| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory or Unexplained Chronic Cough |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066656 |
| E.1.2 | Term | Chronic cough |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary efficacy objective is to assess the effect of BLU-5937 on 24-hour cough frequency in an enriched population of adults with refractory chronic cough (including unexplained chronic cough) at 24 weeks;
The primary safety objective is to determine the effect of BLU-5937 on adverse events and other safety measures (Safety population). |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the effects of BLU-5937 on other measures of cough frequency and PROs (unless otherwise specified, assessed in both Primary and Overall Efficacy populations). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Between 18 and 80 years of age inclusive, at the time of signing the informed consent
2. Capable of understanding the written informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements including being available for the duration of the study
3. After investigation into potential underlying causes of chronic cough, have a diagnosis of RCC defined as:
a) insufficient improvement in cough after treatment for the underlying condition(s) contributing to their cough, OR
b) unexplained cough for which an underlying condition has not been determined despite adequate investigation with diagnostic tests and trials of therapy
4. The Eligibility Adjudicator assessment confirms prior to randomization that the participant’s history meets diagnostic criteria for RCC
5. Persistent cough for ≥ 1 year prior to Screening
6. Chest radiograph or computed tomography of the thorax within the last 5 years from Screening and following the onset of chronic cough that does not show any abnormality considered to be significantly contributing to the chronic cough in the opinion of the Investigator
7. Participants must meet the following cough frequency criteria:
a) Participants in the Primary Efficacy population must have a 24-hour cough frequency of ≥ 20/h at both Screening and Cough Frequency Baseline (Day -7) visits. The Primary Efficacy population will be approximately 150 participants per treatment arm
b) Participants in the Extended Efficacy population will have a 24-hour cough frequency between ≥ 8 and < 40 coughs/h at Screening and a 24-hour cough frequency between ≥ 8 and < 20 coughs/h at Baseline (Day -7). The Extended Efficacy population will be approximately 50 participants per treatment arm
c) Participants in the Exploratory Efficacy population will have a 24-hour cough frequency between > 0 and < 16 coughs/h at Screening and a 24-hour cough frequency between > 0 and < 8 coughs/h at Baseline (Day -7). The exploratory population will enroll up to 25 participants per treatment arm
8. A score of ≥ 40 mm on the CS-VAS at Screening and Baseline (Day 1)
9. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP).
OR
ii) A WOCBP who agrees to follow the contraceptive guidance from Screening through the Follow-Up Visit.
Note: WOCBP must have a negative serum pregnancy test at Screening and negative urine pregnancy test at Baseline and must use a highly effective contraception method from Screening through the Follow up Visit (highly effective methods of birth control in this study include: combined estrogen and progestogen containing or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, and vasectomized partner)
10. Male participants must agree to use contraception from Screening through the Follow-Up Visit and make no donation of sperm from Screening until 3 months after the last dose of study treatment. |
|
| E.4 | Principal exclusion criteria |
1. Current smoker or vaper or current use of tobacco smoke, cannabis smoke, or nicotine vapors
2. Individuals who have given up smoking or vaping within the past 6 months, or those with > 20 pack-year smoking history
3. Diagnosis of chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, pulmonary sarcoidosis, idiopathic pulmonary fibrosis, or
other significant or progressive airway/respiratory disorder that might affect cough based on clinician assessment
4. History of upper and/or lower respiratory tract infection or significant change in pulmonary status within 28 days of Screening or during
Screening or the Single-blind Placebo Run-in
5. Laboratory confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection at Screening or Day -7
6. Medical history of malignancy and treatment completed ≤ 5 years prior to Screening except for adequately treated nonmetastatic
cutaneous squamous cell or basal cell carcinoma and/or carcinoma in situ of the cervix
7. History of a diagnosis of drug or alcohol dependency or abuse within the last 3 years, per Investigator assessment, or a positive urine opioid
drug screen result at Screening. Stable opioid treatment for non-cough indication is permitted (refer to Appendix 4 of the study protocol)
8. Positive serological test for human immunodeficiency virus, hepatitis B, or hepatitis C. Note: Participants with positive hepatitis B or C
serology will have confirmatory testing
9. Previous participation in an investigational study of BLU-5937
For the full list of exclusion criteria please refer to the study protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
24-hour cough frequency at Week 24 by a cough monitor in the Primary Efficacy population of
participants with Baseline 24-hour cough frequency ≥20 coughs/h
• Incidence of TEAEs and treatment-emergent SAEs over the course of the study
• Incidence of treatment-emergent AEMIs including spontaneous taste disturbance AE reporting
• Discontinuations due to TEAEs
• Changes from Baseline in vital signs, clinical laboratory values, including male reproductive
hormones, ECGs, physical examinations over the course of the study |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Efficacy primary endpoint - Week 24. Safety endpoint - week 2 follow-up visit. |
|
| E.5.2 | Secondary end point(s) |
CS-VAS
• Change from Baseline in CS-VAS at Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
• CS-VAS response (proportion of responders with ≥ 30 mm reduction or ≥ 20 mm reduction from Baseline in CS-VAS score) at Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
Objective cough frequency recording
• 24-hour cough frequency in the Overall Efficacy population (participants with Baseline cough frequency ≥ 8 coughs/h) at Week 24
• 24-hour cough frequency at Week 1, Week 4, Week 8, Week 12, Week 16, and Week 20
• Awake cough frequency at Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
• 24-hour cough response (proportion of responders with 30%, 50%, or 70% reduction) at Week 1,
Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
• Awake cough response (proportion of responders with 30%, 50%, or 70% reduction) at Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
• Nighttime cough frequency at Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
LCQ
• Change from Baseline in the LCQ total score at Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
• LCQ response (proportion of responders with ≥ 1.3-point increase from Baseline in total score) at
Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
PGI-C
• PGI-C score at Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
PGI-S
• Change from Baseline in PGI-S at Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
CCD
• Change from Baseline in CCD score at Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
• CCD response (proportion of responders) at Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| double-blind treatment preceded by single-blind run-in and followed by open-label extension |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Taiwan |
| Australia |
| India |
| Korea, Republic of |
| United Kingdom |
| United States |
| Czechia |
| Germany |
| Slovakia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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