Evaluation of Nalbuphine Hydrochloride Extended-Release Tablets for Cough Management in Idiopathic Pulmonary Fibrosis: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-505296-72-00
- Protocol
- NAL03-202
- Sponsor
- Trevi Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **Nalbuphine Extended-Release (NAL ER)** on 24-hour cough frequency, measured in coughs per hour, at Week 6 using objective digital cough monitoring. This is clinically relevant as it aims to assess the efficacy of NAL ER in reducing cough frequency in patients with **Idiopathic Pulmonary Fibrosis (IPF)**, a condition characterized by chronic cough that significantly impacts patient quality of life.
Secondary objectives include:
- Effect of NAL ER on the E-RS®:IPF Cough subscale as collected in the EXACT® tool at Week 6.
- Safety and tolerability of NAL ER in the study population.
- 24-hour cough frequency (coughs per hour).
- Awake cough frequency (coughs per hour).
- Sleep cough frequency (coughs per hour).
- E-RS®:IPF and subscales as collected in the EXACT® tool.
- CS-NRS (Cough Severity Numerical Rating Scale).
- LCQ© (Leicester Cough Questionnaire) total and domain scores (physical, psychological, and social domains).
- L-IPF© (Living with Pulmonary Fibrosis Impacts Questionnaire).
- L-IPF© (Living with Pulmonary Fibrosis Symptoms Questionnaire).
- EQ-5D-5L™.
- PGI-S Cough; PGI-C Cough (Patient Global Impression of Severity and Change for Cough).
- PGI-S IPF; PGI-C IPF (Patient Global Impression of Severity and Change for IPF).
- CGI-S, CGI-C (Clinical Global Impression of Severity and Change).
Participants
The clinical trial involves a total of **135 participants** diagnosed with **Idiopathic Pulmonary Fibrosis (IPF)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of IPF according to ATS/ERS/JRS/ALAT guidelines, a history of chronic cough for at least 8 weeks, and a Cough Severity Score of 4 or higher on the CS-NRS during the screening period. The trial population is characterized by a general health status that includes maintaining a SpO2 of 92% or higher and a Force Vital Capacity (FVC) of 40% or more of the predicted normal value. Additionally, the diffusing capacity of the lungs for carbon monoxide (DLCO) must be 25% or more of the predicted normal value. Participants are required to provide written informed consent and comply with study requirements. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of all participants.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel, 4-arm dose-ranging study** to evaluate the safety and efficacy of Nalbuphine Extended-Release (ER) tablets for the treatment of cough in patients with **Idiopathic Pulmonary Fibrosis (IPF)**. The trial aims to assess the effect of Nalbuphine ER on 24-hour cough frequency at Week 6 using objective digital cough monitoring. The study is expected to commence recruitment on October 1, 2023, and conclude by June 30, 2025, with a maximum treatment period of 6 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of IPF, a Cough Severity Score of 4 or higher, and a history of chronic cough for at least 8 weeks. Baseline assessments will be conducted to establish initial cough frequency and other health parameters. Following randomization, participants will receive either Nalbuphine ER or a placebo, administered orally in the form of film-coated tablets. The trial includes follow-up visits at Weeks 2, 4, and 6 to monitor changes in cough frequency, adverse events, and other health indicators. The end-of-study visit will occur at Week 6, where final assessments will be made to evaluate the primary and secondary endpoints.
The expected length of participant involvement is approximately 6 weeks, with conditions for early termination including significant adverse events or non-compliance with study protocols. The primary endpoint is the relative change from baseline in 24-hour cough frequency at Week 6 for Nalbuphine ER compared with placebo. Secondary endpoints include changes in various cough-related scales and assessments of adverse events, clinical laboratory results, and vital signs. The study is conducted under the sponsorship of Trevi Therapeutics, Inc., with Nalbuphine ER being the investigational product and a placebo serving as the control.
Treatment
The clinical trial involves the administration of **Nalbuphine ER**, an extended-release formulation of **nalbuphine hydrochloride**. This experimental medication is provided in the form of a **film-coated tablet**. The trial includes two dosage regimens: a maximum daily dose of 108 mg and a higher dose of 216 mg. The total maximum dose over the treatment period is 4536 mg and 9072 mg, respectively. The medication is administered orally, and the treatment period extends up to six weeks. The study aims to evaluate the safety and efficacy of Nalbuphine ER in treating cough associated with **idiopathic pulmonary fibrosis**. Participant compliance with the dosing schedule is monitored throughout the trial.
A **placebo** is also utilized in this study as a comparator to the experimental treatment. The placebo is designed to mimic the appearance of the Nalbuphine ER film-coated tablet but does not contain the active substance, **nalbuphine hydrochloride**. The use of a placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias in the assessment of the treatment's efficacy and safety.
Efficacy
The efficacy of Nalbuphine Extended-Release (ER) tablets in the treatment of cough associated with **Idiopathic Pulmonary Fibrosis (IPF)** will be assessed through a randomized, double-blind, placebo-controlled, parallel, 4-arm dose-ranging study. The primary endpoint for evaluating efficacy is the relative change from baseline in 24-hour cough frequency, measured in coughs per hour, at Week 6 for Nalbuphine ER compared with placebo. This will be assessed using objective digital cough monitoring.
Secondary endpoints include a variety of measures to further evaluate efficacy and safety. These include the relative change from baseline in the E-RS:IPF Cough subscale at Week 6, adverse events, clinical laboratory assessments, vital signs, spirometry, and physical examination summaries. Additional assessments involve electrocardiogram (ECG) summaries, Subjective Opiate Withdrawal Scale (SOWS) daily summaries for 14 days following the last dose, and changes in various patient-reported outcomes such as the Cough Severity Numerical Rating Scale (CS-NRS), Leicester Cough Questionnaire (LCQ), and Patient Global Impression of Severity (PGI-S) and Change (PGI-C) scores at specified timepoints.
The study will also evaluate the proportion of responders achieving significant reductions in cough frequency and improvements in patient-reported outcomes at Weeks 2, 4, and 6. These efficacy parameters will be collected and analyzed at multiple timepoints throughout the study to provide a comprehensive assessment of the treatment's impact on cough associated with IPF.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosis of IPF as determined by the 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 – Force Vital Capacity, as determined by spirometry adhering to ATS/ERS guidelines.
- DLCO ≥ 25% predicted of normal - Diffusing capacity of the lungs for carbon monoxide corrected for hemoglobin, assessed within the last 12 weeks, or at the time of screening.
- Males or females ages 18 years and older at the time of consent.
- Willing and able to provide written informed consent, comply with study requirements and restrictions, and agree to the confidential use and storage of all data and use of all anonymized data for publication including scientific publication.
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.
- History of major psychiatric disorder, which in the opinion of the Investigator, could interfere with the assessment of anti-cough efficacy and/or safety events during the study or with the ability of the subject to cooperate with study requirements.
- History of substance abuse, including excessive alcohol consumption, that in the opinion of the investigator, may interfere with the conduct of the study. Alcohol consumption should be limited for the duration of study treatment.
- Significant medical condition or other factors as assessed by the investigator that may interfere with the subject’s ability to successfully complete the study.
- Pregnant or lactating female subject. Women of childbearing potential (WOCBP) must use an acceptable method of birth control and have a negative pregnancy test at the screening and baseline visits. WOCBP and acceptable methods of birth control are defined in the protocol.
- Known intolerance (gastrointestinal, central nervous system symptoms), hypersensitivity, drug allergy following the use of an opioid drug.
- Concurrent or anticipated enrollment in an ongoing interventional clinical trial. Observational or long-term safety follow-up studies (e.g., in a vaccine study) may be allowed upon medical monitor approval.
- Use of opiates is prohibited within 14 days prior to the baseline visit. This includes opiate containing anti-cough agents, and naltrexone. Subjects are prohibited from using opioids for the duration of the study.
- 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 prescribed as cough treatment is prohibited within 4 weeks prior to the baseline visit and for the duration of the study.
- Inadequate swallow reflex as assessed by the ability to sip 3 fluid oz (or 90 mL) of water without coughing or choking.
- 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.
- 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.
- Cardiac Safety: Mean QTcF value of 3 centrally read screening electrocardiograms (ECGs) calculated as: a) ≥470ms if QRS <120ms or b) ≥500ms in the presence of either a Right Bundle Branch Block (RBBB) or QRS ≥120ms.
- Heart Rate: <50 bpm or >100 bpm, as determined by vital signs pulse over 30-60 seconds. a) Subjects with a resting heart rate of <50 bpm will have it repeated once after 5 minutes in the supine position, and if it remains <50 bpm during the repeat, they will be considered a screen failure. b) Subjects with a rate >100 bpm should be considered a screen failure. Rescreening may be possible with the approval of the medical monitor, after medical or alternative management of the atrial fibrillation.
- Kidney Function: Estimated glomerular filtration rate ≤44 mL/min/1.73 m2 at screening.
- Liver Function: Total Bilirubin >3mg/dL [>50umol/L] and Serum Albumin <2.8g/dL at screening.
- Known hypersensitivity to nalbuphine or to NAL ER excipients.
- Use of a medication having a “known risk” of Torsade de Pointes (TdP) categorized as “KR” on the Credible Meds® website, is prohibited within 4 weeks prior to the baseline visit and for the duration of the study. Medications associated with a potential risk of QT prolongation, but not clearly associated with TdP, are permitted at study entry if the following criteria are met: • Subject has been given medication at stable doses for a full 4 weeks prior to baseline. • Medication dose will not be increased after baseline, or during the study, and it is anticipated that the subject will receive the medication for the entirety of the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Oct 2023 | 18 |
 Italy | Not Recruiting | 01 Oct 2023 | 24 |
 The Netherlands | Not Recruiting | 01 Oct 2023 | — |
 Poland | Not Recruiting | 01 Oct 2023 | 21 |
 Spain | Not Recruiting | 01 Oct 2023 | 15 |
| Netherlands | — | — | 12 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Nalbuphine ER | Test | FILM-COATED TABLET | ORAL USE | 108 | 6 | PRD4215727 |
Placebo - Nalbuphine ER | Placebo | N/A | — | — | — | N/A |
Nalbuphine ER | Test | FILM-COATED TABLET | ORAL USE | 216 | 6 | PRD6798693 |