Refractory Chronic Cough Improvement Via NAL ER (RIVER)

Trevi Therapeutics66 enrolled

Overview

The main purpose of this study is to evaluate the effect of NAL ER on 24-hour cough frequency and to assess safety and tolerability of NAL-ER for treatment of refractory chronic cough.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Refractory Chronic Cough

Interventions

NAL ERDRUG

Oral tablets

PlaceboDRUG

Oral tablets

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 Other protocol defined inclusion/exclusion criteria applied.

Locations (14)

McMaster University Medical Centre

Hamilton, Ontario, Canada

Inspiration Research

Toronto, Ontario, Canada

Outcomes

Primary Outcomes

Relative Change From Baseline in 24-hour Cough Frequency at Day 21

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. Baseline was defined as the last non-missing assessment, prior to the first dose of study drug.

Time frame: Baseline, Day 21

Secondary Outcomes

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.

Time frame: Up to Week 15

Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments

The clinical laboratory parameters included urinalysis, hematology, serum chemistry and coagulation. Clinical significance was determined by the investigator.

Time frame: Up to Week 15

Number of Participants With Clinically Significant Changes in Vital Sign Parameters

Vital signs measurements included blood pressure, heart rate, respiration rate, body temperature, pulse oximetry, and weight. Clinical significance was determined by the investigator.

Time frame: Up to Week 15

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)

Data from ClinicalTrials.gov

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CIC Mauricie Inc.

Trois-Rivières, Quebec, Canada

Hull and East Yorkshire Hospitals NHS Trust - Castle Hill Hospital

Cottingham, East Riding Of Yorkshire, United Kingdom

Kings College Hospital NHS Foundation Trust

London, Greater London, United Kingdom

University Hospital of South Manchester NHS Foundation Trust (UHSM) - Wythenshawe Hospital

Manchester, Greater Manchester, United Kingdom

Accellacare South London

Orpington, Kent, United Kingdom

Accellacare North London

Northwood, Middlesex, United Kingdom

Belfast City Hospital

Belfast, Northern Ireland, United Kingdom

North Tyneside General Hospital - Northumbria Healthcare NHS Foundation Trust

North Shields, Tynemouth, United Kingdom

...and 4 more locations

Changes in ECG data such as heart rate, rhythm, and other clinically significant abnormalities (left ventricular hypertrophy, pathological Q-waves) were measured. Clinical significance was determined by the investigator.

Time frame: Up to Week 15

Number of Participants With Clinically Significant Changes in Physical Examination Parameters

Physical examination included examination of the following body systems: general appearance, eyes, ears, nose, throat, head and neck, chest and lungs, cardiovascular, abdomen, musculoskeletal, lymphatic, dermatological, neurological, and extremities. Clinical significance was determined by the investigator.

Time frame: Up to Week 15

Relative Change From Baseline in 24-hour Cough Frequency at Days 7 and 14

Time frame: Baseline, Days 7 and 14

Percentage of Responders With >=30%, 50% and 75% Reduction in 24-hour Cough Frequency

Responders were defined as those with ≥30%, ≥50%, or ≥75% reduction in 24-hour cough frequency from Baseline at Days 7, 14, or 21.

Time frame: Days 7, 14, and 21

Relative Change From Baseline in Awake Cough Frequency at Days 7, 14, and 21

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. Baseline was defined as the last non-missing assessment, prior to the first dose of study drug.

Time frame: Baseline, Days 7, 14, and 21

Relative Change From Baseline in Sleep Cough Frequency at Days 7, 14, and 21

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. Baseline was defined as the last non-missing assessment, prior to the first dose of study drug.

Time frame: Baseline, Days 7, 14 and 21

Change From Baseline in Cough Severity Visual Analogue Scale (CS-VAS) at Days 7, 14, and 21

The CS-VAS is a brief, easily administered patient reported outcome (PRO) questionnaire that is used to assess cough severity in both acute and chronic cough. CS-VAS is a 1-item scale that rates the severity of participants' cough from 0 millimeter (mm) where 0 indicated "no cough" and 100 represented "worst cough ever". A negative change from baseline indicates improvement.

Time frame: Baseline, Days 7, 14, and 21

Change From Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Day 21

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.

Time frame: Baseline, Day 21

Change From Baseline in Patient-Reported Cough Frequency (PR-CF) at Days 7, 14, and 21

Patient-Reported Cough Frequency (PR-CF) is a daily, self-reported, 1 item scale, PRO that is used to assess cough frequency. Participants rate their cough frequency over the past 24 hours using a 5-point Likert scale (0- to 4: 0 = Not at all, 1 = Rarely, 2 = Occasionally, 3 = Frequently, 4 = Almost constantly). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

Time frame: Baseline, Days 7, 14, and 21

Percentage of PR-CF Responders With at Least One Category Improvement at Days 7, 14, and 21

PR-CF is a daily, self-reported, 1 item scale, PRO that is used to assess cough frequency. Participants rate their cough frequency over the past 24 hours using a 5-point Likert scale (0 to 4: 0 = Not at all, 1 = Rarely, 2 = Occasionally, 3 = Frequently, 4 = Almost constantly). A higher score indicates more severe symptoms. PR CF responders were defined as participants with at least a one category improvement at Days 7, 14, and 21.

Time frame: Days 7, 14, and 21

Change From Baseline in Patient Global Impression of Severity (PGI-S) Cough at Days 7, 14, and 21

The PGI-S Cough scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough. Participants rate the severity of their cough in the last week with a 4-point Likert scale ranging from 0 to 3 (0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

Time frame: Baseline, Days 7, 14 and 21

Patient Global Impression of Change for Cough (PGI-C) Score at Days 7, 14, and 21

The PGI-C Cough scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough. Participants rate the severity of their cough in the last week with a 7-point Likert scale ranging from 0 to 7 (0 = No Cough, 1 = Much better, 2 = Moderately better, 3 = A little better, 4 = No change, 5 = A little worse, 6 = Moderately worse, or 7 = Much worse). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

Time frame: Days 7, 14, and 21

Change From Baseline in Clinicians Global Impression of Cough Severity Score (CGI-S) at Day 21

The CGI-S Cough scale is an investigator-reported, single-item categorical scale that is increasingly used when assessing the severity of the condition. Investigator rate the severity of their cough in the last week with a 4-point Likert scale ranging from 0 to 3 (0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

Time frame: Baseline, Day 21

Clinicians Global Impression of Change for Cough Score (CGI-C) at Day 21

The PGI-C Cough scale is an investigator-reported, single-item categorical scale that is increasingly used when assessing the investigator's belief of the participant's overall improvement pre-treatment baseline. Investigator rate the change in improvement in the last week with a 7-point Likert scale ranging from 1 to 7 (1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6= Much worse, or 7= Very much worse). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

Time frame: Day 21