A Phase 3 Study with Open-Label Extension of BLU-5937 to determine Efficacy and Safety in Adult Participants with Refractory Chronic Cough, Including Unexplained Chronic Cough (CALM-1)
Scientific Title of Study
A Phase 3, 52-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Efficacy and Safety Study with Open-Label Extension of BLU-5937 in Adult Participants with Refractory Chronic Cough, Including Unexplained Chronic Cough(CALM-1)
Trial Acronym
NIL
Secondary IDs if Any
Secondary ID
Identifier
BUS-P3-01 (CALM-1) Version 1.0 dated 04 Aug 2022
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Male and female participants are eligible to be included in the study only if all the following criteria apply:
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 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 ≥ 1year 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 coughs/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 Cough Severity Visual Analogue Scale 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:
a) Not a woman of childbearing potential (WOCBP)
OR
b) A WOCBP who agrees to follow the protocol-specified 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 protocol-specified 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.
ExclusionCriteria
Details
Participants are excluded from the study if any of the following criteria apply:
1. Female participants who are pregnant, trying to become pregnant or lactating
2. Current smoker or vaper, or current use of tobacco smoke, cannabis smoke, or nicotine vapors
3. Individuals who have given up smoking or vaping within the past 6 months, or those with > 20 pack-year smoking history
4. 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
5. Uncontrolled asthma, defined as one or both of the following:
a) ≥ 1 clinically significant exacerbation in the last 6 months or ≥ 2 clinically significant exacerbations in the past 12 months. A clinically significant asthma exacerbation is defined as requiring the use of systemic corticosteroids
b) Use of rescue medication ≥ 3 days per week or nighttime awakening > 1 time per week (pre-exercise prophylactic medication use will not be considered rescue medication).
6. Pre-bronchodilator forced expiratory in 1 second (FEV1)/forced vital capacity (FVC) < 60% at Screening or on spirometry testing performed within 2 years before Screening and following the onset of chronic cough
7. Participants who failed to use the cough monitor or who are confirmed to have incorrectly recorded 24-hour cough frequency at Screening or Cough Frequency Baseline (Day -7) Visits. Retest is allowed once only if insufficient recording time is captured and approved by the Medical Monitor. Incorrectly recorded 24-hour cough frequencies are defined as recordings where less than 20 hours of the recording can be assessed for cough frequency
8. 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
9. Current active tuberculosis or nontuberculous mycobacterial infection, a history of latent untreated tuberculosis, or a history of incompletely treated tuberculosis
10. Laboratory confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection at Screening or Day -7
11. History of SARS-CoV-2 infection or Coronavirus Disease-2019 (COVID-19) within 3 months of Screening, history of long COVID, or known exposure to someone with SARS-CoV-2 infection or COVID-19 within 10 days of Screening. History of fully resolved long COVID may be permitted after discussion with the Medical Monitor
12. Requiring concomitant therapy with prohibited medications or non-pharmacological therapy
13. Medical history of hypogeusia/dysgeusia/ageusia or known presence of a dysfunction in ability to taste.Participants with a history of taste disturbance that has fully resolved and was due to prior P2X3 antagonist drug exposure or participation in a previous clinical study of P2X3 antagonist or previous SARS-CoV-2 infection will be eligible
14. 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
15. 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
16. Screening systolic blood pressure > 160 mmHg or a diastolic blood pressure > 90 mmHg
17. Clinically significant abnormal electrocardiogram at Screening, per Investigator discretion
18. Prolonged Fridericia’s corrected QT interval (QTcF; Men: > 450 ms; Women > 470 ms) at Screening
19. Clinically significant abnormal laboratory tests at Screening, after one repeat laboratory test if allowed by the Medical Monitor, including the following:
a) Alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase > 1.50 × the upper limit of normal (ULN)
b) Gamma-glutamyl aminotransferase > 2.0 × ULN if alkaline phosphatase is above ULN
c) Total bilirubin above ULN
d) Severe renal function impairment defined as estimated glomerular filtration rate estimated by Modification of Diet in Renal Disease of < 30 mL/min/1.73m2
e) Unexplained creatine kinase concentration > 3 × ULN, per Investigator discretion
f) Hemoglobin < 10 g/dL, white blood cell count < 2500/mm3, neutrophil count < 1500/mm3, or platelet count < 100 × 103/mm3.
20. Known or suspected diagnosis of Gilbert’s Syndrome
21. 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
22. Acutely ill or febrile 24 hours prior to or at the Screening Visit. Fever is defined as a body temperature≥ 38.0°C/100.4°F
23. History of clinically diagnosed moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment
24. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results, in the opinion of the Investigator
25. Cataract in either eye, except for Grade 1 nuclear sclerosis based on a scale of 1 to 4 (pertains to participants in the Ocular Substudy only, participants meeting this exclusion criterion may still be randomized in the main study)
26. Corneal dystrophy or any corneal opacity due to progressive disease (pertains to participants in the Ocular Substudy only, participants meeting this exclusion criterion may still be randomized in the main study)
27. Known allergy/sensitivity or contraindication to BLU-5937 or any of its excipients
28. Previous participation in an investigational study of BLU-5937
29. Treatment with any other investigational products within the 3 months before first dose of study treatment. Note: COVID-19 vaccine administration is acceptable any time before Screening or during the study as long as the participant is not currently in a COVID-19 vaccine clinical study
30. Treatment with any marketed P2X3 antagonist within the 3 months before first dose of study treatment
31. Noncompliance (< 80%) with Single-blind Placebo Run-in medication up to Day -1
32. Participants who are considered ineligible to participate in the study for any other reason based on the Investigator’s judgment.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Other
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
• 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 12 weeks.
• The primary safety objective is to determine the effect of BLU-5937 on adverse events and other safety measures (Safety population)
• 24-hour cough frequency at Week 12 by a cough monitor in the Primary Efficacy population of participants with Baseline 24-hour cough frequency ≥20 coughs/h
Secondary Outcome
Outcome
TimePoints
• 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)
Change from Baseline in CS-VAS at Week 4, Week 8, and Week 12
Target Sample Size
Total Sample Size="675" Sample Size from India="48" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is a Phase 3, 52-week, multicenter, randomized, double-blind, parallel-arm, placebo-controlled efficacy and safety study of BLU-5937 in adult (18 to 80 years of age) participants who have had persistent cough for ≥ 1 year prior to Screening, with a diagnosis of RCC.
Eligible participants will undergo a minimum 19-day to maximum 23-day Single-blind Placebo Run-in. Following the Single-blind Placebo Run-in, participants who continue to meet all eligibility criteria will be randomized in a 1:1:1 ratio (up to 225 participants/arm) to receive either 1 of 2 BLU-5937 doses (25 mg or 50 mg, twice daily) or placebo (twice daily) for 52 weeks of double-blind treatment.
Participants who complete the Double-blind Treatment Period will continue in a 24-week Open-label Extension. During the Open-label Extension, all participants will receive BLU-5937 at 50 mg, twice daily. At the end of the Open-label Extension, participants will have a 2-Week Follow-up/End of Study Visit at 50 mg, twice daily. At the end of the Open-label Extension, participants will have a
2-Week Follow-up/End of Study Visit.
This Study aims to Evaluate the Efficacy and Safety of BLU-5937 in Patients with Refractory Chronic Cough