INS1007-301

Insmed Incorporated

700 US Highway 202/206, Bridgewater, United States, 08807-1704

Insmed Medical Information, Insmed Incorporated, +1 1-844-446-7633, medicalinformation@insmed.com

Insmed Medical Information, Insmed Incorporated, +1 1-844-446-7633, medicalinformation@insmed.com

Yes

No

No

Final

28 Oct 2024

No

Yes

28 Oct 2024

No

The primary objective of this study was to evaluate the effect of brensocatib at 10 milligram (mg) and 25 mg compared with placebo on the rate of pulmonary exacerbations (PEs) over the 52-week treatment period.

This trial was performed in compliance with Good Clinical Practice (GCP), including the archiving of essential documents, the International Council for Harmonisation (ICH) Guidelines, and is consistent with the ethical principles of the Declaration of Helsinki.

01 Dec 2020

No

Yes

Australia: 90

Argentina: 258

Austria: 2

Belgium: 25

Brazil: 45

Bulgaria: 85

Canada: 7

Chile: 78

Colombia: 19

Denmark: 48

France: 34

Germany: 75

Greece: 10

Hungary: 1

Ireland: 4

Israel: 84

Italy: 57

Japan: 87

Korea, Republic of: 45

Latvia: 2

Malaysia: 11

Mexico: 47

Netherlands: 19

New Zealand: 46

Peru: 41

Poland: 61

Portugal: 9

Serbia: 17

Slovakia: 3

Spain: 55

Taiwan: 27

Thailand: 6

Türkiye: 36

United Kingdom: 46

United States: 241

1721

490

0

0

0

0

0

41

841

832

7

Overall study (overall period)

Randomised - controlled

Yes

Brensocatib

INS1007

Film-coated tablet

Oral use

Participants received 10 mg tablets, once daily, for 52 weeks.

Brensocatib

INS1007

Film-coated tablet

Oral use

Participants received 25 mg tablets, once daily, for 52 weeks.

Placebo

Film-coated tablet

Oral use

Participants received brensocatib matching placebo tablets, once daily, for 52 weeks.

Brensocatib 10 mg

Brensocatib 25 mg

Placebo

Brensocatib 10 mg

Brensocatib 25 mg

Placebo

Pulmonary exacerbation 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 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 will adjudicate reported PE events to see if they fulfil the protocol definition. The rate of PE was analysed using the negative binomial model. The Intent-to-Treat (ITT) analysis set included all participants who were randomised.

Primary

Up to Week 52

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.

Brensocatib 25 mg v Placebo

1138

Pre-specified

0.806

2-sided

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.

Brensocatib 10 mg v Placebo

1146

Pre-specified

0.789

2-sided

PE was defined as 3 or more of these symptoms for at least 48 hours & physician's choice 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. Severe PE=IV antibacterial drug treatment and/or hospitalization. Minimum 14 days between one exacerbation onset and next. Any PE in less than 14 days from prior exacerbation was not considered new. Time to first PE=randomisation date to onset date of first exacerbation. Participants with no exacerbation at end of 52-week treatment were censored at Week 52. Independent adjudication committee with pulmonary physicians will adjudicate reported PE events to see if they fulfil the protocol definition.9999=upper limit of confidence interval was not computable. The ITT analysis set included all participants who were randomised.

Secondary

Up to Week 52

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.

Brensocatib 25 mg v Placebo

1138

Pre-specified

0.825

2-sided

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.

Brensocatib 10 mg v Placebo

1146

Pre-specified

0.813

2-sided

Responder status was based on percentage of participants who were exacerbation free over 52-weeks of treatment period. PE was defined as having 3 or more of these symptoms for at least 48 hours with 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. Minimum of 14 days must have occurred between one PE onset and the next. Any PE in less than 14 days from prior exacerbation was not considered new exacerbation. Independent adjudication committee of pulmonary physicians will adjudicate reported PE events to see if they fulfill protocol definition. For discontinuation prior to Week 52 without having experienced a confirmed PE, responder status imputed by multiple imputation. The ITT analysis set included all participants who were randomised.

Secondary

Up to Week 52

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.

Brensocatib 25 mg v Placebo

1138

Pre-specified

1.4

2-sided

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.

Brensocatib 10 mg v Placebo

1146

Pre-specified

1.412

2-sided

FEV1 was used to assess lung function and is the maximum amount of air that can be exhaled from the lungs in the 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). The ITT analysis set included all participants who were randomised. 'Number of subjects analysed' indicates the number of participants with data available for analyses. Baseline was the most recent non-missing assessment determined as best effort prior to the first dose of the investigational product.

Secondary

Baseline, Week 52

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.

Brensocatib 25 mg v Placebo

1090

Pre-specified

0.038

2-sided

Standard error of the mean

0.0136

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.

Brensocatib 10 mg v Placebo

1103

Pre-specified

0.011

2-sided

Standard error of the mean

0.0132

Pulmonary exacerbation 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 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 will adjudicate reported PE events to see if they fulfil the protocol definition. The rate of PE will be analysed using the negative binomial model. The ITT analysis set included all participants who were randomised.

Secondary

Up to Week 52

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.

Brensocatib 10 mg v Placebo

1146

Pre-specified

0.742

2-sided

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.

Brensocatib 25 mg v Placebo

1138

Pre-specified

0.74

2-sided

QOL-B is validated, self-administered patient-reported outcome (PRO) assessing symptoms, functioning, and health-related quality of life in participants with non-cystic fibrosis bronchiectasis (NCFBE). It includes 37 items across 8 domains: Respiratory Symptoms, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning, Vitality, Health Perceptions, and Treatment Burden. Each item is scored from 1 to 4, with domain scores standardized on 0-100 scale, where higher scores represent fewer symptoms or better functioning. Positive change from Baseline indicates improvement in symptoms. For this outcome, change in respiratory symptoms domain score from Baseline is reported. Baseline refers to most recent assessment on or before study day 1. ITT analysis set included all randomised adult participants, with 'Number of subjects analysed' is number of adult participants with data available for analyses.

Secondary

Baseline, Week 52

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.

Brensocatib 25 mg v Placebo

981

Pre-specified

3.766

2-sided

Standard error of the mean

1.0642

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.

Brensocatib 10 mg v Placebo

973

Pre-specified

2.031

2-sided

Standard error of the mean

1.0775

An adverse event (AE) was 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. The safety analysis set included all participants who were randomised and received at least 1 dose of brensocatib or placebo.

Secondary

Up to Week 56

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. 'Subjects analysed' included those adult participants who were evaluable for this endpoint. Here, 'n’ signifies number of adult participants analysed for this endpoint.

Secondary

2 hours (h) post-dose on Day 1; Pre-dose and 2 h post-dose at Week 28; Pre-dose and 2 h post-dose at Weeks 4 and 40; Pre-dose at Weeks 16 and 52

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. 'Subjects analysed' included those adult participants who were evaluable for this endpoint. Here, 'n’ signifies number of adult participants analysed for this endpoint.

Secondary

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

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.'Subjects analysed' included those adolescent participants who were evaluable for this endpoint. Here, 'n’ signifies number of adolescent participants analysed for this endpoint.

Secondary

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

Up to Week 56

The safety analysis set included all participants who were randomised and received at least 1 dose of brensocatib or placebo.

27.0

Brensocatib 10 mg

Placebo

Brensocatib 25 mg