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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Trevi Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

12 Dec 2023 → 24 Apr 2025

Decision date (initial)

2023-11-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Trevi Therapeutics, Inc.

External identifiers

EU CT number

2023-505296-72-00

ClinicalTrials.gov

NCT05964335

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety, Pharmacodynamic

Effect of NAL ER on 24-hour cough frequency (coughs per hour) at Week 6 using objective digital cough monitoring.

Secondary objectives 14

1. Effect of NAL ER on the E-RS®:IPF Cough subscale (Evaluating Respiratory Symptoms in Idiopathic Pulmonary Fibrosis) as collected in the EXACT® (EXAcerbation of Chronic pulmonary disease Tool Week 6).
2. Safety and tolerability of NAL ER in the study population.
3. 24-hour cough frequency (Coughs per hour).
4. Awake cough frequency (Coughs per hour).
5. Sleep cough frequency (Coughs per hour).
6. E-RS®:IPF (Evaluating Respiratory Symptoms in Idiopathic Pulmonary Fibrosis) and subscales as collected in the EXACT® (EXAcerbation of Chronic pulmonary disease Tool).
7. CS-NRS (Cough Severity Numerical Rating Scale).
8. LCQ© (Leicester Cough Questionnaire) total and domain scores (physical, psychological, and social domains)
9. L-IPF© (Living with Pulmonary Fibrosis Impacts Questionnaire).
10. L-IPF© (Living with Pulmonary Fibrosis Symptoms Questionnaire).
11. EQ-5D-5L™
12. PGI-S Cough; PGI-C Cough (Patient Global Impression of Severity and Change for Cough).
13. PGI-S IPF; PGI-C IPF (Patient Global Impression of Severity and Change for IPF).
14. CGI-S, CGI-C (Clinical Global Impression of Severity and Change).

Conditions and MedDRA coding

Idiopathic Pulmonary Fibrosis (IPF)

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Diagnosis of IPF as determined by the Investigator based on ATS/ERS/JRS/ALAT guidelines.
2. Cough Severity Score ≥ 4 on CS-NRS (Cough Severity Numerical Rating Scale) during the Screening period and Baseline.
3. History of chronic cough for at least 8 weeks before screening.
4. 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).
5. FVC ≥ 40% predicted of normal – Force Vital Capacity, as determined by spirometry adhering to ATS/ERS guidelines.
6. 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.
7. Males or females ages 18 years and older at the time of consent.
8. 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 26

1. 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.
2. 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.
3. 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.
4. Significant medical condition or other factors as assessed by the investigator that may interfere with the subject’s ability to successfully complete the study.
5. 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.
6. Known intolerance (gastrointestinal, central nervous system symptoms), hypersensitivity, drug allergy following the use of an opioid drug.
7. 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.
8. 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.
9. Use of benzodiazepines are prohibited within 14 days prior to the baseline visit and for the duration of the study.
10. 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.
11. 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.
12. Inadequate swallow reflex as assessed by the ability to sip 3 fluid oz (or 90 mL) of water without coughing or choking.
13. Exposure to any investigational medication, including placebo, is prohibited within 4 weeks prior to the baseline visit and for the duration of the study.
14. 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.
15. 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.
16. 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.
17. 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.
18. Upper or lower respiratory tract infection in the last 8 weeks prior to the baseline visit.
19. Clinical history of aspiration pneumonitis.
20. Diagnosis of sleep apnea.
21. 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.
22. 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.
23. Kidney Function: Estimated glomerular filtration rate ≤44 mL/min/1.73 m2 at screening.
24. Liver Function: Total Bilirubin >3mg/dL [>50umol/L] and Serum Albumin <2.8g/dL at screening.
25. Known hypersensitivity to nalbuphine or to NAL ER excipients.
26. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Relative change from Baseline in 24-hour cough frequency (coughs per hour) at Week 6 for NAL ER compared with placebo.

Secondary endpoints 27

1. Relative change from Baseline in the E-RS:IPF Cough subscale at Week 6 for NAL ER compared with placebo.
2. Adverse events, clinical laboratory assessments, vital signs, spirometry and physical examination summaries.
3. Electrocardiogram (ECG) summaries [ECGs will be analyzed in a separate report].
4. Subjective Opiate Withdrawal Scale (SOWS) daily summaries for the 14 days following the last dose of investigational product.
5. Relative change from Baseline in 24-hour cough frequency (coughs per hour) at Week 2, 4, and 6, for NAL ER compared with placebo.
6. 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.
7. Relative change from Baseline in awake cough frequency (coughs per hour) Week 2, 4, and 6, for NAL ER compared with placebo.
8. Relative change from Baseline in sleep cough frequency (coughs per hour) at Week 2, 4, and 6, for NAL ER compared with placebo.
9. Change from Baseline in the E-RS:IPF Cough subscale at Week 1, 2, 3, 4, 5, and 6, for NAL ER compared with placebo.
10. Proportion of E-RS:IPF Cough subscale responders, with response defined as at least a one category improvement at Week 1, 2, 3, 4, 5, and 6 for NAL ER compared with placebo.
11. Change from Baseline in the E-RS:IPF total score, subdomain scores (IPF-Breathlessness, IPF-Cough, IPF-Sputum, and IPF-Chest Symptoms), and individual items at Week 1, 2, 3, 4, 5, and 6, for NAL ER compared with placebo.
12. Change from Baseline in the CS-NRS at Week 1, 2, 3, 4, 5, and 6, for NAL ER compared with placebo.
13. Change from Baseline in the LCQ total scores at Week 6, for NAL ER compared with placebo.
14. Proportion of LCQ total score responders, with response defined as 1.3-point increase at Week 6 for NAL ER compared with placebo.
15. Change from Baseline in the L-IPF at Week 6, for NAL ER compared with placebo (Impacts).
16. Change from Baseline in the EQ-5D-5L at Week 6, for NAL ER compared with placebo.
17. Change from Baseline in the PGI-S Cough at Week 2, 4, and 6, for NAL ER compared with placebo.
18. Change from Baseline in the PGI-S IPF at Week 2, 4, and 6, for NAL ER compared with placebo.
19. Change from Baseline in the CGI-S at Week 6, for NAL ER compared with placebo.
20. Change from Baseline in the L-IPF and its domains at Week 6, for NAL ER compared with placebo (Symptoms).
21. Change from Baseline in the LCQ domains and individual items at Week 6, for NAL ER compared with placebo.
22. PGI-C Cough score at Week 2, 4, and 6 for NAL ER compared with placebo.
23. Proportion of subjects with improvement by ≥1 and ≥2 categories, worsening by ≥1 and ≥2 categories, and no change on the PGI-C and PGI-S cough at each post-baseline timepoint for NAL ER compared with placebo.
24. PGI-C IPF score at Week 2, 4, and 6 for NAL ER compared with placebo.
25. Proportion of subjects with improvement by ≥1 and ≥2 categories, worsening by ≥1 and ≥2 categories, and no change on the PGI-C and PGI-S IPF at each post-baseline timepoint for NAL ER compared with placebo.
26. CGI-C IPF score at Week 6 for NAL ER compared with placebo.
27. Proportion of subjects: improvement by ≥1 and ≥2 categories, worsening by ≥1 and ≥2 categories, and no change on the CGI-C and CGI-S at each post-baseline timepoint for NAL ER compared with placebo.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Trevi Therapeutics Inc.

Sponsor organisation

Trevi Therapeutics Inc.

Address

195 Church Street

City

New Haven

Postcode

06510-2009

Country

United States

Scientific contact point

Organisation

Trevi Therapeutics Inc.

Contact name

Trevi Therapeutics

Public contact point

Organisation

Trevi Therapeutics Inc.

Contact name

Trevi Therapeutics

Third parties 4

Sponsor responsibilities

Contact point sponsor

Trevi Therapeutics Inc.

Locations

5 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 106 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications