
impact on hygiene and impact on ability to exercise strenuously over the past 7 days. 
The PROMIS Fatigue Short Form 7a is provided in Appendix 3.  This scale will be administered 
via the study specific e-diary during onsite visits. 
8.2.6 
Clinical Global Impression of Change Scale 
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 et 
al 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. 
The CGI-C is a one-item measure evaluating change from the initiation of treatment on a seven-
point scale.  Subsequent to 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 
mere symptom checklists.  The CGI-C can track clinical progress across time. 


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The CGI-C will be administered during the Day 21 visits of each treatment period.  The CGI-C is 
provided in Appendix 5. 
8.3 
Pharmacokinetic Assessments 
To determine the plasma concentration of nalbuphine and metabolites, blood samples will be 
collected at the Day 21 visits of each treatment period.   
8.4 
Safety Assessments 
Safety will be assessed based on adverse events, clinical laboratory measurements, locally 
reviewed and central cardiac core laboratory read ECGs, vital signs, spirometry and physical 
examinations. 
Subjects will also complete the SOWS on a daily basis for the 14 days following the last dose of 
investigational product, whenever that occurs and regardless of the reason (unless consent is 
withdrawn). 
An independent Data Safety Monitoring Board will periodically review safety data. 
8.4.1 
Adverse Events 
The Investigator will determine during the course of the study whether any adverse events have 
occurred.  Subjects will be questioned in a general way, and no specific symptoms will be 
suggested.  Section 10 contains additional information with regard to adverse event reporting. 
8.4.2 
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.  Clinical laboratory samples should be obtained following an overnight fast 
(minimum of 8 hours) unless contraindicated due to medication, dietary, or clinical restrictions.  If 
the sample was obtained with less than 8 hours of fasting, the source documents and the lab 
requisition should be marked to indicate that the sample was obtained under non-fasting 
conditions.  Blood samples will be collected and processed as indicated in the central laboratory 
manual. 
The following clinical laboratory analytes will be measured: 
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, alanine aminotransferase, aspartate 
aminotransferase, blood urea nitrogen, calcium, chloride, carbon dioxide, 
creatinine, total bilirubin, gamma-glutamyl transferase, glucose, lactic 


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dehydrogenase, phosphorus, potassium, sodium, total cholesterol, total 
protein, and uric acid 
Urinalysis: 
Color, specific gravity, pH, glucose, ketones, protein, bilirubin, 
urobilinogen, blood, and microscopy (only on urine samples with abnormal 
urinalysis results) 
Coagulation: 
Prothrombin time, international normalized ratio, and activated partial 
thromboplastin time 
8.4.3 
Pregnancy Tests 
Urine and serum pregnancy tests will be performed as specified in the Schedule of Events for 
females of childbearing potential regardless of sexual activity status or method of contraception.  
The subject must have a confirmed negative test prior to randomization.  In addition, during 
Follow-up Visit 6 (Treatment Period 1), the urine pregnancy test must be negative prior to 
providing the subjects will their next supply of study medication.  
8.4.4 
Vital Signs 
Vital signs (blood pressure, heart rate, and respiratory rate), body temperature and pulse oximetry 
will be measured, prior to blood sampling whenever possible, according to the Schedule of Events 
(Table 1 and Table 2).  Blood pressure will be measured with a standard mercury 
sphygmomanometer or an automated oscillometric blood pressure monitor after the subject has 
been in a sitting position for at least 5 minutes.   
8.4.5 
Physical Examination 
A physical examination will be performed at the screening visit and subsequently according to the 
Schedule of Events (Table 1 and Table 2).  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.  A brief physical exam may be performed at Visit 6 (Treatment Period 1) and Visit 10 
(Treatment Period 2) in order to document any changes present since the previous exam. 
8.4.6 
Electrocardiogram Assessments 
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 3-5 minutes.  Whenever possible, ECG 
testing should be performed prior to the collection of vital signs and blood samples (clinical 
laboratory and PK samples). 
 
A standard ECG will be obtained according to the Schedule of Events (Table 1 and Table 2) and 
recorded prior to blood sampling.  Electrocardiograms will be reviewed locally for safety by the 
Investigator and/or their designee. The ECGs will be read centrally for the purpose of meeting the 
ECG study inclusion criteria, study withdrawal criteria and ECG intervals (PR, RR, QRS, QT, and 


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QTcF using nomogram table), rate, rhythm, and other clinically significant abnormalities (e.g., left 
ventricular hypertrophy, pathological Q-waves). 
. 
8.4.7 
Spirometry 
Spirometry will be used to assess FVC in order to exclude subject candidates with severe 
pulmonary ventilation (FVC > 40% predicted of normal required to meet inclusion criteria).  
Spirometry will also be used during the course of the study as a safety measure to objectively 
assess pulmonary breathing mechanics.  Performance of spirometry should adhere to ATS/ERS 
guidelines with reference to predicted equations (predicted values) used locally at the site.  
8.4.8 
DLco 
Diffusing capacity of the lung for carbon monoxide testing, performed within the past 6 months, 
will be used to assess lung function.  Potential subjects with test results indicative of severe gas 
exchange mechanics should be excluded from the study.  Subjects who have not had DLco testing 
within the previous 6 months may be enrolled with medical monitor approval. 
8.4.9 
Swallow Test 
Subjects will be asked to drink 3 fluid oz (or 89 ml) of water uninterrupted and will be evaluated 
by clinical staff for their ability to swallow during and up to one minute after the completion of 
the test.  This test will be used as a screening assessment to verify adequate swallow reflex and 
may be repeated, if necessary. 
8.4.10 Subjective Opiate Withdrawal Scale 
Subjects will complete the SOWS on a daily basis for 14 days following the last dose of 
investigational product in each treatment period.  Any subject discontinued from investigational 
product, prior to completion of the study, will also complete the SOWS daily for the 14 days 
following the last dose of investigational product (unless consent is withdrawn).  The SOWS is a 
self-administered scale for grading opioid withdrawal symptoms. 
The SOWS is provided in Appendix 4.  Subjects will complete the SOWS via the study specific 
e-diary. 


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9 STUDY CONDUCT 
9.1 
Treatments Administered 
The investigational product in this trial is NAL ER tablets or matching placebo tablets.  The 
NAL ER tablets are round, white to off-white, film-coated tablets containing either 27 or 54 mg of 
nalbuphine (equivalent to approximately 30 or 60 mg nalbuphine HCl); The 27 and 54 mg NAL ER 
round tablets are identical in appearance.  The matching placebo tablet supplied is identical in 
appearance to the 27 and 54 mg tablets. 
Following randomization, the subject will be dispensed a blister card containing 22 days of dosing 
for Treatment Period 1.  Dosing will consist of 3 tablets for the AM dose and 3 tablets for the PM 
dose.  In Treatment period 1, subjects assigned to Arm 1 will receive a combination of 
27 mg/54 mg/placebo tablets, and subjects assigned to Arm 2 will receive placebo tablets only.  
Note: There will be no tablets in the blister card for Days 1 and 2 AM and Day 22 PM.  Upon 
completion of Treatment Period 1 and the 2-week washout period, subjects will be provided with 
the appropriate cross over treatment for Treatment Period 2.  For example, subjects in Arm 1, 
receiving a combination of 27 mg/54 mg/placebo tablets in Treatment Period 1, will receive 
placebo tablets in Treatment Period 2.  Subjects in Arm 2, receiving placebo tablets only in 
Treatment Period 1, will receive a combination of 27 mg/54 mg/placebo tablets in Treatment 
Period 2.  The cross over treatments will all be double-blinded. 
For subjects assigned to NAL ER treatment, the dose will be titrated from a starting dose of 27 mg 
QD to the target dose of 162 mg BID over the first 2 weeks of the double-blind treatment period 
and maintained at 162 mg BID during the third week of the treatment period.  The dosing scheme 
is shown in Table 3. 
 
 


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Table 3:  
Dosing Scheme 
 Treatment 
Period 
Visit 
No. 
Treatment 
Day 
Dose (mg) 
Arm 1 
Arm 2 
AM 
PM 
AM 
PM 
 
Treatment 
Period 1 
2 
-1 
— 
— 
— 
— 
 
  
1 
— 
27 
— 
Placebo 
 
  
2 
— 
27 
— 
Placebo 
 
  
3 
27 
27 
Placebo 
Placebo 
 
  
4 
27 
27 
Placebo 
Placebo 
 
  
5 
27 
54 
Placebo 
Placebo 
 
  
6 
54 
54 
Placebo 
Placebo 
 
7 
54 
54 
Placebo 
Placebo 
 
3 
8 
54 
54 
Placebo 
Placebo 
 
  
9 
54 
108 
Placebo 
Placebo 
 
  
10 
108 
108 
Placebo 
Placebo 
 
  
11 
108 
108 
Placebo 
Placebo 
 
  
12 
108 
108 
Placebo 
Placebo 
 
  
13 
108 
108 
Placebo 
Placebo 
 
14 
108 
108 
Placebo 
Placebo 
 
4 
15 
108 
108 
Placebo 
Placebo 
 
  
16 
108 
162 
Placebo 
Placebo 
 
  
17 
162 
162 
Placebo 
Placebo 
 
  
18 
162 
162 
Placebo 
Placebo 
 
  
19 
162 
162 
Placebo 
Placebo 
 
  
20 
162 
162 
Placebo 
Placebo 
 
5 
21 
162 
162 
Placebo 
Placebo 
 
  
22 
162 
— 
Placebo 
— 
 
2-Week Washout 
 
Treatment 
Period 2 
6 
-1 
— 
— 
— 
— 
 
  
1 
— 
Placebo 
— 
27 
 
  
2 
— 
Placebo 
— 
27 
 
  
3 
Placebo 
Placebo 
27 
27 
 
  
4 
Placebo 
Placebo 
27 
27 
 
  
5 
Placebo 
Placebo 
27 
54 
 
  
6 
Placebo 
Placebo 
54 
54 
 
7 
Placebo 
Placebo 
54 
54 
 
7 
8 
Placebo 
Placebo 
54 
54 
 
  
9 
Placebo 
Placebo 
54 
108 
 
  
10 
Placebo 
Placebo 
108 
108 
 
  
11 
Placebo 
Placebo 
108 
108 
 
  
12 
Placebo 
Placebo 
108 
108 
 
  
13 
Placebo 
Placebo 
108 
108 
 
14 
Placebo 
Placebo 
108 
108 
 
8 
15 
Placebo 
Placebo 
108 
108 
 
  
16 
Placebo 
Placebo 
108 
162 
 
  
17 
Placebo 
Placebo 
162 
162 
 
  
18 
Placebo 
Placebo 
162 
162 
 
  
19 
Placebo 
Placebo 
162 
162 
 
  
20 
Placebo 
Placebo 
162 
162 
 
9 
21 
Placebo 
Placebo 
162 
162 
 
  
22 
Placebo 
— 
162 
— 
 
2-Week Washout 


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Investigational product can be taken with or without food.  Tablets must be swallowed whole 
without crushing or chewing.  Subjects will be instructed to take the AM and PM investigational 
product tablets at the same times of the day, approximately 12 hours apart, preferably with at least 
240 mL (approximately 8 ounces) of water.  If the subject does not take a particular dose at the 
planned time, he or she may take it within ± 2 hours. 
Subjects will confirm whether or not they took their dose(s) and the dosing time for both the AM 
and the PM dose.  Any discrepancies between the dosing records and the number of actual versus 
expected tablets returned to the site, should be documented at the actual visit in which the 
investigational product is returned for investigational product drug accountability and 
investigational product compliance assessments. 
Multiple Missed Doses 
If the subject misses 3 (or more) consecutive doses, please contact the study Medical Monitor for 
dosing instructions.  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.  The subject is 
to be instructed on when to resume taking investigational product. 
9.2 
Study Treatment Packaging and Labeling 
Please see the pharmacy manual for additional information on investigational product supplies, 
packaging, storage, dispensation, and accountability. 
9.2.1 
Labeling 
Blister cards will be labeled with, at minimum: contents, storage conditions, expiration date, 
clinical trial statement, and the name of the sponsor (Trevi Therapeutics, Inc). 
9.2.2 
Storage 
NAL ER tablets and placebo tablets should be stored at 20°C to 25°C (68°F to 77°F) with 
excursions permitted between 15°C and 30°C (59°F to 86°F).  The investigational product should 
be stored away from any extreme conditions of temperature, light, or humidity as an additional 
precaution. 
9.2.3 
Blinding and Randomization of Study Treatments 
Randomization will be performed via IVRS/IWRS.  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 NAL ER tablets or placebo tablets for Treatment Period 1.  
Subjects will take the converse study treatment during Treatment Period 2 (the second crossover 
period). 


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9.3 
Procedure for Breaking the Randomization Code 
Under normal circumstances, the blind will not be broken.  In the event of a medical emergency, 
when management of a subject’s condition requires knowledge of the treatment assignment, the 
blind may be broken via the IVRS/IWRS. 
Reasons for unblinding will be documented in the eCRF.  The date and the identity of the person 
responsible for breaking the blind must be also documented. 
9.4 
Subject Compliance 
Drug compliance is a critical data observation in all clinical trials and is assessed through the drug 
accountability records.  Returned blister cards will be compared to subject dosing information to 
assess compliance at each study visit.  An accurate and current accounting of the dispensing and 
return of investigational product for each subject will be maintained on an ongoing basis by a 
member of the study site staff.  The amount of investigational product dispensed and returned by 
the subject will be recorded on the appropriate investigational product accountability forms at each 
visit. 
Compliance is defined as the amount of investigational product that should have been taken by a 
subject based on the dosing instructions provided during the period for which investigational 
product was dispensed.  This is typically expressed as percent (%) compliance and is calculated 
based on the number of tablets actually taken in a particular time interval divided by the number 
of tablets that should have been taken or prescribed for that time interval.  Compliance will be 
documented after each investigational product return, based on the information on the 
investigational product accountability forms.   
Any dosing and/or compliance discrepancies will be noted in source documents for the applicable 
subject visit.   
9.5 
Investigational Product Accountability 
The Investigator must ensure that all investigational product supplies are kept in a secure locked 
area, under controlled temperature, with access limited to those authorized by the Investigator.  
The Investigator must maintain accurate records of the receipt of all investigational product 
shipped by the Sponsor or the Sponsor’s representative, including but not limited to the date 
received, lot number, expiration date, amount received, and the disposition of all investigational 
product. 
9.6 
Concomitant and Prohibited Medications 
9.6.1 
Concomitant Medications 
Subjects may receive all clinically indicated medications during the study with the exceptions 
noted in Section 9.6.2 Prohibited Medications and Appendix 9. 
Any medication taken by a subject within the 14 days prior to the screening period, and during the 
course of the study, will be recorded on the eCRF along with the reason for use.  During the study, 


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each subject will be instructed to report the use of all medication, including over-the-counter 
(OTC) medications, herbal medications, vitamins, and nutritional supplements on the study 
specific medication log.  Sites should instruct subjects to bring the log to each study visit for 
review.  Subjects will also be instructed about the importance of not taking any new medications 
during the study (including OTC medications) without consulting the Investigator.  After 
screening, if the subject begins taking prohibited or restricted medications, they are to be recorded 
on the corresponding Concomitant Medication eCRF. 
9.6.2 
Prohibited Medications 
Use of all other investigational products is prohibited during the study.  A subject who initiates an 
investigational product during the study should be discontinued. 
Subjects are to be washed out of any medications meeting exclusion criteria for at least the minimal 
time periods indicated in the protocol 
9.6.2.1 Use of Other Opioid Medications 
Subjects cannot have used opiate drugs, including opiate containing anti-cough agents for 14 days 
prior to the screening period of the study.  Subjects are prohibited from using opioids, including 
naltrexone, for the duration of the study.  Use of acetaminophen, non-steroidal anti-inflammatory 
medications, and aspirin is permitted.   
Concomitant use of opioid antagonists (e.g., naloxone, naltrexone) is also prohibited during the 
study, unless required for urgent reversal of opioid adverse effects or opioid overdose.  
9.6.2.2 Benzodiazepines and Other CNS Depressant Class Drugs 
Because of the potential for an opioid class drug to cause respiratory depression when used 
concomitantly with other drug classes known to be CNS depressants, the following types of 
medications are prohibited during the course of the study: sedatives/hypnotics, anxiolytics, 
tranquilizers, muscle relaxants, general anesthetics, antipsychotics, general anesthetics and 
antipsychotics.  Alcohol is a known CNS depressant and its use should be limited during the course 
of the study.  Please refer to the “Risk from Concomitant Use with Benzodiazepines or Other CNS 
Depressants” section of the United States Nalbuphine HCl Package Insert (Nalbuphine HCl for 
injection, for intramuscular, subcutaneous or intravenous use (2016)) for additional information. 
9.6.2.3 Serotonergic Class Drugs 
Because of the rare but potentially life-threatening condition of serotonin syndrome that can result 
from the concomitant administration of serotonergic drugs, medications that may induce this 
syndrome are prohibited during the course of the study.  Drug classes to be prohibited are: 
serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine inhibitors (SNRIs), tricyclic 
antidepressants (TCAs), triptans, 5-HT3 receptor antagonists and monoamine oxidase inhibitors 
(MAOIs), tetracyclic antidepressants (i.e. mirtazapine) and 5-HT2 antagonists (i.e. trazadone).  
Other drugs to be excluded are: tramadol, which has mechanistic interactions as both an opioid 
mu-receptor agonist and serotonin reuptake inhibition, the antibiotic linezolid (an oxazolidinone 
organic compound with monoamine oxidase inhibitory activity) and intravenous drug methylene 


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blue (methylthioninium chloride) which is mechanistically a potent monoamine oxidase inhibitor.  
Please refer to the “Drug Interactions” section of the United States Nalbuphine HCl Package Insert 
(Nalbuphine HCl for injection for intramuscular, subcutaneous or intravenous use (2016)) for 
additional information. 
9.6.2.4 Prohibited Medications Related to Risk of Torsades de Pointes 
Subject are not to receive a medication that is classified as having a known risk for Torsade de 
Pointes (see Appendix 9, for cardiovascular related prohibited medications with a known risk of 
Torsade de Pointes, classified as “KR”). 
9.6.3 
Symptom Management 
Nalbuphine use may be associated with nausea, headache and dizziness upon initiation of 
treatment and during titration.  The literature on managing opiate initiation generally recommends 
against prophylactic use, as only about 1 in 5 subjects will experience nausea.  However, at the 
Investigator's discretion, anti-emetics that are NOT classified as having a known risk for Torsade 
de Pointes (see Appendix 9, for cardiovascular related prohibited medications with known risk of 
TdP classified as known risk "KR") may be prescribed at the baseline visit, in which case the 
subject should be educated on the appropriate, as needed use, of early treatment of symptoms.  
Headaches and dizziness can also be treated with agents commonly prescribed for these symptoms 
(e.g., acetaminophen for headache and scopolamine patch for dizziness) during the titration period, 
but these symptoms are less frequent and usually do not warrant prophylaxis.   
9.7 
Termination of the Study 
If, in the opinion of the Investigator, the clinical observations in the study suggest that it may be 
unwise to continue, the Investigator may terminate the study after consultation with the Sponsor.  
A written statement fully documenting the reasons for such a termination will be provided to the 
Sponsor.  In addition, the Sponsor may terminate the study at any time.  Furthermore, if it becomes 
apparent that subject enrollment is unsatisfactory with respect to quality or quantity or that data 
recording is inaccurate or incomplete on a chronic basis, the Sponsor has the right to terminate the 
study and remove all study materials from the investigational site.  A written statement will be 
provided to the Investigator, the Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC), and regulatory authorities, if required.  In the event a serious adverse event (SAE) is part of 
the reason for early termination of the study, all documentation relating to the event(s) must be 
obtained and filed appropriately. 


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10 ASSESSMENT OF SAFETY 
10.1 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.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom whether or not related to the medicinal (investigational) product, or disease temporally 
associated with the use of a medicinal (investigational) product. 
The AE may be any of the following:  
• A new illness  
• Worsening of a pre-existing condition  
• Worsening of a sign or symptom of the condition under treatment or of a concomitant illness  
• An effect of the investigational product, including comparator  
• A combination of 2 or more of these factors  
No causal relationship with the investigational product or with the clinical study itself is implied 
by the use of the term “AE.” 
Surgical procedures themselves are not AEs, they are therapeutic measures for conditions that 
require surgery.  The condition for which the surgery is required may be an AE.  Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs.  
AEs fall into the categories “non-serious” and “serious.” 
10.2 Reporting of Adverse Events 
AEs will be recorded starting with the signing of the informed consent.  All AEs will be collected 
through the follow-up visit of Treatment Period 2.  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 course of the study. 
Beginning at the screening visit, and continuing for the duration of the study, subjects must be 
instructed to record any new AEs on the 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. 
Any AE still unresolved at the Treatment Period 2 Follow-up Visit 10 (Day 36) or at the 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 


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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. 
Serious AEs must be submitted to the Sponsor within 24 hours of their discovery, even if the full 
information about the event is not yet available.  These events should also be reported to the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) as needed based on local 
requirements. 
10.2.1 Severity of Adverse Events 
All adverse events will be reported and graded, if possible, by the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 or later: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
The severity of adverse events that cannot be graded by the most current version of CTCAE will 
be categorized as follows:  
• Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• Grade 2 – Mild to moderate limitation in activity, some assistance may be needed; no or 
minimal medical intervention/therapy required 
• Grade 3 – Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required hospitalizations possible 
• Grade 4 – Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required hospitalization or hospice care probable  
• Grade 5 – Death 
10.2.2 Relationship to Investigational Product 
Association or relatedness to the investigational product will be graded as either “definitely 
related”, “probably related”, “possibly related”, “unlikely related”, or “not related”.  Determination 
of relatedness includes: 
DEFINITELY RELATED – The adverse event: 
• Follows a reasonable temporal sequence from administration of the study intervention 
• Follows a known or expected response pattern to the suspected intervention, that is 
confirmed by improvement on stopping 
• Reappearance of the event on repeated exposure that could not be reasonably explained 
by the known characteristics of the subject’s clinical state 
PROBABLY RELATED – The adverse event: 
• Follows a reasonable temporal sequence from investigational product administration 


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• Abates upon discontinuation of the investigational product 
• Cannot be reasonably explained by the known characteristics of the subject’s clinical state. 
POSSIBLY RELATED – The adverse event: 
• Follows a reasonable temporal sequence from investigational product administration 
• Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
UNLIKELY RELATED – The adverse event: 
• Does not follow a reasonable temporal sequence from investigational product 
administration 
• Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
NOT RELATED – The adverse event: 
• 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 
• Study intervention and/or causal relationship is considered biologically implausible 
10.2.3 Adverse Event of Special Interest 
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 as part of the analysis to 
determine any abuse potential of nalbuphine.  If a subject spontaneously reports an event, a 
symptom or a subjective experience that fits any of the 4 categories of AEs described below, that 
event should be probed with open-ended questions, such as “Can you tell me more about that?” or 
“Have you ever experienced that kind of feeling before?”.  The goal is to better understand the 
context and the potential clinical significance of the event or subjective experience.  Importantly, 
this probing and additional dialogue should take place ONLY if the subject spontaneously 
reports such an event or experience.  Pro-active or suggestive questioning is not recommended, 
since the objective is to understand what the subjects themselves identify as new and different. 
Specifically, terms that relate to the following types of events should trigger the collection of 
additional information under the AESI section of the Adverse Event eCRF: 
Categories of Special Interest: 
• Experiences or events suggestive of euphoria, such as elation, exhilaration, feeling a sense 
of exaggerated well-being, or feeling intoxicated. 
• Experiences or events suggestive of mood changes or effects, such as reports of sedation, 
stimulation, or impaired attention/cognition.  For example, descriptions of: somnolence, 


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sedation, lethargy; or agitation, anxiety, restlessness; or abnormal behaviors, labile affect, 
and depressed mood; or poor attention, and mental or memory impairment. 
• Events or descriptions that suggest dissociative or psychotic experiences, such as reports 
of disorientation, abnormal thoughts, hallucinations, illusions or delusions. 
• Observations that suggest events of drug abuse, misuse, dependence or withdrawal.  These 
experiences or observations may be reported by the subject spontaneously (such as reports 
of feeling addicted, craving investigational product, or complaints of withdrawal after 
stopping the investigational product).  The AE may also be based on direct observations 
made by the Clinician and/or study staff that suggest inappropriate use of the drug, drug 
tampering or drug diversion.  For example, repetitive or significant single-time events of 
missing tablets in drug accountability assessments. 
The AESI section of the AE eCRF provides for recording the following details about any events 
meeting the characteristics described above: 
• A description of the AE event in the subject’s own words. 
• The estimated time between the subject’s most recent dose prior to the AE, and the onset 
time of that AE (e.g., X minutes or Y hours between preceding dose and AE onset). 
• Any prior history of the same, similar or related symptoms or events, and any relevant prior 
diagnoses, treatments or additional details from the subject (if a subject reports dizziness, 
do they have a history of dizziness, vertigo or any past diagnosis of Meniere’s disease?). 
• Investigator comments and/or assessment. 
Finally, the development of a confirmed pattern of behavior that results in a new diagnosis of drug 
dependency or drug abuse should be reported as an SAE. 
10.3 Abnormal Laboratory Values/Vital Signs/Electrocardiograms/Physical 
Examinations 
Laboratory abnormalities will be recorded as adverse events only if they are associated 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. 
Clinically significant worsening in physical examination, vital sign, and ECG findings following 
start of investigational product treatment will be recorded as adverse events.  Clinically significant 
findings noted prior to the start of investigational product treatment will be recorded as medical 
history. 
10.4 Deaths 
Should a death occur within the study period, or within 60 days after the last administration of 
investigational product, an adverse event form and an SAE form should be completed, detailing 
the adverse event that resulted in death (Note: death is an outcome, not an event).  The SAE must 


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be reported to the Medical Monitor within 24 hours of the Investigator becoming aware of the 
event.  The report should contain a comment regarding the co-involvement of progression of 
disease, if appropriate, and should assign main and contributory causes of death. 
10.5 Overdose 
The effects of nalbuphine may be reversed with opioid antagonists such as naloxone.  Please see 
the Guidance to the Investigator section of the Investigator’s Brochure for additional information. 
10.6 Pregnancy 
Female subjects who become pregnant should be immediately discontinued from the study if they 
have not yet received investigational product.  If a subject is found to be pregnant after she has 
received investigational product, she should discontinue dosing, complete all end-of-study 
procedures, and be followed to determine the outcome of the pregnancy.  Generally, follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date.  While pregnancy itself 
is not considered an adverse event or SAE, any pregnancy complications or less than a healthy, 
normal outcome will be recorded as an adverse event or SAE. 
10.7 Serious Adverse Events 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
• Requires subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability and/or incapacity 
• Results in a congenital anomaly or birth defect 
A hospitalization is defined as an inpatient admission lasting 24 hours or more.  Visits to urgent 
care centers and emergency departments that do not result in admission to a hospital for 24 hours 
will not be considered hospitalizations.  Hospitalizations for elective procedures, defined as any 
procedure that was planned prior to signing of the informed consent will not, in and of themselves, 
be considered to fulfill criteria for an SAE.   
The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE.  It does not refer to an SAE that 
hypothetically might have caused death if it were more severe.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should also 
be considered to be SAEs. 


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10.8 Reporting Serious Adverse Events 
Investigators and other site personnel must inform appropriate PAREXEL International Corp. 
(PAREXEL) representatives of any SAE that occurs (whether or not attributable to the 
investigational product) in the course of the study within 24 hours of when he or she becomes 
aware of it. 
All SAE reports must be submitted to the following within 24 hours: 
PAREXEL International 
E-mail:  
 
Fax No.:  
 
Tel No.:  
 
The PAREXEL representative will work with the Investigator to compile all the necessary 
information and ensure that the appropriate Sponsor representative receives a report within 1 day 
(24 hours) for any and all SAEs.  Follow-up information on SAEs must also be reported by the 
Investigator within the same time frames. 


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11 STATISTICAL EVALUATION 
As a companion to this protocol and in an effort to provide a more detailed explanation of the 
statistical methodology to be used for this study, a statistical analysis plan (SAP) will be developed 
prior to locking the database and before unblinding the randomization. 
11.1 Sample Size and Power 
The planned sample size of 44 subjects for the final analysis (22 per sequence) provides at least 
80% power to detect a 40% reduction in Day 22 daytime cough frequency (coughs per hour) with 
NAL ER tablet treatment compared to placebo tablets at the 5% significance level (2-sided).  This 
assumes a CV of 1.00 in log-transformed Day 22 cough frequencies.  The CV estimated from 
Kelsall et al (2011) data on chronic cough in patients without esophageal catheterization is 1.12; 
because Kelsall et al data was on 24-hour cough (including nighttime cough, a period of lower 
coughing rate) and were not taken in a sample of IPF patients only, it is believed that the CV will 
be lower than in Kelsall et al data.  If the CV is larger than planned at 1.25, this sample size 
provides > 80% power to detect a 50% reduction from placebo to NAL ER.  Alternatively, if the 
CV is 0.75, this sample size provides > 80% power to detect a 34% reduction from placebo to 
NAL ER.  
A total of approximately 60 subjects will be randomized to ensure complete data from at least 
44 subjects, assuming up to potentially a 26% dropout rate. 
A statistical update on this Proof-of-Concept (POC) study may be conducted when a minimum of 
12 subjects have completed both study periods for the purposes of determining whether POC can 
be established prior to complete enrollment of the study.  
The analysis will be based on conditional power (CP).  Futility will be declared if the CP is < 10%, 
while efficacy will be declared if the CP > 80% (Mehta and Pocock, 2010).   If the CP is at least 
41%, the number of subjects per treatment arm may be changed to recover the targeted power of 
80%. If it is evident that the outcome is influenced by a baseline imbalance in disease 
characteristics then the baseline imbalance will be taken into account in supplemental analyses. 
11.2 Statistical Analysis Sets 
11.2.1 Safety Population 
The safety population will consist of all randomized subjects who have received at least a single 
dose of investigational product.  The safety population will be used in all safety analyses. 
11.2.2 Completers Population 
The completers population will consist of all subjects who received both study treatments and 
completed both treatment periods in the study.  The completers population will be used in the 
efficacy analyses. 


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11.3 Statistical Methods 
11.3.1 General Principles 
Summary statistics will be presented by treatment group.  For continuous variables, unless 
otherwise stated, the number of available observations (n), mean, standard deviation, median, and 
range will be provided.  For categorical variables, the number and percentage in each category will 
be displayed. 
11.3.2 Missing Data 
Missing or dropout data will not be imputed for the purpose of data analysis except for binary 
“responder” type of efficacy endpoints. 
11.4 Demographic and Baseline Characteristics 
Demographics and baseline disease characteristics, medical history, laboratory data, and physical 
examination findings will be summarized descriptively by treatment group. 
11.5 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. 
11.6 Concomitant Medications 
Concomitant medications will be tabulated by Anatomical and Therapeutic Class (ATC) of World 
Health Organization (WHO) drug, preferred term, and treatment group.  A medication’s usage will 
be considered concomitant if it was started or continued after administration of the study 
medication.  
11.7 Analysis of Efficacy Data 
The primary efficacy endpoint of percent change in daytime cough frequency (coughs per hour) 
will be analyzed using a mixed-effects model with sequence, treatment, and time (Day 22) as fixed 
effects, the baseline value as a covariate, 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.  A log transformation will be applied to daytime cough frequency; in the presentation 
of results, log-scale fitted mean treatment group differences at Day 22 will be back-transformed to 
fitted ratios of geometric means. 
As a sensitivity analysis, a negative binomial model will be fitted with the number of coughs at 
Day 22 as the outcome, with terms for sequence, treatment, and time, as well as baseline cough 
frequency and subject, and duration of daytime (in hours) as an offset.  An autoregressive 
covariance structure will be assumed for study visits, and the site random effect will use an 
unstructured covariance matrix. 


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Secondary efficacy endpoints will be summarized using descriptive statistics.  For continuous 
endpoints (e.g., change from baseline), summaries will include mean, median, standard deviation, 
minimum, and maximum.  For discrete variables (e.g., frequency), summaries will include number 
of instances and percentage of total instances for that category or time period. 
 
 
11.8 Analysis of Safety Data 
11.8.1 Adverse Events 
The incidence of adverse events will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) body system classification and preferred term.  All TEAEs will be 
summarized overall and for each body system and preferred term by treatment group, relationship 
to investigational product, and severity.  For tabulations by severity, only a subject’s most severe 
event within the category (e.g., overall, body system, or preferred term) will be counted.  Adverse 
events will be dichotomized into “related” (probably and possibly) and “unrelated” (unlikely).  
“Treatment-emergent” will be defined as starting or worsening after the first dose of 
investigational product.  If the start date is missing, the event is assumed to be treatment-emergent.  
All SAEs will be tabulated. 
AESIs that code to the most relevant abuse-related MedDRA preferred terms will be tabulated and 
descriptive narratives will be written.  Additional adverse events that are considered “possibly 
related to abuse potential” will be tabulated separately. 
11.8.2 Vital Signs 
Vital signs, including blood pressure, heart rate, and respiration rate, body temperature, pulse 
oximetry, and weight will be summarized by treatment group at baseline and at each scheduled 
visit. 
11.8.3 Clinical Laboratory Assessments 
Clinical safety laboratory data will be summarized descriptively by treatment group at baseline 
and 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. 
11.8.4 Physical Examinations 
Abnormal physical examination findings that suggest a clinically significant worsening from 
baseline will be reported as adverse events 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. 


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11.8.5 Electrocardiograms 
Electrocardiograms are to be reviewed locally for safety and read centrally by a core ECG 
laboratory with real-time feedback to clinical sites regarding any findings relevant to subject 
inclusion or withdrawal.  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 
laboratory. 
11.8.6 Spirometry 
Spirometry parameters, including the FVC, will be summarized by treatment group at baseline and 
the Day 21 visits of each treatment period.  
11.9 Pharmacokinetics Analysis 
Nalbuphine (parent and metabolites) plasma concentration data will be listed by collection time 
and nalbuphine dose where applicable.  Further PK analyses may be conducted if data allow. 


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12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Conduct of the Study 
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, ICH GCP, and applicable 
regulatory requirements. 
This study is to be conducted according to globally accepted standards of GCP (as defined in the 
Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), November 
2016), in agreement with the latest revision of the Declaration of Helsinki, and in keeping with 
local regulations.  
The Investigator should ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-
related duties and functions.  
The Investigator should maintain a list of sub-Investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties.   
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB/IEC, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve(s) only logistical or administrative 
aspects of the study.  Any deviations may result in the subject having to be withdrawn from the 
study and render that subject non-evaluable. 
12.2 Study Monitoring 
Monitoring and auditing procedures, developed or endorsed by the Sponsor, will be followed to 
comply with GCP guidelines.  Access to the on-site study documentation and medical records will 
be ensured.  
The study will be monitored by the Sponsor or its designee.  Throughout the course of the study, 
the clinical research associates (CRA) will make frequent contact with the Investigator.  This will 
include telephone calls and on-site visits.  During the on-site visits, the eCRF will be reviewed for 
completeness and adherence to the protocol.  As part of the data monitoring, source documents 
must be made available to the 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. 
 


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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. 
13 ETHICS 
13.1 Independent Ethics Committee/Institutional Review Board 
Prior to initiation of the study, the Investigator will submit the study protocol, sample informed 
consent form (ICF), and any other documents that pertain to subject information, recruitment 
methods such as subject diaries, and advertisements, to the IRB/IEC.  The Investigator must also 
submit any other information that may be requested to the IRB/IEC for review and approval.  The 
Investigator will request that the IRB/IEC provide written approval of the study and will keep on 
file records of approval of all documents pertaining to this study.  A letter confirming the approval 
must be 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. 
13.2 Written Informed Consent 
Potential subjects must provide written consent to participate after the nature, scope, and possible 
consequences of the clinical study have been explained in a form understandable to them.  
An ICF that includes information about the study will be prepared and given to the subject.  This 
document will contain all the elements required by the ICH E6 Guideline for GCP and any 
additional elements required by local regulations.  The document must be in a language 
understandable to the subject and must specify who informed the potential subject.  Where required 
by local law, the person who informs the potential subject must be a physician. 
After reading the ICF, the potential subject must give consent in writing.  The subject’s consent 
must be confirmed at the time of consent by the personally dated signature of the subject and by 
the personally dated signature of the person conducting the informed consent discussions.  
A copy of the signed ICF must be given to the subject.  The original signed ICFs will be retained 
by the Investigator.  
The Investigator will not undertake any measures specifically required only for the clinical study 
until valid consent has been obtained. 


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14 DATA HANDLING AND RECORD KEEPING 
14.1 Case Report Forms/Source Data Handling 
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. 
14.2 Retention of Essential Documents 
14.2.1 Access to Records 
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 


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• 
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 consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial)  
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. 
14.2.2 Retention of Records 
When the study is completed, the Investigator must retain the essential documents for as long as 
needed to comply with regulatory guidelines and Sponsor requirements.  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.  


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15 PUBLICATION POLICY  
The Sponsor will retain the 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.  All proposed publications based on this study will be subject to the Sponsor’s approval 
requirements. 


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16. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 
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DE, eds.: CRC Press, 2014. 
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promising: A practical guide with examples. Statist. Med. 2011;30:3267-84. 
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V, Danoff SK, Morell F, Flaherty KR, Wells A, Martinez FJ, Azuma A, Bice TJ, Bouros D, 
Brown KK, Collard HR, Duggal A, Galvin L, Inoue Y, Jenkins RG, Johkoh T, Kazerooni 
EA, Kitaichi M, Knight SL, Mansour G, Nicholson AG, Pipavath SNJ, Buendía-Roldán I, 
Selman M, Travis WD, Walsh S, Wilson KC; American Thoracic Society, European 
Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. 
Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical 
Practice Guideline. Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68 
30. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: 
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. 
Am J Respir Crit Care Med. 2011;183(6):788-824. 
31. Ryerson CJ, Cottin V, Brown KK, Collard HR. Acute exacerbation of idiopathic 
pulmonary fibrosis: shifting the paradigm. Eur Respir J. 2015;46(2):512-20. 
32. Swigris JJ, Fairclough DL, Morrison M, et al. Benefits of pulmonary rehabilitation in 
idiopathic pulmonary fibrosis. Respir Care. 2011;56(6):783-9. 


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33. Swigris JJ, Stewart AL, Gould MK, Wilson SR. Patients' perspectives on how idiopathic
pulmonary fibrosis affects the quality of their lives. Health Qual Life Outcomes. 2005 Oct
7;3:61.
34. Torbutrol® (butorphanol tartrate) veterinary injection and tablets [package insert].
Kalamazoo, MI: Zoetis Inc. 2013. United States.
35. The Voice of the Patient: Idiopathic Pulmonary Fibrosis [Report]: Center for Drug
Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), March
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36. Yaksh TL, Wallace MS. Opioids, analgesia and pain management. In: Goodman &
Gilman’s The Pharmacologic Basis of Therapeutics. 12th ed. New York, NY: McGraw
Hill; 2011; Chapter 18: pp 481-525
37. Yorke J, Spencer LG, Duck A, et al. Cross-Atlantic modification and validation of the A
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Open Respir Res. 2014;1(1)


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APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary of Changes: 
APPENDIX 11: 
Summary of Changes 


Page 1 of 8 
Appendix 11 Summary of Changes 
Amendment 6 Rationale: 
Clinical Research Protocol TR12 v7.0 (14 December 2021) was produced for the following 
purposes: 
•
To allow for a potential statistical update when a minimum of 12 subjects have completed
both study periods for the purposes of determining whether POC can be established prior to
complete enrollment of the study.
•
To update the sponsor contact information.
•
To make other administrative updates as needed for consistency with the above changes
(additions to abbreviations list, updated document date and version number).


Page 2 of 8 
Changes* 
Location of changes 
Rationale 
Sponsor contact:  
 
Page 1 
Change in staff. 
The planned sample size of 44 subjects for the final analysis (22 
per sequence) provides at least 80% power to detect a 40% 
reduction in Day 22 daytime cough frequency (coughs per 
hour) with NAL ER tablet treatment compared to placebo 
tablets at the 5% significance level (2-sided).  …  Alternatively, 
if the CV is 0.75, this sample size provides > 80% power to 
detect a 34% reduction from placebo to NAL ER.  
A total of approximately 60 subjects will be randomized to 
ensure complete data from at least 44 subjects, assuming up to 
potentially a 26% dropout rate. 
A statistical update on this Proof-of-Concept (POC) study may 
be conducted when a minimum of 12 subjects have completed 
both study periods for the purposes of determining whether 
POC can be established prior to complete enrollment of the 
study. 
The analysis will be based on conditional power (CP).  Futility 
will be declared if the CP is < 10%, while efficacy will be 
declared if the CP > 80% (Mehta and Pocock, 2011). If the CP 
is at least 41%, the number of subjects per treatment arm may 
be changed to maintain the targeted power of 80%. If it is 
evident that the outcome is influenced by a baseline imbalance 
in disease characteristics then the baseline imbalance will be 
taken into account in supplemental analyses. 
11.1 Sample Size and Power 
To allow for a assessment for the 
purposes of determining whether 
POC can be established prior to 
complete enrollment of the 
study. 
*Additions shown as underlines and deletions shown with strike through.


Page 3 of 8 
Amendment 5 Rationale: 
Clinical Research Protocol TR12 v6.0 (11 June 2021) was produced for the following purposes: 
•
To provide clarification on the QTcF values to prevent exclusion of subjects who present with Right Bundle Branch block
•
To clarify exclusion criteria.
•
To clarify study procedures.
•
To correct minor administrative errors.


Page 4 of 8 
Change 
Location of Text that Changes 
Rationale 
Clarification of exclusion criterion #30 
Previous Wording: 
QTcF interval > 450 ms on any screening ECG tracing 
(triplicate). 
Revised Wording:  
QTcF interval >450 ms (mean of 3 screening ECG QTcF values) if 
QRS <120 ms (mean of 3 screening ECG QRS values); QTcF 
interval >480 ms in the presence of Right Bundle Branch Block 
(RBBB) and/or QRS ≥ 120 ms 
Synopsis: Exclusion Criteria 
Section 7.3 Exclusion Criteria 
To more accurately capture the 
electrophysiological criteria that 
can be identified by ECG that will 
be the basis for excluding subjects 
who would be at potential risk for 
developing a clinically significant 
cardiac arrhythmia. 
In the presence of RBBB measured 
on ECG, the QRS is at least 30 ms 
wider than would otherwise be 
recorded in subjects with normal 
QRS duration.  The QT interval 
will therefore be at least 30 ms 
longer in duration. 
In the absence of RBBB, 
prolonged QRS complexes are 
commonly noted in pulmonary 
disease patients, so the increase in 
QT due to a wide QRS may be 
observed in patients who do not 
have typical RBBB, but instead 
have a nonspecific intraventricular 
conduction defect (IVCD). 


Page 5 of 8 
Change 
Location of Text that Changes 
Rationale 
Clarification of Exclusion Criterion (#32) 
Previous Wording: 
Use of a medication having a “known risk” of Torsade de 
Pointes (categorized as “KR” on the Credible Meds® 
website) is not permitted at entry or during the study (See 
Appendix 9). 
Medications associated with a potential risk of QT 
prolongation, but not clearly associated with Torsade de 
Pointes, are permitted at study entry if the following criteria 
are met: 
•
Subject has been given medication at stable doses for
a full 4 weeks prior to screening.
•
Medication dose will not be increased after
screening, or during the study, and it is anticipated
that the subject will receive the medication for the
entirety of the study
•
QTcF on any ECG tracing obtained at Screening is ≤
450 ms
Deleted Wording: 
QTcF on any ECG tracing obtained at Screening is ≤ 450 
ms 
Synopsis: Exclusion Criteria 
Section 7.3 Exclusion Criteria 
The appropriate QTcF exclusion 
has been added to exclusion 
criterion #30 and no longer 
accurate or required under 
exclusion #32 


Page 6 of 8 
Change 
Location of Text that Changes 
Rationale 
Clarification to the withdrawal Criteria relating to QTcF 
Previous  Wording: 
The subject develops a QTcF > 500 ms or presents with a 
confirmed increase from baseline of > 60 ms. 
Revised Wording: 
Develops a QTcF > 500 ms (mean of 3 ECG QTcF values) 
in subjects who were randomized without ECG findings of 
RBBB and/or QRS ≥ 120 ms.  
Develops QTcF > 530 ms (mean of 3 ECG QTcF values) in 
subjects who were randomized with ECG findings of RBBB 
and/or QRS ≥ 120 ms. 
Increase from QTcF baseline of > 60 ms (mean 
determination from 3 ECG values) 
. 
Section 7.4: Withdrawal Criteria 
To accurately reflect an 
electrophysiologically meaningful 
change on ECG parameters that 
would indicate a potential cardiac 
arrhythmia risk to a subject if they 
continued in the study.  


Page 7 of 8 
Change 
Location of Text that Changes 
Rationale 
Previous  Wording: 
Electrocardiograms will be reviewed locally for safety by the 
Investigator and/or their designee and read centrally for 
clinical significance and ECG intervals (PR, RR, QRS, QT, 
and QTcF using nomogram table), rate, rhythm, and other 
clinically significant abnormalities (e.g., left ventricular 
hypertrophy, pathological Q-waves). 
If a subject develops a QTcF > 500 ms or presents with an 
increase from baseline > 60 ms, the ECG will be repeated at 
least 30 minutes later.  If these parameters are confirmed on 
the second ECG by the Core ECG laboratory, the subject 
will be discontinued from the study. 
Revised Wording: 
Electrocardiograms will be reviewed locally for safety by the 
Investigator and/or their designee. The ECGs will be read 
centrally for the purpose of meeting the ECG study 
inclusion criteria, study withdrawal criteria and ECG 
intervals (PR, RR, QRS, QT, and QTcF using nomogram 
table), rate, rhythm, and other clinically significant 
abnormalities (e.g., left ventricular hypertrophy, pathological 
Q-waves)
Section 8.4.6 Electrocardiogram 
Assessments 
To clarify Local ECG read is for 
safety purposes and central ECG 
read is related to subject 
inclusion/withdrawal. 


Page 8 of 8 
Change 
Location of Text that Changes 
Rationale 
Deleted wording: 
If a subject develops a QTcF > 500 ms or presents with 
an increase from baseline > 60 ms, the ECG will be 
repeated at least 30 minutes later.  If these parameters 
are confirmed on the second ECG by the Core ECG 
laboratory, the subject will be discontinued from the 
study 
Section 8.4.6 Electrocardiogram 
Assessments 
QTcF clarifications and 
appropriate actions to be taken 
clarified in section 7.4 for subject 
discontinuation.   
Previous wording: 
Electrocardiograms are to be reviewed locally and read 
centrally by a core ECG laboratory with real-time feedback 
to clinical sites regarding any findings relevant to safety.   
Additional wording: 
Electrocardiograms are to be reviewed locally for safety and 
read centrally by a core ECG laboratory with real-time 
feedback to clinical sites regarding any findings relevant to 
subject inclusion or withdrawal.   
 
Deleted wording: 
Electrocardiograms are to be reviewed locally and read 
centrally by a core ECG laboratory with real-time feedback 
to clinical sites regarding any findings relevant to safety.   
Section 11.8.5 Electrocardiograms 
To clarify Local ECG read is for 
safety purposes and central ECG 
read is related to subject 
inclusion/withdrawal. 
Administrative changes throughout the protocol 
Various sections of the revised 
protocol document 
To provide functional and 
administrative clarifications. 
 

SAP_001.pdf: 
Official Title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Treatment, 
Two-Period Crossover Efficacy and Safety Study in Idiopathic Pulmonary Fibrosis with 
Nalbuphine ER Tablets for the Treatment of Cough 
NCT Number: NCT04030026
Document Date: Statistical Analysis Plan (Final 2.0): 08 June 2022


Trevi Therapeutics, Inc. 
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P AREXEL International 
P AREXEL International 
Trevi Therapeutics, Inc. 
TR12 
Statistical Analysis Plan 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Treatment, Two-Period 
Crossover Efficacy and Safety Study in Idiopathic Pulmonary Fibrosis with Nalbuphine ER 
Tablets for the Treatment of Cough 
TP-GDO-WW-133-01.a 
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Related to: SOP-GDO-WW-019 
Statistical Analysis Plan 
Version: Final 2.0 
P AREXEL Project Number: 244098 
CONFIDENTIAL 
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P AREXEL International 
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TR12 
SPONSOR SIGNATURE PAGE 
Statistical Analysis Plan 
This document has been approved by sponsor and signed in the separate sign off form by the 
following. 
Approved by: 
TP-GDO-WW-133-01.a 
 
 Clinical Pharmacokinetics 
Trevi Therapeutics, Inc. 
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Trevi Therapeutics, Inc. 
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P AREXEL International 
Statistical Analysis Plan 
PAREXEL SIGNATURE PAGE 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the 
following: 
Author 
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Project Role: 
 
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Trevi Therapeutics, Inc. 
TR12 
TABLE OF CONTENTS 
P AREXEL International 
Statistical Analysis Plan 
SPONSOR SIGNATURE PAGE .................................................................................................... 2 
P AREXEL SIGNATURE PAGE .................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................. 4 
REVISION HISTORY ..................................................................................................................... 6 
LIST OF ABBREVIATIONS .......................................................................................................... ? 
1 
INTRODUCTION .................................................................................................................. 9 
2 
STUDY OBJECTIVES ........................................................................................................ 10 
2.1 
Primary Objective(s) ....................................................................................................... 10 
2.2 
Secondary Objective(s) ................................................................................................... 10 
3 
INVESTIGATIONAL PLAN .............................................................................................. 11 
3 .1 
Overall Study Design and Plan ........................................................................................ 11 
3 .2 
Endpoints and Associated Variables ............................................................................... 12 
3.2.1 
Efficacy Variables ...................................................................................................... 13 
3 .2.2 
Pharmacokinetic Variables ......................................................................................... 17 
3.2.3 
Safety Variables .......................................................................................................... 17 
3.2.4 
Exploratory Variables ................................................................................................. 19 
4 
STATISTICAL METHODS ................................................................................................ 19 
4.1 
Data Quality Assurance ................................................................................................... 19 
4.2 
General Presentation Considerations ............................................................................... 19 
4.2.1 
Treatment Period, Treatment and Sequence ............................................................... 20 
4.2.2 
Relative Study Day ..................................................................................................... 20 
4.2.3 
Baseline Definition ..................................................................................................... 21 
4.2.4 
Data Listings ............................................................................................................... 21 
4.2.5 
Data Summaries .......................................................................................................... 21 
4.2.6 
Figures ........................................................................................................................ 22 
4.3 
Software22 
4.4 
Study Subjects ................................................................................................................. 22 
4.4.1 
Disposition of Subjects ............................................................................................... 22 
4.4.2 
Protocol Deviations .................................................................................................... 23 
4.5 
Analysis Sets ................................................................................................................... 23 
4. 5 .1 
Safety Analysis Set ..................................................................................................... 24 
4.5.2 
Full Analysis Set ......................................................................................................... 24 
4.5.3 
Completers Analysis Set ............................................................................................. 24 
4.5.4 
Per Protocol Set .......................................................................................................... 24 
4.6 
Demographics and Baseline Characteristics ................................................................... 24 
4.7 
DLco 
24 
4.8 
Medical History and Concomitant Illnesses .................................................................... 24 
4.9 
Prior and Concomitant Medications ................................................................................ 25 
4.10 Treatment Exposure I Compliance .................................................................................. 25 
4.10.1 
Treatment Exposure .................................................................................................... 25 
4 .10 .2 
Compliance ................................................................................................................. 26 
4.11 Efficacy Evaluation ......................................................................................................... 27 
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Statistical Analysis Plan 
4.11.1 
Analysis and Data Conventions .................................................................................. 27 
4.11.2 
Analysis of Primary Efficacy Variable ....................................................................... 28 
4.11.3 
Analysis of Secondary Efficacy Variables ................................................................. 30 
4.11.4 
Pharmacokinetics ........................................................................................................ 32 
4.11.5 
Additional Exploratory Efficacy Evaluation .............................................................. 33 
4.12 Number and percentages of subjects with 30%, 50% and 75% reduction from baseline in 
daytime cough counts will be listed and presented by treatment group. Safety Evaluation 
33 
4.12.1 
4.12.2 
4.12.3 
4.12.4 
Adverse Events ........................................................................................................... 33 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 36 
Clinical Laboratory Evaluation ................................................................................... 36 
Safety laboratory data will be summarized by actual treatment received and visit as 
defined in SAP section 4.2.5. Pregnancy .................................................................... 36 
4.12.5 
Vital Signs .................................................................................................................. 36 
4.12.6 
Physical Examination ................................................................................................. 36 
4.12.7 
ECG ............................................................................................................................ 36 
4.12.8 
Spirometry .................................................................................................................. 36 
4.12.9 
Swallow Test .............................................................................................................. 36 
4.12.10 sows ......................................................................................................................... 36 
4.12.11 Data Safety Monitoring Board (DSMB) ..................................................................... 36 
4.13 Other Analyses ................................................................................................................ 37 
4.14 Determination of Sample Size ......................................................................................... 37 
4.15 Changes in the Conduct of the Study or Planned Analysis ............................................. 37 
5 
REFERENCES ..................................................................................................................... 38 
6 
APPENDICES ...................................................................................................................... 39 
6.1 
Schedule of Assessments ................................................................................................. 39 
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Trevi Therapeutics, Inc. 
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REVISION HISTORY 
Version No. 
Effective Date 
Draft 0.1 
20Dec2019 
Draft 0.2 
04Feb2020 
Draft 0.3 
01Feb2021 
Draft 0.4 
03May2021 
Final 1.0 
08Feb2022 
Draft 1.1 
04May2022 
Draft 1.2 
31May2022 
Draft 1.3 
07Jun2022 
Final 2.0 
Date 
of 
signature 
TP-GDO-WW-133-01.a 
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last 
P AREXEL International 
Statistical Analysis Plan 
Summary of Change(s) 
New document 
Comments resolution 
Updates per new Protocol Amendments 
Minor comments implementation 
Updates per new Protocol Amendment and CRF Version. 
Finalization 
Update the SAP to reflect current statistical practices in using 
full analysis set as the primary analysis set and provide 
corresponding clarifications to Analysis and TFLs 
Include information on Interim Analysis 
Include supplementary tables 
Comments resolution 
Adjustments due to new Vitalograph structure: the parameters 
for 24h cough frequency and asleep time cough frequency will 
be received by the vendor and not derived by P AREXEL. 
Document Finalization 
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Statistical Analysis Plan 
LIST OF ABBREVIATIONS 
Abbreviation / Acronym 
AE 
AE-IPF 
AESI 
ATC 
BDRM 
BID 
BLQ 
CGI-C 
CfB 
Cls 
CTCAE 
DLco 
Cough monitor 
CV% 
DSMB 
eCRF 
ER 
E-RS 
EXACT 
FAS 
GM 
GMR 
IA 
ICH 
IMP 
IPF 
LLOQ 
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Definition / Expansion 
Adverse event 
Acute exacerbations of IPF 
Adverse event of special interest 
Anatomical-Therapeutic-Chemical 
Blinded Data Review Meeting 
Twice daily 
Below limit of quantification 
Clinical Global Impression of Change 
Change from Baseline 
Confidence Intervals 
Common Terminology Criteria for Adverse Events 
Diffusing capacity of the Lung for carbon monoxide 
Wearable digital cough monitor hookup (24-hour recording) 
provided by external vendor Vitalograph® 
Coefficient of variation 
Data Safety Monitoring Board 
Electronic Case Report Form 
Extended release 
Evaluating Respiratory Symptoms 
EXAcerbation of Chronic pulmonary disease Tool 
Full Analysis Set 
Geometric mean 
Geometric mean ratio 
Interim Analysis 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
Investigational medicinal product 
Idiopathic pulmonary fibrosis 
Lower limit of quantification 
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Abbreviation / Acronym 
MedDRA 
NALER 
NC 
NIH 
NS 
OTC 
PD 
PRO 
PROMIS 
PT 
SAE 
SAP 
SBP 
SD 
soc 
sows 
TEAE 
UIP 
us 
WHODD 
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P AREXEL International 
Definition / Expansion 
Medical Dictionary for Regulatory Activities 
Nalbuphine extended-release 
Not calculable 
National Institutes of Health 
No sample 
Over-the-counter 
Protocol deviation 
Patient-Reported Outcomes 
Statistical Analysis Plan 
Patient-Reported Outcomes Measurement Information System 
Preferred term 
Serious adverse event 
Statistical Analysis Plan 
Systolic blood pressure 
Standard deviation 
System Organ Class 
Subjective Opiate Withdrawal Scale 
Treatment Emergent Adverse Event 
Usual interstitial pneumonia 
United States 
World Health Organization Drug Dictionary 
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Trevi Therapeutics, Inc. 
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1 
INTRODUCTION 
P AREXEL International 
Statistical Analysis Plan 
Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial 
pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and is 
defined by the histopathological and/or radiologic pattern of usual interstitial pneumonia (UIP). 
Cough and dyspnea are common symptoms of IPF patients with 81 % and 90%, respectively, of 
patients reporting these symptoms at the time of diagnosis. IPF has a poor prognosis with median 
survival of 3.8 years for adults age 65 (Leder and Martinez, 2018). Death in the IPF patient is 
frequently precipitated by an acute respiratory worsening, including the development of "acute 
exacerbations oflPF" (AE-IPF). 
Trevi Therapeutics, Inc. (Trevi) has in-licensed 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 United States 
(US) as Nubain®, on which the presently sold generic injectable formulations are based. Approved 
indications in the US include the relief of moderate to severe pain, as a supplement to balanced 
anesthesia, pre-operative and post-operative analgesia, and obstetrical analgesia during labor and 
delivery (US Nalbuphine Package Insert, December 2016). Nalbuphine remains an unscheduled 
drug in the US (Drug Enforcement Agency, 2013). Commercial availability in the European Union 
(EU) of the parenteral formulation of nalbuphine dates to 1986 (Medicines Evaluation Board in 
the Netherlands, 2010) with approved indications for short-term relief of moderate to severe pain 
and pre- and post-operative analgesia (UK Nalpain SmPC, January 2011). 
Nalbuphine is a member of the "opioid agonist-antagonist" class of drugs with agonistic action at 
kappa opioid receptors and antagonistic activity at mu opioid receptors ( Yaksh and Wallace 2011). 
The clinical development program ofNAL ER tablets has included prior investigational studies 
for the treatment of prurigo nodularis-related pruritus, uremic pruritus in hemodialysis patients as 
well as safety and efficacy analgesic studies. This study protocol is to investigate NAL ER tablets 
as a treatment for cough related to IPF. 
There is medical literature reporting that the opioid drug class may be effective antitussives. 
Morice et al (2007) report in chronic cough subjects that morphine is effective treatment. Opioid 
class drugs are known to reduce pain that is mediated via peripheral sensitization-induced neuronal 
signaling. 
This Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications, tables, figures, and listings. It 
describes the variables and populations, anticipated data transformations and manipulations, and 
other details of the analyses not provided in the clinical study protocol. This SAP covers the 
planned analysis of all data collected on paper (source documents /case report forms [CRFs]), 
captured electronically in Data Labs, and provided by external vendors. 
This SAP will be finalized at least 1 month prior to database lock and describes the statistical 
analysis as it is foreseen when the study is being planned. SAP amendments necessitated by 
protocol amendments will be issued within 1 month of the published protocol amendment. Any 
deviations from the protocol will be addressed in Section 4.14: Changes in the Conduct of the 
Study or Planned Analysis. If circumstances should arise during the study rendering this analysis 
inappropriate or if improved methods of analysis should come to light, different analyses may be 
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P AREXEL International 
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Statistical Analysis Plan 
made. If this occurs, the sponsor will determine how the revision impacts the study and how the 
SAP revision should be implemented. The details of the revision will be documented and described 
in the clinical study report (CSR). 
The structure and content are based upon ICH requirements as detailed in ICH E3 Structure and 
Content of Clinical Study Reports [1] and ICH E9 Statistical Principles for Clinical Trials [2]. 
The analyses described in this SAP are based upon the following study documents: 
• 
Study Protocol, Version 7.0 (December 14, 2021) 
• 
electronic Case Report Form (eCRF), Version 5.0 (August 06, 2021) 
Of note: this is an early phase Proof of Concept study which started in February 2019; at this 
development stage it is not deemed necessary to implement the estimand framework as introduced 
by ICH E9 Addendum: Statistical Principles for Clinical Trials. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
• 
To evaluate the safety and tolerability of nalbuphine extended-release (NAL ER) tablets in 
the study population. 
• 
To evaluate the effect ofNAL ER tablets on the mean daytime cough frequency (coughs 
per hour) at Day 22 (dose 162 mg twice daily [BID]) as compared to placebo. Assessment 
is done using objective digital cough monitoring. Daytime is defined as the time the subject 
is awake in the 24 hours after the digital cough monitor is applied for use. 
2.2 
Secondary Objective(s) 
• 
To evaluate the effect ofNAL ER tablets on the mean relative change from baseline in 24-
hour (combined daytime and nighttime) cough frequency (coughs per hour) at Day 22 
(dose: 162 mg BID). 
• 
To evaluate the effect of NAL ER tablets on the mean relative change from baseline in 
nighttime cough frequency (coughs per hour) at Day 22 (dose: 162 mg BID). 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from 
baseline on the Evaluating Respiratory Symptoms (E-RS™) diary cough scale (E-RS diary 
question number 2) by treatment at Days 9, 16, and 22. 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from 
baseline in the Cough Severity Numerical Rating Scale by treatment at Days 8, 15, and 21 . 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from 
baseline in the E-RS diary breathlessness scale (E-RS diary questions 7, 8, 9, 10, and 11) 
by treatment at Days 9, 16, and 22. 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from 
baseline in the 14-item the EXAcerbation of Chronic pulmonary disease Tool (EXACT®) 
version 1.1 e-diary tool total score by treatment at Days 9, 16, and 22. 
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Statistical Analysis Plan 
• 
To evaluate the effect of escalating doses of NAL ER tablets on the mean change from 
baseline in the Patient Reported Outcomes Measurement Information System (PROMIS®) 
Item Bank vl.0 Fatigue Short Form 7a scale by treatment at Day 21. 
• 
To evaluate the change in the Clinical Global Impression of Change (CGI-C) over time by 
treatment measured at Day 21. 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a double-blind, randomized, placebo-controlled, 2-treatment, 2-period crossover efficacy 
and safety study in IPF subjects with NAL ER tablets for the treatment of cough. 
The study consists of 2 treatment periods of 3 weeks, each followed by a washout period of 2 
weeks. 
During Treatment Period 1, eligible subjects will be randomized (1:1) to one of the following 
treatment arms: 
• 
Arm 1: Active NAL ER tablets followed by crossover Placebo tablets in Treatment Period 
2 
• 
Arm 2: Placebo tablets followed by crossover NAL ER tablets in Treatment Period 2 
Following 3 weeks of dosing in Treatment Period 1, subjects will complete a 2-week washout 
period before entering Treatment Period 2. Subjects assigned to Arm 1 will receive placebo tablets 
and subjects assigned to Arm 2 will receive NAL ER tablets during Treatment Period 2. A final 2-
week washout period will occur at the completion of Treatment Period 2. 
Subjects on NAL ER tablets will have the dose titrated from 27 mg once daily (QD) to 54 mg BID 
over a 5-day period and then maintained at 54 mg BID for approximately 4 days. Doses will be 
subsequently escalated and maintained at 108 mg BID over 1 week and then to 162 mg BID over 
6 days. 
Study visits will include screening to determine eligibility, and for each treatment period: visits at 
Day -1 for baseline assessments, at Days 8, 15, and 21 during treatment, and a follow-up at the 
end of the 2-week washout period. At study screening and the Day 21 visits during each treatment 
period, subjects will have blood drawn for safety analysis. Nalbuphine (and/or metabolites) plasma 
concentration will also be measured at Day 21. Subjects will complete questionnaires for efficacy 
evaluations and undergo safety evaluations including an ECG. At the baseline and Day 21 visits, 
during each treatment period, site staff will place an electronic cough monitor on the subject, which 
will be worn until the evening of the following day in order 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 prior to bedtime. Subjects will complete a daily e-diary twice per 
day. 
Subjects who discontinue investigational product, for reasons other than withdrawal of consent, 
will be considered to have prematurely discontinued treatment and will be asked to complete the 
premature discontinuation and 2-week off-treatment safety follow-up evaluations. 
The schematic of the study design is provided in Figure 1. 
The schedule of assessments is provided in Appendix 1 and Appendix 2. 
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P AREXEL International 
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Statistical Analysis Plan 
Figure 1 - Study Schematic 
Double-blind treatment period 
Oay -1 
D1pm&D2pm D3am-D5am D5pm-D9am D9pm- D16am016pm-022am 
N.;28 I Nalbuphine I 
Predos.e 
27 mg QD 
27 mg BID 
54 mg BID 
108 mg BID 
162 mg BID 
"'C 
C 
.g 
.S! 
(I) 
-
C. 
IC 
(>I) 
-~ 
E 
14-day washout 
.!:: 
C 
0 
(I) 
-0 
C .,, 
.., 
a:: 
Vl 
N=28 I Placebo 
Predose 
Placebo 
Visits on Days: 
-1 
8 
15 
21 
3.2 
Endpoints and Associated Variables 
Primary Efficacy Endpoint 
• 
Mean change in daytime cough frequency ( coughs per hour) from baseline as assessed by 
objective digital cough monitoring at Day 22 by treatment. Daytime is defined as the time 
the subject is awake in the 24 hours after the digital cough monitor is applied for use. 
Secondary Efficacy Endpoints 
• 
Relative change in daytime cough frequency ( coughs per hour) from baseline at Day 22 
(dose: 162 mg BID) by treatment. 
• 
Relative change in 24-hour ( combined daytime and nighttime) cough frequency ( coughs 
per hour) from baseline at Day 22 (dose: 162 mg BID) by treatment. 
• 
Relative change in nighttime cough frequency (coughs per hour) from baseline at Day 22 
(dose: 162 mg BID) by treatment. 
• 
Mean change in the E-RS diary cough subscale (E-RS diary question number 2) from 
baseline, at Days 9, 16, and 22 by treatment. 
• 
Mean change in the Cough Severity Numerical Rating Scale at Days 8, 15, and 21 by 
treatment. 
• 
Mean change in the E-RS diary breathlessness subscale (E-RS diary questions 7, 8, 9, 10, 
and 11) from baseline at Days 9, 16, and 22 by treatment. 
• 
Mean change in the 14-item EXACT vl.1 e-diary tool total score from baseline at Days 9, 
16, and 22 by treatment. 
• 
Mean change in the PROMIS Item Bank vl .0 Fatigue Short Form 7a scale from baseline 
at Day 21 by treatment. 
• 
Mean change in the CGI-C over time measured at Day 21 by treatment. 
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P AREXEL International 
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Safety 
Statistical Analysis Plan 
Safety will be assessed based on adverse events, clinical laboratory measurements, central cardiac 
core laboratory read ECGs, vital signs, spirometry and physical examinations. 
Subjects will also complete the Subjective Opiate Withdrawal Scale (SOWS) on a daily basis via 
e-diary for 14 days following the last dose of investigational product, whenever that occurs and 
regardless of the reason (unless consent is withdrawn). 
An independent Data Safety Monitoring Board (DSMB) will periodically review safety data. 
Pharmacokinetics 
Nalbuphine (and/or metabolites) plasma concentration will be measured. 
3.2.1 
Efficacy Variables 
Cough frequency is recorder via a wearable digital cough monitor hookup (24-hour recording) 
provided by external vendor Vitalograph® hereby referred to as 'cough monitor'. 
Baseline (pre-treatment) recording of cough frequency will be obtained at Visit 2 (day -1) for 
Treatment Period 1 and at Visit 6 ( day -1) for Treatment Period 2. Period 1 baseline will be taken 
as the general study baseline as explained in the baseline definition at section 4.2.3 ofthis SAP. 
Cough frequency will also be recorded at Visit 5 ( day 21) for Treatment Period 1 and at Visit 9 
( day 21) for Treatment Period 2. 
Cough frequency will be captured in a 24-hour recording. 
External vendor Vitalograph® will derive and provide daytime cough frequency at each pertinent 
visit. 
3 .2.1.1 Primary Efficacy Variable 
Daytime cough frequency at Day 22 is the primary efficacy variable. 
Hourly daytime cough frequency is derived by the external vendor and will be received as a 
transfer SAS dataset named 'FA' under variable F AORRES when F ATEST='Cough average 
Score at daytime'. 
"Daytime" is defined as the time the subject is awake in the 24 hours after the digital cough monitor 
is applied for use. Events, including sleep, late attachment and device removal, are identifiable in 
recording via combined assessment of cough monitor algorithms and specially trained cough 
analysts which will identify these periods from the waveform generated and by the content of the 
sounds heard. Vitalograph® analysts are trained in differentiating sleep periods from the subject 
being asleep. Consequently, identification of the possible sleep time is done by Vitalograph® 
analysts and will be indicated in the data transfer as date and time of sleep start and end. 
Of note: 
• 
If the patient gets up for a short period in the night i.e. use the bathroom or drink a glass of 
water, this will be counted as sleep time. 
• 
If the patient gets up for a longer period, this will be classed as awake time. 
• 
If two or more periods of sleep exist in a recording the start and end times of each sleep 
period will be identified. 
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Statistical Analysis Plan 
The following events will be recorded and collected in the data transfer, together with start and 
end date as appropriate: 
Table 1 - Cough Monitor Events 
Event Name 
Description 
Sleep 
Sleep Period 
Device Not Attached 
The recording is on, but the device is not attached to the subject 
Recording Ended Early 
Recording duration is shorter than what was expected 
Flagged Area 
An area/period of the recording where there is an issue with the 
result that this period cannot be analyzed. 
The Vitalograph® data transfer will hold the daytime average coughs per hour based on the 
following calculation, rounded to two decimal places: 
Daytime cough frequency = ((total cough events for a session not within Sleep, Device Not 
Attached, Recording Ended Early, Flagged Area event periods)/ (recording length in seconds -
Sleep, Device Not Attached, Flagged Area event period durations)) x 3600. A session is defined 
as that 24-hour period when cough recording is taking place for an individual subject. For a session 
with 'Recording Ended Early', the recording early end datetime will be the end datetime for the 
session. No events will be collected after the recording early end datetime. 
Recording of daytime cough frequency is expected in treatment period 1 at Visit 2 (Study baseline: 
starting on day -1 and ending at day 1 prior to first IMP intake) and Visit 5 (starting on day 21 and 
ending on day 22), and in treatment period 2 at Visit 6 (Baseline: starting on day -1 and ending at 
day 1 prior to first IMP intake) and Visit 9 (starting on day 21 and ending on day 22). 
A 24-hour recording is required per protocol at each appropriate visit. All recordings considered 
valid per Vitalograph® quality assessment will be used in analysis, irrespective of actual duration. 
Cough frequency will be computed based on the actual recording duration. 
For the primary endpoint analysis, daytime cough frequency will be log transformed on the natural 
log scale; ratios will be then calculated per subject per period as log (Visit cough/ Study baseline 
cough) which would represent, upon back transformation and subtraction from 100%, a percent 
reduction in daytime cough frequency versus study baseline. 
3 .2.1.2 Secondary Efficacy Variables 
3 .2.1.2.1 24-hour cough frequency 
24-hour cough frequency is defined as the total number of cough events recorded in a 24-hour 
period, divided by 24, rounded to the nearest 2 decimal places. 
24-hour cough frequency per hour will be directly provided by Vitalograph® in the data transfer; 
this will be available in FA dataset under variable FAORRES when FATEST = 'Full Average 
Hourly Cough'. 
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The Vitalograph® data transfer will hold the 24-hour cough frequency average per hour 
based on the following calculation, rounded to two decimal places: 
24-hour cough frequency = (total cough events for a session) I (recording length in seconds -
Recording Ended Early, Device Not Attached, Flagged Area event period durations)) x 3600. A 
session is defined as that 24 hour period minus quality event periods when cough recording is 
taking place for an individual subject. For a session with 'Recording Ended Early', the recording 
early end datetime will be the end datetime for the session. No events will be collected after the 
recording early end datetime. 
Of note: will be blank in the vendor file if the session is rejected. 
For 24-hour cough frequency endpoint, a natural log transformation will be applied as described 
for daytime cough frequency in section 3.2.1.1. 
3.2.1.2.2 Nighttime cough frequency 
Nighttime cough frequency will be intended as the average while the subject is flagged as being 
asleep. 
Nighttime (i.e., asleep) cough frequency is derived as the number of coughs counted during 
sleeping time, divided by duration of sleep time, rounded to the nearest 2 decimal places. 
Nighttime (i.e., asleep) cough frequency per hour will be directly provided by Vitalograph® in the 
data transfer; this will be available in FA dataset under variable FAORRES when FATEST = 
'Sleep Average Hourly Cough'. 
The Vitalograph® data transfer will hold the asleep cough frequency average per hour based 
on the following calculation, rounded to two decimal places: 
Nighttime cough frequency = ((total cough events for a session within Sleep event period) / 
(recording length in seconds within Sleep event period)) x 3600. 
Of note: will be blank in the vendor file if the session is rejected. 
For nighttime cough frequency endpoint, a natural log transformation will be applied as described 
for daytime cough frequency in section 3.2.1.1. 
3.2.1.2.3 EXACT 14-item e-Diary Tool 
A copy of the daily diary tool EXACT version 1.1 is provided in Protocol Appendix 1. 
The EXACT is a 14-item Patient Reported Outcome (PRO) daily diary tool that was originally 
developed to quantify and measure exacerbations of COPD. Subjects will complete the EXACT 
scale via the study specific e-diary. E-diary tool will be completed each evening by the subject 
prior to bedtime, throughout study baseline to Period 2 Day 22 or premature discontinuation. 
A higher score indicates a more severe condition. 
Questionnaire is recorded daily, the record collected on the Day 22 visit date will be used as the 
post baseline value in the summary tables; if a record is not available on the exact date then the 
last assessment prior to the Day 22 visit date, within a window of 5 days prior to the visit date, will 
be used. Study baseline value will be the last assessment available prior to the first IMP intake (as 
defined in this SAP at section 4.2.3). 
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3.2.1.2.4 E-RS diary 
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Statistical Analysis Plan 
The E-RS daily diary is a derivative instrument of the EXACT consisting of the 11 respiratory 
symptoms items contained within the 14-item EXACT that measures the effect of treatment on the 
severity of respiratory symptoms. The E-RS is not administered separately from the EXACT, both 
a total 14-item EXACT total score will be computed as a secondary efficacy endpoint and a 
separate analysis of the E-RS 11-items will be done based on the methodology reported in Bacci 
et al (2018). Bacci et al concluded that analyzing the E-RS daily diary instrument into four separate 
respiratory symptom domain scales (with no total E-RS score computed) is a valid, reliable and 
sensitive measure of four distinct respiratory symptoms. 
The four domain scales are: 
• 
breathlessness (E-RS items 7, 8, 9, 10, and 11; score range, 0-17) 
• 
cough (E-RS item 2; score range 0-4) 
• 
sputum (E-RS items 3 and 4; score range, 0-8) 
• 
chest symptoms (E-RS items 1, 5, and 6; score range 0-12). 
A higher score on the scale indicates a more severe grade to the symptom. 
The cough and breathlessness symptom domain scale scores will each be studied as secondary 
efficacy endpoints. 
Questionnaire is recorded daily, the E-RS breathlessness and cough items record collected on the 
Day 22 visit date will be used as the post baseline value in the summary tables; if a record is not 
available on the exact date then the last assessment prior to the Day 22 visit date, within a window 
of 5 days prior to the visit date, will be used. Study baseline value will be the last assessment 
available prior to the first IMP intake (as defined in this SAP at section 4.2.3). 
3.2.1.2.5 Cough Severity Numerical Rating Scale 
The Cough Severity Numerical Rating Scale instrument (Boulet et al 2015) is a single-dimension 
11-point Likert scale ranging from zero ("no cough") to 10 ("worst possible cough"). 
A copy of the Cough Severity Numerical Rating Scale is provided in Protocol Appendix 2. 
The scale will be administered on paper during the Screening Visit. Once a subject is randomized, 
the scale will be administered via the study specific e-diary in treatment period 1 at Visit 2 (Study 
baseline), Visit 3 (day 8), Visit 4 (day 15) and Visit 5 (day 21), in treatment period 2 at Visit 
6(Baseline), Visit 7 (day 8), Visit 8 (day 15) and Visit 9 (day 21) and at premature discontinuation 
visit. 
Questionnaire is recorded daily, the record collected on the Day 22 visit date will be used as the 
post baseline value in the summary tables; if a record is not available on the exact date then the 
last assessment prior to the Day 22 visit date, within a window of 5 days prior to the visit date, will 
be used. Study baseline value will be the last assessment available prior to the first IMP intake (as 
defined in this SAP at section 4.2.3). 
3.2.1.2.6 PROMIS Item Bank vl.0 Fatigue Short Form 7a Scale 
The PROMIS is a US National Institutes of Health (NIH) funded initiative to develop and validate 
PROs for clinical research and practice. 
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Statistical Analysis Plan 
The PROMIS Fatigue Short Form 7a is a self-administered Likert-type rating 5-point scale of 7 
questions that assess tiredness, exhaustion, energy, fatigue limit, tiredness to think, tiredness 
impact on hygiene and impact on ability to exercise strenuously over the past 7 days. 
The PROMIS Fatigue Short Form 7a is provided in Protocol Appendix 3. This scale will be 
administered via the study specific e-diary during onsite visits (in treatment period 1 at Visit 2 
(Study baseline) and Visit 5 ( day 21 ), in treatment period 2 at Visit 6 (Baseline) and Visit 9 ( day 
21) and at premature discontinuation visit. 
Questionnaire is recorded daily, the record collected on the Day 22 visit date will be used as the 
post baseline value in the summary tables; if a record is not available on the exact date then the 
last assessment prior to the Day 22 visit date, within a window of 5 days prior to the visit date, will 
be used. Study baseline value will be the last assessment available prior to the first IMP intake (as 
defined in this SAP at section 4.2.3). 
3.2.1.2.7 Clinical Global Impression of Change Scale 
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. 
The CGI-C is a one-item measure evaluating change from the initiation of treatment on a seven-
point scale. The CGI-C can track clinical progress across time. 
The CGI-C is provided in Protocol Appendix 5. 
The CGI-C is collected in treatment period 1 at Visit 5 (day 21) and in treatment period 2 at Visit 
9 (day 21). 
3.2.2 
Pharmacokinetic Variables 
To determine the plasma concentration of nalbuphine and/or metabolites, blood samples will be 
collected at the Day 21 visits of each treatment period. 
3.2.3 
Safety Variables 
3 .2.3 .1 
Adverse Events 
AEs will be recorded starting with the signing of the informed consent. All AEs will be collected 
through the follow-up visit of Treatment Period 2. 
AEs definitions and analysis are reported in section 4.11.1 of this SAP. 
3.2.3.2 Clinical Laboratory Tests 
Clinical laboratory tests will be performed by a qualified central laboratory. 
The following clinical laboratory analytes will be measured: 
• 
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, alanine aminotransferase, aspartate 
aminotransferase, blood urea nitrogen, calcium, chloride, carbon dioxide, creatinine, total 
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Statistical Analysis Plan 
bilirubin, gamma-glutamyl transferase, glucose, lactic dehydrogenase, phosphorus, 
potassium, sodium, total cholesterol, total protein, and uric acid 
• 
Urinalysis: Color, specific gravity, pH, glucose, ketones, protein, bilirubin, urobilinogen, 
blood, and microscopy ( only on urine samples with abnormal urinalysis results) 
• 
Coagulation: Prothrombin time, international normalized ratio, and activated partial 
thromboplastin time. 
Clinical laboratory tests will be collected at Screening, in treatment period 1 at Visit 5 ( day 21 ), in 
treatment period 2 at Visit 6 (Baseline) and Visit 9 ( day 21) and at premature discontinuation visit. 
3.2.3.3 Pregnancy Tests 
Urine and serum pregnancy tests will be performed for females of childbearing potential. 
Urine pregnancy test will be collected at Screening, in treatment period 1 at Visit 2 (Study baseline) 
and Visit 6 (Follow-up), in treatment period 2 at Visit 10 (Follow-up) and at premature 
discontinuation visit. 
Serum pregnancy test will be collected at Screening, in treatment period 2 at Visit 6 (Baseline) and 
at premature discontinuation visit. 
3 .2.3 .4 Vital signs 
Vital signs (resting blood pressure, heart rate, and respiratory rate), body temperature and pulse 
oximetry will be measured. 
Vital signs will be collected at Screening, in treatment period 1 at Visit 6 (Follow-up), in treatment 
period 2 at Visit 10 (Follow-up) and at premature discontinuation visit. 
3.2.3.5 Physical Examination 
A physical examination will be performed at the screening visit, in treatment period 1 at Visit 6 
(Follow-up), in treatment period 2 at Visit 10 (Follow-up) and at premature discontinuation visit. 
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. 
3.2.3.6 Electrocardiogram Assessments 
ECGs will be performed in triplicate at Screening, in treatment period 1 at Visit 6 (Follow-up), in 
treatment period 2 at Visit 10 (Follow-up) and at premature discontinuation visit. 
A standard ECG will be obtained according to the Schedule of Events and recorded prior to blood 
sampling. Electrocardiograms will be read centrally for clinical significance and ECG intervals 
(PR, RR, QRS, QT, and QTcF using nomogram table), rate, rhythm, and other clinically significant 
abnormalities (e.g., left ventricular hypertrophy, pathological Q-waves). 
ECG can be repeated if a subject develops a QTcF > 500 ms, or presents with an increase from 
study baseline > 60 ms, this can be a cause for discontinuation from the study. 
The mean of the triplicate ECGs parameters will be derived. If no repeats of ECG are performed, 
then the single assessment received will be used in analysis; if ECG was only repeated twice, mean 
of the two assessments will be used; in case of ECG quadruplicate or more, only the fust three 
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Statistical Analysis Plan 
assessments will be used for mean derivation. Unscheduled (including repeated) ECGs will not be 
included in the mean derivation. 
3 .2.3. 7 Spirometry 
Spirometry will be executed at Screening, in treatment period 1 at Visit 5 (day 21), in treatment 
period 2 at Visit 9 ( day 21) and at premature discontinuation visit. 
3.2.3.8 Diffusing capacity of the Lung for carbon monoxide (DLco) 
DLco will be collected at Screening only. 
3.2.3.9 Swallow Test 
The Swallow Test will be assessed at Screening only. 
3.2.3.10 Subjective Opiate Withdrawal Scale (SOWS) 
Subjects will complete the SOWS on a daily basis for 14 days following the last dose of 
investigational product in each treatment period. Any subject discontinued from investigational 
product, prior to completion of the study, will also complete the SOWS daily for the 14 days 
following the last dose of investigational product (unless consent is withdrawn). The SOWS is a 
self-administered scale for grading opioid withdrawal symptoms. 
The SOWS is provided in Protocol Appendix 4. Subjects will complete the SOWS via the study 
specific e-diary. 
3.2.4 
Exploratory Variables 
As an additional exploratory analysis, a flag will be derived for 30%, 50% and 75% reduction from 
baseline in daytime cough counts. 
Daytime cough frequency change from baseline (CfB) will be derived as follow: 
Daytime cough frequency CfB = (Day 22 cough frequency - Study baseline cough frequency) I 
Study baseline cough frequency)* 100. 
Daytime cough frequency CfB will then be categorized as follow: 
-
Daytime cough frequency CfB < 30% 
-
Daytime cough frequency CfB 2: 30% and <50% 
-
Daytime cough frequency CfB 2: 50% and <75% 
-
Daytime cough frequency CfB 2: 75% 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard P AREXEL procedures. 
4.2 
General Presentation Considerations 
With protocol version 5.0 as of 17 July 2020, on site assessments were consistently reduced to 
mitigate risk for subjects to be exposed to COVID19 pandemic. Data will be summarized based 
on schedule of events planned in protocol version 5.0, while all the data collected will be listed. 
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Statistical Analysis Plan 
4.2.1 
Treatment Period, Treatment and Sequence 
In this Study, two treatment periods are planned: Treatment Period 1 includes visits from Screening 
(day -45 to -2) to Visit 6 follow-up (day 36); Treatment Period 2 include visits from Visit 6 
Baseline (day -1) to Visit 10 follow-up (day 36). 
Two treatments are planned for administration to each subject: NAL ER tablets and Placebo tablets. 
Two sequences (arms) are also planned; subjects in sequence 1 will receive active NAL ER 
tablets followed by crossover Placebo tablets in Treatment Period 2; subjects in sequence 2 will 
receive Placebo tablets followed by crossover NAL ER tablets in Treatment Period 2. 
4.2.2 
Relative Study Day 
4.2.2.1 Relative Study Day in Treatment Period 1 
In Treatment Period 1, Study Day 1 is defined as the date of first investigational medicinal product 
(IMP) intake occurring on Treatment Period 1. 
In Treatment Period 1, other study days are defined relative to the Study Day 1 as follow: 
• 
assessments taken before the Treatment Period 1 first IMP administration: 
Relative Study Day = assessment date - Treatment Period 1 first IMP intake date 
• 
assessments on or after the repeat administration: 
Relative Study Day = assessment date - Treatment Period 1 first IMP intake date + 1. 
As soon as the first IMP intake occurs on Treatment Period 2, then the rules outlined in section 
4.2.2.2 will apply. 
4.2.2.2 Relative Study Day in Treatment Period 2 
In Treatment Period 2, Study Day 1 is defined as the date of frrst IMP intake occurring on 
Treatment Period 2. 
In Treatment Period 2, other study days are defined relative to the Study Day 1 as follow: 
• 
assessments taken on or after Treatment Period 1 Visit 6 (Follow-up) and before the 
Treatment Period 2 first IMP intake: 
Relative Study Day = assessment date - Treatment Period 2 first IMP intake date 
• 
assessments on or after the repeat administration: 
Relative Study Day = assessment date - Treatment Period 2 first IMP intake date + 1. 
4.2.2.3 Relative Study Day at Visit 6 
In most instances, the baseline visit for Treatment Period 2 will occur on the same calendar day as 
the Follow-up Visit 6 for Treatment Period 1; in this case, relative Study Day at Visit 6 will be 
calculated for Treatment Periods 1. 
In the instance that baseline visit for Treatment Period 2 will occur on a different calendar day as 
the Follow-up Visit 6 for Treatment Period 1, then rules outlined in section 4.2.2.1 will apply to 
Follow-up Visit 6 for Treatment Period 1, while rules outlined in section 4.2.2.2 will apply to 
baseline visit for Treatment Period 2. 
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4.2.3 
Baseline Definition 
Statistical Analysis Plan 
Unless otherwise specified, in this Study, two Baselines will apply: 
'Study Baseline' coincides with the 'Period 1 Baseline' and is defined as the last available 
assessment prior to the first Treatment Period 1 IMP intake. 
'Period 2 Baseline' is defined as the last available assessment prior to the first Treatment Period 2 
IMP intake. 
Unless otherwise specified, when this SAP refers generically to baseline and change from baseline, 
it is to be intended as the study baseline defined in this section. 
If not otherwise stated, the primary and key secondary endpoints, as well as secondary and 
exploratory endpoints, will utilize study baseline for statistical models, descriptive and graphical 
analysis. 
4.2.4 
Data Listings 
All original and derived parameters will be listed. 
Listings will include both scheduled and unscheduled measurements; such measurements will 
appear in chronological order together with the scheduled time points. 
All listings will be sorted by sequence (i.e. Arm 1: NAL-ER + Placebo; Arm 2: Placebo+ NAL-
ER), subject number and time (visit); actual treatment received at timepoint will always be 
displayed, as appropriate. Study baselines will be flagged in listings. 
Unless otherwise specified, relative study day will be provided for each date, please refer to 
Section 4.2.2 for derivation of relative study days. Study days relative to Treatment Period 1 will 
be printed as 'TPl :XX' (where XX stays for a particular study day); similarly, study days relative 
to Treatment Period 2 will be printed as 'TP2:XX' (where XX stays for a particular study day). In 
most instances, the Baseline visit for Treatment Period 2 will occur on the same calendar day as 
the Follow-up Visit 6 for Treatment Period 1; in this case, 'TPl :XX' will be printed. 
Unless otherwise specified, listings will be presented based on all screened subjects; Screen Failure 
subjects will be included as well under 'Screen Failure:'. 
4.2.5 
Data Summaries 
Subject disposition, Demographics, Medical History, Treatment Exposure and Treatment 
Compliance tables will be summarized by sequence (see definition in section 4.2.1 ). 
In efficacy and safety tables (including concomitant medications), results will be summarized 
under the actual treatment received (NAL-ER or Placebo) independently whether the NAL-ER 
(and Placebo) was received in Treatment Period 1 or 2. In other words, summaries will be 
presented by treatment received. 
In most instances, the baseline visit for Treatment Period 2 will occur on the same calendar day as 
the Follow-up Visit 6 for Treatment Period 1; in any case, Visit 6 results will be used as Follow-
up for Treatment Period 1, while the baseline for the Treatment Period 2 will be the study baseline 
(taking into account baseline definition from section 4.2.3). 
Continuous data will be summarized in terms of the number of subjects with non-missing values, 
mean, standard deviation (SD), median, minimum and maximum, unless otherwise stated. 
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Statistical Analysis Plan 
The following rules will apply to all descriptive statistic displays, where 'd' denotes the decimal 
places in the original reported value: 
• 
n (number of non-missing observations): 0 decimal places (d.p.) 
• 
Mean: d + I d.p. 
• 
SD: d + 2 d.p. 
• 
Median: d + 1 d.p. 
• 
Minimum: d 
• 
Maximum: d 
• 
Statistics in percentage: 1 d.p. 
• 
Confidence Intervals (Cis): d + 1 d.p. 
• 
A maximum of 3 decimal places will be displayed. 
All Cis will be reported as 2-sided and will be assessed at a=0.05 significance level unless 
otherwise stated. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages. The denominator for the proportion 
will be based on the number of subjects who provided non-missing responses to the categorical 
variable. Any planned collapsing of categories will be detailed in the SAP text and the data 
displays. 
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentages will be calculated using n as the denominator. 
In general, for categorical variables showing multiple possible categories, these will be displayed 
following the within variable logic criteria; where such a logic criterium does not exist ( example: 
gender, race, AE SOC, AE PT), categories will be displayed by overall descending frequencies. 
4.2.6 
Figures 
In figures, results will be summarized based on the treatment (NAL-ER and Placebo) 
independently whether the NAL-ER (and Placebo) was received in Treatment Period 1 or 2. 
Figures will be produced in black and white. 
4.3 
Software 
All report outputs will be produced using a server-based SAS® version 9 .3 or a later version in a 
secure and validated environment. The REPORT procedure (SAS PROC Report) will be used to 
produce all tables and listings; SAS/GRAPH will be used to produce all figures. 
All report outputs will be provided to the Sponsor in RTF format. 
4.4 
Study Subjects 
4.4.1 
Disposition of Subjects 
The patient disposition including the date the informed consent was signed, date of randomization, 
date of last dose and the primary reason for End of Study will be listed. 
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Statistical Analysis Plan 
A by subject listing of violated Inclusion/Exclusion criteria will be presented. 
A by subject listing of study visits will be presented. 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to study completion. 
Following disposition summaries will be based on all screened subjects: 
• 
Number of subjects screened for entry into the study; 
• 
Number and percent of subjects randomized; 
• 
Number and percent of the subjects treated (with at least one dose of study medication); 
• 
Number and percent of the subjects included in each analysis set (as defined in section 4.5). 
Following disposition summaries will be based on the Safety Analysis Set (see section 4.5 for 
analysis sets definition): 
• 
Number and percentage of subject's early discontinuing the study treatment (along with 
reasons and treatment period of the discontinuation) by sequence. 
• 
Number and percentage of subject's who completed both treatment periods in the study. 
4.4.2 
Protocol Deviations 
A protocol deviation (PD) is any change, divergence or departure from the study design or 
procedures of a study protocol. Major PDs are defined as those deviations from the protocol likely 
to have an impact on the perceived efficacy and/or safety of study treatments. 
All PDs will be discussed during a Blinded Data Review Meeting (BDRM) shortly before database 
lock/ unblinding and addressed with the final classification; as well their overall effect will be 
evaluated on a subject by subject basis. During the BDRM, all PDs and their possible impacts will 
be discussed between PAREXEL and the Sponsor and will be assessed as 'Minor' or 'Major'. 
The impact of Major PDs on the efficacy and/or safety results will be investigated by assessing the 
robustness of the study results and conclusions to the choice of analysis set, both including and 
excluding data potentially affected by Major PDs. 
This estimation will be performed at the time of BDRM. Results and population assignments will 
be summarized in the BDRM report which will be signed off by all relevant scientific experts. 
All PDs will be listed by subject in the Safety analysis set as defined in SAP section 4.2.4. 
4.5 
Analysis Sets 
A listing will be presented for inclusion of subjects in each of the below defined analysis sets. 
In general, if not otherwise specified, all the efficacy analyses, including primary secondary and 
explorative, will be executed on: 
FAS, as the primary analysis set 
and 
Completers analysis set for assay sensitivity. 
Selected efficacy analyses may be repeated on PPS as an additional robustness analysis. 
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4.5.1 
Safety Analysis Set 
Statistical Analysis Plan 
The safety population will consist of all randomized subjects who have received at least a single 
dose of investigational product. The safety population will be used in all safety analyses. 
4.5.2 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized subjects who have taken at least one 
dose of study medication and provided study baseline and at least one post-baseline primary 
efficacy variable assessment during the treatment period. The FAS will be used for the primary 
efficacy analyses. 
4.5.3 Completers Analysis Set 
The completers population will consist of all subjects who received both study treatments and 
completed both treatment periods in the study. The completers population will be used in the 
sensitivity efficacy analyses. 
4.5.4 Per Protocol Set 
Per Protocol Set (PAS) will consist of all subjects in the completers analysis sets which did not 
experience any protocol deviations affecting study primary analyses. 
4.6 
Demographics and Baseline Characteristics 
Demographic variables include: 
• 
Birth Year 
• 
Age in Years ( as derived in CRF) 
• 
Gender ( and, if female the childbearing potential status) 
• 
Race 
• 
Ethnicity 
Demographic variables will be listed by subject as defined in SAP section 4.2.4. 
Demographic summaries will be based upon the Safety Set as defined in Section 4.5. 
Continuous variable of age in years and categorical demographic variables (Gender, Race and 
Ethnicity) will be summarized descriptively based on Safety analysis set as defined in SAP section 
4.2.5. 
4.7 
DLco 
By subject listings ofDLco data will be provided as defined in SAP section 4.2.4. 
DLco data will be summarized at screening as defined in SAP section 4.2.5. 
4.8 
Medical History and Concomitant Illnesses 
Medical history is assessed at screening and include prior and ongoing medical illnesses and 
conditions and prior surgical procedures not related to the primary diagnosis. 
Medical history summaries will be based upon the Safety Set as defined in Section 4.5. 
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P AREXEL International 
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TR12 
Statistical Analysis Plan 
Medical History terms will be coded usmg Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.0 or later version. 
Medical History terms will be listed by subject. 
4.9 
Prior and Concomitant Medications 
Any medication taken by a subject within the 14 days prior to the screening period, and during the 
course of the study, will be recorded on the eCRF along with the reason for use. During the study, 
each subject will be instructed to report the use of all medication, including over-the-counter 
(OTC) medications, herbal medications, vitamins, and nutritional supplements on the study 
specific medication log. After screening, prohibited or restricted medications are to be recorded 
on the corresponding Concomitant Medication eCRF. 
Medications will be coded using the World Health Organization Drug Dictionary (WHODD), 
version global 2019 March B3 or later version and will be presented by Reported Term, WHODD 
Anatomical-Therapeutic-Chemical (ATC) therapeutic class IV and preferred term (PT). 
• 
Medication start and stop dates will be compared to the dates of IMP intake in both Treatment 
Periods 1 and 2: Medications that start and stop prior to the date of first of IMP intake in 
Treatment Period 1 will be classified as prior; 
• 
A therapy is concomitant to the NAL-ER if it started before the date of first NAL-ER intake 
and stopped on or after the date of first NAL-ER intake or if it started on or after the date of 
first NAL-ER intake and before the date of last NAL-ER intake. 
A therapy is concomitant to the placebo if it started before the date of first placebo intake and 
stopped on or after the date of first placebo intake or if it started on or after the date of first NAL-
ER intake and before the date of last placebo intake.If medication start and/or stop dates are 
missing or partial, the dates will be compared as far as possible with the date of first dose of study 
medication. 
Prior and concomitant medications will be listed by subject as defined in SAP section 4.2.4. 
Concomitant medications summaries will be based upon the Safety Set as defined in Section 4.5. 
Concomitant medications will be tabulated by Anatomical and Therapeutic Class (ATC) of World 
Health Organization (WHO) drug and preferred term, and as defined in SAP section 4.2.5. Of note: 
some medications may be concomitant to both treatment arms; these will be duplicated in the 
corresponding summary table. 
Subgroup of patients with prior and concomitant use of anti-fibrotic therapies will be identified 
based on the review od study medical monitor. Efficacy summaries may be presented in the 
subgroup of patients with anti-fibrotic therapies as described in the relevant sections of this SAP. 
4.10 Treatment Exposure/ Compliance 
Treatment Exposure and Compliance summaries and analyses will be based upon the Safety Set 
as defined in Section 4.5. 
4.10.1 
Treatment Exposure 
Extent of exposure will be calculated in days and will be derived separately in the two treatment 
periods according to treatment received. 
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Statistical Analysis Plan 
Extent of exposure in treatment period (days) = Treatment Period last IMP intake - Treatment 
Period first IMP intake + 1 
Extent of exposure will be listed by subject and summarized based on Safety analysis set as defined 
in SAP sections 4.2.4 and 4.2.5. 
4.10.2 
Compliance 
Compliance is defined as the amount of investigational product that should have been taken by a 
subject based on the dosing instructions provided during the period for which investigational 
product was dispensed. 
Compliance, expressed as percent (% ), is derived at eCRF level based on the number of tablets 
actually taken in a particular time interval divided by the number of tablets that should have been 
taken in that time interval. 
Compliance will be assessed at each study visit ( on-site or phone visit) via the comparison of 
reported as not taken or returned blister cards with subject dosing information. The amount of 
investigational product dispensed and reported as not taken/returned by the subject will be 
recorded on the drug accountability form at each visit. 
Drug accountability variables include: 
• 
KitNumber 
• 
Date Kit Dispensed 
• 
Number of Tablets Dispensed 
• 
Date Kit Returned/ phone visit with reported not-taken kits 
• 
Number of Tablets Returned/Not taken 
• 
Missed doses (Yes/No) 
• 
Number of Tablets Subject was expected to take since last visit 
• 
Number of Tablets Subject actually took since last visit 
• 
Visit Compliance (%) ( derived in CRF) 
At a visit, each subject compliance status will be classified as follow: 
• 
Compliance < 80% 
• 
Compliance between 80% and 120% (inclusive) 
• 
Compliance > 120% 
Drug accountability variables will be listed by subject based on Safety analysis set as defined in 
SAP section 4.2.4. 
Based on Safety analysis set, compliance will be summarized as a continuous variable set as 
defined in SAP section 4.2.5; as well, compliance status will be summarized as a categorical 
variable. 
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4.11 Efficacy Evaluation 
P AREXEL International 
Statistical Analysis Plan 
All efficacy summaries and analyses will be based upon the FAS as defined in Section 4.5, unless 
otherwise specified. 
4.11.1 
Analysis and Data Conventions 
4.11.1.1 Multi-center Studies 
This is a multicenter, multi-country study. 
The statistical model used for assessment of primary endpoint will adjust for site effect. 
4.11.1.2 Adjustments for Covariates 
The primary efficacy analysis will be adjusted for the following covariates: 
1. Subject (random repeated effect) 
2. Study baseline measure of primary efficacy variable 
4 .11.1.3 Handling of Dropouts or Missing Data 
Missing or dropout data will not be imputed for the purpose of data analysis. 
The Primary Efficacy Analysis will be performed on the FAS and on Completers Analysis Set as 
sensitivity analysis; there will not be imputation of primary or secondary efficacy endpoints 
eventually missing at a specific timepoint. 
Rules to handle with AEs partial onset and dates will be detailed in section 4.11. 1. 
4.11.1.4 Multiple Comparisons/Multiplicity 
One primary variable has been defined for this study, one critical treatment contrast [NAL-ER vs. 
Placebo] and one time point of primary interest [Day 22]. 
Based on the Interim Analysis (IA) look (refer to this SAP at section 4.11.1.5), the study has been 
interrupted with no sample size adjustment. No alpha adjustment for multiplicity is introduced. 
4.11.1.5 Interim Analyses 
An interim Analysis has been introduced with Study Protocol, Version 7.0 (December 14, 2021). 
Purpose of the IA was to have an early look into selected efficacy results in an unblinded fashion. 
Safety results were not part of the IA. 
The Conditional Power method was employed to assess study early futility or efficacy. 
Based on the IA results, TREVI took decision not to proceed further with this proof of efficacy 
study. No sample size re assessment has been considered based on IA results. 
IA unblinded results were not disclosed to the main blinded team (including Project Leader, Data 
Management, Biostatistician and Statistical Programmers). 
IA unblinded results were visible only to: 
-
P AREXEL separate unblinded team (including unblinded Biostatistician and unblinded 
Statistical Programmers); 
-
TREVI designated unblinded representative. 
Strategy to prevent unauthorized disclosure of unblinded information are detailed in the Blinding 
Maintenance Plan. 
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4.11.1.6 Examination of Subgroups 
Statistical Analysis Plan 
Primary endpoint summaries will be produced for gender and anti-fibrotic therapies (defined in 
section 4.9 of this SAP) subgroups. 
As described in section 4.11.3, selected secondary endpoint summaries will be produced for gender 
and anti-fibrotic therapies subgroups. 
4.11.2 
Analysis of Primary Efficacy Variable 
The primary variable for the assessment of efficacy is presented at section 3 .2 .1.1 of this SAP. 
The primary analysis for the primary endpoint will be on the natural log scale of the daytime cough 
frequency data. The difference between NAL ER at 162 mg dose level and placebo will be 
estimated using a mixed-effects model with sequence, period and treatment as fixed effects, the 
log-transformed study baseline value as a covariate, , and subject as a random repeated effect. 
While measurements taken at different time points are expected to correlate, measurements taken 
at adjacent time points are assumed to be more correlated than measurements further apart, and 
therefore the compound symmetry covariance structure will be used. 
Sensitivity analysis will be conducted with other covariance structures to evaluate the robustness 
of the compound symmetry structure considered to model the within-subject errors. The following 
covariance structures will be utilized respectively: 
1. 
Unstructured covariance 
2. 
Heterogeneous Toeplitz 
3. 
Autoregressive AR(l) 
A simplified version will be implemented by excluding the site and gender adjustment. The change 
from study baseline in log-transformed scale (i.e., log-transformed daytime cough frequency at 
Day 22 - log-transformed study baseline) will be used as the dependent variable. 
In the above defined statistical model, the sequence effect can be interpreted as the carry-over 
effect: hypothesis testing of sequence effect is equivalent to a test of carry-over effect; should 
sequence results as non-statistically significant, the sequence effect will be removed from the 
model, knowing that a carryover effect can be excluded. 
There will be no imputation for dropouts or missing data for assessments not completed at study 
visits. In case of no cough registered in the daytime, in order to allow the log transformation 1 
cough will be imputed for derivation of daytime cough frequency. 
The following SAS code will be used as reference for the described analysis of primary efficacy 
endpoint: 
proc mixed; 
class SUBJ SEQ PERIOD TRT; 
model log (cough Day 22/ baseline) = PERIOD TRT SEQ/ cl alpha=0.05 est 
solution; 
random site/ type=cs sub=SUBJ (SEQ); 
estimate 'Day 22: Active - Placebo' trt 1 -1 / e cl; 
<Add /modify "lsmeans" and "estimate" statements as needed preserving the 
model> 
run; 
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Statistical Analysis Plan 
In the presentation of results, log-scale fitted means at Day 22 will be exponentiated back and 
percentage changes will be presented in table. A code similar to the below will be used: 
geomean_perc_change=l00*(exp(estimate)-1); 
sdrerrback=((logStdErr**2)*((100*(exp(Estimate)) )**2))**0.5; 
geomean_perc_lowercl=geomean_perc_change-(quantile('NORMAL', 
0.975)*sdrerrback); 
geomean_perc_uppercl=geomean_perc_change+(quantile('NORMAL', 
0.975)*sdrerrback); 
Where SEQ is study Arm (i.e. Arm 1: NAL-ER + Placebo; Arm 2: Placebo + NAL-ER); Period 
corresponds to the Study Period; TRT is actual treatment received at the time of the assessment 
(i.e. NAL-ER; Placebo); SITE is the investigational site. 
The above described primary analysis will be executed also on the FAS, as well the same analysis 
will be repeated on completers as a sensitivity analysis. 
As an additional sensitivity analysis, a negative binomial model will be fitted with the number of 
coughs at Day 22 as the outcome, with terms for sequence, and treatment, as well as study baseline 
cough frequency, and duration of daytime (in hours) as an offset. Site will be a random effect with 
an unstructured covariance matrix. 
Following SAS code will be used as reference for the described sensitivity analysis of primary 
efficacy endpoint: 
proc glimmix; 
class SEQ TRT PERIOD; 
model COUGH= TRT BASE DAYTIME SEQ PERIOD dist=negbinomial solution e cl; 
random intercept/ subject=SITE type=un; 
lsmeans TRT / e cl; 
estimate 'Day 22: Active -
Placebo' trt 1 -1 / e cl; 
<Add /modify "lsmeans", "estimate" statements as needed preserving the model> 
run; 
Where SEQUENCE is study Arm (i.e. Arm 1: NAL-ER + Placebo; Arm 2: Placebo + NAL-ER); 
TRT is actual treatment received at the time of the assessment (i.e. NAL-ER; Placebo); COUGH 
is number of coughs at timepoint; BASE is the study baseline cough frequency; DAYTIME is 
duration of daytime (in hours). 
A by subject listing will be provided for primary variable as defined in SAP section 4.2.4. 
Daytime cough frequency will be summarized by actual treatment received in terms of absolute 
values and change from study baseline as defined in SAP section 4.2.5. A similar summary table 
will be produced for gender and anti-fibrotic therapies subgroups, including presentation of 
stratified means (SAS PROC SURVEYMEANS may be used). 
Plots showing the absolute mean change from study baseline in daytime cough frequency by actual 
treatment received will be provided on both FAS and Completers analysis sets. Similar plots will 
also be presented by gender and anti-fibrotic therapies subgroups. 
From statistical model for primary efficacy endpoint analysis, the geometric mean (GM) for the 
two treatment and the 95% confidence interval for the GMR and the p-value from the hypothesis 
test of no difference between the treatment will be presented. 
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Statistical Analysis Plan 
From statistical model for sensitivity analysis of the primary efficacy end point, the 95% 
confidence interval for the difference between the treatments least squares mean and the p-value 
from the hypothesis test of no difference between the treatment will be presented. 
4.11.3 
Analysis of Secondary Efficacy Variables 
Secondary efficacy endpoints will be summarized using descriptive statistics except where 
specified in the subsequent sections. 
4.11.3.1 24-hour cough frequency 
A by subject listing will be provided for 24-hour cough frequency as defined in SAP section 4.2.4. 
24-hour cough frequency will be summarized by actual treatment received and visit in terms of 
absolute values and changes from study baseline as defined in SAP section 4.2.3. A similar 
summary table will be produced for gender and anti-fibrotic therapies subgroups, including 
presentation of stratified means (SAS PROC SURVEYMEANS may be used). 
Plots showing the absolute mean change from study baseline in 24-hour cough frequency by actual 
treatment received will be provided on both FAS and Completers analysis sets. Similar plots will 
also be presented by gender and anti-fibrotic therapies subgroups. 
Natural log transformed 24-hour cough frequency results will be analyzed with mixed-effects 
model as described for the primary efficacy variable analysis in section 4.10.2; statistical analysis 
results will similarly be interpreted as described for the primary efficacy variable. 
4.11.3.2 This secondary analysis will be executed also on the Completers as a sensitivity 
analysis. Nighttime cough frequency 
A by subject listing will be provided for nighttime cough frequency as defined in SAP section 
4.2.4. 
Nighttime cough frequency will be summarized by actual treatment received and visit in terms of 
absolute values and changes from study baseline as defined in SAP section 4.2.3. A similar 
summary table will be produced for gender and anti-fibrotic therapies subgroups, including 
presentation of stratified means (SAS PROC SURVEYMEANS may be used). 
Natural log transformed nighttime cough frequency results will be analyzed with mixed-effects 
model as described for the primary efficacy variable analysis in section 4.10.2; statistical analysis 
results will similarly be interpreted as described for the primary efficacy variable. 
This secondary analysis will be executed also on the Completers as a sensitivity analysis. 
Plots showing the absolute mean change from study baseline in nighttime cough frequency by 
actual treatment received will be provided on both FAS and Completers analysis sets. Similar plots 
will also be presented by gender and anti-fibrotic therapies subgroups. 
4.11.3.3 EXACT 14-item e-Diary Tool 
A by subject listing will be provided for EXACT 14-item e-Diary Tool scores as defined in SAP 
section 4.2.4. 
EXACT 14-item e-Diary Tool scores results will be summarized by actual treatment received and 
visit in terms of absolute values and changes from study baseline as defined in SAP section 4.2.3; 
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Statistical Analysis Plan 
a ttest will be used to assess statistically significant difference in the changes from study baseline 
by actual treatment. 
A plot showing the absolute mean change from study baseline by actual treatment received will be 
provided. 
This secondary analysis will be executed also on the Completers as a sensitivity analysis. 
4.11.3.4 E-RS diary 
E-RS breathlessness (items 7, 8, 9, 10, and 11) and cough items (item 2) will be flagged in the 
EXACT 14-item e-Diary Tool data listing. 
Scores obtained at the E-RS breathlessness scales will be summarized by actual treatment received 
and visit in terms of absolute values and changes from study baseline as defined in SAP section 
4.2.3; attest will be used to assess statistically significant difference in the changes from study 
baseline by actual treatment. 
A plot showing the absolute mean change from study baseline by actual treatment received will be 
provided. 
4.11.3.5 This secondary analysis will be executed also on the Completers as a sensitivity 
analysis. Cough Severity Numerical Rating Scale 
A by subject listing will be provided for Cough Severity Numerical Rating Scale as defined in 
SAP section 4.2.4. 
Cough Severity Numerical Rating Scale results will be summarized by actual treatment received 
and visit in terms of absolute values and changes from study baseline as defined in SAP section 
4.2.3. 
A plot showing the absolute mean change from study baseline by actual treatment received will be 
provided. 
This secondary analysis will be executed also on the Completers as a sensitivity analysis. 
4.11.3.6 PROMIS Item Bank vl.0 Fatigue Short Form 7a Scale 
A by subject listing will be provided for PRO MIS Item Bank vl .0 Fatigue Short Form 7a Scale as 
defined in SAP section 4.2.4. 
Cough Severity Numerical Rating Scale results will be summarized by actual treatment received 
in terms of absolute values and change from study baseline at Day 21 as defined in SAP section 
4.2.5. 
A plot showing the absolute mean change from study baseline by actual treatment received will be 
provided. 
This secondary analysis will be executed also on the Completers as a sensitivity analysis. 
4.11.3.7 CGI-C 
A by subject listing will be provided for CGI-C as defined in SAP section 4.2.4. 
CGI-C results will be summarized based on FAS by actual treatment received in terms of absolute 
values and change from study baseline at Day 21 as defined in SAP section 4.2.5. 
A boxplot showing the mean CGI-C by actual treatment received will be provided. 
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Statistical Analysis Plan 
This secondary analysis will be executed also on the Completers as a sensitivity analysis. 
4.11.4 
Pharmacokinetics 
4.11.4.1 Pharmacokinetic Concentrations 
Pharmacokinetic plasma concentration of nalbuphine (parent and metabolites), will be listed in 
Separately set according to SAP section 4.2.4. Listings will include actual sampling times relative 
to dose administration. Plasma concentrations below the lower limit of quantification (LLOQ) will 
be presented as Below Limit of Quantification (BLQ) in the listings. 
Plasma concentrations of nalbuphine (parent and metabolites) will be summarized by nominal 
timepoint and as defined in SAP section 4.2.5. The following descriptive statistics will be 
presented for plasma concentrations obtained at each nominal time point: n, arithmetic mean, SD, 
coefficient of variation 
(CV%), 
geometric mean, 
geometric 
CV% (calculated as: 
gCV%=SQRT(e52-l)*l00; where s is the standard deviation of the log-transformed values), 
median, minimum and maximum values. 
The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings of concentration data: 
• 
Source data shall be used in all derived PK concentrations without prior rounding 
• 
The mean, standard deviation (SD), geometric mean and median will be tabulated to one 
more significant digit compared to the source data, but with a maximum of four significant 
digits. 
• 
Minimum and maximum values will be tabulated to the same precision as the source data, 
but with a maximum of four significant digits. 
• 
Geometric coefficient of variation (CV) % and coefficient of variation (CV%) will be 
presented to one decimal place. 
4.11.4.2 Handling of Values Below the Limit of Quantification (BLQ) 
All concentrations BLQ or missing data will be labeled as such in the concentration data listings. 
Missing samples will be reported as no sample ("NS") and excluded from analysis. 
In summary tables, all BLQ values will be set to the ½*lower limit of quantification (LLOQ), and 
all descriptive statistics will be calculated. 
The number ofBLQ values will be reported for each time point 
4.11.4.3 Pharmacokinetic Parameters 
Not Applicable 
4.11.4.4 Pharmacokinetic Analysis 
Nalbuphine (parent and metabolites) plasma concentration data will be listed by collection time 
and nalbuphine dose where applicable. Further PK analyses may be conducted if data allow. 
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4.11.5 
Additional Exploratory Efficacy Evaluation 
Statistical Analysis Plan 
Responder analysis assessing 30%. 50% and 75% reduction in daytime cough counts 
Exploratory variable described in this SAP section 3.2.4 
4.12 Number and percentages of subjects with 30%, 50% and 75% reduction from baseline 
in daytime cough counts will be listed and presented by treatment group. Safety 
Evaluation 
All safety summaries and analyses will be based upon the Safety Set as defined in Section 4.5. 
4.12.1 
Adverse Events 
4.12.1.1 Definition of Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a clinical investigation subject reported 
on or after the first screening date, which does not necessarily have a causal relationship with this 
treatment. Adverse events may include the onset of new illness and the exacerbation of pre-existing 
conditions. 
4.12.1.2 Definition of Treatment Emergent Adverse Event (TEAE) 
A TEAE is an AE occurring on or after the initial administration of investigational product. In this 
study, AEs may be treatment emergent with respect to treatment assumed in treatment period 1 or 
treatment period 2. The following will apply: 
• 
AEs with onset date prior to the date of first of IMP intake in Treatment Period 1 will be 
considered as AEs non treatment emergent. 
• 
AEs with onset date on or after the date of frrst IMP intake in Treatment Period 1 (but before 
first IMP intake in Treatment Period 2) will be considered as Treatment Period 1 TEAE. 
• 
AEs with onset date on or after the date of first IMP intake in Treatment Period 2 will be 
considered as Treatment Period 2 TEAE. 
4.12.1.3 Definition of Serious Adverse Event (SAE) 
AEs fall into the categories "non-serious" and "serious.". 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
• Requires subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability and/or incapacity 
• Results in a congenital anomaly or birth defect 
4.12.1.4 Severity 
All AEs will be graded for severity, if possible, by the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 or later. 
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4.12.1.5 Relationship to Investigational Product 
Statistical Analysis Plan 
Association or relatedness to the investigational product will be graded as either "definitely 
related", "probably related", "possibly related", "unlikely related", or "not related". 
AEs with causal relationship to IMP "definitely related", "probably related", "possibly related" 
will be considered as 'Related' AEs; AEs with causal relationship to IMP "unlikely related", or 
"not related" will be considered as 'Not Related' AEs 
4.12.1.6 Adverse Event of Special Interest (AESI) 
Certain adverse events, spontaneously reported by a subject, will be documented in more detail as 
part of the analysis to determine any abuse potential of nalbuphine. 
The AESI section of the AE eCRF provides for recording the following details about any events 
meeting the characteristics described above: 
• 
Additional Subject's Narrative, i.e. a description of the AE event in the subject's own 
words; 
• 
Investigator comments and/or assessment; 
• 
The estimated time between the subject's most recent dose prior to the AE, and the onset 
time of that AE ( e.g., X minutes or Y hours between preceding dose and AE onset); such 
an estimate is directly collected from eCRF; 
• 
Prior history of this symptom or event. 
4.12.1.7 Handling of AEs partial dates 
If medication start date is missing or partial, the dates will be compared as far as possible with the 
date of first dose of study medication in both Treatment Periods to assess if the AE is treatment 
emergent with respect to one of the two treatment periods. 
4.12.1.8 Analysis of AEs 
All AEs will be listed as defined in SAP section 4.2.4. The following information will be included 
in the listings: Description of AE, System Organ Class (SOC), Preferred Term, onset date, end 
date, TEAE status, CTCAE Severity Grade, Seriousness (Yes/No and seriousness criteria), 
Outcome, Relationship to Study Treatment, Action Taken with Study Treatment, Other Actions 
Taken, AE of Special Interest (Yes/No). 
All AESI will be listed separately following definition in SAP section 4.2.4. The following 
information will be included in the listings: Description of AE, System Organ Class (SOC), 
Preferred Term, onset date, end date, TEAE status, AE of Special Interest (Yes/No), Subject's 
Narrative, Investigator's Comments, onset datetime, estimated time between last dose and onset of 
AESI, prior history of the symptom or event. 
The TEAEs will be presented using summary tables as defined in SAP section 4.2.5, in general, in 
TEAEs summaries number of subjects with an event will be printed as well as number of events. 
Summary tables: 
• 
Patient Overall Summary of TEAEs; this table will include following summaries: 
o Any TEAEs 
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o Any related TEAEs 
o Any Serious TEAEs 
o Any related Serious TEAEs 
o Any treatment emergent AESis 
o Any related treatment emergent AESis 
o Any serious treatment emergent AESis 
o Any related serious treatment emergent AESis 
o Any Grade 3 or higher TEAEs 
o Any Related Grade 3 or higher TEAEs 
o Any TEAEs leading to IMP interruption 
o Any Related TEAEs leading to IMP interruption 
o Any TEAEs leading to IMP withdrawn 
o Any Related TEAEs leading to IMP withdrawn 
o Any FATAL TEAEs 
o Any Related FAT AL TEAEs 
• 
TEAEs by SOC and PT 
• 
Related TEAEs by SOC and PT 
• 
TEAEs by SOC and PT and Worst CTCAE Grade 
• 
Related TEAEs by SOC and PT and Worst CTCAE Grade 
• 
Serious TEAEs by SOC and PT 
• 
Related Serious TEAEs by SOC and PT 
• 
TEAEs Leading to IMP interruption by SOC and PT 
• 
Related TEAEs Leading to IMP interruption by SOC and PT 
• 
TEAEs Leading to IMP withdrawn by SOC and PT 
• 
Related TEAEs Leading to IMP withdrawn by SOC and PT 
• 
Fatal TEAEs by SOC and PT 
• 
Related TEAEs by SOC and PT 
• 
Serious AEs - Key Subject Information 
• 
Adverse Events with Outcome of Death - Key Patient Information 
Statistical Analysis Plan 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.0 or higher. 
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Statistical Analysis Plan 
4.12.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events 
Reporting of Deaths, Serious Adverse Events and other significant Adverse Events is described in 
the above section 4.11.1.1. 
4.12.3 
Clinical Laboratory Evaluation 
By subject listings of safety laboratory data will be provided as defined in SAP section 4.2.4. 
Abnormal safety laboratory data will also be listed separately. 
4.12.4 
Safety laboratory data will be summarized by actual treatment received and visit 
as defined in SAP section 4.2.5. Pregnancy 
Pregnancy test results will be listed as defined in SAP section 4.2.4. 
4.12.5 
Vital Signs 
By subject listings of vital signs will be provided as defined in SAP section 4.2.4. 
Vital signs will be summarized by actual treatment received and visit as defined in SAP section 
4.2.5. 
4.12.6 
Physical Examination 
By subject listings of Physical Examination will be provided as defined in SAP section 4.2.4. 
4.12.7 
ECG 
By subject listings of ECG data will be provided as defined in SAP section 4.2.4. 
ECG data will be summarized by actual treatment received and visit as defined in SAP section 
4.2.5. 
4.12.8 
Spirometry 
Spirometry will not be executed at the end of treatment period 1 (Visit 6), therefore the screening 
spirometry results will be used as study baseline for both period 1 and period 2. 
By subject listings of Spirometry results will be provided as defined in SAP section 4.2.4. 
Spirometry results will be summarized by actual treatment received and visit as defined in SAP 
section 4.2.5. 
4.12.9 
Swallow Test 
By subject listings of Swallow Test data will be provided as defined in SAP section 4.2.4. 
4.12.10 sows 
By subject listings of SOWS results will be provided as defined in SAP section 4.2.4. 
SOWS results will be summarized by actual treatment received and study day as defined in SAP 
section 4.2.5. 
4.12.11 
Data Safety Monitoring Board (DSMB) 
An independent Data Safety Monitoring Board (DSMB) will periodically review safety data. The 
frequency of data review and DSMB processes are outlined in the DSMB charter. 
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P AREXEL International 
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TR12 
4.13 Other Analyses 
Not Applicable 
4.14 Determination of Sample Size 
Original Sample size assumptions 
Statistical Analysis Plan 
The planned sample size of 44 subjects (22 per sequence) provides at least 80% power to detect a 
40% reduction in Day 22 daytime cough frequency (coughs per hour) with NAL ER tablet 
treatment compared to placebo tablets at the 5% significance level (2-sided). This assumes a CV 
of 1.00 in log-transformed Day 22 cough frequencies. The CV estimated from Kelsall et al (2011) 
data on chronic cough in patients without esophageal catheterization is 1.12; because Kelsall et al 
data was on 24-hour cough (including nighttime cough, a period of lower coughing rate) and were 
not taken in a sample of IPF patients only, it is believed that the CV will be lower than in Kelsall 
et al data. If the CV is larger than planned at 1.25, this sample size provides > 80% power to detect 
a 50% reduction from placebo to NAL ER. Alternatively, if the CV is 0.75, this sample size 
provides> 80% power to detect a 34% reduction from placebo to NAL ER. 
A total of approximately 60 subjects will be randomized to ensure complete data from at least 44 
subjects, assuming up to potentially a 26% dropout rate. 
Study early interruption 
As described in this SAP at sections 4.11.1.5 and 4.15, study was terminated before reaching the 
total sample size. 
4.15 Changes in the Conduct of the Study or Planned Analysis 
Following an Interim Analysis, the study recruitment was terminated with the last eligible subjects 
enrolled/randomized on or before 11MAR2022. 
Additional exploratory analysis re added in this SAP, prior than study general unblind. 
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Trevi Therapeutics, Inc. 
TR12 
5 
REFERENCES 
P AREXEL International 
Statistical Analysis Plan 
[1] ICH HARMONISED TRIPARTITE GUIDELINE, STRUCTURE AND CONTENT OF 
CLINICAL STUDY REPORTS, E3, 30 November 1995 (https://www.ich.org/page/efficacy-
guidelines) 
[2] ICH HARMONISED TRIPARTITE GUIDELINE, STATISTICAL PRINCIPLES FOR 
CLINICAL TRIALS, E9, 5 February 1998 (https://www.ich.org/page/efficacy-guidelines) 
[3] SAS® Version 9.2 of the SAS System for Personal Computers. Copyright© 
SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
[ 4] Bacci ED, O'Quinn S, Leidy NK, Murray L, Vernon M. Evaluation of a respiratory symptom 
diary for clinical studies of idiopathic pulmonary fibrosis. Respir Med. 2018 Jan; 134: 130-13 8. 
[5] Bacci ED, O'Quinn S, Leidy NK, Murray L, Vernon M. Evaluation of a respiratory symptom 
diary for clinical studies of idiopathic pulmonary fibrosis. Online supplement (2018). 
https://doi.org/10.1016/j.rmed.2017.11.011 
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Trevi Therapeutics, Inc. 
TR12 
6 
APPENDICES 
6.1 
Schedule of Assessments 
P AREXEL International 
Statistical Analysis Plan 
Appendix 1 
Schedule of Events - Screening and Treatment Period 1 
Srrteniu2 
Visit: 
1 
On-Site Visit 
Treatment Day: 
Infonned consent 
Demo,u-aohics 
Medical h.isto1y 
Inclusion/exclusion criteria 
Hei2ht. wei2ht. and BM! 
Electrocardio2ram (triolicate )5 
Vital s i211s 6 
Soiromeuy7 
D Leo measm·emenr2° 
Swallow test 
Phvsical examination 
Urine pregnancy test 
Senuu pregnancy test 
Clinical laboratory tests• 
PK blood samolin• 
Randomization 
Cou2.h monitor - Disoense/train on use 
Cough monitor - RemoYaVrenuu for 
downloadin2 of data 
Cou2h frequency (,·ia cou2l1 monitor) 
Cou•h Se,·erirv Nmnerical Ratin• Scale 
Fatigue Scale (Sh011 Fonn 7a) 
Clinical Global hnpression of Change 
e-diaiy - Dispense and trnin on use 
e-diatY - Re,·iew comoliance19 
EXACT Yersion I. I e-diaiy tool" 
Subjecti,·e Opiate Withdrawal Scale 
e-diaiv 
Contracepti.Ye counselil12 (if applicable) 
Dispense Subject Medication and 
SvmotomL02 
TP-GDO-WW-133-01.a 
SOP Effective Date: 30 Jan 19 
Related to: SOP-GDO-WW-019 
-45 to -2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X" 
X 
X 
Treatment Period 11 
Premature 
Bas•lin• 
Treatment 
Follow-uo' 
Discontinuation 
2 
3 
4 
5 
6 
Ou-Site \ "isit 
Phone \ "isit 
Phoue, Yisit 
On-Site \ ·isit 
On-Site \ ·isit 
On-Sile \ "isil 
-1 
1' 
8 
15 
21 
22• 
36 
(+/-1 da}·) 
(+/-Ida~-) 
(+/-:?days) 
X 
x is 
X 
X 
X 
X 
xis 
X 
X' 
X 
X 
X 
X 
X 
X 
X 
xt o.11 
x11 
xn 
xn 
X 
xn 
X 
x12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
<----- Recorded tlu-ou2l1out -----> 
X 
xis 
xis 
X 
X 
X 
X 
CONFIDENTIAL 
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Page 39 of 41 


P AREXEL International 
Trevi Therapeutics, Inc. 
TR12 
Statistical Analysis Plan 
TrenttnE'llt Period 11 
Premature 
Screening 
Baseline 
Treatment 
Follow-uo 2 
Disroutinuntion 
Vish: 
1 
l 
3 
4 
5 
6 
On-Site , "isit Ou-She \ ·isit 
Phone Yisit 
Phoue Yisit 
On-Site \ ·isit 
Ou-Site \ ·i.sif 
On-Site , ·isit 
Treatment Day: 
-45 to -2 
-1 
1' 
8 
15 
21 
22' 
36 
(+/-1 <L1y) 
(+/-lday) 
(+/-2da~-s) 
Subject Medication and Symptom Log -
X 
X 
X 
X 
Ren-ie,·e/re,·iew/re-disoense 
RecorcVassess AEs. conmeds. and 
therapies (including restricted/prohibited 
X 
X 
X 
X 
X 
X 
X 
medications)16 
Dispense I.J.n-estigational Product blister 
X 
card/dosll.12 instn.1ctions 
ReYiew lil\'estigat"ional Product 
X 
X 
comoliauce 
Ren-i.eYe lt1Yestigational Product blister 
X 
x" 
xn 
card/re,·iew compliance/re-dispense 
Ren-ieYal of e-diaiy. medication and 
X 
X 
svmotom log 
B~,f] = body mass index: PK= phannacokinetic: AE = adverse event: conmeds = concomitant medications 
J 
lttvestig:ational product administration in each treatment period \\ill be separated by a washout interval of2 weeks benveen dosing:. 
2 
Follow-up will occm 14=2 days after the last adi1t.inistrntion of i.nvestig:ational product. 
3 
First dose of i.tl\'estig:ational product for Treatment Period I is taken the cvcni.t1g of Day I after removal of the cougl1 monitor. 
4 
Last dose ofiiffcstigational product for Treatment Period 1 is the momi.t1g dose of Day 22. 
5 
Electrocardiogram (ECG) to be recorded p1ior to blood sampling: when possible at scheduled visits where PK and/or clinical labs arc obtained. Subjects should be in the 
supine position for at least 5 nllnutes prior to obtai.ui.t1g: ECGs with alt 3 traci.t1gs capmrcd withi.t1 a 3-5 nllnutc window. 
6 
Includes hca11 rate. blood pressure. rcspirato1y rate. body tcmpcranu·c. and pulse oximct1y. Vital signs should be taken prior to blood sampling and measured after the 
subject has been seated for at least 5 minutes. 
Pcrfonuancc of spi.tumet1y should adhere to A TSIERS guidelines: required a.s part of mccti.ttg: inclusion criterion #2. 
8 
A negative uri.t1e pregnancy test will be confmned prior to randomizing auy female subjects of childbearing potential. 
9 
Blood and rni.ne samples for clinical laborato1y testing: should be obtained after 8 hours of fa.sting: whenever possible. Cli.t1ical chc11Ust1y. hem,.1tology. tui.nalysis. and 
coa2ulation will be assessed. 
JO 
Bas~linc values for the purposes of the statistical analysis of treatment effect Oil daytime cough frequency during that crossover period. FU-st dose of i.t1vestigatio11al product 
on Treatment Day I will be taken after remo,·al of the cough monitor. 
J J 
Monitor \\ill be placed on the subject by site staff at the end of the visit. 
J 2 
Digital cough monitor hookup (24-hom· recordi.ttg): mo1Utor will be ,,·om m1til the evening of the following day in order to obtain at least a full 24-hour recordi.t1g period of 
cough frequency. At the end of each recordi.t1g: se'iision. the monitor will be rcino,·ed at home by the subject p1ior to bedtime. On Treatment Day 1. the monitor will be 
removed p1ior to taking: the first dose of i.i1,·cstigational product. Subject to be pro,idcd with approp1iate shippi.ttg material to rcnu,1 monitor for dom1loadi11g: of cough d1ta 
(after removal). 
13 
Administered Oil paper for screening: required as part of 111ccti.t1g: inclusion crite1ion #6. 
14 
E-RS consists of item munbers 1-11 on the 14-item EX.A.CT ,·ersion I.I e-diruy tool. E-diruy tool will be completed each cveni.i1g by the subject p1ior to bedti.tue. Subject 
will be reminded to complete this daily at each approp1iate smcly ,isit. 
15 
Subjective Opiate \Vithdi-awal Scale will be completed cfaily ,ia c-diruy for 14 days foUowi.t1g: discontinuation of i.trvestig:ational pmduct regardless of when this occm-s (i.e. 
Day 23 or premanire disconti.imation). Site will log into the e-diruy po11al to confu,n subject is completi.t1g entries as requfred during the washout period. 
16 
Spontruteous AE repo11ing will be continuous tlu-oughout the sn1dy: howe\·er. AE assessments will be perfonned at each \·isit using non-leadi.t1g questions. 
17 
Rcuie,·etre\·iew compliance at 1hese visits: investigational product and packet will not be re-dispensed. 
18 
ECG ru1d physical exrun do not need to be repeated at Visit 6 if pre\·iously pe1fonned for Preman1re Disconti.tmation Vi.sic. A b1ief physical exam may be pe1fonned at Visit 
6 to docmuent any changes from the previous exam. 
J 9 
During: all visits (i.ncludi.t1g those conducted by telephone). site will review c-diary cut1ics for compliance. Site will also rctmin the subject on use of e-dia1y if needed. 
20 
Subjects ,,idiom DLco testing i.i1 the prc\ious 6 months may be enrolled with medical monitor approval. 
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P AREXEL International 
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TR12 
Appendix 2 
Schedule of Events -Treatment Period 2 
Baseline 
Visit: 
6 
Treatment Period 21 
Treatment 
7 
8 
9 
On-Site , ·isit 
Phone- , -isit 
Phone \ 'isit 
On-site Visit 
Treaunent Day: 
-1 
l ' 
8 
15 
21 
C+/-l da,·) 
/+1-1 d,-·) 
Elecn·ocardiosmun (n·iplicate)5 
Vital si!ms6 
Soiromenv7 
X 
Physical examination 
Urine pregnancy test 
Semm pree:nancy test 
X 
Clinical laborato1v tests9 
X 
X 
PK blood samolii12 
X 
Cough monitor - Dispense/train on use 
x•o.11 
x11 
Cough monitor - RemoYal/renim for do\\11loading of 
x12 
data 
Cou2h frequency (Yia cou!tl1 monitor) 
X 
x12 
X 
Cou2.h SeYeritv NW11erical Rating Scale 
X 
X 
X 
X 
Fati2ue Scale (Shon Fonn 7a) 
X 
X 
Clinical Global Impression of Chan2e 
X 
e-diary - Re-train on use 
X 
e-dia1y - ReYiew compliance18 
X 
X 
X 
X 
EXACT Yersion 1.1 e-diruy tool13 
<----- Recorded tlu-ornzhont -----> 
Snblecti\·e Ooiate \Vithdrawal Scale e-diarv 
X14 
Contraceoti,·e c01mseli112 (if aoolicable) 
X 
X 
X 
X 
Dispense Subject ?vledication Symptom Lo2 
X 
Subject Medication and Symptom Log: -
X 
X 
X 
retrie\·e/re\·iew/re-disvense 
RecorcVassess AEs. comneds. ru1d therapies (including: 
X 
X 
X 
X 
restricted/urohibited medications)15 
Dispense I.J.1Yestigational Product blister card/dosing 
x• 
instmctions 
ReYiew hn·estigational Product compliance 
X 
X 
Reni.eYe lt1Yestig:ational Product blister card/ reYiew 
X 
compliance/re-dispense 
Final retrieYal of e-diarv. medication and svmotom 102 
PK= phanuacokinetic: AE = ad,·erse event: comneds = concomitant medications 
Statistical Analysis Plan 
Premature 
Follow-u1>2 
Discontinuation 
10 
On-Site Yiisit 
224 
36 
(+/-2d.1n) 
x" 
X 
X 
X 
x11 
X 
X 
X 
X 
X 
xn 
x12 
X 
X 
X 
X" 
X 
X 
X" 
x16 
X 
X 
J 
Investigational product administration in each treatment period will be separated by a washout ituerval of2 weeks between dosing. 
2 
Follow-up will occm· 14=2 days after the last administration of it1vestigational product. 
3 
Fit~t dose of i.t1Yestigational product for Treatment Pe1iod 2 is taken the evenit1g of Day 1 after removal of the cough monitor. 
4 
Last dose of lll,·estigational product for Treatment Pe1iod 2 is the momi.11g dose of Day 22. 
5 
Electrocardiogram (ECG) to be recorded p1ior to blood sampling: when possible at scheduled visits where PK and/or cli.t-1ical labs an: obtait1cd. Subjects should be it1 the 
supine position for at lea.st 5 minutes prior to obtaining: ECGs with all 3 u·acings capnired withit1 a 3-5 minute window. 
6 
Includes heru1 rate. blood pressure. respirato1y rate. body tempcranu·e. and pulse oximetry. Vital sign> should be taken p1ior to blood sampling ru1d measured after the 
subject has been seated for at least S nlllmtes. 
7 
Pe1fonnance of spit·omeuy should adhere to ATS/ERS guideli.t1es. 
8 
A negati,·e mine pregnancy test will be confmned p1ior to randomizing ru1y female subjects of childbearing potential. 
9 
Blood and mine samples for clinical laborato1y testing. should be obtained after 8 hours of fasting. whenever possible. Clinical chemist1y. hematology. urinalysis. and 
coagulation will be assessed. 
JO 
Basclit1e values for the pmposes of tl1e statistical analysis of treatment effect on daytime cough frequency during that crossover pe1iod. First dose of lln·estigatioual 
product on Treatment Day I will be taken after remo,·al of the cough monitor. 
11 
Monitor will be placed on the subject by site staff at tl1e end of the ,·isit. 
12 
Digital cough monitor hookup (24-hou.r recordit1g): monitor wilt be wom tmtil the e,·enit1g of the foltowll1g day in order to obtain at least a full 24-hour recordll1g period 
of cough frequency. At tl1e end of each recordit1g session. the monitor will be remo,·ed at home by the subject p1ior to bedtitue. On Treatment Day l. the monitor will be 
removed prior to taking the fu-st dose of investig:ational product. Subject to be pro,·idcd with approp1iate shippit1g matciial to remm monitor for downloadit1g of cough 
data (after remo,·al). 
13 
E-RS consists of item munbers 1-11 on the 14-item EXACT version 1.1 e-dia1y tool. E-cliaiy tool will be completed each e,-enll1g by the subject p1ior to bedtime. 
Subject will be renlll1ded to complete this daily at each appropriate snidy visit. 
14 
Subjective Opiate \Vithdrawal Scale will be completed daily via e-diruy for 14 day.s followi.t1g discontinuation of i.t1,·estigational product regai·dless of when this occm-s 
(i.e. Day 23 or prciuanu·e discontllmation). Site will log into the e-dimy p011al to confmn subject is completing ent1ies as required dtui.ng the \Ya.shout period. 
15 
Spontru1eou.s AE repo11i.t1g will be conti.tmous throughout the .smdy: hO\ve,·ci-. AE assessments will be pcrfonncd at each ,·isit using non-leadi.ttg questions. 
16 
Ret1ieve1review compliance at these vi.sirs: investigational product aitd packet will not be re-dispensed. 
17 
ECG ru1d physical exam do not need to be repeated at Visit 10 if previou.sly peifonned for Premanire Discontllmation Visit. A b1ief physical exrun may be pe1fonned at 
Visit 10. 
18 
Dming: all vi.sits (including those conducted by telephone). site will review e-dia1y ent1ies for compliru1ce. Site will also retralll the subject on use of e-dia1y if needed. 
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