A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, and Tolerability of Brensocatib Administered Once Daily for 52 Weeks in Subjects With Non-Cystic Fibrosis Bronchiectasis - The ASPEN Study
Phase: PHASE3
Conditions: Non-Cystic Fibrosis Bronchiectasis
Sponsor: Insmed Incorporated

Oﬃcial Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Eﬃcacy, Safety, and Tolerability of Brensocatib 
Administered Once Daily for 52 Weeks in Subjects With Non-Cystic 
Fibrosis Bronchiectasis - The ASPEN Study 
NCT Number: NCT04594369 
  Document Date: Protocol Version 7: 14 Feb 2024 

Signature Page for INS1007-301 Version 7.0 Global Protocol Amendment 4
Approve
14-Feb-2024 13:16:54 GMT+0000

CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy, Safety, and Tolerability of Brensocatib Administered Once Daily for 
52 Weeks in Subjects with Non-Cystic Fibrosis Bronchiectasis – The ASPEN 
Study 
 
Study Number INS1007-301 
 
IND Number: 133790 
EudraCT Number: 2020-003688-25 
ClinicalTrials.gov Identifier: NCT04594369 
 
Insmed Incorporated 
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
 
 
Version Number 
Amendment 
Date 
Global Amendment 4 
7.0 
4 
13 FEB 2024 
Global Amendment 3 
6.0 
3 
09 AUG 2022 
Global Amendment 2 
5.0 
2 
07 DEC 2021 
Global Amendment 1 
4.0 
1 
12 MAR 2021 
Original Protocol 
1.0 
 
31 JUL 2020 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Insmed Incorporated. The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement. Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Insmed Incorporated. 
 

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INVESTIGATOR’S AGREEMENT 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, 
and Tolerability of Brensocatib Administered Once Daily for 52 Weeks in Subjects with 
Non-Cystic Fibrosis Bronchiectasis – The ASPEN Study 
Investigator’s Signature: 
I have read and understood the current version of the protocol (as listed above). 
 
I understand that information contained in or pertaining to this protocol is confidential and 
should not be disclosed, other than to those directly involved in the execution or the ethical 
review of the study, without written authorization from the Sponsor. It is, however, permissible 
to provide information to a subject to obtain consent. 
I agree to conduct this study per this protocol and to comply with its requirements, subject to 
ethical and safety considerations and guidelines, and to conduct the study in accordance with the 
Declaration of Helsinki, the International Council for Harmonisation guidelines on Good Clinical 
Practice (ICH E6 [R2] GCP), and applicable local laws, regulations and guidelines. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects’ study records to verify the data that I have entered into the case report 
forms. I am aware of my responsibilities as an Investigator as provided by the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
 
 
 
 
 
 
Print Name 
 
Signature 
 
 
 
 
 
 
 
Title 
 
Date (DD MMM YYYY) 
 
 

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IMPORTANT CONTACTS 
 
Insmed Incorporated 
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
 
Insmed Medical Monitor and Clinical Operations 
Name 
Title 
Telephone  
e-Mail Address 
MD, MPH 
 
 

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Revision 
Rationale 
Location of Revision 
Clarified analysis for adult-only 
subgroup 
To align with Health Authority 
feedback 
• 
Section 10.4.6.5  
Added age group (adult, 
adolescent) as a potential 
covariate in the primary analysis 
model for the primary endpoint 
To align with Health Authority 
feedback 
• 
Synopsis 
• 
Section 10.4.6.1.2  
Removed safety estimand 
To remove unnecessary 
specification of safety estimand 
while the analyses remain 
unchanged as descriptive summary 
by each treatment group  
• 
Synopsis 
• 
Section 2.2  
• 
Section 10.4.7  
Updated end of study reference 
to end of Week 52 treatment 
period 
To fix typo and maintain 
consistency with statistical sections 
• 
Synopsis 
• 
Section 7.1  
Updated “Nonwhite” race to 
specific subcategories 
To align with agency guidances 
• 
Section 10.4.6.5  
Corrected footnoting in 
Schedule of Assessments and 
Procedures Table  
The footnoting associated with 
V11 and V12 has been corrected 
from “v” to “w” 
• 
Table 5  
Updated language for sample 
collection for biomarkers in 
sputum  
Removed "for substudy subjects 
only" and "for all newly enrolled 
and substudy subjects only", as this 
text is not applicable in the bulleted 
list  
• 
Section 8.4.1  
Updated the percentages 
regarding subject enrollment  
The enrollment target for North 
America, Western Europe, Asia 
Pacific and Latin America, and the 
enrollment cap for any single 
country (except the US) was 
increased to support 
implementation 
• 
Synopsis 
• 
Section 1.5  
• 
Section 3.1  
• 
Section 5.2  
• 
Section 10.1 

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PROTOCOL SYNOPSIS 
IND Number: 
EudraCT Number: 
133790 
2020-003688-25 
Protocol Number: 
INS1007-301 
Amendment Number: 
Version 6.0, Global Amendment 3  
Investigational 
Product: 
Brensocatib (INS1007) oral tablets 
Active 
Ingredient(s)/INN: 
Brensocatib 
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Efficacy, Safety, and Tolerability of Brensocatib Administered Once 
Daily for 52 Weeks in Subjects with Non-Cystic Fibrosis Bronchiectasis – 
The ASPEN Study 
Study Phase: 
3 
Indication Under 
Investigation: 
Non-cystic fibrosis bronchiectasis 
Objectives and Estimands: 
Unless otherwise noted, for each of the estimands described below, the population comprises subjects 
with non-cystic fibrosis bronchiectasis (NCFBE). The treatment regimen is standard of care plus 
randomized investigational product (ie, study treatment; brensocatib 10 mg once daily [QD], 
brensocatib 25 mg QD, or placebo) and/or addition of chronic antibiotic (efficacy estimands). 
The efficacy objectives will utilize a treatment policy strategy for handling of intercurrent events 
(ICEs) related to early discontinuation of randomized IP, early discontinuation from standard of care, 
and related to addition of chronic antibiotics (ICH E9(R1) Addendum).  
Objective 
Variable 
(or Endpoint) 
Population Level 
Summary 
Primary  
 
 
To evaluate the effect of brensocatib at 
10 mg and 25 mg compared with placebo on 
the rate of pulmonary exacerbations (PEs) 
Annualized rate of PEs  
Rate ratio 
Secondary  
 
 
To evaluate the effect of brensocatib 
compared with placebo on 
Time to first PE  
Hazard ratio 
 
Responder status for exacerbation free 
Odds ratio 
 
Change in postbronchodilator forced 
expiratory volume in 1 second (FEV1) 
at Week 52 
Mean difference 
 
Annualized rate of severe PEs  
Rate ratio 
 
Change in QOL-B Respiratory 
Symptoms Domain Score at Week 52  
Population: adult subjects 
Mean difference 

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IND Number: 
EudraCT Number: 
133790 
2020-003688-25 
To evaluate the effect of brensocatib 
compared with placebo on  
Adverse events  
— 
Clinical laboratory parameters, vital 
signs, and ECG 
— 
To evaluate brensocatib exposure in adults 
and adolescents 
Brensocatib plasma concentrations over 
time 
— 
See Section 2.3 for exploratory objectives and endpoints. 
Study Design: 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
multinational study to assess the efficacy, safety, and tolerability of 2 dosage strengths of brensocatib 
compared with placebo in subjects with non-cystic fibrosis bronchiectasis (NCFBE). Approximately 
1620 adult subjects, defined as subjects ≥18 to ≤85 years of age, will be randomized in a 1:1:1 ratio to 
3 treatment arms (540 subjects per arm) to receive brensocatib 10 mg once daily (QD), brensocatib 
25 mg QD, or matching placebo QD for 52 weeks.  
• 
Randomization will be stratified based on geographic region (North America, Europe, Japan, and 
the Rest of the World), sputum sample being classified as positive or negative for Pseudomonas 
aeruginosa at Screening Visit, and the number of prior PEs (2, or ≥ 3) in the previous 12 months.  
• 
Randomization will be enforced to have approximately 30% of adult subjects with 3 or more prior 
PEs, to have no more than 20% of subjects older than 75 years of age, to have approximately no 
more than 20% of subjects with eosinophil count in peripheral blood ≥300/mm3 at Screening, and 
to have no more than 20% of subjects with COPD as comorbidity.  
• 
Enrollment targets have been established for adult subjects with up to 13% of subjects from 
Eastern Europe and with North America, Western Europe, Asia Pacific, and Latin America 
contributing between 20% and 30% each. No single country (except the US) will contribute more 
than 15% of the overall randomized population. 
For this study, the adolescent population is defined as subjects ≥12 to <18 years of age at Screening. 
Adolescent subjects are required to have at least 1 PE in the prior 12 months. Approximately 
40 adolescent subjects will be randomized in a 2:2:1 ratio to 3 treatment arms (16:16:8 subjects per 
arm, respectively) to receive brensocatib 10 mg QD, brensocatib 25 mg QD, or matching placebo QD 
for 52 weeks. Sputum sample will be classified as positive or negative for Pseudomonas aeruginosa at 
Screening Visit. Subjects in this age group who are not able to produce a sputum sample will be 
marked as negative. No stratification will be applied to this age group. 
During the study, subjects will be assessed for PEs and will undergo clinical laboratory tests, PK and 
PD evaluations (adults only), vital sign measurements, patient-reported outcome measures, collection 
of the days of work and/or school missed due to PE, and collection of healthcare visit information.  
This study will also include 2 substudies: 
• 
Pharmacokinetic/pharmacodynamic (PK/PD) substudy - The substudy will include approximately 
300 adult subjects who are not receiving cyclic antibiotics at Baseline and from whom additional 
blood PK and sputum PD samples will be collected, with blood PD samples collected from 
approximately 40 of these subjects. Blood PK and sputum PD samples will be collected from all 
adolescent subjects who are not receiving cyclic antibiotics at Baseline (blood PD samples will not 
be collected from adolescent subjects). 
• 
Computed tomography (CT) scan substudy - The substudy will include approximately 225 adult 
subjects who will undergo high-resolution CT scanning at Screening and End of Treatment. 

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IND Number: 
EudraCT Number: 
133790 
2020-003688-25 
Study Duration: 
The maximum study duration is 62 weeks total for an individual participant, including a Screening 
Period of up to 6 weeks, a treatment period of 52 weeks, and an End of Study Visit 4 weeks following 
the end of treatment. 
Study Sites and Locations: 
The subjects in this study will be enrolled at over 400 study sites located in North America, Europe, 
Japan, and the Rest of the World. 
The adolescent subjects will be enrolled in participating countries and sites where local regulations, 
countries, and/or institutional policies allow for patients <18 years of age to participate. 
Subject Eligibility Criteria: 
Key Inclusion Criteria: 
• 
Adult subjects 
− 
Provided their signed informed consent 
− 
Male or female ≥18 years and ≤85 years of age 
− 
Body mass index ≥18.5 kg/m2 at Screening (Visit 1) 
− 
Clinical history consistent with NCFBE confirmed by chest CT 
− 
At least 2 PEs in the past 12 months  
• 
Adolescent subjects 
− 
Provided their signed assent (if required per local requirements) and parent or legal guardian 
provided their signed informed consent 
− 
Male or female ≥12 to <18 years of age at Screening in participating countries and sites 
where local regulations, countries, and/or institutional policies allow for patients <18 years of 
age to participate 
− 
Body weight ≥30 kilograms at Screening  
− 
Clinical history consistent with NCFBE confirmed by chest CT 
− 
At least 1 PE in the past 12 months  
• 
For more comprehensive details of the inclusion criteria, refer to Section 4.1.1 of this protocol. 
Key Exclusion Criteria: 
• 
Subjects who have certain conditions or are receiving certain treatments that could adversely affect 
the subject’s participation in the study, put the subject at unreasonable risk by participating in the 
study, or interfere with assessment of the effect of treatment will not be eligible for enrollment in 
the study.  
• 
For more comprehensive details of the exclusion criteria refer to Section 4.1.2 of this protocol.  
Study Treatment:  
Study subjects will be assigned to 1 of 3 treatment arms. Based on treatment assignment, subjects will 
be supplied either brensocatib 10 mg oral tablets, brensocatib 25 mg oral tablets, or matching placebo 
oral tablets. Study treatment will be taken by subjects QD by mouth with water in the morning before 
breakfast. 

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IND Number: 
EudraCT Number: 
133790 
2020-003688-25 
Sample Size Determination: 
The study is designed to demonstrate superiority of brensocatib 10 mg and/or 25 mg over matching 
placebo as measured by the primary efficacy endpoint of the rate of PEs over the 52-week treatment 
period. Assuming the annualized PE rate in the placebo arm is 1.2 events with a negative binomial 
distribution with dispersion of 1, 1620 adult subjects will yield 90% power if the true exacerbation rate 
is 0.70 between any of the brensocatib treatment arms and placebo after 52 weeks of treatment. This 
estimate is based on study-wise two-sided Type I error of 0.01 or 0.005 for each primary comparison 
between brensocatib and placebo. 
The adolescent sample size of approximately 40 subjects is based on the Sponsor’s feasibility 
assessment as well as the prevalence of NCFBE in this age group.  The sample size is expected to 
provide a description of the safety profile of brensocatib in this age group and offer the possibility to 
observe directional trends in efficacy. 
Statistical Analyses: 
The planned database lock is based on the time when the targeted 1620 adult subjects (originally 
planned sample size) complete the 52-week treatment period or discontinue from the study before 
Week 52. All adult and adolescent data collected up to this database lock will be included in the 
primary efficacy and safety analyses for the Clinical Study Report (CSR). Additional data collected 
between database lock and the last adolescent subject completing the last visit will be summarized in a 
CSR addendum. Additional analyses of efficacy and safety data will be detailed in the SAP. 
Primary Endpoint 
The primary efficacy endpoint is the annualized rate of PEs that have been confirmed through the event 
adjudication process. 
The rate of PEs will be analyzed using the negative binomial model for the primary analysis when the 
last adult subject completes the 52-week treatment period. This analysis will be based on the Intent-to-
Treat (ITT) Analysis Set. The model will include treatment group and randomization stratification 
factors (geographic region [North America, Europe, Japan, and the Rest of the World], sputum sample 
being classified as positive or negative for Pseudomonas aeruginosa at Screening Visit, and the number 
of prior PEs in the previous 12 months), and age group (adult, adolescent) as fixed effects, and the time 
at risk (log scale) as an offset variable. The PE rate (PEs per subject per year) per treatment group, the 
ratios of PE rates between each brensocatib dose and placebo, and the associated 95% CIs will be 
estimated from the negative binomial model. 
Secondary Endpoints 
Secondary efficacy endpoints will be analyzed as follows: 
• 
For time to first PE, the survival curves will be compared between the brensocatib dose and 
placebo using a Cox proportional hazards model based on the ITT Analysis Set. The covariate will 
include the stratification factors used for the randomization. 
• 
For the proportion of subjects who are exacerbation free, the comparison between brensocatib and 
placebo will be analyzed using logistic regression with treatment group and randomization 
stratification factors as fixed effects. 
• 
Absolute change from Baseline in postbronchodilator FEV1 will be analyzed using a linear 
repeated measures model with fixed effects of treatment, stratification factors, visit, treatment-by-
visit interaction, as well as the continuous, fixed covariate of Baseline value. An unstructured 
variance-covariance matrix will be fit. 

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IND Number: 
EudraCT Number: 
133790 
2020-003688-25 
• 
The rate of severe PEs will be analyzed using the same method as the primary endpoint. 
• 
The change from Baseline in QOL-B Respiratory Symptoms Domain Scores in the adult 
population will be analyzed using a linear repeated measures model with fixed effects of treatment, 
stratification factors, visit, treatment-by-visit interaction, as well as the continuous, fixed covariate 
of Baseline value. The variance-covariance structure will be compound symmetric with the robust 
sandwich variance estimator. 
Safety endpoints including incidence and severity of treatment-emergent adverse events, clinical 
laboratory test results, vital signs, and electrocardiogram (ECG) will be descriptively summarized by 
treatment. 
Brensocatib concentration data will be listed and summarized by dose level over each scheduled 
sampling time using descriptive statistics. Individual plasma concentration data versus time will be 
listed. Individual and geometric mean plasma concentration-time data will be graphically displayed. 
Adjustment of Multiplicity for Efficacy Analysis 
In this study, the enhanced mixture-based gatekeeping procedure will be used as the multiplicity 
adjustment method to control the overall type I error rate at a full alpha (𝛼= 0.05) with a two-sided 
test for the multiple tests of the primary and secondary endpoints across the two brensocatib doses 
relative to placebo.  
To demonstrate substantial evidence of effectiveness, the adjusted p-values for the comparisons of 
brensocatib 25 mg versus placebo and brensocatib 10 mg versus placebo for the primary endpoint, the 
annualized rate of PEs, will also be compared against the two-sided 𝛼= 0.01. 
Rejecting either or both null hypotheses and accepting the corresponding alternative hypotheses with 
lower rate of PEs in the brensocatib treatment arms, for the ITT Analysis Set, will be considered as a 
successful demonstration of efficacy. 
Data Monitoring Committee and Other Committees:  
An independent, external Data Monitoring Committee (DMC) will review all adverse events and 
serious adverse events to ensure the safety of subjects enrolled into this study. The DMC members will 
review the data in a semi-blinded or unblinded manner at predetermined intervals. 
An independent adjudication committee composed of pulmonary physicians will adjudicate all reported 
PE events to determine if they fulfill the protocol definition.  
An independent Steering Committee will be established to provide study oversight, including but not 
limited to the medical, scientific, operational, safety, and external communication of the study.  

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TABLE OF CONTENTS 
IMPORTANT CONTACTS ............................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
PROTOCOL SYNOPSIS ................................................................................................................6 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF IN-TEXT TABLES ........................................................................................................17 
LIST OF IN-TEXT FIGURES.......................................................................................................17 
LIST OF ABBREVIATIONS ........................................................................................................18 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................22 
1.1. 
Non-Cystic Fibrosis Bronchiectasis ...........................................................................22 
1.2. 
Brensocatib .................................................................................................................22 
1.2.1. 
Nonclinical Data .........................................................................................................23 
1.2.2. 
Clinical Data ...............................................................................................................24 
1.2.2.1. 
Phase 1 Studies D6190C00001 (SAD/MAD Study) and D6190C00003 
(Coadministered with CYP3A4 Inhibitors) ................................................................24 
1.2.2.2. 
Phase 1 Ethnic Pharmacokinetic Study INS1007-101 ................................................25 
1.2.2.3. 
Phase 2 Clinical Study INS 1007-201 ........................................................................26 
1.3. 
Study Rationale and Dose Justification ......................................................................27 
1.3.1. 
Study Rationale ...........................................................................................................27 
1.3.2. 
Dose Justification ........................................................................................................27 
1.3.3. 
Study Population .........................................................................................................27 
1.3.4. 
Treatment and Duration of Exposure .........................................................................28 
1.3.5. 
Efficacy Endpoints and Placebo Control ....................................................................28 
1.4. 
Benefits and Risks for Study Subjects ........................................................................28 
1.4.1. 
Potential Benefits ........................................................................................................28 
1.4.2. 
Risks and Mitigation Strategies ..................................................................................28 
1.5. 
Randomization and Blinding ......................................................................................29 
1.6. 
Treatment, Route, Dosage, Treatment Period ............................................................29 
1.7. 
Compliance Statement, Ethics, and Regulatory Compliance .....................................29 
1.7.1. 
Subject Confidentiality ...............................................................................................30 
1.7.2. 
Informed Consent Procedure ......................................................................................30 
1.7.3. 
Regulatory Compliance ..............................................................................................31 
2. 
STUDY OBJECTIVES AND ESTIMANDS .............................................................32 

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2.1. 
Primary Objective and Estimand ................................................................................32 
2.2. 
Secondary Objectives and Estimands .........................................................................32 
2.3. 
Exploratory Objectives and Endpoints .......................................................................34 
3. 
STUDY DESIGN .......................................................................................................36 
3.1. 
Overall Plan ................................................................................................................36 
3.2. 
Data Monitoring Committee and Steering Committee ...............................................38 
3.3. 
Duration of Subject Participation ...............................................................................39 
3.4. 
End of Study ...............................................................................................................39 
4. 
STUDY POPULATION .............................................................................................40 
4.1. 
Enrollment ..................................................................................................................40 
4.1.1. 
Inclusion Criteria ........................................................................................................40 
4.1.2. 
Exclusion Criteria .......................................................................................................42 
4.2. 
Discontinuation of Study Treatment and Participant 
Discontinuation/Withdrawal .......................................................................................44 
4.2.1. 
Discontinuation of Study Treatment ...........................................................................44 
4.2.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................44 
4.2.2.1. 
Reasons for Withdrawal/Early Discontinuation .........................................................45 
4.2.2.2. 
Early Discontinuation Procedures ..............................................................................46 
4.2.2.3. 
Lost to Follow-up .......................................................................................................46 
4.2.3. 
Subject Replacement ..................................................................................................46 
4.2.4. 
Subject Rescreening Procedures .................................................................................46 
4.3. 
Premature Termination of the Study ...........................................................................46 
5. 
STUDY TREATMENT ..............................................................................................48 
5.1. 
Study Treatments Administered .................................................................................48 
5.1.1. 
Brensocatib .................................................................................................................48 
5.1.2. 
Placebo ........................................................................................................................48 
5.2. 
Methods of Assigning Subjects to Treatment .............................................................48 
5.3. 
Study Treatment Administration ................................................................................49 
5.4. 
Dose Interruption ........................................................................................................49 
5.5. 
Method of Assessing Treatment Compliance .............................................................49 
5.6. 
Emergency Unblinding ...............................................................................................50 
5.7. 
Labeling and Packaging ..............................................................................................50 
5.8. 
Storage ........................................................................................................................50 

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5.9. 
Dispensing of Study Drug ..........................................................................................50 
5.10. 
Drug Accountability ...................................................................................................51 
5.11. 
Concomitant Medications ...........................................................................................51 
5.11.1. 
Prohibited Medications and Procedures .....................................................................51 
5.11.2. 
Permitted Medications and Procedures ......................................................................52 
5.11.3. 
Rescue Therapy ..........................................................................................................53 
6. 
STUDY PROCEDURES ............................................................................................54 
6.1. 
Schedule of Assessments ............................................................................................54 
6.2. 
Protocol Deviations ....................................................................................................60 
6.3. 
Public Health Emergency Situations ..........................................................................60 
6.3.1. 
Continuation or Suspension of the Study ...................................................................60 
6.3.1.1. 
Study Recruitment ......................................................................................................61 
6.3.1.2. 
Subjects Already Enrolled in the Study ......................................................................61 
6.3.2. 
Subjects Infected by COVID-19 .................................................................................61 
7. 
EFFICACY ASSESSMENTS ....................................................................................62 
7.1. 
Pulmonary Exacerbation .............................................................................................62 
7.2. 
Sputum ........................................................................................................................62 
7.2.1. 
Sputum Culture ...........................................................................................................62 
7.2.2. 
Sputum for PK/PD Substudy ......................................................................................62 
7.3. 
Pulmonary Function Tests ..........................................................................................63 
7.4. 
Bronchiectasis Severity Index ....................................................................................64 
7.5. 
Patient-Reported Outcome Measures .........................................................................65 
7.5.1. 
Bronchiectasis Exacerbation and Symptoms Tool .....................................................65 
7.5.2. 
Quality of Life Questionnaire – Bronchiectasis .........................................................65 
7.5.3. 
PGI-S and PGI-C ........................................................................................................66 
7.5.4. 
EuroQoL-5D-5L .........................................................................................................66 
7.5.5. 
QOL-PCD ...................................................................................................................66 
7.6. 
Chest CT Scan ............................................................................................................66 
7.6.1. 
CT Scan Substudy CT Scan Assessment ....................................................................67 
7.6.2. 
Image Analysis in the CT Scan Substudy...................................................................68 
7.6.2.1. 
BEST-CT Scoring Method .........................................................................................68 
7.6.2.2. 
Airway-Artery Method ...............................................................................................69 

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8. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................70 
8.1. 
Pharmacokinetic Endpoints ........................................................................................70 
8.2. 
Pharmacokinetic Sampling .........................................................................................70 
8.3. 
Pharmacodynamic Endpoints .....................................................................................71 
8.4. 
Pharmacodynamic Sampling ......................................................................................71 
8.4.1. 
Sample Collection for Biomarkers in Sputum ............................................................71 
8.4.2. 
Sample Collection for Biomarkers in Blood ..............................................................71 
8.5. 
Pharmacokinetic-Pharmacodynamic Endpoints .........................................................71 
9. 
ASSESSMENT OF SAFETY .....................................................................................72 
9.1. 
Vital Signs and Pulse Oximetry ..................................................................................72 
9.2. 
Physical Examination, Height, and Weight ................................................................72 
9.3. 
Chest CT Scan ............................................................................................................72 
9.4. 
Electrocardiogram .......................................................................................................72 
9.5. 
Clinical Laboratory Assessments ...............................................................................72 
9.6. 
Dental Hygiene Education ..........................................................................................73 
9.7. 
Serology Tests ............................................................................................................73 
9.8. 
Serum or Urine Pregnancy Test ..................................................................................73 
9.9. 
Estimated Glomerular Filtration Rate .........................................................................74 
9.10. 
Adverse Events ...........................................................................................................74 
9.10.1. 
Definition of an Adverse Event ..................................................................................74 
9.10.2. 
Definition of a Serious Adverse Event .......................................................................74 
9.10.3. 
Adverse Event of Special Interest ...............................................................................75 
9.10.3.1. 
Hyperkeratosis ............................................................................................................75 
9.10.3.2. 
Periodontitis/Gingivitis ...............................................................................................76 
9.10.3.3. 
Other Infections ..........................................................................................................76 
9.10.4. 
Assessment of Severity ...............................................................................................76 
9.10.5. 
Assessment of Causality .............................................................................................76 
9.10.6. 
Assessment of Adverse Event Outcome .....................................................................77 
9.11. 
Reporting Requirements .............................................................................................77 
9.11.1. 
Adverse Events ...........................................................................................................77 
9.11.2. 
Serious Adverse Events ..............................................................................................77 
9.11.3. 
Pregnancy ...................................................................................................................77 

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9.11.4. 
Overdose .....................................................................................................................78 
9.12. 
Follow-up of Adverse Events and Serious Adverse Events .......................................78 
9.13. 
Regulatory Aspects .....................................................................................................78 
10. 
STATISTICS ..............................................................................................................79 
10.1. 
Sample Size and Power Considerations .....................................................................79 
10.2. 
Analysis Sets ...............................................................................................................80 
10.2.1. 
Screened Analysis Set .................................................................................................80 
10.2.2. 
Intent-to-Treat Analysis Set ........................................................................................80 
10.2.3. 
Safety Analysis Set .....................................................................................................80 
10.2.4. 
Pharmacodynamic Analysis Set .................................................................................80 
10.2.5. 
Pharmacokinetic Concentration Analysis Set .............................................................80 
10.2.6. 
CT Scan Analysis Set .................................................................................................81 
10.3. 
General Considerations ...............................................................................................81 
10.4. 
Statistical Analysis ......................................................................................................81 
10.4.1. 
Subject Disposition .....................................................................................................81 
10.4.2. 
Medical History ..........................................................................................................81 
10.4.3. 
Prior and Concomitant Medications ...........................................................................81 
10.4.4. 
Major Protocol Deviations ..........................................................................................81 
10.4.5. 
Treatment Exposure and Compliance .........................................................................82 
10.4.6. 
Efficacy Analyses .......................................................................................................82 
10.4.6.1. 
Analysis of Primary Efficacy Endpoint ......................................................................82 
10.4.6.2. 
Analysis of Secondary Efficacy Endpoints ................................................................83 
10.4.6.3. 
Analysis of Exploratory Endpoints .............................................................................84 
10.4.6.4. 
Adjustment of Multiplicity for Efficacy Analysis ......................................................84 
10.4.6.5. 
Subgroup Analyses .....................................................................................................84 
10.4.7. 
Safety Analysis ...........................................................................................................85 
10.4.7.1. 
Adverse Events ...........................................................................................................85 
10.4.7.2. 
Clinical Laboratory Tests ...........................................................................................85 
10.4.7.3. 
Vital Signs ..................................................................................................................86 
10.4.7.4. 
ECGs ...........................................................................................................................86 
10.4.8. 
Pharmacodynamic Analysis........................................................................................86 
10.4.9. 
Pharmacokinetic Analysis ..........................................................................................86 

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10.4.10. 
Population Pharmacokinetic Analysis ........................................................................87 
10.4.11. 
Pharmacodynamic-Pharmacodynamic Analysis ........................................................87 
10.4.12. 
CT Analysis ................................................................................................................87 
10.5. 
Interim Analysis ..........................................................................................................87 
11. 
DATA INTEGRITY AND QUALITY ASSURANCE ..............................................88 
11.1. 
Source Documents ......................................................................................................88 
11.2. 
Data Collection ...........................................................................................................88 
11.3. 
Study Record Retention ..............................................................................................88 
12. 
FINANCING AND INSURANCE .............................................................................89 
12.1. 
Finances ......................................................................................................................89 
12.2. 
Reimbursement, Indemnity, and Insurance ................................................................89 
13. 
STUDY ADMINISTRATIVE INFORMATION .......................................................90 
13.1. 
Financial Disclosure by the Investigator ....................................................................90 
13.2. 
Study Registration and Results Disclosure .................................................................90 
13.3. 
Study Files and Materials ...........................................................................................90 
13.4. 
Use of Stored Samples and Data ................................................................................90 
13.5. 
Disposition of Stored Samples and Data ....................................................................91 
13.6. 
Initiation of Study .......................................................................................................91 
13.7. 
Subject Reimbursement, Liability, and Insurance ......................................................91 
13.8. 
Subject Identification and Confidentiality ..................................................................92 
13.9. 
Study Monitoring ........................................................................................................92 
13.10. 
Protocol Amendments ................................................................................................92 
13.11. 
Audits and Inspections ................................................................................................93 
13.12. 
Publication Policy .......................................................................................................93 
14. 
REFERENCES ...........................................................................................................94 
15. 
APPENDICES ............................................................................................................97 
APPENDIX 1. SPUTUM INDUCTION GUIDELINES ............................................................98 
APPENDIX 2. CALCULATION OF BRONCHIECTASIS SEVERITY INDEX ...................101 
APPENDIX 3. THE MEDICAL RESEARCH COUNCIL BREATHLESSNESS 
SCALE ......................................................................................................................102 
APPENDIX 4. HY’S LAW CASES .........................................................................................103 
APPENDIX 5. SCHEDULE OF PHARMACOKINETIC SAMPLE COLLECTION.............106 
APPENDIX 6. SCHEDULE OF PHARMACODYNAMIC SAMPLE COLLECTION .........107 

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APPENDIX 7. COMPARABLE NSAID DOSE LEVELS ......................................................108 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Primary Objective and Estimand ................................................................................32 
Table 2: 
Secondary Objectives and Estimands .........................................................................32 
Table 3: 
Exploratory Objectives and Endpoints .......................................................................34 
Table 4: 
Minimum Time Intervals for Restricted Medication Use Prior to Spirometry 
Testing ........................................................................................................................52 
Table 5: 
Schedule of Assessments and Procedures ..................................................................55 
Table 6: 
Clinical Laboratory Parameters ..................................................................................73 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Schematic for Study INS1007-301 .............................................................................38 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation  
Term 
AA 
Airway-Artery (method) 
ABPA 
allergic bronchopulmonary aspergillosis 
AC 
adjudication committee 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransaminase 
ANC 
absolute neutrophil count 
ARDS 
adult respiratory distress syndrome 
AST 
aspartate aminotransaminase 
ATS 
American Thoracic Society 
AUC 
area under the concentration versus time curve  
BCRP 
breast cancer resistance protein 
BE-CT 
Bronchiectasis-Computed Tomography (score) 
BEST 
Bronchiectasis Exacerbation and Symptom Tool 
BEST-CT 
Bronchiectasis Scoring Technique for Computed Tomography  
BMI 
body mass index 
BP 
blood pressure 
BSI 
Bronchiectasis Severity Index 
CatG 
cathepsin G 
CDC 
Centers for Disease Control 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
Cmax 
maximum observed concentration 
CO2 
carbon dioxide 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
2019 corona virus disease 
CSR 
clinical study report 
CT 
computed tomography 
CYP 
cytochrome P450 
dECG 
digital electrocardiogram 
DICOM 
Digital Imaging and Communications in Medicine 

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Abbreviation  
Term 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DPP1 
dipeptidyl peptidase 1 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
electrocardiogram 
EOS 
end of study 
EOT  
end of treatment 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EQ-5D-5L 
EuroQoL-5 Dimension-5 Level Questionnaire 
ER 
emergency room 
ERS 
European Respiratory Society 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FEF(25-75%) 
forced expiratory flow between 25% and 75% of forced vital capacity 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus  
HIV 
human immunodeficiency virus 
HL 
Hy’s Law 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICS 
inhaled corticosteroid 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon gamma 

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Abbreviation  
Term 
IND 
Investigational New Drug 
INS1007 
drug code for “brensocatib” 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
LABA 
long-acting beta agonist 
LAM 
lactational amenorrhea method 
LAMA 
long-acting muscarinic antagonist 
LDH 
lactic dehydrogenase 
MAR 
missing-at-random (assumption) 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputations 
MNAR 
missing-not-at-random (assumption) 
mPR3 
membrane-bound proteinase-3 
NCFBE 
non-cystic fibrosis bronchiectasis 
NE 
neutrophil elastase 
NOAEL 
no-observed-adverse-effect level 
NSP 
neutrophil serine protease 
NTM 
nontuberculous mycobacteria 
PCD 
primary ciliary dyskinesia 
PD 
pharmacodynamic 
PE 
pulmonary exacerbation 
PEFR 
peak expiratory flow rate 
PFT 
pulmonary function test 
PGI-C 
Patient Global Impression of Change scale 
PGI-S 
Patient Global Impression of Severity scale 
P gp 
P-glycoprotein 
PHL 
potential Hy’s Law 
PLS 
Papillon-Lefѐvre syndrome 
PK 
pharmacokinetic 
PMM 
Pattern Mixture Model 
ppFEV1 
percent predicted forced expiratory flow in 1 second  

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Abbreviation  
Term 
PR3 
proteinase 3 
PRO 
patient-reported outcome 
PT 
Preferred Term 
QD 
once daily 
QOL-B 
Quality of Life Questionnaire - Bronchiectasis 
QOL-PCD 
Quality of Life instrument for Primary Ciliary Dyskinesia 
QTcF 
corrected QT interval by Fridericia’s formula 
RNA 
ribonucleic acid 
RR 
respiratory rate 
SABA 
short-acting beta agonist 
SAE 
serious adverse event 
SAMA 
short-acting muscarinic antagonist 
SAP 
statistical analysis plan 
SD 
standard deviation 
SFTP 
Safe File Transfer Protocol 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected serious adverse reaction 
T 
temperature 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 

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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Non-Cystic Fibrosis Bronchiectasis 
Non-cystic fibrosis bronchiectasis (hereafter referred to as NCFBE) is a chronic inflammatory 
disease defined by permanent dilatation of the bronchi (Barker, 2002). Subjects suffer from daily 
cough and sputum production and experience frequent exacerbations. The prevalence of NCFBE 
has steadily increased over the past 10 years in both the United States and Europe (Henkle et al., 
2018; Quint et al., 2016). Despite an urgent need for treatment that can break the cycle of 
inflammation, infection, and irreversible progressive lung damage, there are no approved 
therapies specifically targeting this disease. 
A European study (Lonni et al., 2015) included a total of 1,258 patients with NCFBE enrolled 
within the 7 centers (median age, 67 years; age range, 18–94 years; 40% males). Among the 
entire study population, the etiology of bronchiectasis was identified in 60% of patients (range 
among cohorts, 46%–82%). Excluding idiopathic bronchiectasis, the first 5 most commonly 
identified etiologies were post-infective (20%), COPD related (15%), connective tissue disease 
related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). Of note, a 
significantly higher prevalence of COPD-related bronchiectasis was detected in patients with 
severe disease (22%) in comparison to those with mild disease (2.8%) and moderate disease 
(8.1%), according to BSI categories (P<0.001). 
In a systematic review comprising 989 children with NCFBE from 12 studies, 63% of the 
subjects had an underlying disorder. Infectious diseases (17%), primary immunodeficiency 
(16%), aspiration (10%), ciliary dyskinesia (9%), congenital malformation (3%), and secondary 
immunodeficiency (3%) were the most common disease categories; 999 etiologies were 
identified. Severe pneumonia of bacterial or viral etiology and B cell defects were the most 
common disorders identified (Brower et al., 2014). In a recent study of 69 children with NCFBE 
at a center in the Netherlands, etiology was established in 91% of patients (n=63; median age 9 
[3 to 18 years]). Post-infection (29%), and immunodeficiency (29%) were most common, 
followed by congenital anomalies (10%), aspiration (7%), asthma (6%), and PCD (1%) 
(Beckeringh et al., 2019). 
1.2. 
Brensocatib 
Brensocatib is being investigated in NCFBE for its potential role targeting neutrophil-mediated 
inflammation. Inflammation in bronchiectasis is dominated by neutrophils (Chalmers et al., 
2017; Finch et al., 2019). Activation of neutrophils in the airway leads to release of NSPs, 
including NE, which is believed to be central to the pathophysiology of bronchiectasis (Chalmers 
and Chotirmall, 2018). Elevated NE, PR3, and CatG overwhelm natural inhibitors, such as 
alpha-1 antitrypsin and secretory leukoproteinase inhibitor (Dubois et al., 2012; Sibila et al., 
2019), which leads to damaged airway walls (Chalmers and Chotirmall, 2018), mucus 
hypersecretion (Voynow et al., 1999), exacerbated inflammation (Finch et al., 2019), and 
disabled neutrophil and macrophage functions, increasing the risk of infection. NSPs are 
activated during neutrophil maturation in the bone marrow through the action of the enzyme 
DPP1, also known as cathepsin C. DPP1 removes the N-terminal dipeptide sequence of NSPs, 
allowing active enzymes to be packaged into granules prior to release into the circulation 
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Several factors may cause NCFBE, including severe respiratory infections (eg, bacterial 
pneumonia or tuberculosis), allergic bronchopulmonary aspergillosis, impairment of ciliary 
clearance (eg, primary ciliary dyskinesia), and primary or secondary immunodeficiency, and it 
may be associated with other diseases, such as COPD and severe asthma. 
Subjects with NCFBE experience PEs with an average frequency ranging from 1.5 to 6 per year 
(Chalmers et al., 2014; Goeminne PC, 2014), and have poor quality of life. Frequent 
exacerbations of bronchiectasis are independently associated with worse quality of life, 
decreased lung function, and substantial morbidity and mortality (Barker, 2002; Chalmers et al., 
2018; Quittner et al., 2015). 
There is currently no therapy approved by regulatory authorities in the United States or Europe 
for the treatment of NCFBE. The primary goal of treatment is to treat the underlying cause, 
prevent disease progression, maintain or improve lung function, and improve the symptoms and 
quality of life. 
Thus, the pediatric and adult populations differ significantly in the etiologies that cause the 
disease. Although infections are a common cause in both children and adults, pediatric age 
groups have a higher frequency of immune disorders compared to adults, in which the etiology 
of the disease is driven by other causes, including COPD and asthma. Despite these differences 
in etiology between adult and pediatric patients, the pathophysiology of NCFBE (once 
established in the airway) and the pharmacological rationale for brensocatib, are similar in adult 
and pediatric patients with NCFBE (Chalmers et al., 2017). Elevated levels of NE have been 
observed in children, which support extrapolation of efficacy and safety from adults with 
NCFBE to children with NCFBE. 
Brensocatib ((2S)-N-{(1S)-1-cyano-2- [4-(3-methyl-2-oxo-2,3-dihydro- 1,3-benzoxazol-5-yl) 
phenyl] ethyl -1,4-oxazepane-2-carboxamide monohydrate) is a highly potent, selective, small 
molecule competitive and reversible inhibitor of DPP1 that is currently being developed for the 
treatment of NCFBE. Brensocatib (developed under the investigational product code INS1007) 
has been shown to inhibit NSP activity in blood in animal models and in healthy volunteers after 
2 weeks to 1 month of dosing (Palmér et al., 2018). Treatment with brensocatib could therefore 
reduce neutrophilic inflammation in the systemic circulation and the lungs, leading to reduced 
risk of exacerbations in patients with NCFBE. Studies with naïve and lipopolysaccharide-
induced pulmonary inflammation models in the rat showed that DPP1 inhibition with oral 
brensocatib translates well in vivo, as significant decreases in the activities of NSPs were 
observed. 
1.2.1. 
Nonclinical Data 
Human primary neutrophil studies showed that brensocatib significantly inhibits the activation of 
NSPs, resulting in decreased elastolytic ability of the cells in vitro. Furthermore, brensocatib 
produced concentration-dependent reduction in both the percentage of neutrophils with 
membrane-bound PR3 and the overall surface expression of PR3 in differentiating human 
neutrophils in vitro. Studies with naïve and lipopolysaccharide-induced pulmonary inflammation 
models in the rat showed that DPP1 inhibition with oral brensocatib translates well in vivo, as 
significant decreases in the activities of NSPs were observed. 

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Safety pharmacology studies of brensocatib showed no concerning cardiovascular, respiratory, or 
central nervous system effects at a notable safety margin to the systemic exposure in humans at a 
dose level of 40 mg. 
The absorption, distribution, and metabolism of brensocatib have been studied in vivo in rat and 
dog and in vitro in mouse, rat, rabbit, dog, and human biomaterials. Brensocatib was highly 
bioavailable following oral administration in rats and dogs (75% and 92%, respectively). The 
fraction of unbound brensocatib in rat, dog, rabbit, mouse, and human plasma was 6.06%, 
29.7%, 22.7%, 16.5%, and 12.8%, respectively. Quantitative whole-body autoradiography in the 
rat confirmed rapid absorption and widespread distribution of [14C] brensocatib, with the highest 
concentrations associated with melanin-containing tissues. Pregnant rats showed evidence of 
fetal exposure. Slow metabolism of brensocatib were detected in rat, dog and human 
hepatocytes. A few minor metabolites detected (each less than 2% of total radioactivity) were 
mediated by CYP3A4/5 and no unique human metabolite was identified. In vitro evaluation at 
concentrations up to 30 µM showed that brensocatib did not inhibit CYP isozymes (IC50 >30 µM 
for CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4/5) nor induced CYP1A2, 2B6 and 3A4. 
Evaluation on transport inhibition showed that brensocatib did not inhibit solute carrier 
transporters, such as OATPs, OATs, and OCTs but had minor inhibitory effect on efflux 
transporters (IC50 > 11 µM), such as Pgp, BCRP, MATE1 and MATE2. Thus, at a clinically 
relevant concentration range, drug-drug interactions caused by brensocatib involving CYPs and 
transporters are unlikely. 
The completed 6-month toxicology studies in rats and dogs are considered appropriate in support 
of including adolescent patients in the study, as the age of the animals at the start of the study 
was 6-7 weeks, and 5-6 months, respectively. This indicates that the animals at the start of the 
study entered puberty in both species (ICH S11). The completed 9-month dog study support 
clinical dosing beyond 6 months of duration. 
1.2.2. 
Clinical Data 
The clinical development program of brensocatib to date includes 2 completed Phase 1 studies 
conducted in healthy adult male volunteers (Study D6190C00001, Study D6190C00003), a 
completed Phase 1 study conducted in healthy male and female Japanese and Caucasian subjects 
(Study INS1007-101) and a completed Phase 2 study in subjects with NCFBE 
(Study INS1007-201). 
1.2.2.1. 
Phase 1 Studies D6190C00001 (SAD/MAD Study) and D6190C00003 
(Coadministered with CYP3A4 Inhibitors) 
In Phase 1 Studies D6190C00001 and D6190C00003, brensocatib was well tolerated up to the 
highest dose levels assessed (single dose of 65 mg and multiple doses of 40 mg/day for 28 days). 
No trends were observed in clinical laboratory results, 12-lead ECGs, telemetry, physical 
examination, or spermatogram results. Abnormal findings observed in vital signs were not 
considered to be clinically significant. All TEAEs were mild or moderate, and the most common 
TEAE was headache (generally mild and considered related to the study treatment). There were 
no deaths or SAEs. Treatment discontinuation due to a TEAE was rare. Consistent with the 
protocol, 1 subject in Study D6190C00001 discontinued 25 mg/day brensocatib on Day 13 of a 
planned 28-day treatment period due to an AE of “drug eruption, lichen planus-like.” AEs of the 

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gingiva and skin of the palms and soles were of special interest with brensocatib because of their 
presence in Papillon-Lefèvre syndrome, a human genetic model of reduced DPP1 activity 
(Guarino et al., 2017; Pham et al., 2004; Sorensen et al., 2014). Mild skin and subcutaneous 
tissue disorders were observed in subjects receiving brensocatib. 
In the presence of CYP3A4 inhibitors, the systemic exposure of brensocatib at 25 mg was not 
significantly affected. When coadministered with verapamil (240 mg), the Cmax and AUC of 
brensocatib increased by 53% (592 vs 386 nmol/L) and 32% (8857 vs 6697 h*nmol/L), 
respectively. When coadministered with itraconazole (200 mg), brensocatib AUC increased by 
14% (7615 vs 6697 h*nmol/L), while Cmax decreased by 40% (234 vs 386 nmol/L). The 
elimination t1/2 of brensocatib without or with coadministration of verapamil or itraconazole 
remained relatively unchanged (23.4, 20.4 and 27.9 hours, respectively). 
1.2.2.2. 
Phase 1 Ethnic Pharmacokinetic Study INS1007-101 
Study INS1007-101 was a two-part, randomized, double-blind, placebo-controlled Phase 1 study 
to evaluate the safety, tolerability, PK, and PD properties of single and multiple oral doses of 
INS1007, including ethnic PK assessment. Part A evaluated the safety, tolerability, PK, and PD 
of single and multiple oral doses of brensocatib in healthy adult Japanese and Caucasian 
subjects. Part B was an open-label, 2-period, and 2-sequence crossover food effect study. 
Analysis of the effect of Japanese/Caucasian descent on brensocatib dose-normalized PK 
parameters showed that exposure was moderately greater for Caucasian subjects compared to 
Japanese subjects. On Day 1 (single dose), Japanese subjects had an approximately 12% (Cmax) 
and 17% (AUC0-τ) lower geometric mean exposure. This pattern continued on Day 30 (multiple 
dose), as the Japanese subjects had an approximately 19% (Cmax) to 26% (AUC0-τ) lower 
exposure. 
For the Caucasian subjects, the AUC parameter increase with dose was more than 
dose-proportional on Day 1; by Day 30 the AUC increases were dose-proportional. Cmax 
increased in a dose-proportional manner on both Day 1 and Day 30 for Caucasian subjects. For 
the Japanese subjects, the AUC and Cmax parameters increased in a dose-proportional manner on 
Day 1 and Day 30. 
A total of 65 TEAEs were reported in 37 of 82 subjects (45.0%), for Part A and Part B 
collectively, and of these, 27 TEAEs were reported in 19 of 40 Caucasian subjects (47.5%), and 
38 TEAEs were reported in 18 of 42 Japanese subjects (42.9%). In Caucasian subjects, 
25 TEAEs were reported in 17 of 40 subjects (42.5%) under fasted conditions, and 2 TEAEs 
were reported in 2 of 10 subjects (20.0%) under fed conditions. In Japanese subjects, 34 TEAEs 
were reported in 15 of 42 subjects (35.7%) under fasted conditions, and 4 TEAEs were reported 
in 3 of 9 subjects (33.3%) under fed conditions. The majority of TEAEs were of mild intensity; 
no severe TEAEs were reported. There were no deaths or other SAEs in this study. 
The most frequently-occurring AESI overall was skin exfoliation (3 subjects [7.5%] in the 
pooled Caucasian group and 4 subjects [9.4%] in the pooled Japanese group). The next most 
frequently-occurring AESI was nasopharyngitis (2 subjects [5.0%] in the pooled Caucasian 
group, and 1 subject [2.4%] in the pooled Japanese group). 

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1.2.2.3. 
Phase 2 Clinical Study INS 1007-201 
In a Phase 2, randomized, double-blind, parallel-group, placebo-controlled study, 256 subjects 
with a clinical history consistent with bronchiectasis (cough, chronic sputum production and/or 
recurrent respiratory infections) confirmed by chest CT were randomized (1:1:1) to receive 
brensocatib 10 mg QD, brensocatib 25 mg QD, or placebo QD for 24 weeks. Subjects were 
required to have ≥2 documented PEs in the past 12 months, a history of chronic sputum 
expectoration, sputum color at Screening rated as mucopurulent or purulent per validated color 
chart (Murray et al., 2009), and were able to provide a sputum sample during Screening. 
Exacerbations during the study period were defined using a modified consensus definition (Hill 
et al., 2017). The primary endpoint was the time to first pulmonary exacerbation over the 
24-week treatment period. 
AESIs included periodontal disease and skin hyperkeratosis that were informed by the clinical 
presentation of PLS. All subjects, excluding those who were edentulous, underwent dental 
assessment at Baseline and at Weeks 8 and 24. Severe infections were also monitored as AESI. 
Demographics and clinical characteristics at Baseline were similar across treatment groups; 
subjects were predominately Caucasian and female and over 60 years of age; 19% of subjects 
were >75 years at enrollment. Approximately 33% of subjects had 3 or more exacerbations in the 
previous 12 months. 
The study achieved its primary endpoint of prolonging time to first pulmonary exacerbation for 
both brensocatib dosing strengths compared to placebo. Forty-two (42) subjects (48.3%) in the 
placebo group experienced an exacerbation compared to 26 subjects (31.7%) and 29 subjects 
(33.3%) in the 10 mg and 25 mg groups, respectively. The median time to first exacerbation in 
the placebo group was 189 days, while the median time to first exacerbation could not be 
estimated for either INS1007 group due to the low number of exacerbations in each group. The 
stratified log-rank test 1-sided P values for superiority for time to first exacerbation compared to 
placebo were P=0.014 and P=0.022 for the 10 mg and 25 mg groups, respectively. The 
unstratified log-rank test 1-sided P values were 0.010 and 0.028 for the 10 mg and 25 mg 
treatment groups respectively. 
The proportion of subjects reporting any protocol-defined pulmonary exacerbation was 
significantly lower (Cochran-Mantel-Haenszel test) in the brensocatib 10 mg (26 subjects 
[31.7%]; P=0.017) and 25 mg (29 subjects [33.3%]; P=0.019) groups compared with placebo 
(42 subjects [48.3%]). 
The annualized rates of PEs were significantly lower (negative binomial model) in the 
brensocatib 10 mg (0.80 [95% CI: 0.57, 1.12]) and 25 mg (0.96 [95% CI: 0.71, 1.30]) groups 
compared with placebo (1.25 [95% CI: 0.96, 1.63]). 
The incidence of AEs and the number of subjects with a TEAE that led to study discontinuation 
were similar across treatment groups. Most TEAEs were mild to moderate. More subjects in the 
placebo group experienced a serious TEAE than in either INS1007 group. TEAEs leading to 
treatment and/or study discontinuation occurred once per Preferred Term with no obvious trends 
or relationship to treatment. Two subjects discontinued the study due to an AESI: placebo, n=1 
(pneumonia); brensocatib 25 mg, n=1 (palmar erythema). One death (attributed to bronchiectasis 

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progression) occurred in a brensocatib 25 mg-treated
-year-old 
with multiple 
comorbidities. 
1.3. 
Study Rationale and Dose Justification 
1.3.1. 
Study Rationale 
Treatment with brensocatib is hypothesized to reduce levels of active NSPs in the sputum of 
patients with NCFBE, thus decreasing pulmonary inflammation and mucus hypersecretion, and 
consequently reducing the risk of PEs. The Phase 2 Study INS1007-201 investigated that 
hypothesis and demonstrated that brensocatib treatment reduced PEs and decreased 
inflammatory markers (eg, NE in sputum) in subjects with NCFBE over a treatment period of 
24 weeks, as compared with placebo. 
This study will investigate the efficacy, safety, and tolerability of brensocatib in the clinical 
management of subjects with NCFBE over 52 weeks. The goals are to confirm the findings from 
Study INS1007-201 and, if successful, to support marketing authorizations for brensocatib for 
the treatment of patients aged 12 years and older with NCFBE. 
1.3.2. 
Dose Justification 
Brensocatib has been studied using solution and tablet formulations in healthy volunteers, with 
dosing strengths ranging from 5 mg to 65 mg, and repeated administrations for 10 mg, 25 mg, 
and 40 mg across the formulations that support similar conclusions of dose proportionality. 
Phase 2 experience in subjects with NCFBE supports the efficacy of 6 months’ exposure to 
10 mg and 25 mg on reduction of PEs. Both doses demonstrated an acceptable safety profile as 
most TEAEs were mild to moderate in intensity across groups; those reported in ≥10% of 
brensocatib-treated subjects were cough, headache, increased sputum, and dyspnea, with some 
potential indication of dose dependency for events that may reflect DPP1 inhibition. Modeling 
and simulations using data from the Phase 2 study support that a reduction of sputum NE below 
quantification levels is associated with a reduction of exacerbations, and that such reduction is 
dose-dependent. The modeling and simulations did not support that lower doses were likely to 
yield equivalent efficacy to 10 mg nor that doses higher than 25 mg were likely to yield 
meaningful incremental efficacy. The current study therefore includes 10 mg and 25 mg as the 
two dosage strengths to be evaluated. 
Using an adult population PK model, brensocatib exposure for adolescent patients at 10 and 
25 mg was simulated based on the height and weight distributions for the age group reported by 
the Centers for Disease Control and Prevention (Kuczmarski et al., 2002). The simulated steady 
state AUC values were within the 95% CIs of those in adults with NCFBE for both dose levels 
(10 and 25 mg). This suggests that the adolescent subjects can receive the same dose levels of 
brensocatib as the adults and achieve a similar systemic exposure. 
1.3.3. 
Study Population 
The proposed study population will consist of adult male and female subjects diagnosed with 
NCFBE who are ≥18 years and ≤85 years of age and adolescent male and female subjects ≥12 to 
<18 years of age in participating countries and sites where local regulations, countries, and/or 
institutional policies allow for patients <18 years of age to participate. Subjects ≥18 years must 

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have a BMI ≥18.5 kg/m2 at Screening. Adolescent subjects must have a body weight ≥30 kg at 
Screening. The goal is to randomize approximately 1620 adult subjects in a 1:1:1 ratio 
(540 subjects per treatment arm) and approximately 40 adolescent subjects in a 
2:2:1 randomization scheme (16:16:8). 
1.3.4. 
Treatment and Duration of Exposure 
Approximately 1620 adult subjects and 40 adolescent subjects will be randomly assigned to 
receive brensocatib 10 mg QD, brensocatib 25 mg QD, or placebo QD for 52 weeks. 
1.3.5. 
Efficacy Endpoints and Placebo Control 
This study will assess the impact of brensocatib on the rate of PEs, lung function, and quality of 
life. Pulmonary exacerbations are key events in the natural history of patients with NCFBE and 
have the greatest impact on patient welfare, lung function, and healthcare utilization. Therefore, 
it is adequate to conduct the study in a double-blinded fashion, given that some of the endpoints 
incorporate patient symptomatology. This design will minimize biased responses based on 
knowledge of potentially receiving active agent(s) regardless of the study group to which a 
subject is randomized. A placebo comparator allows for the determination of the incremental 
benefit of brensocatib for this study population. 
1.4. 
Benefits and Risks for Study Subjects 
1.4.1. 
Potential Benefits 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of brensocatib is available in the Investigator’s Brochure. 
Brensocatib was previously investigated in a Phase 2 study in adult subjects with NCFBE 
(Study INS1007-201), during which subjects with NCFBE receiving brensocatib 10 mg or 
brensocatib 25 mg experienced statistically significant reductions in the occurrence of PEs on an 
annualized basis compared with subjects who received placebo (Section 1.2.2.3). Administration 
of brensocatib may result in beneficial effects for patients suffering from NCFBE via decreasing 
inflammation and mucus hypersecretion, leading to an improvement in respiratory symptoms 
(eg, cough and sputum production) and lung function (eg, FEV1) and a decrease in exacerbation 
rate. Since brensocatib prevents maturation of NSPs, it may lead to a meaningful decrease of the 
inflammatory cascade. 
1.4.2. 
Risks and Mitigation Strategies 
Potential study subjects will be screened for study eligibility according to predetermined 
inclusion and exclusion criteria in order to ensure an appropriate benefit/risk balance for study 
participants and validity of efficacy and safety assessments. Procedures to ensure double-
blinding of study drug and placebo will be in place. Measures to ensure validity of study efficacy 
results as well as subject safety will include specific guidance/prohibitions for use of 
concomitant medications and standardized safety reporting processes and procedures. A 
validated and well-defined primary efficacy endpoint has been established. Multiple safety 
assessments will be conducted; AESIs were predefined based on the mechanism of action for 
brensocatib (decreasing DPP1 activity) and safety findings from preclinical and clinical studies. 

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Procedures for detecting and reporting AESIs are specified in Section 9.10.3. Papillon-Lefѐvre 
syndrome is a rare autosomal recessive disease characterized by mutations of the DPP1 gene and 
near complete loss of DPP1 function and NSP activity. Patients with PLS do not suffer from 
major infections; and their main symptoms include palmoplantar hyperkeratosis and severe 
periodontitis. Based on these known symptoms of PLS and brensocatib as a DPP1 inhibitor, the 
AESIs associated with exposure to brensocatib include hyperkeratosis (Section 9.10.3.1), 
periodontitis/gingivitis (Section 9.10.3.2), and infections (Section 9.10.3.3). 
Overall, the aforementioned measures aim to provide an appropriate set of mitigation strategies 
to ensure the well-being of subjects enrolled in the trial. 
1.5. 
Randomization and Blinding 
In the adult population, upon meeting all inclusion criteria and none of the exclusion criteria, 
subjects will be randomized through IWRS (1:1:1) to brensocatib 10 mg QD, brensocatib 25 mg 
QD, or placebo QD. The randomization will be stratified by: (a) region (North America, Europe, 
Japan, and Rest of World), (b) Pseudomonas aeruginosa culture status at Screening (positive or 
negative), (c) the number of PEs (2 or ≥3) in the prior 12 months. In addition, randomization will 
be enforced to have approximately 30% of adult subjects with 3 or more prior PEs, to have no 
more than 20% of subjects older than 75 years of age, to have approximately no more than 20% 
of subjects with eosinophil count in peripheral blood ≥300/mm3 at Screening, and to have no 
more than 20% of subjects with COPD as comorbidity. 
Enrollment targets have been established for adult subjects with up to 13% of subjects from 
Eastern Europe and with North America, Western Europe, Asia Pacific, and Latin America 
contributing between 20% and 30% each. No single country (except the US) will contribute 
more than 15% of the overall randomized population. 
Adolescent subjects who meet all inclusion criteria and none of the exclusion criteria will be 
randomized through IWRS (2:2:1) to brensocatib 10 mg QD, brensocatib 25 mg QD, or placebo 
QD. There will be no stratification criteria applied to adolescent subjects. 
Investigators and Sponsor will be blinded to treatment group assignments throughout the study. 
Unblinding is only to occur in the case of subject emergencies (Section 5.6) and at the 
conclusion of the study. 
1.6. 
Treatment, Route, Dosage, Treatment Period 
Eligible subjects with NCFBE who have signed the ICF (or assent form if required per local 
requirements) will receive treatment as follows: 
• Brensocatib 10 mg QD, orally, before breakfast, for 52 weeks 
• Brensocatib 25 mg QD, orally, before breakfast, for 52 weeks 
• Matching placebo for brensocatib QD, orally, before breakfast, for 52 weeks 
1.7. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles derived from 
international guidelines including the Declaration of Helsinki, the Council for International 

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Organizations of Medical Sciences, International Ethical Guidelines, ICH, GCP Guidelines, and 
applicable local regulatory requirement(s) and laws. 
1.7.1. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The Sponsor will observe the rules laid down in the European Data Protection Directive 
2016/679 of 27 April 2016 on the protection of natural persons with regard to the processing of 
personal data and the free movement of such data. 
The Investigator must ensure that the subject’s anonymity is maintained. On the eCRF or other 
documents submitted to Sponsor, subjects should be identified by a unique subject identifier as 
designated by the Sponsor. Documents that are not for submission to Sponsor (eg, signed ICFs) 
should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the EC or 
IRB direct access to review the subject’s original medical records for verification of study-
related procedures and data. The Investigator is obligated to inform the subject that his/her study-
related records will be reviewed by the above-named representatives without violating the 
confidentiality of the subject. 
1.7.2. 
Informed Consent Procedure 
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject or legally acceptable representative after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study and 
before any protocol-specific screening procedures or any study drugs are administered. A legally 
acceptable representative is an individual or other body authorized under applicable law to 
consent, on behalf of a prospective subject, to the subject’s participation in the clinical study. An 
informed consent document that includes both information about the study and the consent form 
will be prepared and given to the subject. This document will contain all the elements required 
by the ICH E6 (R2) Guideline for GCP and any additional elements required by local 
regulations. The written ICF should be prepared in the local language(s) of the potential subject 
population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the IRB/EC and by the health authority where applicable prior to being provided to 
potential subjects. 
The subject’s written informed consent (written or electronic) should be obtained prior to his/her 
participation in the study and should be documented in the subject’s medical records, as required 
by applicable regulations. The ICF should be signed and personally dated by the subject or a 
legally acceptable representative, and by the person who conducted the informed consent 
discussion (not necessarily the Investigator). The signed ICF should be retained in accordance 
with institutional policy, and a copy of the signed consent form should be provided to the subject 

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or legal representative. The date that informed consent was given should be recorded in the 
eCRF. 
Adolescent subjects must sign a study assent form (if required per local requirements) to 
participate in the study, and the subject’s parent or legal guardian must sign and date a study-
specific consent form. Adolescent subjects must be reconsented if they reach the age of majority 
during the study, in order to continue participating. The assent form (if required per local 
requirements) will comply with all applicable regulations governing the protection of human 
subjects. An assent form (if required per local requirements) must be approved by the IRB/EC 
and by the health authority, where applicable, prior to being provided to potential subjects. 
1.7.3. 
Regulatory Compliance 
The study protocol, subject information and consent form, adolescent assent form (if required per 
local requirements), the Investigator brochure, any subject diary card or written instructions to be 
given to the subject, available safety information, subject recruitment procedures (eg, 
advertisements), information about payments and compensation available to the subjects and 
documentation evidencing the Investigator’s qualifications should be submitted to the IRB/EC 
for ethical review and approval according to local regulations, prior to the study start. The 
written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
All protocol amendments and changes to the ICFs and assent form (if required per local 
requirements) or changes of the investigational site, facilities, or personnel (when applicable) 
must be submitted to the IRB/EC (and the health authority, if applicable), and where necessary, 
approval from the IRB/EC (and the health authority, if applicable) must be obtained. The 
Investigator should notify the IRB/EC of deviations from the protocol or SAEs occurring at the 
site and other AE reports received from the Sponsor, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group will ensure all 
legal aspects are covered, and approval of the appropriate regulatory bodies obtained, prior to 
study initiation, and that implementation of changes to the initial protocol and other relevant 
study documents happen only after the appropriate notification of or approval by the relevant 
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2. 
STUDY OBJECTIVES AND ESTIMANDS 
The primary estimand for efficacy endpoints is the On-Study estimand. The treatment regimen in 
the On-Study estimand will be the randomized IP (ie, study treatment) plus standard of care 
taken up to 52 weeks irrespective of whether a new chronic antibiotic is added during the 
treatment period for prevention of future PE.  
The supportive estimand for efficacy endpoints is the On-Treatment estimand as described in 
Section 10.4.6.1.4. The treatment regimen in the On-Treatment estimand for efficacy endpoints 
will include only the randomized study treatment plus standard of care taken up to 52 weeks 
without addition of new chronic antibiotics during the treatment period. 
Additional details will be provided in the SAP. 
2.1. 
Primary Objective and Estimand 
The primary objective and estimand in subjects with NCFBE are presented in Table 1. 
Table 1: 
Primary Objective and Estimand 
Objective 
Variable 
(or Endpoint) 
Population 
Level 
Summary 
Estimand 
Name 
Treatment 
Regimena 
ICEs/Strategy 
To evaluate the effect of 
brensocatib at 10 mg 
and 25 mg compared 
with placebo 
Annualized rate 
of PEs 
Rate ratio 
Primary: 
On-Study 
Standard of care 
+ randomized IP 
and/or addition of 
a chronic 
antibiotic 
Early discontinuation from 
randomized IP/ Treatment 
Policy 
Early discontinuation from 
standard of care/ Treatment 
Policy 
Addition of chronic 
antibiotics/ Treatment Policy 
a Randomized IP (ie, study treatment) includes brensocatib 10 mg QD, brensocatib 25 mg QD, or placebo in a 
1:1:1 ratio for adult subjects and a 2:2:1 ratio for adolescent subjects. 
PE = pulmonary exacerbation; ICE = intercurrent event; IP = investigational product 
2.2. 
Secondary Objectives and Estimands 
The secondary objectives and estimands in subjects with NCFBE are presented in Table 2.  
Table 2: 
Secondary Objectives and Estimands 
Objective 
Variable 
(or Endpoint) 
Population 
Level 
Summary 
Estimand 
Name 
Treatment 
Regimena 
ICEs/Strategy 
Efficacy 
 
 
 
 
 
To evaluate the effect 
of brensocatib 
compared with placebo 
on 
Time to first PE 
Hazard ratio 
Primary: 
On-Study 
Standard of care 
+ randomized IP 
and/or addition of 
a chronic 
antibiotic 
Early discontinuation from 
randomized IP/ Treatment 
Policy 
Early discontinuation from 
standard of care/ Treatment 
Policy 
Addition of chronic 
antibiotics/ Treatment Policy 

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Objective 
Variable 
(or Endpoint) 
Population 
Level 
Summary 
Estimand 
Name 
Treatment 
Regimena 
ICEs/Strategy 
 
Responder status 
for exacerbation 
free 
Odds ratio 
Primary: 
On-Study 
Standard of care 
+ randomized IP 
and/or addition of 
a chronic 
antibiotic 
Early discontinuation from 
randomized IP/ Treatment 
Policy 
Early discontinuation from 
standard of care/ Treatment 
Policy 
Addition of chronic 
antibiotics/ Treatment Policy 
 
Change in 
postbronchodilat
or FEV1 at 
Week 52 
Mean 
difference 
Primary: 
On-Study 
Standard of care 
+ randomized IP 
and/or addition of 
a chronic 
antibiotic 
Early discontinuation from 
randomized IP/ Treatment 
Policy 
Early discontinuation from 
standard of care/ Treatment 
Policy 
Addition of chronic 
antibiotics/ Treatment Policy 
 
Annualized rate 
of severe PEs 
Rate ratio 
Primary: 
On-Study 
Standard of care 
+ randomized IP 
and/or addition of 
a chronic 
antibiotic 
Early discontinuation from 
randomized IP/ Treatment 
Policy 
Early discontinuation from 
standard of care/ Treatment 
Policy 
Addition of chronic 
antibiotics/ Treatment Policy 
 
Change in QOL-
B Respiratory 
Symptoms 
Domain Score at 
Week 52b 
Mean 
difference 
Primary: 
On-Study 
Standard of care 
+ randomized IP 
and/or addition of 
a chronic 
antibiotic 
Early discontinuation from 
randomized IP/ Treatment 
Policy 
Early discontinuation from 
standard of care/ Treatment 
Policy 
Addition of chronic 
antibiotics/ Treatment Policy 
Safety 
 
 
 
 
 
To evaluate the effect 
of brensocatib 
compared with placebo 
on    
Adverse events 
— 
— 
— 
— 
Clinical 
laboratory 
parameters, vital 
signs, and ECGs 
— 
— 
— 
— 
Pharmacokinetic 
 
 
 
 
 
To evaluate brensocatib 
exposure in adults and 
adolescents 
 
Brensocatib 
plasma 
concentrations 
over time 
— 
— 
— 
— 
ECG = electrocardiogram; FEV1 = forced expiratory volume in 1 second; ICE = intercurrent event; 
IP = investigational product; PE = pulmonary exacerbation; QoL-B = Quality of Life Questionnaire – 
Bronchiectasis. 
a Randomized IP (ie, study treatment) includes brensocatib 10 mg QD, brensocatib 25 mg QD, or placebo in a 
1:1:1 ratio for adult subjects and a 2:2:1 ratio for adolescent subjects. 
b The population for change in QOL-B Respiratory Symptoms Domain Score at Week 52 will be adult subjects with 
NCFBE. 
 

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2.3. 
Exploratory Objectives and Endpoints 
The exploratory objectives and endpoints are presented in Table 3.  
Table 3: 
Exploratory Objectives and Endpoints 
Objective 
Endpoint 
1. To evaluate the effect of brensocatib 
compared with placebo on daily symptoms, as 
assessed by the average daily BEST score 
over the 52-week treatment period 
Average daily change from Baseline in BEST 
score over the 52-week treatment period 
2. To evaluate the effect of brensocatib 
compared with placebo on the average 
duration of PEs over the 52-week treatment 
period 
Duration of adjudicated PEs over the 52-week 
treatment period 
3. To evaluate the effect of brensocatib 
compared with placebo on the number of days 
of hospitalization due to PEs over the 52-week 
treatment period 
Days hospitalized due to adjudicated PEs per 
patient year over the 52-week treatment period  
4. To evaluate the effect of brensocatib 
compared with placebo on the number of days 
of absence from work (or number of days of 
school absence in case the subject is of school 
age) due to PEs over the 52-week treatment 
period 
Days of absence from work/school due to 
adjudicated PEs per patient year over the 52-week 
treatment period 
5. To evaluate the effect of brensocatib 
compared with placebo on lung function, as 
measured by change in pulmonary function 
parameters including prebronchodilator and 
postbronchodilator FEV1, FVC, PEFR, 
ppFEV1, and FEF(25-75%) over the 52-week 
treatment period 
Change from Baseline in prebronchodilator and 
postbronchodilator FEV1, FVC, PEFR, ppFEV1, 
and FEF(25-75%) at Weeks 16, 28, 40, 52, and over 
52 weeks 
6. To evaluate the effect of brensocatib 
compared with placebo on health care 
resource utilization (outpatient visits, ER 
visits, hospitalization for any reason) over the 
52-week treatment period 
Outpatient visits, ER visits, and hospitalizations 
for any reason  
7. To evaluate the effect of brensocatib 
compared with placebo on quality of life, as 
assessed by the age-appropriate QOL-PCD 
domain scores over the 52-week treatment 
period in adolescent subjects (≥12 to 
<18 years of age) with PCD 
Change in QOL-PCD domain scores from 
Baseline to Weeks 16, 28, 40, 52, and Over 
52 Weeks in adolescent subjects (≥12 to 
<18 years of age) with PCD 
8. To evaluate the effect of brensocatib 
compared with placebo on quality of life, as 
Change from Baseline in EQ-5D-5L score from 
Baseline to Week 52 

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Objective 
Endpoint 
assessed by the EuroQoL-5D-5L over the 
52-week treatment period 
9. To evaluate the effect of brensocatib 
compared with placebo on QOL, as assessed 
by the QOL-B domains over the 52-week 
treatment period in adult subjects 
Change from Baseline in QOL-B domain scores 
to Weeks 16, 28, 40, and 52 in adult subjects 
10. To evaluate the effect of brensocatib 
compared with placebo on PGI-S and PGI-C 
scales over the 52-week treatment period in 
adult subjects 
Change in PGI-S and PGI-C from Baseline to 
Weeks 16, 28, 40, and 52 in adult subjects 
11. To evaluate the effect of brensocatib 
compared with placebo on the rate of decline 
in prebronchodilator and postbronchodilator 
FEV1 over the 52-week treatment period 
Rate of change in prebronchodilator and 
postbronchodilator FEV1 over the 52-week 
treatment period 
12. To evaluate the effect of brensocatib 
compared with placebo on the progression of 
lung damage as evaluated by CT scan over the 
52-week treatment period 
Change from Baseline in BEST-CT and Airway-
Artery scores at Week 52  
13. To evaluate the effect of brensocatib 
compared with placebo on the concentration 
of biomarkers (NE, CatG, PR3) in sputum 
over the 52-week treatment period 
Change in concentration of sputum NE, CatG, and 
PR3 from Baseline to Week 52 
14. To evaluate the effect of brensocatib 
compared with placebo on the concentration 
of biomarkers (NE, CatG, PR3) and neutrophil 
functions in blood over the 52-week treatment 
period 
Change in concentration of blood NE, CatG, PR3, 
and neutrophil functions from Baseline to 
Week 52 
15. Population PK analysis  
Estimated PK parameters (eg, Cmax, AUC, t½) 
using population PK analysis approach. Specified 
in a separate SAP 
16. Population PK/PD relationship evaluation 
Relationships between brensocatib exposure and 
response (safety, efficacy, and biomarker 
measurements) over the 52-week treatment 
period. Specified in a separate SAP 
AUC = area under the concentration versus time curve; BEST = Bronchiectasis Exacerbation and Symptom Tool; 
BEST-CT = Bronchiectasis Scoring Technique for Computed Tomography; CatG = cathepsin G; Cmax = maximum 
observed concentration; CT = computed tomography; ER = emergency room; EuroQoL-5D-5L and 
EQ-5D-5L = EuroQoL-5 Dimension-5 Level Questionnaire; FEF(25 75%) = forced expiratory flow between 25% and 
75% of forced vital capacity; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; 
NE = neutrophil elastase; PD = pharmacodynamic; PE = pulmonary exacerbation; PEFR = peak expiratory flow 
rate; PGI-C = Patient Global Impression of Change scale; PGI-S = Patient Global Impression of Severity scale; 
PK = pharmacokinetic; ppFEV1 = percent predicted forced expiratory flow in 1 second; PR3 = proteinase 3; QOL-
B = Quality of Life Questionnaire - Bronchiectasis; QOL-PCD = Quality of Life instrument for Primary Ciliary 
Dyskinesia; SAP = statistical analysis plan; t½ = half-life. 

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3. 
STUDY DESIGN 
3.1. 
Overall Plan 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
multinational study to assess the efficacy, safety, and tolerability of 2 doses of brensocatib 
compared with placebo in subjects with NCFBE.  
Approximately 1620 adult subjects will be randomized in a 1:1:1 ratio to 3 treatment arms 
(540 subjects per treatment arm) to receive brensocatib 10 mg QD, brensocatib 25 mg QD, or 
matching placebo QD for 52 weeks. Randomization will be stratified based on the geographic 
region (North America, Europe, Japan, and the Rest of the World), sputum sample testing 
positive or negative for Pseudomonas aeruginosa at Screening Visit, and the number of prior 
PEs (2, or ≥3) in the previous 12 months. In addition, randomization will be enforced to have 
approximately 30% of adult subjects with 3 or more prior PEs, to have no more than 20% of 
subjects older than 75 years of age, to have approximately no more than 20% of subjects with 
eosinophil count in peripheral blood ≥300/mm3 at Screening, and to have no more than 20% of 
subjects with COPD as a comorbidity. Enrollment targets have been established for adult 
subjects with up to 13% of subjects from Eastern Europe and with North America, Western 
Europe, Asia Pacific, and Latin America contributing between 20% and 30% each. No single 
country (except the US) will contribute more than 15% of the overall randomized population.  
For this study, the adolescent population is defined as subjects ≥12 to <18 years of age at 
Screening. Approximately 40 adolescent subjects will be randomly assigned in a 2:2:1 ratio to 
receive brensocatib 10 mg QD, brensocatib 25 mg QD, or matching placebo QD for 52 weeks. 
No stratification criteria will be applied to randomization of adolescent subjects. 
All adult subjects will produce a sputum sample at the Screening Visit to evaluate the 
presence/absence of Pseudomonas aeruginosa as per the stratification criteria. Adolescent 
subjects will not be required to produce a sputum sample at the Screening Visit if they are unable 
to do so. Spontaneous or induced sputum is a reliable and accessible source of specimens for 
microbiological analysis in adults; however, collecting sputum from young children is 
problematic as they find it difficult to expectorate (Pizzutto et al., 2017). Adolescent subjects 
who are unable to produce a sputum sample will have their P. aeruginosa test result recorded as 
negative. 
Subjects will receive instruction for entering data into electronic devices. After Baseline, subjects 
will return to the study site for in-clinic visits at Weeks 4, 16, 28, 40, 52 (EOT), and 56 (EOS), 
during which they will be assessed for PEs, and undergo clinical laboratory tests, PK and PD 
evaluations (adults only), vital sign measurements, and patient-reported outcome measures 
(Section 7.5). In addition, collection of the days of work and/or school missed due to PE will 
occur along with collection of healthcare visit information (eg, type of visit [hospitalization, 
doctor, or E R]), reason for visit, visit date). Telephone visits will occur at Weeks 10, 22, 34, 46, 
during which collection of AEs, concomitant medications, smoking status, periodontal 
complaints, patient-reported outcome measures (as mentioned above), urine pregnancy test 
results from WOCBP, and assessment for occurrence of PEs will occur. At Visit 11 
(Week 52/EOT) subjects will discontinue all study treatment and will be followed for a 1-month 
follow-up period, during which initiation of any new medical or non-medical therapy for NCFBE 

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should be avoided. At Visit 12 (Week 56/EOS), subjects will complete all protocol-specified 
assessments and EOS procedures. The Schedule of Assessments is provided in Table 5. 
PK/PD Substudy 
The study will include a PK/PD substudy at select sites with proper laboratory capabilities. The 
substudy will include approximately 300 adult subjects who are not receiving cyclic antibiotics 
at Baseline and from whom additional blood PK and sputum PD samples will be collected, with 
blood PD samples collected from approximately 40 of these subjects. In addition, blood PK and 
sputum PD samples will be collected from all adolescent subjects who are not receiving cyclic 
antibiotics at Baseline (blood PD samples will not be collected from adolescents). Adult subjects 
must provide informed consent to participate in the PK/PD substudy and the blood PD aspect of 
the PK/PD substudy; the parent or legal guardian must provide informed consent for adolescent 
subjects.  
Sample collections for each aspect of the PK/PD substudy are listed below: 
• Blood PK component of the substudy: Blood samples for concentration of study drug 
will be collected as indicated in Appendix 5. 
• Sputum PD component of the substudy: A sputum sample (approximately 3 mL) for 
NE, CatG, and PR3 concentrations will be collected as indicated in Appendix 6. 
Sputum induction is allowed for PD sputum sample collection except at Screening 
(Appendix 1). Adolescent subjects will not be required to produce a sputum sample if 
they are unable to do so. 
• Blood PD component of the substudy (adult subjects in the US only): Blood samples 
for evaluation of NE, CatG, PR3 and other neutrophil functions will be collected as 
indicated in Appendix 6. 
The PK/PD substudy is described in detail in Section 8. 
CT Scan Substudy 
The study will also include a CT scan substudy with approximately 225 adult subjects. This 
substudy will include 2 study-specific high-resolution CT scans to be conducted at the Screening 
Visit and the Week 52 Visit as described in Section 7.6. Subjects must provide informed consent 
to participate in the CT scan substudy. 
Please note: Participation in both the PK/PD and CT scan substudies is permitted; ie, 
participation in one of the substudies does not preclude participation in the other.  
A study schematic is provided in Figure 1. The procedures and assessments conducted at each 
study visit in the study are provided in Table 5. 

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Figure 1: 
Schematic for Study INS1007-301 
 
3.2. 
Data Monitoring Committee and Steering Committee 
An independent, external DMC will be set up to review all AEs and SAEs to ensure the safety of 
subjects enrolled into this study. The DMC members will review the data in a semi-blinded or 
unblinded manner at predetermined intervals. If significant safety issues arise in between 
scheduled meetings, ad hoc meetings will be scheduled to review those data. Further details of 
the DMC will be provided separately in the DMC Charter. 
The primary endpoint parameter of this study is PE. An independent adjudication committee 
(AC) composed of pulmonary physicians will adjudicate all reported PE events to determine if 
they fulfill the protocol definition. Adjudication outcomes will be used in creation of analysis 
datasets. Details of the AC will be provided separately in the AC charter. 
In addition, an independent Steering Committee will be established to provide study oversight 
including but not limited to the medical, scientific, operational, safety, and external 
communication of the study. Details of the Steering Committee will be provided separately in the 
Steering Committee Charter. 

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3.3. 
Duration of Subject Participation 
The maximum study duration will be up to 62 weeks for an individual participant, including a 
Screening Period of up to 6 weeks, a treatment period of 52 weeks, and an EOS Visit 4 weeks 
following the end of treatment. 
3.4. 
End of Study 
The EOS visit date for analysis of subjects is defined as the date of the last visit for the last 
subject in the study. 
A subject will be considered to have completed the study if he/she has completed all study visits, 
including the Week 52 Visit.  

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4. 
STUDY POPULATION 
4.1. 
Enrollment 
The subjects in this study will be enrolled at over 400 study sites located in North America, 
Europe, Japan, and the Rest of the World. The adolescent subjects will be enrolled in 
participating countries and sites where local regulations, countries, and/or institutional policies 
allow for patients <18 years of age to participate.  
To be eligible for enrollment, subjects must meet all of the following inclusion criteria and none 
of the following exclusion criteria. 
4.1.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Provide their signed study informed consent to participate. 
a. Adolescent subjects must have signed study assent form (if required per local 
requirements) to participate, and the adolescent’s parent or legal guardian must have 
provided signed informed consent for the adolescent to participate 
2. Male or female ≥18 years and ≤85 years of age at Screening. 
a. Adolescent subjects – male or female ≥12 to <18 years of age at Screening in 
participating countries and sites where local regulations, countries, and/or 
institutional policies allow for subjects <18 years of age to participate 
3. Adult subjects must have a BMI ≥18.5 kg/m2 at Screening. 
a.  Adolescent subjects must have a weight of ≥30 kg at Screening 
4. Clinical history consistent with NCFBE (cough, chronic sputum production and/or 
recurrent respiratory infections) that is confirmed by chest CT demonstrating 
bronchiectasis affecting one or more lobes (confirmation may be based on prior chest 
CT). 
a. For each subject, the most recent chest CT scan (but not older than 5 years before the 
Screening date) will be selected for transfer to the central reading facility for 
confirmation of the diagnosis of NCFBE. 
b. If the CT scan cannot be read by the reviewers due to quality issues, a new 
high-resolution CT scan will be performed. 
c. In case a chest CT scan in the last 5 years is not available, a new high-resolution chest 
CT scan must be obtained for confirmation of the diagnosis of NCFBE by the central 
reading facility. 
5. Postbronchodilator FEV1 at the Screening Visit ≥30% of predicted normal value, 
calculated using National Health and Nutrition Examination Survey reference equations 
and must have an absolute value ≥750 mL. 
6. Adult subjects: Current sputum producer with a history of chronic expectoration of at 
least 3 months in the past 12 months, and able to provide sputum sample during 
Screening (Visit 1). If a subject is unable to produce sputum spontaneously during 

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Screening, the subject will be considered a screen failure. The subject should not undergo 
a sputum induction procedure during Screening to meet inclusion criterion. 
a. Adolescent subjects are exempt from the requirement to provide a sputum sample if 
they are unable to do so and should not undergo a sputum induction procedure during 
Screening. 
7. Mucopurulent or purulent sputum color assessed at the Screening Visit by color chart 
developed by MP Murray (Murray et al., 2009). Adolescent subjects who are unable to 
provide a sputum sample at Screening are exempt from this requirement. 
8. 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 subjects are required to have at least 1 pulmonary exacerbation in the 
prior 12 months 
9. 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. Such methods include true 
abstinence (refraining from heterosexual intercourse during the study); combined 
(estrogen and progestogen-containing) or progestogen-only hormonal contraception 
associated with inhibition of ovulation and supplemented with a double barrier 
(preferably male condom); intrauterine devices; intrauterine hormone-releasing systems; 
or vasectomized partner. The Investigator or designee should explain the acceptable 
methods of birth control to the subject and instruct the subject to follow the direction. For 
WOCBP ≤45 years of age, testing of FSH level should be performed; a threshold of 
>40 mIU/mL should be met to be considered infertile. 
Note: Abstinence is only considered to be a highly effective method of contraception 
when this is the preferred and usual lifestyle of a subject. Periodic abstinence (calendar, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method are not acceptable methods of contraception. 
10. Male subjects with female partners of childbearing potential must be using effective 
contraception from Day 1 to at least 90 days after the last dose. Acceptable methods 
include true abstinence (refraining from intercourse during the study), combined 
(estrogen and progestogen-containing) or progestogen-only hormonal contraception 
associated with inhibition of ovulation, intrauterine devices, intrauterine hormone- 
releasing systems. 
11. Male subjects with pregnant or non-pregnant WOCBP partners must use condoms to 
avoid potential exposure to the embryo/fetus. 

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4.1.2. 
Exclusion Criteria 
Subjects are not eligible to participate in the study if they meet any of the following criteria: 
1. A primary diagnosis of COPD or asthma as judged by the Investigator. Patients with 
comorbid COPD and/or asthma can be enrolled if bronchiectasis is their primary 
diagnosis. 
2. Subjects receiving supplemental oxygen >12 hours per day. 
3. Bronchiectasis due to cystic fibrosis. 
4. Current smokers as defined per CDC: an adult who has smoked 100 cigarettes in his or 
her lifetime and who currently smokes cigarettes. 
5. No evidence of bronchiectasis according to the BE-CT scoring system. 
6. Known or suspected immunodeficiency disorder, including history of invasive 
opportunistic infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent 
infections of abnormal frequency, or prolonged infections suggesting an immune-
compromised status, as judged by the Investigator. 
7. Known history of HIV infection. 
8. Established diagnosis of hepatitis B viral infection at the time of Screening, or positive 
for HBsAg at the time of Screening. 
Subjects who have gained immunity for hepatitis B virus infection after vaccination 
(subjects who are HBsAg-negative, HBsAb-positive, and HBcAb-negative are eligible 
for the study). 
Subjects with positive HBcAb are eligible for the study only if hepatitis B virus DNA 
level is undetectable. 
9. Established diagnosis of HCV infection at the time of Screening. Subjects positive for 
hepatitis C antibody are eligible for the study only if HCV RNA is negative. 
10. Currently being treated for NTM lung infection, allergic bronchopulmonary aspergillosis, 
or TB. 
11. Active and current symptomatic infection by COVID-19. 
12. Unable to perform technically acceptable spirometry that meet the ATS/ERS 
acceptability criteria with at least 3 acceptable flow-volume curves, at least 2 of which 
meet the ATS/ERS repeatability criteria for FEV1 during Screening. 
13. Inability to follow the procedures of the study (eg, due to language problems or 
psychological disorders). 
14. Receiving medications or therapy that are prohibited as concomitant medications (see 
Section 5.11.1 for prohibited concomitant medications). 
15. Started oral or inhaled antibiotics as chronic treatment for NCFBE <3 months prior to the 
Screening Visit. 

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a. Subjects on antibiotics as chronic treatment should be on such treatment for at least 
3 months prior to Screening while meeting all other inclusion criteria and none of the 
exclusion criteria. 
16. Chronic treatment with oral steroids (irrespective of the indication) is prohibited 
17. Subjects who have adjustments to their baseline medications within 1 month before 
Screening; they can be rescreened a month after the new treatment has been initiated. 
18.  Abnormal renal function test result (eGFR <30 mL/min by Chronic Kidney Disease - 
Epidemiology Collaboration equation formula) at Screening. 
19. Active liver disease or hepatic dysfunction manifested as follows: 
a. ALT or AST >3 × ULN. 
b. Total bilirubin >2 × ULN (isolated bilirubin >2 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
c. Known hepatic or biliary abnormalities, not including Gilbert's syndrome or 
asymptomatic gallstones. 
d. Child-Pugh class C. 
20. History of malignancy in the past 5 years, except completely treated in situ carcinoma of 
the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the 
skin. 
21. Previously participated in a clinical trial for brensocatib. 
22. An absolute neutrophil count <1,000/mm3 at the Screening Visit. 
23. Received any live attenuated vaccine within 4 weeks prior to Screening. If a live vaccine 
has been administered the subject should wait 4 weeks prior to Screening. During the 
study, subjects may not receive any live attenuated vaccine. 
24. Significant hemoptysis (≥300 mL or requiring blood transfusion) within 6 weeks prior to 
the Screening Visit or during the Screening Period. 
25. Have diagnosed periodontal disease and are either: 
a.  Currently treated by a dentist for this condition or 
b.  Expected to have periodontal disease-related procedures within the study period. 
26. Suffering an exacerbation 4 weeks before Screening or during the Screening Period. In 
this case, subjects will be considered a screen failure. Subjects are eligible for rescreen 
only after recovery and 4 weeks after last dose of antibiotic treatment (see Section 4.2.4, 
Subject Rescreening Procedures). 
27. Adult subjects 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. 
28. Participated in any other interventional clinical studies within 3 months before Screening 
Visit. 
29. Clinical diagnosis of Papillon-Lefèvre Syndrome. 

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30. Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect 
the subject's participation in the study. Examples include but are not limited to short life 
expectancy, uncontrolled diabetes, cardiovascular conditions (eg, NYHA Class III or IV 
cardiac failure), severe renal conditions (eg, severe nephrotic syndrome), hepatobiliary 
conditions, neurological conditions (eg, demyelinating diseases), active major 
autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), 
other severe endocrinologic, gastrointestinal, metabolic, pulmonary, or lymphatic 
diseases. The specific justification for subjects excluded under this criterion will be noted 
in study documents (chart notes, eCRF, etc.). 
31. Any clinically significant abnormal laboratory values at Screening or diseases or 
disorders (eg, survivors of severe COVID-19 disease including ARDS, cardiovascular, 
pulmonary, gastrointestinal, liver, kidney, neurological, musculoskeletal, endocrine, 
metabolic, psychiatric, physical impairment, or a lung transplantation) that, in the opinion 
of the Investigator, may put the subject at risk by participating in the study, or interfere 
with the subject's treatment, assessment, or influence the results of the study, or have 
compliance issues with the study or have a planned or anticipated major surgical 
procedure during the study. 
32. History of alcohol or drug abuse within 6 months prior to the Screening Visit. 
33. Any other medical or psychological condition including relevant laboratory abnormalities 
at Screening that, in the opinion of the Investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the study subject as a result of 
his/her participation in this clinical trial, may make subject’s participation unreliable, or 
may interfere with study assessments. The specific justification for subjects excluded 
under this criterion will be noted in study documents. 
34. 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. 
35. Known history of hypersensitivity to brensocatib or any of its excipients. 
4.2. 
Discontinuation of Study Treatment and Participant 
Discontinuation/Withdrawal 
4.2.1. 
Discontinuation of Study Treatment 
All subjects are encouraged to stay in the study regardless of study treatment discontinuation. 
Any subject who discontinues from the study treatment will have the reason for discontinuing 
treatment recorded and will be encouraged to continue to attend the remaining scheduled study 
visits and to complete patient-reported outcome measures assessed between study visits (Table 5, 
Section 7.5 ).  
4.2.2. 
Participant Discontinuation/Withdrawal from the Study 
A subject may decide to withdraw from the study at any time, for any reason. The Investigator 
and/or Sponsor also have the right to withdraw a subject from the study if it is no longer in the 
interest of the subject to continue in the study, or if the subject’s continuation in the study places 
the scientific outcome of the study at risk (eg, if a subject does not or cannot follow study 

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procedures). All subjects who are withdrawn from the study should complete protocol-specified 
early discontinuation procedures (Section 4.2.2.2). 
4.2.2.1. 
Reasons for Withdrawal/Early Discontinuation 
A subject may decide to withdraw from the study at any time, for any reason, without prejudice 
to subsequent care or treatment by the Investigator. When this occurs, the subject should 
complete all the procedures for the Week 52 (EOT) Visit. Subjects who discontinue the 
treatment due to AEs should remain under observation until the resolution or stabilization of the 
AEs. A subject may be discontinued from the study drug treatment before completion for any of 
the following reasons: 
1. Subject death 
2. Subject experiences an AE(s)/SAE(s) that warrants discontinuation, as judged by the 
Investigator and/or Insmed Medical Director 
3. A major protocol deviation, which, in the opinion/discretion of the Investigator and/or 
Insmed, compromises the data integrity of the study 
4. Subject is noncompliant with the study drug treatment (defined as <80% compliance after 
at least 2 reeducation efforts) 
5. Withdrawal by subject 
6. Termination of the study by the Sponsor 
7. Investigator discretion 
8. Subject lost to follow-up 
9. Subject pregnancy 
10. Periodontal criteria met (see Section 9.10.3.2) 
11. Skin criteria met (see Section 9.10.3.1) 
12. Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin 
13. Serious infection, defined as any infection other than associated with a pulmonary 
exacerbation that: 
a. Requires parenteral treatment with an antibiotic requiring admission to the hospital, 
or parenteral treatment with an antifungal, antiviral, antiparasitic, or antiprotozoal 
agent 
b. Is opportunistic, such as TB or other infections whose nature or course may suggest 
an immunocompromised status 
14. Subjects who develop neutropenia defined as ANC <1000/mm3 
15. Subjects who have the following: 
a.  ALT and/or AST values >3 × ULN and total bilirubin >2 × ULN, excluding 
confirmed Gilbert’s Syndrome 
b. Confirmed AST and/or ALT >5 × ULN (for more than 2 weeks). 

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Except for those subjects who withdraw consent, die, or are lost to follow-up, subjects who 
discontinue their assigned study drug will be encouraged to continue to participate in their 
remaining scheduled study visits. Every effort should be made by the Investigator to keep these 
subjects in the study through Visit 11. “Lost to follow-up” should be marked only in an 
exceptional case when all documented attempts to reach the subject by the Investigator or other 
staff members were unsuccessful. 
4.2.2.2. 
Early Discontinuation Procedures 
If a subject prematurely discontinues the study, the subject will have: 
• An EOT Visit; however, the Investigator should contact the medical monitor to 
determine if the EOT CT assessment will be needed for subjects in the CT scan 
substudy. 
If a subject withdraws from the study, the Investigator will complete and report the observations 
as thoroughly as possible up to the date of withdrawal including the date of last treatment and the 
reasons for withdrawal. 
If the subject is discontinued from the study due to an AE, the Investigator will follow the 
subject as described in Section 9.10  and Section 9.12 . 
4.2.2.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up from the study if the site is unable to contact the 
subject after 3 reasonable efforts have been made and a certified letter has been sent to 
subject/family. 
4.2.3. 
Subject Replacement 
Subjects who prematurely discontinue from the study after randomization will not be replaced, 
except for those who are replaced due to the war in Ukraine as agreed with FDA and EMA. 
4.2.4. 
Subject Rescreening Procedures 
Subjects who meet all inclusion criteria but fail Screening due to active PE, adjustment of 
Baseline medications within 1 month prior to Screening, or use of chronic oral or inhaled 
antibiotics for NCFBE ≤3 months prior to Screening can be rescreened up to 2 times with the 
Sponsor’s Medical Director approval. Subjects who are undergoing standard dental care may be 
enrolled if the dental care is not related to periodontal disease and after consultation with the 
Medical Director. If a subject is approved for rescreening, the Medical Director will determine if 
some or all Screening assessments must be repeated. Rescreened subjects will be assigned a new 
Subject Number by the IWRS system. 
4.3. 
Premature Termination of the Study 
The Investigator may terminate a subject’s participation in the study prematurely at their own 
discretion; if this occurs, the Investigator must contact the Sponsor immediately. The Sponsor 
may decide to terminate the participation of a site in the study or decide to terminate the study 
prematurely; if this occurs, written notification of the study termination is required to be sent to 
the site. 

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Conditions that may warrant study termination may include the following: 
• Discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled 
in the study 
• Failure of the Investigator to enter study subjects at an acceptable rate 
• Insufficient adherence to protocol requirements (eg, noncompliance) by the subject 
and/or the study site 
• Decision on the part of the Sponsor to suspend or discontinue development of the 
drug 
• Decision by a regulatory authority or the Sponsor to stop the study at any time, where 
applicable 
In the event of study discontinuation, subjects will discontinue study treatment. Refer to 
Section 4.2.2.2 for early discontinuation procedures. 
The Sponsor will notify the regulatory authorities in all countries where the study is being 
conducted regarding the reason for terminating the study. 

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5. 
STUDY TREATMENT 
The Investigator must ensure that the study treatment will be used only in accordance with the 
protocol. 
5.1. 
Study Treatments Administered 
5.1.1. 
Brensocatib 
Brensocatib oral tablets have been developed for clinical studies and will be available for this 
study in strengths of 10- and 25-mg. The 2 strengths are round, biconvex, brown film-coated 
tablets, identical in size and appearance. The tablets are an immediate-release dosage form. 
Each tablet contains the active ingredient brensocatib drug substance and the following inactive 
United States Pharmacopoeia/National Formulary or European Pharmacopoeia compendial 
ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, sodium starch 
glycolate, silicon dioxide, and glyceryl behenate. The film-coating system consists of polyvinyl 
alcohol, polyethylene glycol, titanium dioxide, iron oxide red, iron oxide yellow, iron oxide 
black, and talc. 
In the current study, brensocatib oral tablets of 10- and 25-mg will be supplied to subjects based 
on treatment assignment. 
5.1.2. 
Placebo 
The matching placebo without the active ingredient is a film-coated tablet identical to 
brensocatib film-coated tablets in shape, size, and color. 
In the current study, placebo film-coated tablets, identical in appearance to brensocatib 10- and 
25-mg tablets will be supplied to subjects based on treatment assignment. 
5.2. 
Methods of Assigning Subjects to Treatment 
After meeting all inclusion criteria and none of the exclusion criteria, adult subjects will be 
randomized through an IWRS in a 1:1:1 ratio to 1 of the 3 treatment groups: brensocatib 10 mg, 
brensocatib 25 mg, or matching placebo (approximately 540 subjects per treatment arm). 
Randomization will be stratified based on a geographic region (North America, Europe, Japan, 
and the Rest of the World), sputum sample being classified as positive or negative for 
Pseudomonas aeruginosa at Screening Visit, and the number of prior PEs (2, or ≥3) in the 
previous 12 months.  
Randomization will be enforced to have approximately 30% of adult subjects with 3 or more 
prior PEs, to have no more than 20% of subjects older than 75 years of age, to have 
approximately no more than 20% of subjects with eosinophil count in peripheral blood 
≥300/mm3 at Screening, and to have no more than 20% of subjects with COPD as a comorbidity. 
Additionally, enrollment targets have been established for adult subjects with up to 13% of 
subjects from Eastern Europe and with North America, Western Europe, Asia Pacific, and Latin 
America contributing between 20% and 30% each. No single country (except the US) will 
contribute more than 15% of the overall randomized population. 

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Approximately 40 adolescent subjects will be randomized through an IWRS in a 2:2:1 ratio to 1 
of 3 treatment groups: brensocatib 10 mg, brensocatib 25 mg, or matching placebo 
(approximately 16:16:8 subjects per treatment arm, respectively). Adolescent subjects will not be 
required to produce a sputum sample at the Screening Visit if they are unable. There will be no 
stratification for adolescent subjects. 
Investigators (including independent evaluator/raters and clinicians providing care to the 
subject), Sponsor, and subjects/caregivers will be blinded to treatment group assignments 
throughout the study. 
Study personnel and subjects are strongly discouraged from discussing any aspect of study 
treatment, with the exception of safety issues, in order to maintain treatment blinding and study 
integrity. 
Selected individuals not involved in the conduct of the study may have access to unblinded data 
as needed for safety review or other data review (Section 3.2). 
Unblinding is only to occur in the case of subject emergencies (Section 5.6) and at the 
conclusion of the study. 
5.3. 
Study Treatment Administration 
Brensocatib 10 mg, brensocatib 25 mg, or placebo will be administered QD by mouth with water 
in the morning before breakfast; tablets must not be broken or chewed. Subjects will be 
instructed to record each daily dose of study drug administered in an electronic dosing diary. On 
the days of clinical study visits, including Visit 11 (Week 52), study drug will be administered at 
the study site by study personnel after collection of all applicable patient-reported outcome 
measures (Section 7.5) and after sputum collection (Table 5).  
5.4. 
Dose Interruption 
The Investigator may interrupt dosing for safety reasons. 
5.5. 
Method of Assessing Treatment Compliance 
Subjects will be required to bring all their used and unused study drug bottles as well as their 
electronic dosing diary to each in-clinic study visit during the treatment period. 
Accountability for study drugs administration during the study is the responsibility of the 
Investigator or designees. Drug accountability will be recorded at each in-clinic study visit by 
review of eCRF data and count of returned study drugs. 
A subject will be considered noncompliant with study drugs if treatment adherence is less than 
75% or more than 120% unless instructed by the Investigator to interrupt dosing for safety 
reasons (Section 5.4). Subjects who are noncompliant with study drug should be retrained. 
Continued noncompliance may result in premature discontinuation of study treatment 
(Section 4.2). 

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5.6. 
Emergency Unblinding 
Unblinding of treatment assignment for a subject may be necessary due to a medical emergency, 
or any other significant medical event (eg, pregnancy). 
In the case of a rare emergency where, in the opinion of the Investigator, discontinuation of study 
treatment is not sufficient, and the study treatment must be unblinded to evaluate further course 
of action, the Investigator can unblind study treatment for a specific subject. After unblinding, it 
is suggested that the Investigator contact the Insmed Medical Monitor or appropriate Insmed 
study personnel to inform of the unblinding. The Investigator must be able to confirm that 
unblinding of the subject is necessary and directly impacts the subject’s immediate medical 
management or welfare of the subject. The subject will be considered discontinued from the 
study. 
The Investigator must notify the Sponsor of the unblinding as soon as possible. The date and 
reason for unblinding must be documented in the source documents and signed by the study 
Investigator. The originally signed copy (eg, Note to File) is maintained in the study file at the 
site, and a copy is provided to the Sponsor or its designee. The Investigator should follow the 
steps in the IWRS system and enter the unblinding date.  
5.7. 
Labeling and Packaging 
Subjects will receive bottles containing tablets of brensocatib 10 mg, brensocatib 25 mg, or 
placebo. 
Labels will be prepared in accordance with GMP requirements and local regulatory guidelines. 
Label text will be translated into local language(s). 
5.8. 
Storage 
Study drug will be shipped to the study site after the first subject is screened. Brensocatib must 
be stored between 2°C and 30°C (36°F to 86°F). Do not freeze. 
At the study site, all study drugs must be stored in a secured, environmentally controlled, and 
monitored location with restricted access in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. Refer to the pharmacy manual for 
more detailed information on shelf-life and storage conditions. 
5.9. 
Dispensing of Study Drug 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply, prepare, or administer study treatment. The IWRS system will be used to track 
and record the dispensing of study treatments throughout the study.  
At each in-clinic visit, subjects will be dispensed adequate study drugs to allow for daily dosing, 
including extra supply for potential study visit scheduling delays. Study drug may be dispensed 
directly to the subject’s home by courier if dispensing at the site is not feasible. 

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5.10. 
Drug Accountability 
Drug accountability records will be maintained for all clinical supplies.  All transactions will be 
recorded on the drug accountability records including shipment receipts and study subject doses. 
All transactions will be recorded on a real-time basis. 
The pharmacy will maintain detailed documentation of the number and identification of bottles 
and dispensing units with copies of these documents to be provided to the Sponsor at the end of 
the study. Study drug accountability should follow institutional SOP, or a plan agreeable by 
Insmed, including appropriate actions during monitoring visits or other form of drug 
accountability monitoring through remote methods. Upon completion of the drug inventory by 
the study monitor, used and any unused vials and tablets will be disposed of in accordance with 
instructions provided to sites and according to site destruction policies. The drug may be 
destroyed at site per site SOP or returned to the local drug depot in the case that destruction is 
not possible. Study treatment that is returned to the local drug depot must be documented in the 
accountability documentation. Documentation of destruction should be provided to the Sponsor 
5.11. 
Concomitant Medications 
Any medications the subject takes other than the study drugs, including all vaccinations received, 
from Visit 2 (Baseline, Day 1) to Visit 12 (EOS, Week 56) are considered concomitant 
medications and will be collected and documented in the study eCRF. 
Prior medications are those medications taken before the first dose of study drug. Concomitant 
medications are those medications taken after the first dose of study drug. A medication that 
starts prior to first dose but continues after the first dose of study drug is classified both in prior 
and concomitant medications. Any procedures performed, including all diagnostic tests, from 
Visit 2 (Baseline, Day 1) to Visit 12 (EOS, Week 56) are considered concomitant procedures and 
will be collected and documented in the study eCRF. 
5.11.1. 
Prohibited Medications and Procedures 
Prohibited medications are as follows: 
• Use of any immunomodulatory agents within 4 weeks before the Screening Visit 
(including but not limited to: bortezomib, ixazomib, thalidomide, cyclophosphamide, 
mycophenolate, Janus kinase inhibitors, IFN-γ, and azathioprine) is prohibited during 
the study through Visit 12 (EOS) 
• Continuous use of high dose non-steroidal anti-inflammatory drugs is prohibited 
during the study through Visit 12 (EOS) (see Appendix 7, Comparable NSAID Dose 
Levels) 
• Chronic treatment with systemic steroids (irrespective of the indication) is prohibited 
Note: Chronic treatment is considered >14 days of continuous use 
• Live attenuated vaccines are prohibited during the study (until 4 weeks after the last 
dose of study drug) 
• Use of investigational drugs within 3 months of the Screening Visit 
The following procedures are prohibited during study participation: 

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• Major elective surgical procedures 
• Elective periodontal procedures 
Subjects who have already scheduled a major surgical procedure or who have a prescheduled 
periodontal procedure are not eligible to participate in the study. 
5.11.2. 
Permitted Medications and Procedures 
Any concurrent ongoing medications, including over-the-counter drugs are allowed if not 
prohibited by the protocol (see Section 5.11.1). 
Subjects should continue their maintenance doses of oral or inhaled antibiotics or inhaled 
corticosteroids during the study. Subjects can use LABA, LAMA, anticholinergic 
bronchodilators, PDE4 inhibitors, and their reliever medication (SABA, SAMA) during the study 
if prescribed by their physicians. Subjects are also allowed to continue their airway clearance 
maintenance treatment/procedures such as use of hypertonic saline/isotonic saline, mucolytics, 
and pulmonary rehabilitation. However, except under unforeseeable clinical circumstances, the 
airway clearance maintenance treatment/procedures and pulmonary rehabilitation should 
continue unchanged throughout the duration of the study through Visit 12 (EOS). 
There is a minimum time interval restriction for some of the medication use before and after 
spirometry testing. The minimum time intervals of the restricted medications are summarized in 
Table 4. 
Table 4: 
Minimum Time Intervals for Restricted Medication Use Prior to Spirometry 
Testing 
Medication 
Minimal Time Interval From Last 
Medication Dose Prior to 
Spirometry Testing 
Inhaled SABA (Salbutamol/Albuterol, Terbutaline) 
6 Hours 
Inhaled LABA, Including ICS/LABA Combination Products 
12 Hours 
12 Hours 
24 Hours 
24 Hours 
Formoterol 
Salmeterol 
Olodaterol 
Indacaterol 
Oral β2-Agonists: 
Short-Acting 
Long-Acting 
6 Hours 
24 Hours 
Transdermal β2-Agonists 
24 Hours 
Inhaled SAMA (ipratropium bromide) 
6 Hours 
Inhaled LAMA, Including LAMA/LABA and ICS/LAMA 
Combination Products 
Aclidinium 
Tiotropium 
 
 
12 Hours 
24 Hours 

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Medication 
Minimal Time Interval From Last 
Medication Dose Prior to 
Spirometry Testing 
Glycopyrrolate 
Umeclidinium 
24 Hours 
24 Hours 
Xanthines 
Twice Daily 
Once Daily 
 
12 Hours 
24 Hours 
Roflumilast 
24 Hours 
Ephedrine -Containing Drugs 
6 Hours 
Leukotriene Receptor Antagonists 
Allowed 
ICS = inhaled corticosteroid; LABA = long-acting beta agonist; LAMA = long-acting muscarinic antagonist; 
SABA = short-acting beta agonist; SAMA = short-acting muscarinic antagonist. 
5.11.3. 
Rescue Therapy 
Not applicable. 

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6. 
STUDY PROCEDURES 
6.1. 
Schedule of Assessments 
The Schedule of Assessments and Procedures is presented in Table 5. 
 

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Table 5: 
Schedule of Assessments and Procedures 
Study Period 
Screen 
Treatment Period 
Follow-Up 
Study Days 
Study Weeks 
Days  
-42 to -1 
D1 
(Baseline) 
D28 
Wk4 
D70 
Wk10 
D112 
Wk16 
D154 
Wk22 
D196 
Wk28 
D238 
Wk34 
D280 
Wk40 
D322 
Wk46 
D364 
Wk52 
(EOT or E/D)a 
D392 
Wk56 
(EOS) 
Visit 
V1 
V2 
V3 
Phone 
V4b 
V5 
Phone 
V6b 
V7 
Phone 
V8b 
V9 
Phone 
V10b 
V11 
V12 
Obtain informed consent (and 
assent if required per local 
requirements for adolescent 
population) 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
historyc 
X 
Xb 
 
 
 
 
` 
 
 
 
 
 
Smoking status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight, and BMI 
calculationd 
X 
 
 
 
 
 
 
 
 
 
Xd  
 
Vital signs (BP, HR, T, RR, O2 
saturation)e 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Clinical laboratory tests 
(hematology, blood chemistry, 
and urinalysis) e,f 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
PFT by spirometry (FEV1, 
ppFEV1, FVC, FEF[25-75%], 
PEFR)g 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Chest CT scan for eligibilityh 
X 
 
 
 
 
 
 
 
 
 
 
 
CT scan substudyi 
X 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECGj 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
 
HBcAb, HBsAb, HBsAg, HIV, 
and HCV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine pregnancy  
testk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH level for WOCBP 
≤45 years of age 
X 
 
 
 
 
 
 
 
 
 
 
 

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Study Period 
Screen 
Treatment Period 
Follow-Up 
Study Days 
Study Weeks 
Days  
-42 to -1 
D1 
(Baseline) 
D28 
Wk4 
D70 
Wk10 
D112 
Wk16 
D154 
Wk22 
D196 
Wk28 
D238 
Wk34 
D280 
Wk40 
D322 
Wk46 
D364 
Wk52 
(EOT or E/D)a 
D392 
Wk56 
(EOS) 
Visit 
V1 
V2 
V3 
Phone 
V4b 
V5 
Phone 
V6b 
V7 
Phone 
V8b 
V9 
Phone 
V10b 
V11 
V12 
Estimated glomerular filtration 
rate calculation per CKD-EPI 
Formula 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Sputum sample collection for 
sputum color and P aeruginosa 
determinationl 
X 
 
 
 
 
 
 
 
 
 
 
 
Dental hygiene educationm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationn 
 
X 
 
 
 
 
 
 
 
 
 
 
Assess for pulmonary 
exacerbation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bronchiectasis Severity Index 
calculation (by sites)
 
 
X 
 
 
 
 
 
 
 
 
 
 
BEST electronic subject diary 
completiono 
------------------------------------------------------------------------------------Complete every day------------------------------------------------------ 
QOL-B completion and 
reviewp 
 
X 
----------------------------------------------------Complete every 2 weeks ----------------------------------------------- 
PGI-Sq 
 
X 
----------------------------------------------------Complete every 2 weeks ------------------------------------------------ 
PGI-Cq 
 
 
----------------------------------------------------Complete every 2 weeks ------------------------------------------------ 
EQ-5D-5L/ QOL-PCD – 
Completion at siter 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood PK sampless 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Sputum PD samplet 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
For substudy only: blood PDu 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Health resource utilizationv 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Study Period 
Screen 
Treatment Period 
Follow-Up 
Study Days 
Study Weeks 
Days  
-42 to -1 
D1 
(Baseline) 
D28 
Wk4 
D70 
Wk10 
D112 
Wk16 
D154 
Wk22 
D196 
Wk28 
D238 
Wk34 
D280 
Wk40 
D322 
Wk46 
D364 
Wk52 
(EOT or E/D)a 
D392 
Wk56 
(EOS) 
Visit 
V1 
V2 
V3 
Phone 
V4b 
V5 
Phone 
V6b 
V7 
Phone 
V8b 
V9 
Phone 
V10b 
V11 
V12 
Collect days of work/ school 
missed 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study drug, 
accountability of returned drug, 
and review of dosing diaryw 
 
X 
X 
 
X 
 
X 
 
X 
 
Xw 
Xw 
Adverse events collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of skin conditions 
(hyperkeratosis of palm and 
soles)x 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Assessment of periodontitisy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Note: for each of the Study Visits from Visit 3 to End of Study (Visit 12), there is a ±7-day window. 
a Visit 11 (Week 52) is completed for those who finish study treatment per protocol. The visit is alternatively completed for those who discontinue early from 
study treatment. 
b For Phone Visits, collect data outlined in Phone Visit Sheet: exacerbations, safety events, hospitalizations, or emergency room visits (including start and end 
date, follow-up with facility to retrieve source documentation), days of work missed (including start and end date), IV antibacterial drug use (including start 
and end dates), list of new rescue medications (including name, and start and end dates). 
c Demographics and medical history: At Visit 2 (Baseline) only medical history collected. 
d Height, weight, and BMI: Body weight will be measured at Screening and at the Week 52 (Visit 11; EOT). For adult subjects, the measurement of height, 
without shoes, will be performed at Screening Visit only. For adolescent subjects, measurement of height, without shoes, will be performed at Screening Visit 
and Visit 11 (EOT). 
e Vital signs and clinical laboratory blood samples will be collected at the Screening Visit and prior to the first dose of the study drug on Day 1 (Baseline), and at 
every in-clinic visit. Vital signs include the following: systolic and diastolic blood pressure, respiratory rate (breaths per minute), pulse (beats per minute), body 
temperature (°C), and oxygen saturation. Clinical laboratory parameters are listed in Table 6. 
f Clinical laboratory blood samples should be collected in a fasted state (after an overnight fast for morning sample collection or at least 4 hours without food at 
other times) if possible. 
g Spirometry will be performed preferably in the morning (at the same time of day each time) and performed after withholding the last dose of SABA for 
6 hours, or LABA for 12 hours or LAMA for 24 hours or ultra-long LABA for 24 hours. 

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h Perform high-resolution chest CT scan at the Screening Visit if subject does not have prior radiological confirmation of NCFBE diagnosis or CT scan is older 
than 5 years from date of the Screening Visit or the existing CT scan cannot be read due to quality issues. 
i For the CT scan substudy (n=approximately 225 adult subjects), a new high-resolution CT scan must be performed during the Screening Period and at the 
Week 52 Visit. The Investigator should contact the medical monitor for any patient who prematurely discontinues from the study to determine if the EOT 
assessment is needed. 
j It is recommended to obtain the 12-lead ECG before PFT by spirometry when scheduled at the same visit. 
k Serum and urine pregnancy tests will be performed for WOCBP. A serum pregnancy test will be performed at the Screening Visit; a urine pregnancy test for 
WOCBP including adolescent female subjects will be performed at Baseline (Day 1) and all other visits. In addition to the pregnancy tests required by the 
Schedule of Assessments, monthly urine pregnancy tests should be performed by WOCBP in countries where it is required by local health authority. During the 
treatment period, adolescent female subjects who have reached menarche will perform a urine pregnancy test at all clinical visits (and monthly where required 
by local health authority). Please note that on days of Phone Visits, WOCBP will be provided with urine pregnancy kits; the test should be performed at home 
on the day of the Phone Visit, and the results reported during the Phone Visits.  
l All subjects will provide sputum at Screening for a microbiology culture for Pseudomonas aeruginosa and color evaluation. The result will be reviewed at 
Baseline and used for randomization stratification. A subject should not undergo a sputum induction procedure during the Screening Visit (Visit 1) to meet the 
inclusion criterion. Adolescent subjects are exempt from requirement to provide a sputum sample if they are unable to do so. 
m Dental hygiene education includes instructions on daily teeth brushing and flossing. 
n Randomization: Eligibility should be reassessed prior to randomization at Visit 2 (Baseline). Subjects who do not meet all inclusion/exclusion criteria will NOT 
be randomized and will be considered a screen failure. However, subjects who meet all inclusion criteria but fail Screening due to active pulmonary 
exacerbation, adjustment of Baseline medications within 1 month prior to Screening, or use of oral or inhaled antibiotics for NCFBE ≤3 months prior to 
Screening Visit can be rescreened up to 2 times upon Sponsor (Medical Director) approval. Subjects who are undergoing standard dental care may be enrolled 
if the dental care is not related to periodontal disease and after consultation with the Medical Director. If a subject is approved for rescreening, the Medical 
Director will determine if some or all Screening assessments must be repeated. Rescreened subjects will be assigned a new Subject Number within the IWRS 
system. 
o BEST questionnaire: Adult subjects should complete the BEST questionnaire (in the evening) on an electronic diary DAILY from the Screening Visit through 
EOS Visit (Week 56). If there is an increase of symptoms (as per the algorithm programmed in the electronic data capture system) the site and the subject will 
be alerted. The subject will be asked to contact the site within 1 business day and the site will receive a message to contact the subject within 1 business day. 
The goal is to assess if a pulmonary exacerbation or any other medically relevant event is taking place. Subjects should be trained on completion of the 
questionnaires at Visit 1 (Screening). Subjects should be retrained if the compliance falls below 75% between each on-site visit after randomization. 
p QOL-B: where validated translations are available in the local language, all adult subjects will complete the QOL-B on an electronic diary on Day 1 (Baseline) 
and every 2 weeks thereafter through Week 56. The QOL-B is considered “modified” because the first page, which only collects demographics information, 
will be deleted from the questionnaire since demographics are collected on the appropriate eCRF page instead. 
q PGI-S and PGI-C: Newly enrolled adult subjects will complete the PGI-S and PGI-C on an electronic device where validated translations are available in the 
local language. Existing subjects will not complete the PGI-S and PGI-C. 
r EQ-5D-5L: All subjects (adult and adolescent) will complete the EQ-5D-5L at the site on an electronic device at Visit 2 (Baseline), and at every scheduled 
in-clinic visit. Where validated translations are available in the local language, adolescent subjects with PCD will complete the age-appropriate QOL-PCD. The 
questionnaires should be reviewed by the Investigator during each visit. Subjects should be trained before administration of the first dose of their assigned 
study drug on Visit 2 (Day 1). Subjects will be retrained on how to complete the questionnaires correctly if needed. 

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s Blood PK samples: Predose blood PK samples will be collected from all subjects at the designated visits, with an optional 2-hour (±30 minutes) postdose 
sample collected at select visits (ie, Day 1, Week 4, Week 28, and Week 40) (Appendix 5). Approximately 300 adult subjects and 40 adolescent subjects who 
are not receiving cyclic antibiotics at Baseline from selected sites will participate in the PK substudy in which blood PK samples will be collected at the same 
designated visits, with collections at additional timepoints as indicated in Appendix 5. 
t Sputum PD samples: At designated study visits, predose sputum PD samples will be collected from all newly enrolled subjects and from subjects participating 
in the PK/PD substudy who are not receiving cyclic antibiotics at Baseline (see Appendix 6). Approximately 3 mL of sputum will be collected at each 
timepoint. Sputum induction is allowed only after the Screening Visit. Adolescent subjects are exempt from providing a sputum sample at the Screening Visit if 
they are unable to provide. 
u Blood PD samples: Of the approximately 300 adult subjects participating in the PK/PD substudy who are not receiving cyclic antibiotics at Baseline, 
approximately 40 subjects at selected sites will participate in the blood PD substudy. Blood samples will be collected at the Screening Visit, at 0 (predose) on 
Day 1, at predose at Week 4, Week 16, Week 28, Week 40, Week 52, and at Week 56 (follow-up) (see Appendix 6). 
v Health Resource Utilization: Collect healthcare visit information such as the type of visit (hospitalization, doctor, or ER), reason for visit, and visit date. 
w On study visit days, study drug will be administered at the study site by study personnel after collection of available PRO instruments and after sputum 
collection. Study drug is not dispensed at the Week 52 or the Week 56 visits. 
x Skin examination, especially palms and soles, dorsum of the hands and feet, Achilles tendon area, knees, and elbows, will be performed by the Investigator at 
each in-clinic visit. If there are any signs or symptoms of hyperkeratosis or erythema or deterioration of the pre-existing conditions that warrant further 
evaluation upon Investigator discretion, the subject will be referred to a dermatologist for further assessment. The skin evaluation by the dermatologist for the 
subject should then be assessed thereafter on an interval per the dermatologist discretion until end of the study. 
y Questions about the presence of any periodontal complaint will be asked at every visit (including telephone visits). For adolescents, an oral and dental 
inspection for any signs or symptoms of gingivitis or periodontitis will be performed by the Investigator at each visit. If there are any signs or symptoms of 
gingivitis or periodontitis that warrant further evaluation upon Investigator discretion, the subject will be referred to a dentist for further assessment. The oral 
and dental evaluation by the dentist for the subject should then be assessed thereafter on an interval per the dentist’s discretion until the EOS Visit.  
BEST=Bronchiectasis Exacerbation and Symptoms Tool, BMI=body mass index, BP=blood pressure, CKD-EPI=Chronic Kidney Disease Epidemiology 
Collaboration, CT=computed tomography, ECG=electrocardiogram, eCRF=electronic case report form, E/D=Early Discontinuation; EOS=End of Study, 
EOT=End of Treatment, EQ-5D-5L=EuroQoL-5 Dimension-5 Level Questionnaire, FVC=forced vital capacity, FEF25-75%=forced expiratory flow between 25% 
and 75% of forced vital capacity, FEV1=forced expiratory volume in 1 second, FSH=follicle-stimulating hormone, HBcAb=hepatitis B core antibody, 
HBsAb=hepatitis B surface antibody, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus, HIV=human immunodeficiency virus, HR=heart rate, 
IV=intravenous, IWRS=interactive web response system, NCFBE=non-cystic fibrosis bronchiectasis, PD=pharmacodynamic, PEFR=peak expiratory flow rate, 
PGI-C=Patient Global Impression of Change scale, PGI-S=Patient Global Impression of Severity scale, PFT=pulmonary function test(s), PK=pharmacokinetic, 
ppFEV1=percent predicted forced expiratory volume in 1 second, PRO=patient report outcomes, QoL-B=Quality of Life Questionnaire – Bronchiectasis, QOL-
PCD=Quality of Life Questionnaire – Primary Ciliary Dyskinesia, RR=respiration rate, T=temperature, WOCBP=women of childbearing potential. 
 

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6.2. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol as agreed to by 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRB/IEC. 
The Investigator should notify the IRB/IEC of deviations from the protocol in accordance with 
local procedures. 
As of May 2020, due to concern regarding COVID-19, there may be restrictions to subject 
attendance at in-clinic visits. In the event subjects are restricted to attend in-clinic visits, or if the 
subject has concern regarding travel and attending in-clinic visits (due to potential public health 
concerns), the site should contact the Sponsor on how to conduct the scheduled assessments, and 
decisions should be documented in the source documentation. Where necessary, in-clinic visits 
may be conducted via telemedicine link and home health care visits. 
6.3. 
Public Health Emergency Situations 
During the COVID-19 public health emergency, the Sponsor, IRB/IECs, and Investigators shall 
follow the most current version of local guidance to assure the safety of study subjects, maintain 
compliance with GCP, and minimize risks to study integrity. In anticipation that the COVID-19 
pandemic may have an impact on the conduct of clinical studies, the Sponsor does not intend to 
screen any new subjects in this study unless the impact of the COVID-19 pandemic is deemed 
manageable and no longer interfering with the conduct of the study at individual sites, and 
subjects can safely participate in this study. The continuity of clinical study conduct and 
oversight may require implementation of temporary or alternative mechanisms, which will 
remain in effect only for the duration of the local public health emergency. Examples of such 
mechanisms may include, but are not limited to, any of the following: telephone contact, virtual 
visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use of local 
clinic or laboratory locations, and home visits by skilled staff. The site should contact the 
Sponsor on how and when to implement temporary and/or alternative mechanism of scheduled 
assessments, and all decisions taken should be documented in the source documentation. 
Additionally, all temporary mechanisms utilized, and the resulting deviations from planned study 
procedures are to be documented as being related to COVID-19. 
In a situation where local health authorities declare a public health emergency while the trial is 
ongoing, the suggested guidance in the following subsections should be followed. 
6.3.1. 
Continuation or Suspension of the Study 
Ensuring the safety of trial participants is paramount. The Sponsor (Insmed Incorporated), in 
consultation with clinical Investigators and IRB/IEC, will determine if the protection of a 
participant’s safety, welfare, and rights are best served by continuing or stopping the trial at the 
specific site. Such decision will depend on specific circumstances, including the ability to 
conduct appropriate safety monitoring, the potential impact on the investigational product supply 
chain, and other considerations. 
If the decision is to continue the study, the following considerations will be taken into account. 

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6.3.1.1. 
Study Recruitment 
The Sponsor will communicate to the sites the decision on whether to continue or suspend 
recruitment after considering the specific circumstances of each site, recommendation by the 
IRB/EC, and its local health authority mandates. If, due to COVID-19, study discontinuation 
exceeds the assumed rate, the Sponsor may allow enrollment past the assumed sample size. 
6.3.1.2. 
Subjects Already Enrolled in the Study 
If the decision is to continue the participation of subjects already enrolled, the following steps 
should be taken: 
• If a subject is not able to complete a protocol-specified study visit, it may be necessary to 
adjust the visit schedule, convert in-clinic visits to telemedicine visits, and/or postpone 
study procedures until the next available in-clinic study visit. If there is information 
available from previous visits (ie, laboratory assessments) that requires follow-up 
procedures or other safety assessments, the Investigator will decide if an on-site visit or 
home healthcare visit is required or whether the subject's safety can be preserved by other 
means 
• If study participants no longer have access to investigational product, specific procedures 
should be put in place to ensure delivery of investigational product to subject provided all 
safety considerations and applicable health authority requirements have been addressed. 
6.3.2. 
Subjects Infected by COVID-19 
If a subject has had a past documented infection by COVID-19 prior to enrollment in the trial but 
the subject has recovered and the current diagnostic tests are negative (negative antigen by any 
diagnostic laboratory kit), the subject can be rescreened if the disease (COVID-19) was mild or 
moderate, excluding those subjects who experienced hospitalization, severe disease, and/or 
COVID-19 ARDS. 
If a subject has a documented infection by COVID-19 while in the trial: 
• The event will be reported as an AE or SAE, depending on the criteria. 
The site will follow the guidance provided by health authorities in the treatment of those 
subjects. 

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7. 
EFFICACY ASSESSMENTS 
7.1. 
Pulmonary Exacerbation 
A pulmonary exacerbation is defined by having ≥3 of the following symptoms for at least 
48 hours, resulting in a physician’s decision to prescribe systemic antibiotics: 
• Increased cough 
• Increased sputum volume or change in sputum consistency 
• Increased sputum purulence 
• Increased breathlessness and/or decreased exercise tolerance 
• Fatigue and/or malaise 
• Hemoptysis 
Note: Subjects on chronic macrolide therapy whose only change in therapy is dose or frequency 
adjustment will not meet the definition of PE. 
A severe pulmonary exacerbation is defined as those requiring IV antibacterial drug treatment 
and/or hospitalization. 
Any pulmonary exacerbation in the study after randomization through the end of the 52-week 
treatment period will be included in the primary endpoint calculation (provided it meets the 
protocol-defined criteria). A minimum of 14 days must occur between the end date of one 
pulmonary exacerbation and the start date of the next pulmonary exacerbation. Any 
exacerbations that occur less than 14 days from the prior exacerbation will not be considered a 
new exacerbation. 
The time to the first pulmonary exacerbation is calculated from the randomization date to the 
onset date of the first exacerbation. Subjects who do not have an exacerbation at the end of the 
52-week treatment period will be censored at the date of Week 52. Subjects who have ≥1 PE 
during the study will have event counts and corresponding time to event calculations. 
7.2. 
Sputum 
7.2.1. 
Sputum Culture 
All patients will provide a sputum sample at the Screening Visit to assess the color of the sample 
and whether P aeruginosa is present, for stratification purposes. Adolescent subjects are exempt 
from the requirement to produce a sputum sample at Screening if they are unable to do so. 
Detailed instructions for collecting, processing, and shipping sputum specimens will be provided 
in the site laboratory manual. 
7.2.2. 
Sputum for PK/PD Substudy 
The PK/PD substudy will include subjects who are not receiving cyclic antibiotics at Baseline. 
Adult subjects enrolled in the PK/PD substudy and adolescent subjects who are able to do so will 
provide a sputum sample at Screening (sputum induction procedure is not allowed at Screening). 

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The sample will be sent to the PK/PD laboratory to assess the presence of NSPs (NE, CatG and 
PR3).  
Predose expectorated or induced sputum specimens (approximately 3 mL) are collected from 
adult and adolescent subjects at each clinic visit as specified in the Schedule of Assessments 
(Table 5). If a subject is unable to produce sputum spontaneously, sputum may be induced as 
suggested in Appendix 1, if these suggestions are safe for the subject. If after induction, a subject 
is still unable to produce sputum despite reasonable efforts, and the site does not consider any 
alternative for obtaining the sputum sample, this will be recorded as non-productive at that time 
point. At the scheduled visit, once sputum is collected (spontaneously or by induction), study 
drug can be administered. 
Detailed instructions for collecting, processing, and shipping sputum specimens will be provided 
in the site laboratory manual. 
7.3. 
Pulmonary Function Tests 
Pulmonary function tests include the following: pre- and postbronchodilator FEV1, pre- and 
postbronchodilator ppFEV1, FVC, FEF(25-75%), and PEFR. 
Pre- and postbronchodilator PFT by spirometry (FEV1, ppFEV1, FVC, PEFR, and FEF[25-75%]) 
will be performed per the ATS/ERS criteria (Miller et al., 2005) at Visit 1 (Screening), Visit 2 
(Baseline), Visit 5 (Week 16), Visit 7 (Week 28), Visit 9 (Week 40), and Visit 11 (Week 52) 
(Table 5). Subjects should be provided with detailed instruction on how to conduct the FVC 
maneuver per ATS/ERS spirometry standardization before performing the test. 
Subjects should be advised to withhold short-acting inhaled drugs (eg, the β-agonist 
albuterol/salbutamol or the anticholinergic agent ipratropium bromide) within 6 hours prior to 
the test. Long-acting β-agonist bronchodilators (eg, salmeterol or formoterol) or long-acting 
muscarinic bronchodilators (eg, tiotropium) or oral therapy with aminophylline or slow release 
β-agonists should be withheld for 12 to 24 hours depending on the medication used (refer to 
Table 4 for the minimum time intervals for a list of restricted medications) prior to the testing. 
In the event a subject has taken a restricted medication during the specified time interval before 
the test, the test should be rescheduled for another visit within the protocol-specified visit 
window. If rescheduling the visit is not feasible for the subject, the test should be conducted as 
usual with appropriate notation in the source documents. 
Spirometry should be performed preferably in the morning (AM) at approximately the same time 
each visit. The same spirometer and standard spirometric techniques, including calibration, will 
be used to perform spirometry at all visits and, whenever possible, the same person should 
perform the measurements. Pulmonary function tests will be measured in the sitting position; 
however, if necessary, to undertake the testing with the subject standing or in another position, 
this should be noted on the spirometry report. For any subject, the position should be consistent 
throughout the study. Three (3) measurements fulfilling the ATS acceptability and repeatability 
criteria should be obtained at every visit. The acceptability criteria must be applied before the 
repeatability criteria. Unacceptable maneuvers must be discarded before applying the 
repeatability criteria. If a subject fails to provide repeatable maneuvers, an explanation should be 
recorded in the eCRF. At least 2 acceptable curves must be obtained. The largest FEV1 and 
largest FVC should be recorded after the data are examined from all of the acceptable curves, 

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even if they do not come from the same curve. The FEF(25-75%) should be obtained from the 
single curve that meets the acceptability criteria and gives the largest sum of FVC plus FEV1 
(best test). Automated best efforts, which combine FEV1 and FVC are not acceptable. The 
spirometer must be calibrated following the principles of the ATS/ERS guidelines every day that 
a study subject is assessed and spirometry is carried out. The calibration records should be kept 
in a reviewable log. It is preferred that the calibration equipment (ie, 3-liter syringe) that is used 
to calibrate the spirometer be subjected to a validated calibration according to the manufacturer’s 
specifications. 
Subjects should be advised to rest at least 30 minutes, and not to eat a large meal for at least 
2 hours prior to the test. If a subject is scheduled to have pulmonary rehabilitation on the day of 
their visit, they should be advised to have the PFT done before the rehabilitation on that day.  
Postbronchodilator spirometry tests will be performed per the following instructions:  
• When an inhaled SABA is used, 4 puffs of albuterol/salbutamol, 
levalbuterol/levosalbutamol, or terbutaline will be administered. A postbronchodilator 
PFT will be performed 15 to 30 minutes after the administration of albuterol or 
levalbuterol. 
• When an inhaled SAMA is used, 4 puffs of ipratropium will be administered. A 
postbronchodilator PFT will be performed within 20 to 30 minutes after the 
administration of ipratropium. 
• If a subject cannot perform an inhalation, the SABA or SAMA can be nebulized. 
Pulmonary function tests should be performed within 20 to 30 minutes after 
finalization of nebulization. 
NOTE: If a subject used SABA in the first assessment of PFTs, the same SABA and mode of 
administration should be used in subsequent assessments. If a subject used SAMA in the first 
assessment of PFTs, the SAMA and mode of administration should be used in subsequent 
assessments. 
Detailed instructions on how to conduct the spirometry and document the results are provided in 
a separate spirometry manual. 
7.4. 
Bronchiectasis Severity Index 
The Bronchiectasis Severity Index (BSI) is a scoring system based on a combination of clinical, 
radiological and microbiological features that can be used to assess subjects’ NCFBE severity. 
The BSI was validated in 1,310 subjects across 4 European bronchiectasis centers. The BSI has 
been shown to give excellent predictions of mortality and hospital admissions and be predictive 
of exacerbations and QOL giving a broad assessment of disease severity (Chalmers et al., 2014). 
The BSI score will be calculated at Baseline and documented in the study source document and 
eCRF. Appendix 2 presents the methodology for the scoring of the BSI. 

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7.5. 
Patient-Reported Outcome Measures 
7.5.1. 
Bronchiectasis Exacerbation and Symptoms Tool 
Bronchiectasis Exacerbation and Symptom Tool (Artaraz et al., 2020) is a novel symptom diary 
for bronchiectasis symptom burden and detection of exacerbations, named the BEST diary. The 
BEST diary measures day-to-day changes in patient symptoms but also accurately detects 
exacerbations. The BEST symptom diary shows convergent validity with existing health 
questionnaires and is responsive at onset and recovery from exacerbation.  
Adult subjects should complete the BEST symptom diary daily in the evening, from the 
Screening Visit through EOS Visit (Week 56). Subjects should be retrained if the compliance 
falls below 75% between each on-site visit after randomization. Compliance will be calculated 
by adding the number of days the questionnaire was completed divided by the number of days 
between on-site visits.  
If there is an increase of symptoms (as per the algorithm programmed in the electronic data 
capture system) the site and the subject will be alerted. The subject will be asked to contact the 
site within 1 business day and the site will receive a message to contact the subject within 
1 business day. The goal is to assess if a pulmonary exacerbation or any other medically relevant 
event is taking place. Subjects should be trained on completion of the questionnaire at Visit 1 
(Screening). 
7.5.2. 
Quality of Life Questionnaire – Bronchiectasis 
The QOL-B is a validated, self-administered PRO that assesses symptoms, functioning, and 
health-related quality of life for subjects with NCFBE (Quittner et al., 2015). The QOL-B 
contains 37 items in 8 domains (Respiratory Symptoms, Physical Functioning, Role Functioning, 
Emotional Functioning, Social Functioning, Vitality, Health Perceptions and Treatment Burden). 
The QOL-B page 1 (demographics page) will be removed as demographics are collected on a 
separate eCRF page. The modified QOL-B, where validated translations are available in the local 
language, will be provided to all adult subjects in an electronic format on an electronic diary 
after randomization. Subjects will be required to complete the QOL-B after the training and prior 
to the administration of the first dose of their assigned study drug at Visit 2 (Day 1; Baseline). 
Subjects will complete the questionnaire directly on the electronic diary every 2 weeks from 
Day 1 to Week 56 (Table 5). 
The subjects will complete the questionnaire while they are in the clinic if the study visit 
coincides with the availability of the questionnaire (in validated translation of the local language) 
and at home for the weeks in between the study visits. It is important for the site staff to remind 
the subjects to bring their electronic diaries with them to each clinic visit. 
On days when the subject is at home (ie, days without study center visits), patient-reported 
outcome assessments are to be completed when they become available on the electronic diary. 
The completed questionnaires will be reviewed during each visit. Subjects will be retrained on 
how to complete the questionnaires correctly, if needed. For adults, the Respiratory Symptoms 
Domain score of the QOL-B will be assessed as a secondary endpoint, with the other domain 
scores of the QOL-B assessed as exploratory endpoints. 

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7.5.3. 
PGI-S and PGI-C 
The PGI-S and the PGI-C scales will be used to assess the subject’s overall perception of the 
severity and change in NCFBE status. These scales are intended to confirm a meaningful change 
threshold for the QOL-B Respiratory Symptoms Domain endpoint (Guy, 1976). The PGI-S and 
PGI-C are both 1-item questionnaires using balanced Likert scales that ask the subject to rate the 
severity of NCFBE (PGI-S, a single-state 5-point categorical scale) or to rate at a particular time 
point the perceived change in NCFBE status in response to treatment (PGI-C, a transitional 
7-point categorical scale).   
All newly enrolled adult subjects will complete the PGI-S and PGI-C at the time points indicated 
in Table 5 where translations are available in the local language (existing subjects will not 
complete either questionnaire). Subjects will be trained on how to complete the questionnaires 
using an electronic diary. The questionnaires will be completed in the clinic on clinic visit days 
and at home when completion is scheduled between clinic visits. 
7.5.4. 
EuroQoL-5D-5L 
The EuroQoL-5D-5L (EQ-5D-5L) is a 2-page instrument suitable for use in subjects ages 
12 years and older with 2 components: the EQ-5D descriptive system and the EQ visual 
analogue scale (EQ VAS) (Herdman et al., 2011). The descriptive system comprises 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
domain evaluates severity on a 5-level scale: having no problems, having slight problems, having 
moderate problems, having severe problems, and being unable to do/having extreme problems. 
The EQ-5D-5L questionnaire VAS component allows respondents to report their perceived 
health status with a grade ranging from 0 (the worst possible health status) to 100 (the best 
possible health status). All subjects (adult and adolescent) will complete the EQ-5D-5L at the 
site on an electronic device at the time points indicated in Table 5. 
7.5.5. 
QOL-PCD 
QOL-PCD is a specific quality of life questionnaire for patients with PCD. The questionnaire 
was developed using the most recent guidance from FDA and EMA and has undergone cognitive 
testing in pediatric patients from several English-speaking countries. The questionnaire will be 
completed by adolescent subjects in whom PCD is the cause of NCFBE and where a validated 
translation is available in the local language. The QOL-PCD questionnaire has 4 age-specific 
versions (adults ≥18 years, adolescents 13-17 years, children 6-12 years and a parent-proxy 
questionnaire for children 6-12 years). Age-appropriate versions of the QOL-PCD (at the time of 
randomization) will be used in the trial for all adolescent subjects. The questionnaire has 
9 subscales in the 13-17 years of age group: Physical Functioning (n=5), Vitality (n=3), 
Emotional Functioning (n=5), Treatment Burden (n=4), Upper Respiratory Symptoms (n=4), 
Lower Respiratory Symptoms (n=6), Role (n=4), Social Functioning (n=3), Hearing Symptoms 
(n=2). Higher scores in each subscale represent increased health-related quality of life (Dell et 
al., 2016). 
7.6. 
Chest CT Scan 
At the Screening Visit, a chest CT scan image(s) for all subjects will be sent to the central reader 
for advanced centralized image analysis to evaluate if the NCFBE meets the enrollment criteria. 

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Only after this evaluation has been done and the CT scan has been read by the reviewers, can the 
subject be enrolled in the trial. 
For each subject, the most recent chest CT (taken within 5 years of the Screening Visit) will be 
collected for centralized scoring by an independent Core Laboratory (LungAnalysis, Erasmus 
MC, The Netherlands). Before sending the chest CT scan, in DICOM format, to the central 
reading facility, the CT scan must be deidentified and coded by the study site. For those sites not 
familiar with deidentification instructions of chest CT scans, the central reading facility can 
consult and assist in the deidentification process. 
For transfer of the deidentified chest CT scan, the central reading facility will use a Safe File 
Transfer Protocol. For secure large dataset transfer, SFTP file transfer will be used on web 
browser SURFfilesender services using data transfer vouchers. The options for secure transfer of 
the chest CT images will be described in the CT Scan Manual. 
After transfer, LungAnalysis will perform a quality assessment of the CT scan(s). Next, the chest 
CT scan will be evaluated by a certified observer to confirm the diagnosis of bronchiectasis 
using the BE-CT scoring system. In case no or only minor bronchiectasis is identified using the 
BE-CT scoring system, the CT scan will be evaluated by a board-certified LungAnalysis chest 
radiologist on the presence or absence of bronchiectasis. 
The screening for bronchiectasis will be determined using the BE-CT method. Each lobe will be 
assessed for presence and extent of bronchiectasis, as follows: 
• 0=no bronchiectasis 
• 1=bronchiectasis present in 0% to 32% of the lung lobe 
• 2=bronchiectasis present in 33% to 66% of the lung lobe 
• 3=bronchiectasis present in 67% to 100% of the lung lobe 
The lingula will be assessed as the sixth lung lobe. Hence, the maximum BE-CT score is 
6 × 3 = 18. In case of a BE-CT score of 3 or lower, a reassessment by a chest radiologist will be 
performed. 
7.6.1. 
CT Scan Substudy CT Scan Assessment 
A subgroup of adult subjects will be included in an evaluation of lung damage through high-
resolution CT scan at enrollment (Screening Visit) and EOT (Week 52). Those subjects will have 
a guided inspiratory and expiratory CT scan done during the Screening Period and at the end of 
12 months of treatment. Approximately 225 subjects (75 subjects per study arm) will be included 
in the substudy. A CT Scan Substudy Manual will be provided to the sites. 
All sites participating in the CT substudy will be certified through the LungAnalysis Core 
Laboratory. The certification includes the following: 
1. Certification of the site personnel involved in the CT scan substudy: 
a. Respiratory Therapy Personnel: Training and coaching of the study subjects for the 
breathing maneuvers during the chest CT acquisition. 
b. Site Radiologist: Compliance with the CT requirements and quality control of the 
imaging data. 

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c. Site Pulmonologist: Compliance with the study protocol, including the training and 
coaching of study subjects. 
2. Characterization of the CT scanner that will be used for the study (at the Screening 
Period and end of treatment [Week 52]) at each site, and definition of the specific chest 
CT protocol for that scanner: 
a. Specific procedures will be developed for each site, as determined by the scanner 
model, specification, and study requirements. 
b. A phantom scan will be made using the specified chest CT protocol for calibration 
purposes. 
7.6.2. 
Image Analysis in the CT Scan Substudy 
7.6.2.1. 
BEST-CT Scoring Method 
The BEST-CT scoring method was developed specifically for NCFBE to phenotype the chest CT 
and to assess the severity of structural lung changes. The training and assessment of observers 
for BEST-CT is well standardized. CT scans are analyzed in batches and in random order by 
2 trained and certified observers. BEST-CT is a grid-based scoring system (software program: 
Saldsegvol). For inspiratory scans a grid is placed on a minimum of 10 equally spaced axial CT 
slices (size dependent), and the content in each grid box is annotated according to the following 
subscores in a hierarchical order: 
1. Atelectasis or consolidation 
2. Bronchiectasis with partial mucus plugging 
3. Bronchiectasis without mucus plugging 
4. Airway wall thickening 
5. Mucus plugging 
6. Ground-glass opacities 
7. Emphysema or bullae 
8. Healthy airways 
9. Healthy parenchyma 
Each subscore is expressed as a percent of the total lung volume. For the diagnosis of 
bronchiectasis, the sum of bronchiectasis with and without mucus plugging should be higher 
than 0. 
The observers are trained for this scoring method by completing a training module consisting of 
standardized scoring instructions and by analyzing 20 training CT scans in 4 batches. The 
performance of the observer is evaluated after completing a batch of 5 CT scans and the observer 
receives feedback from gold standard scores for corrections. 

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7.6.2.2. 
Airway-Artery Method 
7.6.2.2.1. Manual Airway-Artery Method 
For each CT scan, all visible airways are segmented semi-automatically. Next, the bronchial tree 
is reconstructed in a 3D-view, and cross sectional CT reconstructions are generated based on the 
airway’s center-line. One measurement per airway branch is made when both airways and artery 
are clearly visible. AA pairs with movement artifacts or too much noise for reliable 
measurements are excluded. In addition, AA pairs of airways that do not show a visible inner 
lumen (eg, due to mucus plugging) and airways without a clear identifiable adjacent artery (eg, 
due to atelectasis or severe cystic bronchiectasis without a traceable artery) are excluded. Inner 
and outer airway diameters are divided by artery diameter to compute ratios. Wall thickness 
(difference between outer and inner airway diameter) is divided by the artery diameter to 
compute its ratio. The manual method is time consuming (8 to 16 hours analysis time per CT 
scan). The number of AA pairs that can be assessed ranges between 500 and 1000 AA pairs. 
7.6.2.2.2. Automated Airway-Artery Method 
The process as described for the manual method is done automatically. The system automatically 
segments all visible airways and arteries and identifies AA pairs. Next, the system automatically 
measures AA dimensions at multiple positions for each airway segment. 
CTs for the brensocatib study will be analyzed automatically. For quality assurance, 5 scans will 
be measured manually and compared to the automated method. 

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8. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
Pharmacokinetic samples will be collected from all adult subjects enrolled in the study 
(Section 8.2), and sputum PD samples will be collected from all newly enrolled adult subjects 
(Section 8.4.1). 
A PK/PD substudy will be conducted at a select number of sites in subjects who are not 
receiving cyclic antibiotics at Baseline. Subjects who agree will undergo intensive PK and PD 
sampling (Section 8.2 and Section 8.4). Approximately 300 adult subjects and all adolescent 
subjects will be included in the PK/PD substudy). 
8.1. 
Pharmacokinetic Endpoints 
Non-compartmental PK parameters will not be determined in this study. Population PK analysis 
will be conducted using a nonlinear mixed-effect model. PK parameters, such as Cmax, AUC, 
elimination t1/2, CL/F and Vz/F, etc., as appropriate, will be estimated via simulated 
concentration data. The scope of the analysis will be described in a PK/PD analysis plan. 
8.2. 
Pharmacokinetic Sampling 
Predose blood PK samples will be collected from all subjects on Day 1, Week 4, Week 16, 
Week 28, Week 40, and Week 52, with an optional 2-hour (±30 minutes) postdose sample 
collected at select visits (ie, Day 1, Week 4, Week 28, and Week 40). NOTE: While collection of 
the 2-hour postdose PK sample is optional, it is valuable for PK evaluation; therefore, collection 
of the 2-hour postdose sample is highly recommended.  
A PK substudy will be conducted at a select number of sites in subjects who are not receiving 
cyclic antibiotics at Baseline. Pharmacokinetic samples will be collected at 0 (predose), 0.5 hour 
(±10 min), 2 hours (±30 min), and 4 to 8 hours postdose on Day 1 and Week 28. At Week 4 and 
Week 40, PK samples will be collected at predose and 2 hours (±30 min) postdose. At Week 16 
and Week 52 visits, PK will be collected at predose only. Before blood PK sampling is 
conducted, the site staff will review the dosing diary and record the dosing time for the last 
2 days.  
The details of the blood PK sampling scheme are described in Appendix 5. 
All subjects will be advised to do their best to take their study drug around the same time every 
day. On the day of PK sample collection, the date and time of the previous 2 doses should be 
recorded. 
Blood PK samples will be collected into vacutainers with K2EDTA. Detailed instructions for PK 
sample collection, processing, labeling, storage, and shipping will be provided in the Study 
Laboratory Manual. 
Pharmacokinetic samples will be stored frozen (-20°C or lower) until shipment. Plasma 
concentration of INS1007 will be analyzed using a validated LC-MS/MS method. 

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8.3. 
Pharmacodynamic Endpoints 
Sputum: The concentration change from Baseline for active NE, CatG, and PR3 in sputum will 
be evaluated. 
Blood: In a small subset of subjects, changes from Baseline for active NE, CatG, and PR3, and 
other neutrophil functions in blood will be evaluated. 
8.4. 
Pharmacodynamic Sampling 
Detailed instructions for PD sputum and blood sample collection, processing, labeling, and 
storage are provided in the Study Laboratory Manual. Details of the PD sampling scheme for 
sputum and blood are described in Appendix 6. 
8.4.1. 
Sample Collection for Biomarkers in Sputum 
Sputum samples for analysis of NE, CatG, and PR3 will be collected at the following time 
points: 
• Screening Visit  
• 0 hour (predose) on Day 1, Week 4, Week 16, Week 28, Week 40, and Week 52  
• Week 56 (Follow-up Visit)  
8.4.2. 
Sample Collection for Biomarkers in Blood 
Blood samples for analysis of NE, CatG, PR3 and other neutrophil functions will be collected at 
the following time points: 
• Screening Visit 
• 0 hour (predose) on Day 1, Week 4, Week 16, Week 28, Week 40, and Week 52 
• At Week 56 (Follow-up Visit) 
8.5. 
Pharmacokinetic-Pharmacodynamic Endpoints 
Pharmacokinetic-efficacy relationships (eg, PEs and concentrations of active NE in sputum) will 
be explored using a population PK-PD approach. 
Pharmacokinetic-safety relationship (eg, AESI) will be explored using a population PK-PD 
approach. 
The analysis plan will be described in a PK/PD SAP. 

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9. 
ASSESSMENT OF SAFETY 
9.1. 
Vital Signs and Pulse Oximetry 
Five-minute sitting BP (systolic and diastolic blood pressures), pulse rate (bpm), body 
temperature (°C), respiration rate (breaths per minute), and oxygen saturation will be recorded in 
the eCRF at the Screening Visit, and at all in-clinic study visits, as specified in the Schedule of 
Assessments (Table 5). 
9.2. 
Physical Examination, Height, and Weight 
A physical examination of the head (external), eyes, ears, nose and throat, lungs, cardiovascular 
system, abdomen, musculoskeletal system, skin, lymph nodes, central nervous system, and, as 
appropriate, other body systems will be performed during the Screening Visit (Visit 1) and at 
Week 52 (Table 5). Any abnormalities noticed at Screening will be recorded in the medical 
history or as AE if occurred after randomization. The physical examination will also include 
measurement of height, body weight, and calculation of BMI. Body weight will be measured at 
the Screening Visit (Visit 1) and at the Week 52 Visit (Visit 11; EOT). For adult subjects, the 
measurement of height, without shoes, will be performed at the Screening Visit only. For 
adolescent subjects, measurement of height, without shoes, will be performed at the Screening 
Visit and Visit 11 (EOT). 
9.3. 
Chest CT Scan 
A high-resolution chest CT scan will be performed at the Screening Visit if the subject does not 
have prior radiological confirmation of NCFBE diagnosis or if the available CT scan was 
obtained more than 5 years prior to the subject’s Screening Visit or the existing CT scan cannot 
be read due to quality issues (Table 5). A prior chest CT scan may be used if this CT scan was 
obtained within 5 years from the subject’s Screening Visit. 
9.4. 
Electrocardiogram 
A 12-lead ECG will be performed at Screening, Baseline, Weeks 4, 28, 40, and 52 (EOT) 
(Table 5). It is recommended to obtain the 12-lead ECG before PFT by spirometry when 
scheduled at the same visit. 
9.5. 
Clinical Laboratory Assessments 
Clinical laboratory tests of hematology, blood chemistry, and urinalysis will be performed via 
the study-designated laboratory at the Screening Visit, Baseline, and at all in-clinic study visits, 
as specified in the Schedule of Assessments (Table 5). The clinical laboratory test parameters are 
listed in Table 6. 

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Table 6: 
Clinical Laboratory Parameters 
Category 
Laboratory Parameters 
Clinical Chemistry 
Sodium, chloride, potassium, CO2, magnesium, calcium, glucose, phosphate, total 
bilirubin (with direct and indirect fractionation, if total bilirubin is elevated > 2 × ULN), 
alkaline phosphatase, LDH, AST, ALT, albumin, total protein, creatinine, urea-nitrogen, 
uric acid, estimated glomerular filtration rate from the Chronic Kidney Disease - 
Epidemiology Collaboration equation formula (described in Section 9.9)  
Hematology 
Hemoglobin, erythrocytes, hematocrit, MCH, MCV, MCHC, leukocytes, differential 
blood count of neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
platelets 
Urinalysis 
Qualitative analysis of glucose, ketones, nitrites, protein, pH, leukocytes, blood, 
bilirubin, specific gravity; microscopic examination for cells, casts, and bacteria 
Special Tests 
For WOCBP ≤45 years, a testing of FSH level is required at Screening; a threshold of 
>40 mIU/mL should be met to be considered infertile 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CO2=carbon dioxide, FSH=follicle-stimulating 
hormone, LDH=lactate dehydrogenase, MCH=mean corpuscular hemoglobin, MCHC=mean corpuscular 
hemoglobin concentration, MCV=mean corpuscular volume, ULN=upper limit of normal, WOCBP=women of 
childbearing potential. 
9.6. 
Dental Hygiene Education 
Dental hygiene education includes instruction in daily brushing and flossing. Subjects will be 
reminded at every visit on the need to maintain an appropriate dental hygiene. 
If there are any signs or symptoms of gingivitis or periodontitis that warrant further evaluation 
upon Investigator discretion, the subject will be referred to a dentist/periodontist for further 
assessment. The oral and dental evaluation by the dentist for the subject should be assessed 
thereafter on an interval per the dentist’s discretion until EOS Visit. 
9.7. 
Serology Tests 
Testing for HBcAb, HBsAb, HBsAg, HIV, and HCV will be conducted at Screening only. 
9.8. 
Serum or Urine Pregnancy Test 
A serum pregnancy test will be performed on WOCBP at Screening. A urine pregnancy test will 
be performed on WOCBP on Day1 (Baseline) and all other visit days, as specified in the 
Schedule of Assessments (Table 5). In addition to the pregnancy tests required by the Schedule 
of Assessments, monthly urine pregnancy tests should be conducted by WOCBP in countries 
where it is required by a local health authority. Adolescent female subjects who reach menarche 
during the course of the study should undergo urine pregnancy testing at the next clinic visit and 
at all following clinical visits (monthly where required by local health authority).  
Please note that for days of Phone Visits (and monthly home tests, where applicable), WOCBP 
will be provided with urine pregnancy kits; the test should be performed at home on the day of 
the Phone Visit (or on the scheduled monthly frequency, where applicable) and the results 
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Women not of childbearing potential are defined as pre-menarche, postmenopausal (ie, 
amenorrheic for at least 1 year), or surgically or naturally sterile. 
9.9. 
Estimated Glomerular Filtration Rate 
The eGFR calculation per CKD-EPI equation will be analyzed for each subject at Visit 1 
(Screening) and at Week 16, Week 28, and Week 52 (EOT). 
The CKD-EPI equation described below will be used to calculate the eGFR of creatinine 
clearance in mL/min. 
GFR = 141 × min (Scr/κ, 1) α × max (Scr/κ, 1)-1.209 × 0.993 Age × 1.018 [if female] × 1.159 [if 
Black] 
where: 
Scr is the serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr/κ or 1,  
max indicates the maximum of Scr/κ or 1. 
9.10. 
Adverse Events 
The Investigator is responsible for detecting, documenting, and reporting AEs (refer to 
Section 9.10.1 and Section 9.10.2 for the definition of AEs and SAEs, respectively). 
The Investigator remains responsible for following up all AEs. At the EOS Visit, the Investigator 
will record the AE status (stable or unstable) in the eCRF.  
9.10.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject 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 (ICH E2A Guideline. Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, October 1994). Protocol-defined PEs (Section 7.1) are 
collected as efficacy endpoints via the eCRF. These events should not be reported as AEs unless 
they fulfill a seriousness criterion. 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings that should be considered AEs. 
9.10.2. 
Definition of a Serious Adverse Event 
Any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 

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• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, October 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
Note: 
• A procedure is not an AE or SAE, but the reason for the procedure may be an AE or 
SAE. 
• Pre-planned (prior to signing the ICF) procedures or treatment requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not 
SAEs. 
9.10.3. 
Adverse Event of Special Interest 
AESIs are defined as events known as related to treatment with DPP1 inhibitors. Additional 
information on AESIs will be collected in the eCRF. The AESI category groups and preferred 
terms include the following: hyperkeratosis, infection, and periodontal/gingival events. 
9.10.3.1. Hyperkeratosis 
The subjects’ skin will be monitored throughout the study. 
At each study visit the Investigator (or designated healthcare professional in case of a public 
health emergency) will perform a careful skin evaluation, especially of the palmar and plantar 
surfaces, the dorsal surfaces of the hands and feet, the Achilles tendon area, knees, and elbows. If 
there are any signs or symptoms of hyperkeratosis or erythema or deterioration of the pre-
existing conditions that warrant further evaluation upon Investigator discretion, the subject will 
be referred to a dermatologist for further assessment. The skin evaluation by the dermatologist 
for the subject should then be assessed thereafter on an interval per the dermatologist discretion 
until the end of the study. 
Skin exfoliation or signs of skin thickening in the palms, soles, dorsum of the hands and feet, 
Achilles tendon area, knees, or elbows should always warrant evaluation by the dermatologist. 
Decisions to discontinue the subject from the study will be made by the Investigator after 
consulting with the dermatologist. Upon receiving the dermatologist’s evaluation, the 

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Investigator should decide whether to continue the subject in the study or initiate early 
discontinuation of the subject. 
9.10.3.2. Periodontitis/Gingivitis 
Adult subjects will be advised to conduct self-monitoring of their oral soft tissue, gingiva, and 
tooth mobility, and report any findings. For adolescents, oral and dental inspection for any signs 
or symptoms of gingivitis or periodontitis will be performed by the Investigator at each visit. 
Occurrence of periodontitis during the study will be considered an AESI. If there are any signs or 
symptoms of periodontitis or gingivitis that warrant further evaluation upon Investigator 
discretion, the subject will be referred to a dentist/periodontist for further assessment and 
treatment. Subjects will be discontinued from the trial if they develop severe periodontal disease 
as defined by: 
• Pocket depth measurement and attachment loss ≥6 mm on 2 or more teeth 
• Have Class 3 mobility or Class 3 furcation involvement 
9.10.3.3. Other Infections 
Subjects will be monitored throughout the study for potential infections. Any severe infection, 
defined as any infection requiring treatment with parenteral antibiotics/antiviral/antifungal agent, 
any clinical endoparasitosis, and any opportunistic infection should be considered as AESI. 
Generally, all uncommon, atypical, or unusually persistent infections should be reported as 
AESIs. 
Note: Pulmonary exacerbations do not fall into this AESI category. Protocol-defined PEs are 
collected as efficacy endpoints (Section 9.10.1).  
Pneumonia will be a specific subcategory within the other infections AESI and will be monitored 
through the study. 
9.10.4. 
Assessment of Severity 
The following definitions should be used to assess intensity of AEs: 
• Mild: Awareness of sign or symptom, but easily tolerated, ie, does not interfere with 
subject’s usual function. 
• Moderate: Discomfort enough to cause interference with usual activity. 
• Severe: Incapacitating with inability to work or do usual activity, ie, interferes 
significantly with subject’s usual function. 
9.10.5. 
Assessment of Causality 
The Investigator who identifies an AE will determine the causality of each based on the temporal 
relationship to administration of study drug and clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
• Related: A reaction that follows a reasonable temporal sequence from administration 
of study drug; that follows a known or expected response pattern to the study drug; 

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that disappears or decreases on cessation or reduction in study drug dose; and/or that 
reappears or worsens when the study drug is administered. Could not be reasonably 
explained by other factors such as underlying disease, complications, concomitant 
drugs, or concurrent treatments. 
• Not Related: A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug. 
9.10.6. 
Assessment of Adverse Event Outcome 
The Investigator will record the outcome of the AE as either resolved or ongoing on the AE page 
of the eCRF. Adverse events of unknown outcome or resolution date will be followed until 
resolved, condition has stabilized, or is no longer clinically relevant. 
9.11. 
Reporting Requirements 
9.11.1. 
Adverse Events 
All AEs will be reported on the Adverse Events Form of the eCRF. Adverse events that occur 
between the time subject signs the ICF for the study and the time when subject receives his/her 
first dose of study treatment on Day 1 will be summarized as medical history and not as a TEAE 
unless the event meets the definition of an SAE as defined below. 
9.11.2. 
Serious Adverse Events 
All SAEs, regardless of causality, must be reported to the organization delegated by the Sponsor 
on a Serious Adverse Event Report Form within 24 hours of becoming aware of the event; 
corrections and additions are required to be submitted within 24 hours as well.  
Study-specific email address and back-up fax number for SAE reporting information: 
• Email: safety@insmed.com   
• Back-up fax number: 1-908-450-1549 
Unexpected drug related SAEs as assessed by Sponsor or authorized person qualify for expedited 
reporting and will be reported to the IRB/EC, regulatory authorities, participating Investigators 
and, if cross reporting is required for SUSARs, in accordance with all applicable global laws and 
regulations. A SUSAR is a Serious Adverse Reaction, which is suspected to be caused by the 
investigational medicinal product and which is unexpected, ie, its nature or severity is not 
consistent with the information in the relevant Reference Safety Information. SAEs, including 
those that do not meet requirements for expedited reporting, and all other AEs will be reported to 
the regulatory agencies as appropriate (ie, for the FDA these are reported in the Investigational 
New Drug annual report and for the European Medicines Agency, these are reported in the 
Development Safety Update Report). 
9.11.3. 
Pregnancy 
Any pregnancy, including the pregnancy of a male subject’s female partner, that occurs during 
any phase of the study must be reported to the Sponsor or designated organization within 
24 hours of learning of the pregnancy using a Clinical Study Pregnancy Form. 

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The study treatment should be discontinued for female subjects only, and the pregnancy should 
be followed to term. The details of termination must also be reported, including details of birth, 
the presence or absence of birth defects, congenital abnormalities or maternal and newborn 
complications, or whether termination was spontaneous or voluntary. 
9.11.4. 
Overdose 
An overdose is defined as a dose greater than the dose level(s) evaluated in this study. An 
overdose itself is not an AE. However, if the overdose results in clinical signs and symptoms, it 
requires an expedited reporting as if it is an SAE. In the case of a symptomatic overdose, the 
Investigator should use clinical judgment in treating the overdose and should inform the Sponsor 
immediately. The Investigators should refer to the relevant documents for detailed information 
regarding warnings, precautions, contraindications, AEs, and other significant data pertaining to 
the study treatment used in the study. Such documents may include, but not limited to, the 
Investigator’s Brochure. 
9.12. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to follow-up on each subject who 
experienced the AE at subsequent visits or contacts.  
Unless the subject is lost to follow-up (as defined in Section 4.2.2.3 ), all subjects with SAEs will 
be followed until the SAE is resolved, stabilized, or the event is otherwise explained. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
9.13. 
Regulatory Aspects 
The Sponsor has a legal responsibility to notify the United States Food and Drug Administration, 
National Competent Authorities, and Central Ethics Committees of the European Union, and any 
other foreign regulatory competent agency, as well as all sites, about the safety of the drug. The 
Investigator has the responsibility to notify the local IRB/IEC about SUSARs. 
The Investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review 
and regulatory inspection(s), providing direct access to source data/documents. Copies of the 
notification to the ethics committee must be sent to the Sponsor. 

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10. 
STATISTICS 
A detailed SAP will be developed for this study. The SAP will be finalized and approved prior to 
the database lock. 
This study will include approximately 1620 adult subjects with NCFBE. In addition, 
approximately 40 adolescents will be randomized to provide an adequate description of the 
safety profile of brensocatib in this age group and offer the possibility to observe directional 
trend in terms of efficacy. In the interest of providing information to prescribers on the use of 
brensocatib in adult patients in a timely fashion, the planned database lock is based on the time 
when the targeted 1620 adult subjects (originally planned sample size) complete the 52-week 
treatment period or discontinue from the study before Week 52, irrespective of whether the 
adolescent subjects have completed the study. All adult and adolescent data collected up to this 
database lock will be included in the primary efficacy and safety analyses for the CSR. 
Additional data collected between database lock and the last adolescent subject completing the 
last visit will be summarized in a CSR addendum. Any additional analyses of efficacy and safety 
data will be detailed in the SAP. 
All of the efficacy and safety data that have already been collected from 44 Ukraine subjects 
impacted by the war in Ukraine will be listed only and not included in the formal efficacy and 
safety analyses, as agreed with FDA and EMA. 
10.1. 
Sample Size and Power Considerations 
The study is designed to demonstrate superiority of brensocatib treatment at 10 mg and/or 25 mg 
over matching placebo as measured by the primary efficacy endpoint of the rate of PEs over the 
52-week treatment period. Assuming the annualized PE rate in the placebo arm is 1.2 events with 
a negative binomial distribution with dispersion of 1, 1620 adult subjects will yield 90% power if 
the ratio of exacerbation rate is 0.70 (brensocatib over placebo) between any of the brensocatib 
treatment arms and placebo after 52 weeks of treatment. This estimate is based on study-wise 
two-sided Type I error of 0.01 or 0.005 for each primary comparison between brensocatib and 
placebo.   
Randomization will be stratified based on a geographic region (North America, Europe, Japan, 
and the Rest of the World), Screening sputum sample positive or negative for Pseudomonas 
aeruginosa, and the number of prior PEs (2, or ≥3) in the previous 12 months.  
It is well known that among subjects with NCFBE, there is significant heterogeneity across 
regions in terms of distribution of phenotypes, baseline lung function, symptom scores, presence 
of comorbidities, and treatment patterns (Jauhiainen et al., 2020; Rabe et al., 2019).The ASPEN 
study was launched with a global outreach to more than 30 countries so that meaningful 
conclusions could be drawn on the effect of brensocatib in a representative population. 
Furthermore, the study was designed to ensure an adequate representation of all types of 
standards of care and of individual phenotypes worldwide. 
In order to have a representative population of NCFBE across all regions, enrollment targets 
have been established for adult subjects. Up to 13% of subjects will come from Eastern Europe. 
North America, Western Europe, Asia Pacific, and Latin America will contribute between 20% 

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and 30% each. No single country (except the US) will contribute more than 15% of the overall 
randomized population.  
In order to have a representative population in the study, similar to what is described in the 
literature, randomization will be enforced to have approximately 30% of adult subjects with 3 or 
more prior PEs, to have no more than 20% of subjects older than 75 years of age, to have 
approximately no more than 20% of subjects with eosinophil count in peripheral blood 
≥300/mm3 at Screening, and to have no more than 20% of subjects with COPD as a comorbidity. 
The adolescent sample size of approximately 40 subjects is based on the Sponsor’s consultation 
with several pediatric investigators in this field and from a survey across a number of global sites 
with pediatric experience conducted by the study CRO; the sample size also takes into 
consideration the potential challenges with enrollment and the low prevalence of the disease in 
this age group. The sample size is expected to provide a description of the safety profile of 
brensocatib in this age group and offer the possibility to observe directional trends in efficacy. 
The PK/PD substudy will include approximately 300 adult and 40 adolescent subjects who are 
not receiving cyclic antibiotics at Baseline; the sample size is based on clinical considerations. 
The CT substudy will include approximately 225 adult subjects; the sample size is based on 
clinical considerations. 
10.2. 
Analysis Sets 
10.2.1. 
Screened Analysis Set 
The Screened Analysis Set comprises all subjects who provide written informed consent. 
10.2.2. 
Intent-to-Treat Analysis Set 
The ITT Analysis Set comprises all subjects who were randomized subjects. This set will be 
analyzed using the treatment to which the subject was randomized, regardless of the treatment 
actually received. 
10.2.3. 
Safety Analysis Set 
The Safety Analysis Set comprises all participants who were randomized and received at least 
1 dose of brensocatib or placebo. The Safety Analysis Set will be analyzed using the actual 
treatment received. 
10.2.4. 
Pharmacodynamic Analysis Set 
The PD Analysis Set comprises subjects who have consented to participate in the PD substudy, 
have received at least 1 dose of study drug, and have at least 1 predose and 1 postdose 
measurement of biomarkers. The PD Analysis Set will be analyzed using the actual treatment 
received. 
10.2.5. 
Pharmacokinetic Concentration Analysis Set 
All subjects with PK postdose data, either in the main study or PK/PD substudy, will be included 
in the PK Concentration Analysis Set. The PK Concentration Analysis Set comprises participants 
who have consented to participate in the PK substudy, have received at least 1 dose of 

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brensocatib, and have at least 1 postdose plasma concentration of brensocatib. Participants will 
be classified according to treatment received regardless of the treatment group to which they 
were randomized. 
10.2.6. 
CT Scan Analysis Set 
The CT Analysis Set comprises subjects who have both Baseline and postbaseline CT 
measurement data. 
10.3. 
General Considerations 
All original and derived parameters as well as demographic and disposition data will be listed 
and tabulated using descriptive statistics. Frequency counts (n and percentages) will be made for 
each qualitative variable. Descriptive statistics (n, mean, SD, median, minimum and maximum) 
will be calculated for each quantitative variable (unless otherwise stated). All data will be 
summarized by treatment where appropriate. In addition to tabulated descriptive statistics, 
graphical data displays may be used to summarize the data. 
Data will be pooled across centers and countries within a region. 
Baseline is defined as the last observation before or on the randomization date, unless otherwise 
specified. 
Statistical analyses will be performed using SAS® (SAS Institute Inc., Cary, NC, US) 
Version 9.4 or higher unless otherwise specified. 
10.4. 
Statistical Analysis 
10.4.1. 
Subject Disposition 
Subject disposition will be listed and summarized including the number and percentage of 
subjects completing or prematurely discontinuing the treatment and/or study and the primary 
reason for withdrawal. Subjects excluded from any analysis sets will be listed including the 
reasons for exclusions. 
Demographic data and baseline characteristics will be summarized and presented in data listings. 
10.4.2. 
Medical History 
Medical history will be presented in data listings. 
10.4.3. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded by Preferred Term using the World Health 
Organization Drug Dictionary (WHODRUG). Prior medications are defined as those taken 
before the first dose of randomized drug. Concomitant medications are defined as any 
medication, taken after the first dose of randomized drug, or those starting before but continuing 
after. Prior and concomitant medications will be summarized and presented in data listings. 
10.4.4. 
Major Protocol Deviations 
The major protocol deviations will be identified based on a review of the study data prior to the 
database lock and unblinding. Major deviations may include the following: 

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• Violation of inclusion and/or exclusion criteria; 
• Noncompliance with the dosing schedule (ie, subjects for whom compliance during 
the double-blind treatment period was not between 75% and 120%); 
• Administration of prohibited concomitant medications that are expected to influence 
the measurement of the primary endpoints. 
Major protocol deviations will be summarized and presented in data listings. 
10.4.5. 
Treatment Exposure and Compliance 
The cumulative exposure to study drug, including duration of treatment, total number of doses 
received, and cumulative amount of drug received (mg), will be summarized by treatment group. 
Treatment compliance will be calculated as: 
Compliance (%) at Visit X = (Number of doses taken up to the day preceding Visit X / 
Number of expected doses up to the day preceding Visit X) * 100 
Treatment compliance will be listed by subject and summarized by treatment, based on the 
Safety Analysis Set. 
10.4.6. 
Efficacy Analyses 
10.4.6.1. Analysis of Primary Efficacy Endpoint 
10.4.6.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the annualized rate of PEs that have been confirmed through 
the event adjudication process. 
A minimum of 14 days must occur between the end date of one pulmonary exacerbation and the 
start date of the next pulmonary exacerbation. Any exacerbations that occur less than 14 days 
from the prior exacerbation will not be considered a new exacerbation. Any adjudicated PE that 
meets the protocol criteria after randomization through the end of study will be included in the 
primary endpoint calculation. 
Subject’s time at risk will be the time on study excluding the time during exacerbations. 
10.4.6.1.2. Main Analysis for Primary Endpoint 
The primary estimand is the On-Study estimand in which all observed data up to Week 52 will 
be included in the analysis. The ITT Analysis Set will be used for this estimand. 
The rate of PEs will be analyzed using negative binomial regression with robust estimate for the 
covariance matrix. The model will include treatment group and the randomization stratification 
factors (geographic region [North America, Europe, Japan, and the Rest of the World], sputum 
sample being classified as positive or negative for Pseudomonas aeruginosa at Screening Visit, 
the number of prior PEs [<3 or ≥3] in the previous 12 months), and age group (adult, adolescent) 
as fixed effects. If the age group covariate creates estimability issues, it may be removed.  The 
time at risk (log scale) will be included in the model as an offset variable. 

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The annualized rate of PE (PEs per subject per year; #PEs/time at risk * 365.25) for each 
treatment group, the ratios of PE rates between each brensocatib dose and placebo, and the 
associated 95% CIs will be estimated from the negative binomial model.  
10.4.6.1.3. Sensitivity Analyses for Primary Endpoint 
Sensitivity analyses will be conducted to assess the robustness of the primary results in the 
presence of missing data. 
In the event that there are study participants who discontinue randomized IP early and also 
decline to remain in the study, ascertainment of data will be incomplete, and a true treatment 
policy/ITT analysis cannot be achieved. A MAR assumption for the missing data is made 
implicitly for the On-Study estimand using the observed data alone, and a hypothetical strategy 
is inherently implemented for the ICEs of early study withdrawn. 
The main analysis using the negative binomial model is unbiased under the MAR assumption for 
the missing data. However, in some instances, the fact that data are missing may be directly 
related to the unobserved values (ie, MNAR). Therefore, robustness of the main analysis to 
departures from the MAR assumption will be assessed using tipping-point analyses. Due to the 
inherent difficulties in identifying the missing data mechanism in practice, all missing data will 
be assumed MNAR, and the tipping-point penalties will be applied accordingly. 
Full details of the sensitivity analyses will be described in the SAP. 
10.4.6.1.4. Supportive Analyses for Primary Endpoint 
The supportive estimand for the primary endpoint is the On-Treatment estimand and will utilize 
the ITT Analysis Set. The same negative binomial regression model will be implemented for this 
estimand; however, only data up until the occurrence of a relevant ICE (ie, early discontinuation 
of randomized study treatment, early discontinuation of standard of care, or addition of chronic 
antibiotics) will be included in the analysis. Time at risk will be defined as the time of exposure 
until the occurrence of an ICE or until the last dosing date of IP if no ICE occurred. Time during 
an exacerbation will be excluded from the time at risk. 
10.4.6.2. Analysis of Secondary Efficacy Endpoints 
10.4.6.2.1. Main Analysis of Secondary Efficacy Endpoints 
All inferential analyses for PE-related endpoints will be based on PEs that have been confirmed 
through the adjudication process. The primary estimand for the secondary endpoints will be On-
Study estimand in which all observed data (ITT Analysis Set) will be included in the analysis. 
• For time to first PE, the survival curves will be compared between the brensocatib 
dose and placebo using a Cox proportional hazards model based on the ITT Analysis 
Set. The covariate will include the stratification factors used for the randomization 
(see Section 10.4.6.1).  
• For the proportion of subjects who are exacerbation free, the comparison between 
brensocatib and placebo will be analyzed using logistic regression with treatment 
group and randomization stratification factors as fixed effects. 

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• 
Absolute change from Baseline in postbronchodilator FEV1 will be analyzed using 
linear repeated measures model with fixed effects of treatment, stratification factors 
as noted above, visit, treatment-by-visit interaction, as well as the continuous, fixed 
covariate of Baseline value. An unstructured variance-covariance matrix will be fit. 
• Rate of severe PEs will be analyzed using the same method as the primary endpoint. 
• Change from Baseline in the QOL-B Respiratory Symptoms Domain scores will be 
analyzed using linear repeated measures model with fixed effects of treatment, 
stratification factors, visit, treatment-by-visit interaction, as well as the continuous, 
fixed covariate of Baseline value. The variance-covariance structure will be 
compound symmetric with the robust sandwich variance estimator. The subgroup of 
adult subjects will be included in the analysis because the QOL-B is completed by 
adult subjects only. 
Further analysis details and sensitivity analyses as well as supplementary analyses for secondary 
endpoints will be described in the SAP. 
10.4.6.3. Analysis of Exploratory Endpoints 
Other exploratory endpoints will be analyzed using the methods suitable for the type of endpoint. 
Further details will be described in the SAP. 
10.4.6.4. Adjustment of Multiplicity for Efficacy Analysis 
In this study, the enhanced mixture-based gatekeeping procedure (Kordzakhia et al, 2018) will 
be used as the multiplicity adjustment method to control the overall type I error rate at a full 
alpha (𝛼= 0.05) with a two-sided test for the multiple tests of the primary and secondary 
endpoints across the two brensocatib doses relative to placebo. The enhanced mixture-based 
method is based on the closed testing procedure and thus protects the overall type I error rate in a 
strong sense. Adjusted p-values will be reported. 
To demonstrate substantial evidence of effectiveness, the adjusted p-values for the comparisons 
of brensocatib 25 mg versus placebo and brensocatib 10 mg versus placebo for the primary 
endpoint, the annualized rate of PEs, will also be compared against the two-sided 𝛼= 0.01. 
Rejecting either or both null hypotheses and accepting the corresponding alternative hypotheses 
with lower rate of PEs in the brensocatib treatment arms, for the ITT Analysis Set, will be 
considered as a successful demonstration of efficacy. Full details of the multiplicity adjustment 
process of the enhanced mixture-based gatekeeping procedure will be described in the SAP. 
10.4.6.5. Subgroup Analyses 
Consistency of observed treatment effect on the rate of PEs will be explored across major 
subgroups as shown in the list below, if deemed appropriate. 
• Age (12 to <18 years, 18 to <65 years, ≥65 years; <75 years, ≥75 years) 
• Sex (Male, Female) 
• Race (White, Asian, American Indian or Alaska Native, Black or African American, 
Native Hawaiian or Other Pacific Islander, Other) 

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• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Number of PEs in prior 12 months (1, 2, or ≥3) 
• Chronic use of antibiotics at Baseline (Yes, No) 
• Maintenance use of macrolides at Baseline (Yes, No) 
• Pseudomonas aeruginosa colonization status at Baseline (Positive, Negative) 
• Baseline BSI score (≤4, 5 to 8, ≥9) 
• Baseline BSI score (< median, ≥ median) 
• Baseline CT scan score (< median, ≥ median) 
• Baseline FEV1 % Predicted (<50%, ≥50%) 
• Geographical region (North America, Europe, Japan, the Rest of World). 
Subgroup analysis will be based on a negative binomial model as used for the primary analysis. 
One model per subgroup will be fitted, omitting the fixed effect if it is identical to the subgroup. 
The ITT Analysis Set will be used. A summary for each level of subgroup presenting the same 
data as for the primary analysis will be produced. A forest plot of subgroups with rate of PEs and 
95% CI displayed for each level of subgroup. 
The main analysis for the primary and secondary endpoints will be repeated for the adolescent 
subgroup (12- <18 years of age), and separately for the adult subgroup for the On-Study 
estimand. 
Additional subgroup analyses may also be performed if deemed appropriate. 
10.4.7. 
Safety Analysis 
All safety data will be summarized by treatment received using descriptive statistics based on the 
Safety Analysis Set. All safety data will be listed for each subject as well. 
10.4.7.1. Adverse Events 
Adverse events will be coded using MedDRA. Treatment-emergent adverse events will be 
summarized by SOC and PT by treatment group. Non-emergent adverse events will be presented 
in the data listings. 
The number and percentage of subjects with AEs will be presented by treatment and dose group. 
The severity of AEs, the relationship to study drug, AEs causing study discontinuation, and 
SAEs will be similarly presented. All AEs reported during the study will be listed. 
10.4.7.2. Clinical Laboratory Tests 
All clinical safety laboratory data (blood chemistry, hematology, and urinalysis) will be listed for 
each subject. Laboratory values outside the normal ranges will be flagged. If applicable, 
summary statistics (mean, range) for actual values and change from Baseline by treatment will 
be provided for each time point. 

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10.4.7.3. Vital Signs 
Vital signs will be listed and summarized including actual values and changes from Baseline. 
10.4.7.4. ECGs 
Heart rate and corrected QT interval by Fridericia’s formula will be derived from the dECG at 
each time point. The dECG data will be listed and summarized descriptively; outlier analyses for 
QTcF will also be performed. 
10.4.8. 
Pharmacodynamic Analysis 
The NE activity in sputum and blood will be calculated as percentage inhibition from the 
pretreatment activity. The pretreatment value is defined as the mean value of NE activities at 
Screening and Baseline and will be listed and summarized. All other biomarker levels at pre- and 
postdose levels will be listed and summarized. 
Pharmacodynamic parameters that are planned to be analyzed are NE, CatG, PR3, and neutrophil 
functions including oxidative and bactericidal assays, neutrophil adhesion chemotaxis and others. 
The results of NE, CatG, and PR3 activities, neutrophil functions, ANC, and other biomarkers 
will be listed by subject and time point. Note that ANC will be included in both safety and 
PD-related analyses. 
The observed time to maximum inhibition and maximum inhibition for NE, CatG, and PR3 
activities, neutrophil functions and ANC will be reported and listed for each subject. The NE 
activity in sputum and blood will be calculated as percent inhibition from the pretreatment 
activity. The pretreatment value is defined as the mean value of NE activities at Screening and 
Baseline and will be listed and summarized. 
Descriptive statistics for NE, CatG, and PR3 activities, neutrophil functions, ANC, and derived 
activity parameters (maximum inhibition and time to maximum inhibition) will be presented by 
dose levels of brensocatib and placebo. 
Individual figures of NE, CatG, and PR3 activities, neutrophil functions and ANC versus time 
will be presented with all subjects overlaid on the same plot for each dose level (spaghetti plots). 
Mean plots versus time will also be presented with all dose levels and pooled placebo overlaid on 
the same plot. 
Plasma concentration data for brensocatib will be pooled with corresponding data from other 
studies for population PK/PD modeling of the exposure response relationship. The methods and 
results of any population PK/PD analyses will be described and reported separately. 
10.4.9. 
Pharmacokinetic Analysis 
For subjects participating in the PK/PD substudy and subjects with postdose PK samples in the 
main study, plasma concentrations of brensocatib will be listed and summarized by dose level 
over each scheduled sampling time using descriptive statistics (including arithmetic mean, SD, 
median, minimum and maximum, geometric mean, and percent coefficient of variation of the 
geometric mean, as appropriate). Individual plasma concentration data versus time for the PK/PD 
substudy will be presented in data listings, along with graphical plots of individual and geometric 
mean plasma concentration-time plots presented in linear and semi-logarithmic scale. 

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Actual sampling times and brensocatib plasma concentrations from sparse sampling will be listed 
but not summarized. The modeling output will be reported outside of the CSR. 
Brensocatib plasma concentration data from this study will be pooled with data from other 
studies for the purposes of developing a population PK model. After an adequate structural 
model is identified, covariate analysis may be performed to evaluate the effect of intrinsic and 
extrinsic factors on the PK model parameters. 
A detailed SAP for the population PK parameters and reporting will be developed. The PK SAP 
will be finalized and approved by signature prior to the database lock to preserve the integrity of 
the statistical analysis and study conclusions. 
10.4.10. 
Population Pharmacokinetic Analysis 
Plasma concentration data from this study will be utilized in population PK analysis as an 
exploratory measure. The individual PK parameters, such as Cmax, Tmax, AUC0-24, elimination t½, 
CL/F, and Vd/F, will be determined using a population PK model. PK covariates will be 
evaluated. The results will be reported separately. 
10.4.11. 
Pharmacodynamic-Pharmacodynamic Analysis 
Brensocatib PD data from this study will be pooled with data from other studies for the purposes 
of developing a population PK/PD model. Covariate analysis may be performed to evaluate the 
effect of intrinsic and extrinsic factors on the PD model parameters. A stand-alone modeling and 
simulation analysis plan will be written for the PK/PD and PD models. The modeling output will 
be reported outside of the CSR. 
The relationship between brensocatib PD biomarkers of DPP1 inhibition (eg, NE, CatG, and PR3 
levels and neutrophil functions) and outcome measures (ie, PE, FEV1, etc.) will be explored 
graphically. If appropriate, linear or nonlinear models may be used to further describe their 
relationship. In addition to the PD-PD analysis, other analysis methodologies, such as nonlinear 
mixed-effect modeling, may be employed to further characterize the PD/PD relationship of 
brensocatib. 
10.4.12. 
CT Analysis 
Descriptive statistics will be provided for BEST-CT scores. AA ratio will be presented by 
brensocatib doses and placebo. The results of BEST-CT scores and AA ratio will be listed by 
subject and time point. 
10.5. 
Interim Analysis 
No interim analysis of efficacy data is planned. 

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11. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, IRB/EC review 
and regulatory inspections by providing direct access to source data/documents. Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
11.1. 
Source Documents 
Study data will be collected on source documents. The Investigator is responsible for assuring 
that collected data are complete and accurate. Source documentation (the point of initial 
recording of a piece of data) should support data collected on the eCRF. Source documents 
include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. 
11.2. 
Data Collection 
All data obtained for this study will be entered into a local regulation (ie, 21 CFR Part 11 in the 
USA) compliant Data Management System provided by the Sponsor or its designee. These data 
will be recorded with an EDC system using eCRFs. The Investigator will ensure the accuracy 
and completeness of the data reported to the Sponsor. All data entry, modification or deletion 
will be recorded automatically in an electronic audit trail. 
The Investigator will provide access to his/her original records to permit a representative from 
the Sponsor to verify the proper transcription of data. Data reported in the eCRFs should be 
consistent with and substantiated by the subject’s medical record and original source documents. 
The eCRF data will be monitored by the Sponsor or designee. The final, completed eCRF 
Casebook for each subject must be electronically signed and dated by the PI within the EDC 
system to signify that the Investigator has reviewed the eCRF and certifies it to be complete and 
accurate. 
The Sponsor will retain the final eCRF data and audit trail. A copy of all completed eCRFs will 
be provided to the Investigator. 
11.3. 
Study Record Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of the Sponsor. It is the responsibility of the Sponsor to inform the Investigator 
when these documents no longer need to be retained. 

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12. 
FINANCING AND INSURANCE 
12.1. 
Finances 
Prior to starting the study, the Investigator and/or institution will sign a clinical study agreement 
with Sponsor. This agreement will include the financial information agreed upon by the parties. 
12.2. 
Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 

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13. 
STUDY ADMINISTRATIVE INFORMATION 
 
13.1. 
Financial Disclosure by the Investigator 
The disclosed financial interest of the Investigator must be collected before Screening of the first 
subject, following study completion at the Investigator site and 1 year following overall study 
completion. The Investigator should promptly update this information if any relevant changes 
occur during this period. 
13.2. 
Study Registration and Results Disclosure 
The Sponsor will provide study information for inclusion in national registries according to 
national/local regulatory requirements. 
Results of this study will be disclosed according to the relevant national regulatory requirements. 
13.3. 
Study Files and Materials 
Before the start of any study-related procedures, all initial documents required by ICH GCP, 
Good Pharmacoepidemiology Practice, and applicable local regulations must be available in the 
relevant files maintained by the Sponsor (or delegate) and the Investigator. An Investigator Study 
File prepared by the Sponsor (or delegate), containing all applicable documents for use at the 
study site, will be made available to the Investigator before the start of the study. A list of 
personnel and organizations responsible for conduct of the study as well as the list of 
Investigators at each site will be included in the Investigator Study File. The respective files will 
be kept and updated by the Sponsor (or delegate) and the Investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by the Sponsor’s study monitor (or delegate) to determine that 
all required documentation is present and correct. 
The study may be audited by qualified delegates from the Sponsor or a competent regulatory 
authority. 
13.4. 
Use of Stored Samples and Data 
Stored samples will be labeled with study and subject information and kept in a locked room 
with limited access. Electronic data will be kept in password protected computers at the 
laboratory and then transferred to the Sponsor or CRO, as applicable, for data analysis. Samples 
and corresponding data will be tracked using the laboratory’s specimen tracking system. 
Prior Sponsor and IRB approval are required before using or sharing study samples or data in 
ways not specifically specified in the study protocol during conduct of this study. 
Any loss or unanticipated destruction of samples (eg, freezer malfunction) or data (eg, loss of a 
data sheet with individually identifiable information) that violates or compromises the scientific 
integrity of study data must be reported to the Sponsor and the IRB/EC. 
At any time, subjects may inform the Investigator that they do not wish to have their samples 
stored beyond the completion (termination) of the study. In this case, the Investigator will 

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request that all known remaining samples be destroyed and report the disposition of samples to 
the requesting subjects and the IRB/EC. 
At the completion (termination) of the study, samples will continue to be stored for a period of 
up to 5 years or longer if required by the institution participating in the study. The information 
already collected, including biological samples, will continue to be used to evaluate the study 
results and in future medical and pharmaceutical research activities. However, the stored samples 
will not be used for genetic evaluation unless stated in a separate consent document. 
Additionally, with subject’s consent, samples may be used for further research by Insmed or 
others such as universities or other companies to contribute to the understanding of NCFBE or 
other diseases, the development of related or new treatments, or research methods. 
13.5. 
Disposition of Stored Samples and Data 
Access to stored samples will be limited by using a locked room. Samples stored by the central 
laboratories will be labeled with the subject’s study identification information. Data will be kept 
in password protected computers at the laboratory and then transferred to the vendor for data 
analysis. Samples and corresponding data acquired will be tracked using the laboratory’s 
specimen tracking system. 
In the future, if other Investigators may wish to study these samples and/or data, they need to 
obtain Sponsor approval before any sharing of samples and/or data. 
Any loss or unanticipated destruction of samples (eg, due to freezer malfunction) or data (eg, 
loss of a data sheet with individually identifiable information) that results in a violation that 
compromises the scientific integrity of the data collected for the study will be reported to the 
Sponsor and the IRB/EC. 
Additionally, subjects may decide at any point not to have their samples stored for a period of up 
to 5 years beyond the duration of the study. In this case, the PI will request the destruction of all 
known remaining samples and report what was done to both the subject and to the IRB/EC. This 
decision will not affect the subject’s participation in this protocol. 
13.6. 
Initiation of Study 
Before the start of the study at each study site, the Sponsor’s study monitor (or delegate) shall 
confirm adequacy of the facilities by study site visit or other acceptable methods. 
The Investigator may not enroll any subject into the study before the Sponsor has received 
written approval or a favorable opinion from the health authority, where applicable, and the EC 
or IRB for conducting the study and a formal meeting has been conducted by the Sponsor’s study 
monitor (or delegate) to initiate the study. This meeting will include a detailed review of the 
study plan, and completion of the eCRF. 
13.7. 
Subject Reimbursement, Liability, and Insurance 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 

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The Sponsor will provide insurance to the Investigator if required by the applicable regulatory 
and legal requirement(s). 
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
13.8. 
Subject Identification and Confidentiality 
Subject names will not be supplied to the Sponsor. A Subject Number will be recorded in the 
eCRF, and if the subject name appears on any other document (eg, laboratory report), it must be 
obliterated on the copy of the document to be supplied to the Sponsor. All records will be kept 
confidential to the extent provided by federal, state, and local laws. The subjects will be 
informed that representatives of the Sponsor, IRB/EC, or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
The Investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
13.9. 
Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative will review the protocol, eCRF, IB, and any study-related materials with the 
Investigators and their staff. During the study, the study Sponsor monitor or its designee will 
visit the site regularly to check the completeness of subject records, the accuracy of entries on 
the eCRFs, adherence to the protocol, adherence to ICH GCP and applicable regulatory 
requirements, the progress of enrollment, and also to ensure that study drug is being stored, 
dispensed, and accounted for according to specifications. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the eCRF entries. Subject confidentiality will be maintained by the study 
center. The study Sponsor monitoring standards require full verification for the presence of 
informed consent (and assent if required per local requirements), adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of primary activity and 
safety variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific monitoring plan. 
13.10. 
Protocol Amendments 
Any substantial change or addition to this protocol requires a written protocol amendment that 
must be approved by the Sponsor, before implementation. Amendments significantly affecting 
the safety of subjects, the scope of the investigation, or the scientific quality of the study, require 
additional approval by the applicable regulatory authority(ies) and IRBs/IECs. Copies of the 
applicable written approvals must be given to the site monitor or their designee. 
The requirements for approval should in no way prevent any immediate action from being taken 
by the Investigator or by the Sponsor in the interests of preserving the safety of all subjects 
included in the study. If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, the study Sponsor or its agent 

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should be notified and the applicable regulatory authority(ies)/IRBs/IECs should be informed 
within 10 working days. Any other regional reporting requirements must be adhered to. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or regulatory authority/IRB/EC approval, but the regulatory 
authority(ies)/IRBs/IECs must be kept informed of such administrative changes in accordance 
with country-specific requirements. 
13.11. 
Audits and Inspections 
Domestic and foreign regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, case report forms, and other study 
documentation for on-site audit or inspection. Direct access to these documents must be 
guaranteed by the Investigator, who must provide support at all times for these activities. 
Medical records and other study documents may be copied during audit or inspection provided 
that subject names are obliterated on the copies to ensure confidentiality. 
If an inspection is requested by a regulatory authority, the Investigator will inform the study 
Sponsor, immediately that this request has been made. 
13.12. 
Publication Policy 
Any formal presentation or publication of data collected from this study will be considered as a 
joint publication by the Investigator(s) and the appropriate personnel of the study Sponsor. 
Authorship will be determined by mutual agreement. For multicenter studies, it is mandatory that 
the first publication be based on data from all centers, analyzed as stipulated in the protocol by 
the study Sponsor and statisticians, and not by the Investigators themselves. Investigators 
participating in multi center studies agree not to present data gathered from a single center or a 
small group of centers before the full, initial publication, unless formally agreed to by all other 
Investigators and study Sponsor. 
The study Sponsor must receive copies of any intended communication in advance of publication 
(at least 15 working days for an abstract or oral presentation and 45 working days for a journal 
submission). The study Sponsor will review the communications for accuracy (thus avoiding 
potential discrepancies with submissions to regulatory authorities), verify that confidential 
information is not being inadvertently divulged, and to provide any relevant supplementary 
information. Authorship of communications arising from pooled data may include members from 
each of the contributing centers as well as the study Sponsor personnel. 
At the conclusion of the study, after the data are analyzed, the results of study will be reported in 
a CSR. 

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Quint JK, Millett ER, Joshi M, Navaratnam V, Thomas SL, Hurst JR, Smeeth L, Brown JS. 
Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 
2013: a population-based cohort study. Eur Respir J. 2016;47(1):186-93. 
 
Quittner AL, O'Donnell AE, Salathe MA, Lewis SA, Li X, Montgomery AB, O'Riordan TG, 
Barker AF. Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and 
determination of minimal important difference scores. Thorax. 2015;70(1):12-20. 
 
Rabe KF, Wedzicha J, Calverley PMA, De La Hoz A, Voß F, Anzueto A, Jenkins C. Regional 
analysis of COPD exacerbation rates in the DYNAGITO trial. European Respiratory Journal. 
2019;54(suppl 63):PA5232. 
 
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat. 2013;12(6):337-47. 
 
Sibila O, Perea L, Canto E, Shoemark A, Cassidy D, Smith AH, Suarez-Cuartin G, Rodrigo-
Troyano A, Keir HR, et al. Antimicrobial peptides, disease severity and exacerbations in 
bronchiectasis. Thorax. 2019;74(9):835-42. 
 
Sorensen OE, Clemmensen SN, Dahl SL, Ostergaard O, Heegaard NH, Glenthoj A, Nielsen FC, 
Borregaard N. Papillon-Lefevre syndrome patient reveals species-dependent requirements for 
neutrophil defenses. J Clin Invest. 2014;124(10):4539-48. 
 
Voynow JA, Young LR, Wang Y, Horger T, Rose MC, Fischer BM. Neutrophil elastase 
increases MUC5AC mRNA and protein expression in respiratory epithelial cells. Am J Physiol. 
1999;276(5):L835-43. 
 
 

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15. 
APPENDICES 

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APPENDIX 1. SPUTUM INDUCTION GUIDELINES 
Collection of good sputum samples is critical to this study. Sputum samples will be collected at 
the clinical site. To facilitate the collection of good sputum samples during study visits, sputum 
induction may be performed at all visits except Screening if the subject is unable to expectorate 
approximately 3.0 mL of sputum. 
Note: If an adult subject is unable to produce sputum spontaneously during Screening (Visit 1), 
the subject will be considered a screen failure. Adult subjects may not undergo a sputum 
induction procedure during Screening (Visit 1) to meet eligibility (Section 4.1.1, Exclusion 
Criterion 6). Adolescent subjects are not required to produce a sputum sample for Screening if 
they are unable. 
Purpose 
The purpose of this guideline is to provide recommendations to the clinical sites for obtaining a 
sputum sample by induction if the subject is unable to expectorate a sputum sample on their own 
or after chest percussion. 
Required Equipment 
• Standard handheld nebulizer used in the site or the subject can be asked to bring the 
nebulizer they use at home for pulmonary hygiene 
• The nebulizer should be thoroughly disinfected to ensure no cross-contamination 
• Sputum specimen containers with label – sputum collection tube provided by central 
laboratory 
• Sodium chloride solution (saline) – 3% and 7%, and possibly 10% 
• Standard clinic supplies (eg, disinfectant/germicidal/alcohol wipes, tissues, paper 
towels, etc.) 
Procedure 
General Instructions: 
• At the study site, sputum induction should occur in a private, contained room. 
Specific processes in place at the clinic to prevent contamination and ensure 
sterilization before and after sputum induction should be followed. 
• Clinic personnel should wear gloves and a mask during the entire procedure. 
• Only 1 subject should be induced at a time. 
• All collection containers should have a sputum collection label clearly completed 
with subject identifiers, visit name, date and time. 
• The subject should have been instructed not to eat at least within 1 hour of sputum 
induction procedure. 
• An explanation should be provided to the subject that the purpose of this procedure is 
to help him/her cough up a sputum sample and that the success of the procedure is 
dependent on the subject’s active participation. 

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Inhalation and Collection Procedures: 
• The induction procedure should start by utilizing either 3% or 7% saline based on the 
Investigator’s preference. 
• Approximately 3 to 6 mL of the selected saline should be placed in the nebulizer. 
• The subject should be sitting up or in a semi-Fowler position. 
• The subject may wear a nose clip during the nebulization. 
• The subject should breathe slowly and deeply through the nebulizer mouthpiece 
inhaling the salt water mist. Remind the subject not to breathe quickly but to have 
slow, deep breaths pausing at peak inspiration to allow deposition of particles. 
• The nebulization time is 10 minutes. 
• At the end of this time, the subject should take a few deep breaths, swallow the extra 
saliva in his/her mouth and try to cough up a sputum sample. 
• The subject should be encouraged to cough forcefully using the deep coughing 
method and/or “huffing” cough method. 
• All sputum should be deposited in the specimen container. The container should not 
be opened until the specimen is ready to be deposited. The container should be closed 
immediately after depositing the sample. 
• The sputum sample should be approximately 3 mL – slightly below the bottom line 
(5 mL) on the collection container. 
• If a sufficient sputum sample is not collected and the subject appears to be tolerating 
the induction procedure well, the subject can complete another 10-minute 
nebulization period. 
− If a second 10-minute nebulization period is required, the recommendation is to 
increase the sodium chloride concentration (ie, if 3% was used first then 7% 
should be used for the subsequent nebulization; if 7% was used first then 10% 
should be used for the subsequent nebulization). 
− Closely monitor the subject for tolerability issues or side effects. 
− No more than two 10-minute nebulization periods should be completed. 
• The sputum sample should be refrigerated until it is sent to the microbiology 
laboratory. 

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Side Effects 
• The subject may experience side effects from the sputum induction procedure. The 
most common side effects include: 
− coughing 
− sore throat 
− wheezing 
− nausea 
− lightheadedness 
− headache 
− shortness of 
breath 
− chest 
tightness 
• Other possible side effects include hyperventilation or bronchospasm. For 
bronchospasm, ensure subject receives the necessary medical management. 
Miscellaneous 
• If the subject needs to expectorate during nebulization, turn off the nebulizer and 
allow the subject to cough up sputum into the container. If a sufficient specimen is 
not collected, the subject should then resume the nebulization to complete the 
10minute nebulization duration. 
• The subject should be encouraged to blow his/her nose as often as needed during the 
induction procedure to help prevent nasal sections from becoming mixed with sputum 
specimen.

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APPENDIX 2. CALCULATION OF BRONCHIECTASIS SEVERITY 
INDEX 
Severity Criteria 
0 Point 
1 Point 
2 Point 
3 Point 
4 Point 
5 Point 6 Point 
Age (Years) 
< 50 
- 
50 to 69 
- 
70 to 79 
- 
80+ 
BMI (kg/m2) 
> 18.5 
- 
< 18.5 
- 
- 
- 
- 
FEV1 
(% Predicted) 
> 80% 
50 to 80% 
30 to 49% 
< 30% 
- 
- 
- 
Hospital Admissions Due 
to Bronchiectasis 
Exacerbation in the Past 
2 Years 
No 
- 
- 
- 
- 
Yes 
- 
Exacerbation Frequency in 
Last 12 Months 
0 to 2 
- 
3 or More 
- 
- 
- 
- 
MRC Dyspnea Scorea 
1-3 
- 
4 
5 
- 
- 
- 
Colonization Status 
Not 
Colonized 
Chronic 
Colonization 
- 
Pa 
Colonization 
- 
- 
- 
Radiological Severity 
< 3 Lobes 
Involved 
3 or More 
Lobes or 
Cystic 
Changes 
 
 
 
 
 
Note: Estimated outcomes are those observed across 5 European treatments in the original derivation and validation 
study (Chalmers et al., 2014). 
BMI = body mass index, FEV1 = forced expiratory volume in 1 second, MRC = Medical Research Council; 
Pa = Pseudomonas aeruginosa. 
a Use Appendix 3. 
 
 

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APPENDIX 3. THE MEDICAL RESEARCH COUNCIL 
BREATHLESSNESS SCALE 
Grade 
Degree of Breathlessness Related to Activities 
1 
Not troubled by breathlessness except on strenuous exercise 
2 
Short of breath when hurrying on the level or walking up a slight hill 
3 
Walks slower than most people on the level stops after a mile or so, or stops after 15 minutes 
walking at own pace  
4 
Stops for breath after walking about 100 yards or after walking a few minutes on level ground 
5 
Too breathless to leave the house, or breathless when undressing 
 
 
 

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APPENDIX 4. HY’S LAW CASES 
Actions Required in Cases of Combined Increase of Aminotransferase and Total Bilirubin 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Insmed clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than DILI caused by the IMP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
AEs and SAEs according to the outcome of the review and assessment in line with standard 
safety reporting processes. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
AST or ALT ≥3 × ULN and TBL ≥2 × ULN at any point during the study irrespective of an 
increase in ALP. The elevations do not have to occur at the same time or within a specified time 
frame. 
Hy’s Law (HL) 
AST or ALT ≥3 × ULN and TBL ≥2 × ULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral 
hepatitis, another drug. The elevations do not have to occur at the same time or within a specified 
time frame. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥3 x ULN 
• AST ≥3 x ULN 
• TBL ≥ 2 x ULN 
The Investigator will review without delay each new laboratory report and if the identification 
criteria are met will: 
• Notify the Insmed representative 
• Determine whether the subject meets PHL criteria (see DEFINITIONS of this 
Appendix) by reviewing laboratory reports from all previous visits 

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FOLLOW-UP 
POTENTIAL HY’S LAW CRITERIA NOT MET 
• If the subject does not meet PHL criteria the Investigator will: 
• Inform the Insmed representative that the subject has not met PHL criteria. 
• Perform follow-up on subsequent laboratory results according to the guidance 
provided in the clinical study protocol 
POTENTIAL HY’S LAW CRITERIA MET 
If the patient does meet PHL criteria the Investigator will: 
• Notify the Insmed representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. Subsequent to this 
contact the Investigator will: 
• Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or Baseline levels, or as long as medically 
indicated 
• Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
• If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed for all cases where PHL criteria were met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than drug-induced liver injury caused 
by the IMP. The Insmed Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
• If there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF accordingly and 
follow the Insmed standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 

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• Report an SAE (report term ‘Hy’s Law’) according to Insmed standard processes. 
− The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
− As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review 
REFERENCES 
FDA Guidance for Industry (issued July 2009). ‘Drug-induced liver injury: Premarketing clinical 
evaluation.’ 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-liver-
injury-premarketing-clinical-evaluation 
 
 

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APPENDIX 5. SCHEDULE OF PHARMACOKINETIC SAMPLE 
COLLECTION 
Day/Week 
Collection Time 
Collection Window 
All Adult Subjects 
Substudy Subjectsa 
Day 1 
0 hour (predose) 
− 
X 
X 
 
0.5 hour postdose 
± 10 min 
− 
X 
 
2 hours postdose 
± 30 min 
X (optional)b 
X 
 
4 to 8 hours postdose 
− 
− 
X 
Week 4 
0 hour (predose) 
− 
X 
X 
 
2 hours postdose 
± 30 min 
X (optional)b 
X 
Week 16 
0 hour (predose) 
− 
X 
X 
Week 28 
0 hour (predose) 
− 
X 
X 
 
0.5 hour postdose 
± 10 min 
− 
X 
 
2 hours postdose 
± 30 min 
X (optional)b 
X 
 
4 to 8 hours postdose 
− 
− 
X 
Week 40 
0 hour (predose) 
− 
X 
X 
 
2 hours postdose 
± 30 min 
X (optional)b 
X 
Week 52 
0 hour (predose) 
− 
X 
X 
a Additional PK blood samples will be collected from all adult subjects who participate in the PK/PD substudy, and 
PK blood samples will be collected from all adolescent subjects enrolled in the study. The PK/PD substudy will 
include subjects who are not receiving cyclic antibiotics at Baseline. 
b While collection of the 2-hour postdose PK sample is optional, it is valuable for PK evaluation; therefore, 
collection of the optional 2-hour postdose sample is highly recommended. 
Note: The blood sample collected for all adult subjects will be used for the substudy when substudy sample 
collection is scheduled at the same timepoint (no extra samples will be collected). 
PD = pharmacodynamic; PK = pharmacokinetic. 
 
 

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APPENDIX 6. SCHEDULE OF PHARMACODYNAMIC SAMPLE 
COLLECTION 
 
 
All Adult Subjectsa 
Substudy Subjectsb 
Day/Week 
Collection Time 
Sputum Sample 
Blood Samplec 
Sputum Sampled 
Screening Visit 
During Screening Visit 
X 
X 
X 
Day 1 
0 hour (predose) 
X 
X 
X 
Week 4 
0 hour (predose) 
X 
X 
X 
Week 16 
0 hour (predose) 
X 
X 
X 
Week 28 
0 hour (predose) 
X 
X 
X 
Week 40 
0 hour (predose) 
X 
X 
X 
Week 52 
0 hour (predose) 
X 
X 
X 
Week 56 
At Follow-up visit 
X 
X 
X 
a Pharmacodynamic sputum samples will be collected from all newly enrolled adult subjects.  
b The PK/PD substudy will include subjects who are not receiving cyclic antibiotics at Baseline. 
c PD blood samples will be collected from approximately 40 adult subjects enrolled in the PK/PD substudy at select 
sites in the United States.  
d PD sputum samples will be collected from all adult subjects enrolled in the PK/PD substudy. Sputum samples will 
also be collected from all adolescent subjects who are enrolled in the study and are able to produce a sputum 
sample. 
Note: The sputum sample collected for all subjects will be used for the substudy when substudy sample collection is 
scheduled at the same timepoint (no extra samples will be collected). 
PD = pharmacodynamic; PK = pharmacokinetic. 
 
 
 
 
 

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APPENDIX 7. COMPARABLE NSAID DOSE LEVELS 
 
Source: https://www.ncbi.nlm.nih.gov/sites/books/NBK65646/