Cough Reduction in IPF With Nalbuphine ER

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: nalbuphine ER 27 mg
* Drug: Placebo
* Drug: nalbuphine ER 54 mg
* Drug: nalbuphine ER 108 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NAL ER 27 mg<br>BID | Drug: nalbuphine ER 27 mg<br>* Oral tablets<br>* Other names: Active;|
| Experimental: NAL ER 54 mg<br>BID | Drug: nalbuphine ER 54 mg<br>* Oral Tablets<br>* Other names: Active;|
| Experimental: NAL ER 108 mg<br>BID | Drug: nalbuphine ER 108 mg<br>* Oral tablets<br>* Other names: Active;|
| Placebo Comparator: Placebo<br>Placebo, tablets BID | Drug: Placebo<br>* Oral tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Awake cough frequency (Coughs per hour) | Relative change from Baseline in awake cough frequency (coughs per hour) versus placebo. | Weeks 2, 4, 6 | 
| Sleep cough frequency (Coughs per hour) | Relative change from Baseline in sleep cough frequency (coughs per hour) at versus placebo. | Weeks 2, 4, 6 | 
| 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 | 
| CS-NRS (Cough Severity Numerical Rating Scale) | Change from Baseline in the CS-NRS versus placebo. | Weeks 1, 2, 3, 4, 5, 6 | 
| 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 | 
| L-IPF© (Living with Pulmonary Fibrosis Impacts Questionnaire) | Change from Baseline in the L-IPF© versus placebo. | Week 6 | 
| L-IPF© (Living with Pulmonary Fibrosis Symptoms Questionnaire) | Change from Baseline in the L-IPF© versus placebo. | Week 6 | 
| EQ-5D-5L™ | Change from Baseline in the EQ-5D-5L™ versus placebo. | Week 6 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cough, Nalbuphine