Refractory Chronic Cough Improvement Via NAL ER (RIVER) (RIVER)

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

The main purpose of this study is to evaluate the effect of NAL ER on 24-hour cough frequency and to assess safety and tolerability of NAL-ER for treatment of refractory chronic cough.

Study Overview

• Status: Completed
• Conditions: Refractory Chronic Cough
• Intervention / Treatment: Drug: Placebo; Drug: NAL ER

Detailed Description

A double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of cough with NAL ER in subjects with Refractory Chronic Cough.

Based on the screening cough monitor results, the study will enroll subjects in a 1:1 ratio to subgroups of 10-19 coughs/hour and ≥20 coughs/hour.

After meeting eligibility during the screening period, subjects will be randomly assigned to one of the following sequences:

• NAL ER in Treatment Period 1, followed by Placebo (PBO) in Treatment Period 2 OR
• PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2.

Each treatment period lasts 21 days and are separated by a 21-day washout period. Subjects on NAL ER will have the dose titrated from 27 mg once a day (QD) to 108 mg twice a day (BID).

Study visits in each treatment period will be at Day -1 for Baseline cough assessments, and at Days 6, 13, and 20. Subjects will have blood drawn for pharmacokinetic (PK) analysis of nalbuphine plasma concentration. Subjects will also complete questionnaires for efficacy evaluations and undergo safety evaluations including an electrocardiogram (ECG).

At the Screening and Baseline visits and on Days 6, 13, and 20 during each treatment period, site staff will place an electronic cough monitor on the subject, which will be worn for a 24-hour recording period to assess cough frequency. At the end of each recording session (Days 7, 14, and 21), the monitor will be removed at home by the subject, and the subjects will complete Patient Reported Outcomes (PROs) questionnaires in the electronic diary.

Subjects will be taken off study drug at the end of Treatment Period 2 and followed off treatment for an additional 2 weeks.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Medical Centre
    • Toronto, Ontario, Canada, M5T 3A9
      • Inspiration Research
  • Quebec
    • Trois-Rivières, Quebec, Canada, G8T 7A1
      • CIC Mauricie inc.
• United Kingdom
  • High Wycombe, United Kingdom, HP11 2QW
    • Egin Research Ltd
  • East Riding Of Yorkshire
    • Cottingham, East Riding Of Yorkshire, United Kingdom, HU16 5JQ
      • Hull and East Yorkshire Hospitals NHS Trust - Castle Hill Hospital
  • Greater London
    • London, Greater London, United Kingdom, SE5 9RS
      • Kings College Hospital NHS Foundation Trust
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M23 9LT
      • University Hospital of South Manchester NHS Foundation Trust (UHSM) - Wythenshawe Hospital
  • Kent
    • Orpington, Kent, United Kingdom, BR5 3QG
      • Accellacare South London
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • Accellacare North London
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT9 7AB
      • Belfast City Hospital
  • Tynemouth
    • North Shields, Tynemouth, United Kingdom, NE29 8NH
      • North Tyneside General Hospital - Northumbria Healthcare NHS Foundation Trust
  • Warwickshire
    • Coventry, Warwickshire, United Kingdom, CV3 4FJ
      • Accellacare Warwickshire
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2GW
      • University Hospitals Birmingham NHS Foundation Trust
  • Yorkshire
    • Shipley, Yorkshire, United Kingdom, BD18 3SA
      • Accellacare Yorkshire

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Diagnosis of refractory chronic cough (RCC) for at least one year
• Chest radiograph or CT of thorax within 24 months or during screening not demonstrating any significant abnormalities contributing to RCC

Exclusion Criteria:

• Diagnosis of sleep apnea
• Respiratory tract infection within 6 weeks of Baseline
• History of bronchiectasis, COPD, or IPF
• History of uncontrolled asthma
• Current smokers/vapers, quit smoking with <=12 months, using nicotine supplements, or history of >=20 pack years
• History of major psychiatric disorder
• History of substance abuse
• Pregnant or lactating females
• Known intolerance to opioids
• Abnormal kidney or liver functions based on Screening lab results.
• Known hypersensitivity to nalbuphine or to NAL ER excipients
• Previous participation in a nalbuphine ER clinical study
• Use of opiates, benzodiazepines, or MAOIs within 14 days of Baseline
• Use of pregabalin, gabapentin, thalidomide for treatment of cough within 14 days of Baseline
• Use of ACE inhibitors within 12 weeks of Baseline
• Use of a medication having a "known risk" of Torsade de Pointes (categorized as "KR" on the Credible Meds® website.) 4 weeks prior to Baseline
• Use of unstable doses of medications associated with a potential risk of QT prolongation but not clearly associated with Torsade de Pointes within 4 weeks of screening.
• Use of unstable doses of cough suppressants within 14 days of Baseline
• Use of unstable doses of medications that affect serotonergic neurotransmission that may cause serotonin syndrome with opioids within14 days of Baseline
• Use of unstable doses of P450 isozyme inhibitors/inducers within 14 days of Baseline

Other protocol defined inclusion/exclusion criteria applied.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: First NAL ER, then Placebo; Participants received NAL ER at escalating doses (27 mg QD to BID, 54 mg BID, and 108 mg BID) in Treatment Period 1, followed by placebo matched to NAL ER in Treatment Period 2.	Drug: Placebo; Oral tablets; Drug: NAL ER; Oral tablets; Other Names: Nalbuphine
Experimental: First Placebo then NAL ER; Participants received placebo matched to NAL ER in Treatment Period 1, followed by NAL ER at escalating doses (27 mg QD to BID, 54 mg BID, and 108 mg BID) in Treatment Period 2.	Drug: Placebo; Oral tablets; Drug: NAL ER; Oral tablets; Other Names: Nalbuphine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change From Baseline in 24-hour Cough Frequency at Day 21	Relative 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 non-missing assessment, prior to the first dose of study drug.	Baseline, Day 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced at Least One Treatment Emergent Adverse Events (TEAEs)	An adverse event (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 Week 15
Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments	The clinical laboratory parameters included urinalysis, hematology, serum chemistry and coagulation. Clinical significance was determined by the investigator.	Up to Week 15
Number of Participants With Clinically Significant Changes in Vital Sign Parameters	Vital signs measurements included blood pressure, heart rate, respiration rate, body temperature, pulse oximetry, and weight. Clinical significance was determined by the investigator.	Up to Week 15
Number of Participants With Clinically Significant Abnormalities in 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 Week 15
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 Week 15
Relative Change From Baseline in 24-hour Cough Frequency at Days 7 and 14	Relative 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 non-missing assessment, prior to the first dose of study drug.	Baseline, Days 7 and 14
Percentage of Responders With >=30%, 50% and 75% Reduction in 24-hour Cough Frequency	Responders were defined as those with ≥30%, ≥50%, or ≥75% reduction in 24-hour cough frequency from Baseline at Days 7, 14, or 21.	Days 7, 14, and 21
Relative Change From Baseline in Awake Cough Frequency at Days 7, 14, and 21	Awake cough was defined as cough that occurs between the time that the participant is awaken 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 non-missing assessment, prior to the first dose of study drug.	Baseline, Days 7, 14, and 21
Relative Change From Baseline in Sleep Cough Frequency at Days 7, 14, and 21	Sleep 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 non-missing assessment, prior to the first dose of study drug.	Baseline, Days 7, 14 and 21
Change From Baseline in Cough Severity Visual Analogue Scale (CS-VAS) at Days 7, 14, and 21	The CS-VAS is a brief, easily administered patient reported outcome (PRO) questionnaire that is used to assess cough severity in both acute and chronic cough. CS-VAS is a 1-item scale that rates the severity of participants' cough from 0 millimeter (mm) where 0 indicated "no cough" and 100 represented "worst cough ever". A negative change from baseline indicates improvement.	Baseline, Days 7, 14, and 21
Change From Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Day 21	LCQ is a self-reporting quality of life measure of chronic cough. It consists of 19 items with a 7-point Likert response scale ranging from 1 to 7. The responses are as follows: 1 = all of the time, 2 = most of the time, 3 = a good bit of the time, 4 = some of the time, 5 = a little of the time, 6 = hardly any of the time, and 7 = none of the time. Each item is designed to assess cough symptoms and the impact of cough across three main domains, physical (8 items), psychological (7 items), and social (4 items). Domain scores are calculated as the total score from items in the domain divided by the number of items in the domain and range from 1 to 7. The LCQ total score is calculated by summing the individual domain scores and ranges from 3 to 21, with higher scores indicating better health status.	Baseline, Day 21
Change From Baseline in Patient-Reported Cough Frequency (PR-CF) at Days 7, 14, and 21	Patient-Reported Cough Frequency (PR-CF) is a daily, self-reported, 1 item scale, PRO that is used to assess cough frequency. Participants rate their cough frequency over the past 24 hours using a 5-point Likert scale (0- to 4: 0 = Not at all, 1 = Rarely, 2 = Occasionally, 3 = Frequently, 4 = Almost constantly). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.	Baseline, Days 7, 14, and 21
Percentage of PR-CF Responders With at Least One Category Improvement at Days 7, 14, and 21	PR-CF is a daily, self-reported, 1 item scale, PRO that is used to assess cough frequency. Participants rate their cough frequency over the past 24 hours using a 5-point Likert scale (0 to 4: 0 = Not at all, 1 = Rarely, 2 = Occasionally, 3 = Frequently, 4 = Almost constantly). A higher score indicates more severe symptoms. PR CF responders were defined as participants with at least a one category improvement at Days 7, 14, and 21.	Days 7, 14, and 21
Change From Baseline in Patient Global Impression of Severity (PGI-S) Cough at Days 7, 14, and 21	The PGI-S Cough scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough. Participants rate the severity of their cough in the last week with a 4-point Likert scale ranging from 0 to 3 (0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.	Baseline, Days 7, 14 and 21
Patient Global Impression of Change for Cough (PGI-C) Score at Days 7, 14, and 21	The PGI-C Cough scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough. Participants rate the severity of their cough in the last week with a 7-point Likert scale ranging from 0 to 7 (0 = No Cough, 1 = Much better, 2 = Moderately better, 3 = A little better, 4 = No change, 5 = A little worse, 6 = Moderately worse, or 7 = Much worse). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.	Days 7, 14, and 21
Change From Baseline in Clinicians Global Impression of Cough Severity Score (CGI-S) at Day 21	The CGI-S Cough scale is an investigator-reported, single-item categorical scale that is increasingly used when assessing the severity of the condition. Investigator rate the severity of their cough in the last week with a 4-point Likert scale ranging from 0 to 3 (0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.	Baseline, Day 21
Clinicians Global Impression of Change for Cough Score (CGI-C) at Day 21	The PGI-C Cough scale is an investigator-reported, single-item categorical scale that is increasingly used when assessing the investigator's belief of the participant's overall improvement pre-treatment baseline. Investigator rate the change in improvement in the last week with a 7-point Likert scale ranging from 1 to 7 (1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6= Much worse, or 7= Very much worse). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.	Day 21

Collaborators and Investigators

• Sponsor: Trevi Therapeutics
• Investigators: Study Director: Chief Development Officer, Trevi Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2023
• Primary Completion (Actual): January 6, 2025
• Study Completion (Actual): January 6, 2025

Study Registration Dates

• First Submitted: July 7, 2023
• First Submitted That Met QC Criteria: July 18, 2023
• First Posted (Actual): July 27, 2023

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Cough; RCC; Nalbuphine
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Chronic Cough; Cough; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Nalbuphine
• Other Study ID Numbers: NAL04-201

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
• product manufactured in and exported from the U.S.: Yes