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-Rivières, Quebec, Canada, G8T 7A1
      • CIC Mauricie Inc.
• Chile
  • Concepción, Chile, 4040324
    • Hospital Clinico Regional Dr. Guillermo Grant Benavente
  • Quillota, Chile, 2260877
    • Centro Respiratorio Integral Ltda
  • Santiago, Chile, 7620157
    • Clínica Universidad de los Andes
  • Talca, Chile, 3467384
    • Centro de Investigacion del Maule
  • Valparaíso, Chile, 2352499
    • Hospital Carlos Van Buren
  • Villa Del Mar, Chile, 2520598
    • Centro de Investigaciones de Enfermedades Respiratorias e Immunologic Limitada
• Germany
  • Essen, Germany, 45239
    • Universitatsklinik Ruhrlandklinik, Westdeutsches Lungenzentrum
  • Frankfurt am Main, Germany, 60596
    • IKF Institut fuer klinische Forschung Frankfurt
  • Hanover, 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
  • Groningen, Netherlands, 9728 NT
    • Martini Ziekenhuis
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medisch Centrum 1
  • The Hague, Netherlands, 2512 VA
    • HMC (Haaglanden Medisch Centrum) Bronovo
• 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 Wojewodzki 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 (Türkiye)
  • Ankara, Turkey (Türkiye), 06010
    • Gulhane Askeri Tip Akademisi (GATA) - Gulhane Askeri Tip Fakultesi (Gulhane Military Medical Academy and Medical School)
  • Antalya, Turkey (Türkiye), 7070
    • Akdeniz University Faculty of Medicine
  • Istanbul, Turkey (Türkiye), 34854
    • Sureyyapasa Gogus Hastaliklari ve Gogus Cerrahisi Egitim ve Arastirma Hastanesi
  • Izmir, Turkey (Türkiye), 35100
    • Ege University Medical Faculty
  • Konya, Turkey (Türkiye), 42130
    • Selcuk Universty Medical Faculty
  • Çanakkale, Turkey (Türkiye), 17020
    • Canakkale Onsekiz Mart Universitesi (COMU) - Tip Fakultesi Hastanesi
• 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; Participants were titrated over 2 weeks to NAL ER 27 mg BID, then maintained at the fixed dose for 4 weeks (total 6 weeks of treatment).	Drug: NAL ER; Oral tablets; Other Names: Nalbuphine; Drug: NAL ER; Oral Tablets; Other Names: Nalbuphine
Experimental: NAL ER 54 mg; Participants were titrated over 2 weeks to NAL ER 54 mg BID, then maintained at the fixed dose for 4 weeks (total 6 weeks of treatment).	Drug: NAL ER; Oral tablets; Other Names: Nalbuphine; Drug: NAL ER; Oral Tablets; Other Names: Nalbuphine
Experimental: NAL ER 108 mg; Participants were titrated over 2 weeks to NAL ER 108 mg BID, then maintained at the fixed dose for 4 weeks (total 6 weeks of treatment).	Drug: NAL ER; Oral tablets; Other Names: Nalbuphine; Drug: NAL ER; Oral Tablets; Other Names: Nalbuphine
Placebo Comparator: Placebo; Participants received a matching placebo BID, using the same 2-week blinded titration schedule and 4-week fixed-dose period as the active treatment arms (6 weeks total).	Drug: Placebo; Oral tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change From Baseline in 24-hour Cough Frequency at Week 6	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. The relative change from baseline = [ (Post-baseline - Baseline) / Baseline] × 100. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change From Baseline in Evaluating Respiratory Symptoms in Idiopathic Pulmonary Fibrosis (E-RS:IPF) Cough Subscale at Week 6	The E-RS:IPF is a respiratory symptom subscale of the exacerbation of chronic pulmonary disease tool (EXACT) and consists of 11 items and was developed for use in IPF. The Cough subscale includes a single item (item 2: How often did you cough today?). The possible score range is 0 (not at all) to 4 (almost constantly). Higher scores indicate more severe symptoms. The relative change from baseline values is presented below. The relative change from baseline = [ (Post-baseline - Baseline) / Baseline] × 100. A positive change from baseline indicates worsening. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
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 12
Relative Change From Baseline in 24-hour Cough Frequency at Week 6	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. The relative change from baseline = [ (Post-baseline - Baseline) / Baseline] × 100. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Weeks 6
Percentage of Responders With ≥30%, ≥50% and ≥75% Reduction in the 24-Hour Cough Frequency at Week 6	Responders were defined as those with ≥30%, ≥50%, or ≥75% reduction in 24-hour cough frequency from Baseline at Week 6. Percentages were rounded off to the nearest decimal.	At Week 6
Relative Change From Baseline in Awake Cough Frequency at Week 6	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. The relative change from baseline = [ (Post-baseline - Baseline) / Baseline] × 100. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Relative Change From Baseline in Sleep Cough Frequency at Week 6	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. The relative change from baseline = [ (Post-baseline - Baseline) / Baseline] × 100. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Relative Change From Baseline in E-RS: IPF Cough Subscale at Week 6	The E-RS:IPF is a respiratory symptom subscale of the EXACT and consists of 11 items and was developed for use in IPF. The Cough subscale includes a single item (item 2: How often did you cough today?) with a score range of 0 (not at all) to 4 (almost constantly). The relative change from baseline values is presented below. The relative change from baseline = [ (Post-baseline - Baseline) / Baseline] × 100. A positive change from baseline indicates worsening. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Percentage of E-RS: IPF Cough Subscale Responders With At Least One Category Improvement at Week 6	The E-RS:IPF is a respiratory symptom subscale of the EXACT and consists of 11 items and was developed for use in IPF. The Cough subscale includes a single item (item 2) with a score range of 0 (not at all) to 4 (almost constantly). Responders are defined as those with at least one category reduction (improvement) by ≥1 point at Week 6. Percentages were rounded off to the nearest decimal.	At Week 6
Change From Baseline in E-RS:IPF Total Score at Week 6	The Total E-RS:IPF includes all 11 items from the scale and was developed for use in IPF. Items assignments to domains of the E-RS:IPF are as follows: the RS-Breathlessness domain (Items 7-11) has a score range of 0-23; the IPF-Chest domain (Items 1, 5, and 6) has a score range of 0-12; the IPF-Cough domain (Item 2) has a score range of 0-4; the IPF-Sputum domain (Items 3 and 4) has a score range of 0-8; and the E-RS:IPF total score (Items 1-11) ranges from 0-47. For each day, the sum of the item-level raw scores forms the E-RS:IPF total score. Higher scores indicate more severe symptoms. A negative change from Baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in IPF-Breathlessness Subdomain Score at Week 6	The E-RS:IPF consists of a subset of 11 items from the EXACT and was developed for use in IPF. The Breathlessness subdomain score includes 5 items (Item 7: Were you breathless today, Item 8: Describe how breathless you were today, Item 9: Were you short of breath today when performing your usual personal care activities like washing or dressing, Item 10: Were you short of breath today when performing your usual indoor activities like cleaning or household work, Item 11: Were you short of breath today when performing your usual activities outside the home such as yard work or errands), all of which required the participant to report the effect of activities on shortness of breath. The possible score range is 0 to 23. A negative change from Baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study. A higher score indicates more severe symptoms.	Baseline, Week 6
Change From Baseline in IPF-Cough Subdomain Score at Week 6	The E-RS:IPF is a respiratory symptom subscale of the EXACT and consists of 11 items and was developed for use in IPF. The Cough subdomain score includes single item (item 2: How often did you cough today?) The possible score range is 0 (not at all) to 4 (almost constantly). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in IPF-Sputum Subdomain Score at Week 6	The E-RS:IPF is a respiratory symptom subscale of the EXACT and consists of 11 items and was developed for use in IPF. The Sputum subdomain score includes 2 items (Item 3: How much mucus (phlegm) did you bring up when coughing today? and Item 4: How difficult was it to bring up mucus (phlegm) today?), which ask about quantity and difficulty in bringing up phlegm. The possible score range is 0-8. Higher score indicates more severe symptoms. A negative change from baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in IPF-Chest Subdomain Score at Week 6	The E-RS:IPF is a respiratory symptom subscale of the EXACT and consists of 11 items and was developed for use in IPF. The Chest subdomain score includes 3 items (Item 1: (Did your chest feel congested today?), Item 5: (Did you have chest discomfort today?), and Item 6: (Did your chest feel tight today?)). These questions solicited information on chest congestion, discomfort, and tightness. The possible score range is 0-12. A higher score indicates more severe symptoms. A negative change from baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in Cough Severity Numerical Rating Scale (CS-NRS) at Week 6	The CS-NRS is a single item scale in which participants described the severity of their cough in the past 24 hours on a scale of 0 (no cough) to 10 (worst possible cough). A negative change from Baseline indicates improvement. A higher score indicates more severe symptoms. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Week 6	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. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Percentage of LCQ Total Score Responders With 1.3-Point Increase Response at Week 6	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. Percentage of LCQ Total Score responders are presented in this outcome measure. Percentages were rounded off to the nearest decimal.	At Week 6
Change From Baseline in LCQ Domains at Week 6	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 each domain score ranges from 1 to 7. Higher scores indicate better physical, psychological, and social status respectively. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in Living With Pulmonary Fibrosis Impacts Questionnaire (L-IPF©) Impacts Raw Sum Score at Week 6	The L-IPF questionnaire is a 35-item questionnaire with two modules: symptoms (15 items) and impacts (20 items). The Impacts module yields a single Impacts score that is presented in this outcome measure. Each item's score ranges from 0-3. The score range for the L-IPF overall impacts raw sum score is 0-60, with higher scores indicating severe adverse impact. A negative change from Baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in L-IPF Symptoms Domain Scores at Week 6	The L-IPF questionnaire is a 35-item questionnaire with two modules: symptoms (15 items) and impacts (20 items). The L-IPF Symptoms module measures the various symptoms associated with IPF. The module contains 15 items that fall into 3 domains: Dyspnea, Cough, and Energy. Each item consists of a 0-3 score range. Dyspnea consists of 7 items and has a raw sum score range of 0-21 with higher scores indicating worsening dyspnea symptoms, Cough consists of 5 items and has a raw sum score range of 0-15 with higher scores indicating worsening cough symptoms, and Energy consists of 3 items and has a raw sum score range of 0-9 with higher scores indicating worsening energy. A negative change from Baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Number of Participants With Shift From Baseline in European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L™) at Week 6	The EQ-5D-5L is a participant reported outcome and comprises of a descriptive system with 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The recall period was the day that the questions were being completed. Each of the 5 dimensions in the descriptive system had 5 levels: 1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe problems, and 5 = extreme problems. Higher scores indicate worsening. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Change From Baseline in Patient Global Impression of Severity (PGI-S) Cough Score at Week 6	The PGI-S cough scale is a self-reported, single-item categorical scale used for assessing chronic cough. Participants rated the severity of their cough in the last week with a 4-point Likert scale (0-3: 0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. A negative change from Baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
Patient Global Impression of Change (PGI-C) Cough Score at Week 6	The PGI-C cough is a self-reported single-item 7-point scale that assesses participants' ratings of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1 = a little better, 0 = no change, 1 = a little worse, 2 = moderately worse, or 3 = much worse. Higher scores indicate worsening. A negative change from Baseline indicates improvement.	At Week 6
Percentage of Participants With Improvement by ≥1 and ≥ 2 on PGI-C Cough	The PGI-C cough is a self-reported single-item 7-point scale that assesses participants' ratings of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1 = a little better, 0 = no change, 1= a little worse, 2 = moderately worse, or 3 = much worse. Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Worsening by ≥1 and ≥2 on PGI-C Cough	The PGI-C cough is a self-reported single-item 7-point scale that assesses participants' ratings of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1 = a little better, 0 = no change, 1= a little worse, 2 = moderately worse, or 3 = much worse. Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With no Change on PGI-C Cough	The PGI-C cough is a self-reported single-item 7-point scale that assesses participants' ratings of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1 = a little better, 0 = no change, 1= a little worse, 2 = moderately worse, or 3=much worse. Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Improvement by ≥1 and ≥2 on PGI-S Cough	The PGI-S cough scale is a self-reported, single-item categorical scale used for assessing chronic cough. Participants rated the severity of their cough in the last week with a 4-point Likert scale (0-3: 0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Worsening by ≥1 and ≥2 and PGI-S Cough	The PGI-S cough scale is a self-reported, single-item categorical scale used for assessing chronic cough. Participants rated the severity of their cough in the last week with a 4-point Likert scale (0-3: 0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With no Change on PGI-S Cough	The PGI-S cough scale is a self-reported, single-item categorical scale used for assessing chronic cough. Participants rated the severity of their cough in the last week with a 4-point Likert scale (0-3: 0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Change From Baseline in PGI-S IPF at Week 6	PGI-S IPF scale is a self-reported, single-item categorical scale that was used to assess symptoms of IPF. Participants rated the symptoms of IPF in the last week with a 4-point Likert scale (0-3: 0 = No symptoms, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. A negative change from Baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
PGI-C IPF Score at Week 6	The PGI-C IPF is a self-reported, single-item 7-point scale assessing a participant's rating of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1 = a little better, 0 = no change, 1 = a little worse, 2 = moderately worse, or 3 = much worse. Higher scores indicate worsening. A negative change from Baseline indicates improvement.	At Week 6
Percentage of Participants With Improvement by ≥1 and ≥2 on PGI-C IPF	The PGI-C IPF is a self-reported, single-item 7-point scale assessing a participant's rating of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1 = a little better, 0 = no change, 1= a little worse, 2 = moderately worse, or 3 = much worse. Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Worsening by ≥1 and ≥2 on PGI-C IPF	The PGI-C IPF is a self-reported, single-item 7-point scale assessing a participant's rating of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1= a little better, 0 = no change, 1= a little worse, 2 = moderately worse, or 3 = much worse. Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With no Change on PGI-C IPF	The PGI-C IPF is a self-reported, single-item 7-point scale assessing a participant's rating of cough over the past 7 days. Participants rated their change as -3 = much better, -2 = moderately better, -1= a little better, 0 = no change, 1= a little worse, 2 = moderately worse, or 3 = much worse. Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Improvement by ≥1 and ≥2 on PGI-S-IPF	PGI-S IPF scale is a self-reported, single-item categorical scale that was used to assess symptoms of IPF. Participants rated the symptoms of IPF in the last week with a 4-point Likert scale (0-3: 0 = No symptoms, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Worsening by ≥1 and ≥2 on PGI-S-IPF	PGI-S IPF scale is a self-reported, single-item categorical scale that was used to assess symptoms of IPF. Participants rated the symptoms of IPF in the last week with a 4-point Likert scale (0-3: 0 = No symptoms, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With no Change on PGI-S-IPF	PGI-S IPF scale is a self-reported, single-item categorical scale that was used to assess symptoms of IPF. Participants rated the symptoms of IPF in the last week with a 4-point Likert scale (0-3: 0 = No symptoms, 1 = Mild, 2 = Moderate, or 3 = Severe). Higher scores indicate worsening. Percentages were rounded off to the nearest decimal.	At Week 6
Change From Baseline in Clinicians Global Impression of Severity (CGI-S) Score at Week 6	The CGI-S is a single-item measure on which the clinician rates the participant's cough. CGI-S have score range of 0-3. (0 = no cough, 1 = mild, 2 = moderate, 3 = severe). Higher scores indicate greater severity of cough. A negative change from Baseline indicates improvement. The baseline value was defined as the last non-missing observation prior to the date of the first dose of study.	Baseline, Week 6
CGI-C IPF Score at Week 6	The CGI-C is a one-item measure evaluating change from the initiation of treatment on a seven-point scale. CGI-C have score range 1-7 (1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. Higher scores indicate greater severity of cough.	At Week 6
Percentage of Participants With Improvement by ≥1 and ≥2 on the Clinicians Global Impression of Change (CGI-C) at Week 6	The CGI-C is a one-item measure evaluating change from the initiation of treatment on a seven-point scale. CGI-C have score range 1-7 (1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. Higher scores indicate greater severity of cough. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Worsening by ≥1 and ≥2 on the CGI-C at Week 6	The CGI-C is a one-item measure evaluating change from the initiation of treatment on a seven-point scale. CGI-C have score range 1-7 (1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. Higher scores indicate greater severity of cough. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With no Change on the CGI-C at Week 6	The CGI-C is a one-item measure evaluating change from the initiation of treatment on a seven-point scale. CGI-C have score range 1-7 (1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. Higher scores indicate greater severity of cough. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Improvement by ≥1 and ≥2 on the Clinicians Global Impression of Severity (CGI-S) at Week 6	The CGI-S is a single-item measure on which the clinician rates the participant's cough. CGI-S have score range 0-3 (0 = no cough, 1= mild, 2 = moderate, 3 = severe). Higher scores indicate greater severity of cough. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With Worsening by ≥1 and ≥2 on the CGI-S at Week 6	The CGI-S is a single-item measure on which the clinician rates the participant's cough. CGI-S have score range 0-3 (0 = no cough, 1= mild, 2 = moderate, 3 = severe). Higher scores indicate greater severity of cough. Percentages were rounded off to the nearest decimal.	At Week 6
Percentage of Participants With no Change on the CGI-S at Week 6	The CGI-S is a single-item measure on which the clinician rates the participant's cough. CGI-S have score range 0-3 (0 = no cough, 1= mild, 2 = moderate, 3 = severe). Higher scores indicate greater severity of cough. Percentages were rounded off to the nearest decimal.	At Week 6

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Molyneaux PL, Mogulkoc N, Gunen H, Doboszynska A, Kreuter M, Neustifter B, Mathur V, Cassella J; CORAL Study Group. Oral Nalbuphine in Idiopathic Pulmonary Fibrosis-Associated Cough: The CORAL Randomized Clinical Trial. JAMA. 2026 Mar 24;335(12):1050-1059. doi: 10.1001/jama.2025.26179.

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 26, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Cough; Nalbuphine
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Lung Diseases, Interstitial; Pulmonary Fibrosis; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Idiopathic Pulmonary Fibrosis; 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: 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