Cough Reduction in IPF with Nalbuphine ER

Phase 2

Recruiting

• Conditions: Idiopathic Pulmonary Fibrosis
• Interventions: Drug: nalbuphine ER 27 mg; Drug: nalbuphine ER 54 mg; Drug: nalbuphine ER 108 mg; Drug: Placebo

• Registration Number: NCT05964335
• Lead Sponsor: Trevi Therapeutics

Brief Summary

This is a multi-center randomized, double-blind, placebo-controlled, parallel, 4-arm study of nalbuphine ER (NAL ER).

After meeting eligibility during the Screening Period, subjects will be randomized (1:1:1:1) to one of four treatment arms with placebo and increasing doses of nalbuphine ER. Each arm will be titrated to their fixed dose during the blinded 2-week Titration period followed by the 4-week Fixed Dose Period for a total of 6 weeks on drug.

For more information see the country specific approved websites:

Germany, Netherlands, Poland, Spain, Italy, Chile: TheCoralTrial.com United Kingdom, Australia, Canada: CoralCoughTrial.com Turkey: please refer to the list of locations and reach out to the site directly

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 Timeline

• Study First Submitted: 2023-07-07
• Study First Submitted QC: 2023-07-19
• Study First Posted: 2023-07-27
• Study Start: 2024-02-06
• Status Verified: 2024-10
• Last Update Submitted: 2024-11-24
• Last Update Posted: 2024-11-27
• Primary Completion: 2025-04
• Study Completion: 2025-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 160

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.

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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 subject's ability to successfully complete the study.
• Pregnant or lactating female subject.
• 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NAL ER 27 mg	nalbuphine ER 27 mg	BID
NAL ER 54 mg	nalbuphine ER 54 mg	BID
NAL ER 108 mg	nalbuphine ER 108 mg	BID
Placebo	Placebo	Placebo, tablets BID

Primary Outcome Measures

Name	Time	Method
Effect of NAL ER on 24-hour cough frequency (coughs per hour)	Week 6	Relative change from Baseline in 24-hour cough frequency versus placebo

Secondary Outcome Measures

Name	Time	Method
CS-NRS (Cough Severity Numerical Rating Scale)	Weeks 1, 2, 3, 4, 5, 6	Change from Baseline in the CS-NRS versus placebo.
PGI-C IPF (Patient Global Impression of Change in IPF symptoms)	Weeks 2, 4, 6	1 item measure rating the symptoms of IPF. (Past 7 days); * Much better; * Moderately better; * A little better; * No change; * A little worse; * Moderately worse; * Much worse
CGI-C	Week 6	A one-item measure evaluating change from the initiation of treatment on a seven point scale.; 1. = Very much improved; 2. = Much improved; 3. = Minimally improved; 4. = No change; 5. = Minimally worse; 6. = Much worse; 7. = Very much worse
24-hour cough frequency (Coughs per hour)	Weeks 2, 4, 6	Relative change from Baseline in 24-hour cough frequency (coughs per hour) versus placebo; • Proportion of responders with ≥30%, ≥50% and ≥75% reduction in the 24-hour cough frequency at Week 2, 4, and 6, for NAL ER compared with placebo.
Safety and tolerability of NAL ER	Screening through 14 day post last dose	Adverse event, vitals signs, ECGs, clinical laboratory tests, spirometry, physical examinations, Subjective Opiate Withdrawal Scale (SOWS)
Sleep cough frequency (Coughs per hour)	Weeks 2, 4, 6	Relative change from Baseline in sleep cough frequency (coughs per hour) at versus placebo.
Effect of NAL ER on the EXAcerbation of Chronic pulmonary disease Tool	Week 6	Relative change from Baseline in the EXACT© question 2 at Week 6 versus placebo
CGI-S, (Clinicians Global Impression of Severity)	Baseline and Week 6	A one-item measure evaluating severity of the condition. No Symptoms Mild Moderate Severe
Awake cough frequency (Coughs per hour)	Weeks 2, 4, 6	Relative change from Baseline in awake cough frequency (coughs per hour) versus placebo.
LCQ© (Leicester Cough Questionnaire)	Week 6	Change from Baseline in the LCQ© total score versus placebo. Proportion of LCQ© responders, with response defined as 1.3-point increase versus placebo
EQ-5D-5L™	Week 6	Change from Baseline in the EQ-5D-5L™ versus placebo.
EXACT© (EXAcerbation of Chronic pulmonary disease Tool) (EXAcerbation of Chronic pulmonary disease Tool)	Weeks 1, 2, 3, 4, 5, 6	Change from Baseline in the EXACT© question 2 compared with placebo. Proportion of EXACT© question 2 responders, with response defined as at least a one category improvement versus placebo. Change from Baseline in the EXACT© sub-domains and individual items versus placebo.
L-IPF© (Living with Pulmonary Fibrosis Impacts Questionnaire)	Week 6	Change from Baseline in the L-IPF© versus placebo.
L-IPF© (Living with Pulmonary Fibrosis Symptoms Questionnaire)	Week 6	Change from Baseline in the L-IPF© versus placebo.
PGI-S Cough (Patient Global Impression of Severity for Cough)	Weeks 2, 4, 6	1 item measure rating the severity of cough past 7 days from No cough, Mild, Moderate or Severe
PGI-S IPF (Patient Global Impression of Severity and Change for IPF)	Weeks 2, 4, 6	1 item measure rating the symptoms of IPF past 7 days from No symptoms, Mild, Moderate or Severe
PGI-C Cough; (Patient Global Impression of Change for Cough)	Weeks 2, 4, 6	1 item measure rating the symptoms of IPF. (past 7 days); * Much better; * Moderately better; * A little better; * No change; * A little worse; * Moderately worse; * Much worse

Trial Locations

Locations (58)

Eastern Health-Box Hill Hospital; 🇦🇺 Box Hill, Australia

Concord Repatriation General Hospital; 🇦🇺 Concord, Australia

Austin Hospital; 🇦🇺 Heidelberg, Australia

Respiratory Clinical Trials Pty Ltd; 🇦🇺 Kent Town, Australia

TrialsWest Pty Ltd; 🇦🇺 Spearwood, Australia

Westmead Hospital; 🇦🇺 Westmead, Australia

CIC Mauricie Inc.; 🇨🇦 Trois-Rivieres, Quebec, Canada

Dynamic Drug Advancement; 🇨🇦 Ajax, Canada

Centre for Lung Health Clinic; 🇨🇦 Vancouver, Canada

The Pacific Lung Health Centre - St. Pauls Hospital; 🇨🇦 Vancouver, Canada

Hospital Clinico Regional Dr. Guillermo Grant Benavente; 🇨🇱 Concepcion, Chile

Centro de Investigaciones Medicas Cemedin Ltda.; 🇨🇱 Quillota, Chile

Clinica Universidad de los Andes; 🇨🇱 Santiago, Chile

Centro de Investigacion del Maule; 🇨🇱 Talca, Chile

Hospital Carlos Van Buren; 🇨🇱 Valparaiso, Chile

Oncocentro APYS; 🇨🇱 Vina del Mar, Chile

Universitatsklinik Ruhrlandklinik, Westdeutsches Lungenzentrum; 🇩🇪 Essen, Germany

IKF Institut fuer klinische Forschung Frankfurt; 🇩🇪 Frankfurt am Main, Germany

Medizinische Hochschule Hannover, Hannover Medical School; 🇩🇪 Hannover, Germany

University Hospital of Leipzig; 🇩🇪 Leipzig, Germany

University Medical Center of Johannes Gutenberg-University Mainz; 🇩🇪 Mainz, Germany

IKF Pneumologie Mainz, Helix Medical Excellence Center Mainz; 🇩🇪 Mainz, Germany

Krankenhaus Bethanien; 🇩🇪 Solingen, Germany

Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele- Ospedale Gaspare Rodolico; 🇮🇹 Catania, Italy

Azienda Ospedaliero Universitaria Ospedali Riuniti Di Foggia; 🇮🇹 Foggia, Italy

Azienda Ospedaliera San Gerardo di Monza; 🇮🇹 Monza, Italy

Azienda Ospedaliera di Padova; 🇮🇹 Padua, Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS; 🇮🇹 Rome, Italy

Jeroen Bosch Ziekenhuis; 🇳🇱 's-Hertogenbosch, Netherlands

HMC (Haaglanden Medisch Centrum) Bronovo; 🇳🇱 Den Haag, Netherlands

Martini Ziekenhuis; 🇳🇱 Groningen, Netherlands

Erasmus Medisch Centrum 1; 🇳🇱 Rotterdam, Netherlands

Uniwersyteckie Centrum Kliniczne (UCK); 🇵🇱 Gdansk, Poland

Niepubliczny Zaklad Opieki Zdrowotnej Centrum Medyczne ProMiMed sp z o.o., sp.k.; 🇵🇱 Krakow, Poland

Uniwersytecki Szpital Kliniczny nr 1 im. N. Barlickiego; 🇵🇱 Lodz, Poland

Warminsko Mazurskie Centrum Chorob Pluc w Olsztynie; 🇵🇱 Olsztyn, Poland

Samodzielny Publiczny Wojewodzki Szpital Zespolony w Szczecinie; 🇵🇱 Szczecin, Poland

Clinica Mi Tres Torres Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitari de Bellvitge; 🇪🇸 Barcelona, Spain

Hospital La Milagrosa; 🇪🇸 Madrid, Spain

HUMV; 🇪🇸 Santander, Spain

Gulhane Askeri Tip Akademisi (GATA) - Gulhane Askeri Tip Fakultesi (Gulhane Military Medical Academy and Medical School); 🇹🇷 Ankara, Turkey

Akdeniz University Faculty of Medicine; 🇹🇷 Antalya, Turkey

Canakkale Onsekiz Mart Universitesi (COMU) - Tip Fakultesi Hastanesi; 🇹🇷 Canakkale, Turkey

Sureyyapasa Gogus Hastaliklari ve Gogus Cerrahisi Egitim ve Arastirma Hastanesi; 🇹🇷 Istanbul, Turkey

Ege University Medical Faculty; 🇹🇷 Izmir, Turkey

Selcuk Universty Medical Faculty; 🇹🇷 Selcuklu, Turkey

Royal Papworth Hospital; 🇬🇧 Cambridge, United Kingdom

Hull and East Yorkshire - Castle Hill Hospital; 🇬🇧 Cottingham, United Kingdom

Royal Infirmary Of Edinburgh; 🇬🇧 Edinburgh, United Kingdom

Altnagelvin Area Hospital; 🇬🇧 Londonderry, United Kingdom

University College London; 🇬🇧 London, United Kingdom

Royal Brompton Hospital; 🇬🇧 London, United Kingdom

Wythenshawe Hospital; 🇬🇧 Manchester, United Kingdom

Norfolk and Norwich University Hospital; 🇬🇧 Norwich, United Kingdom

Nottingham City Hospital; 🇬🇧 Nottingham, United Kingdom

Churchill Hospital; 🇬🇧 Oxford, United Kingdom

Southampton General Hospital; 🇬🇧 Southampton, United Kingdom