Clinical trial NCT02628600
Conditions: NTM Lung Infection Due to MAC
Keywords: ALIS ARIKAYCE
Sponsor: Insmed Incorporated
Start date: 2016-02-05; Completion date: 2018-10-17
Enrollment: 163 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label safety extension study to assess the safety and tolerability of once daily dosing of 590 mg Liposomal Amikacin for Inhalation (LAI) added to a multi-drug regimen in participants with nontuberculous mycobacterial (NTM) lung infections due to Mycobacterium avium complex (MAC) who were refractory to therapy and failed to convert in Study INS-212 (NCT02344004).

Detailed description:
Safety and tolerability of once daily dosing of 590 mg Liposomal Amikacin for Inhalation (LAI) added to a multi-drug regimen in participants with non-tuberculous mycobacterium (NTM) lung infections due to Mycobacterium avium complex (MAC) who are refractory to therapy and failed to convert in Study INS-212.

Participants participating in Study INS-212 who had not achieved the INS-212 protocol definition of culture conversion (3 consecutive monthly negative sputum cultures) or who had experienced a relapse or recurrence (agar positive or more than 2 consecutive broth positive results after culture conversion had occurred) by Month 6, as determined by their sputum culture results from Day 1 through Month 6 and confirmed at their scheduled Month 8 visit, were eligible to participate in Study INS-312. For participants who chose to participate in Study INS-312, the Month 8 visit of Study INS-212 became their end of treatment (EOT) visit; these participants were then asked to provide written informed consent for Study INS-312 and were enrolled directly into Study INS-312 after having met all eligibility criteria.

Participants in Study INS-212 had either received 590 mg LAI plus an MDR (LAI + MDR arm) or a multidrug regimen alone (MDR alone arm). All participants in this safety extension study were to continue the multidrug antimycobacterial regimen that they were receiving during Study INS-212 and will receive LAI 590 mg administered daily (QD) for up to 12 months. The participants will remain in the study for up to a total of 13 months (up to 12 months on-treatment plus 1 month off LAI treatment for safety follow up).

Arms: arm 1: Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. arm 2: Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.
Interventions: intervention 1: LAI 590 mg intervention 2: Multi-drug regimen
Intervention descriptions: intervention 1: LAI 590 mg QD: administered by inhaling drug product that had been aerosolized in an investigational eFlow nebulizer over approximately 14 minutes intervention 2: Multidrug antimycobacterial regimen from study INS-212

Protocol documents:
Prot_001.pdf: 
NCT02628600

























































































































































































SAP_000.pdf: 
Clinical Study Report INS-312
16.1 Study Information
9.
DOCUMENTATION OF STATISTICAL METHODS
The following documents are provided in this section: 
Statistical Analysis Plan
Final Version 2.0
13 November 2018
Final Version 1.0
06 June 2017
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STATISTICAL ANALYSIS PLAN
PHASE III
VERSION: 2.0
DATE OF PLAN:
13-NOVEMBER-2018
BASED ON:
Protocol: INS-312 Amendment 3.1
CRF A.000139 WTT 
STUDY DRUG:
amikacin liposome inhalation suspension 
PROTOCOL NUMBER:
INS-312 
STUDY TITLE:
AN OPEN-LABEL, SAFETY EXTENSION STUDY OF A MULTICENTER STUDY 
OF LIPOSOMAL AMIKACIN FOR INHALATION (ALIS) IN ADULT PATIENTS 
WITH NONTUBERCULOUS MYCOBACTERIAL (NTM) LUNG INFECTIONS 
CAUSED BY MYCOBACTERIUM AVIUM COMPLEX (MAC) THAT ARE 
REFRACTORY TO TREATMENT
SPONSOR:
Insmed Incorporated 
10 Finderne Avenue 
Building 10 
Bridgewater, NJ 08807 
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS.......................................................................................7 
2.
INTRODUCTION ........................................................................................................8 
3.
STUDY OBJECTIVES AND ENDPOINTS ................................................................9 
3.1. 
Study Objectives ...........................................................................................................9 
3.1.1. 
Primary Objective .........................................................................................................9 
3.1.2. 
Secondary Objectives ...................................................................................................9 
3.1.3. 
Exploratory Objectives .................................................................................................9 
3.2. 
Study Endpoints ............................................................................................................9 
3.2.1. 
Primary Endpoints ........................................................................................................9 
3.2.2. 
Secondary Endpoints ....................................................................................................9 
3.2.3. 
Exploratory Endpoints ................................................................................................10 
4.
STUDY DESIGN .......................................................................................................11 
4.1. 
Summary of Study Design ..........................................................................................11 
4.2. 
Definition of Study Drugs ..........................................................................................11 
4.3. 
Sample Size ................................................................................................................11 
4.4. 
Randomization ............................................................................................................11 
4.5. 
Clinical Assessments ..................................................................................................11 
5.
PLANNED ANALYSES ............................................................................................12 
5.1. 
Initial Analyses ...........................................................................................................12 
6.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND
HANDLING ...............................................................................................................13 
6.1. 
Data Presentation Conventions ...................................................................................13 
6.2. 
Analysis Populations ..................................................................................................14 
6.2.1. 
Safety Population ........................................................................................................14 
6.3. 
Baseline Definition .....................................................................................................14 
6.4. 
Derived and Transformed Data ..................................................................................14 
6.4.1. 
Sustained Conversion .................................................................................................14 
6.4.2. 
Baseline Age ...............................................................................................................14 
6.4.3. 
Study Day ...................................................................................................................14 
6.4.4. 
Study Month ...............................................................................................................15 
6.4.5. 
Duration ......................................................................................................................15 
6.4.6. 
Change-from-baseline .................................................................................................15 
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
6.4.7. 
ALIS Treatment ..........................................................................................................15 
6.4.8. 
CTC Grading of Audiology Results ...........................................................................16 
6.4.9. 
Visit Windows ............................................................................................................16 
6.4.10. 
Multiple Assessments .................................................................................................17 
6.5. 
Handling of Missing Data ...........................................................................................17 
6.5.1. 
Missing Efficacy Endpoints ........................................................................................17 
6.5.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................17 
6.5.3. 
Missing Start and Stop Dates for Adverse Events ......................................................18 
7.
STUDY POPULATION .............................................................................................20 
7.1. 
Subjects Disposition ...................................................................................................20 
7.1.1. 
End of Study Disposition ............................................................................................20 
7.1.2. 
End of Treatment Disposition .....................................................................................20 
7.2. 
Screen Failures ............................................................................................................20 
7.3. 
Protocol Deviations ....................................................................................................21 
7.4. 
Demographic and Baseline Characteristics ................................................................21 
7.5. 
Medical History and Medical Conditions Present at Entry ........................................22 
7.6. 
Prior Medication History and Medications Present at Baseline .................................22 
8.
EFFICACY .................................................................................................................23 
8.1. 
General Considerations ...............................................................................................23 
8.2. 
Statement of the Null and Alternate Hypotheses ........................................................23 
8.3. 
Subgroup Analyses .....................................................................................................23 
8.4. 
Multiple Comparisons and Multiplicity......................................................................23 
8.5. 
Analysis of the Primary Efficacy Endpoint ................................................................23 
8.5.1. 
Primary Efficacy Analysis ..........................................................................................23 
8.5.2. 
Sensitivity Analyses of the Primary Efficacy Results ................................................23 
8.6. 
Analysis of the Secondary Efficacy Endpoints ..........................................................23 
8.6.1. 
Culture Conversion .....................................................................................................23 
8.6.2. 
Time to Culture Conversion .......................................................................................23 
8.6.3. 
Six-minute Walk Test .................................................................................................24 
8.7. 
Analysis of Exploratory Efficacy Endpoints ..............................................................24 
8.7.1. 
St. George’s Respiratory Questionnaire .....................................................................24 
8.7.2. 
EQ-5D-3L ...................................................................................................................24 
8.7.3. 
Health Care Resource Utilization ...............................................................................24 
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
8.8. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses .......................................................................................................27 
9.
SAFETY AND TOLERABILITY ..............................................................................28 
9.1. 
Overall Summary of Adverse Events .........................................................................28 
9.1.1. 
Overall Summary of Treatment-emergent Adverse Events ........................................28 
9.1.2. 
Overall Summary of Adverse Events Resulting in Hospitalization ...........................29 
9.1.3. 
Adverse Events of Special Interest .............................................................................29 
9.2. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............31 
9.2.1. 
Tabulations of Adverse Events ...................................................................................31 
9.2.2. 
Summaries of Duration of Adverse Events ................................................................34 
9.3. 
Total Duration and Compliance of ALIS Therapy .....................................................34 
9.4. 
Concomitant and Other Medications ..........................................................................35 
9.5. 
Routine Laboratory Data ............................................................................................35 
9.6. 
Vital Signs ..................................................................................................................35 
9.7. 
Audiology Tests ..........................................................................................................35 
9.8. 
Physical Examination .................................................................................................35 
10.
REFERENCES ...........................................................................................................36 
11.
APPENDIX.................................................................................................................37
11.1. 
Table of Contents for Data Display Specifications ....................................................37 
11.2. 
Data Display Specifications ........................................................................................46 
11.3. 
Schedule of Events .....................................................................................................47 
11.4. 
INS-312 Study Schematic ...........................................................................................50 
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
LIST OF TABLES
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
Study Regions .............................................................................................................14 
Table 3: 
Hearing Loss CTC Grade ...........................................................................................16 
Table 4: 
Visit Windows (Days) ................................................................................................16 
Table 5: 
Multi-drug Regimen Classification ............................................................................22 
Table 6: 
Adverse Events of Special Interest .............................................................................29 
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
1.
LIST OF ABBREVIATIONS
Sample text is provided in the table below.  The list should be tailored to the specific 
requirements of the protocol and the terminology used in the analysis plan. 
Table 1: 
List of Abbreviations 
Abbreviation
Term
AE
Adverse Event
ALIS
Amikacin Liposome Inhalation Suspension 
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
CMH
Cochran Mantel-Haenszel
CRF
Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report 
DOB
Date of Birth
dy
Days
GCP
Good Clinical Practices
IRB
Institutional Review Board
ITT
Intent-to-Treat Population 
LLN
Lower Limit of Normal
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities Terminology 
mo
Months 
N 
Total Sample Size
PP
Per-Protocol Population 
StdDev
Standard Deviation 
SAE
Serious Adverse Event
SAS
Statistical Analysis System 
ULN
Upper Limit of Normal 
VAS
Visual Analogue Scale 
WHO
World Health Organization  
yr
Years
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the confirmatory analyses (referred to as the 
‘second analyses’ in earlier versions) tabulations, summaries, and inferential analyses to evaluate  
to assess safety and tolerability of ALIS 590 mg QD added to a multidrug regimen (MDR) in 
subjects with NTM lung infections due to MAC.  The initial analyses performed for the sub-part 
H submission to the FDA are described in version 3 (06Jun2017) version of the SAP. 
The statistical analysis plan is based on: 
x
Protocol INS-312, Amendment 3.1, dated May 25, 2017
x
ICH guidelines E6 and E9 (Statistical Principles for Clinical Trials)
x
Discussions with the FDA
The purpose of this document is to provide details on study populations and on how the variables 
will be derived, how missing data will be handled as well as details on statistical methods to be 
used for the final confirmatory analyses of the safety and efficacy data for Study Protocol INS-
312. The initial analyses performed for the FDA sub-part H submission are detailed in version 3,
June 6, 2017 of the SAP.
The document may evolve over time, for example, to reflect the requirements of protocol 
amendments or regulatory requests.  However, the final SAP must be finalized, approved by the 
Sponsor, and placed on file before database is locked.  Deviations from the final approved plan 
will be noted in the clinical study report.
The use of the acronym ALIS (amikacin liposome inhalation suspension) is consistent feedback 
from the Food and Drug Administration (FDA) in June 2017 regarding the anticipated 
established name of the product.  Previously, the product has been referred to as liposomal 
amikacin for inhalation (LAI) as an internal acronym as well as in publications. As such, the 
acronym LAI was used in the INS-312 protocol.  This SAP using the ALIS acronym. 
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
3.
STUDY OBJECTIVES AND ENDPOINTS
3.1.
Study Objectives
3.1.1.
Primary Objective
The primary objective is to evaluate long term safety and tolerability of ALIS (590 mg) 
administered once daily (QD) for up to 12 months in subjects who were refractory to standard 
multi-drug treatment and failed to convert in Study INS-212.   
3.1.2.
Secondary Objectives 
These are the secondary objectives for the confirmatory analyses.
1. To evaluate the number of subjects achieving culture conversion (3 consecutive monthly
negative sputum cultures) by Month 12/End of Treatment (EOT);
2. To evaluate the number of subjects achieving culture conversion by Month 6;
3. To evaluate the time to culture conversion;
4. To evaluate the change in the 6MWT distance at Month 6 and Month 12/EOT.
3.1.3.
Exploratory Objectives 
Exploratory objectives of the confirmatory analyses are: 
1. To assess subject-reported symptoms of NTM and change from Baseline (Day1) in
quality of life scores on the St. George’s Respiratory Questionnaire (SGRQ) and quality
of life scores on the SGRQ – Part II (Activity) at Month 6 and Month 12/EOT;
2. To assess the change from Baseline (Day 1) in the 3-level version of the EuroQol5-
dimensional questionnaire (EQ-5D-3L) subject-reported health outcomes at Month 6 and
Month 12/EOT.
3.2.
Study Endpoints
3.2.1.
Primary Endpoints
The primary endpoint is the frequency of treatment-emergent adverse events (TEAEs), TEAEs 
leading to withdrawal from study, treatment-emergent serious adverse events (SAEs), AEs of 
special interest, clinically significant abnormal laboratory test results, and vital signs 
measurements. The primary endpoint will evaluate the overall population and describe the 
subjects by treatment arm assigned in the INS-212 study (ALIS added to a multi-drug regimen 
arm and a MDR alone).  
3.2.2.
Secondary Endpoints
The secondary efficacy endpoints are: 
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Statistical Analysis Plan Version: Final 2.0
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NOV 13, 2018 
1. Proportion of subjects achieving culture conversion (3 consecutive monthly negative
sputum cultures without relapse or recurrence) by Month 12/EOT.
2. Proportion of subjects achieving culture conversion by Month 6.
3. Time to culture conversion. The date of conversion is defined by the date of the first of at
least 3 consecutive monthly culture specimens that are MAC negative.
4. The mean change from Baseline in 6MWT distance a Month 6 and Month 12/EOT
3.2.3.
Exploratory Endpoints 
The exploratory efficacy endpoints are:
1. The mean change from Baseline at Month 6 and Month 12/EOT in the overall SGRQ and
SGRQ – Part II (Activities of Daily Living) .
2. The mean change from Baseline at Month 6 and Month 12/EOT in the EQ-5D-3L.
3. Radiological changes in CT scan at EOT, within a sub-set of subjects
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
4.
STUDY DESIGN
4.1.
Summary of Study Design
Eligible subjects will have successfully completed their Month 6 visit in the INS-212 study. At 
or after all the INS-212 Month 6 visit assessments have been completed, the investigator will 
remind the subject of the potential opportunity to enroll in INS-312 at their scheduled Month 8 
visit, to allow sufficient time for the subject to make an informed decision. At the scheduled 
Month 8 visit, eligible subjects will be confirmed to have not achieved the INS-212 protocol 
definition of culture conversion (3 consecutive negative sputum cultures) or to have experienced 
a relapse or recurrence (agar positive or more than 2 consecutive broth positive results after 
culture conversion has occurred), as determined by the subjects’ Day 1 through Month 6 sputum 
assessments in INS-212. The scheduled Month 8 visit will become the EOT visit. Subjects will 
be asked to provide written informed consent and will enroll directly from the INS-212 study at 
their EOT visit when all sputum results from Day 1 through Month 6 are known, and after 
having met all eligibility criteria.
All enrolled subjects will receive ALIS administered QD added to a multi-drug regimen for 12 
months. All subjects will return 1 month after EOT for an off-ALIS treatment follow-up visit at 
the end of study (EOS) visit. 
The study schematic is in Appendix X.  The study time and events schedule is in Appendix Y.
4.2.
Definition of Study Drugs
The study drug for Study INS-312 is amikacin sulfate is encapsulated in liposomes composed of 
DPPC and cholesterol (2:1 w:w lipid ratio) formulated as a suspension at a targeted 
concentration equivalent to 70 mg amikacin/mL in 10 mL of water for injection. The study drug 
is aerosolized in an eFlow nebulizer and inhaled over approximately 14 minutes. 
4.3.
Sample Size
There was no sample size determination as this study followed the INS-212 study; eligible
subjects who consented after Month 6 and complete the EOT visit of Study INS-212 determined 
the sample size of this ongoing study. 
4.4.
Randomization
Not applicable. 
4.5.
Clinical Assessments
Efficacy assessments are sputum samples for MAC culturing, 6-minute walk test, SGRQ, and 
EQ-5D-3L.  Safety assessments are adverse events, concomitant medications, clinical laboratory 
samples, CT scans (interpretation only), vital signs including pulse oximetry, and audiology 
tests.   Other assessments collected include health care resource utilization (HCRU), and 
exploratory biomarkers (IL-6 and CRP).  See the event schedule in Section 11.3 for details.  
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
5.
PLANNED ANALYSES
5.1.
Initial Analyses
Analyses were performed to support a sub-part H accelerated approval application to the FDA.
These analyses were performed on data cut at the time of the last subject’s Month 6 visit in study 
INS-212 (07 July 2017).  
The initial analyses are described in version 3.1 (06 June 2017) of the SAP.     
No multiplicity adjustments are necessary for initial or the confirmatory analyses as there were
no formal statistical hypothesis for the primary endpoints of this study for the initial or 
confirmatory analyses.  
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
6.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND
HANDLING
6.1.
Data Presentation Conventions
Continuous variables will be summarized with means, standard deviations, medians, minimums, 
and maximums, and, if appropriate, by clinically relevant discretization’s. Categorical variables 
will be summarized by counts and by percentage of subjects in corresponding categories. All 
data that meaningfully contribute to the objectives of the study will be included. Footnotes will 
specify the basis for the percentages. For counts of subjects, however, the denominator will 
generally be the number of subjects in the Safety population and treatment arm (based on 
treatment assignment in INS-212). All summary tables will be presented by treatment arm. A 
total summary column may be included in some summary tables wherever relevant. 
Summaries of continuous variables that have some values recorded using approximate values 
(e.g., < or >) will use the numeric part of the value in calculations. Listings will present the data 
in its original format. 
For summaries where rounding is required, rounding will be done to the nearest roundoff unit. 
For example, if the round-RIIXQLWLVWKHRQHVSODFHLHLQWHJHUVYDOXHV;;ZLOOEHURXQGHG
up to XX+1 while values < XX.5 will be rounded down to XX.  
Individual subject data obtained from the electronic case report forms (eCRFs), and any derived 
data will be presented by treatment, site, and subject in data listings. 
An unscheduled visit can be used in the determination of baseline values, if it provides the last 
non-missing value prior to the first dose of the study drug. Post-baseline unscheduled visit data 
will be presented in the listings only (i.e., unscheduled visit data will not be summarized in 
tables). If subject has more than one data at a specific visit for any reason, average of the data at 
that visit will be considered in summary tables.
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock. Any other analyses performed will be considered post-hoc. Posthoc analyses will 
be labeled as such on the output and identified in the CSR.
All analyses and tabulations will be performed using SAS® version 9.4 or higher. Tables, 
listings, and figures will be created in rich text format. 
All tables are broken down by region, country, and site including the overall groups within each.  
The first group will always be the overall group.  The definition of regions and order of 
presentation is in Table 2. Countries will be ordered by the number of enrolled subjects within 
the country and presented in descending order (ie, country with the most subjects first). Sites will 
be ordered by the number of enrolled subjects within the sites and presented in descending order 
(ie, site with the most subjects first).
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Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Table 2:
Study Regions
Presentation 
Order
Region
Name
Region 
Abbreviation
Countries in Region
1 
All
All
Austria, Germany, Spain, France, Great Britain, Italy, 
Netherlands, Poland, Israel, Japan, USA, Canada, Australia, and 
New Zealand
2 
North America
N.Amer
USA and Canada
3 
Japan
JPN
Japan
4 
Europe
EU
Austria, Germany, Spain, France, Great Britain, Italy, 
Netherlands, Poland, Israel, and Sweden
5
Asia
Asia 
(Excluding 
Japan)
South Korea, Thailand
6 
Oceania
Oceania
Australia and New Zealand
6.2.
Analysis Populations
6.2.1.
Safety Population 
The safety population is the set of subjects who received at least 1 dose of ALIS.
6.3.
Baseline Definition
Any non-missing value from any procedure at a subjects EOT visit in study INS-212 will be 
denoted as their baseline value. If that result from the aforementioned visit is missing, then the 
non-missing value at the subsequent visit in the INS-312 study.  
6.4.
Derived and Transformed Data
6.4.1.
Sustained Conversion
For subjects who convert (ie, 3-consecutive negative monthly MAC cultures), the conversion 
will be considered ‘sustained’ if there are no positive solid media and no more than 2 
consecutive positive monthly broth MAC cultures from conversion through End of Treatment.
6.4.2.
Baseline Age 
Use subject’s age as reported on the CRF. 
6.4.3.
Study Day
Study day, the number of days from enrollment, is derived using the following formula: 
STUDYDAY = (assessment– enrollment date) + (assessment >= enrollment date); 
there is no study day 0. 
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Statistical Analysis Plan Version: Final 2.0
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NOV 13, 2018 
6.4.4.
Study Month
Study month, the number of months from enrollment is derived using the following formula: 
STUDYMON = STUDYDAY/30. 
6.4.5.
Duration 
Duration is the time between two dates and may be expressed in days, months, or years.  The 
formulae for deriving duration are: 
x
Duration (days) = end – start dates + 1
x
Duration (months) = (duration [days])/30.4
x
Duration (years) = (duration [days])/365.25
6.4.5.1.
Total Duration 
Total duration is the duration within a reporting group (eg, SOC).  Total duration is derived with 
the subject and is the sum of all durations in the reporting group. 
6.4.5.2.
Maximum Duration
Maximum duration is the longest duration within a reporting group (eg, SOC).     
6.4.5.3.
Mean Duration
Mean duration is the average duration within a reporting group (eg, SOC), derived as the total 
duration divided by the number of events in the reporting group.   
6.4.6.
Change-from-baseline
Change-from-baseline is calculated as (post-baseline result – baseline result).
Percent change-from-baseline is calculated as (100 * change-from-baseline/baseline result).
If either the baseline or the post-baseline result is missing, the change-from-baseline and
percentage change-from-baseline are also missing.
6.4.7.
ALIS Treatment
Study drug (ALIS) was the only study treatment provided by the sponsor.  Therefore, compliance 
can only be determined for ALIS and then compliance can only be determined based on vial 
counts.   
The MDR treatments are captured in the concomitant medication log, but compliance with 
dosing was not tracked during the study.  However, since subjects came to the study on MDR 
and continued MDR treatment through the study and after leaving the study, duration of MDR is 
not informative. 
6.4.7.1.
Duration of ALIS  
Duration of ALIS will be derived as the last dose – first dose + 1 as captured on the CRF. 
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Statistical Analysis Plan Version: Final 2.0
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NOV 13, 2018 
6.4.7.2.
Compliance with ALIS 
Because ALIS is a once a day dosing, prescribed number of doses is the same as the duration.  
Therefore, compliance with ALIS will be derived as the number of vials taken / duration of 
ALIS. Protocol allowed ALIS treatment interruptions, were not captured in a manner that these 
interruptions can be accounted for in compliance.   
6.4.8.
CTC Grading of Audiology Results 
Hearing loss will be graded based on the CTC grading criteria in Table 3 . 
Table 3: 
Hearing Loss CTC Grade
Grade
Criteria
1 
Threshold shift of 15 - 25 dB averaged at 2 contiguous test frequencies in at least one ear.
2 
Threshold shift of >25 dB averaged at 2 contiguous test frequencies in at least one ear.
3 
Threshold shift of >25 dB averaged at 3 contiguous test frequencies in at least one ear; therapeutic 
intervention indicated.
4 
Decrease in hearing to profound bilateral loss (absolute threshold >80 dB hearing loss at 2 kHz 
and above); non-serviceable hearing.
The baseline hearing test is the threshold for deriving the grade.  Subjects who do not meet any 
of the above CTC grades will have a CTC grade of zero (0).
6.4.9.
Visit Windows
Nominal visit windows will be used for all visits, except for EOT and EOS visits.  Because EOT 
and EOS visits are conducted in place of the planned visit for subjects who prematurely end 
treatment or study participation, these visits also need to be mapped to the coincident visit.   
For example, a subject discontinues treatment at the Month 4 visit.  The site will conduct the 
EOT visit at Month 4 rather than the Month 4 visit, but for analysis purposes this visit should be 
used for the Month 4 summary as well as the EOT summary.  Similarly, for the EOS visit.  Thus, 
should it be appropriate, the EOT and EOS visit need to be mapped to the corresponding visit.  
Should the EOT or EOS visit map to a time that doesn’t coincide with a scheduled visit, it will 
not be mapped.   
Subjects who prematurely discontinue from the study, may not have an EOT visit. In this case 
the EOS visit will also be the EOT visit and should be mapped accordingly.
Table 4: 
Visit Windows (Days)
Visit Name
Visit Number
Target Anchor
Relative Target Day
Visit Window
Baseline
1 
Last visit from 
Study INS-212
1 
-2 to 1
Month 1
2 
30
23 to 37
Month 2
3 
60
53 to 67
Month 3
4 
90
83 to 97
Month 4
5 
120
113 to 127
Month 5
6 
150
143 to 157
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Visit Name
Visit Number
Target Anchor
Relative Target Day
Visit Window
Month 6
7 
180
173 to 187
Month 7
8 
210
203 to 217
Month 8
9 
240
233 to 247
Month 9
10
270
263 to 277
Month 10
11
300
293 to 307
Month 11
12 
330
323 to 337
Month 12 (EOT)
13 
365
353 to 367
Month 13 (EOS)
14 
420
413 to 427
6.4.10.
Multiple Assessments
Sputum samples will be captured daily starting two days before each visit.  Thus, each visit will 
have up to three sputum samples.  For the determination of culture conversion, should any 
sputum samples at that visit be MAC culture positive, that visit is considered positive for MAC.  
When determining if a subject had 3-consecutive monthly negative sputum cultures, only 
schedule monthly samples will be used.  However, subjects with a positive unscheduled sputum 
sample culture among the 3-consecutive monthly negative sputum cultures will not be deemed as 
achieving culture conversion. 
For the determination of sustained culture conversion, if a subject has any positive solid media 
culture whether scheduled or unscheduled after conversion or with at least 3 consecutive positive 
scheduled monthly liquid media cultures, that subject will not have achieved sustained culture 
conversion.    
6.5.
Handling of Missing Data
6.5.1.
Missing Efficacy Endpoints
6.5.1.1.
Conversion 
A sputum culture will be considered missing at the visit only if there are no sputum samples at 
that visit to culture.  Visits with missing sputum cultures prior to subject converting will be 
considered as positive cultures.  This results in the most conservative outcome, ie, most 
conversion failures.   
6.5.2.
Missing Start and Stop Dates for Prior and Concomitant Medication 
Medications with partial start and stop dates may be considered as a prior, concomitant, or both. 
If time is needed for analysis purpose, all missing or partial times will be replaced by 00:00 
(HH:MM) for start times and 23:59 for stop times using 24-hour clock.
The following algorithm will be applied to missing and incomplete start and stop dates, stop 
dates should be imputed before start dates: 
Concomitant Medication Stop Dates: 
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
x
If the stop date is completely missing, the stop date year is missing, or the medication
is ongoing, then set the stop date to the last available subject visit date.
x
If the day portion of the stop date is missing, then set the day to the last day of the
month, if available otherwise set the day to the 31st.
x
If the month portion of the stop date is missing, then set the month to December
(‘DEC’).
Concomitant Medication Start Dates:
x
If the imputed stop date is after the first dose of study drug (ALIS), then impute the
missing portion of the start date as follows:

If only the day portion of the start date is missing, then the day will be set to the
first (‘01’) of the month.

If both the day and month portions of the start date are missing, then the day and
month will be set to the first (‘01’) of the month and the month will be set to
January (‘JAN’).

If the start date is completely missing, then the start date will be imputed first day
of the same year (ie, 01Jan) as the stop date.
x
If the imputed stop date is on or before the first dose of study drug (ALIS) or
completely missing (ie, ongoing), then impute the missing portion of the start date as
follows:

If the day portion of the stop date is missing, then set the day to the first (‘01’).

If the month portion of the stop date is missing, then set the month to January
(‘JAN’).

If the year is missing, then set the year to the screening visit year.
After start dates have been imputed, check that the imputed start date is on or before the imputed 
stop date.  If imputed start date is after the imputed stop date, set the imputed start date to the 
imputed stop date. 
6.5.3.
Missing Start and Stop Dates for Adverse Events
For AEs, missing or incomplete onset or end dates will be imputed such that the AE is assumed 
to have occurred during the study treatment phase (i.e., considered a TEAE) unless the partial 
onset date or end date, indicates differently. If time is needed for analysis purpose, all missing or 
partial times will be replaced by 00:00 (HH:MM) for start times and 23:59 for stop times using 
24-hour clock.
The following algorithm will be applied to missing and incomplete onset and end dates, end 
dates should be imputed before onset dates: 
Adverse Event End Dates 
x
If the end date is completely missing or the year portion of end date is missing (even
if day or month are present), or the AE is ongoing, then set the end date to the last
available subject visit date.
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
x
If the month portion of the end date is missing and the year is present, then set the
month to December.
x
If only the day portion of the end date is missing, then set the day to the last day of
the month.
Adverse Event Onset Dates:
x
If the imputed end date is on or after the first dose of study drug (ALIS), then impute
the missing portion of the onset date as follows:

If only the day portion of the onset date is missing, and the month and year are the
same as the month and year of the first dose of ALIS; otherwise the missing day
will be set to the first (‘01’) of the month.

If month portion of the onset date is missing and the year is present, and the year
is the same year as the first dose of ALIS; otherwise set the month to  January
(‘JAN’).

If the onset date is completely missing or the year portion of onset date is missing,
the onset date will be imputed to the date of first dose of ALIS.
x
If the imputed end date is before the first dose of study drug (ALIS), then impute the
missing portion of the onset date as follows:

If only the day portion of the end date is missing, then set the day to the first
(‘01’).

If the month portion of the onset date is missing and the year is present, then set
the month to January (‘JAN’).

If the onset date is completely missing or the year portion of onset date is missing,
then set the year to the end date year.
x
After onset dates have been imputed, check that the imputed onset date is on or before
the imputed end date.  If imputed onset date is after the imputed end date, set the
imputed onset date to the imputed end date.
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
7.
STUDY POPULATION
7.1.
Subjects Disposition
All disposition tables will present the data by INS-212 randomized treatment and total groups as 
columns in the table.  all percentages on disposition tables will use the Safety population as the 
denominator. 
7.1.1.
End of Study Disposition
End of Study Disposition - Overall
The end of study disposition overall table will present the number of subjects that were enrolled 
(ie, screened), safety population, completed study, discontinued from study, and reasons for 
discontinuation from study.  Percentages will only be presented for completed and discontinued 
study, and reasons for discontinuation.  
End of Study Disposition – by Visit
The end of study disposition table by visit will present the number of subjects who discontinued 
at that visit and the reasons for discontinuation.    
7.1.2.
End of Treatment Disposition
End of treatment disposition will present the number and percentage of subjects who completed 
and discontinued treatment for any reason, and the reasons for treatment discontinuation (death, 
adverse event, protocol deviation, noncompliance with study drug, lack of efficacy, withdrawal 
by subject, lost to follow-up, physician decision, site terminated by sponsor, study terminated by 
sponsor, rescue medication, and other).  Except for completed, these reasons will appear on both 
overall and by visit end of treatment disposition tables.  The reasons for discontinuation should 
be presented in descending order of the total column subject count. 
End of Treatment Disposition - Overall
The end of treatment disposition overall table will present the number of subjects that completed 
treatment, discontinued treatment, and reasons for treatment discontinuation.   
End of treatment Disposition – by Visit
The end of treatment disposition table by visit will present the number of subjects who 
discontinued at that visit and the reasons for discontinuation.  Percentages on this table will use 
the Safety population as the denominator.  
7.2.
Screen Failures
Not applicable. 
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
7.3.
Protocol Deviations
The protocol deviation tables will present the Safety population.  The number and percentage of 
subjects will be presented. 
7.4.
Demographic and Baseline Characteristics
Demographics and baseline characteristics will be tabulated or summarized as appropriate with 
treatment arm (based on study INS-212) and total columns for the safety population.   
Demographic parameters are age, race, ethnicity, sex, and childbearing potential (females only).
Baseline characteristics are contraception (childbearing females only),  St. George’s Respiratory 
Questionnaire (SGRQ) total score, SGRQ symptoms score, SGRQ activity score, SGRQ impacts 
score, SGRQ question ‘how do you describe your current health?’, SGRQ question ‘what best 
describes your respiratory problems affect you?’,  EQ-5D-3L visual analog score (VAS), EQ-
5D-3L mobility score, EQ-5D-3L self-care score, EQ-5D-3L usual activities score, EQ-5D-3L 
pain/discomfort score, EQ-5D-3L anxiety/depression score, CRP (biomarker), IL-6 (biomarker), 
6-minute walk test (6MWT) distance, 6MWT supplemental oxygen use, 6MWT early
termination, 6MWT remaining time (for early termination subjects only), 6MWT distribution of
the number of rests, 6MWT vital signs (pre-test, post-test, and change-from-pre-test in heart rate,
respiratory rate, systolic and diastolic blood pressures, and oxygen saturation), 6MWT dyspnea
score (pre-test, post-test, and change-from-pre-test), 6MWT distribution of dyspnea scores (pre-
test and post-test),  6MWT fatigue score (pre-test, post-test, and change-from-pre-test), 6MWT
distribution of fatigue scores (pre-test and post-test),  audiology tests (decibels at 250, 500, 1000,
2000, 4000, and 8000 Hz in each ear), visit vital signs (height, weight, body mass index [BMI],
temperature, pulse rate, respiratory rate, systolic and diastolic blood pressures, and oxygen
saturation).
Age, SGRQ scores (total, symptoms, activity, impacts), EQ-5D-3L scores (VAS, mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression), biomarkers (CRP, IL-6), 6MWT 
(distance, time remaining, vital signs, dyspnea score, and fatigue score), audiology (for each ear 
within each frequency), and vital signs will be summarized descriptively (n, mean, standard 
deviation, median, minimum, and maximum).   
Age will also be categorized into groups 18-45, 46-64, 65+, 75+, and 85+.  The groups 65+, 75+ 
and 85+ are not mutually exclusive, thus the 65+ group will contain all subjects in the 75+ and 
85+ groups and the 75+ group will include the 85+ group. 
Age groups, race, ethnicity, sex, childbearing potential (females only), contraception 
(childbearing females only), SGRQ question ‘how do you describe your current health?’, SGRQ 
question ‘what best describes your respiratory problems affect you?’,  6MWT (supplemental 
oxygen use, early termination, number of rests, dyspnea score, and fatigue score),  and PFT prior 
bronchodilator use status will be tabulated presenting the number and percentage of subjects in 
each category.
Subject reporting multiple races will appear in each race they reported.  Thus, the total number of 
subjects with the race groups may exceed the total number of subjects in that column.  A group 
of ‘not recorded’ will be included with the race groups to account for subjects who declined 
reporting their race.
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
7.5.
Medical History and Medical Conditions Present at Entry
Medical history will be tabulated by treatment and total for the safety population.  The number 
and percentage of subjects will be presented for subjects reporting at least one medical history 
and by body system/organ class and preferred term within body system organ class.  Medical 
history is coded using MedDRA 19.1. 
7.6.
Prior Medication History and Medications Present at Baseline
Prior and concomitant medications are coded using the Who Drug Sept16 dictionary. Prior 
medications, prior MDR (indicated on the CRF) for NTM-MAC, and concomitant medications 
are presented in separate tables.  The number and percentage of subjects reporting at least one 
medication and by anatomical therapeutic class level 4 (ATC4) and preferred term within ATC4 
will be presented.
The number and regimen of prior MDR for NTM-MAC at baseline will be tabulated.  This table 
was provided with the initial analyses (14.1.9.1).  Multi-drug regimen medications are classified 
into ethambutol, macrolide, rifamycin, or other as follows: 
Table 5: 
Multi-drug Regimen Classification 
Classification
Medications
Ethambutol 
Ethambutol, Ethambutol Di1hydrochloride, Myrin Plus1
Macrolide 
Azithromycin, Clarithromycin, Erythromycin, Roxithromycin 
Rifamycin
Rifampicin, Rifabutin, Rifamycin, Rifinah, Rifater, Myrin Plus1
Other
Any medication flagged as part of MDR that doesn’t fit the above classifications.
1 Myrin Plus is a combination product containing an ethambutol and rifamycin.
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
8.
EFFICACY
8.1.
General Considerations
All analyses of efficacy endpoints will be sorted by the patient’s treatment in study INS-212 and 
will use the Safety Population.
8.2.
Statement of the Null and Alternate Hypotheses
Not applicable 
8.3.
Subgroup Analyses
Not applicable.  
8.4.
Multiple Comparisons and Multiplicity
As described in section 5.1, multiplicity adjustments are not necessary for initial or the 
confirmatory analyses as there were no formal statistical hypothesis for the primary endpoints of 
this study for the initial or confirmatory analyses.
8.5.
Analysis of the Primary Efficacy Endpoint
8.5.1.
Primary Efficacy Analysis 
There is no primary efficacy endpoint for Study INS-312; all efficacy endpoints were 
secondary or exploratory. 
8.5.2.
Sensitivity Analyses of the Primary Efficacy Results
Not applicable. 
8.6.
Analysis of the Secondary Efficacy Endpoints
8.6.1.
Culture Conversion 
Culture conversion through 6 months and 12 months of treatment will be analyzed across all 
groups and within groups. 
8.6.2.
Time to Culture Conversion
The traditional failure time analysis of culture conversion will be based solely on the INS-312 
Safety population.  
Kaplan-Meier estimates of the time-to-conversion curves will be produced with and without 
stratification by the prior 2 treatment groups (from INS-212). Median time to conversion 
together with the 25th and 75th percentiles and their associated 95% CIs will be presented by 
treatment group and overall. Kaplan-Meier curve for time to Culture Conversion will be 
provided in a figure. 
The following lines provide sample SAS code for the Kaplan-Meier estimates.
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
PROC LIFETEST DATA=input_data METHOD=KM;
TIME DAYS*CENSOR(1);
STRATA TRT / NOTEST; 
RUN;
For the survival curve, DAYS is the number of days from baseline to culture conversion; TRT is 
the treatment and CENSOR is an indicator variable that indicates whether the subject was 
classified as having converted (CENSOR = 0) or not having converted (CENSOR = 1). 
8.6.3.
Six-minute Walk Test
The 6MWT is performed at baseline, Month 6, and Month 12/EOT visits.  
The 6MWT distance actual, baseline and change-from-baseline will be summarized by visit 
based on those subjects within the ITT population who have data at that visit.  At each visit the 
baseline summary will reflect those subjects who provided data at that visit.
8.7.
Analysis of Exploratory Efficacy Endpoints
The St George’s Respiratory Questionnaire and the EQ-5D-3L questionnaire comprise the 
exploratory endpoints for confirmatory analysis. This confirmatory analysis of exploratory 
endpoints will not compare prior INS-212 study treatments.  The Safety population will be used 
for this analysis. 
8.7.1.
St. George’s Respiratory Questionnaire 
The SGRQ is captured at baseline, Month 6, Month 12/EOT, and EOS.  
The SGRQ scores (total, symptoms, activities, impacts) actual, baseline and change-from-
baseline will be summarized by visit based on those subjects who have data at that visit.  At each 
visit the baseline summary will reflect those subjects who provided data at that visit.
8.7.2.
EQ-5D-3L 
The EQ-5D-3L is captured at baseline, Month 6, Month 12/EOT, and EOS.  
The EQ-5E-3L scores (VAS, Mobility, Self-care, Usual Activities, Pain/Discomfort, and 
Anxiety/Depression) actual, baseline and change-from-baseline will be summarized by visit 
based on those subjects who have data at that visit.  At each visit the baseline summary will 
reflect those subjects who provided data at that visit. 
8.7.3.
Health Care Resource Utilization
Health care resource utilization (HCRU) is a questionnaire based on subject recall asking about 
the use of hospitalizations, emergency room (ER) visits, doctor visits, and other information.  
The questionnaire was administered at baseline, Month 1, Month 3, Month 6, Month 9, Month 
12/EOT visits.
All summaries of HCRU data will be done by visit.
For subjects who have more than one hospitalization, the duration of hospitalizations for the 
HCRU summaries is the sum of all hospitalizations durations for the subject.  Durations for 
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
unplanned hospitalizations, planned hospitalization, ICU Admissions, hospitalizations due to 
NTM, and ICU admissions due to NTM will be derived in a similar manner for the summaries. 
Hospitalizations
For each hospitalization since the last study visit subjects were asked the following:
x
Since your last visit, were you admitted to the hospital?
x
Was this a planned hospitalization?
x
Dates of admission and release.
x
Was the hospital admission related to NTM?
x
If you were admitted to the hospital, did it result in being admitted to the ICU?

If yes, dates of ICU admission and release.
The number and percentage of subjects within each treatment and total will be presented for the 
following: 
x
Since your last visit, were you admitted to the hospital? (yes/no)
x
Number of hospitalizations
x
Number of unplanned hospitalizations
x
Number of planned hospitalizations
x
ICU admission (yes/no)
o
Number of ICU admissions
x
Admission related to NTM (yes/no)
o
Number of NTM hospitalizations
o
Number of NTM ICU admissions
Summary statistics (n, mean, standard deviation, median, minimum, maximum) will be presented 
for the following:
x
Duration of all hospitalizations
x
Duration of unplanned hospitalizations
x
Duration of planned hospitalizations
x
Duration of ICU admissions
x
Duration of hospitalizations due to NTM
x
Duration of ICU admissions due to NTM
Emergency Room Visits
For each ER visit subjects were asked the following:
x
Since your last visit, did you visit the ER?
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 

ER Visit Date

Did your visit to the ER result in being admitted to the hospital?
The number and percentage of subject responses (yes/no) to the questions ‘since your last visit, 
did you visit the ER’ and ‘did your visit to the ER result in being admitted to the hospital’ will be 
presented.
Doctor Visits
Regarding doctor visits subjects were asked the following: 
x
Since your last visit, how many times did you visit a doctor (other than your study
related visits)?
x
Were doctor's visits related to NTM?
x
Reason for Doctor Visits other than NTM
The distribution of the number of times subjects visited the doctor (0, 1, 2, >2) and the question 
“were doctor's visits related to NTM” (yes/no) will be presented indicating the number and 
percentage of subjects at each level by treatment and total.
Other
For the ‘other’ subjects were asked the following: 
x
Are you working?

If Yes, how many days did you miss work since your last visit?

If Yes, was missed work related to NTM?
x
Have you been placed on disability/social security related to you having NTM since
your last visit?
x
How many hours of sleep (on average) have you been getting since your last visit?
x
Have you refrained from certain family/social/work activities based on the symptoms
associated with NTM since your last visit?
x
Have you added back into your daily routine any previously discontinued activities
since your last visit?

If Yes, please describe
The number and percentage of subjects within each treatment and total will be presented for the 
following: 
x
Response (yes/no) to
o
Placed on disability/social security
o
Refrained from family/social/work activities
o
Added routine activities previously discontinued
o
Working
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
o
If yes, were

work days missed

work days missed due to NTM
x
Distributions of
o
Number of work days missed
o
Number of work days missed due to NTM
Summary statistics (n, mean, standard deviation, median, minimum, maximum) will be presented 
for the following: 
x
Average number of hours slept per day
x
Number of work days missed
x
Number of work days missed due to NTM
8.8.
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses
Not applicable 
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
9.
SAFETY AND TOLERABILITY
Safety and tolerability summaries will present data for all subjects treated (ie, Safety Population) 
overall and by the prior INS-212 study treatment the subject received. 
The analyses of safety and tolerability data include an overall summary of adverse events (AE),
AE preferred terms by body/organ system, drug exposure (duration of treatment), ALIS 
treatment compliance, concomitant medications, clinical laboratory results, vital signs, , and
audiology tests. Adverse events summaries are broken into the 2 groups,  treatment-emergent, 
and post-treatment.  
Unless otherwise specified, percentages for all safety tables will be based on the number of 
subjects in the Safety Population for the total column and treated in the treatment columns. 
9.1.
Overall Summary of Adverse Events
9.1.1.
Overall Summary of Treatment-emergent Adverse Events
The overall summary of AEs will present the number and percentage of subjects meeting the 
following criteria:
1. At least one TEAE
2. At least one serious TEAE
3. At least one TEAE leading to study drug withdrawn
4. At least one TEAE leading to multi-drug regimen for NTM withdrawn
5. At least one TEAE leading to study drug and MDR multi-drug regimen for NTM
withdrawn
6. At least one Serious TEAE leading to study drug withdrawn
7. At least one TEAE leading to death
8. At least one TEAE which is Pulmonary Exacerbation
9. At least one Serious TEAE which is Pulmonary Exacerbation
10. At least one TEAE which is a cough event
11. At least one TEAE related to nebulizer device used for study drug administration
12. Maximum Reported Severity
a.
Grade 1 (mild)
b.
Grade 2 (moderate)
c.
Grade 3 (severe)
d.
Grade 4 (life threatening)
e.
Grade 5 (death)
13. Closest Relationship to Study Drug
a.
Related (Definitely, Possibly, or Probably Related)
b.
Not related
14. Other suspect therapy
a.
None
b.
Azithromycin
c.
Clarithromycin
d.
Ethambutol
e.
Rifampin
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
f.
Rifabutin
g.
Other
Subjects will be counted only once in Items 1 through 13.  Subjects will be counted at the highest 
severity reported in Item 12.  Subjects will be counted at the closet relationship to study drug 
(ALIS) in Item 13.  In Item 14 subjects will be counted only once for each suspect therapy 
reported; if any suspect therapy is reported, the subject will not be counted in the ‘none’ 
category.
9.1.2.
Overall Summary of Adverse Events Resulting in Hospitalization  
For AEs that resulted in hospitalization, the overall summary will present the following 
information: 
1. Number and percent
a.
Of subjects with at least one hospitalization AE
b. Number of hospitalizations per subject
9.1.3.
Adverse Events of Special Interest
Table 6 lists the adverse events of special interest (AESI) by AESI group, system organ class and 
preferred term.   
Table 6: 
Adverse Events of Special Interest
AESI Group
System organ class
Preferred term
Neuromuscular
Musculoskeletal and connective 
tissue disorders
Muscular weakness
Nervous system disorders
Balance disorder
Neurotoxcity
Neuropathy peripheral
Peripheral sensory neuropathy
Nephrotoxicity
Renal and urinary disorders
Haematuria
Proteinuria
Renal failure
Azotaemia
Bilirubinuria
Leukocyturia
Nitrituria
Renal impairment
Investigations
Blood creatinine increased
Blood urine present
Creatinine renal clearance increased
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
AESI Group
System organ class
Preferred term
Glomerular filtration rate abnormal
Glomerular filtration rate decreased
Red blood cells urine positive
Urine bilirubin increased
Urinary casts present
Ototoxicity
Ear and labyrinth disorders
Deafness
Deafness bilateral
Deafness neurosensory
Deafness unilateral
Hearing impaired
Hypoacusis
Tinnitus
Vertigo
Nervous system disorders
Balance disorder
Dizziness
Presyncope
Alveolitis Allergic
Respiratory, thoracic and 
mediastinal disorders
Alveolitis allergic
Eosinophilic pneumonia
Interstitial lung disease
Pneumonitis
Bronchospasm
Respiratory, thoracic and 
mediastinal disorders
Asthma
Bronchial disorder
Bronchial hyperreactivity
Bronchospasm
Dyspnoea
Dyspnoea exertional
Prolonged expiration
Tachypnoea
Throat tightness
Wheezing
Investigations
Forced expiratory volume decreased
Pulmonary function test decreased
Infective Exacerbation of 
Respiratory, thoracic and 
Chronic obstructive pulmonary disease
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
AESI Group
System organ class
Preferred term
Underlying Disease
mediastinal disorders
Infections and infestations
Infective exacerbation of bronchiectasis
Infective exacerbation of chronic 
obstructive airways disease
Infective pulmonary exacerbation of cystic 
fibrosis
Infective exacerbation of chronic 
obstructive airways disease
Haemoptysis
Respiratory, thoracic and 
mediastinal disorders
Haemoptysis
Other Respiratory
Respiratory, thoracic and 
mediastinal disorders
All preferred terms not mentioned in 
another group
Exacerbation of COPD
Infections and infestations
Infective exacerbation of chronic 
obstructive airways disease
Respiratory, thoracic and 
mediastinal disorders
Chronic obstructive pulmonary disease
9.2.
Adverse Event Preferred Term and Body/Organ System Summary 
Tables
Adverse events will be presented for the treatment-emergent, and post-treatment periods.  
Treatment-emergent period is the day of first dose of ALIS through 28 days after the last dose of 
study medication, end of treatment visit, or end of study visit, whichever is earlier. 
9.2.1.
Tabulations of Adverse Events 
Adverse events will be tabulated presenting the incidence and percentage of subjects along with 
the number of events by and across prior INS-212 treatment arms.  Incidence of an adverse event 
is the number of subjects reporting the adverse event at least once.  The denominator for the 
percentage is the number of subjects receiving the treatment within the analysis population for 
the by treatment arm tabulation and total number of subjects enrolled and receiving treatment for 
the total.
Incidence, percentage, and number of AEs will be reported for subjects reporting at least one AE, 
within the system/organ class (SOC), and by preferred term within the SOC.  Adverse 
tabulations will be generated for the following:
x
Pre-treatment AEs
o
All
o
Serious

All

Fatal
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 

Leading to hospitalization
x
Treatment-Emergent
o
AEs

All

Common (>=5%)

Related to study treatment

Leading to withdrawal from study

Leading to withdrawal of study treatment

Leading to withdrawal of ALIS

Leading to withdrawal of MDR

Leading to withdrawal of both ALIS and MDR

Resulting in study drug interruption

Resulting in interruption of ALIS

Resulting in interruption of MDR

Resulting in interruption of both ALIS and MDR

By maximum toxicity grade

By relationship to ALIS

Related to nebulizer
o
Serious AEs

All

Common (>=5%)

Related to study treatment

Leading to withdrawal from study

Leading to withdrawal of study treatment

Leading to withdrawal of ALIS

Leading to withdrawal of MDR

Leading to withdrawal of both ALIS and MDR

Resulting in study drug interruption

Resulting in interruption of ALIS

Resulting in interruption of MDR

Resulting in interruption of both ALIS and MDR

By maximum toxicity grade
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 

By relationship to ALIS

Resulting in hospitalization

Related to nebulizer

Fatal
o
AEs of Special Interest

All

Common (>=5%)

Related to study treatment

Leading to withdrawal from study

Leading to withdrawal of study treatment

Leading to withdrawal of LAI

Leading to withdrawal of MDR

Leading to withdrawal of both LAI and MDR

Resulting in study drug interruption

Resulting in interruption of LAI

Resulting in interruption of MDR

Resulting in interruption of both LAI and MDR

By maximum toxicity grade

By relationship to LAI

Related to nebulizer
o
Serious AEs of Special Interest

All

Common (>=5%)

Related to study treatment

Leading to withdrawal from study

Leading to withdrawal of study treatment

Leading to withdrawal of LAI

Leading to withdrawal of MDR

Leading to withdrawal of both LAI and MDR

Resulting in study drug interruption

Resulting in interruption of LAI

Resulting in interruption of MDR
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 

Resulting in interruption of both LAI and MDR

By maximum toxicity grade

By relationship to LAI

Related to nebulizer
x
Post-Treatment AEs
o
All
o
Serious

All

Fatal

Leading to hospitalization
For related AEs tabulations and for adverse event tabulations by relationship to ALIS, an AE will 
be considered related if it is ‘definitely’, ‘probably’, or ‘possibly’ as indicated on the CRF.  The 
related AEs tabulations will present only those AEs deemed related.  The adverse event 
tabulations by relationship to ALIS will present a column for related and another for not related 
AEs.
Tabulations by maximum toxicity grade will report subjects only once at the highest toxicity 
grade reported with the summary level (eg, SOC, preferred term).
9.2.2.
Summaries of Duration of Adverse Events
The duration of serious AEs, serious AEs resulting in hospitalization, and AEs in the 
‘respiratory, thoracic and mediastinal disorders’ body system will be summarized.
The  duration of AEs will be summarized (n, mean, standard deviation, median, minimum, and 
maximum) for each system/organ class and preferred term within the system organ class.  The 
total duration is the sum of the duration for all AEs within a subject at the SOC level, for the 
SOC summaries and within the preferred term for preferred term summary.  The maximum 
duration is the maximum of the durations for all AEs within a subject at the SOC level, for the 
SOC summaries, and within preferred term for the preferred term summary.  The mean duration 
is the mean of the durations for all AEs within a subject at the SOC level, for the SOC 
summaries, and within preferred term for the preferred term summary. 
The summary table of AE durations will also include a tabulation of the number of events per 
subject reported in the summary level (ie, SOC, preferred term level).
9.3.
Total Duration and Compliance of ALIS Therapy
Duration and compliance summaries (ALIS only) will be presented by baseline to Month 6, 
Baseline to EOT, and Month 6 to EOT study periods.  Duration of treatment and compliance will 
be summarized (n, mean, standard deviation, median, minimum, and maximum).  Compliance 
will be categorized (>120%, 80-120%, <80%) and tabulated (number and percentage of 
subjects).
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
9.4.
Concomitant and Other Medications
Concomitant medications will be coded using the WHO Drug Sept2016 dictionary.  Tabulations 
will be done for the safety, populations.  The number and percentage of subjects reporting the 
medication will be presented for subjects using at least 1 medication, at least one medication at 
the Anatomical Therapeutic Class Level 4 (ATC4) level, and by preferred term within ATC4.   
9.5.
Routine Laboratory Data
All clinical laboratory data summaries and tabulations will be based on the safety population.
At each visit, only those subjects providing data at the visit will appear on the tables. 
The actual, baseline and change-from-baseline of the clinical laboratory results (blood chemistry 
and hematology) will be summarized (n, mean, standard deviation, median, minimum, and 
maximum) by visit for each prior treatment and total groups.  At each visit the baseline summary 
will reflect those subjects who provided data at that visit.
Shifts-from-baseline-to-visit in categorization of result by normal ranges (low, normal, high, 
total) will be tabulated clinical laboratory results (blood chemistry and hematology) presenting 
the number and percentage of subjects in each cell. These shift tables will also be presented for 
clinically significant labs.
9.6.
Vital Signs
All vital signs data summaries and tabulations will be based on the safety population. 
At each visit, only those subjects providing data at the visit will appear on the tables. 
The actual, baseline and change-from-baseline of the vital signs will be summarized (n, mean, 
standard deviation, median, minimum, and maximum) by visit and timepoint (pre-dose and post-
dose) for each prior treatment and overall. At each visit the baseline summary will reflect those 
subjects who provided data at that visit.   
9.7.
Audiology Tests
All audiology testing data summaries and tabulations will be based on the safety population. 
At each visit, only those subjects providing data at the visit will appear on the tables. 
The actual, baseline and change-from-baseline audiology test results at each will be summarized 
(n, mean, standard deviation, median, minimum, and maximum) by visit, frequency, and ear for 
each prior treatment and overall. At each visit the baseline summary will reflect those subjects 
who provided data at that visit.
The audiology results will be tabulated (number and percentage of subjects) by CTC grade (0, 1, 
2, 3, 4) and total for either, left, and right ears within treatment and total groups.
9.8.
Physical Examination
The site was instructed to report any changes found during the physical exam as AEs.  There is 
no summary for physical examination. 
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
10.
REFERENCES
1.
John L. Hankinson, Steven M. Kawut, Eyal Shahar, Lewis J. Smith, Karen Hinckley Stukovsky
and R. Graham Barr.  Study of Atherosclerosis (MESA) Lung Study Reference Values in a
Multiethnic Sample of Adults : The Multi-Ethnic Performance of American Thoracic Society-
Recommended Spirometry Chest 2010;137; 138-145; Prepublished online September 9, 2009
Confidential
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
11.
APPENDIX
11.1.
Table of Contents for Data Display Specifications
Tables
Number
Title1
Title2
Title3
14.1.1.1
SUBJECT DISPOSITION (END OF STUDY) 
OVERALL 
ALL 
SUBJECTS
14.1.1.2
SUBJECT DISPOSITION (END OF STUDY) 
BY VISIT 
ENROLLED 
SUBJECTS
14.1.2.1
SUBJECT DISPOSITION (END OF TREATMENT) 
OVERALL 
ENROLLED 
SUBJECTS
14.1.2.2
SUBJECT DISPOSITION (END OF TREATMENT) 
BY VISIT 
ENROLLED 
SUBJECTS
14.1.3.2
SUMMARY OF ALL PROTOCOL DEVIATIONS 
SAFETY POPULATION
14.1.4.1
SUMMARY OF DEMOGRAPHICS 
SAFETY POPULATION
14.1.5.1
SUMMARY OF BASELINE CHARACTERISTICS 
CHILDBEARING, 
CONTRACEPTION, 
RESCREENING, 
CURRENT MULTI-DRUG 
REGIMEN STATUS, 
SMOKING STATUS, 
PREVIOUS NEBULIZED 
AMIKACIN 
SAFETY 
POPULATION
14.1.5.2
SUMMARY OF BASELINE CHARACTERISTICS 
ST GEORGE’S 
RESPIRATORY 
QUESTIONNAIRE 
SAFETY 
POPULATION
14.1.5.3
SUMMARY OF BASELINE CHARACTERISTICS 
EQ-5D-3L 
SAFETY 
POPULATION
14.1.5.4
SUMMARY OF BASELINE CHARACTERISTICS 
6-MINUTE WALK TEST
SAFETY 
POPULATION
14.1.5.5
SUMMARY OF BASELINE CHARACTERISTICS 
AUDIOLOGY 
SAFETY 
POPULATION
14.1.5.6
SUMMARY OF BASELINE CHARACTERISTICS 
PULMONARY 
FUNCTION TEST 
SAFETY 
POPULATION
14.1.5.7
SUMMARY OF BASELINE CHARACTERISTICS 
VITAL SIGNS 
SAFETY 
POPULATION
14.1.5.8
SUMMARY OF BASELINE CHARACTERISTICS 
BIOMARKERS C-
REACTIVE PROTEIN, 
INTERLEUKIN-6
SAFETY 
POPULATION
14.1.6
TABULATION OF MEDICAL HISTORY 
SAFETY POPULATION
14.1.7.1
TABULATION OF PRIOR MEDICATIONS 
SAFETY POPULATION
14.1.7.2
TABULATION OF PRIOR MULTI-DRUG REGIMEN 
MEDICATIONS 
SAFETY POPULATION
14.1.8.1
SUMMARY OF NUMBER OF DRUGS IN THE MULTI-
DRUG REGIMEN AT BASELINE 
SAFETY POPULATION
14.1.8.2
SUMMARY OF DURATION (YEARS) OF PRIOR 
MULTI-DRUG REGIMEN MEDICATIONS 
SAFETY POPULATION
14.1.9
SUMMARY OF LAI EXPOSURE AND COMPLIANCE 
SAFETY POPULATION
14.1.10
TABULATION OF CONCOMITANT MEDICATIONS 
SAFETY POPULATION
14.1.11
TABULATION OF CONCOMITANT MULTI-DRUG 
REGIMEN MEDICATIONS 
SAFETY POPULATION
14.2.1
SUMMARY OF CONVERSION BY TIME POINT 
SAFETY POPULATION
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
14.2.2
SUMMARY OF SUSTAINED CONVERSION BY TIME 
FROM CONVERSION
SAFETY POPULATION
14.2.3
SUMMARY OF 6-MINUTE WALK TEST BY VISIT 
OBSERVED DATA 
SAFETY 
POPULATION
14.2.4
SUMMARY OF SAINT GEORGE’S RESPIRATORY 
QUESTIONNAIRE BY VISIT 
SAFETY POPULATION
14.2.5
SUMMARY OF EUROQOL 5D (EQ-5D-3L) BY VISIT 
SAFETY POPULATION
14.2.6
SUMMARY OF BODY MASS INDEX (KG/M2) BY VISIT 
SAFETY POPULATION
14.2.7
SUMMARY OF BIOMARKERS 
SAFETY POPULATION
14.2.8.1
SUMMARY OF HEALTH CARE RESOURCE 
UTILIZATION 
HOSPITALIZATIONS 
SAFETY 
POPULATION
14.2.8.2
SUMMARY OF HEALTH CARE RESOURCE 
UTILIZATION 
EMERGENCY ROOM 
VISITS 
SAFETY 
POPULATION
14.2.8.3
SUMMARY OF HEALTH CARE RESOURCE 
UTILIZATION 
DOCTOR VISITS 
SAFETY 
POPULATION
14.2.8.4
SUMMARY OF HEALTH CARE RESOURCE 
UTILIZATION 
OTHER 
SAFETY 
POPULATION
14.3.1.1
OVERALL SUMMARY OF TREATMENT-EMERGENT 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.1.2
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.1.3
TABULATION OF COMMON (>= 5%) TREATMENT-
EMERGENT ADVERSE EVENTS 
SAFETY POPULATION
14.3.1.4
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS RELATED TO STUDY 
TREATMENT 
SAFETY POPULATION
14.3.1.5
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS LEADING TO WITHDRAWAL 
FROM STUDY 
SAFETY POPULATION
14.3.1.6.1
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
STUDY TREATMENT 
SAFETY POPULATION
14.3.1.6.2
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
LAI 
SAFETY POPULATION
14.3.1.6.3
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.1.6.4
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
BOTH LAI AND MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.1.7.1
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
STUDY TREATMENT 
SAFETY POPULATION
14.3.1.7.2
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
LAI 
SAFETY POPULATION
14.3.1.7.3
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.1.7.4
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
BOTH LAI AND MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.1.8
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS BY MAXIMUM TOXICITY GRADE 
SAFETY POPULATION
14.3.1.9
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS BY RELATIONSHIP TO LAI 
SAFETY POPULATION
14.3.1.10
SUMMARY OF DURATION OF TREATMENT-
SAFETY POPULATION
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
EMERGENT ADVERSE EVENTS IN THE 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS BODY SYSTEM 
14.3.1.11
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS RELATED TO NEBULIZER 
SAFETY POPULATION
14.3.2.1
OVERALL SUMMARY OF TREATMENT-EMERGENT 
SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.2.2.1
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.2.2.2
TABULATION OF COMMON (>= 5%) TREATMENT-
EMERGENT SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.2.3.1
TABULATION OF FATAL TREATMENT-EMERGENT 
SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.2.3.2
TABULATION OF FATAL TREATMENT-EMERGENT 
SERIOUS ADVERSE EVENTS RELATED TO STUDY
TREATMENT 
SAFETY POPULATION
14.3.2.4
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS RELATED TO STUDY 
TREATMENT 
SAFETY POPULATION
14.3.2.5
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS LEADING TO WITHDRAWAL 
FROM STUDY 
SAFETY POPULATION
14.3.2.6.1
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
STUDY TREATMENT 
SAFETY POPULATION
14.3.2.6.2
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
LAI 
SAFETY POPULATION
14.3.2.6.3
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.2.6.4
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS LEADING TO WITHDRAWAL OF 
BOTH LAI AND MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.2.7.1
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
STUDY TREATMENT 
SAFETY POPULATION
14.3.2.7.2
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
LAI 
SAFETY POPULATION
14.3.2.7.3
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.2.7.4
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS RESULTING IN INTERRUPTION OF 
BOTH LAI AND MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.2.8
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS BY MAXIMUM TOXICITY GRADE 
SAFETY POPULATION
14.3.2.9
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS BY RELATIONSHIP TO LAI 
SAFETY POPULATION
14.3.2.10
SUMMARY OF DURATION OF SERIOUS 
TREATMENT-EMERGENT ADVERSE EVENTS 
SAFETY POPULATION
14.3.2.11.1
OVERALL SUMMARY OF HOSPITALIZATIONS DUE 
TO TREATMENT-EMERGENT SERIOUS ADVERSE 
EVENTS 
SAFETY POPULATION
14.3.2.11.2
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS RESULTING IN 
HOSPITALIZATION 
SAFETY POPULATION
14.3.2.11.3
SUMMARY OF DURATION OF TREATMENT-
EMERGENT SERIOUS ADVERSE EVENTS RESULTING 
SAFETY POPULATION
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
IN HOSPITALIZATION 
14.3.2.12
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS RELATED TO NEBULIZER 
SAFETY POPULATION
14.3.3.1.1
OVERALL SUMMARY OF POST-TREATMENT 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.3.1.2
TABULATION OF POST-TREATMENT ADVERSE 
EVENTS 
SAFETY POPULATION
14.3.3.2.1
OVERALL SUMMARY OF POST-TREATMENT 
SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.3.2.2
TABULATION OF POST-TREATMENT SERIOUS 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.3.2.1.1
TABULATION OF FATAL POST-TREATMENT 
SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.3.2.1.2
TABULATION OF FATAL POST-TREATMENT 
SERIOUS ADVERSE EVENTS RELATED TO STUDY 
TREATMENT 
SAFETY POPULATION
14.3.3.3.1
OVERALL SUMMARY OF HOSPITALIZATIONS DUE 
TO POST-TREATMENT SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.3.3.2
TABULATION OF POST-TREATMENT SERIOUS 
ADVERSE EVENTS RESULTING IN 
HOSPITALIZATION 
SAFETY POPULATION
14.3.3.3.3
SUMMARY OF DURATION OF POST-TREATMENT 
SERIOUS ADVERSE EVENTS RESULTING IN 
HOSPITALIZATION 
SAFETY POPULATION
14.3.4.1.1
OVERALL SUMMARY OF PRE-TREATMENT 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.4.1.2
TABULATION OF PRE-TREATMENT ADVERSE 
EVENTS 
SAFETY POPULATION
14.3.4.2.1.1
OVERALL SUMMARY OF PRE-TREATMENT SERIOUS 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.4.2.1.2
TABULATION OF PRE-TREATMENT SERIOUS 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.4.2.2.1
TABULATION OF FATAL PRE-TREATMENT SERIOUS 
ADVERSE EVENTS 
SAFETY POPULATION
14.3.4.2.2.2
TABULATION OF FATAL PRE-TREATMENT SERIOUS 
ADVERSE EVENTS RELATED TO STUDY 
TREATMENT 
SAFETY POPULATION
14.3.4.3.1
OVERALL SUMMARY OF HOSPITALIZATIONS DUE 
TO PRE-TREATMENT SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.4.3.2
TABULATION OF PRE-TREATMENT SERIOUS 
ADVERSE EVENTS RESULTING IN 
HOSPITALIZATION 
SAFETY POPULATION
14.3.4.3.3
SUMMARY OF DURATION OF PRE-TREATMENT 
SERIOUS ADVERSE EVENTS RESULTING IN 
HOSPITALIZATION 
SAFETY POPULATION
14.3.5.1
OVERALL SUMMARY OF HOSPITALIZATIONS DUE 
TO SERIOUS ADVERSE EVENTS 
SAFETY POPULATION
14.3.5.2
TABULATION OF SERIOUS ADVERSE EVENTS 
RESULTING IN HOSPITALIZATION 
SAFETY POPULATION
14.3.5.3
SUMMARY OF DURATION OF SERIOUS ADVERSE 
EVENTS RESULTING IN HOSPITALIZATION 
SAFETY POPULATION
14.3.6.1
OVERALL SUMMARY OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST 
SAFETY POPULATION
14.3.6.2
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST 
SAFETY POPULATION
14.3.6.3
TABULATION OF COMMON (>= 5%) TREATMENT-
EMERGENT ADVERSE EVENTS OF SPECIAL 
INTEREST 
SAFETY POPULATION
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Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
14.3.6.4
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST RELATED 
TO STUDY TREATMENT 
SAFETY POPULATION
14.3.6.5
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL FROM STUDY 
SAFETY POPULATION
14.3.6.6.1
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF STUDY TREATMENT 
SAFETY POPULATION
14.3.6.6.2
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF LAI 
SAFETY POPULATION
14.3.6.6.3
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.6.6.4
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF BOTH LAI AND MULTI-DRUG 
REGIMEN 
SAFETY POPULATION
14.3.6.7.1
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF STUDY 
TREATMENT 
SAFETY POPULATION
14.3.6.7.2
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF LAI 
SAFETY POPULATION
14.3.6.7.3
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF MULTI-DRUG 
REGIMEN 
SAFETY POPULATION
14.3.6.7.4
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF BOTH LAI AND 
MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.6.8
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST BY 
MAXIMUM TOXICITY GRADE 
SAFETY POPULATION
14.3.6.9
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST BY 
RELATIONSHIP TO LAI 
SAFETY POPULATION
14.3.6.10
SUMMARY OF DURATION OF TREATMENT-
EMERGENT ADVERSE EVENTS OF SPECIAL 
INTEREST IN THE RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS BODY SYSTEM 
SAFETY POPULATION
14.3.6.11
TABULATION OF TREATMENT-EMERGENT 
ADVERSE EVENTS OF SPECIAL INTEREST RELATED 
TO NEBULIZER 
SAFETY POPULATION
14.3.7.1
OVERALL SUMMARY OF TREATMENT-EMERGENT 
SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST 
SAFETY POPULATION
14.3.7.2
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST 
SAFETY POPULATION
14.3.7.3.1
TABULATION OF FATAL TREATMENT-EMERGENT 
SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST 
SAFETY POPULATION
14.3.7.3.2
TABULATION OF FATAL TREATMENT-EMERGENT 
SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST 
RELATED TO STUDY TREATMENT 
SAFETY POPULATION
14.3.7.4
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST RELATED 
TO STUDY TREATMENT 
SAFETY POPULATION
Confidential
Page 42 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
14.3.7.5
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL FROM STUDY 
SAFETY POPULATION
14.3.7.6.1
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF STUDY TREATMENT 
SAFETY POPULATION
14.3.7.6.2
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF LAI
SAFETY POPULATION
14.3.7.6.3
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.7.6.4
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST LEADING 
TO WITHDRAWAL OF BOTH LAI AND MULTI-DRUG 
REGIMEN 
SAFETY POPULATION
14.3.7.7.1
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF STUDY 
TREATMENT 
SAFETY POPULATION
14.3.7.7.2
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF LAI 
SAFETY POPULATION
14.3.7.7.3
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF MULTI-DRUG 
REGIMEN 
SAFETY POPULATION
14.3.7.7.4
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST 
RESULTING IN INTERRUPTION OF BOTH LAI AND 
MULTI-DRUG REGIMEN 
SAFETY POPULATION
14.3.7.8
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST BY 
MAXIMUM TOXICITY GRADE 
SAFETY POPULATION
14.3.7.9
TABULATION OF TREATMENT-EMERGENT SERIOUS 
ADVERSE EVENTS OF SPECIAL INTEREST BY 
RELATIONSHIP TO LAI 
SAFETY POPULATION
14.3.7.10
SUMMARY OF DURATION OF SERIOUS 
TREATMENT-EMERGENT ADVERSE EVENTS OF 
SPECIAL INTEREST 
SAFETY POPULATION
14.3.8.1
SUMMARY OF TREATMENT-EMERGENT COUGH 
CHARACTERISTICS 
SAFETY POPULATION
14.3.8.2
SUMMARY OF TREATMENT-EMERGENT SERIOUS 
COUGH CHARACTERISTICS 
SAFETY POPULATION
14.3.9.1.1
SUMMARY OF CLINICAL LABORATORY RESULTS 
CHEMISTRY 
SAFETY 
POPULATION
14.3.9.2.1
SUMMARY OF CLINICAL LABORATORY RESULTS 
HEMATOLOGY 
SAFETY 
POPULATION
14.3.9.1.2
SHIFT TABLE OF CLINICAL LABORATORY RESULTS 
CHEMISTRY 
SAFETY 
POPULATION
14.3.9.2.2
SHIFT TABLE OF CLINICAL LABORATORY RESULTS 
HEMATOLOGY 
SAFETY 
POPULATION
14.3.10
SUMMARY OF VITAL SIGNS 
SAFETY POPULATION
14.3.11.1
SUMMARY OF AUDIOLOGY TESTS (DECIBELS) 
SAFETY POPULATION
14.3.11.2
TABULATION OF AUDIOLOGY HEARING LOSS BY 
VISIT 
SAFETY POPULATION
14.3.11.3
SHIFT TABLE OF AUDIOLOGY HEARING LOSS BY 
VISIT 
SAFETY POPULATION
Confidential
Page 43 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
14.3.13
TABULATION OF ELECTROCARDIOGRAM RESULTS 
SAFETY POPULATION
Figures
Number
Title1
Title2
Title3
14.2.1
FIGURE OF TIME TO CONVERSION (MONTHS) 
SAFETY POPULATION
14.2.3.1
PLOT OF MEAN 6-MINUTE WALK TEST DISTANCE 
(M) BY VISIT
OBSERVED DATA 
SAFETY 
POPULATION
14.2.3.2
PLOT OF MEAN CHANGE-FROM-BASELINE IN 6-
MINUTE WALK TEST DISTANCE (M) BY VISIT 
OBSERVED DATA 
SAFETY 
POPULATION
14.2.6.1
PLOT OF MEAN BODY MASS INDEX (KG/M2) BY 
VISIT 
SAFETY POPULATION
14.2.6.2
PLOT OF MEAN CHANGE-FROM-BASELINE IN BODY 
MASS INDEX (KG/M2) BY VISIT 
SAFETY POPULATION
14.3.11.1.1
PLOT OF MEAN AUDIOLOGY TESTS (DECIBELS) 
SAFETY POPULATION
14.3.11.1.2
PLOT OF MEAN CHANGE-FROM-BASELINE IN 
AUDIOLOGY TESTS (DECIBELS) 
SAFETY POPULATION
Listings
Number
Title1
Title2
Title3
16.2.1
SUBJECT TREATMENT
ENROLLED SUBJECTS
16.2.2
STUDY POPULATIONS 
ENROLLED SUBJECTS
16.2.3
STUDY EXIT STATUS 
ALL SUBJECTS
16.2.4
END OF TREATMENT 
ENROLLED SUBJECTS
16.2.5
PROTOCOL DEVIATIONS 
ENROLLED SUBJECTS
16.2.6
INCLUSION/EXCLUSION CRITERIA FAILURES 
ALL SUBJECTS
16.2.7
INFORMED CONSENT 
ALL SUBJECTS
16.2.8
SCREENING SUBJECT IDS 
ALL SUBJECTS
16.2.9.1
DEMOGRAPHICS 
ALL SUBJECTS
16.2.9.2
DEMOGRAPHICS – IF FEMALE, 
ALL FEMALE SUBJECTS
16.2.10
MEDICAL HISTORY 
ALL SUBJECTS
16.2.11
VISIT VITAL SIGNS 
ENROLLED SUBJECTS
16.2.13
AUDIOLOGY 
ENROLLED SUBJECTS
16.2.14
ELECTROCARDIOGRAM 
ENROLLED SUBJECTS
16.2.15
CT SCAN 
CT SUB-STUDY 
SUBJECTS
16.2.16.1
SPUTUM SAMPLE CRF 
ALL SUBJECTS
16.2.16.2
SPUTUM SAMPLE CULTURE RESULTS 
ALL SUBJECTS
16.2.17
PREGNANCY TEST 
ALL FEMALE SUBJECTS 
OF CHILDBEARING 
POTENTIAL
16.2.18.1.1
CLINICAL LABORATORY RESULTS 
STANDARDIZATION
HEMATOLOGY
ALL 
SUBJECTS
16.2.18.1.2
CLINICAL LABORATORY RESULTS 
STANDARDIZATION
CHEMISTRY
ALL 
SUBJECTS
Confidential
Page 44 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
16.2.18.1.3
CLINICAL LABORATORY RESULTS 
STANDARDIZATION
URINALYSIS
ALL 
SUBJECTS
16.2.18.1.4
CLINICAL LABORATORY RESULTS 
STANDARDIZATION
BIOMARKERS
ALL 
SUBJECTS
16.2.18.2.1
CLINICAL LABORATORY STANDARDIZED RESULTS
HEMATOLOGY
ALL 
SUBJECTS
16.2.18.2.2
CLINICAL LABORATORY STANDARDIZED RESULTS
CHEMISTRY
ALL 
SUBJECTS
16.2.18.2.3
CLINICAL LABORATORY STANDARDIZED RESULTS
URINALYSIS
ALL 
SUBJECTS
16.2.18.2.4
CLINICAL LABORATORY STANDARDIZED RESULTS
BIOMARKERS
ALL 
SUBJECTS
16.2.18.3.1
CLINICAL LABORATORY SAMPLE COMMENTS
HEMATOLOGY
ALL 
SUBJECTS
16.2.18.3.2
CLINICAL LABORATORY SAMPLE COMMENTS
CHEMISTRY
ALL 
SUBJECTS
16.2.18.3.3
CLINICAL LABORATORY SAMPLE COMMENTS
URINALYSIS
ALL 
SUBJECTS
16.2.18.3.4
CLINICAL LABORATORY SAMPLE COMMENTS
BIOMARKERS
ALL 
SUBJECTS
16.2.20
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.21
EUROQOL 5D (EQ-5D-3L) 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.22.1
6-MINUTE WALK TEST – PART 1
DISTANCE WALKED 
ALL 
SUBJECTS
16.2.22.2
6-MINUTE WALK TEST – PART 2
VITAL SIGNS 
ALL 
SUBJECTS
16.2.22.3
6-MINUTE WALK TEST – PART 3
NOT DONE REASONS 
ALL 
SUBJECTS
16.2.22.4
6-MINUTE WALK TEST – PART 4
ADMINISTRATOR NOTE 
ALL 
SUBJECTS
16.2.22.5
6-MINUTE WALK TEST – PART 5 – COMMENTS
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.23.1
ADVERSE EVENTS 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.23.2
SERIOUS ADVERSE EVENTS 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.23.3
FATAL ADVERSE EVENTS 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.23.4
ADVERSE EVENTS RESULTING IN 
HOSPITALIZATION 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.23.6
COUGH ADVERSE EVENTS 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.23.7
ADVERSE EVENTS OF SPECIAL INTEREST 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.23.8
SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.24
MEDICATIONS 
ALL SUBJECTS
ALL 
SUBJECTS
16.2.26.1
HEALTH CARE RESOURCE UTILIZATION –
HOSPITALIZATIONS 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.26.2
HEALTH CARE RESOURCE UTILIZATION –
HOSPITALIZATIONS – ICU ADMISSIONS 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.26.3
HEALTH CARE RESOURCE UTILIZATION –
EMERGENCY ROOM VISITS 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.26.4
HEALTH CARE RESOURCE UTILIZATION – DOCTOR 
VISITS 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.26.5
HEALTH CARE RESOURCE UTILIZATION – OTHER 
ENROLLED SUBJECTS
ALL 
Confidential
Page 45 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
Number
Title1
Title2
Title3
SUBJECTS
16.2.27.1
LAI ADMINISTRATION – ON-SITE ADMINISTRATION 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.27.2
LAI ADMINISTRATION – SUBJECT DOSING 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.27.3
LAI DRUG ACCOUNTABILITY 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.27.4
LAI MISSED DOSES 
ENROLLED SUBJECTS
ALL 
SUBJECTS
16.2.27.5
LAI COMPLIANCE 
ENROLLED SUBJECTS
ALL 
SUBJECTS
Confidential
Page 46 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
11.2.
Data Display Specifications
File formats 
Unless otherwise specified, all outputs should be in RTF file format. 
Page format 
For submissions in the US, all outputs are presented in landscape orientation on 8.5x11 inch 
paper with Times New Roman or Courier New type face, 9-point font unless otherwise specified, 
and 1-inch margins on all sides.   
For submissions in the EU, all outputs are presented in landscape orientation on A4 paper with 
Times New Roman or Courier New type face, 9-point font unless otherwise specified, and 2cm
margins on all sides.   
The hyphen (-) in table titles in the mock-ups indicates a line break.
Regions 
Regions are, in order of appearance, ‘All’, ‘North America’, ‘Japan’, ‘Europe’, ‘Oceania’, and 
‘Asia (excluding Japan)’.  When presenting data by region, there should be an ‘All’ group for 
each country and then the sites within that country should appear following the country.  For 
categorical data, all categories should appear within each site.    
Within each region the countries will be ordered by descending number of subjects enrolled to 
sites within that country.  Similarly, within country the sites will be ordered by descending 
number of subjects enrolled to the sites.
On all tables by region, country, and site put a page break after each site. 
Percentages
Unless otherwise indicated, percentages presented on a table will be based on the number of 
subjects in the column.  Exceptions to this rule will be indicated in the footnote of those tables.  
If the count in a table is zero (0), only the count (0) should appear in the cell on the table (ie, no 
percentages or, in the case of AE tables, event counts).  If there is a 100% there should be no 
decimal places presented (ie, 100% is 100).
Change-from-baseline Summaries
Tables of continuously valued parameters presenting change-from-baseline summaries will 
present, within each visit, 3 blocks of summary statistics for the observed cases (ie available 
data).  The first block will present the ‘actual’, the second block will present, ‘baseline’ and the 
third block will present the ‘change-from-baseline’.  The ‘actual’ block will summarize the value 
collected at that visit.  The ‘baseline’ block will summarize the baseline value for those subjects 
who have non-missing ‘actual’ values at the visit.  The ‘change-from-baseline’ block will 
summarize the change-from-baseline value for subjects with non-missing ‘actual’ and ‘baseline’ 
values at the visit.
Mock-ups
Mock-ups of tables and listings are provided in separate documents. 
Confidential
Page 47 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
11.3.
Schedule of Events
INS-312 
TREATMENT PHASE 
OFF-ALIS 
TREATMENT 
PHASE 
Baseline 
Month 1 
Month 2a 
Month 3 Month 4 a Month 5 a 
Month 6 Month 7 a Month 8 a 
Month 9 Month 10 a Month 11 a 
EOT 
Month 12 
EOS 
up to 
Month 13 
(V1) 
(V2) 
(V3) 
(V4) 
(V5) 
(V6) 
(V7) 
(V8) 
(V9) 
(V10) 
(V11) 
(V12) 
(V13) 
(V14) 
Visit Window 
Day 1 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
Informed Consentb
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Medical Historyc
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Pregnancy testd
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
SGRQ (Part I and II) 
X 
– 
– 
– 
– 
– 
X 
– 
– 
– 
– 
– 
X 
X 
EQ-5D-3L 
X 
– 
– 
– 
– 
– 
X 
– 
– 
– 
– 
– 
X 
X 
Physical 
examination 
X 
X 
– 
X 
– 
– 
X 
– 
– 
X 
– 
– 
X 
X 
Body weight 
X 
X 
– 
X 
– 
– 
X 
– 
– 
X 
– 
– 
X 
X 
Vital signs and pulse 
oximetrye
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6 minute walk test 
X 
– 
– 
– 
– 
– 
X 
– 
– 
– 
– 
– 
X 
– 
Audiology test 
Xf 
– 
– 
– 
– 
– 
X 
– 
– 
– 
– 
– 
X 
– 
Concomitant 
medicationsg
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Healthcare 
Resource Utilization 
X 
X 
– 
X 
– 
– 
X 
– 
– 
X 
– 
– 
X 
– 
AE assessmenth
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sputum collection 
for microbiology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
Confidential
Page 48 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
INS-312 
TREATMENT PHASE 
OFF-ALIS 
TREATMENT 
PHASE 
Baseline 
Month 1 
Month 2a 
Month 3 Month 4 a Month 5 a Month 6 Month 7 a Month 8 a Month 9 Month 10 a Month 11 a 
EOT 
Month 12 
EOS 
up to 
Month 13 
(V1) 
(V2) 
(V3) 
(V4) 
(V5) 
(V6) 
(V7) 
(V8) 
(V9) 
(V10) 
(V11) 
(V12) 
(V13) 
(V14) 
Visit Window 
Day 1 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
Chemistry 
X 
X 
– 
X 
– 
– 
X 
– 
– 
X 
– 
– 
X 
– 
Hematology 
X 
X 
– 
X 
– 
– 
X 
– 
– 
X 
– 
– 
X 
– 
Urinalysis 
X 
X 
– 
X 
– 
– 
X 
– 
– 
X 
– 
– 
X 
– 
Serum for 
biomarkers 
(CRP and IL-6) 
X 
– 
– 
– 
– 
– 
X 
– 
– 
– 
– 
– 
X 
– 
Sub-Study: 
CT scan of chesti
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
X 
– 
Sub-Study: 
CT scan of chestj 
(Japan) 
X 
– 
– 
– 
– 
– 
X 
– 
– 
– 
– 
– 
X 
– 
Send sputum 
collection 
containers 
home 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
– 
Administer study 
drug at site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
– 
Dispense study 
drugk
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
– 
Collection of study 
drug vials 
– 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
a Home Healthcare visits may be available for sites with IRB/EC approval to conduct Home Healthcare visits, and for qualifying subjects who may have difficulty attending 
clinic visits.
b Subjects will be asked to provide written informed consent at their INS-212 EOT visit.
c All ongoing medical history conditions from INS-212 must be listed within the medical history eCRF for INS-312. Any chronic conditions that require medication must be 
listed in the medical history eCRF.
d Urine pregnancy testing will be performed on all women of child bearing potential. Women not of child bearing potential are defined as postmenopausal (i.e., amenorrheic 
for at least 1 year), or surgically or naturally sterile.
e At visits where study drug is administered, vital signs and pulse oximetry will be performed before and after study drug administration.
f The Baseline audiology examination must be performed on Day 1 before the administration of study drug.
g All ongoing medication(s) from the INS-212 study must be documented in the concomitant medication eCRF for INS-312; this includes any ongoing medication(s) that were 
recorded in INS-212 prior to the first dosing in INS-312.
Confidential
Page 49 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
h All ongoing AEs from the INS-212 study will be documented as medical history for INS-312. At visits where study drug is administered, AEs will be assessed before and 
after administration of study drug. Any AE that has occurred and resolved before administration of the study drug on Day 1 (Baseline) will be documented for studyINS-212.
i Only for subjects who agreed to participate in the CT Scan sub-study in INS-312. Subjects will have a chest CT scan at Baseline (Day 1), if not already done at the INS-212 
EOT Visit. Subjects will have a follow-up chest CT scan at the EOT visit, provided the last chest CT scan was not obtained within the prior 6 months. High resolution CT 
scan is preferred, if available. Please refer to APPENDIX 3 for additional details on the CT Scan sub-study. 
j Only for subjects in Japan. Subjects will have a chest CT scan at Baseline (Day 1), if not already done at the INS-212 Month 6 visit. Subjects will also have chest CT scans at 
Month 6 and at the EOT visit, provided the last chest CT scan was not obtained within the prior 6 months. High resolution CT scan is preferred, if available. Please refer to 
APPENDIX 4 for additional details on the Japan specific CT Scan sub-study.
k Study drug will be dispensed to all subjects up to and including the Month 11 visit.
Confidential
Page 50 of 83


Insmed Incorporated
Statistical Analysis Plan Version: Final 2.0
Protocol: INS-312 Amendment #3.1 
NOV 13, 2018 
11.4.
INS-312 Study Schematic
Confidential
Page 51 of 83










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Confidential
Page 56 of 83


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