A Study of Nalbuphine (Extended Release) ER in Idiopathic Pulmonary Fibrosis (IPF) for Treatment of Cough (CANAL)

A Phase 2, Double-blind, Randomized, Placebo-controlled, Two-Treatment, Two-Period Crossover Efficacy and Safety Study in Idiopathic Pulmonary Fibrosis (IPF) With Nalbuphine ER Tablets for the Treatment of Cough

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.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: NAL ER; Drug: Placebo

Detailed Description

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 followed by crossover Placebo in Treatment Period 2
• Arm 2: Placebo followed by crossover NAL ER 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 and subjects assigned to Arm 2 will receive NAL ER 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 will have the dose titrated from 27 mg once daily (QD) to 54 mg twice a day (BID) over a 5-day period and then maintained at 54 mg twice a day (BID) for approximately 4 days. Doses will be subsequently escalated and maintained at 108 mg twice a day (BID) over 1 week and then to 162 mg twice a day (BID) over 6 days.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB23 3RE
    • 09
  • Cottingham, United Kingdom, HU16 5JQ
    • 08
  • Dundee, United Kingdom, DD1 9SY
    • 17
  • Edinburgh, United Kingdom
    • 13
  • London, United Kingdom, NW1 2BU
    • 04
  • London, United Kingdom, SW3 6NP
    • 01
  • Manchester, United Kingdom, M23 9LT
    • 02
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • 10
  • Nottingham, United Kingdom, NG5 1PB
    • 06
  • Oxford, United Kingdom
    • 14
  • Southampton, United Kingdom, SO16 6YD
    • 03

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Individuals diagnosed with Idiopathic Pulmonary Fibrosis
2. Chronic cough > 8 weeks.
3. Daytime cough severity score ≥ 4 on Cough Severity Numerical Rating Scale at screening.

Exclusion Criteria:

1. The following conditions are excluded:

   1. Interstitial lung disease (ILD) known to be caused by domestic and occupational environmental exposures.
   2. Interstitial lung disease (ILD) known to be caused by connective tissue disease.

   3. Interstitial lung disease (ILD) known to be caused by drug related toxicity.

      2. Currently on continuous oxygen therapy.

      3. History of substance abuse that, as determined by the Investigator, may interfere with the conduct of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAL ER then placebo; 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.	Drug: NAL ER; Participants received NAL ER 27 mg QD, 27 mg BID, 54 mg BID, 108 mg BID, 162 mg BID.; Other Names: Nalbuphine; Drug: Placebo; Participants received Placebo tablet (matching NAL ER ).; Other Names: Placebo matched to NAL ER
Experimental: Placebo then NAL ER; 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.	Drug: NAL ER; Participants received NAL ER 27 mg QD, 27 mg BID, 54 mg BID, 108 mg BID, 162 mg BID.; Other Names: Nalbuphine; Drug: Placebo; Participants received Placebo tablet (matching NAL ER ).; Other Names: Placebo matched to NAL ER

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced at Least One Treatment Emergent Adverse Events (TEAEs)	An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A TEAE was defined as any AE that occurs after the first dose of study drug. TEAEs included both serious and non-serious TEAEs.	Up to Day 72
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters	The clinical laboratory parameters included the urinalysis, hematology, serum chemistry, coagulation and liver function parameters. Clinical significance was determined by the investigator.	Up to Day 72
Number of Participants With Clinically Significant Changes in Vital Sign Parameters	Vital signs measurements included blood pressure, heart rate, and respiration rate, body temperature, pulse oximetry, and weight. Clinical significance was determined by the investigator.	Up to Day 72
Number of Participants With Clinically Significant Changes in Physical Examination Parameters	Physical examination included 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. Clinical significance was determined by the investigator.	Up to Day 72
Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG)	Changes in ECG data such as heart rate, rhythm, and other clinically significant abnormalities (left ventricular hypertrophy, pathological Q-waves) were measured. Clinical significance was determined by the investigator.	Up to Day 72
Change From Baseline in Forced Vital Capacity (FVC) at Day 21	Spirometry was used to assess FVC. It was used to assess pulmonary breathing mechanics.	Baseline, Day 21
Subjective Opiate Withdrawal (SOWS) Total Raw Score	The SOWS is a self-administered scale for grading opioid withdrawal symptoms and was collected via the study issued e-diary. It consisted of 16 symptoms related to how the participant felt. Each symptom was scored between 0 to 4. The total score ranges between 0 to 64, higher score indicates more severe symptoms.	Up to Day 72
Daytime Cough Frequency at Baseline	Daytime cough was defined as cough that occurs between the time that the participant is a wake in the 24 hours after the digital cough monitor was applied for use. Assessment was done using objective digital cough monitoring. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	At Baseline
Percent Change From Baseline in Daytime Cough Frequency at Day 22	Daytime cough was defined as cough that occurs between the time that the participant is a wake in the 24 hours after the digital cough monitor was applied for use. Assessment was done using objective digital cough monitoring. Percent change in daytime cough frequency (coughs per hour) from baseline was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Day 22

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Daytime Cough Frequency at Day 22	Daytime cough was defined as cough that occurs between the time that the participant wakes up and the time that the participant goes to bed. Assessment was done using objective digital cough monitoring. The change in daytime cough frequency (coughs per hour) from baseline was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Day 22
Percent Change From Baseline in 24-Hour Cough Frequency at Day 22	Percent change in 24-hour (combined daytime and nighttime) cough frequency (coughs per hour) from baseline was assessed. Assessment was done using objective digital cough monitoring. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Day 22
Percent Change From Baseline in Nighttime Cough Frequency at Day 22	Nighttime cough frequency was intended as the average coughs per hour while the participant was flagged as being asleep. Assessment was done using objective digital cough monitoring. Percent change in cough frequency (coughs per hour) from baseline was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Day 22
Mean Change From Baseline in the Evaluating Respiratory Symptoms (E-RS) Diary Cough Subscale at Days 9, 16, and 22	E-RS daily diary instrument has four separate respiratory symptom domain scales which is a valid, reliable and sensitive measure of four distinct respiratory symptoms. The four domain scales that included cough [E-RS item 2- How often did you cough today?;score range 0 (not at all)-4 (almost constantly)], and other items such as breathlessness [score 0(not at all)-23(severe symptoms)], sputum [0(not at all)-8(severe symptoms)], and chest symptoms [0(not at all)-12(severe symptoms)]. The raw totals for the E-RS score and for each of the subscales were converted to a scale range of 0 to 100 (least symptomatic to most symptomatic). A higher score on the scale indicates a more severe grade to the symptom. Negative score indicates improvement in the symptom. The mean change from baseline in the E-RS diary cough scores was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Days 9, 16, and 22
Mean Change From Baseline in E-RS Breathlessness Score at Days 9, 16, and 22	E-RS daily diary instrument has four separate respiratory symptom domain scales which is a valid, reliable and sensitive measure of four distinct respiratory symptoms. The four domain scales included breathlessness [E-RS items 7 (were you breathless today), 8 (how breathless were you today), 9 (breathlessness doing personal care activities),10 (breathlessness doing indoor activities) & 11 (breathlessness doing outdoor activities); score =0: not at all) - 23: almost constantly]. Other items were cough (0: not at all-4: severe), sputum (0: not at all-8: severe), and chest symptoms (0: not at all)-12: severe symptoms). The raw totals for the E-RS score and for subscales were converted to a scale of 0 to 100 (least to most symptoms). Higher score=more severe grade to the symptom. Negative score=improvement in symptom. The mean change from baseline was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Days 9, 16, and 22
Mean Change From Baseline in the Cough Severity Numerical Rating Scale (NRS) at Days 8, 15, and 21	The Cough Severity NRS instrument is a single-dimension 11-point Likert scale ranging from 0 (no cough) to 10 (worst possible cough). Negative score indicates improvement in the symptoms. Participants completed the cough numerical severity rating via the study specific e-diary. The mean change from baseline in the Cough Severity Numerical Rating Scale was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Days 8, 15, and 21
Mean Change From Baseline in the 14-item EXAcerbation of Chronic Pulmonary Disease Tool (EXACT) v1.1 e-Diary Tool Total Score at Days 9, 16, and 22	The EXACT tool is a 14-item Daily Diary Tool Patient-reported outcome (PRO) instrument that was developed to quantify and measure exacerbations of chronic obstructive pulmonary disease (COPD). It provides a total score and subscale scores for breathlessness, cough and sputum, and chest symptoms. The 14 items have interval-level scale ranging between 0 to 100. The total score of each domain of breathlessness, cough and sputum, and chest symptoms ranges from 0 to 100. A higher score indicates a more severe condition. Negative score indicated improvement in the symptoms. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Days 9, 16, and 22
Mean Change From Baseline in the Patient Reported Outcomes Measurement Information System (PROMIS) Item Bank v1.0 Fatigue Short Form 7a Scale Total Score at Day 21	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. It consisted of 7 items with each item was scored between 1 to 5. The total score could range between 1 to 35, higher score indicates more severe symptoms. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.	Baseline, Day 21
Clinical Global Impression of Change (CGI-C) Over Time Measured at Day 21	The CGI-C is a one-item measure evaluating change from the initiation of treatment on a 7-point scale. It 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 total score ranges between 0 (very much improved) to 7 (very much worse). The lower scores indicate an improvement in respiratory symptoms.	At Day 21

Collaborators and Investigators

• Sponsor: Trevi Therapeutics
• Collaborators: Parexel
• Investigators: Study Director: Thomas Sciascia, Trevi Therapeutics, Inc

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2019
• Primary Completion (Actual): May 27, 2022
• Study Completion (Actual): May 27, 2022

Study Registration Dates

• First Submitted: July 11, 2019
• First Submitted That Met QC Criteria: July 22, 2019
• First Posted (Actual): July 23, 2019

Study Record Updates

• Last Update Posted (Actual): May 29, 2025
• Last Update Submitted That Met QC Criteria: May 12, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Cough; Idiopathic Pulmonary Fibrosis; Nalbuphine
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics; Analgesics, Opioid; Narcotics; Nalbuphine
• Other Study ID Numbers: TR12; 2018-004744-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No