Non-Cystic Fibrosis Bronchiectasis
Conditions
Keywords
ASPEN, Brensocatib, INS1007
Brief summary
The primary objective of this study is to evaluate the effect of brensocatib at 10 mg and 25 mg compared with placebo on the rate of pulmonary exacerbations (PEs) over the 52-week treatment period.
Interventions
Oral tablet.
Oral tablet.
DRUGPlacebo
Brensocatib-matching oral tablet.
Sponsors
Insmed Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Provide their signed study informed consent to participate. a. Adolescent participants must have signed study assent form to participate, and the adolescent's parent or legal guardian must have provided signed informed consent for the adolescent to participate. 2. Clinical history consistent with non-cystic fibrosis bronchiectasis (NCFBE) (cough, chronic sputum production and/or recurrent respiratory infections) that is confirmed by chest computerized tomography (CT) scan. 3. At least 2 PEs defined by need for antibiotic prescription by a physician for the signs and symptoms of respiratory infections in the past 12 months before the Screening Visit. a. Adolescent participants are required to have at least 1 pulmonary exacerbation in the prior 12 months. 4. Women must be postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, or using highly effective contraception (ie, methods that can achieve a failure rate \<1% per year when used consistently and correctly) from Day 1 to at least 90 days after the last dose. 5. Male participants with female partners of childbearing potential must be using effective contraception from Day 1 to at least 90 days after the last dose. 6. Male participants with pregnant or non-pregnant women of child-bearing potential partners must use condoms to avoid potential exposure to the embryo/fetus.
Exclusion criteria
1. A primary diagnosis of chronic obstructive pulmonary disease (COPD) or asthma as judged by the Investigator. 2. Bronchiectasis due to cystic fibrosis. 3. Current smokers as defined per Centers for Disease Control (CDC). 4. Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections. 5. Known history of human immunodeficiency virus (HIV) infection. 6. Currently being treated for nontuberculous mycobacteria (NTM) lung infection, allergic bronchopulmonary aspergillosis, or tuberculosis (TB). 7. Active and current symptomatic infection by 2019 corona virus disease (COVID-19). 8. Inability to follow the procedures of the study (eg, due to language problems or psychological disorders). 9. Receiving medications or therapy that are prohibited as concomitant medications. 10. Previously participated in a clinical trial for brensocatib. 11. Received any live attenuated vaccine within 4 weeks prior to the first administration of brensocatib. 12. Suffering an exacerbation 4 weeks before Screening or during the Screening period. 13. Adult participants only: Have compliance issues with completion of electronic diary entries during the Screening Period and in the opinion of the Investigator, compliance is unlikely to improve during the study. 14. Participated in any other interventional clinical studies within 3 months before Screening Visit. 15. History of alcohol or drug abuse within 6 months prior to the Screening Visit. 16. Is the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study. 17. Known history of hypersensitivity to brensocatib or any of its excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Pulmonary Exacerbations (PEs) | Up to Week 52 | PE was defined as having 3 or more of these symptoms for at least 48 hours resulting in a physician's decision to prescribe antibiotics: 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis. A severe pulmonary exacerbation was that required intravenous (IV) antibacterial drug treatment and/or hospitalization. A minimum of 14 days must have occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 14 days from the prior exacerbation was not considered a new exacerbation. Independent adjudication committee with pulmonary physicians adjudicated reported PE events to see if they fulfil the protocol definition. The rate of PE was analyzed using the negative binomial model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Responder Status for Exacerbation-Free Over the 52-Week Treatment Period | Up to Week 52 | Responder status was based on percentage of participants who were exacerbation free over 52-weeks of treatment period. Pulmonary exacerbation was defined as having 3 or more of the following symptoms for at least 48 hours resulting in a physician's decision to prescribe antibiotics: 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis. A minimum of 14 days must have occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 14 days from the prior exacerbation was not considered a new exacerbation. Independent adjudication committee of pulmonary physicians adjudicated reported PE events to see if they fulfill protocol definition. For discontinuation prior to Week 52 without having experienced a confirmed PE, responder status was imputed by multiple imputation. |
| Change From Baseline at Week 52 in Postbronchodilator Forced Expiratory Volume in 1 Second (FEV1) | Baseline, Week 52 | FEV1 was used to assess lung function and is the maximum amount of air that can be forced out in one second after first second after taking a forced expiration as measured by spirometer. Postbronchodilator FEV1 tests included spirometry tests performed referred to the spirometry performed within 30 minutes after administration of bronchodilator (4 puffs of salbutamol/albuterol, terbutaline or ipratropium). A positive change from baseline indicates an improvement in lung function. Baseline was the most recent non-missing assessment determined as best effort prior to the first dose of the investigational product. |
| Annualized Rate of Severe PEs | Up to Week 52 | Pulmonary exacerbation was defined as having 3 or more of the following symptoms for at least 48 hours resulting in a physician's decision to prescribe antibiotics: 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis. A severe PE was defined as those requiring IV antibacterial drug treatment and/or hospitalization. A minimum of 14 days must have occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 14 days from the prior exacerbation was not considered a new exacerbation. Independent adjudication committee with pulmonary physicians adjucated reported PE events to see if they fulfil the protocol definition. The rate of PE was analyzed using the negative binomial model. |
| Change From Baseline at Week 52 in Quality of Life Questionnaire - Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score in Adult Participants | Baseline, Week 52 | The QOL-B is a validated, self-administered patient-reported outcome (PRO) that assesses symptoms, functioning, and health-related quality of life for participants with non-cystic fibrosis bronchiectasis (NCFBE). It contains 37 items in 8 domains (Respiratory Symptoms, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning, Vitality, Health Perceptions and Treatment Burden). Each of the 37 items is scored from 1 to 4, and each of the 8 domains scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning. A positive change from Baseline indicates improvement in symptoms. For this outcome measure, change in the respiratory symptoms domain score from Baseline was reported. Baseline refers to most recent assessment on or before study Day 1. |
| Time to First PE | Up to Week 52 | PE was defined as having 3 or more of following symptoms for at least 48 hours resulting in physician's decision to prescribe antibiotics:1.Increased cough2.Increased sputum volume or change in sputum consistency3.Increased sputum purulence4.Increased breathlessness &/or decreased exercise tolerance5.Fatigue &/or malaise6.Hemoptysis.Severe PE were those requiring IV antibacterial drug treatment &/or hospitalization. Minimum of 14 days must have occurred between one exacerbation onset and next. Any exacerbation that occurred within 14 days of prior exacerbation was not considered a new exacerbation. Time to first PE was calculated from randomization date to onset date of the first exacerbation. Participants who did not have exacerbation at end of 52-week treatment period were considered as censored at date of Week 52 in Cox proportional hazard model. Independent adjudication committee with pulmonary physicians adjudicated reported PE events to see if they fulfil protocol definition. |
| Plasma Concentration of Brensocatib in Adults (Main Study) | 2 hours (h) post-dose on Day 1; Pre-dose and 2 h post-dose at Weeks 4, 28 and 40; Pre-dose at Weeks 16 and 52 | — |
| Plasma Concentration of Brensocatib in Adults (PK Substudy) | 0.5 h, 2 h, and 4 to 8 h post-dose on Day 1and at Week 28; Pre-dose and 2 h post-dose at Weeks 4 and 48; Pre-dose at Weeks 16 and 52 | — |
| Plasma Concentration of Brensocatib in Adolescents (Main Study) | 0.5 h, 2 h, and 4 to 8 h post-dose on Day 1 and at Week 28; Pre-dose and 2 h post-dose at Weeks 4 and 48; Pre-dose at Weeks 16 and 52 | — |
| Number of Participants Who Experienced at Least One Treatment-Emergent Adverse Events (TEAEs) | Up to Week 56 | An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs are AEs that occurred on or after the date of first dose of study drugs and within 28 days after the end of treatment. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Latvia, Malaysia, Mexico, Netherlands, New Zealand, Peru, Poland, Portugal, Serbia, Slovakia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 373 sites in 36 countries from 01 Dec 2020 to 28 Oct 2024.
Pre-assignment details
A total of 2296 participants were screened, 1767 participants with non-cystic fibrosis bronchiectasis were enrolled in the study. Due to the war in Ukraine, 44 participants from Ukraine were discontinued and excluded from all analyses. There were 2 additional participants who were excluded from all analyses due to serious Good Clinical Practice (GCP) non-compliance. A total of 1721 participants were randomized and analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Brensocatib 10 mg Participants received brensocatib 10 mg tablets, orally, once daily, for 52 weeks. | 583 |
| Brensocatib 25 mg Participants received brensocatib 25 mg tablets orally, once daily, for 52 weeks. | 575 |
| Placebo Participants received a brensocatib matching placebo tablets orally, once daily, for 52 weeks. | 563 |
| Total | 1,721 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 10 | 9 |
| Overall Study | Death | 2 | 4 | 8 |
| Overall Study | Lost to Follow-up | 10 | 2 | 4 |
| Overall Study | Physician Decision | 2 | 2 | 3 |
| Overall Study | Protocol deviation | 1 | 3 | 2 |
| Overall Study | Reason not specified | 60 | 56 | 43 |
| Overall Study | Withdrawal by Subject | 40 | 32 | 37 |
Baseline characteristics
| Characteristic | Brensocatib 10 mg | Total | Placebo | Brensocatib 25 mg |
|---|---|---|---|---|
| Age, Continuous | 59.8 Years STANDARD_DEVIATION 15.92 | 60.2 Years STANDARD_DEVIATION 15.72 | 60.0 Years STANDARD_DEVIATION 15.44 | 60.6 Years STANDARD_DEVIATION 15.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 177 Participants | 511 Participants | 170 Participants | 164 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 391 Participants | 1161 Participants | 373 Participants | 397 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 49 Participants | 20 Participants | 14 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 8 Participants | 23 Participants | 9 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Asian | 63 Participants | 191 Participants | 64 Participants | 64 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 10 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Race More than one race | 15 Participants | 37 Participants | 11 Participants | 11 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 15 Participants | 39 Participants | 11 Participants | 13 Participants |
| Race/Ethnicity, Customized Race Unknown or Not Reported | 48 Participants | 153 Participants | 59 Participants | 46 Participants |
| Race/Ethnicity, Customized Race White | 431 Participants | 1266 Participants | 405 Participants | 430 Participants |
| Sex: Female, Male Female | 385 Participants | 1107 Participants | 362 Participants | 360 Participants |
| Sex: Female, Male Male | 198 Participants | 614 Participants | 201 Participants | 215 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 582 | 4 / 574 | 8 / 563 |
| other Total, other adverse events | 197 / 582 | 213 / 574 | 203 / 563 |
| serious Total, serious adverse events | 101 / 582 | 97 / 574 | 108 / 563 |
Outcome results
Primary
Annualized Rate of Pulmonary Exacerbations (PEs)
PE was defined as having 3 or more of these symptoms for at least 48 hours resulting in a physician's decision to prescribe antibiotics: 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis. A severe pulmonary exacerbation was that required intravenous (IV) antibacterial drug treatment and/or hospitalization. A minimum of 14 days must have occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 14 days from the prior exacerbation was not considered a new exacerbation. Independent adjudication committee with pulmonary physicians adjudicated reported PE events to see if they fulfil the protocol definition. The rate of PE was analyzed using the negative binomial model.
Time frame: Up to Week 52
Population: The ITT analysis set included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brensocatib 10 mg | Annualized Rate of Pulmonary Exacerbations (PEs) | 1.015 exacerbation per participant-year |
| Brensocatib 25 mg | Annualized Rate of Pulmonary Exacerbations (PEs) | 1.036 exacerbation per participant-year |
| Placebo | Annualized Rate of Pulmonary Exacerbations (PEs) | 1.286 exacerbation per participant-year |
Comparison: Model treatment \& randomization stratification factor=geographic region, sputum sample (Pseudomonas aeruginosa) at start \& PE last 12 months, age group (fixed effects) \& time at risk (log scale) as offset variable. Robust sandwich covariance estimator used.p-value: =0.001995% CI: [0.68, 0.916]Negative binomial regression
Comparison: Model treatment \& randomization stratification factor=geographic region, sputum sample (Pseudomonas aeruginosa) at start \& PE last 12 months, age group (fixed effects) \& time at risk (log scale) as offset variable. Robust sandwich covariance estimator used.p-value: =0.004695% CI: [0.694, 0.936]Negative binomial regression
Secondary
Annualized Rate of Severe PEs
Pulmonary exacerbation was defined as having 3 or more of the following symptoms for at least 48 hours resulting in a physician's decision to prescribe antibiotics: 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis. A severe PE was defined as those requiring IV antibacterial drug treatment and/or hospitalization. A minimum of 14 days must have occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 14 days from the prior exacerbation was not considered a new exacerbation. Independent adjudication committee with pulmonary physicians adjucated reported PE events to see if they fulfil the protocol definition. The rate of PE was analyzed using the negative binomial model.
Time frame: Up to Week 52
Population: The ITT analysis set included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brensocatib 10 mg | Annualized Rate of Severe PEs | 0.137 exacerbation per participant-year |
| Brensocatib 25 mg | Annualized Rate of Severe PEs | 0.137 exacerbation per participant-year |
| Placebo | Annualized Rate of Severe PEs | 0.185 exacerbation per participant-year |
Comparison: Analysis based on a negative binomial model including treatment, sputum sample for Pseudomonas aeruginosa at screening, PE \[\<3 or ≥3\] in previous 12 months, stratification region and age group. Robust sandwich covariance estimator used.p-value: =0.127795% CI: [0.505, 1.089]Negative binomial regression
Comparison: Analysis based on a negative binomial model including treatment, sputum sample for Pseudomonas aeruginosa at screening, PE \[\<3 or ≥3\] in previous 12 months, stratification region and age group. Robust sandwich covariance estimator used.p-value: =0.102595% CI: [0.515, 1.062]Negative binomial regression
Secondary
Change From Baseline at Week 52 in Postbronchodilator Forced Expiratory Volume in 1 Second (FEV1)
FEV1 was used to assess lung function and is the maximum amount of air that can be forced out in one second after first second after taking a forced expiration as measured by spirometer. Postbronchodilator FEV1 tests included spirometry tests performed referred to the spirometry performed within 30 minutes after administration of bronchodilator (4 puffs of salbutamol/albuterol, terbutaline or ipratropium). A positive change from baseline indicates an improvement in lung function. Baseline was the most recent non-missing assessment determined as best effort prior to the first dose of the investigational product.
Time frame: Baseline, Week 52
Population: The ITT analysis set included all participants who were randomized. 'Overall number of participants analyzed' indicates the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brensocatib 10 mg | Change From Baseline at Week 52 in Postbronchodilator Forced Expiratory Volume in 1 Second (FEV1) | -0.050 liter (L) | Standard Error 0.0093 |
| Brensocatib 25 mg | Change From Baseline at Week 52 in Postbronchodilator Forced Expiratory Volume in 1 Second (FEV1) | -0.024 liter (L) | Standard Error 0.0099 |
| Placebo | Change From Baseline at Week 52 in Postbronchodilator Forced Expiratory Volume in 1 Second (FEV1) | -0.062 liter (L) | Standard Error 0.0094 |
Comparison: Analysis on linear repeated measure model=treatment visit, sputum sample for Pseudomonas aeruginosa at start, PE \[\<3 or ≥3\] last 12 months, stratification region, age group (fixed effect) \& baseline (covariate). Robust sandwich covariance estimator used.p-value: =0.384195% CI: [-0.014, 0.037]Linear repeated measures model
Comparison: Analysis on linear repeated measure model=treatment visit, sputum sample for Pseudomonas aeruginosa at start, PE \[\<3 or ≥3\] last 12 months, stratification region, age group (fixed effect) \& baseline (covariate). Robust sandwich covariance estimator used.p-value: =0.005495% CI: [0.011, 0.065]Linear repeated measures model
Secondary
Change From Baseline at Week 52 in Quality of Life Questionnaire - Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score in Adult Participants
The QOL-B is a validated, self-administered patient-reported outcome (PRO) that assesses symptoms, functioning, and health-related quality of life for participants with non-cystic fibrosis bronchiectasis (NCFBE). It contains 37 items in 8 domains (Respiratory Symptoms, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning, Vitality, Health Perceptions and Treatment Burden). Each of the 37 items is scored from 1 to 4, and each of the 8 domains scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning. A positive change from Baseline indicates improvement in symptoms. For this outcome measure, change in the respiratory symptoms domain score from Baseline was reported. Baseline refers to most recent assessment on or before study Day 1.
Time frame: Baseline, Week 52
Population: The ITT analysis set included all participants who were randomised. Overall number of participants analyzed indicates the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brensocatib 10 mg | Change From Baseline at Week 52 in Quality of Life Questionnaire - Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score in Adult Participants | 6.841 score on scale | Standard Error 0.7706 |
| Brensocatib 25 mg | Change From Baseline at Week 52 in Quality of Life Questionnaire - Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score in Adult Participants | 8.575 score on scale | Standard Error 0.7556 |
| Placebo | Change From Baseline at Week 52 in Quality of Life Questionnaire - Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score in Adult Participants | 4.809 score on scale | Standard Error 0.75 |
Comparison: Analysis based on a linear repeated measures model with treatment group, visit, sputum sample for Pseudomonas aeruginosa at screening, pulmonary exacerbations \[\<3 or ≥3\] in previous 12 months, stratification region fixed effect, baseline as covariate.p-value: =0.059495% CI: [-0.081, 4.143]linear repeated measures model
Comparison: Analysis based on a linear repeated measures model with treatment group, visit, sputum sample for Pseudomonas aeruginosa at screening, pulmonary exacerbations \[\<3 or ≥3\] in previous 12 months, stratification region fixed effect, baseline as covariate.p-value: =0.000495% CI: [1.68, 5.852]linear repeated measures model
Secondary
Number of Participants Who Experienced at Least One Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs are AEs that occurred on or after the date of first dose of study drugs and within 28 days after the end of treatment.
Time frame: Up to Week 56
Population: The Safety analysis set included all participants who were randomized and received at least 1 dose of brensocatib or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brensocatib 10 mg | Number of Participants Who Experienced at Least One Treatment-Emergent Adverse Events (TEAEs) | 452 Participants |
| Brensocatib 25 mg | Number of Participants Who Experienced at Least One Treatment-Emergent Adverse Events (TEAEs) | 440 Participants |
| Placebo | Number of Participants Who Experienced at Least One Treatment-Emergent Adverse Events (TEAEs) | 448 Participants |
Secondary
Plasma Concentration of Brensocatib in Adolescents (Main Study)
Time frame: 0.5 h, 2 h, and 4 to 8 h post-dose on Day 1 and at Week 28; Pre-dose and 2 h post-dose at Weeks 4 and 48; Pre-dose at Weeks 16 and 52
Population: The PK concentration analysis set included adolescent participants who consented to participate in the main study and received at least 1 dose of brensocatib, and had at least 1 postdose plasma concentration of brensocatib. 'Overall number of participants analyzed' indicates the number of participants with data available for analysis. 'Number analyzed' signifies number of adolescent participants with data available for analysis at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Day 1: 4-8 h post-dose | 56.07 ng/ml | Geometric Coefficient of Variation 24.1 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: 0.5 h post-dose | 123.4 ng/ml | Geometric Coefficient of Variation 49.1 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 4: 2 h post-dose | 134.9 ng/ml | Geometric Coefficient of Variation 52.8 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: 2 h post-dose | 118.5 ng/ml | Geometric Coefficient of Variation 30.5 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Day 1: 2 h post-dose | 68.33 ng/ml | Geometric Coefficient of Variation 32.5 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: 4-8 h post-dose | 115.4 ng/ml | Geometric Coefficient of Variation 27.7 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 16: Pre-dose | 40.62 ng/ml | Geometric Coefficient of Variation 51.6 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 40: Pre-dose | 37.30 ng/ml | Geometric Coefficient of Variation 52.5 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 4: Pre-dose | 44.10 ng/ml | Geometric Coefficient of Variation 64.2 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 40: 2 h post-dose | 110.4 ng/ml | Geometric Coefficient of Variation 43.9 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: Pre-dose | 43.74 ng/ml | Geometric Coefficient of Variation 57.2 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 52: Pre-dose | 43.02 ng/ml | Geometric Coefficient of Variation 64.8 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Day 1: 0.5 h post-dose | 63.20 ng/ml | Geometric Coefficient of Variation 51.7 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 52: Pre-dose | 104.0 ng/ml | Geometric Coefficient of Variation 57.8 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Day 1: 0.5 h post-dose | 109.3 ng/ml | Geometric Coefficient of Variation 139.1 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Day 1: 2 h post-dose | 202.5 ng/ml | Geometric Coefficient of Variation 50.7 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Day 1: 4-8 h post-dose | 196.1 ng/ml | Geometric Coefficient of Variation 52.4 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 4: Pre-dose | 126.6 ng/ml | Geometric Coefficient of Variation 90.4 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 4: 2 h post-dose | 432.9 ng/ml | Geometric Coefficient of Variation 44.3 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 16: Pre-dose | 158.1 ng/ml | Geometric Coefficient of Variation 95.7 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: Pre-dose | 132.9 ng/ml | Geometric Coefficient of Variation 96.3 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: 0.5 h post-dose | 321.6 ng/ml | Geometric Coefficient of Variation 93.8 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: 2 h post-dose | 336.9 ng/ml | Geometric Coefficient of Variation 77.7 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 28: 4-8 h post-dose | 309.9 ng/ml | Geometric Coefficient of Variation 48 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 40: Pre-dose | 84.39 ng/ml | Geometric Coefficient of Variation 102.3 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adolescents (Main Study) | Week 40: 2 h post-dose | 262.8 ng/ml | Geometric Coefficient of Variation 77.6 |
Secondary
Plasma Concentration of Brensocatib in Adults (Main Study)
Time frame: 2 hours (h) post-dose on Day 1; Pre-dose and 2 h post-dose at Weeks 4, 28 and 40; Pre-dose at Weeks 16 and 52
Population: The Pharmacokinetics (PK) concentration analysis set included adult participants who consented to participate in the main study in adult's cohort, received at least 1 dose of brensocatib, and had at least 1 postdose plasma concentration of brensocatib. 'Overall number of participants analyzed' indicates the number of participants with data available for analysis. 'Number analyzed' signifies number of adult participants with data available for analysis at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 4: Pre-dose | 52.60 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 68.7 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 28: 2 h post-dose | 91.79 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 45.3 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 16: Pre-dose | 45.19 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 55 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 40: Pre-dose | 45.71 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 54.2 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 4: 2 h post-dose | 100.5 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 32.8 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 40: 2 h post-dose | 107.3 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 45 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Pre-dose at Week 28 | 49.30 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 63.9 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 52: Pre-dose | 45.78 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 61.7 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Day 1: 2 h post-dose | 40.52 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 69.1 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 52: Pre-dose | 135.4 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 60.3 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Day 1: 2 h post-dose | 134.9 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 51.4 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 4: Pre-dose | 157.4 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 70.8 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 4: 2 h post-dose | 293.6 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 35.1 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 16: Pre-dose | 131.6 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 69 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Pre-dose at Week 28 | 143.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 64.6 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 28: 2 h post-dose | 323.7 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 40.1 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 40: Pre-dose | 136.8 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 63.4 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (Main Study) | Week 40: 2 h post-dose | 302.6 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 40.7 |
Secondary
Plasma Concentration of Brensocatib in Adults (PK Substudy)
Time frame: 0.5 h, 2 h, and 4 to 8 h post-dose on Day 1and at Week 28; Pre-dose and 2 h post-dose at Weeks 4 and 48; Pre-dose at Weeks 16 and 52
Population: The PK concentration analysis set included adult participants who consented to participate in the PK substudy and received at least 1 dose of brensocatib, and had at least 1 postdose plasma concentration of brensocatib. 'Overall number of participants analyzed' indicates the number of participants with data available for analysis. 'Number analyzed' signifies number of adult participants with data available for analysis at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 4: Pre-dose | 57.53 ng/ml | Geometric Coefficient of Variation 53.4 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: 0.5 h post-dose | 89.75 ng/ml | Geometric Coefficient of Variation 46 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Day 1: 4-8 h post-dose | 38.13 ng/ml | Geometric Coefficient of Variation 52.9 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: 2 h post-dose | 95.33 ng/ml | Geometric Coefficient of Variation 35.3 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 4: 2 h post-dose | 100.3 ng/ml | Geometric Coefficient of Variation 44.1 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: 4-8 h post-dose | 86.27 ng/ml | Geometric Coefficient of Variation 40.7 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Day 1: 2 h post-dose | 44.52 ng/ml | Geometric Coefficient of Variation 55 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 40: Pre-dose | 51.80 ng/ml | Geometric Coefficient of Variation 54.4 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 16: Pre-dose | 50.24 ng/ml | Geometric Coefficient of Variation 58.1 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 40: 2 h post-dose | 93.74 ng/ml | Geometric Coefficient of Variation 32.1 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Day 1: 0.5 h post-dose | 34.51 ng/ml | Geometric Coefficient of Variation 97.9 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 52: Pre-dose | 49.93 ng/ml | Geometric Coefficient of Variation 72.2 |
| Brensocatib 10 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: Pre-dose | 50.33 ng/ml | Geometric Coefficient of Variation 54.7 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 52: Pre-dose | 131.6 ng/ml | Geometric Coefficient of Variation 56.5 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Day 1: 0.5 h post-dose | 85.13 ng/ml | Geometric Coefficient of Variation 103.5 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Day 1: 4-8 h post-dose | 108.5 ng/ml | Geometric Coefficient of Variation 46.9 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 4: Pre-dose | 131.3 ng/ml | Geometric Coefficient of Variation 60.2 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 4: 2 h post-dose | 286.7 ng/ml | Geometric Coefficient of Variation 38.4 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 16: Pre-dose | 138.0 ng/ml | Geometric Coefficient of Variation 64.5 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: Pre-dose | 124.6 ng/ml | Geometric Coefficient of Variation 59.8 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: 0.5 h post-dose | 235.5 ng/ml | Geometric Coefficient of Variation 53.3 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: 2 h post-dose | 271.9 ng/ml | Geometric Coefficient of Variation 46 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 28: 4-8 h post-dose | 246.4 ng/ml | Geometric Coefficient of Variation 43.7 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 40: Pre-dose | 119.3 ng/ml | Geometric Coefficient of Variation 51.3 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Week 40: 2 h post-dose | 271.2 ng/ml | Geometric Coefficient of Variation 45 |
| Brensocatib 25 mg | Plasma Concentration of Brensocatib in Adults (PK Substudy) | Day 1: 2 h post-dose | 120.0 ng/ml | Geometric Coefficient of Variation 56.2 |
Secondary
Responder Status for Exacerbation-Free Over the 52-Week Treatment Period
Responder status was based on percentage of participants who were exacerbation free over 52-weeks of treatment period. Pulmonary exacerbation was defined as having 3 or more of the following symptoms for at least 48 hours resulting in a physician's decision to prescribe antibiotics: 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis. A minimum of 14 days must have occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 14 days from the prior exacerbation was not considered a new exacerbation. Independent adjudication committee of pulmonary physicians adjudicated reported PE events to see if they fulfill protocol definition. For discontinuation prior to Week 52 without having experienced a confirmed PE, responder status was imputed by multiple imputation.
Time frame: Up to Week 52
Population: The ITT analysis set included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brensocatib 10 mg | Responder Status for Exacerbation-Free Over the 52-Week Treatment Period | 48.5 percentage of participants |
| Brensocatib 25 mg | Responder Status for Exacerbation-Free Over the 52-Week Treatment Period | 48.5 percentage of participants |
| Placebo | Responder Status for Exacerbation-Free Over the 52-Week Treatment Period | 40.3 percentage of participants |
Comparison: Missing responder status was imputed 100 times. Dataset was analyzed via logistic regression with treatment group, sputum P. aeruginosa status, prior PEs (\<3/≥3), region, and age group as fixed effects. Results were then combined using Rubin's rules.p-value: =0.005995% CI: [1.105, 1.806]Logistic Regression
Comparison: Missing responder status was imputed 100 times. Dataset was analyzed via logistic regression with treatment group, sputum P. aeruginosa status, prior PEs (\<3/≥3), region, and age group as fixed effects. Results were then combined using Rubin's rules.p-value: =0.007495% CI: [1.095, 1.792]Logistic Regression
Secondary
Time to First PE
PE was defined as having 3 or more of following symptoms for at least 48 hours resulting in physician's decision to prescribe antibiotics:1.Increased cough2.Increased sputum volume or change in sputum consistency3.Increased sputum purulence4.Increased breathlessness &/or decreased exercise tolerance5.Fatigue &/or malaise6.Hemoptysis.Severe PE were those requiring IV antibacterial drug treatment &/or hospitalization. Minimum of 14 days must have occurred between one exacerbation onset and next. Any exacerbation that occurred within 14 days of prior exacerbation was not considered a new exacerbation. Time to first PE was calculated from randomization date to onset date of the first exacerbation. Participants who did not have exacerbation at end of 52-week treatment period were considered as censored at date of Week 52 in Cox proportional hazard model. Independent adjudication committee with pulmonary physicians adjudicated reported PE events to see if they fulfil protocol definition.
Time frame: Up to Week 52
Population: The ITT analysis set included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brensocatib 10 mg | Time to First PE | 49.000 weeks |
| Brensocatib 25 mg | Time to First PE | 50.714 weeks |
| Placebo | Time to First PE | 36.714 weeks |
Comparison: Estimate of Cox proportional hazard model=effect for treatment, sputum sample for Pseudomonas aeruginosa at screening and PE \[\<3 or ≥3\] in last 12 months, stratification region and age group. Robust sandwich covariance estimator used.p-value: =0.0195% CI: [0.695, 0.952]Cox proportional hazard
Comparison: Estimate of Cox proportional hazard model=effect for treatment, sputum sample for Pseudomonas aeruginosa at screening and PE \[\<3 or ≥3\] in last 12 months, stratification region and age group. Robust sandwich covariance estimator used.p-value: =0.018295% CI: [0.703, 0.968]Cox proportional hazard