Cough Reduction in IPF With Nalbuphine ER (CORAL)

A Randomized, Double-Blind, Placebo-Controlled, Parallel, 4-Arm Dose Ranging Study of the Safety and Efficacy of Nalbuphine Extended-Release Tablets (NAL ER) for the Treatment of Cough in Idiopathic Pulmonary Fibrosis (IPF)

The main purpose of the study is to evaluate the effect of NAL ER on 24-hour cough frequency using objective digital cough monitoring and to assess safety and tolerability of NAL ER.

Study Overview

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

Detailed Description

This is a multi-center randomized, double-blind, placebo-controlled, parallel, 4-arm study.

After meeting eligibility during the Screening Period, subjects will be randomized (1:1:1:1) to one of four treatment arms.

• Arm 1: Placebo
• Arm 2: 27 mg nalbuphine ER
• Arm 3: 54 mg nalbuphine ER
• Arm 4: 108 mg nalbuphine ER

Each arm will be titrated to their fixed dose during the blinded 2-week Titration period according to Table: Dosing Scheme, followed by the 4-week Fixed Dose Period for a total of 6 weeks on drug.

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

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Box Hill, Australia, 3128
    • Eastern Health-Box Hill Hospital
  • Concord, Australia, 2139
    • Concord Repatriation General Hospital
  • Heidelberg, Australia, 3084
    • Austin Hospital
  • Kent Town, Australia, 5067
    • Respiratory Clinical Trials PTY Ltd
  • Spearwood, Australia, 6163
    • TrialsWest Pty Ltd
  • Westmead, Australia, 2145
    • Westmead Hospital
• Canada
  • Ajax, Canada, L1S 2J5
    • Dynamic Drug Advancement
  • Vancouver, Canada, V5Z 1M9
    • Centre for Lung Health Clinic
  • Vancouver, Canada, V6Z 1Y6
    • The Pacific Lung Health Centre - St. Pauls Hospital
  • Quebec
    • Trois-Rivieres, Quebec, Canada, G8T 7A1
      • CIC Mauricie inc.
• Chile
  • Concepcion, Chile, 4040324
    • Hospital Clinico Regional Dr. Guillermo Grant Benavente
  • Quillota, Chile, 2260877
    • Centro de Investigaciones Medicas Cemedin Ltda.
  • Santiago, Chile, 7620157
    • Clinica Universidad de Los Andes
  • Talca, Chile, 3467384
    • Centro de Investigacion del Maule
  • Valparaiso, Chile, 2352499
    • Hospital Carlos Van Buren
  • Vina del Mar, Chile, 2520598
    • Oncocentro Apys
• Germany
  • Essen, Germany, 45239
    • Universitatsklinik Ruhrlandklinik, Westdeutsches Lungenzentrum
  • Frankfurt am Main, Germany, 60596
    • IKF Institut fuer klinische Forschung Frankfurt
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover, Hannover Medical School
  • Leipzig, Germany, 04103
    • University Hospital of Leipzig
  • Mainz, Germany, 55131
    • University Medical Center of Johannes Gutenberg-University Mainz
  • Mainz, Germany, 55128
    • IKF Pneumologie Mainz, Helix Medical Excellence Center Mainz
  • Solingen, Germany, 42699
    • Krankenhaus Bethanien
• Italy
  • Catania, Italy, 95123
    • Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele- Ospedale Gaspare Rodolico
  • Foggia, Italy, 71122
    • Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia
  • Monza, Italy, 20900
    • Azienda Ospedaliera San Gerardo di Monza
  • Padua, Italy, 35128
    • Azienda Ospedaliera di Padova
  • Rome, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Netherlands
  • 's-Hertogenbosch, Netherlands, 5223 GZ
    • Jeroen Bosch Ziekenhuis
  • Den Haag, Netherlands, 2512 VA
    • HMC (Haaglanden Medisch Centrum) Bronovo
  • Groningen, Netherlands, 9728 NT
    • Martini Ziekenhuis
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medisch Centrum 1
• Poland
  • Gdansk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne (UCK)
  • Lodz, Poland, 90-153
    • Uniwersytecki Szpital Kliniczny nr 1 im. N. Barlickiego
  • Olsztyn, Poland, 10-357
    • Warminsko Mazurskie Centrum Chorob Pluc w Olsztynie
  • Szczecin, Poland, 70-891
    • Samodzielny Publiczny Wojewódzki Szpital Zespolony w Szczecinie
• Spain
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge
  • Barcelona, Spain, 08017
    • Clinica Mi Tres Torres Barcelona
  • Madrid, Spain, 28010
    • Hospital La Milagrosa
  • Santander, Spain, 39008
    • HUMV
• Turkey
  • Ankara, Turkey, 06010
    • Gulhane Askeri Tip Akademisi (GATA) - Gulhane Askeri Tip Fakultesi (Gulhane Military Medical Academy and Medical School)
  • Antalya, Turkey, 7070
    • Akdeniz University Faculty of Medicine
  • Canakkale, Turkey, 17020
    • Canakkale Onsekiz Mart Universitesi (COMU) - Tip Fakultesi Hastanesi
  • Istanbul, Turkey, 34854
    • Sureyyapasa Gogus Hastaliklari ve Gogus Cerrahisi Egitim ve Arastirma Hastanesi
  • Izmir, Turkey, 35100
    • Ege University Medical Faculty
  • Konya, Turkey, 42130
    • Selcuk Universty Medical Faculty
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • Queen Elizabeth Hospital Birmingham - University Hospitals Birmingham NHS Foundation Trust
  • Cambridge, United Kingdom, CB2 0AY
    • Royal Papworth Hospital
  • Cottingham, United Kingdom, HU16 5JQ
    • Hull and East Yorkshire - Castle Hill Hospital
  • Edinburgh, United Kingdom, EH16 4SA
    • Royal Infirmary of Edinburgh
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
  • London, United Kingdom, NW1 2PG
    • University College London
  • Londonderry, United Kingdom, BT47 6SB
    • Altnagelvin Area Hospital
  • Manchester, United Kingdom, M23 9LT
    • Wythenshawe Hospital
  • Norwich, United Kingdom, NR4 7UY
    • Norfolk and Norwich University Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham City Hospital
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital
  • Portadown, United Kingdom, BT63 5QQ
    • Southern Health & Social Care Trust, Craigavon Area Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosis of IPF as determined by the Principal Investigator based on ATS/ERS/JRS/ALAT guidelines.
• Cough Severity Score ≥ 4 on CS-NRS (Cough Severity Numerical Rating Scale) during the Screening period and Baseline.
• History of chronic cough for at least 8 weeks before screening.
• SpO2 ≥ 92%, taken after at least 5 minutes in a sitting position, undisturbed and non-stimulated (Saturation of Hemoglobin with Oxygen as Measured by Pulse Oximetry).
• FVC ≥ 40% predicted of normal - Forced Vital Capacity, as determined by spirometry adhering to ATS/ERS guidelines.
• DLCO ≥ 25% predicted of normal - Diffusing capacity of the lung for carbon monoxide corrected for hemoglobin, assessed within the last 12 weeks, or at the time of screening.

Exclusion Criteria:

• 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.
• Inadequate swallow reflex as assessed by the ability to sip 3 fluid oz (or 89 mL) of water without coughing or choking.
• Upper or lower respiratory tract infection in the last 8 weeks prior to the baseline visit.
• Clinical history of aspiration pneumonitis.
• Diagnosis of sleep apnea.
• Abnormal kidney or liver functions based on Screening lab results.
• Known hypersensitivity to nalbuphine or to NAL ER excipients
• History of major psychiatric disorder.
• History of substance abuse.
• Significant medical condition or other factors that may interfere with the participant's ability to successfully complete the study.
• Pregnant or lactating female participant.
• Known intolerance (gastrointestinal, central nervous system symptoms), hypersensitivity, drug allergy following the use of an opioid drug.
• Use of opiates is prohibited within 14 days prior to the baseline visit.
• Use of benzodiazepines are prohibited within 14 days prior to the baseline visit and for the duration of the study.
• Monoamine oxidase inhibitors (MAOIs) including methylene blue (methylthioninium chloride) and the antibiotic linezolid are prohibited within 14 days prior to the baseline visit and for the duration of the study.
• Use of oral corticosteroid cough treatment is prohibited within 4 weeks prior to the baseline visit and for the duration of the study.
• Exposure to any investigational medication, including placebo, is prohibited within 4 weeks prior to the baseline visit and for the duration of the study.
• Medications prescribed as cough suppressants are prohibited unless on a stable dose 14-days prior to the baseline visit and are expected to remain on that dose for the duration of the study.
• Use of medications that affect serotonergic neurotransmission and that when used concomitantly with opioids can increase the risk of serotonin syndrome are prohibited unless on a stable dose 14-days prior to the baseline visit and are expected to remain on that dose for the duration of the study.
• Anti-fibrotic medications are prohibited unless on a stable dose for 8 weeks prior to the baseline visit and are expected to remain on that dose for the duration of the study.
• Strong inhibitors/inducers of the P450 Isozymes are prohibited unless on a stable dose for 14-days prior to baseline visit and are expected to remain on that dose for the duration of the study.
• 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.

Other protocol defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAL ER 27 mg; BID	Drug: NAL ER; Oral tablets; Other Names: Nalbuphine; Drug: NAL ER; Oral Tablets; Other Names: Nalbuphine
Experimental: NAL ER 54 mg; BID	Drug: NAL ER; Oral tablets; Other Names: Nalbuphine; Drug: NAL ER; Oral Tablets; Other Names: Nalbuphine
Experimental: NAL ER 108 mg; BID	Drug: NAL ER; Oral tablets; Other Names: Nalbuphine; Drug: NAL ER; Oral Tablets; Other Names: Nalbuphine
Placebo Comparator: Placebo; Placebo, BID	Drug: Placebo; Oral tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Relative Change From Baseline in 24-hour Cough Frequency at Week 6	Baseline, Week 6

Secondary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in Evaluating Respiratory Symptoms in Idiopathic Pulmonary Fibrosis (E-RS:IPF) Cough subscale at Week 6	Baseline, Week 6
Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs)	Up to Week 12
Relative Change From Baseline in 24-hour Cough Frequency at Weeks 2,4, and 6	Baseline, Weeks 2, 4, and 6
Percentage of Responders With ≥30%, ≥50% and ≥75% Reduction in the 24-Hour Cough Frequency at Week 2, 4, and 6	At Weeks 2, 4, and 6
Relative Change From Baseline in Awake Cough Frequency at Week 2, 4, and 6	Baseline, Weeks 2, 4, and 6
Relative Change From Baseline in Sleep Cough Frequency at Week 2, 4, and 6	Baseline, Weeks 2, 4, and 6
Change From Baseline in E-RS: IPF Cough Subscale at Weeks 1, 2, 3, 4, 5, and 6	Baseline, Weeks 1, 2, 3, 4, 5, 6
Percentage of E-RS: IPF Cough Subscale Responders With At least one Category Improvement at Weeks 1, 2, 3, 4, 5, and 6	At Weeks 1, 2, 3, 4, 5, and 6
Change From Baseline in E-RS: IPF Total Score, Subdomain Scores (IPF-Breathlessness, IPF-Cough, IPF-Sputum, and IPF-Chest Symptoms) and Individual Items at Weeks 1, 2, 3, 4, 5, and 6	Baseline, Weeks 1, 2, 3, 4, 5, and 6
Change From Baseline in Cough Severity Numerical Rating Scale (CS-NRS) at Weeks 1, 2, 3, 4, 5, and 6	Baseline, Weeks 1, 2, 3, 4, 5, and 6
Change From Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Week 6	Baseline, Week 6
Percentage of LCQ Total Score Responders With 1.3-Point Increase Response at Week 6	At Week 6
Change From Baseline in LCQ Domains and Individual Items at Week 6	Baseline, Week 6
Change From Baseline in Living With Pulmonary Fibrosis Impacts Questionnaire (L-IPF©) at Week 6	Baseline, Week 6
Change From Baseline in Living With Pulmonary Fibrosis Symptoms Questionnaire (L-IPF) and its Domains at Week 6	Baseline, Week 6
Change from Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L™) at Week 6	Baseline, Week 6
Change From Baseline in Patient Global Impression of Severity (PGI-S) Cough at Weeks 2, 4, and 6	Baseline, Weeks 2, 4, and 6
Absolute Values of PGI-C Cough Score at Weeks 2, 4, and 6	At Weeks 2, 4, and 6
Percentage of Participants With Improvement by ≥1 and ≥2 Categories, Worsening by ≥1 and ≥2 Categories, and no Change on PGI-C and PGI-S Cough at Each Post-Baseline Timepoint	At Weeks 2, 4, and 6
Change from Baseline in PGI-S IPF at Weeks 2, 4, and 6	Baseline, Weeks 2, 4, and 6
Absolute Values of PGI-C IPF at Weeks 2, 4, and 6	At Weeks 2, 4, and 6
Percentage of Participants With Improvement by ≥1 and ≥2 Categories, Worsening by ≥1 and ≥2 Categories, and no Change on the PGI-C and PGI-S IPF at Weeks 2, 4, and 6	At Weeks 2, 4, and 6
Change From Baseline in Clinicians Global Impression of Severity (CGI-S) score at Week 6	Baseline, Week 6
Absolute Values for CGI-C IPF Score at Week 6	At Week 6
Percentage of Participants With Improvement by ≥1 and ≥2 Categories, Worsening by ≥1 and ≥2 Categories, and no Change on the CGI-C and CGI-S at Week 6	At Week 6

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2024
• Primary Completion (Actual): April 24, 2025
• Study Completion (Actual): April 24, 2025

Study Registration Dates

• First Submitted: July 7, 2023
• First Submitted That Met QC Criteria: July 19, 2023
• First Posted (Actual): July 27, 2023

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 23, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Cough; 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: NAL03-202

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