Chronic Refractory Cough
Conditions
Keywords
Unexplained or refractory chronic cough, P2X3 antagonists
Brief summary
This is a multi-center, randomized, double-blind, placebo-controlled, crossover, dose escalation study of BLU-5937 in subjects with unexplained or refractory chronic cough
Detailed description
This study will have two 16-day treatment periods (four escalating doses or matching placebo at four days interval) separated by a 10 to 14-day washout period. There will be a 14-day follow-up period.
Interventions
DRUGBLU-5937
Four escalating doses of BLU-5937 administered BID over the course of the study
DRUGPlacebo
Matching placebo for BLU-5937
Sponsors
Bellus Health Inc. - a GSK company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Two-arm, Two-Period, crossover assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Unexplained or refractory chronic cough for at least one year * Chest radiograph or CT thorax within the last 60 months not demonstrating any abnormality considered to be significantly contributing to the chronic cough * Cough count of ≥ 10 per hour (Awake Cough Count) at Screening * Score of ≥ 40mm on the Cough Severity VAS at Screening * Women of child-bearing potential must have a negative serum pregnancy test at Screening * Women of child-bearing potential must use a highly effective contraception method from Screening through the Follow-Up Visit * Male subjects and their partners of child-bearing potential must use 2 methods of acceptable birth control
Exclusion criteria
* Current smoker or individuals who have given up smoking within the past 6 months, or those with \>20 pack-year smoking history * Diagnosis of COPD, bronchiectasis, idiopathic pulmonary fibrosis * Treatment with an ACE-inhibitor as the potential cause of a subject's cough, or requiring treatment with an ACE-inhibitor during the study, or within 12 weeks prior to the Screening Visit * FEV1/FVC \< 60% * History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit * History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening * History of a diagnosis of drug or alcohol dependency or abuse within the last 3 years * Clinically significant abnormal electrocardiogram (ECG) or laboratory tests at Screening * Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Awake Objective Cough Frequency on Log-transformed Scale | Period 1: baseline (Day 0) and 24 hours after Day 4, 8, 12, 16 doses ; Period 2: baseline (Day 30) and 24 hours after Day 34, 38, 42, 46 doses | Change in awake cough frequency (average hourly cough frequency while the subject is awake ) evaluated using the VitaloJAK cough monitor with 24-hour sound recordings collected |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | Period 1: baseline (Day 0) and 24 hours after Day 4, 8, 12, 16 doses ; Period 2: baseline (Day 30) and 24 hours after Day 34, 38, 42, 46 doses | Change in awake cough frequency (average hourly cough frequency while the subject is awake) in the a pre-specified subgroup of participants with awake cough frequency \> or = 20 coughs/hour at baseline evaluated using the VitaloJAK cough monitor with 24-hour sound recordings collected |
| Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | Period 1: baseline (Day 0) and 24 hours after Day 4, 8, 12,16 doses ; Period 2: baseline (Day 30) and 24 hours after Day 34, 38, 42, 46 doses | Change in awake cough frequency (average hourly cough frequency while the subject is awake) in the a pre-specified subgroup of participants with awake cough frequency \> or = median (32.4 coughs/hour) at baseline evaluated using the VitaloJAK cough monitor with 24-hour sound recordings collected |
Countries
United Kingdom, United States
Participant flow
Recruitment details
Participants were recruited at 16 clinical trial sites in the United-Kingdom and in United States.
Pre-assignment details
A total of 68 participants were randomized to receive the study drug (BLU-5937) followed by placebo (33 participants) or placebo followed by the study drug (35 participants).
Participants by arm
| Arm | Count |
|---|---|
| BLU-5937 > Placebo Randomized crossover design of 4 different doses (25, 50, 100, 200 mg BID) of BLU-5937 tablets to be administered orally BID
BLU-5937: Four escalating doses of BLU-5937 administered BID over the course of the study followed by matching Placebo | 33 |
| Placebo > BLU-5937 Randomized crossover design of matching placebo tablets to be administered orally BID
Placebo: Matching placebo for BLU-5937 followed by four escalating doses of BLU-5937 | 35 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Physician Decision | 1 | 1 |
| Period 1 | Protocol Violation | 1 | 0 |
| Period 1 | Study terminated by Sponsor | 1 | 3 |
| Period 1 | Withdrawal by Subject | 4 | 3 |
| Period 2 | Study terminated by Sponsor | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo > BLU-5937 | Total | BLU-5937 > Placebo |
|---|---|---|---|
| Age, Continuous | 63.7 years STANDARD_DEVIATION 9.7 | 64.0 years STANDARD_DEVIATION 10.53 | 64.3 years STANDARD_DEVIATION 11.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 63 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 33 Participants | 66 Participants | 33 Participants |
| Sex: Female, Male Female | 30 Participants | 58 Participants | 28 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 61 | 0 / 60 | 0 / 58 | 0 / 61 |
| other Total, other adverse events | 10 / 61 | 14 / 61 | 15 / 60 | 10 / 58 | 19 / 61 |
| serious Total, serious adverse events | 0 / 61 | 0 / 61 | 0 / 60 | 0 / 58 | 1 / 61 |
Outcome results
Primary
Change in Awake Objective Cough Frequency on Log-transformed Scale
Change in awake cough frequency (average hourly cough frequency while the subject is awake ) evaluated using the VitaloJAK cough monitor with 24-hour sound recordings collected
Time frame: Period 1: baseline (Day 0) and 24 hours after Day 4, 8, 12, 16 doses ; Period 2: baseline (Day 30) and 24 hours after Day 34, 38, 42, 46 doses
Population: Analysis population consisted of all randomized subjects who took at least one dose of study drug and provided at least one baseline and at least one post-baseline cough frequency measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BLU-5937 - 25 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.19 Log coughs/hour |
| Placebo Comparator - 25 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.07 Log coughs/hour |
| BLU-5937 - 50 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.20 Log coughs/hour |
| Placebo Comparator - 50 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.14 Log coughs/hour |
| BLU-5937 - 100 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.25 Log coughs/hour |
| Placebo Comparator - 100 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.17 Log coughs/hour |
| BLU-5937 - 200 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.33 Log coughs/hour |
| Placebo Comparator - 200 mg | Change in Awake Objective Cough Frequency on Log-transformed Scale | -0.14 Log coughs/hour |
p-value: 0.142495% CI: [-23.5, 4]Mixed Models Analysis
p-value: 0.460295% CI: [-20.8, 11.2]Mixed Models Analysis
p-value: 0.418195% CI: [-24.4, 12.5]Mixed Models Analysis
p-value: 0.085595% CI: [-32.3, 2.6]Mixed Models Analysis
Other Pre-specified
Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline
Change in awake cough frequency (average hourly cough frequency while the subject is awake) in the a pre-specified subgroup of participants with awake cough frequency \> or = 20 coughs/hour at baseline evaluated using the VitaloJAK cough monitor with 24-hour sound recordings collected
Time frame: Period 1: baseline (Day 0) and 24 hours after Day 4, 8, 12, 16 doses ; Period 2: baseline (Day 30) and 24 hours after Day 34, 38, 42, 46 doses
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BLU-5937 - 25 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | -0.23 Log coughs/hour |
| Placebo Comparator - 25 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | 0.00 Log coughs/hour |
| BLU-5937 - 50 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | -0.29 Log coughs/hour |
| Placebo Comparator - 50 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | -0.09 Log coughs/hour |
| BLU-5937 - 100 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | -0.33 Log coughs/hour |
| Placebo Comparator - 100 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | -0.12 Log coughs/hour |
| BLU-5937 - 200 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | -0.41 Log coughs/hour |
| Placebo Comparator - 200 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = 20 Coughs/Hour at Baseline | -0.09 Log coughs/hour |
p-value: 0.00195% CI: [-29.9, -9.5]Mixed Models Analysis
p-value: 0.018695% CI: [-29.9, -3.3]Mixed Models Analysis
p-value: 0.03295% CI: [-33.9, -1.9]Mixed Models Analysis
p-value: 0.002695% CI: [-40.3, -10.8]Mixed Models Analysis
Other Pre-specified
Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline
Change in awake cough frequency (average hourly cough frequency while the subject is awake) in the a pre-specified subgroup of participants with awake cough frequency \> or = median (32.4 coughs/hour) at baseline evaluated using the VitaloJAK cough monitor with 24-hour sound recordings collected
Time frame: Period 1: baseline (Day 0) and 24 hours after Day 4, 8, 12,16 doses ; Period 2: baseline (Day 30) and 24 hours after Day 34, 38, 42, 46 doses
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BLU-5937 - 25 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | -0.31 Log coughs/hour |
| Placebo Comparator - 25 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | 0.02 Log coughs/hour |
| BLU-5937 - 50 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | -0.42 Log coughs/hour |
| Placebo Comparator - 50 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | -0.08 Log coughs/hour |
| BLU-5937 - 100 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | -0.44 Log coughs/hour |
| Placebo Comparator - 100 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | -0.09 Log coughs/hour |
| BLU-5937 - 200 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | -0.49 Log coughs/hour |
| Placebo Comparator - 200 mg | Change in Awake Cough Frequency on Log-transformed Scale in the Subgroup of Participants With Awake Cough Frequency > or = Median (32.4 Coughs/Hour) at Baseline | -0.10 Log coughs/hour |
p-value: 0.000595% CI: [-39.5, -14.5]Mixed Models Analysis
p-value: 0.000395% CI: [-39.7, -15]Mixed Models Analysis
p-value: 0.001495% CI: [-42.7, -13.2]Mixed Models Analysis
p-value: 0.000695% CI: [-45.3, -16.4]Mixed Models Analysis