Conditions: Cystic Fibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 57
Healthy volunteers: no

Brief summary:
A Rollover Safety Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous for F508del.

Detailed description:

Arms:
arm 1: LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.

Interventions: intervention 1: LUM/IVA
Intervention descriptions: intervention 1: Participants received LUM/IVA every q12h.

Protocol document:
Prot_000.pdf: 


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2 
PROTOCOL SYNOPSIS 
Title A Phase 3, Rollover Study to Evaluate the Safety of Long-term Treatment With 
Lumacaftor/Ivacaftor Combination Therapy in Subjects Aged 2 Years and Older 
With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation 
Brief Title A Rollover Safety Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Years and 
Older With Cystic Fibrosis, Homozygous for F508del 
  
Clinical Phase and 
Clinical Study Type  
Phase 3 safety 
  
Objectives Primary Objective 
To evaluate the long-term safety of lumacaftor/ivacaftor (LUM/IVA) combination 
therapy in subjects aged 2 years and older with cystic fibrosis (CF), homozygous 
for F508del 
Secondary Objective  
To evaluate the pharmacodynamics (PD) of long-term LUM/IVA combination 
therapy in subjects aged 2 years and older with CF, homozygous for F508del 
  
Endpoints Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), changes in 
clinical laboratory values, electrocardiograms (ECGs), vital signs, pulse oximetry, 
ophthalmological examinations (OEs), and spirometry 
Secondary Endpoints 
The following endpoints will be analyzed using baseline values in the previous 
study (i.e., Study VX15-809-115 Part B [Study 115B]): 
• 
Absolute change from baseline in sweat chloride 
• 
Absolute change from baseline in body mass index (BMI) and BMI-for-age 
z-score 
• 
Absolute change from baseline in weight and weight-for-age z-score 
• 
Absolute change from baseline in stature and stature-for-age z-score 
• 
Time-to-first pulmonary exacerbation from baseline 
• 
Number of pulmonary exacerbations from baseline 
• 
Number of CF-related hospitalizations from baseline 
• 
Absolute change from baseline in fecal elastase-1 (FE-1) levels  
• 
Absolute change from baseline in serum levels of immunoreactive 
trypsinogen (IRT)  
• 
Change from baseline in microbiology cultures 
• 
Absolute change from baseline in lung clearance index (LCI)2 5  
• 
Absolute change from baseline in LCI5 0  
 


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Number of Subjects Approximately 56 subjects are potentially eligible to be enrolled 
  
Study Population Treatment Cohort 
Male and female subjects who completed LUM/IVA treatment and the Safety 
Follow-up Visit in Study 115B 
Observational Cohort 
Male and female subjects who received at least 4 weeks of LUM/IVA treatment in 
Study 115B and completed visits up to Week 24 and the Safety Follow-up Visit, if 
required, in Study 115B, but do not meet eligibility criteria for enrollment in the 
Treatment Cohort or who choose not to enroll in the Treatment Cohort 
  
Investigational Drug Active Substance: LUM/IVA fixed-dose combination 
 Activity: CFTR corrector and potentiator (chloride ion [Cl-] secretion) 
 Strength and Route of Administration  
• 
LUM 100-mg/IVA 125-mg granules for oral administration 
• 
LUM 150-mg/IVA 188-mg granules for oral administration 
• 
LUM 100-mg/IVA 125-mg tablets for oral administration 
Doses Investigated 
Subjects 2 through 5 years of age at enrollment 
• 
LUM 100 mg/IVA 125 mg every 12 hours (q12h) for subjects weighing 
<14 kg at enrollment 
• 
LUM 150 mg/IVA 188 mg q12h for subjects weighing ≥14 kg at enrollment 
Notes: Doses may be adjusted upward for changes in weight and age. Doses above 
are those planned for Study 115B. Based on results from Study 115A and 115B, 
doses for subjects <6 years of age in Study VX16-809-116 (Study 116) may be 
modified.  
Subjects ≥6 years of age at enrollment 
LUM 200 mg/IVA 250 mg q12h (2 × LUM 100-mg/IVA 125-mg tablet q12h)  
  
Study Duration Treatment Cohort 
Up to 98 weeks (96 weeks for the Treatment Period and 2 weeks for safety 
follow-up, if applicable)  
Observational Cohort 
96 weeks 
  
Study Design The Treatment Cohort includes the following: 
• 
Treatment Period (Day 1 through Week 96; the last dose of study drug is the 
dose before the Week 96 Visit). 
• 
Safety Follow-up Visit (2 weeks ± 4 days after the last dose of LUM/IVA) 
The Observational Cohort includes 2 long-term follow-up telephone contacts at 
Week 48 and Week 96. 
  
Assessments Treatment Cohort 
Safety: AEs, clinical laboratory values (serum chemistry, hematology, 
coagulation, and urinalysis), ECGs, vital signs, pulse oximetry, physical 
examinations, spirometry (subjects ≥3 years old at screening in Study 115B), 
and OEs 


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Pharmacodynamics: Sweat chloride, BMI/BMI-for-age z-score, weight/weight-
for-age z-score, stature/stature-for-age z-score, spirometry (subjects ≥3 years old 
at screening in Study 115B), pulmonary exacerbations, CF-related 
hospitalizations, FE-1, IRT, qualitative microbiology cultures, and LCI (subjects 
≥3 years old at screening in Study 115B who consent/assent to the optional LCI 
Substudy in Study 115B and Study 116) 
Observational Cohort 
Safety: Serious adverse events (SAEs) 
  
Statistical Analyses Approximately 56 subjects are potentially eligible to be enrolled. Assuming a 
10% dropout rate in Study 115B, 50 subjects are expected to be enrolled in 
Study 116. 
Treatment Cohort 
The analysis will be performed over the Cumulative Study Period. 
Safety Analysis 
All treatment-emergent AE (TEAE) summaries will be described using the 
incidence of TEAEs and number of events per 100 patient-years (number of 
events adjusted for the total duration of exposure) for the Cumulative Study 
Period. 
Continuous safety endpoints will be summarized descriptively at each visit during 
the Cumulative Study Period.  
For the categorical laboratory, vital, and ECG variables, the number and 
percentage of subjects in each category during the Treatment-emergent Period of 
the Cumulative Study Period will be summarized. 
The safety analysis for the Cumulative Study Period will be based on the Safety 
Set, which will include all subjects who received at least 1 dose of study drug in 
Study 115B. 
Pharmacodynamic Analysis 
For all continuous PD endpoints, raw values and absolute change from 
Cumulative Study Baseline at each visit in the Cumulative Study Period will be 
summarized based on the Full Analysis Set (FAS), which includes all subjects 
who were enrolled and exposed to any amount of study drug in Study 115B. 
Time-to-first pulmonary exacerbation will be estimated using the Kaplan-Meier 
method based on the FAS for the Cumulative Study Period.  
The number of pulmonary exacerbations starting during the Cumulative Study 
Period normalized by the time spent in the Cumulative Study Period will be 
summarized. 
The number of CF-related hospitalizations through last visit will be summarized 
similarly. 
Observational Cohort 
Listings will be provided for SAEs in Study 116 based on all subjects enrolled in 
the Observational Cohort. 
  
IDMC Reviews An independent data monitoring committee (IDMC) will be formed using the 
Cystic Fibrosis Foundation Data Safety Monitoring Board. The IDMC objectives 
and operational details will be defined in a separate document (IDMC Charter), 
which will be finalized before the first subject is enrolled. The IDMC will conduct 
regular planned reviews of study data for the purpose of safety monitoring as 
outlined in the IDMC Charter. 


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3 
SCHEDULE OF ASSESSMENTS  
3.1 
Treatment Cohort 
Table 3-1 
Study VX16-809-116: Treatment Cohort - Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT Visitb 
Safety Follow-up Visitc 
Day 1d 
Day 3 
(± 1 Day) 
Day 15 
(± 3 Days) 
Weeks 12, 24, 36, 48, 
60, 72, 84 (± 7 Days) 
Week 96 
(± 7 Days) 
As Soon as 
Possible After the 
Last Dose  
2 Weeks (± 4 Days) 
After the Last Dose 
Informed consent/assent 
X 
 
 
 
 
 
 
Clinic visit 
X 
 
X 
X 
X 
X 
X 
Telephone contacte 
 
X 
 
 
 
 
 
Stature and weightf 
X 
 
X 
X 
X 
X 
X 
Vital signsg 
Xh 
 
X 
X 
X 
X 
X 
Pulse oximetryg 
X 
 
X 
X 
X 
X 
X 
OEsi 
X 
 
 
Week 48j 
Xj,k 
Xj,k 
Xj,k 
Full PEl 
X 
 
 
Weeks 24, 48, 72 
X 
X 
X 
Abbreviated PE 
Xm 
 
 
 
 
 
 
 
a 
Assessments will be performed before LUM/IVA dosing unless noted otherwise. 
b 
If the ETT Visit occurs 10 days or later after the last dose of LUM/IVA, the Safety Follow-up Visit will not be required (Section 9.1.2.3). Subjects who prematurely 
discontinue LUM/IVA treatment for AEs should be followed until the AE is considered resolved. 
c 
The Safety Follow-up Visit is required for 1) subjects who complete their ETT Visit <10 days after the last dose of LUM/IVA (footnote b and Section 9.1.2.3); and 2) subjects 
who interrupt LUM/IVA treatment and complete their Week 96 Visit <10 days after the last dose of LUM/IVA; it is not required for subjects who continue onto 
commercially-available, physician-prescribed LUM/IVA within 2 weeks (± 4 days) of completing LUM/IVA treatment at the Week 96 or ETT Visit. 
d 
For subjects at sites activated by the time of their Study 115B Safety Follow-up Visit, their Study 116 Day 1 Visit will be on the same day as their Study 115B Safety 
Follow-up Visit, and any Study 116 Day 1 assessments that were specified to be performed at the Study 115B Safety Follow-up Visit do not need to be repeated. If the 
Study 116 Day 1 Visit does not coincide with the subject’s Study 115B Safety Follow-up Visit, the subject will complete all Study 116 Day 1 assessments (except the OE if it 
was performed within the last 3 months before the visit). See Section 9.1.1 for details. 
e 
Telephone contacts will be made to assess the subject's status, any AEs, medications, treatments, and procedures. 
f 
If subjects can stand unassisted and follow directions, stature should be measured as height; otherwise, stature will be measured as length. Stature and weight must be 
measured with shoes off and while wearing light clothing. BMI will be derived from this assessment. See Section 11.4.3 for details. 
g 
The subject should rest for at least 5 minutes before having vital signs and pulse oximetry measured. See Section 11.6.4 for details. 
h  Vital signs will be measured predose and at 1 hour (± 15 minutes), 2 hours (± 15 minutes), and 4 hours (± 15 minutes) postdose on Day 1. 
i 
An OE will be conducted by a licensed ophthalmologist. Subjects with documentation of bilateral lens removal do not need the OE. See Section 11.6.6 for details.  
j  
Subjects may complete the OE within ± 1 week of the scheduled visit. 
k  An OE will be conducted at the Week 96 Visit (or the ETT Visit if the subject does not have a Week 96 Visit, unless the discontinuation is due to initiation of treatment 
 
with commercially-available LUM/IVA), or the Safety Follow-up Visit. 
l 
Symptom-directed PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. See Section 11.6.4 for details. 
m  An abbreviated PE will be performed 4 hours (± 30 minutes) postdose on Day 1. See Section 11.6.4 for details. 


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Table 3-1 
Study VX16-809-116: Treatment Cohort - Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT Visitb 
Safety Follow-up Visitc 
Day 1d 
Day 3 
(± 1 Day) 
Day 15 
(± 3 Days) 
Weeks 12, 24, 36, 48, 
60, 72, 84 (± 7 Days) 
Week 96 
(± 7 Days) 
As Soon as 
Possible After the 
Last Dose  
2 Weeks (± 4 Days) 
After the Last Dose 
Standard 12-lead ECGsn 
X 
 
X 
Week 48 
X 
X 
X 
Serum chemistryo 
X 
 
X 
Weeks 12, 24, 36, 48, 72 
X 
X 
X 
Hematologyo 
 
 
 
Weeks 12, 24, 36, 48, 72 
X 
X 
X 
Coagulation studieso 
 
 
 
Week 48 
X 
 
 
Urinalysiso 
X 
 
 
Week 48 
X 
 
 
Qualitative microbiology 
culturesp 
X 
 
 
Weeks 24, 48, 72 
X 
X 
 
Immunoreactive trypsinogen 
X 
 
 
Week 48 
X 
 
X 
Fecal elastase-1q 
X 
 
 
Week 48 
X 
 
X 
Sweat chlorider 
X 
 
 
Weeks 24, 48 
X 
 
X 
LCI (optional)s 
X 
 
 
Weeks 24, 48 
X 
 
X 
Spirometryt 
Xu 
 
X 
Weeks 24, 48 
X 
X 
X 
Other events related to 
outcomev 
X 
 
X 
X 
X 
X 
X 
LUM/IVA dosingw 
LUM/IVA q12h 
 
 
Observation 4 hours after the 
first dose 
X 
 
 
 
 
 
 
Study drug count 
X 
 
X 
X 
X 
X 
 
 
n 
A standard 12-lead ECG will be performed. The subject will be instructed to rest in the supine position for at least 5 minutes, if possible, before having an ECG performed. The 
ECG will be performed before any other procedures that may affect heart rate, such as blood draws. See Section 11.6.5 for details. 
o 
See Section 11.6.2 for details. 
p 
See Section 11.4.7 for details. 
q 
Samples will be collected at the study center during the study visit; however, samples may be collected by the subject up to 24 hours before the study visit (e.g., at home) and 
brought to the study visit (Section 11.4.5). The sample may be collected pre- or postdose. 
r 
The sweat chloride test will be conducted at approximately the same time as predose blood collections. At each time point, 2 samples will be collected, 1 sample from each arm 
(left and right). See Section 11.4.1 for details. 
s 
The LCI assessment (only subjects who are ≥3 years of age at Study 115B screening who consent/assent to the optional LCI Substudy in Study 115B and Study 116) should be 
performed pre-bronchodilator. See Sections 11.1 and 11.4.2 for details. The assessment will be performed in multiple replicates and before the spirometry assessment. 
t 
Spirometry (only subjects who are ≥3 years of age at Study 115B screening) should be performed pre-bronchodilator. See Sections 11.1 and 11.6.7 for details. 
u  Day 1 spirometry will be performed before LUM/IVA dosing and at 2 hours (± 30 minutes) and 4 hours (± 30 minutes) postdose.  
v 
Other events related to outcome include assessments relating to pulmonary exacerbations, administration of antibiotic therapy for sinopulmonary signs or symptoms, and 
hospitalizations (Section 11.4.4). 
w LUM/IVA will be administered q12h (± 2 hours) within 30 minutes of consuming fat containing food (Section 9.6). On days of scheduled visits, the dose will be administered 
at the site after predose assessments have been completed. The last dose will be the dose administered before the Week 96 Visit. See Section 9.6 for dose determination details. 
 


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Table 3-1 
Study VX16-809-116: Treatment Cohort - Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT Visitb 
Safety Follow-up Visitc 
Day 1d 
Day 3 
(± 1 Day) 
Day 15 
(± 3 Days) 
Weeks 12, 24, 36, 48, 
60, 72, 84 (± 7 Days) 
Week 96 
(± 7 Days) 
As Soon as 
Possible After the 
Last Dose  
2 Weeks (± 4 Days) 
After the Last Dose 
Medications, treatments, and 
procedures review 
Continuous from signing of ICF through Safety Follow-up Visit (if required) 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit (if required) 
AE: adverse event; BMI: body mass index; ECG: electrocardiogram; ETT: Early Termination of Treatment; ICF: informed consent form; IVA: ivacaftor; LCI: lung clearance 
index; LUM: lumacaftor; OE: ophthalmological examination; PE: physical examination; q12h: every 12 hours 


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3.2 
Observational Cohort 
Table 3-2 
Study VX16-809-116: Observational Cohort 
Event/Assessment 
Day 1a 
Long-term Follow-up Telephone 
Contact 
Weeks 48 and 96 (± 4 weeks) 
Early Termination Telephone 
Contactb  
Informed consent/assent 
X 
 
 
Clinic visit 
X 
 
 
Telephone contact 
 
X 
X 
Serious adverse events 
Continuous from signing of ICF through Week 96 or Early Termination Telephone 
Contact 
ICF: informed consent form; IVA: ivacaftor; LUM: lumacaftor 
a 
For subjects at sites activated by the time of their applicable Study 115B visit (i.e., the Week 24 Visit or the 
Safety Follow-up Visit, if required), their Study 116 Day 1 Visit will be the same day as their applicable 
Study 115B visit, and any Study 116 Day 1 assessments that were specified to be performed at the applicable 
Study 115B visit do not need to be repeated. If the Study 116 Day 1 Visit does not coincide with the subject’s 
applicable Study 115B visit, the subject will complete all Study 116 Day 1 assessments. See Section 9.1.1 for 
details. 
b 
Subjects who become eligible to receive commercially-available, physician-prescribed LUM/IVA, and who 
choose to continue onto commercially-available LUM/IVA, must have an Early Termination Telephone Contact 
to terminate study participation. 
 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 2 
3 
Schedule of Assessments........................................................................................................ 5 
3.1 
Treatment Cohort .............................................................................................................. 5 
3.2 
Observational Cohort ........................................................................................................ 8 
4 
Table of Contents ................................................................................................................... 9 
List of Tables............................................................................................................................ 12 
List of Figures .......................................................................................................................... 12 
List of Abbreviations................................................................................................................ 13 
5 
Introduction.......................................................................................................................... 15 
5.1 
Background ..................................................................................................................... 15 
5.2 
Study Rationale .............................................................................................................. 15 
6 
Study Objectives .................................................................................................................. 15 
6.1 
Primary Objective ........................................................................................................... 15 
6.2 
Secondary Objective ....................................................................................................... 15 
7 
Study Endpoints ................................................................................................................... 16 
7.1 
Primary Endpoint ............................................................................................................ 16 
7.2 
Secondary Endpoints ...................................................................................................... 16 
 
 
8 
Study Population .................................................................................................................. 16 
8.1 
Inclusion Criteria ............................................................................................................ 16 
8.2 
Exclusion Criteria (Treatment Cohort Only) .................................................................. 17 
9 
Study Implementation ......................................................................................................... 18 
9.1 
Study Design .................................................................................................................. 18 
9.1.1 
Timing of Study 116 Day 1 Visit ........................................................................... 19 
9.1.2 
Treatment Cohort .................................................................................................... 20 
9.1.3 
Observational Cohort .............................................................................................. 21 
9.1.4 
Lost to Follow-up ................................................................................................... 21 
9.1.5 
Independent Data Monitoring Committee .............................................................. 21 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 21 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 21 
9.3.1 
Study Design........................................................................................................... 21 
9.3.2 
Study Drug Dose and Duration .............................................................................. 22 
9.3.3 
Rationale for Study Assessments ........................................................................... 22 
9.4 
Study Restrictions ........................................................................................................... 23 
9.5 
Medications (Treatment Cohort Only) ........................................................................... 23 
9.5.1 
Prohibited Medications and Medications to Use With Caution ............................. 23 
9.5.2 
Prior and Concomitant Medications ....................................................................... 24 
9.6 
Administration ................................................................................................................ 24 
9.7 
Dose Modification for Toxicity ...................................................................................... 26 
9.8 
Removal of Subjects ....................................................................................................... 26 
9.9 
Replacement of Subjects ................................................................................................ 26 
10 Study Drug Information and Management ....................................................................... 26 
10.1 Preparation and Dispensing ............................................................................................ 26 


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10.2 Packaging and Labeling ................................................................................................. 26 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 26 
10.4 Drug Accountability ....................................................................................................... 27 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 27 
10.6 Compliance ..................................................................................................................... 27 
10.7 Blinding and Unblinding ................................................................................................ 28 
11 Assessments .......................................................................................................................... 28 
11.1 Timing of Assessments ................................................................................................... 28 
11.2 Subject and Disease Characteristics ............................................................................... 28 
11.3 Pharmacokinetics ............................................................................................................ 28 
11.4 Pharmacodynamics ......................................................................................................... 29 
11.4.1 
Sweat Chloride ....................................................................................................... 29 
11.4.2 
Lung Clearance Index ............................................................................................. 29 
11.4.3 
Weight, Stature, and BMI ....................................................................................... 29 
11.4.4 
Other Events Related to Outcome .......................................................................... 29 
11.4.5 
Fecal Elastase-1 ...................................................................................................... 31 
11.4.6 
Immunoreactive Trypsinogen ................................................................................. 31 
11.4.7 
Microbiology Cultures ............................................................................................ 31 
11.4.8 
Spirometry .............................................................................................................. 31 
11.5 Efficacy ........................................................................................................................... 31 
11.6 Safety .............................................................................................................................. 31 
11.6.1 
Adverse Events ....................................................................................................... 31 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 31 
11.6.3 
Elevation of Liver Function Test Parameters ......................................................... 32 
11.6.4 
Physical Examinations and Vital Signs .................................................................. 33 
11.6.5 
Electrocardiograms ................................................................................................. 34 
11.6.6 
Ophthalmologic Examination ................................................................................. 35 
11.6.7 
Spirometry .............................................................................................................. 35 
11.6.8 
Contraception and Pregnancy ................................................................................. 35 
12 Statistical and Analytical Plans .......................................................................................... 36 
12.1 Sample Size and Power .................................................................................................. 36 
12.2 Analysis Sets .................................................................................................................. 36 
12.3 Statistical Analysis ......................................................................................................... 37 
12.3.1 
General Considerations ........................................................................................... 37 
12.3.2 
Background Characteristics .................................................................................... 38 
12.3.3 
Pharmacodynamic Analysis ................................................................................... 40 
12.3.4 
Safety Analysis ....................................................................................................... 41 
12.3.5 
Interim and IDMC Analyses ................................................................................... 44 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 44 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 44 
13.1.1 
Adverse Events ....................................................................................................... 44 
13.1.2 
Serious Adverse Events .......................................................................................... 48 
13.2 Administrative Requirements ......................................................................................... 49 
13.2.1 
Ethical Considerations ............................................................................................ 49 
13.2.2 
Subject Information and Informed Consent ........................................................... 49 


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13.2.3 
Investigator Compliance ......................................................................................... 50 
13.2.4 
Access to Records ................................................................................................... 50 
13.2.5 
Subject Privacy ....................................................................................................... 50 
13.2.6 
Record Retention .................................................................................................... 50 
13.2.7 
Study Termination .................................................................................................. 51 
13.3 Data Quality Assurance .................................................................................................. 51 
13.4 Monitoring ...................................................................................................................... 51 
13.5 Electronic Data Capture ................................................................................................. 52 
13.6 Publications and Clinical Study Report .......................................................................... 52 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 52 
14 Reference  ............................................................................................................................. 53 
15 Protocol Signature Pages .................................................................................................... 54 
15.1 Sponsor Signature Page .................................................................................................. 54 
15.2 Investigator Signature Page ............................................................................................ 55 
 


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List of Tables 
Table 3-1 
Study VX16-809-116: Treatment Cohort - Treatment Period and Safety 
Follow-up Visit ....................................................................................................... 5 
Table 3-2 
Study VX16-809-116: Observational Cohort ......................................................... 8 
Table 9-1 
Study Restrictions ................................................................................................. 24 
Table 9-2 
Study Drug Administration ................................................................................... 25 
Table 10-1 
Study Drug ............................................................................................................ 27 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 32 
Table 13-1 
Grading of AE Severity ........................................................................................ 46 
Table 13-2 
Classifications for AE Causality ........................................................................... 46 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 47 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 47 
List of Figures 
Figure 9-1 
Schematic of Study Design ................................................................................... 19 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomic class 
BMI 
body mass index 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Cl- 
chloride ion 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ETT 
early termination of treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the 
wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FE-1 
fecal elastase-1 
FEF25-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
immunoreactive trypsinogen 
IV 
intravenous 
IVA 
ivacaftor 
LCI 
lung clearance index 


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Abbreviation 
Definition 
LCI2 5 
number of lung turnovers required to reduce the end tidal inert gas concentration to 
1/40th of its starting value 
LCI5 0 
number of lung turnovers required to reduce the end tidal inert gas concentration to 
1/20th of its starting value 
LFT 
liver function test 
LLN 
lower limit of normal 
LUM 
lumacaftor 
MBW 
multiple-breath washout 
MedDRA 
Medical Dictionary for Regulatory Activities 
OE 
ophthalmological examination 
P 
probability 
PD 
pharmacodynamics(s) 
PE 
physical examination 
PK 
pharmacokinetic(s) 
ppFEV1 
percent predicted FEV1 
PR 
PR interval 
PT 
preferred term 
q12h 
every 12 hours 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SI 
SI units (International System of Units) 
SOC 
system organ class 
SUSAR 
suspected, unexpected, serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality and at present, there is no cure. CF affects 
approximately 70,000 individuals worldwide,1 with approximately 30,000 individuals in the 
US.1,2 Despite progress in the treatment of CF with antibiotics and mucolytics, the predicted 
median age of survival for a person with CF is approximately 40 years.2-4 Although the disease 
affects multiple organs, progressive loss of lung function is the leading cause of mortality.5 
CF is caused by a defect in the gene encoding CFTR, an epithelial chloride (Cl-) ion channel that 
is responsible for aiding in the regulation of salt and water absorption and secretion in various 
tissues.6 This function is defective in patients with CF due to a loss of cell surface expression 
and/or function of CFTR. 
Lumacaftor (LUM; VX-809)/ivacaftor (IVA; VX-770) combination therapy (Orkambi™) is the 
first medicine designed to treat the underlying molecular defect and enhance the function of 
CFTR in patients homozygous for F508del. Orkambi is approved in the US for patients 6 years 
and older who are homozygous for F508del, and in the EU, Canada, Australia, and Switzerland 
for patients 12 years and older who are homozygous for F508del. The LUM/IVA development 
program is designed to support the hypothesis that an oral chronic treatment restoring CFTR 
function can lead to improved pulmonary and extrapulmonary manifestations of CF, prevent 
progressive lung damage, and ultimately prolong survival. 
Details about the LUM/IVA development program can be found in the Investigator’s Brochure.7 
5.2 
Study Rationale 
Approximately half of the total CF patient population is <18 years of age.8 Even before the 
widespread adoption of newborn screening, the majority of patients with CF were diagnosed in 
infancy or early childhood due to manifestations of the disease. Pancreatic destruction leading to 
pancreatic exocrine insufficiency begins in utero, and lung involvement is manifest by 
pulmonary inflammation and infection that begins shortly after birth.  
The primary objectives of Study VX15-809-115 (Study 115) are to obtain pharmacokinetic (PK) 
and safety information to support a proposed indication expansion of LUM/IVA in subjects aged 
2 through 5 years, homozygous for F508del. The primary objective of Study VX16-809-116 
(Study 116) is to evaluate the long-term safety of LUM/IVA in subjects aged 2 years and older 
with CF, homozygous for F508del, who participated in Study 115.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the long-term safety of LUM/IVA combination therapy in subjects aged 2 years and 
older with CF, homozygous for F508del 
6.2 
Secondary Objective 
To evaluate the pharmacodynamics (PD) of long-term LUM/IVA combination therapy in 
subjects aged 2 years and older with CF, homozygous for F508del 


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7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), changes in clinical laboratory 
values, electrocardiograms (ECGs), vital signs, pulse oximetry, ophthalmological examinations 
(OEs), and spirometry 
7.2 
Secondary Endpoints 
The following endpoints will be analyzed using baseline values in the previous study 
(i.e., Study 115 Part B [Study 115B]): 
• Absolute change from baseline in sweat chloride 
• Absolute change from baseline in body mass index (BMI) and BMI-for-age z-score 
• Absolute change from baseline in weight and weight-for-age z-score 
• Absolute change from baseline in stature and stature-for-age z-score 
• Time-to-first pulmonary exacerbation from baseline 
• Number of pulmonary exacerbations from baseline 
• Number of CF-related hospitalizations from baseline 
• Absolute change from baseline in fecal elastase-1 (FE-1) levels  
• Absolute change from baseline in serum levels of immunoreactive trypsinogen (IRT)  
• Change from baseline in microbiology cultures 
• Absolute change from baseline in lung clearance index (LCI)2.5  
• Absolute change from baseline in LCI5.0  
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
for the study. 
8.1 
Inclusion Criteria 
1. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) will 
sign and date an informed consent form (ICF) and the subject will sign and date an assent 
form (if applicable).  


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2. Subjects entering the Treatment Cohort must meet the following criteria:  
• Completed 24 weeks of LUM/IVA treatment and the Safety Follow-up Visit in 
Study 115B  
o Subjects who had study drug interruptions are eligible if they completed study visits 
up to the Safety Follow-up Visit of Study 115B. Subjects who are not taking 
LUM/IVA at the end of the Study 115B Treatment Period (i.e., Week 24), including 
subjects who have LUM/IVA treatment temporarily interrupted as of Day 1 in 
Study 116, must receive Vertex approval for enrollment in the Treatment Cohort.  
Subjects entering the Observational Cohort must meet 1 of the following criteria: 
• Completed 24 weeks of LUM/IVA treatment and the Safety Follow-up Visit in 
Study 115B, but do not want to enroll in the Treatment Cohort. 
• Received at least 4 weeks of LUM/IVA treatment and completed visits up to Week 24 
and the Safety Follow-up Visit, if required, of Study 115B but are not taking LUM/IVA 
at the end of the Study 115B Treatment Period (i.e., Week 24) because of a drug 
interruption and either did not receive Vertex approval to enroll in the Treatment Cohort 
or do not want to enroll in the Treatment Cohort.  
• Permanently discontinued LUM/IVA in Study 115B after receiving at least 4 weeks of 
treatment and remained in the study from the time of treatment discontinuation through 
the Week 24 Visit and Safety Follow-up Visit, if required.  
3. Willing to remain on a stable CF medication regimen through the Safety Follow-up Visit 
(Treatment Cohort only). 
4. As deemed by the investigator, the subject’s legally appointed and authorized representative 
(e.g., parent or legal guardian) must be able to understand protocol requirements, restrictions, 
and instructions. The subject’s legally appointed and authorized representative should be able 
to ensure that the subject will comply with, and is likely to complete, the study as planned. 
8.2 
Exclusion Criteria (Treatment Cohort Only) 
1. Prematurely discontinued LUM/IVA treatment in Study 115B. 
2. History of any comorbidity or laboratory abnormality that, in the opinion of the investigator, 
might confound the results of the study or pose an additional risk in administering LUM/IVA 
to the subject (e.g., cirrhosis with portal hypertension).  
3. History of drug intolerance or other serious reactions to LUM/IVA in Study 115B that would 
pose an additional risk to the subject in the opinion of investigator, and which should be 
discussed with the Vertex medical monitor.  
4. Subjects with a history of allergy or hypersensitivity to LUM/IVA. 
5. Liver function test (LFT) abnormality meeting criteria for LUM/IVA treatment interruption 
at the completion of Study 115B, for which no convincing alternative etiology is identified.  
6. QTc value at the completion of Study 115B that would pose an additional risk to the subject 
in the opinion of investigator, and which should be discussed with the Vertex medical 
monitor (e.g., remained above the threshold value [>45 msec from baseline or >500 msec] on 


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repeated measurement or was noted on 2 or more occasions with no identified alternative 
etiology for the increased QTc). 
7. History of poor compliance with LUM/IVA and/or procedures in Study 115B as deemed by 
the investigator. 
8. Participation in an investigational drug trial (including studies investigating LUM and/or 
IVA) other than Study 115B. NOTE: participation in a non-interventional study is permitted 
(including observational studies, registry studies, and studies requiring blood collections 
without administration of study drug). 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, open-label, multicenter study with a Treatment Cohort and an Observational 
Cohort (Figure 9-1).  
Procedural details are described in Sections 9.1.1 and 9.1.3. 




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9.1.1.2 
Treatment Cohort 
Subjects at sites activated by the time of their applicable Study 115B visit (Section 9.1.1.1) may 
return within 1 calendar day to complete the remaining Day 1 assessments specific to Study 116 
(including administration of the Day 1 dose). Predose vital sign and spirometry assessments must 
be repeated before dosing on the following calendar day.  
Subjects who were enrolled but had Day 1 LUM/IVA administration procedures (Section 9.6) 
delayed more than 1 calendar day will repeat all assessments that were specified to be performed 
at the Day 1 visit before receiving their first dose of LUM/IVA (except for the OE if it was 
performed within the last 3 months before the visit). 
9.1.2 
Treatment Cohort 
9.1.2.1 
Treatment Period  
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4). 
Treatment Period assessments are listed in Table 3-1. Subjects will be outpatients during the 
Treatment Period. All visits should occur within the windows specified. 
The Treatment Period is 96 weeks; LUM/IVA will be administered every 12 hours (q12h) from 
Day 1 through Week 96. The dose before the Week 96 Visit will be the last dose. Administration 
and management details are provided in Sections 9.6 and 10. 
Procedures for subjects who prematurely discontinue LUM/IVA treatment are described in 
Section 9.1.2.3. 
9.1.2.2 
Follow-up  
The Safety Follow-up Visit is required for 1) subjects who complete their Early Termination of 
Treatment (ETT) Visit <10 days after the last dose of LUM/IVA (Section 9.1.2.3); and 
2) subjects who interrupt LUM/IVA treatment and complete their Week 96 Visit <10 days after 
the last dose of LUM/IVA; it is not required for subjects who continue onto 
commercially-available, physician-prescribed LUM/IVA within 2 weeks (± 4 days) of 
completing LUM/IVA treatment at the Week 96 or ETT Visit. 
The Safety Follow-up Visit is scheduled to occur 2 weeks (± 4 days) after the last dose of 
LUM/IVA. Safety Follow-up Visit assessments are listed in Table 3-1.  
9.1.2.3 
Early Termination of Treatment  
Subjects who prematurely discontinue LUM/IVA treatment will be asked to complete the ETT 
Visit as soon as possible after the last dose of LUM/IVA. The assessments to be completed are 
listed in Table 3-1. If the ETT Visit occurs 10 days or later following the last dose of LUM/IVA, 
then the ETT Visit will replace the Safety Follow-up Visit, (i.e., the assessments performed will 
be those specified for the ETT Visit), and a Safety Follow-up Visit will not be required.  


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9.1.3 
Observational Cohort 
Observational Cohort assessments are listed in Table 3-2. The Observational Cohort will include 
the following: 
• Day 1 Visit  
• Long-term follow-up telephone contacts at Weeks 48 and 96 
Subjects who become eligible to receive commercially-available, physician-prescribed 
LUM/IVA, and who choose to continue onto commercially-available LUM/IVA, must have an 
Early Termination Telephone Contact to terminate their participation in the study. 
9.1.4 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• Subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• Subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts 
9.1.5 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will be formed using the Cystic Fibrosis 
Foundation Data Safety Monitoring Board. The IDMC objectives and operational details will be 
defined in a separate document (IDMC Charter), which will be finalized before the first subject 
is enrolled. The IDMC will conduct regular planned reviews of study data for the purpose of 
safety monitoring as outlined in the IDMC Charter. 
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. Randomization is not required. Subjects in the Treatment Cohort will 
be treated with LUM/IVA based on their weight and age. Subjects in the Observational Cohort 
will not receive LUM/IVA. 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
Vertex has established efficacy, safety, and PK profiles for LUM/IVA in subjects 12 years of age 
and older, homozygous for F508del (Studies VX12-809-103 [Study 103] and VX12-809-104 
[Study 104]). Because the underlying genetic and molecular etiology of the disease is identical 
between younger and older patients, and the outcome of therapy is likely to be comparable, 
extrapolation of efficacy from older to younger patients is appropriate and PK studies in younger 
patients, together with safety studies, can provide adequate information for use.9  
Safety and PK profiles for LUM/IVA have been established in subjects 6 through 11 years of 
age, homozygous for F508del (Study VX13-809-011 [Study 011]). Study 115, a Phase 3, 2-part, 
open-label study, which includes a 24-week Treatment Period in Part B, is designed to obtain PK 
and safety information to support a proposed indication expansion of LUM/IVA in subjects aged 
2 through 5 years, homozygous for F508del. 


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Study 116 is a Phase 3, open-label, multicenter study in subjects aged 2 years and older with CF, 
homozygous for F508del, who participated in Study 115B. This study, which includes a 96-week 
Treatment Period, is designed to evaluate the long-term safety of LUM/IVA in subjects aged 
2 years and older with CF, homozygous for F508del. 
9.3.2 
Study Drug Dose and Duration 
Dose of LUM/IVA 
Study 115A is designed to characterize the safety and PK of LUM and IVA in subjects 2 through 
5 years of age. The plasma concentration versus time data from Study 115A is intended to 
inform the appropriateness or necessary adjustment of planned doses for Study 115B and 
Study 116. As data from Study 115B become available, the doses may be modified for subjects 
<6 years of age in Study 116. A population PK model with allometric scaling of clearance and 
volume of distribution as a function of weight was used to project exposures of LUM and IVA 
for comparison with clinical experiences with both drugs and to select doses to be evaluated in 
this study population. No safety issues were identified in prior clinical or nonclinical studies that 
would preclude the dosing regimen proposed for Study 116.  
Duration of Dosing 
Subjects who receive LUM/IVA in Study 115B as well as Study 116 may receive treatment for 
up to approximately 2.5 years, thus providing information on the long-term safety of LUM/IVA 
in subjects aged 2 years and older with CF, homozygous for F508del. 
9.3.3 
Rationale for Study Assessments 
The safety and PK assessments are standard parameters for clinical studies in drug development 
and are generally recognized as reliable, accurate, and relevant to the study of subjects with CF. 
OEs and spirometry assessments were added as part of safety monitoring. Assessments were 
added to evaluate the PD effects of LUM/IVA. The following PD assessments are standard 
assessments used in studies in the LUM/IVA development program: weight, stature, BMI, sweat 
chloride, and other events related to outcome, e.g., pulmonary exacerbations. Rationale is 
provided below for the following PD assessments: LCI, exocrine pancreatic function, and 
microbiology. 
OEs: A juvenile rat toxicity study performed to support dosing of IVA in subjects <2 years of 
age demonstrated lens opacities in some animals.7 Prior studies in rats and dogs of older age did 
not demonstrate similar findings. Given substantial differences between human and rat lens 
development, the finding is of unlikely relevance to humans. Periodic OEs for pediatric subjects 
receiving IVA or IVA in combination with a CFTR corrector are being performed to confirm this 
interpretation. The overall data acquired to-date does not suggest an association between IVA 
treatment and cataract development; however, a potential association has not been fully 
excluded.  
Spirometry: Spirometry is included as part of standard safety monitoring. Because the 
quantitative assessment of pulmonary function in young children is difficult, spirometry testing 
will be performed only on subjects who were ≥3 years of age at screening in Study 115B. Even 
with this age stipulation, it is anticipated that reproducible spirometry will be obtained in a 
minority of the study population. 


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Optional LCI Assessment: LCI is a measure of ventilation inhomogeneity that is based on tidal 
breathing techniques that have been evaluated in patients as young as infants.10,11 LCI correlates 
with FEV1 in its ability to measure airway disease in patients with mild to moderate lung disease 
but can also detect lung disease at an earlier stage than spirometry.12,13 Data from 
Study VX10-770-106 in subjects with CF with an FEV1 >90% showed LCI to be a more 
sensitive outcome measure than FEV1. Given the potential advantages of a more sensitive 
measurement during the early stages of disease progression, LCI will be used in this study. As 
with spirometry testing, performing LCI assessments in young children can be difficult.14 
Therefore, only subjects who were ≥3 years of age at screening in Study 115B and who 
consent/assent to the optional LCI Substudy will undergo the LCI assessments. LCI will be done 
only at selected sites that have the capability to perform these assessments. 
Exocrine Pancreatic Function: The pancreas is one of the earliest and most seriously affected 
organs in patients with CF who are homozygous for F508del, a high fraction of which develop 
pancreatic insufficiency. 
• FE-1: FE-1 is a diagnostic measure of pancreatic exocrine sufficiency, with a lack of elastase 
output in stool being considered indicative of CF (<200 µg/g). The increasing use of FE-1 in 
the clinic is a result of the ease of collecting samples for its assessment and the establishment 
of diagnostic cut-offs for pancreatic exocrine function.15 FE-1 represents a feasible measure 
to evaluate exocrine pancreatic function during the study, with the hypothesis that rescue of 
pancreatic function will result in an increase in FE-1 levels. 
• IRT: Trypsinogen is a protein produced by the pancreas that can be detected in the blood via 
the IRT assay and is used in clinical practice for neonatal screening test for CF, wherein 
elevated levels are associated with disease. Blood samples for IRT testing will be collected at 
multiple time points to evaluate potential changes in exocrine pancreatic function during the 
Treatment Period. 
Microbiology: Microbiological endpoints, such as bacterial colony counts and selection of 
resistant bacterial strains, are well-established endpoints used to evaluate antimicrobial therapies 
in CF. Because compounds, such as IVA, that restore CFTR function may increase hydration of 
airway secretions and lead to a decrease in acquisition of bacteria in the CF airway, acquisition 
of bacteria is included as another secondary endpoint in this study. Because the majority of 
subjects in this study will not expectorate spontaneously, oropharyngeal swabs will be used to 
obtain airway cultures. 
9.4 
Study Restrictions 
See Section 9.5 for guidance for concomitant medications. 
A nonexhaustive list of study prohibitions and cautions for food and medication will be provided 
in the Study Reference Manual. 
9.5 
Medications (Treatment Cohort Only) 
9.5.1 
Prohibited Medications and Medications to Use With Caution 
Prohibited medications and certain foods are not allowed as summarized in Table 9-1. 


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Table 9-1 
Study Restrictions 
Restricted Medication/Food 
Treatment Period 
Strong CYP3A inducers 
None allowed 
Strong CYP3A inhibitors 
Use with caution 
CYP: cytochrome P450 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee. 
Use of CYP3A substrates is not prohibited, but investigators need to be aware that LUM appears 
to be a strong inducer of CYP3A. Therefore, the efficacy of drugs extensively metabolized by 
CYP3A may be affected.  
Use of CYP2C and 2B6 substrates is not prohibited, but investigators need to be aware that LUM 
has been shown in vitro to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of 
CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that 
IVA may inhibit CYP2C9. Therefore, concomitant use of LUM/IVA with CYP2B6, CYP2C8, 
CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates.  
Each investigator should evaluate the benefit-risk ratio of using CYP3A, CYP2B6, CYP2C8, 
CYP2C9, and CYP2C19 substrates with LUM and IVA and discuss their use with the medical 
monitor or authorized designee. 
9.5.2 
Prior and Concomitant Medications 
It is recommended that subjects remain on a stable medication regimen for their CF from 
Study 115B through the Safety Follow-up Visit in Study 116. Stable medication regimen is 
defined as the current medication regimen for CF that subjects have been following for at least 
28 days before Day 1 of Study 115B.  
Subjects who are using a bronchodilator should have their LCI and spirometry assessments 
performed according to the guidelines provided in Section 11.6.7. 
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered at, or after, 
the Safety Follow-up Visit in Study 115B through the Safety Follow-up Visit of this study will 
be recorded in each subject’s source documents. In addition, concomitant medication dose(s) 
may be collected. 
9.6 
Administration 
LUM/IVA will be administered orally as shown in Table 9-2. Subjects in the Observational 
Cohort will not receive LUM/IVA. 
At each study visit the LUM/IVA dose for each subject will be reassessed based on age and body 
weight and adjusted upward if necessary.  


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Table 9-2 
Study Drug Administration 
Population 
Dose 
Time 
LUM/IVA 
(Number of Stick 
Packs/Tablets) 
Subjects <6 years of age and weight <14 kg at 
enrollmenta 
LUM 100 mg/IVA 125 mg q12hb 
AM 
1 stick pack 
PM 
1 stick pack 
Subjects <6 years of age and weight ≥14 kg at 
enrollmenta 
LUM 150 mg/IVA 188 mg q12hb 
AM 
1 stick pack 
PM 
1 stick pack 
Subjects ≥6 years of age at enrollmenta 
LUM 200 mg/IVA 250 mg q12h 
AM 
2 tablets 
PM 
2 tablets 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
a 
No downward dose adjustments will be made if a subject’s weight decreases. Doses may be adjusted upward as follows: 
• If a subject who is <6 years of age at enrollment enters weighing <14 kg and subsequently weighs ≥14 kg at 2 consecutive 
visits without becoming ≥6 years of age at these visits, the dose will be adjusted to LUM 150 mg/IVA 188 mg q12h, at the 
second visit where weight ≥14 kg. 
• If a subject who is <6 years of age at enrollment becomes 6 years of age during the study, the dose and formulation will be 
adjusted to LUM 200 mg/IVA 250 mg q12h administered as tablets for oral administration, regardless of weight, at the 
next scheduled visit. 
b 
Doses are those planned for Study 115B. Based on results from Study 115A and 115B, doses for subjects <6 years of age in 
Study 116 may be modified. 
LUM/IVA will be administered within 30 minutes from the start of consuming fat-containing 
food such as a standard “CF” high-fat, high-calorie meal or snack according to the following 
guidelines: 
1. LUM/IVA will be administered approximately q12h (± 2 hours) on each dosing occasion 
(e.g., if the morning dose is administered at 0800 on Day 1, the evening dose on Day 1 
should be administered between 1800 and 2200 and all subsequent morning doses should be 
administered between 0600 and 1000). 
2. The granule formulation will be dispensed by opening the stick packs containing the granules 
and mixing the granules with the approved foods and liquids listed in the Study Reference 
Manual. Each dose will be comprised of the approved food or liquids into which the granules 
from the stick packs are mixed. Details on preparing LUM/IVA will be provided in the 
Pharmacy Manual. 
3. On the Day 1 Visit, all subjects will be observed for 4 hours after the first dose of LUM/IVA. 
4. On days of scheduled visits (Table 3-1), with the exception of afternoon visits addressed 
below, the morning LUM/IVA dose will be administered at the site after predose assessments 
have been completed. 
5. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used for administering either the morning or evening dose: 
• If the dose in the clinic will be within 6 hours of the subject’s scheduled morning 
LUM/IVA dose, the subject should withhold their morning dose and the morning dose 
will be administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
LUM/IVA dose, the subject should take the morning dose at home and the evening dose 
will be administered in the clinic. In this event, all assessments will be collected relative 
to the evening dose. 


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6. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused 
LUM/IVA materials to the site; LUM/IVA will be dispensed at each visit, as appropriate. 
7. At the Week 96 Visit, the LUM/IVA dose will NOT be administered. The last LUM/IVA 
dose will be the dose administered before the Week 96 Visit.  
9.7 
Dose Modification for Toxicity 
Modifications of the LUM/IVA dose are prohibited. Should any unacceptable toxicity arise, 
individual subjects will be withdrawn from the study treatment. 
9.8 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request or at the request of their 
legally appointed and authorized representative (e.g., parent or legal guardian). Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed as noted 
in Sections 9.1.2.2 and 9.1.2.3, provided the subject/caregiver has not withdrawn consent.   
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject’s parent or legal guardian. In any circumstance, reasonable effort will be made to 
document subject outcome. The investigator will inquire about the reason for withdrawal, request 
that the subject’s parent or legal guardian return all unused investigational product(s), request 
that the subject return for an ETT Visit and Safety Follow-up Visit, if applicable (see 
Sections 9.1.2.2 and 9.1.2.3), and follow up with the subject regarding any unresolved AEs. 
If the subject withdraws consent for the study, no further evaluations will be performed and no 
additional data will be collected. Vertex may retain and continue to use any data collected before 
such withdrawal of consent. 
9.9 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the Treatment Period will not be replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
LUM/IVA may be dispensed only under the supervision of the investigator or an authorized 
designee to the subject’s legally appointed and authorized representative (e.g., parent or legal 
guardian) and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Vertex will supply the LUM/IVA granules in stick packs and LUM 100-mg/IVA 125-mg tablets 
in child-resistant weekly blister cards. Study drug labeling will be in compliance with applicable 
local and national regulations. Additional details regarding packaging, labeling, and dispensing 
for LUM/IVA will be included in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 


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requirements. To ensure adequate records, all study drugs will be accounted for as described in 
Section 10.4. Detailed instructions regarding the storage, handling, and dispensation of 
LUM/IVA will be provided in the Pharmacy Manual. 
Table 10-1 
Study Drug 
Drug 
Name 
Formulation/ 
Route 
Packaging (Formulation Strength) 
Storage 
Condition 
LUM/IVA 
Granules/ 
Oral 
Supplied as 100-mg LUM/125-mg IVA granules in 1 stick pack  Store at ≤25°C 
(77°F) with 
excursions to 
30°C (86°F) 
LUM/IVA  
Granules/ 
Oral 
Supplied as and 150-mg LUM/188-mg IVA granules in 1 stick 
pack  
Store at ≤25°C 
(77°F) with 
excursions to 
30°C (86°F) 
LUM/IVA 
Fixed-dose 
tablet/ 
Oral 
Supplied as 100-mg LUM/125-mg IVA tablets 
Store at ≤25ºC 
(77ºF) with 
excursions to 
30ºC (86ºF) 
IVA: ivacaftor; LUM: lumacaftor 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee until inventoried by the study monitor. The study 
monitor will review study drug records and inventory throughout the study. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject/caregiver of study drug dosing requirements. 
Compliance will also be assessed by ongoing study drug count. 
If a subject/caregiver demonstrates continued noncompliance of study drug dosing despite 
educational efforts, the investigator should contact the medical monitor to discuss 
discontinuation of the subject from the study treatment while remaining in the study. 


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10.7 
Blinding and Unblinding 
This will be an open-label study. However, subjects and their legally appointed and authorized 
representative (e.g., parent or legal guardian) should not be informed of their study-related 
spirometry, sweat chloride, and LCI results during the study even if the subject permanently 
discontinued treatment. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 and Table 3-2.  
Additional timing notes for LCI and spirometry 
LCI assessments derived from N2-multiple-breath washout (MBW) testing (Section 11.4.2) 
should be performed before the spirometry assessment (Section 11.6.7). MBW and spirometry 
testing should be performed pre-bronchodilator, which is defined as testing performed for 
subjects who have 
• withheld their short-acting bronchodilator (e.g., albuterol) or anticholinergic (e.g., Atrovent®) 
for more than 4 hours before the testing; 
• withheld their long-acting bronchodilator (e.g., salmeterol) more than 12 hours before the 
testing; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the testing. 
If a subject forgets to withhold bronchodilator(s), testing should be performed as follows: 
• If a subject’s Day 1 testing is pre-bronchodilator, but on a subsequent visit, the subject 
forgets to withhold bronchodilator use, post-bronchodilator testing will be obtained for that 
visit only, and the visit will not be rescheduled. 
• If on Day 1, the subject forgets to withhold their dose of bronchodilator, testing should be 
performed post-bronchodilator and all subsequent testing should be performed 
post-bronchodilator. 
• Each test will be recorded in the source documents as pre-bronchodilator or 
post-bronchodilator. 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, stature, 
and weight. Select demographic and baseline characteristic data and medical history will be 
derived from the previous study. 
Age, sex, race, and ethnicity will be derived from the previous study because these data are 
required for the normalization of spirometry values using the Global Lung Function Initiative 
(GLI) method (Section 11.6.7). 
11.3 
Pharmacokinetics 
Not applicable 


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11.4 
Pharmacodynamics  
11.4.1 
Sweat Chloride 
Collection of sweat samples will be performed using an approved collection device. Sweat 
samples will be sent to a central laboratory for testing and interpretation of results. Individual 
sweat chloride test results will not be disclosed to the study sites. Specific instructions for 
collection, handling, processing, and shipping of sweat chloride samples to the central laboratory 
will be provided separately. The sweat chloride test will be conducted at approximately the same 
time as predose blood collections. At each time point, 2 samples will be collected, 1 sample from 
each arm (left and right). 
Subjects and their parent/caregiver should not be informed of their study-related sweat chloride 
results during the study even if the subject prematurely discontinued treatment. 
11.4.2 
Lung Clearance Index  
LCI assessments derived from N2-MBW testing will be performed only on subjects who are 
≥3 years of age at Study 115B screening and who consent/assent to the optional LCI Substudy in 
Study 115B and Study 116.  
MBW should be performed “pre-bronchodilator.” See Section 11.1 for pre-bronchodilator 
definitions and instructions if a subject forgets to withhold bronchodilator(s).  
Each MBW will be performed in multiple replicates at each visit, and the final LCI value will be 
calculated from the technically acceptable washout replicates.  
Detailed LCI procedures will be supplied in the Study Reference Manual. 
Subjects and their parent/caregiver should not be informed of their study-related LCI results 
during the study even if the subject prematurely discontinued treatment. 
11.4.3 
Weight, Stature, and BMI 
See Section 11.6.4. 
11.4.4 
Other Events Related to Outcome 
11.4.4.1 
Antibiotic Therapy for Sinopulmonary Sign/Symptoms 
Given the absence of a consensus definition for pulmonary exacerbation in clinical studies in this 
population, the definition below will be applied to signs and symptoms for the analysis of 
pulmonary exacerbations.  
Definition: New or changed treatment with oral, inhaled, or intravenous (IV) antibiotics AND 
fulfillment of 1 criterion from List A (below) or 2 criteria from List B (below), within the period 
3 days before antibiotic start date through antibiotic stop date.16 
The occurrence of any new or changed antibiotic therapy (IV, inhaled, oral) and the presence of 
the following signs and symptoms will be recorded in the source documents:  
List A:  
• Decrease in FEV1 ≥10% change from highest value in the past 6 months before the first dose, 
unresponsive to albuterol (if applicable)  
• Oxygen saturation <90% on room air or ≥5% decrease from baseline  


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• New lobar infiltrate(s) or atelectasis on chest x-ray 
• Hemoptysis (more than streaks on more than 1 occasion in past week) 
List B: 
• Increased work of breathing or respiratory rate (duration ≥3 days) 
• New or increased adventitial sounds on lung examination (duration ≥3 days) 
• Weight loss ≥5% decrease from highest value or decrease across 1 major percentile for age in 
past 6 months  
• Increased cough (duration ≥3 days) 
• Worked harder to breathe during physical activity (duration ≥3 days) 
• Increased chest congestion or change in sputum (duration ≥3 days) 
It is recommended that LUM/IVA should not be interrupted during a pulmonary exacerbation 
unless, in the opinion of the investigator, it would be in the best interest of the subject. 
The following information will be determined for protocol-defined pulmonary exacerbations: 
• Number of pulmonary exacerbations 
• Number of days with pulmonary exacerbations 
• Time-to-first pulmonary exacerbation 
• Number of pulmonary exacerbations requiring hospitalizations 
• Number of days hospitalized for pulmonary exacerbations 
• Time-to-first hospitalization for pulmonary exacerbation 
• Number of pulmonary exacerbations requiring IV antibiotic therapy 
• Number of days on IV antibiotic therapy for pulmonary exacerbations 
• Time-to-first IV antibiotic therapy for pulmonary exacerbations 
11.4.4.2 
Hospitalization for CF 
Subjects will be queried about planned and unplanned hospitalizations lasting ≥24 hours. The 
dates for hospitalizations and the reasons for hospitalizations will be documented. 
If the hospitalization is unplanned, the procedures for safety reporting should also be followed 
(Section 13.1.2.3). 
The following information will be determined: 
• Number of planned hospitalizations for CF (i.e., prophylactic antibiotic therapy) 
• Number of all unplanned hospitalizations 
• Number of days of all unplanned hospitalizations 
• Time-to-first unplanned hospitalization 


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11.4.5 
Fecal Elastase-1 
Stool samples for assessment of FE-1 will be collected at the study center during the study visit; 
however, samples may be collected by the subject’s caregiver up to 24 hours before the study 
visit (e.g., at home) and brought to the study visit. Instructions for the collection, processing, and 
shipment of samples will be provided in a separate Laboratory Manual. 
11.4.6 
Immunoreactive Trypsinogen 
Instructions for the collection, processing, and shipment of samples for assessment of IRT will 
be provided in a separate Laboratory Manual.  
11.4.7 
Microbiology Cultures 
Specific instructions for the collection, processing, and shipment of samples for assessment of 
microbiology cultures will be provided in a separate Laboratory Manual. 
11.4.8 
Spirometry 
See Section 11.6.7. 
11.5 
Efficacy 
All efficacy-related assessments are listed in Section 11.4, Pharmacodynamics. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments (hematology, chemistry, 
coagulation studies, and urinalysis), clinical evaluation of vital signs, pulse oximetry, ECGs, 
PEs, spirometry, and OEs. 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments 
The safety laboratory test panels are shown in Table 11-1. Additional clinical laboratory 
evaluations will be performed at other times if judged to be clinically appropriate. Laboratory 
test results that are abnormal and considered clinically significant will be reported as AEs (see 
Section 13.1). 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogen   
Creatinine  
Sodium 
Potassium 
Calcium 
Chloride  
Magnesium 
Bicarbonate 
Inorganic phosphate 
Total bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase (=SGOT) 
Alanine aminotransferase (=SGPT) 
Lactate dehydrogenase 
Gamma-glutamyl transferase (GGT) 
Total protein 
Albumin 
Creatine kinase 
Hemoglobin 
Erythrocytes: 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelets 
Reticulocytes (absolute) 
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Monocytes 
Coagulation Studies 
Activated partial thromboplastin time 
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
Leukocyte esterase 
Nitrite 
Urobilinogen 
Urine protein 
pH 
Urine blood 
Specific gravity 
Urine ketones 
Urine bilirubin 
Urine glucose 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
For purposes of study conduct and data analysis, blood and urine samples will be analyzed at a 
central laboratory. However, at the discretion of the local investigator, samples may be analyzed 
at a local laboratory for management of urgent medical issues, including if a subject cannot 
return to the clinical study site for the mandatory liver function testing (Section 11.6.3). If a local 
laboratory test value is found to be abnormal and clinically significant, it will be verified by the 
central laboratory as soon as possible after the investigator becomes aware of the abnormal 
result. If it is not possible to send a timely specimen to the central laboratory (e.g., the subject 
was hospitalized elsewhere), the investigator may base the assessment of an AE on the local 
laboratory value. 
11.6.3 
Elevation of Liver Function Test Parameters 
Mandatory Liver Function Testing 
Liver function testing (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
gamma-glutamyl transferase [GGT], alkaline phosphatase [ALP], and total bilirubin) must be 
performed while subjects are receiving LUM/IVA treatment (see Table 3-1 and Section 11.6.2). 
These blood samples should be processed and shipped immediately per the Laboratory Manual. 
Subjects with new ALT or AST elevations of ≥3 × upper limit of normal (ULN) and clinical 
symptoms will be followed closely, including repeat confirmatory testing performed by the 
central laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of 
ALT and AST levels, as clinically indicated. If a subject cannot return to the site for liver 
function testing, a local laboratory may be used. Elevations in LFTs (ALT or AST ≥3 × ULN) at 
the local laboratory must be reported immediately to the medical monitor AND the subject must 


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have the tests repeated and sent to the central laboratory as soon as possible (ideally within 48 to 
72 hours). 
Study Drug Interruption 
LUM/IVA administration must be interrupted immediately, and the Vertex medical monitor or 
designee must be notified if any of the following criteria is met: 
• ALT or AST ≥8 × ULN 
• ALT or AST ≥5 × ULN for more than 2 weeks 
• ALT or AST ≥3 × ULN in association with total bilirubin ≥2 × ULN and/or clinical jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Resumption of Study Drug 
If a convincing alternative etiology is identified for the elevated liver tests (ALT, AST, and total 
bilirubin), LUM/IVA may be resumed when levels return to baseline or are ≤2 × ULN, 
whichever is higher. Approval of the Vertex medical monitor or designee is required before 
resumption of LUM/IVA. Upon resumption of LUM/IVA, transaminases should be assessed 
weekly for 4 weeks. If a protocol-defined liver test elevation occurs within 4 weeks of 
rechallenge with LUM/IVA, then LUM/IVA must be discontinued, regardless of the presumed 
etiology. 
Discontinuation of Study Drug 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST levels 
have improved, LUM/IVA treatment must be discontinued, after consulting with the Vertex 
medical monitor or authorized designee. Subjects in whom treatment is discontinued for elevated 
transaminases should have their transaminases monitored closely until levels normalize or return 
to baseline. 
11.6.4 
Physical Examinations and Vital Signs 
A physical examination (PE) of all body systems and vital signs assessment will be performed at 
select study visits (see Table 3-1). At other visits, symptom-directed PEs and symptom-directed 
vital sign assessments can be performed at the discretion of the investigator or healthcare 
provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
An abbreviated PE will be performed at some visits (see Table 3-1). The abbreviated PE will 
include an assessment of the following body systems: head/neck/thyroid, EENT, cardiovascular 
system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, 
respiration rate, and pulse oximetry. The subject should rest for at least 5 minutes before having 


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vital signs measured; additional instructions will be included in a separate Study Reference 
Manual. 
Weight and stature will be assessed and BMI will be derived. If subjects can stand unassisted and 
follow directions, stature should be measured as height; otherwise, stature will be measured as 
length. Stature and weight must be measured with shoes off and while wearing light clothing. 
BMI will be calculated using the following equation:  
BMI (kg/m2) = body weight (kg) ÷ stature2 (m2) 
11.6.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Standard 12-lead ECGs 
will be performed with central over-reading. All sites will be provided with ECG machine(s) and 
associated materials by the central ECG diagnostic service.  
Additional standard 12-lead ECGs will be performed at any other time if clinically indicated. 
The performance of all ECGs will adhere to the following guidelines: 
• The subject will be instructed to rest in the supine position for at least 5 minutes, if possible, 
before having an ECG performed. 
• The ECG will be performed before any other procedures that may affect heart rate, such as 
blood draws. 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through the end of study participation will be recorded as AEs.  
A hard copy of the ECG will be printed and signed by the investigator at the site. To ensure the 
safety of the subjects, the investigator or designee at the investigator site will make comparisons 
to the predose measurement at Day 1 (baseline). If the QTcF is increased by >45 msec from the 
shortest baseline QTcF or the absolute QTcF value is >500 msec for any scheduled ECG, 
2 additional ECGs will be performed approximately 2 to 4 minutes apart to confirm the original 
measurement. If either of the QTcF values from these repeated ECGs remains above the 
threshold value (>45 msec from baseline or >500 msec), a single ECG must be repeated at least 
hourly until QTcF values from 2 successive ECGs fall below the threshold value that triggered 
the repeat measurement. 
If the QTc value remains above the threshold value (>45 msec from baseline or >500 msec) on 
repeated measurement or is noted on 2 or more occasions with no identified alternative etiology 
for the increased QTc, then discontinuation from LUM/IVA treatment may be required after 
discussion with the Vertex medical monitor or designee. Subjects who have treatment 
discontinued for increased QTcF should have their QTcF monitored closely until it normalizes or 
returns to baseline. 
ECG data will be transmitted via modem to the central ECG diagnostic service. A cardiologist at 
the central ECG diagnostic service will review each ECG to confirm if intervals were calculated 
correctly and to provide an interpretation including a suggested clinical significance, as 
applicable. A report containing this information will be provided to the site for review and 
signature by the investigator. This report will be filed with the machine ECG report for each time 
point in the subject’s source documents. The values reported by the central ECG diagnostic 
service will be used for data analysis. 


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11.6.6 
Ophthalmologic Examination 
The OE includes 
• measurement of best corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
OEs must be conducted by a licensed ophthalmologist. Subjects with documentation of bilateral 
lens removal do not need the OE. 
If a cataract or lens opacity is identified and determined to be clinically significant by a licensed 
ophthalmologist at the Day 1 OE, the subject/caregiver will be notified. After discussion with the 
site principal investigator, and in collaboration with the Vertex medical monitor, the 
subject/caregiver may elect to participate or not to participate in the study. If the subject 
continues in the study, more frequent ophthalmologic monitoring should be considered. 
If a cataract or lens opacity is identified and determined to be clinically significant by a licensed 
ophthalmologist after dosing, the subject/caregiver will be notified. After discussion with the site 
principal investigator and in collaboration with the Vertex medical monitor, the subject/caregiver 
may elect to continue or discontinue LUM/IVA. If the subject discontinues LUM/IVA, the 
subject will be asked to remain in the study and complete the study assessments as noted in 
Section 9.1.2.3. If the subject continues, more frequent ophthalmologic monitoring should be 
considered. 
Additional OEs may be conducted at the discretion of the investigator. The Vertex medical 
monitor or designee should be notified of any additional OEs. 
11.6.7 
Spirometry  
Spirometry will be performed according to the American Thoracic Society Guidelines.17 
Spirometry will be performed only on subjects who are ≥3 years of age at screening of 
Study 115B.  
Spirometry should be performed “pre-bronchodilator.” See Section 11.1 for pre-bronchodilator 
definitions and instructions if a subject forgets to withhold bronchodilator(s). 
The parameters listed below will be normalized using the standards of GLI.18 
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow (FEF25%-75%) (L/s) 
The central spirometry service will provide all sites with spirometers and associated materials to 
be used for all study assessments. Spirometry data will be transmitted to a centralized spirometry 
service for quality review. 
Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results during the study even if the subject prematurely discontinued treatment. 
11.6.8 
Contraception and Pregnancy 
Not applicable 


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12 
STATISTICAL AND ANALYTICAL PLANS  
Analysis of long-term safety and PD will be performed by Vertex or its designee, and will be 
presented in the corresponding statistical analysis plan (SAP). 
12.1 
Sample Size and Power 
No formal sample size calculations have been performed.  
This is a long-term extension that plans to enroll subjects rolled over from Study 115B. 
Approximately 56 subjects are potentially eligible to be enrolled in this rollover study. Assuming 
a 10% dropout rate in Study 115B, 50 subjects are expected to enroll in this study. 
12.2 
Analysis Sets 
All Subjects Set is defined as all subjects who have signed informed consent (and assent, if 
applicable) and enrolled or dosed in Study 115B.  
116 All Subjects Set is defined as all subjects who have signed informed consent (and assent, if 
applicable) and enrolled or dosed in the Study 116 Treatment Cohort.  
Safety Sets 
Safety Set: The Safety Set will include all subjects who received at least 1 dose of study drug in 
Study 115B.  
116 Safety Set: The 116 Safety Set will include all subjects dosed in Study 115B who are 
exposed to any amount of study drug in the Study 116 Treatment Cohort. 
Efficacy Sets 
Full Analysis Set (FAS): The FAS will include all subjects who were enrolled and exposed to 
any amount of study drug in Study 115B.  
Other Analysis Sets 
LCI Substudy Set will include all subjects who have signed informed consent (and assent, if 
applicable) to the optional LCI Substudy and enrolled and dosed in Study 115B. 
116 LCI Substudy Set is a subset of LCI Substudy Set, who are enrolled and exposed to any 
amount of study drug in the Study 116 Treatment Cohort. 
Analysis Period 
Cumulative Study Period starts from the first dose of study drug in the previous study to the 
last day in Study 116, regardless of 1) the planned 2-week Washout Period in Study 115B; or 
2) the rollover gap between Study 115B and Study 116. For subjects not enrolled in Study 116, 
the Cumulative Study Period will start from the first dose of study drug in the previous study to 
the last day in the previous study.  
Treatment-emergent Period for the Cumulative Study Period 
The Treatment-emergent Period for the Cumulative Study Period is the period on or after the 
first dose of study drug in the previous study to 14 days (inclusive) after the last dose of study 
drug in Study 116 or up to the last day in Study 116, whichever occurs first. For subjects not 
enrolled in Study 116, the Treatment-emergent Period for the Cumulative Study Period will be 


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the period on or after the first dose of study drug in the previous study to 14 days (inclusive) 
after the last dose of the previous study, or last date of the previous study, whichever occurs first. 
Other specific periods may be defined in the SAP and used for any targeted analysis as deemed 
necessary. 
12.3 
Statistical Analysis 
Statistical Analysis System Version 9.2 or higher will be used to generate all statistical outputs 
(tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the SAP that will be finalized 
before the data cut/lock. 
12.3.1 
General Considerations 
For the Treatment Cohort, all individual subject data will be presented in data listings based on 
All Subjects Set.  
For the Observational Cohort, listings will be provided only for disposition, demographics, and 
serious adverse events (SAEs). Listings will be provided based on all subjects enrolled in the 
Observational Cohort.  
Continuous variables will be summarized using descriptive summary statistics: number of 
subjects, mean, standard deviation (SD), standard error (SE), median, minimum value, and 
maximum value.  
Categorical variables will be summarized using counts and percentages.  
Baseline value: 
• Baseline of Cumulative Study Period:  
The baseline value is defined as the most recent non-missing measurement before intake of 
the first dose of study drug in Study 115B. 
o For LCI-related parameters, the values at each visit will be calculated from the 
technically acceptable washout replicates. The baseline of LCI will be the most recent 
non-missing value calculated from the technically acceptable replicates before the initial 
administration of study drug of Study 115B. 
o For sweat chloride, the values at each visit will be based on the averaged measurements 
from left and right arms. The baseline will be defined as the average of the values at 
screening and the pretreatment measurement on Day 1 of Study 115B. If only 1 pre-first 
dose measurement of sweat chloride is available, that measurement will be considered the 
baseline. 
Change (Absolute Change) from baseline will be calculated as post baseline value − baseline 
value. 
Relative change from baseline will be calculated and presented in percentage as 100 × (post 
baseline value − baseline value)/baseline value. 


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12.3.2 
Background Characteristics 
Treatment Cohort 
Summary will be provided overall and by the initial dosing groups (LUM 100 mg/ 
IVA 125 mg q12h; LUM 150 mg/IVA 188 mg q12h) as supplementary information. 
12.3.2.1 
Subject Disposition 
Numbers of the following categories for the population will be provided: 
• All Subjects Set 
• 116 All Subjects Set  
• Safety Set 
• 116 Safety Set 
• FAS 
• LCI Substudy Set 
• 116 LCI Substudy Set 
Treatment Cohort 
Subject disposition categories will be summarized for Study 116 based on the 116 Safety Set. 
Numbers and percentages of subjects will be provided with the number in the 116 Safety Set as 
denominator. The number of subjects enrolled but never dosed in Study 116 will be provided 
without a percentage. 
• Enrolled but never dosed (only showing number of subjects) 
• Completed treatment 
• Prematurely discontinued treatment and the reasons for discontinuations 
• Completed study (any subject who has completed the Safety Follow-up Visit) 
• Prematurely discontinued the study and the reasons for discontinuations 
• Last scheduled on treatment visit completed for subjects who discontinued treatment 
A similar disposition table will be provided based on the 116 LCI Substudy Set. 
Observational Cohort 
Subject disposition will be listed based on all subjects enrolled in the Study 116 Observational 
Cohort.  
12.3.2.2 
Demographics and Baseline Characteristics 
Treatment Cohort 
Demographics, baseline characteristics, and medical history will be summarized with respect to 
the start of Study 115B overall and by initial dosing of Study 115B separately for the 116 Safety 
Set, and the 116 LCI Substudy Set.  


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Important protocol deviations/violations will be provided as a subject data listing only based on 
the 116 All Subjects Set. The rules used to define the important protocol deviations/violations 
will be provided in the SAP. 
Observational Cohort 
Demographics and baseline characteristics will be listed with respect to the start of Study 115B 
overall using all subjects enrolled in the Observational Cohort.  
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced and categorized as the following:  
• Prior medication: medication continued or newly received before initial dosing of study 
drug in the previous study.  
• Post-treatment medication: any medication continued or newly received after the end of the 
Treatment-emergent Period of the Cumulative Study Period 
• Concomitant medication: medication continued or newly received during the 
Treatment-emergent Period of the Cumulative Study Period.  
A given medication can be classified as a prior medication, concomitant medication, or a 
post-treatment medication; both concomitant and post-treatment; both prior and concomitant; 
prior, concomitant, and post-treatment. Incidence of prior medication will be summarized based 
on the 116 Safety Set by 1) preferred name; 2) anatomic class (ATC) level 1; ATC level 2; and 
preferred name. 
Incidence of concomitant medication as well as the exposure adjusted number of concomitant 
medication will be summarized based on the Safety Set for the Cumulative Study Period by 
1) preferred name; 2) ATC level 1; ATC level 2; and preferred name.  
All medications in the Cumulative Study Period will be listed for each subject.   
12.3.2.4 
Study Drug Exposure and Compliance 
Study Drug Exposure 
Duration of study drug exposure is defined as follows: last dose date of the Cumulative Study 
Period − first dose date of the Cumulative Study Period + 1 day, regardless of any dose 
interruptions.  
Duration of study drug exposure as well as number of sticks administered defined as (total 
number of sticks dispensed) − (total number of sticks returned) will be summarized descriptively 
overall based on Safety Set for the Cumulative Study Period. Additionally, the total duration of 
treatment exposure, defined as the sum of the subject’s duration of treatment exposure and 
expressed in subject-years, will be provided. Duration of exposure will also be summarized as a 
categorical variable. 
Study Drug Compliance 
Study drug compliance will be calculated as follows: 100 × (1 − [total number of days of study 
drug interruption in the Cumulative Study Period] / [duration of study drug exposure in the 
Cumulative Study Period). The total number of days of study drug interruption is defined as the 


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sum of (number of days of each study drug interruption in the Cumulative Study Period), where 
number of days of each study drug interruption is defined as the interruption end date − the 
corresponding interruption start date + 1. 
Treatment compliance percentages will be summarized descriptively (number, mean, SD, 
median, minimum, and maximum) overall based on Safety Set for the Cumulative Study Period. 
The number and percentage of subjects whose compliance is <80% or ≥80% will be 
summarized. 
12.3.3 
Pharmacodynamic Analysis 
12.3.3.1 
Analysis of Primary Variables 
Not applicable 
12.3.3.2 
Analysis of Secondary Pharmacodynamic Endpoints 
12.3.3.2.1 
Absolute Change from Baseline: Sweat Chloride, BMI, BMI-for-Age Z-
score, Weight, Weight-for-Age Z-score, Stature, Stature-for-Age Z-
score, and LCI 
For the secondary endpoint of sweat chloride, raw and absolute change from the Cumulative 
Study Baseline in sweat chloride at each visit in the Cumulative Study Period (including all 
measurements from Study 115B and Study 116, including the Safety Follow-up Visit of 
Study 116, both on-treatment measurements and measurements after treatment discontinuation), 
will be summarized based on FAS. Descriptive statistics including number of subjects, mean, 
SD, SE, median, minimum, and maximum, along with the 95% CI and within-group P value 
based on Normal approximation, will be provided for the absolute change from the Cumulative 
Study Baseline. The mean (95% CI) of the absolute change from baseline will be plotted. The 
following secondary endpoints will be summarized similarly as described above for sweat 
chloride based on FAS: 
• Absolute change from Cumulative Study Baseline in BMI and BMI-for-age z-score 
• Absolute change from Cumulative Study Baseline in weight and weight-for-age z-score 
• Absolute change from Cumulative Study Baseline in stature and stature-for-age z-score 
• Absolute change from Cumulative Study Baseline in LCI2.5  
• Absolute change from Cumulative Study Baseline in LCI5.0 
12.3.3.2.2 
Analysis of Pulmonary Exacerbation-related Other Secondary 
Pharmacodynamic Variables 
• Time-to-first pulmonary exacerbation: Time-to-first pulmonary exacerbation, defined as 
days from study drug initiation in the previous study to first pulmonary exacerbation, will be 
analyzed using Kaplan-Meier method based on Safety Set for the Cumulative Study Period. 
Cumulative incidence of pulmonary exacerbation will be summarized and plotted. Subjects 
without an exacerbation will be considered censored at the end date of the Cumulative Study 
Period.  


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• Number of pulmonary exacerbations: The number of pulmonary exacerbations starting 
during the Cumulative Study Period (including both on-treatment events and events after 
treatment discontinuation), normalized by the time spent in the Cumulative Study Period (last 
date in the Cumulative Study Period – first date in the Cumulative Study Period + 1), will be 
summarized for the Cumulative Study Period. 
• Number of CF-related hospitalizations through last visit: For number of CF-related 
hospitalizations occurring during the Cumulative Study Period, the analysis will be similar to 
the analysis of number of pulmonary exacerbations. 
12.3.3.2.3 
Absolute Change in FE-1 Levels From Baseline  
Raw values and absolute change from Cumulative Study Baseline in FE-1 levels at each visit in 
the Cumulative Study Period will be summarized descriptively based on FAS, similar to sweat 
chloride. 
12.3.3.2.4 
Absolute Change in Serum Levels of IRT From Baseline  
Raw values and absolute change from Cumulative Study Baseline in IRT at each visit in the 
Cumulative Study Period will be summarized descriptively based on FAS, similar to sweat 
chloride. 
12.3.3.2.5 
Change in Microbiology from Baseline 
Raw values and absolute change from Cumulative Study Baseline in microbiology at each visit 
in the Cumulative Study Period will be summarized descriptively based on FAS, similar to sweat 
chloride. Percentage of subjects with cultures positive at each visit in the Cumulative Study 
Period will be summarized descriptively based on the FAS for each possibly-detected organism.  
Additional analysis may be added in the SAP, if any. 
12.3.4 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (serum chemistry, hematology, coagulation studies, and urinalysis) 
• ECGs (standard 12-lead) 
• Vital signs 
• Pulse oximetry 
• OEs 
• Spirometry (subjects ≥3 years age at screening in Study 115B) 


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The safety analysis will be based on the Safety Set. All listings will be provided based on the All 
Subjects Set. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or 
post-treatment AEs.  
• Pretreatment AEs: AEs occurred before initial dosing of study drug in the previous study.  
• TEAE: any AE that increased in severity or that was newly developed during the 
Treatment-emergent Period of the Cumulative Study Period.  
• Post-treatment TEAE: any AE that increased in severity or that was newly developed after 
the end of the Treatment-emergent Period of the Cumulative Study Period. 
AEs with missing or partial start dates, if there is no clear evidence that the AEs started before or 
after study treatment, then the AEs will be classified as TEAEs. 
All TEAE summaries will be described, using number and percentages of subjects, as well as 
number of events per 100 patient-years (number of events adjusted for the total duration of 
exposure) for the Cumulative Study Period. An overview of the TEAE profile will be provided, 
including total number of TEAEs, with number and percentage of subjects as well as number of 
events per 100 patient-years for the following categories: (1) all TEAEs; (2) Grade 3/4 TEAEs; 
(3) TEAEs by relationship; (4) TEAEs by maximum severity; (5) TEAEs leading to treatment 
interruption; (6) TEAEs leading to treatment discontinuation; (7) serious TEAEs; (8) related 
serious TEAEs; and (9) TEAEs leading to death.  
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs  
• Grade 3/4 TEAEs 
• TEAEs by relationship  
• TEAEs by maximal severity 
• TEAEs leading to treatment interruption 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
• Frequently reported TEAEs 
Summaries will be presented by MedDRA system organ class (SOC) and preferred term (PT) 
using frequency counts and percentages and number of events per 100 patient-years (i.e., number 
and percentage of subjects with an event as well as exposure-adjusted number of events). When 
summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once, only the maximum 
severity level will be presented in the severity summaries, and the worst/highest relationship 


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level in the relationship summaries. In addition, listings containing individual subject data for all 
TEAEs leading to treatment interruption, TEAEs leading to treatment discontinuation, deaths, 
and SAEs will be provided separately. All AEs, including pre- and post-treatment AEs, will be 
presented in individual subject data listings. 
A listing of SAEs for the Observational Cohort will be provided based on all subjects enrolled in 
the Observational Cohort. 
12.3.4.2 
Clinical Laboratory Assessments 
For the laboratory measurements, the raw values and change from Cumulative Study Baseline of 
the continuous hematology and chemistry results will be summarized in SI units at each visit in 
the Cumulative Study Period. 
For hematology and chemistry, the number and percentage of subjects with abnormal low 
(<lower limit of normal [LLN]) value and with abnormal high (>ULN) value at each scheduled 
time point in the Cumulative Study Period will be summarized. 
The number and percentage of subjects with at least 1 categorical change during the Treatment-
emergent Period of the Cumulative Study Period will be provided. 
The categorical criteria will be provided in the SAP. 
Results of urinalysis will be listed in individual subject data listings only. In addition, a listing 
containing individual subject hematology, chemistry, and coagulation values outside the 
reference ranges will be provided. This listing will include data from scheduled and unscheduled 
time points. 
12.3.4.3 
Electrocardiogram 
For the ECG measurements, a summary of raw values and change from Cumulative Study 
Baseline values will be provided at each scheduled time point of the Cumulative Study Period, 
for the following standard digital ECG measurements: PR, QT, and QT corrected for HR (QTc) 
intervals (Fridericia's correction [QTcF = QT/RR1/3], QRS duration, and HR. In addition, the 
mean value at each time point will be plotted for QTcF. 
The number and percentage of subjects with at least 1 categorical change during the 
Treatment-emergent Period of the Cumulative Study Period will be summarized. 
The categorical criteria will be provided in the SAP. 
The number and percentage of subjects with shift changes from Cumulative Study Baseline 
(normal/missing, not clinically significant, and potentially clinically significant according to 
overall ECG evaluation) to the worst ECG evaluation during the Treatment-emergent Period of 
the Cumulative Study Period will be summarized. 
12.3.4.4 
Vital Signs 
For the vital signs measurements, the raw values and change from Cumulative Study Baseline 
values will be summarized at each scheduled time point of the Cumulative Study Period: systolic 
and diastolic blood pressure (mm Hg), body temperature (oC), pulse rate (beats per minute), and 
respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 categorical change during the 
Treatment-emergent Period of the Cumulative Study Period will be summarized.  


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The categorical criteria will be provided in the SAP. 
12.3.4.5 
Pulse Oximetry 
For the pulse oximetry measurements, a summary of raw values and change from Cumulative 
Study Baseline values will be provided at each scheduled time point of the Cumulative Study 
Period for the percent of oxygen saturation by pulse oximetry.  
The number and percentage of subjects with shift changes from Cumulative Study Baseline 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the Treatment-emergent Period of the Cumulative Study Period will be 
summarized. 
12.3.4.6 
Ophthalmological Examinations  
OE findings will be presented as a data listing. 
12.3.4.7 
Spirometry 
Spirometry data will be summarized descriptively at each visit based on the Safety Set for 
subjects who are ≥3 years of age at screening in Study 115B. The raw values and absolute 
change/relative change from Cumulative Study baseline values will be summarized at each 
scheduled time point of the Cumulative Study Period. 
12.3.4.8 
Physical Examination 
PE findings will be presented as a data listing only. 
12.3.4.9 
Other Safety Analysis 
Not applicable 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
No interim analysis is planned but interim analyses may take place at any time during the study 
if warranted by the ongoing data, and/or deemed necessary by the internal Vertex team. 
12.3.5.2 
IDMC Analysis 
Details of the IDMC (Section 9.1.5) analysis will be provided in the IDMC Analysis Plan. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  


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An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following time points: 
• Withdrawal of consent 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 18 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 10 days or later following the last dose of study drug (see 
Section 9.1.2.3) 
NOTE: Only SAEs will be collected for the Observational Cohort. 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject’s source documents. The following data will be documented 
for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 


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• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity  
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
September 2016). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In 
considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in the 
CTCAE. The severity of an AE that does not appear in the CTCAE will be determined according 
to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject's medical record). 
 


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13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved With 
Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 


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13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject's life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
Global Patient Safety (GPS). In addition, all SAEs that occur after the Safety Follow-up Visit 
and are considered related to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 


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severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email:
 (preferred choice) 
Fax: 
  
Contact Telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. In addition, Vertex, or authorized designee, will be responsible for the submission of 
safety letters to central independent ethics committees (IECs).  
It is the responsibility of the investigator or designee to promptly notify the local institutional 
review board (IRB)/local IEC of all unexpected serious adverse drug reactions involving risk to 
human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 


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ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) and associated regulations an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 


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Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance  
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 


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13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a CD or other electronic media will be placed in the investigator’s study file. 
13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


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14 
REFERENCE  
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 26 September 2016. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2013 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2014. 
3 
Stern M, Wiedemann B, Wenzlaff P. From registry to quality management: the German 
Cystic Fibrosis Quality Assessment project 1995 - 2006. Eur Respir J. 2008;31(1):29-35. 
4 
Cystic Fibrosis Trust. UK Cystic Fibrosis Trust Annual Review 2010. Bromley, Kent, 
UK: Cystic Fibrosis Trust; 2012. 
5 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
6 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
7 
Vertex Pharmaceuticals Incorporated. Lumacaftor/Ivacaftor Investigator's Brochure, 
Version 2.0. Report date: 11 July 2016. 
8 
Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, et 
al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after 
newborn screening. J Pediatr. 2009;155(5):623-28. 
9 
ICH E11. Clinical Investigation of Medicinal Products in the Pediatric Population. 
20 July 2000. 
10 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99. 
11 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70. 
12 
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout 
and spirometry versus structural lung disease in cystic fibrosis. Thorax. 
2007;63(2):129-34. 
13 
Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection 
of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. 
Thorax. 2007;62(4):341-47. 
14 
Kent L, Reix P, Innes JA, Zielen S, Le Bourgeois M, Braggion C, et al. Lung clearance 
index: Evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 
2014;13(2):123-38. 
15 
Borowitz D, Baker SS, Duffy L, Baker RD, Fitzpatrick L, Gyamfi J, et al. Use of fecal 
elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr. 
2004;145(3):322-26. 
16 
Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, et al. 
Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected 
with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 
2010;303(17):1707-15. 
17 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
18 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43.  




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15.2 
Investigator Signature Page 
Protocol #:  
VX16-809-116 
Version #: 
1.1 
Version Date: 
10 October 2016 
Study Title: A Phase 3, Rollover Study to Evaluate the Safety of Long-term Treatment With 
Lumacaftor/Ivacaftor Combination Therapy in Subjects Aged 2 Years and Older With Cystic 
Fibrosis, Homozygous for the F508del-CFTR Mutation 
 
 
I have read Protocol VX16-809-116, Version 1.1, and agree to conduct the study according to its 
terms. I understand that all information concerning LUM/IVA and this protocol supplied to me 
by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 

SAP_001.pdf: 
Vertex Pharmaceuticals Incorporated 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan (Methods) 
For Final Analysis 
 
Protocol Number:  VX16-809-116 
 
 
A Phase 3, Rollover Study to Evaluate the Safety of Long-term 
Treatment With Lumacaftor/Ivacaftor Combination Therapy in 
Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous 
for the F508del-CFTR Mutation 
 
Author of SAP:  
  
 
Version: 1.0 
Version Date of SAP: 20 May 2019 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
 




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10.3.2.4 Absolute Change from Baseline in stature and stature-for-age z-score ............... 17 
10.3.2.5 Absolute change from Baseline in LCI2.5 and LCI5.0 ........................................... 18 
10.3.2.6 Analysis of Pulmonary Exacerbation-related Other Secondary 
Pharmacodynamic Variables ................................................................................ 18 
10.3.2.7 Absolute Change in FE-1 Levels From Baseline ................................................. 18 
10.3.2.8 Absolute Change in Serum Levels of IRT From Baseline................................... 19 
10.3.2.9 Analysis in Microbiology Cultures ...................................................................... 19 
 
 
10.4 Efficacy Analysis ............................................................................................................... 19 
10.5 Safety Analysis ................................................................................................................... 19 
10.5.1 
Adverse Events ........................................................................................................... 20 
10.5.2 
Clinical Laboratory ..................................................................................................... 21 
10.5.3 
Electrocardiogram ...................................................................................................... 21 
10.5.4 
Vital Signs .................................................................................................................. 22 
10.5.5 
Pulse Oximetry ........................................................................................................... 23 
10.5.6 
Ophthalmological Examinations ................................................................................ 23 
10.5.7 
Spirometry .................................................................................................................. 23 
10.5.8 
Physical Examination ................................................................................................. 23 
10.5.9 
Other Safety Analysis ................................................................................................. 23 
11 Summary of Interim and IDMC Analyses ............................................................................ 24 
11.1 Interim Analysis ................................................................................................................. 24 
11.2 IDMC Analysis ................................................................................................................... 24 
12 References ................................................................................................................................. 25 
13 List of Appendices ................................................................................................................... 26 
Appendix A: Schedule of Assessments ....................................................................................... 26 
Appendix B: Standards for Safety and Efficacy Variable Display in TFLs ................................ 32 
Appendix C: Analysis Visit Windows for Safety and  Pharmacodynamic Assessments ......... 33 
Appendix D: Imputation Rules for Missing Prior/Concomitant Medication Dates..................... 35 
Appendix E: Imputation Rules for Missing AE dates .................................................................. 36 
Appendix F: Criteria for Threshold Analysis .............................................................................. 37 
Appendix G: Details of GLI Equation for Calculating ppFEV1 .................................................. 40 
 
Appendix I:  Programmable Important Protocol Deviation Programming Rules (Based on the 
Clinical Database) .............................................................................................................. 42 
 


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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest  
ATC 
anatomic class 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator protein  
CI 
confidence interval 
CRF 
case report form 
DMC 
Data monitoring committee 
ECG 
electrocardiogram  
eCRF 
electronic CRF 
ETT 
early termination of treatment 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine 
codon corresponding to position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FE-1 
fecal elastase-1 
FEV1 
forced expiratory volume in 1 second 
GLI 
Global Lung Function Initiative  
HR 
heart rate 
ICF 
informed consent form 
IDMC 
independent data monitoring committee 
IPD 
important protocol deviation 
IRT 
immunoreactive trypsinogen  
IVA 
ivacaftor 
LCI 
lung clearance index 
LCI2.5 
number of lung turnovers required to reduce the end tidal inert gas 
concentration to 1/40th of its starting value 
LCI5.0 
number of lung turnovers required to reduce the end tidal inert gas 
concentration to 1/20th of its starting value 
LFT 
liver function test  
LLN 
lower limit of normal  
LUM 
lumacaftor 
Max 
maximum value 
Min 
minimum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
OE 
ophthalmological examination 
PD 
pharmacodynamics(s)  
PE 
physical examination  
ppFEV1 
percent predicted FEV1  
PR 
PR interval 
PT 
preferred term  
q12h 
every 12 hours 


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QRS 
the portion of an ECG comprising the Q, R, and S waves, together 
representing ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SD 
standard deviation 
SE 
standard error 
SI 
SI units (International System of Units)  
SOC 
system organ class 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary  
 




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4 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of study VX16-809-116 (Study 116) and 
is based on the:  
 approved clinical study protocol, dated 10 October 2016, Version 1.1  
 approved eCRF, dated 21 August 2017, v2.0 
Study 116 is a Phase 3, rollover study to evaluate the safety of long-term treatment with 
lumacaftor/ivacaftor (LUM/IVA) combination therapy in subjects aged 2 years and older with CF, 
homozygous for F508del . This study consists of a Treatment Cohort and an Observational Cohort. 
These two cohorts will be enrolled in parallel for Study VX15-809-115 (Study 115) subjects who 
meet the inclusion criteria. 
This SAP (Methods) documents the planned statistical methods and data presentations of final 
analysis for subjects who previously participated in Study 115 and enrolled in Study 116. It also 
documents additional analyses not prespecified in the protocol, but necessary for the scientific 
understanding of the drug entity. 
ICON has been contracted by Vertex to perform the statistical analysis. SAS® Software (SAS 
Institute, Cary, North Carolina, USA) Version 9.3 or higher will be used to generate all statistical 
outputs (tables, figures, listings and datasets).   
The SAP (Methods) for the final analysis will be finalized and approved before the final clinical 
database lock. Any changes made to the SAP Methods after the clinical database lock has occurred 
will be documented in the clinical study report for this study. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the long-term safety of LUM/IVA combination therapy in subjects aged 2 years and 
older with CF, homozygous for F508del 
5.2 
Secondary Objective 
To evaluate the pharmacodynamics (PD) of long-term LUM/IVA combination therapy in subjects 
aged 2 years and older with CF, homozygous for F508del 
5.3 
Other Objectives 
Not Applicable 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), changes in clinical laboratory 
values, electrocardiograms (ECGs), vital signs, pulse oximetry, ophthalmological examinations 
(OEs), and spirometry. 
6.2 
Secondary Endpoints 
The following endpoints will be analyzed using baseline values in the previous (parent) study (i.e., 
Study 115 Part B [Study 115B]): 
 Absolute change from baseline in sweat chloride 


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 Absolute change from baseline in body mass index (BMI) and BMI-for-age z-score 
 Absolute change from baseline in weight and weight-for-age z-score 
 Absolute change from baseline in stature and stature-for-age z-score 
 Time-to-first pulmonary exacerbation from baseline 
 Number of pulmonary exacerbations from baseline 
 Number of CF-related hospitalizations from baseline 
 Absolute change from baseline in fecal elastase-1 (FE-1) levels 
 Absolute change from baseline in serum levels of immunoreactive trypsinogen (IRT) 
 Change from baseline in microbiology cultures 
 Absolute change from baseline in lung clearance index LCI2.5 
 Absolute change from baseline in LCI5.0 
7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3, open-label, multicenter study in subjects aged 2 years and older with CF who are 
homozygous for the F508del-CFTR mutation and who participated in Study 115 and meet the 
inclusion criteria. Study 116 is designed to evaluate the long-term safety and PD of LUM/IVA 
combination therapy.  
This study consists of a Treatment Cohort and an Observational Cohort. These two cohorts will be 
enrolled in parallel as shown in Figure 7-1. 


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Figure 7-1  
Schematic of Study Design 
 
 
 
ETT: Early Termination of Treatment; IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
a 
Doses may be adjusted upward for changes in weight and age. See the rules for dose adjustments in Section 9.6 of the 
protocol. 
b 
Doses are those planned for Study 115B. Based on results from Study 115A and 115B, doses for subjects <6 years of 
age in Study 116 may be modified. 
c 
The Safety Follow-up Visit is required for 1) subjects who complete their ETT Visit <10 days after the last dose of 
LUM/IVA (Section 9.1.2.3 of the protocol); and 2) subjects who interrupt LUM/IVA treatment and complete their Week 
96 Visit <10 days after the last dose of LUM/IVA; it is not required for subjects who continue onto commercially-
available, physician-prescribed LUM/IVA within 2 weeks (± 4 days) of completing LUM/IVA treatment at the Week 96 or 
ETT Visit. 
d 
See Section 9.1.1 of the protocol for details regarding the timing of the Day 1 Visit. 
 
 


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7.2 
Sample Size and Power 
No formal sample size calculations have been performed. 
This is a long-term extension study that will enroll subjects rolled over from Study 115B. 
Approximately 56 subjects were potentially eligible to be enrolled in this rollover study. 
Assuming a 10% dropout rate in Study 115B, 50 subjects are expected to enroll in this study. 
7.3 
Randomization 
This is an open-label study. No randomization is planned.  
Subjects in the Treatment Cohort will be treated with LUM/IVA based on their weight and 
age. Subjects in the Observational Cohort will not receive LUM/IVA. 
7.4 
Blinding and Unblinding 
This is an open-label study. However, subjects and their legally appointed and authorized 
representative (e.g., parent or legal guardian) should not be informed of their study-related 
spirometry, sweat chloride, and LCI results during the study even if the subject permanently 
discontinued treatment. 
8 
ANALYSIS SETS 
Enrolled subjects are those who signed informed consent/assent form and had an enrollment 
date on the CRF. 
116 All Subjects Set is defined as all subjects who were enrolled or exposed to any amount 
of study drug in the Study 116 Treatment Cohort. 
8.1 
Efficacy Sets 
Full Analysis Set (FAS): The FAS will include all subjects who were enrolled and exposed 
to any amount of study drug in Study 115B. 
116 Full Analysis Set (116 FAS): The 116 FAS will include all subjects who were enrolled 
and exposed to any amount of study drug in Study 116 Treatment Cohort. 
8.2 
Safety Set 
116 Safety Set: The 116 Safety Set will include all subjects dosed in Study 115B who are 
exposed to any amount of study drug in the Study 116 Treatment Cohort. 
8.3 
Other Analysis Set 
116 LCI Substudy Set: The 116 LCI Substudy Set will include all subjects who signed 
informed consent/assent to the optional LCI Substudy and are enrolled and exposed to any 
amount of study drug in the Study 116 Treatment Cohort.  


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9 
ANALYSIS PERIODS 
9.1 
Current Study Period 
The Current Study Period starts from the first dose date of study drug in Study 116 to the 
last day in Study 116. 
The Treatment-Emergent Period for the Current Study Period starts on or after the first 
dose date of study drug in Study 116 to 14 days (inclusive) after the last dose of study drug in 
Study 116 or up to the last day in Study 116, whichever occurs first.  
9.2 
Cumulative Study Period 
The Cumulative Study Period starts from the first dose date of study drug in Study 115B to 
the last day in Study 116, regardless of  
1) the planned 2-week Washout Period in Study 115B; and/or 
2) the rollover gap between Study 115B and Study 116 (if any).  
For subjects not enrolled in Study 116, the Cumulative Study Period will start from the first 
dose date of study drug in Study 115B to the last day in Study 115B. 
10 
STATISTICAL ANALYSIS 
10.1 
General Considerations 
For the Treatment Cohort, all individual subject data will be presented in data listings based 
on the 116 All Subjects Set. 
For the Observational Cohort, listings will be provided only for disposition, demographics, 
and serious adverse events (SAEs). Listings will be provided based on all subjects enrolled in 
the Observational Cohort. 
Treatment Cohort 
Continuous variables will be summarized using descriptive summary statistics: number of 
subjects, mean, standard deviation (SD), standard error (SE), median, minimum value (Min), 
and maximum value (Max). Precisions of the summary for continuous variables are detailed 
in Appendix B.  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place.  
Baseline: The baseline value is defined as the most recent non-missing measurement 
(scheduled or unscheduled) before intake of the first dose of study drug in Study 115B, 
except specified otherwise.  
 For ECGs, the baseline will be defined as the average of the pretreatment measurements 
on the start of Study 115 B.  
 For LCI-related parameters, the values at each visit will be calculated from the 
technically acceptable replicates. The baseline of LCI will be the most recent non-


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missing value calculated from the technically acceptable replicates before the initial 
administration of study drug in the Study 115B. 
 For sweat chloride, the values at each visit will be based on the averaged measurements 
from left and right arms. The baseline is defined as the average of the values at screening 
and the pretreatment measurement on Day 1 of Study 115B. For assessments where there 
is only 1 pre-first dose sweat chloride measurement available, that measurement will be 
considered the baseline. 
Change (Absolute Change) from baseline will be calculated as  
Post-baseline value – Baseline value. 
Relative change from baseline will be calculated and presented in percentage as  
100 × (Post-baseline value − Baseline value)/Baseline value. 
Unscheduled visits: Unscheduled visit measurements will be included in the analysis as 
follows: 
 In scheduled visit windows per specified visit windowing rules.  
 In the derivation of baseline measurements. 
 In individual subject data listings as appropriate. 
Visit windowing rules: Appendix C defines the visit window mapping rules to derive the 
analysis visits for study 116. 
Repeated observations within the same visits window: 
 For all PD parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used. If there are no measurements at the scheduled 
visit, then 1) the record closest to the target day will be used; or 2) if there are multiple 
records with the same distance to the target day, the latest record will be used.  
 For all safety parameters, if there are multiple measurements within a visit window, then 
1) the record closest to the target day will be used; or 2) if there are multiple records with 
the same distance to the target day, the latest record will be used. 
BMI, weight, and stature will follow visit window rules for PD parameters when being 
considered as PD endpoints; they will follow visit window rules for safety parameters when 
being considered as safety endpoints. Their corresponding z-scores will be assigned to 
analysis visits same as BMI, weight, and stature, respectively. Spirometry will follow the PD 
parameter window rule.  
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless specified otherwise. 
Multiplicity: No multiplicity adjustment will be performed and there is no hypothesis 
testing. 


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10.2 
Background Characteristics  
Treatment Cohort 
10.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized: 
 116 All Subjects Set 
 Full Analysis Set 
 116 Full Analysis Set 
 116 Safety Set 
 116 LCI Substudy Set 
The number and percentages of subjects will be provided with the number in the 116 Safety 
Set as denominator. The number of subjects enrolled but never dosed in Study 116 will be 
provided without a percentage. 
 Enrolled but never dosed (only showing number of subjects) 
 Completed treatment 
 Prematurely discontinued treatment and the reasons for discontinuations 
 Last scheduled on-treatment visit completed for subjects who discontinued treatment 
 Completed study (any subject who has completed the Safety Follow-up Visit) 
 Prematurely discontinued the study and the reasons for discontinuations 
Subjects prematurely discontinue treatment before Week 96 due to commercial drug 
available will be captured in the CRF pages, with primary reason for dosing ended under the 
“Other” category of “Discontinued” and free text to describe treatment discontinuation due to 
commercial drug available. 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation.  
10.2.2 
Demographics and Baseline Characteristics 
Treatment Cohort 
Demographics, baseline characteristics, and medical history will be summarized. 
Demographic data (at Study 115B baseline) will include the following: 
 Age at baseline (months) 
 Age Group at Baseline (< 3 and ≥ 3 years) 
 Sex (female and male) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 


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 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Not Collected per Local Regulations and 
Other) 
Baseline characteristics will include the following: 
 Weight (kg) 
 Weight Group at Baseline (<14 kg and ≥14 kg) 
 Stature (cm) 
 BMI (kg/m2) 
 Weight-for-age z-score   
 Stature-for-age z-score   
 BMI-for-age z-score  
 Sweat Chloride 
 FEV1 (L) 
 Percent predicted FEV1 (ppFEV1, percentage points) 
 LCI2.5 and LCI5.0  
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). All demographic and baseline characteristic data will be listed. 
10.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary (WHODD, March 2018, Format B3 or higher) and categorized as the following: 
 Prior medication: any medication continued or newly received before initial dosing of 
study drug in Study 115B. 
 Concomitant medication: medication continued or newly received during the 
Treatment-emergent Period of the Current Study Period. 
 Post-treatment medication: medication continued or newly received after the end of the 
treatment-emergent Period of the Current Study Period. 
A given medication can be classified as a prior medication, concomitant medication, or a 
post-treatment medication; both concomitant and post-treatment; both prior and concomitant; 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and it cannot be determined whether it was taken before initial 
dosing, concomitantly, or more than 14 days after the last dose of study drug, it will be 
considered as prior, concomitant, and post-treatment. 
Incidence of prior medications will be summarized based on the 116 Safety Set by 1) 
Preferred name; 2) Anatomic class (ATC) level 1, ATC level 2, and preferred name. 


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Incidence of concomitant medications will be summarized based on 116 Safety Set for 
Current Study Period by 1) Preferred name; 2) Anatomic class (ATC) level 1, ATC level 2, 
and preferred name.  
All medications in the Current Study Period will be listed for each subject. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix D. 
10.2.4 
Study Drug Exposure  
Study drug exposure will be summarized for the Current Study Period based on 116 Safety 
Set.  
Duration of study drug exposure is defined as: last available dose date of the Current Study 
Period − first dose date of the Current Study Period + 1 day, regardless of unplanned 
interruptions. 
Duration of study drug exposure as well as number of sticks/tablets administered defined as 
(total number of sticks and/or tablets dispensed) − (total number of sticks and/or tablets 
returned) will be summarized descriptively. Additionally, the total duration of treatment 
exposure, defined as the sum of the subject’s duration of treatment exposure and expressed in 
subject-years (1 subject with 48 weeks of treatment exposure is considered 1 subject-year) 
will be provided.  
Duration of exposure will also be summarized as a categorical variable (>0 to ≤8 weeks, >8 
to ≤24 weeks, >24 to ≤48 weeks, >48 to ≤72 weeks, >72 to ≤96 weeks, >96 weeks). 
10.2.5 
Study Drug Compliance  
Study drug compliance will be summarized for the Current Study Period based on 116 Safety 
Set.  
Study drug compliance will be calculated for the Current Study Period as follows: 100 × (1 − 
[Total number of days of study drug interruption in Current Study Period] / [Duration of 
study drug exposure in Current Study Period + Total number of days study drug interrupted 
after last dose in Current Study Period, if any]). The total number of days of study drug 
interruption is defined as the sum of (number of days of each study drug interruption in the 
Current Study Period), where number of days of each study drug interruption is defined as 
the interruption end date − the corresponding interruption start date + 1. 
Treatment compliance percentages will be summarized descriptively (number, mean, SD, 
median, minimum, and maximum). The number and percentage of subjects whose 
compliance is <80% or ≥80% will be also be summarized. 
In calculating the total number of days of study drug being interrupted, only the interruptions 
with duration of ≥3 days will be considered. An interruption with duration of < 3 days will 
not be considered in the calculation. 
Study drug exposure and compliance data for each subject will also be listed. 


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10.2.6 
Important Protocol Deviations  
IPDs will be identified from the clinical database and/or site deviation log. Important 
protocol deviations will be provided as a subject data listing, indicating the source (clinical 
database versus site deviation log). All potential IPDs from both sources will be reviewed by 
the study team before the final database lock to determine IPD status. 
The rules for identifying programmable IPDs based on the clinical database are defined in 
Appendix I. 
IPDs will be provided as a subject data listing based on the 116 All Subjects Set. 
10.3 
Pharmacodynamic Analysis 
10.3.1 
Analysis of Primary Endpoints 
Not applicable. 
10.3.2 
Analysis of Secondary Pharmacodynamic Endpoints 
10.3.2.1 
Absolute Change from Baseline in Sweat Chloride 
For each subject and at each time point, 2 sweat chloride measurements will be collected: 
1 from the right arm and 1 from the left arm. Of the 2 measurements, only the sweat chloride 
value obtained from a sample volume ≥15 µL will be included in any analysis (i.e., a sample 
volume of 15 µL is required for testing and therefore any samples with volumes <15 µL will 
not be included in the analysis). The sweat chloride results for the left and right arms will be 
averaged and used in the analysis if the sweat chloride values for the left and right arms are 
both ≥15 µL; if only 1 arm is ≥15 µL, then only that value will be used. Any sweat chloride 
values outside of the reportable range (i.e. <10 mmol/L or >160 mmol/L) will not be 
included in the analysis.  
Raw values and absolute change from parent study baseline in sweat chloride at each visit in 
the Current Study Period (including all measurements from Study 116, including the Safety 
Follow-up Visit of Study 116, both on-treatment measurements and measurements after 
treatment discontinuation), will be summarized for the overall group based on 116 FAS. 
Descriptive statistics including number of subjects, mean, SD, SE, median, minimum, and 
maximum will be provided for the absolute change from parent study baseline. In addition, 
the 95% CI and the within-group P value based on Normal approximation will be provided. 
The mean (95% CI) of the absolute change from parent study baseline will be plotted. 
10.3.2.2 
Absolute Change from Baseline in BMI/BMI-for-Age Z- score 
BMI z-score will be calculated by using Centers for Disease Control and Prevention (CDC) 
growth charts. The BMI z-score will be calculated as follows: 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
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

























0
,
ln
0
,
1
L
S
M
X
L
LS
M
X
z
L
 
Where X is the derived BMI value in kg/m2 based on the raw weight and raw height and L, 
M, and S are selected from the CDC BMI-for-age chart by subject sex and age. The 
BMIAGE file contains these parameters by sex (1=male, 2=female) and age; it is available 
at: http://www.cdc.gov/growthcharts/percentile_data_files.htm. Additionally, SAS code for 
calculating percentiles and z-scores is available at:  
http://www.cdc.gov/growthcharts/computer_programs.htm. 
NOTE: The CDC BMI-for-age charts are designed for use in pediatric populations (2 to 
20 years of age). 
Raw values and absolute change from parent study baseline in BMI and BMI-for-age z-score 
at each visit in the Current Study Period will be summarized descriptively. The 95% CI based 
on Normal approximation will also be provided. The mean (95% CI) of the absolute change 
from parent study baseline will be plotted.  
10.3.2.3 
Absolute Change from Baseline in Weight, Weight-for-Age Z-
score 
The calculation of weight z-score is similar to that of BMI z-score (using the CDC growth 
charts and the derivation described above). Using the same equation above, X in the equation 
is the collected weight and L, M, and S parameters are selected from the CDC weight-for-age 
chart. The WTAGE file contains these parameters by sex and age; it is available at the 
website http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
NOTE: The CDC growth charts are designed for use in pediatric populations (2 to 20 years 
of age).   
Weight and weight-for-age z-score will be analyzed in a similar way to BMI and BMI-for-
age z-score. 
10.3.2.4 
Absolute Change from Baseline in stature and stature-for-age z-
score 
The calculation of stature z-score is similar to that of BMI z-score (using the CDC growth 
charts and the derivation described above). Using the same equation above, X in the equation 
is the collected stature and L, M, and S parameters are selected from the CDC stature -for-age 
chart. The STATAGE file contains these parameters by sex and age; it is available at the 
website http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
NOTE: The CDC growth charts are designed for use in pediatric populations (2 to 20 years 
of age). 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
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Stature and stature-for-age z-score will be analyzed in a similar way to BMI and BMI-for-age 
z-score. 
10.3.2.5 
Absolute change from Baseline in LCI2.5 and LCI5.0 
The LCI assessment at scheduled visits will be performed in multiple replicates. The LCI 
values at each visit included in the analysis will be the value calculated from the technically 
acceptable washout replicates.  
When there is only one LCI value considered acceptable by the LCI central reader, the value 
will NOT be used. The assessment for that subject at the corresponding visit will not be 
included in the analysis; when there are at least 2 LCI values considered acceptable by the 
LCI central reader, the arithmetic mean of the values from the accepted trials will be 
calculated as the value at the corresponding visit. 
LCI2.5 and LCI5.0 will be analyzed in a similar way to BMI and BMI-for-age z-score.  
10.3.2.6 
 Analysis of Pulmonary Exacerbation-related Other Secondary 
Pharmacodynamic Variables 
Time-to-first pulmonary exacerbation: Time-to-first pulmonary exacerbation, defined as 
days from study drug initiation in the Study 115B to first pulmonary exacerbation, will be 
analyzed using Kaplan-Meier (KM) method based on the FAS for the Cumulative Study 
Period. Cumulative incidence of pulmonary exacerbation will be summarized for the overall 
group. Subjects without an exacerbation will be considered censored at the end date of the 
Cumulative Study Period. 
Number of pulmonary exacerbations: The number of pulmonary exacerbations starting 
during the Cumulative Study Period (including both on-treatment events and events after 
treatment discontinuation), normalized by the time spent in the Cumulative Study Period (last 
date in the Cumulative Study Period – first date in the Cumulative Study Period + 1), will be 
summarized for the overall group based on the FAS. 
 
Number of CF-related hospitalizations through last visit: The number of CF-related 
hospitalizations occurring during the Cumulative Study Period (including both on-treatment 
events and events after treatment discontinuation), normalized by the time spent in the 
Cumulative Study Period (last date in the Cumulative Study Period – first date in the 
Cumulative Study Period + 1), will be summarized for the overall group based on the FAS. 
10.3.2.7 
 Absolute Change in FE-1 Levels From Baseline 
 
The raw values and absolute change from parent study baseline in FE-1 will be summarized 
at each scheduled visit during the Current Study Period for the overall group based on the 
116 FAS. In addition, the number and percentage of subjects with shift changes from parent 
study baseline [<15 µg/g, >=15 µg/g to <200 µg/g (consistent with pancreatic insufficient), 
and >=200 µg/g (consistent with pancreatic sufficient)] at each visit and at any visits (<15 
µg/g, >=15 µg/g to <200 µg/g, and >=200 µg/g) in the Current Study Period will be 
provided. A spaghetti plot of the FE-1 values will also be provided including Study 115B 
baseline, and visits in the Current Study Period. 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
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10.3.2.8 
Absolute Change in Serum Levels of IRT From Baseline 
The raw values and absolute change from parent study baseline in IRT will be summarized at 
each scheduled visit during the Current Study Period for the overall group based on the 116 
FAS. A spaghetti plot of the IRT values will also be provided including Study 115B baseline, 
and visits in the Current Study Period. 
10.3.2.9 
Analysis in Microbiology Cultures 
The presence of bacteria will be descriptively summarized by subjects’ counts and 
percentages. Number and percentage of subjects with microbiology cultures in each 
category during the Current Study Period will be summarized descriptively by visit based on 
the 116 FAS, for each possibly-detected organism. 
10.4 
Efficacy Analysis  
 Not Applicable.  
10.5 
Safety Analysis 
Observational Cohort 
Listings of SAEs will be provided based on all subjects enrolled in the Observational Cohort. 
Treatment Cohort 
Evaluating safety of long-term LUM/IVA treatment in the Treatment Cohort is the primary 
objective of this study. The overall safety profile of study drug will be assessed in terms of 
the following safety and tolerability endpoints: 
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (serum chemistry, hematology, coagulation studies and 
urinalysis) 
 ECGs (standard 12-lead) 
 Vital signs 
 Pulse oximetry 
 OEs 
 Spirometry (subjects ≥3 years age at screening in Study 115B) 
The safety analysis will be performed based on the 116 Safety Set for the Current Study 
Period. Only descriptive summary statistics of safety data will be provided (i.e., no statistical 
hypothesis testing will be performed). All listings will be provided based on the 116 All 
Subjects Set. 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
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The safety summaries described in the sections below will be performed for the Treatment 
Cohort based on the Current Study Period only.  
10.5.1 
Adverse Events  
For analysis purposes, AEs will be classified as TEAEs, or post-treatment AEs. 
 TEAE: any AE that increased in severity or that was newly developed during the 
Treatment-emergent Period of the Current Study Period. 
 Post-treatment AE: any AE that increased in severity or that was newly developed after 
the end of the Treatment-emergent Period of the Current Study Period. 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study treatment, then the AEs will be classified as TEAEs. Details for 
imputing missing or partial start dates of AEs are described in Appendix E. 
TEAE summaries will be presented using number and percentages of subjects for the Current 
Study Period based on 116 Safety Set. 
An overview of the TEAE profile will be provided, including total number of TEAEs, with 
number and percentage of subjects for the  following categories: 1) all TEAEs; 2) Grade 3/4 
TEAEs; 3) TEAEs by relationship; 4) TEAEs by maximum severity; 5) TEAEs leading to 
treatment interruption; 6) TEAEs leading to treatment discontinuation; 7) serious TEAEs; 8) 
serious TEAEs related to study drug; and 9) TEAEs leading to death. 
AE summary tables will be presented for TEAEs only and will include the following: 
 All TEAEs  
 Grades 3/4 TEAEs 
 TEAEs by relationship to study drug 
 TEAEs by maximal severity 
 TEAEs leading to treatment interruption 
 TEAEs leading to treatment discontinuation 
 Serious TEAEs 
 Serious TEAEs related to study drug 
 TEAEs leading to death 
 Frequently reported TEAEs (>=5% at the preferred term level for the overall column) 
Summaries will be presented by MedDRA SOC and PT using frequency counts and 
percentages (i.e., number and percentage of subjects). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, only the maximum severity level will be presented in 
the severity summaries, and the worst/highest relationship level in the relationship 
summaries. 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
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In addition, listings containing individual subject data for all TEAEs leading to treatment 
interruption, TEAEs leading to treatment discontinuation, deaths, and SAEs will be provided 
separately. All AEs, including pre- and post-treatment AEs, will be presented in individual 
subject data listings. 
Analysis of AEs of special interest (AESI):  
Three categories of AESI are defined: elevated transaminases, respiratory symptom AESI 
and respiratory event AESI. Treatment-emergent AESIs will be summarized by 
 Number and percentage of subjects by PT 
 Number and percentage of subjects by maximum severity 
 Summary of duration of events (days) with descriptive summary 
 Summary of time-to-first onset (relative to first dose date) 
 Number and percentage of subjects with 1) TEAE leading to treatment interruption; 2) 
TEAE leading to treatment discontinuation; 3) serious TEAEs; 4) related serious TEAEs; 
and 5) TEAE leading to death. 
10.5.2 
Clinical Laboratory 
For the laboratory measurements, the raw values and change from parent study baseline of 
the continuous hematology and chemistry results will be summarized in SI units at each visit 
in the Current Study Period (including all measurements from Study 116) for the overall 
group based on the 116 Safety Set.  
For hematology and chemistry, the number and percentage of subjects with abnormal low 
(<lower limit of normal [LLN]) value and with abnormal high (>ULN) value at each 
scheduled time point in the Current Study Period will be summarized for the overall group 
based on the 116 Safety Set.  
The number and percentage of subjects meeting the defined threshold criteria during the 
Treatment-emergent Period of the Current Study Period will be provided based on the 116 
Safety Set. The threshold criteria are provided in Appendix F. 
Results of urinalysis will be listed in individual subject data listings only. In addition, a 
listing containing individual subject hematology, chemistry, and coagulation values outside 
the reference ranges will be provided. This listing will include data from scheduled and 
unscheduled time points. 
10.5.3 
Electrocardiogram 
For the ECG measurements, a summary of raw values and change from parent study baseline 
will be provided at each scheduled time point of the Current Study Period (including all 
measurements from Study 116) based on the 116 Safety Set for the overall group, for the 
following standard digital ECG measurements: RR, PR, QT, and QT corrected for HR (QTc) 
intervals (Fridericia's correction [QTcF = QT/RR1/3], QRS duration, and HR. In addition, the 
mean value at each time point will be plotted for QTcF.  


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
Vertex Pharmaceuticals Incorporated 
 
The number and percentage of subjects meeting the defined threshold criteria during the 
Treatment-emergent Period of the Current Study Period will be summarized based on 116 
Safety Set. The threshold criteria are provided in Appendix F. 
The number and percentage of subjects with shift changes from parent study baseline 
(normal/missing, not clinically significant, and potentially clinically significant according to 
overall ECG evaluation) to the worst ECG evaluation during the Treatment-emergent Period 
of the Current Study Period will be summarized based on 116 Safety Set.  
Listings will be provided for the ECG measurements. 
10.5.4 
Vital Signs 
For the vital signs measurements, the raw values and change from parent study baseline 
values will be summarized at each scheduled time point of the Current Study Period 
(including all measurements from Study 116) based on the 116 Safety Set: systolic and 
diastolic blood pressure (mm Hg), body temperature (oC), pulse rate (beats per minute), 
respiratory rate (breaths per minute), as well as weight, stature, and BMI.  
The number and percentage of subjects meeting the defined threshold criteria during the 
Treatment-emergent Period of the Current Study Period will be summarized based on 116 
Safety Set. The threshold criteria are provided in Appendix F.  
Potentially abnormal SBP and DBP by their percentiles adjusted for sex, age and stature will 
be provided, including 
 Number and percentage of subjects with categories: ≥90%-<95%, ≥95%-<99% + 5 
mmHg and ≥99% + 5 mmHg during the treatment-emergent period of the Current Study 
Period 
 Number and percentage of subjects with SBP and DBP percentiles ≥95% once and twice 
during the treatment-emergent period of the Current Study Period 
 Number and percentage of subjects with SBP and DBP percentiles ≥95% at each visit in 
the Current Study Period 
The stature adjustment will be based on stature-for-age z-scores and their corresponding 
percentiles using the standard normal distribution (Appendix H). The stature percentiles will 
be further mapped per the following rules: 
Table 10-1 
Grouped Percentiles for stature-for-age Z-scores 
Calculated Percentiles (%) 
Grouped Percentiles (%) 
0 – <7.5 
5 
7.5 – <17.5 
10 
17.5 – <37.5 
25 
37.5 – <62.5 
50 
62.5 – <82.5 
75 
82.5 – <92.5 
90 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
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92.5 – 100 
95 
The sex and age-adjusted normal range for SBP and DBP for each grouped stature 
percentiles is based on the SBP/DBP table in the National Heart, Lung, and Blood Institute 
(NHLBI) 
website 
(http://www.nhlbi.nih.gov/health-pro/guidelines/current/hypertension-
pediatric-jnc-4/blood-pressure-tables). The mean value at each time point will be plotted for 
SBP and DBP. Listings will be provided for the vital signs parameters. Listing of subjects 
with potentially abnormal SBP or DBP will also be provided. 
10.5.5 
Pulse Oximetry 
For the pulse oximetry measurements, a summary of raw values and change from parent 
study baseline will be provided at each scheduled time point in the Current Study Period for 
the percent of oxygen saturation based on the 116 Safety Set. 
The number and percentage of subjects with shift changes from parent study baseline 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the Treatment-emergent Period of the Current Study Period, will be 
summarized based on the 116 Safety Set.  
Listings will be provided for the pulse oximetry measurements. 
10.5.6 
Ophthalmological Examinations 
OE findings will be presented as a data listing. 
10.5.7 
Spirometry 
Spirometry data will be summarized descriptively at each Study 116 visit based on the 116 
Safety Set for subjects who are ≥3 years of age at screening in Study 115B based on 116 
FAS. Spirometry measurements from subjects who turn 3 years of age during the Study 115B 
or Study 116 will not be included in the summary. The raw values and absolute 
change/relative change from parent study baseline will be summarized at each scheduled time 
point of the Current Study Period.  
The following parameters: forced expiratory volume in 1 second (FEV1 (L)), percent 
predicted FEV1 (ppFEV1),  forced vital capacity (FVC (L)), percent predicted FVC (ppFVC), 
FEV1/FVC and ppFEV1/FVC as well as forced expiratory flow (FEF25%-75% (L/s)) and 
percent predicted FEF (ppFEF25%-75%) will be summarized using descriptive statistics at each 
visit in the Current Study Period. The percent predicted values ppFEV1, ppFVC, 
ppFEV1/FVC and ppFEF25%-75% will be calculated using the standards of Global Lungs 
Initiative1 (GLI) as described in Appendix G.  
In addition, a listing containing individual subject data will be provided. 
10.5.8 
Physical Examination  
Physical Examination findings will be presented as a data listing only.  
10.5.9 
Other Safety Analysis 
Not Applicable 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
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11 
SUMMARY OF INTERIM AND IDMC ANALYSES 
11.1 
Interim Analysis 
No interim analysis is planned. 
11.2 
IDMC Analysis 
Safety and tolerability data was reviewed by the IDMC to ensure the safety of the subjects in 
the study based on the data cut as of 09 March 2018. Procedural details of the IDMC's 
structure and function and data planned for review is outlined in the IDMC charter. The 
statistical analysis methodology was specified in the IDMC analysis plan. DMC charter and 
IDMC SAP were finalized before the IDMC review meeting. 
 


Statistical Analysis Plan (Methods) 
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12 
REFERENCES 
1Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 




Statistical Analysis Plan (Methods) 
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k 
An OE will be conducted at the Week 96 Visit (or the ETT Visit if the subject does not have a Week 96 Visit, unless the discontinuation is due to initiation of 
treatment with commercially-available LUM/IVA), or the Safety Follow-up Visit. 
l 
Symptom-directed PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. See Section 11.6.4 of the protocol for 
details. 
      m     An abbreviated PE will be performed 4 hours (± 30 minutes) postdose on Day 1. See Section 11.6.4 of the protocol for details 
 
 
 
 
 
 




Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
 
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v 
Other events related to outcome include assessments relating to pulmonary exacerbations, administration of antibiotic therapy for sinopulmonary signs or 
symptoms, and hospitalizations (Section 11.4.4 of the protocol). 
w      LUM/IVA will be administered q12h (± 2 hours) within 30 minutes of consuming fat containing food (Section 9.6 of the protocol). On days of scheduled visits, the 
dose will be administered at the site after predose assessments have been completed. The last dose will be the dose administered before the Week 96 Visit. See 
Section 9.6 of the protocol for dose determination details. 
 
 
 
 




Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
 
Vertex Pharmaceuticals Incorporated 
 
 
Table 13-2 
Study VX16-809-116: Observational Cohort 
 
Event/Assessment 
Day 1a 
Long-term Follow-up Telephone 
Contact 
Weeks 48 and 96 (± 4 weeks) 
Early Termination Telephone 
Contactb 
Informed consent/assent 
X 
Clinic visit 
X 
Telephone contact 
X 
X 
Serious adverse events 
Continuous from signing of ICF through Week 96 or Early Termination Telephone 
Contact 
ICF: informed consent form; IVA: ivacaftor; LUM: lumacaftor 
a 
For subjects at sites activated by the time of their applicable Study 115B visit (i.e., the Week 24 Visit or the Safety Follow-up Visit, if required), their Study 116 Day 
1 Visit will be the same day as their applicable Study 115B visit, and any Study 116 Day 1 assessments that were specified to be performed at the applicable Study 115B 
visit do not need to be repeated. If the Study 116 Day 1 Visit does not coincide with the subject’s applicable Study 115B visit, the subject will complete all Study 116 Day 
1 assessments. See Section 9.1.1 of the protocol for details. 
b 
Subjects who become eligible to receive commercially-available, physician-prescribed LUM/IVA, and who choose to continue onto commercially-available 
LUM/IVA, must have an Early Termination Telephone Contact to terminate study participation




Statistical Analysis Plan (Methods) 
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Appendix C: Analysis Visit Windows for Safety and  Pharmacodynamic 
Assessments 
Table 13-3 Visit Window Mapping Rules for Safety Measurements (809-116) 
Assessments 
Study 116 Visit 
Target Study Day 
Visit Window  
(in study days) 
 Weight and stature 
 Vital signs 
 Pulse oximetry 
 
116 Day 15 
15 
(1, 50] 
116 Week 12 
85 
[51, 127] 
116 Week 24 
169 
[128, 211] 
116 Week 36 
116 Week 48 
116 Week 60 
116 Week 72 
116 Week 84 
116 Week 96 
116 Follow-up Visit 
253 
337 
421 
505 
589 
673 
687 
[212, 295] 
[296, 379] 
[380, 463] 
[464, 547] 
[548, 631] 
[632, 680] 
Nominal Visit 
 Standard digital ECG 
116 Day 15 
116 Week 48 
116 Week 96 
116 Follow-up Visit 
15 
337 
673 
687 
(1, 176] 
[177, 505] 
[506, 680] 
Nominal Visit 
 Labs 
o Chemistry  
 
116 Day 15 
116 Week 12 
116 Week 24 
116 Week 36 
116 Week 48 
116 Week 72 
116 Week 96 
116 Follow-up Visit 
15 
85 
169 
253 
337 
505 
673 
687 
(1, 50]  
[51, 127] 
[128, 211] 
[212, 295] 
[296, 421] 
[422, 589] 
[590, 680] 
Nominal Visit 
 Labs 
o Hematology 
 
116 Week 12 
116 Week 24 
116 Week 36 
116 Week 48 
116 Week 72 
116 Week 96 
116 Follow-up Visit 
85 
169 
253 
337 
505 
673 
687 
(1, 127] 
[128, 211] 
[212, 295] 
[296, 421] 
[422, 589] 
[590, 680] 
Nominal Visit 
 Labs 
o Coagulation 
 
116 Week 48 
116 Week 96 
116 Follow-up Visit 
337 
673 
687 
(1, 505] 
[506, 680] 
Nominal Visit 
 Spirometry 
 
116 Day 15 
116 Week 24 
116 Week 48 
116 Week 96 
116 Follow-up Visit 
15 
169 
337 
673 
687 
(1, 92] 
[93, 253] 
[254, 505] 
[506, 680] 
Nominal Visit 
 Sweat chloride 
 LCI                                      
116 Week 24 
116 Week 48 
116 Week 96 
116 Follow-up Visit 
169 
337 
673 
687 
(1, 253] 
[254, 505] 
[506, 680] 
Nominal Visit 


Statistical Analysis Plan (Methods) 
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Protocol VX16-809-116, (Version 1.1, 10 October 2016) 
 
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 FE-1 
 IRT                                      116 Week 48 
116 Week 96 
116 Follow-up Visit 
337 
673 
687 
(1, 505] 
[506, 680] 
Nominal Visit 
 
The study days are based on the first dose in 116. 
 
Special handling for vitals signs and spirometry: 
 Day 1 post-dose measurements by hour, assign analysis visit = nominal visit. 


Statistical Analysis Plan (Methods) 
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Appendix D: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date. 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop 
date. 
In summary, the prior, concomitant or post categorization of a medication is described below. 
Table 13-4 
Prior, Concomitant, and Post Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date 
and ≤ End Date of 
Treatment-emergent  
Period 
> End Date of 
Treatment-emergent  
Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of Treatment-
emergent period 
- 
C 
CA 
> End date of Treatment-
emergent period 
- 
- 
A 
A: Post; C: Concomitant; P: Prior 
 


Statistical Analysis Plan (Methods) 
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Appendix E: Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
 If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute the 
AE start day as 1. 
 Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with Treatment-Emergent period to determine whether 
the AE is pretreatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1. 
 Otherwise, impute the AE start MONTH as January and the DAY as 1. 
Compare the imputed AE start date with Treatment-Emergent period to determine whether 
the AE is pretreatment AE, TEAE or post-treatment AE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE. 


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Appendix F: Criteria for Threshold Analysis 
Table 13-5 
Threshold Analysis Criteria for Laboratory Tests 
Parameter 
Categorical change 
Comments 
Clinical Chemistry 
ALT 
≤3xULN*(Not a categorical change) 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009.  
AST 
≤3xULN*( Not a categorical change) 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
ALT>3xULN or AST>3xULN 
Vertex LFT working group 2014 
ALT or AST 
ALT>5xULN or AST>5xULN 
 
ALT or AST 
ALT>8xULN or AST>8xULN 
 
Alkaline 
Phosphatase 
>1.5xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>1.5x - ≤2xULN 
>2xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment phase, 
whatever the interval between measurements. 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment phase, 
whatever the interval between measurements. 
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
Vertex LFT working group 2014 
CPK 
>3x - ≤ 10xULN 
>10xULN 
FDA criteria Feb 2005. 
Am J Cardiol April 2006. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Chloride 
<85 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 


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Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
Albumin 
≤25 g/L 
 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
 
 


Statistical Analysis Plan (Methods) 
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Table 13-6 
Threshold Analysis Criteria for ECGs 
Parameter 
Categorical change 
Comments 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
<40 bpm 
<50 bpm 
>90 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
 
Absolute values (ms) 
Borderline: 431-450 ms (Male); 451-470 ms 
(Female) 
Prolonged: >450 ms (Male); >470 ms (Female) 
≥500 ms 
 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
Table 13-7 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Categorical change 
Comments 
Pulse Rate 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA criteria Feb 2007. 
 


Statistical Analysis Plan (Methods) 
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Appendix G: Details of GLI Equation for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja 
Stanojevic, Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at: http://www.ers-
education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-2012-regression-
equations-and-lookup-tables.aspx. Accessed 08 December 2015.  
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. 
Cole, 
Janet 
Stocks. 
Version 
19 
July 
2015. 
Available 
at: 
http://www.ers-
education.org/guidelines/global-lung-function-initiative/gli-2012-explained.aspx. 
Accessed 
08 December 2015.   
GLI-2012 - SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at: 
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx. 
Accessed 08 December 2015. 
  




Statistical Analysis Plan (Methods) 
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Appendix I:  Programmable Important Protocol Deviation Programming Rules 
(Based on the Clinical Database) 
Important Protocol Deviations during the Treatment Period: 
 Compliance < 80% in the Treatment Cohort of Study 116