Refractory Chronic Cough
Conditions
Keywords
RCC, Cough, Nalbuphine
Brief summary
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.
Interventions
DRUGNAL ER
Oral tablets
DRUGPlacebo
Oral tablets
Sponsors
Trevi Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in 24-hour Cough Frequency at Day 21 | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced at Least One Treatment Emergent Adverse Events (TEAEs) | Up to Week 15 | 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. |
| Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments | Up to Week 15 | The clinical laboratory parameters included urinalysis, hematology, serum chemistry and coagulation. Clinical significance was determined by the investigator. |
| Number of Participants With Clinically Significant Changes in Vital Sign Parameters | Up to Week 15 | Vital signs measurements included blood pressure, heart rate, respiration rate, body temperature, pulse oximetry, and weight. Clinical significance was determined by the investigator. |
| Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) | Up to Week 15 | 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. |
| Number of Participants With Clinically Significant Changes in Physical Examination Parameters | Up to Week 15 | 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. |
| Relative Change From Baseline in 24-hour Cough Frequency at Days 7 and 14 | Baseline, Days 7 and 14 | 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. |
| Percentage of Responders With >=30%, 50% and 75% Reduction in 24-hour Cough Frequency | Days 7, 14, and 21 | Responders were defined as those with ≥30%, ≥50%, or ≥75% reduction in 24-hour cough frequency from Baseline at Days 7, 14, or 21. |
| Relative Change From Baseline in Awake Cough Frequency at Days 7, 14, and 21 | Baseline, 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. |
| Relative Change From Baseline in Sleep Cough Frequency at Days 7, 14, and 21 | Baseline, 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. |
| Change From Baseline in Cough Severity Visual Analogue Scale (CS-VAS) at Days 7, 14, and 21 | Baseline, 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. |
| Change From Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Day 21 | Baseline, 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. |
| Change From Baseline in Patient-Reported Cough Frequency (PR-CF) at Days 7, 14, and 21 | Baseline, 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. |
| Percentage of PR-CF Responders With at Least One Category Improvement at Days 7, 14, and 21 | 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. |
| Change From Baseline in Patient Global Impression of Severity (PGI-S) Cough at Days 7, 14, and 21 | Baseline, 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. |
| Patient Global Impression of Change for Cough (PGI-C) Score at Days 7, 14, and 21 | 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. |
| Change From Baseline in Clinicians Global Impression of Cough Severity Score (CGI-S) at Day 21 | Baseline, 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. |
| Clinicians Global Impression of Change for Cough Score (CGI-C) at Day 21 | 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. |
Countries
Canada, United Kingdom
Contacts
STUDY_DIRECTORChief Development Officer
Trevi Therapeutics
Participant flow
Recruitment details
Participants were enrolled at 14 sites from 30 November 2023 to 06 January 2025.
Pre-assignment details
A total of 142 participants were screened, of which 66 participants were enrolled and randomized to receive treatment in this study.
Baseline characteristics
| Characteristic | — |
|---|---|
| 24-hour Cough Frequency | 45.869 coughs per hour STANDARD_DEVIATION 54.7593 |
| Age, Continuous | 60.2 years STANDARD_DEVIATION 10.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 61 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 59 |
| other Total, other adverse events | 50 / 63 | 32 / 59 |
| serious Total, serious adverse events | 0 / 63 | 0 / 59 |
Outcome results
None listed