Refractory Chronic Cough Improvement Via NAL ER (RIVER)

Study Overview
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Brief Summary
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A 2-period crossover study for the treatment of cough in patients with Refractory Chronic Cough via Nalbuphine ER (NAL ER). Each period will last 21 days and are separated by 21 days. Subjects will be randomized in Treatment Period 1 to either NAL ER or matching placebo and evaluated for 21 days. After completion of the first phase, subjects who received NAL ER will crossover to placebo and subjects who received placebo will crossover to NAL ER to complete Treatment Period 2.

Detailed Description
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A double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of cough with NAL ER in subjects with Refractory Chronic Cough. Based on the screening cough monitor results, the study will enroll subjects in a 1:1 ratio to subgroups of 10-19 coughs/hour and ≥20 coughs/hour. After meeting eligibility during the screening period, subjects will be randomly assigned to one of the following sequences: NAL ER in Treatment Period 1, followed by Placebo (PBO) in Treatment Period 2 OR PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2. Each treatment period lasts 21 days and are separated by a 21-day washout period. Subjects on NAL ER will have the dose titrated from 27 mg once a day (QD) to 108 mg twice a day (BID). Study visits in each treatment period will be at Day -1 for Baseline cough assessments, and at Days 6, 13, and 20. Subjects will have blood drawn for pharmacokinetic (PK) analysis of nalbuphine plasma concentration. Subjects will also complete questionnaires for efficacy evaluations and undergo safety evaluations including an electrocardiogram (ECG). At the Screening and Baseline visits and on Days 6, 13, and 20 during each treatment period, site staff will place an electronic cough monitor on the subject, which will be worn for a 24-hour recording period to assess cough frequency. At the end of each recording session (Days 7, 14, and 21), the monitor will be removed at home by the subject, and the subjects will complete Patient Reported Outcomes (PROs) questionnaires in the electronic diary. Subjects will be taken off study drug at the end of Treatment Period 2 and followed off treatment for an additional 2 weeks.

Official Title
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A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period Crossover Efficacy and Safety Study of Nalbuphine ER Tablets for the Treatment of Refractory Chronic Cough

Conditions
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Refractory Chronic Cough

Intervention / Treatment
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* Drug: Nalbuphine ER
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of refractory chronic cough (RCC) for at least one year Chest radiograph or CT of thorax within 24 months or during screening not demonstrating any significant abnormalities contributing to RCC Exclusion Criteria: Diagnosis of sleep apnea Respiratory tract infection within 6 weeks of Baseline History of bronchiectasis, COPD, or IPF History of uncontrolled asthma Current smokers/vapers, quit smoking with <=12 months, using nicotine supplements, or history of >=20 pack years History of major psychiatric disorder History of substance abuse Pregnant or lactating females Known intolerance to opioids Abnormal kidney or liver functions based on Screening lab results. Known hypersensitivity to nalbuphine or to NAL ER excipients Previous participation in a nalbuphine ER clinical study Use of opiates, benzodiazepines, or MAOIs within 14 days of Baseline Use of pregabalin, gabapentin, thalidomide for treatment of cough within 14 days of Baseline Use of ACE inhibitors within 12 weeks of Baseline 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. Use of unstable doses of cough suppressants within 14 days of Baseline Use of unstable doses of medications that affect serotonergic neurotransmission that may cause serotonin syndrome with opioids within14 days of Baseline Use of unstable doses of P450 isozyme inhibitors/inducers within 14 days of Baseline

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NAL ER<br>NAL ER, tablets, 27 mg QD to BID, 54 mg BID, 108 mg BID | Drug: Nalbuphine ER<br>* Oral tablets<br>* Other names: Active;|
| Placebo Comparator: Placebo<br>Placebo, tablets, 0 mg QD to BID, 0 mg BID, 0 mg 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 |
| --- | --- | --- |
| 24 hr cough frequency | Relative change in frequency (coughs per hour) versus Placebo | Day 21 versus Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment related adverse events, as assessed by CTCAE v.5.0 | Adverse events, clinical labs, vital signs, physical exams, electrocardiograms | Baseline through follow-up | 
| Subjective Opiate Withdrawal Scale | 16 item questionnaire for 14 days following last dose of study drug | Daily for 14 days after last dose in Period 2 | 
| 24 hour cough frequency | Relative change in frequency (coughs per hour) versus Placebo | Days 7 and 14 versus Baseline | 
| 24 hour cough frequency | Proportion of responders with >=30%, 50% and 75% reduction in frequency versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Awake cough frequency | Relative change in frequency (coughs per hour) versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Sleep cough frequency | Relative change in frequency (coughs per hour) versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Cough Severity Visual Analogue Scale | 1 item scale with minimum score of 0 (no cough) to 10 (worst cough) versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Leicester Cough Questionnaire | 19 item questionnaire with a grading of 1 (all the time ) to 7 (none of the time) versus Placebo | Day 21 versus Baseline | 
| Patient-Reported Cough Frequency (change) | Change versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Patient-Reported Cough Frequency (proportion) | Proportion of responders with improvement in at least one category versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Patient Global Impression of Cough Severity | 1 item question with a grading from no cough, to mild, moderate or severe versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Patient Global Impression of Cough Change | 1 item question with a 7 point grading from much better to much worse versus Placebo | Days 7, 14, and 21 versus Baseline | 
| Clinicians Global Impression of Cough Severity | 1 item question with a grading from no cough, to mild, moderate or severe versus Placebo | Day 21 versus Baseline (both treatment periods) | 
| Clinicians Global Impression of Cough Change | 1 item question with a 7 point grading from very much improved to very much worse versus Placebo | Day 21 versus Baseline (both treatment periods) | 

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