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

A 2-period crossover study for the treatment of cough in patients with Refractory Chronic Cough via Nalbuphine ER (NAL ER). Each period will last 21 days and are separated by 21 days. Subjects will be randomized in Treatment Period 1 to either NAL ER or matching placebo and evaluated for 21 days. After completion of the first phase, subjects who received NAL ER will crossover to placebo and subjects who received placebo will crossover to NAL ER to complete Treatment Period 2.

Study Overview

• Status: Recruiting
• Conditions: Refractory Chronic Cough
• Intervention / Treatment: Drug: Placebo; Drug: Nalbuphine 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 (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sherry Minor; Phone Number: 203-684-1308; Email: Sherry.Minor@trevitherapeutics.com
• Study Contact Backup: Name: Connie Crum, RN; Phone Number: 203-599-0265; Email: Connie.Crum@trevitherapeutics.com

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Recruiting
      • McMaster University Medical Centre
      • Contact: Imran Satia; Phone Number: 76228 905-521-2100; Email: satiai@mcmaster.ca
    • Toronto, Ontario, Canada, M5T 3A9
      • Recruiting
      • Inspiration Research
      • Contact: Kayla Johnston; Phone Number: 416-944-9602; Email: kjohnston@inspirationresearch.ca
  • Quebec
    • Trois-Rivières, Quebec, Canada, G8T 7A1
      • Recruiting
      • CIC Mauricie Inc.
      • Contact: Sonia Groleau; Phone Number: 5 819-373-1128; Email: groleau@cic-mauricie.ca
• United Kingdom
  • East Riding Of Yorkshire
    • Cottingham, East Riding Of Yorkshire, United Kingdom, HU16 5JQ
      • Recruiting
      • Hull and East Yorkshire Hospitals NHS Trust - Castle Hill Hospital
      • Contact: Caroline Wright; Phone Number: 1482624067; Email: C.Wright@hull.ac.uk
  • Greater London
    • London, Greater London, United Kingdom, SE5 9RS
      • Recruiting
      • Kings College Hospital NHS Foundation Trust
      • Contact: Katie Rhatigan; Phone Number: +44 2032991096; Email: k.rhatigan@nhs.net
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M23 9LT
      • Recruiting
      • University Hospital of South Manchester NHS Foundation Trust (UHSM) - Wythenshawe Hospital
      • Contact: Swapnika Putla; Phone Number: 1612915031; Email: Swapnika.Putla@mft.nhs.uk
  • Kent
    • Sidcup, Kent, United Kingdom, DA14 6LT
      • Recruiting
      • Accellacare South London
      • Contact: Nowshin Rahman; Phone Number: 02033 013 000; Email: nowshin.rahman@accellacare.com
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • Recruiting
      • Accellacare North London
      • Contact: Charlotte Savill; Phone Number: 01923 742 400; Email: charlotte.savill@accellacare.com
  • Northamptonshire
    • Corby, Northamptonshire, United Kingdom, NN18 9EZ
      • Recruiting
      • Accellacare Northamptonshire
      • Contact: June Jacob; Email: june.jacob@accellacare.com
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT9 7AB
      • Recruiting
      • Belfast City Hospital
      • Contact: Danielle Dawson; Phone Number: 02895048253; Email: danielle.dawson@belfasttrust.hscni.net
  • Tynemouth
    • North Shields, Tynemouth, United Kingdom, NE29 8NH
      • Recruiting
      • North Tyneside General Hospital - Northumbria Healthcare NHS Foundation Trust
      • Contact: Jane Luke; Phone Number: 8448118111; Email: jane.luke@northumbria-healthcare.nhs.uk
  • Warwickshire
    • Coventry, Warwickshire, United Kingdom, CV3 4FJ
      • Recruiting
      • Accellacare Warwickshire
      • Contact: Jackie Smith; Phone Number: +44 (0) 1926290289; Email: Jackie.Smith@accellacare.com
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B9 5SS
      • Recruiting
      • University Hospitals Birmingham NHS Foundation Trust
      • Contact: Emma Bruce; Email: emma.bruce@uhb.nhs.uk
  • Yorkshire
    • Shipley, Yorkshire, United Kingdom, BD18 3SA
      • Recruiting
      • Accellacare Yorkshire
      • Contact: Amy Rosie; Email: Amy.rosie@accellacare.com

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

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: NAL ER; NAL ER, tablets, 27 mg QD to BID, 54 mg BID, 108 mg BID	Drug: Nalbuphine ER; Oral tablets; Other Names: Active
Placebo Comparator: Placebo; Placebo, tablets, 0 mg QD to BID, 0 mg BID, 0 mg BID	Drug: Placebo; Oral tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24 hr cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Day 21 versus Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment related adverse events, as assessed by CTCAE v.5.0	Adverse events, clinical labs, vital signs, physical exams, electrocardiograms	Baseline through follow-up
24 hour cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Days 7 and 14 versus Baseline
24 hour cough frequency	Proportion of responders with >=30%, 50% and 75% reduction in frequency versus Placebo	Days 7, 14, and 21 versus Baseline
Awake cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Days 7, 14, and 21 versus Baseline
Sleep cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Days 7, 14, and 21 versus Baseline
Patient-Reported Cough Frequency (change)	Change versus Placebo	Days 7, 14, and 21 versus Baseline
Patient-Reported Cough Frequency (proportion)	Proportion of responders with improvement in at least one category versus Placebo	Days 7, 14, and 21 versus Baseline
Subjective Opiate Withdrawal Scale	16 item questionnaire for 14 days following last dose of study drug	Daily for 14 days after last dose in Period 2
Cough Severity Visual Analogue Scale	1 item scale with minimum score of 0 (no cough) to 10 (worst cough) versus Placebo	Days 7, 14, and 21 versus Baseline
Leicester Cough Questionnaire	19 item questionnaire with a grading of 1 (all the time ) to 7 (none of the time) versus Placebo	Day 21 versus Baseline
Patient Global Impression of Cough Severity	1 item question with a grading from "no cough, to mild, moderate or severe" versus Placebo	Days 7, 14, and 21 versus Baseline
Patient Global Impression of Cough Change	1 item question with a 7 point grading from "much better to much worse" versus Placebo	Days 7, 14, and 21 versus Baseline
Clinicians Global Impression of Cough Severity	1 item question with a grading from "no cough, to mild, moderate or severe" versus Placebo	Day 21 versus Baseline (both treatment periods)
Clinicians Global Impression of Cough Change	1 item question with a 7 point grading from "very much improved to very much worse" versus Placebo	Day 21 versus Baseline (both treatment periods)

Collaborators and Investigators

• Sponsor: Trevi Therapeutics
• Investigators: Study Director: David Clark, MD, Trevi Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2023
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): October 1, 2024

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): May 1, 2024
• Last Update Submitted That Met QC Criteria: April 30, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Cough; RCC; Nalbuphine
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Cough; Chronic Cough; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; 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