Cough Reduction in IPF With Nalbuphine ER

Idiopathic Pulmonary Fibrosis Clinical Trial

— CORAL  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05964335
• Other study ID #: NAL03-202
• Status: Recruiting
• Phase: Phase 2
• Start date: February 6, 2024
• Est. completion date: October 14, 2024

Study information

• Verified date: May 2024
• Source: Trevi Therapeutics
• Contact: Beata Dworakowska
• Phone: 203-654-3284
• Email: Beata.Dworakowska[@]trevitherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. - 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 followed by the 4-week Fixed Dose Period for a total of 6 weeks on drug.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: October 14, 2024
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 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.

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• nalbuphine ER 27 mg
Oral tablets
• Placebo
Oral tablets
• nalbuphine ER 54 mg
Oral Tablets
• nalbuphine ER 108 mg
Oral tablets

Locations

Country	Name	City	State
Australia	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
Canada	Dynamic Drug Advancement	Ajax
Canada	Centre for Lung Health Clinic	Vancouver
Canada	The Pacific Lung Health Centre - St. Pauls Hospital	Vancouver
Chile	Hospital Regional de Concepcion	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
Germany	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	IKF Pneumologie Mainz, Helix Medical Excellence Center Mainz	Mainz
Germany	Krankenhaus Bethanien	Solingen
Italy	AOU-S.Orsola-Malpighi - Universita degli Studi di Bologna	Bologna
Italy	Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele- Ospedale Gaspare Rodolico	Catania
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti Di Foggia	Foggia
Italy	Ospedale San Giuseppe Multimedica SpA	Milano
Italy	Azienda Ospedaliera San Gerardo di Monza	Monza
Italy	Azienda ospedaliera dei colli /Universita degli Studi di Napoli Federico II	Napoli
Italy	Azienda Ospedaliera di Padova	Padua
Italy	Istituto Mediterraneo Per I Trapianti E Terapie Ad Alta Specializzazione (Ismett) Di Palermo	Palermo
Italy	Università Degli Studi Tor Vergata - Roma - Prof. Vespasiani	Roma
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Rome
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
Netherlands	HMC (Haaglanden Medisch Centrum) Bronovo	Den Haag
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	Erasmus Medisch Centrum 1	Rotterdam
Poland	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	Pulmag Grzegorz Gasior Marzena Kociolek Sp. Cywilna	Sosnowiec
Poland	Samodzielny Publiczny Wojewodzki Szpital Zespolony w Szczecinie	Szczecin
Spain	Clinica Mi Tres Torres Barcelona	Barcelona
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	Hospital La Milagrosa	Madrid
Spain	HUMV	Santander
Turkey	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	Kocaeli University Medical Faculty	Izmit
Turkey	Selcuk Universty Medical Faculty	Selcuklu
United Kingdom	Royal Papworth Hospital	Cambridge
United Kingdom	Hull and East Yorkshire - Castle Hill Hospital	Cottingham
United Kingdom	Royal Infirmary Of Edinburgh	Edinburgh
United Kingdom	Royal Brompton Hospital	London
United Kingdom	University College London	London
United Kingdom	Altnagelvin Area Hospital	Londonderry
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

Sponsors (1)

Lead Sponsor	Collaborator
Trevi Therapeutics

Countries where clinical trial is conducted

Australia,  Canada,  Chile,  Germany,  Italy,  Netherlands,  Poland,  Spain,  Turkey,  United Kingdom, 

Outcome

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