Clinical trial NCT02797132
Conditions: Cystic Fibrosis
Keywords: CF
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-05-01; Completion date: 2017-09-01
Enrollment: 62 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study evaluating the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (PD) of multiple doses of lumacaftor/ivacaftor (LUM/IVA) in subjects 2 through 5 years of age (inclusive) with cystic fibrosis (CF), homozygous for F508del. Subjects who participate in Part A may participate in Part B, if they meet the eligibility criteria.

Detailed description:

Arms: arm 1: Part A (\<14 kg): Participants weighing less than (\<) 14 kilograms (kg) at screening received LUM 100 milligram (mg)/IVA 125 mg fixed-dose combination every 12 hours for 15 days in Part A.

Part A (\>=14 kg): Participants weighing greater than or equal to (\>=) 14 kg at screening received LUM 150 mg/IVA 188 mg fixed-dose combination every 12 hours for 15 days in Part A.

Part B (\<14 kg): Participants weighing \<14 kg at screening received LUM 100 mg/IVA 125 mg fixed-dose combination every 12 hours for 24 weeks in Part B.

Part B (\>=14 kg): Participants weighing \>=14 kg at screening received LUM 150 mg/IVA 188 mg fixed-dose combination every 12 hours for 24 weeks in Part B.
Interventions: intervention 1: LUM/IVA
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 




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PROTOCOL SYNOPSIS 
Title A Phase 3, 2-Part, Open-label Study to Evaluate the Safety and Pharmacokinetics 
of Lumacaftor/Ivacaftor Combination Therapy in Subjects Aged 2 Through 5 Years 
With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation
Brief Title Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 
2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del
 
Clinical Phase and 
Clinical Study Type  
Phase 3 safety and pharmacokinetics (PK)
 
Objectives Primary Objectives
Part A
To evaluate the PK of lumacaftor (LUM) and ivacaftor (IVA) and their respective 
metabolites in subjects aged 2 through 5 years with cystic fibrosis (CF), 
homozygous for F508del
Part B
To evaluate the safety of LUM/IVA combination therapy in subjects aged 
2 through 5 years with CF, homozygous for F508del
Secondary Objectives
Part A
To evaluate the safety of LUM/IVA combination therapy in subjects aged 
2 through 5 years with CF, homozygous for F508del
Part B
• To evaluate the pharmacodynamics (PD) of LUM/IVA combination therapy in 
subjects aged 2 through 5 years with CF, homozygous for F508del
• To evaluate the off-drug PD response after the Washout Period
• To evaluate the PK of LUM and IVA and their respective metabolites in subjects 
aged 2 through 5 years with CF, homozygous for F508del
 
Endpoints Primary Endpoints
Part A
PK parameters of LUM and IVA
Part B 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values (serum chemistry, hematology, coagulation studies, and 
urinalysis), standard 12-lead electrocardiograms (ECGs), vital signs, pulse 
oximetry, ophthalmological examinations, and spirometry
Secondary Endpoints
Part A
• PK parameters of the metabolites of LUM and IVA
• Safety and tolerability assessments based on AEs, clinical laboratory values 
(serum chemistry, hematology, coagulation studies, and urinalysis), standard 
12-lead ECGs, vital signs, pulse oximetry, and spirometry


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Part B
• Absolute change from baseline in sweat chloride at Week 24
• Absolute change from baseline in body mass index (BMI) and BMI-for-age 
z-score at Week 24
• Absolute change from baseline in weight and weight-for-age z-score at Week 24
• Absolute change from baseline in stature and stature-for-age z-score at Week 24
• Time-to-first pulmonary exacerbation through Week 24
• Number of pulmonary exacerbations through Week 24
• Number of CF-related hospitalizations through Week 24
• Absolute change in fecal elastase-1 (FE-1) levels from baseline at Week 24
• Absolute change in serum levels of immunoreactive trypsinogen (IRT) from 
baseline through Week 24
• Change in microbiology cultures from baseline at Week 24
• Absolute change from baseline in percent predicted forced expiratory volume in 
1 second (ppFEV1) at Week 24
• Absolute change in sweat chloride from Week 24 at Week 26
• Acceptability/palatability of LUM/IVA granules at Day 1
• Absolute change from baseline in lung clearance index (LCI)2.5 at Week 24
• Absolute change from baseline in LCI5.0 at Week 24
• PK parameters of LUM, IVA, and their respective metabolites
 
Number of Subjects Part A
Approximately 12 subjects are planned for enrollment. Assuming a 10% dropout 
rate, approximately 10 subjects should complete Part A. Approximately half of the 
subjects should complete the study in each of the following weight groups: <14 kg 
and ≥14 kg at screening. Subjects who participate in Part A may participate in 
Part B. 
A review of safety, tolerability, and available PK data will be completed by an 
internal team at Vertex Pharmaceuticals Incorporated (Vertex) after Part A to 
determine the dose(s) to be evaluated in Part B. Additional subjects or treatment 
cohorts may be enrolled, if data from the initial, planned, 12 subjects are 
inadequate to make a determination of the dose(s) to be evaluated in Part B.
Part B
Approximately 56 subjects are planned for enrollment. Assuming a 10% dropout 
rate, approximately 50 subjects should complete Part B; at least 10 subjects must be 
<3 years of age. Subjects should be ≥3 years of age for enrollment in the optional 
LCI Substudy at a subset of sites. Additional subjects may be enrolled at the 
sponsor’s discretion to achieve up to 30 subjects in the LCI Substudy.
 
Study Population Part A and Part B
Male and female subjects 2 through 5 years of age (inclusive) with CF who are 
homozygous for the F508del-CF transmembrane conductance regulator (CFTR)
mutation 
 
Investigational Drug 
Active substance: LUM and IVA fixed-dose combination 
 Activity: CFTR corrector and potentiator (chloride ion [Cl-] secretion)


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 Strength and Route of Administration 
x LUM 100-mg/IVA 125-mg granules for oral administration
x LUM 150-mg/IVA 188-mg granules for oral administration
Doses Investigated and Dose Adjustment in Part A:
x LUM 100 mg/IVA 125 mg q12h for subjects weighing <14 kg at screening
x LUM 150 mg/IVA 188 mg q12h for subjects weighing ≥14 kg at screening
Doses are based on the subject’s weight at screening of Part A.
No dose adjustments will be made across the duration of treatment.  
Doses Investigated and Dose Adjustment in Part B:
A review of safety, tolerability, and available PK data will be completed by an 
internal Vertex team after Part A to determine the dose(s) chosen for evaluation in 
Part B. Two doses will be evaluated based on weight at screening of Part B:
x LUM 100 mg/IVA 125 mg q12h for subjects weighing <14 kg at screening
x LUM 150 mg/IVA 188 mg q12h for subjects weighing ≥14 kg at screening
No dose adjustments will be made across the duration of treatment. 
Note: doses listed above are the planned doses for Part B. Depending on the results 
from Part A, a single dose from Part A may be selected for all subjects or a 
previously unspecified dose or doses may be selected for Part B. 
 
Study Duration Part A
The total duration is approximately 53 days (up to 28 days for the Screening 
Period, 15 days for the Treatment Period, and 10 days for the Safety Follow-up 
Period).
Part B
The total duration is approximately 30 weeks (up to 28 days for the Screening 
Period, 24 weeks for the Treatment Period, and 2 weeks for the Safety Follow-up 
Period).
 
Study Design Part A
Part A includes the following:
• Screening Period (Day -28 through Day -1)
• Treatment Period (Day 1 through Day 15 ± 2 days; the last dose of LUM/IVA in 
Part A is the morning dose on Day 15)
• Safety Follow-up Visit (10 ± 3 days after the last dose of LUM/IVA)
A review of safety, tolerability, and available PK data will be completed by an 
internal Vertex team after Part A to confirm or adjust the dose(s) chosen for Part B. 
Pending PK data from Part A, the dose planned for Part B may be adjusted. 
Additional subjects or treatment cohorts may be enrolled, if data from the initial, 
planned, 12 subjects are inadequate to make a determination of the dose(s) to be 
evaluated in Part B.
 Part B
Part B includes the following:
• Screening Period (Day -28 through Day -1)
• Treatment Period (Day 1 through Week 24 ± 5 days; the last dose of LUM/IVA 
in Part B is the evening dose before the Week 24 visit.)


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• Washout Period (Week 24 to Week 26 ± 4 days)
• Safety Follow-up Visit (Week 26 [2 weeks ± 4 days after the last dose of 
LUM/IVA])
Subjects who permanently discontinue LUM/IVA treatment will be asked to 
remain in the study and to complete the study assessments from the time of 
LUM/IVA treatment discontinuation through the Week 24 Visit, or Safety 
Follow-up Visit as applicable, in Part B. 
Assessments Safety (Part A and Part B)
AEs, clinical laboratory values (serum chemistry, hematology, coagulation, and 
urinalysis), ECGs, vital signs, pulse oximetry, physical examinations, spirometry 
(subjects ≥3 years of age at screening of Part A or Part B), and ophthalmologic 
examinations (Part B)
Pharmacokinetic (Part A and Part B)
PK parameters of LUM, IVA, and their respective metabolites 
Pharmacodynamic (Part B only)
Sweat chloride test, BMI/BMI-for-age z-score, weight/weight-for-age z-score, 
stature/stature-for-age z-score, spirometry (subjects ≥3 years of age at screening of 
Part B), LCI (subjects ≥3 years of age at screening of Part B who consent/assent to 
the optional LCI Substudy), pulmonary exacerbations, CF-related hospitalizations, 
FE-1, IRT, qualitative microbiology cultures, and acceptability/palatability of 
LUM/IVA granules
 
Statistical Analyses Part A
No formal sample size calculations have been performed. The number of subjects 
participating in each weight group is common in early clinical pharmacology 
studies and is considered sufficient to achieve the PK objectives of Part A.
Details of the analysis will be provided in the Part A statistical analysis plan.
Part B
No formal sample size calculations have been performed. The number of subjects 
in Part B is deemed adequate to meet the primary safety objective. 
Approximately 56 subjects are planned for enrollment. Assuming a 10% dropout 
rate, approximately 50 subjects will complete Part B. Given a total sample size of 
50 subjects (completers), there is a 92.3% chance of observing AEs in at least 
1 subject if the true incidence rate is 5%, and a 99.5% chance of observing AEs in 
at least 1 subject if the true incidence rate is 10%. 
For primary safety analyses, overall summary statistics will be provided for 
treatment-emergent adverse events (TEAEs), clinical laboratory assessments 
(serum chemistry, hematology, and coagulation studies), standard 12-lead ECGs, 
vital signs, pulse oximetry, and spirometry (subjects ≥3 years of age at screening). 
If weight-based dosing is used for Part B, summary by dosing groups will also be 
provided as supplementary information.
Details of the analysis will be provided in the Part B statistical analysis plan.
 
IDMC Reviews An independent data monitoring committee (IDMC) is planned for Part B only. 
Before the start of Part B, the IDMC may be consulted at the discretion of the 
sponsor. The IDMC objectives and operational details will be defined in a separate 
document (the IDMC Charter), which will be finalized before the first subject is 
enrolled in Part B. 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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SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in the following tables: 
Table 3-1 for the Part A Screening Period 
Table 3-2 for the Part A Treatment Period and Safety Follow-up Visit 
Table 3-3 for the Part B Screening Period 
Table 3-4 for the Part B Treatment Period and Safety Follow-up Visit 


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Table 3-1 
Study VX15-809-115: Part A Screening 
Assessment
Screening Visit
Day -28 through Day -1
Informed consent/assent
X
Demographics
X
Medical and ophthalmological history
X
Stature, weight, and vital signsa,b
X
Pulse oximetryb
X
Ophthalmologic examinationc
X
Full physical examination
X
Standard 12-lead ECGd
X
Spirometrye
X
CFTR genotypef
X
Serum chemistryg
X
Hematologyg
X
Coagulation studiesg
X
Urinalysisg
X
Medications reviewh
Continuous from signing of ICF through Safety Follow-up Visit
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit
BMI: body mass index; CFTR: cystic fibrosis transmembrane conductance regulator gene;
ECG: electrocardiogram; ICF: informed consent form
a
If children 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. Refer to Section 11.4.3 for details. 
b
The subject should rest for at least 5 minutes before having vital signs and pulse oximetry measured. Refer 
to Section 11.6.4 for details.
c 
An ophthalmologic examination will be conducted by a licensed ophthalmologist. The examination does 
not need to be repeated if there is documentation of an examination meeting protocol criteria that was 
conducted within 3 months before the Screening Visit. Subjects with documentation of bilateral lens 
removal do not need the ophthalmologic examination. Refer to Section 11.6.6 for details. 
d 
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. Refer to Section 11.6.5 for details.  
e 
Spirometry (subjects t3 years of age at screening only) may be performed pre- or post-bronchodilator. 
Refer to Section 11.6.7 for details.  
f  
All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype 
laboratory report. Refer to Section 11.6.2 for details.  
g 
Refer to Section 11.6.2 for details.  
h 
Refer to Section 9.4.2 for details. 






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Table 3-3 
Study VX15-809-115: Part B Screening 
Assessment
Screening Visit
Day -28 through Day -1
Informed consent/assent
X
Demographics
X
Medical and ophthalmological history
X
Stature, weight, and vital signsa,b
X
Pulse oximetryb
X
Ophthalmologic examinationc
X
Full physical examination
X
Standard 12-lead ECGd
X
CFTR genotypee
X
Serum chemistryf
X
Hematologyf
X
Coagulation studiesf
X
Urinalysisf
X
Sweat chlorideg
X
LCI (optional)h
X
Spirometryi
X
Medications reviewj
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)
BMI: body mass index; CFTR: cystic fibrosis transmembrane conductance regulator gene; ECG: electrocardiogram; 
ICF: informed consent form; LCI: lung clearance index
a 
If children 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. Refer to Section 11.4.3 for details. 
b 
The subject should rest for at least 5 minutes before having vital signs and pulse oximetry measured. Refer to 
Section 11.6.4 for details.
c 
An ophthalmologic examination will be conducted by a licensed ophthalmologist. The examination does not need to be 
repeated if there is documentation of an examination meeting protocol criteria that was conducted within 3 months 
before the Screening Visit. Subjects with documentation of bilateral lens removal do not need the ophthalmologic 
examination. Refer to Section 11.6.6 for details. 
d 
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. Refer to Section 11.6.5 for details. 
e  
All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype laboratory 
report. Refer to Section 11.6.2 for details. However, this assessment does not need to be repeated for confirmed 
subjects in Part A who may participate in Part B.
f 
Refer to Section 11.6.2 for details. 
g
If an eligible historical sweat chloride result is documented in the subject’s medical record, that result alone (and not 
the Screening Visit result) may be used to determine eligibility. For subjects using an historical sweat chloride value 
documented in their medical record to determine eligibility, the sweat chloride test at the Screening Visit is still 
required. At screening, 2 samples may be collected, 1 sample from each arm (left and right). 
h 
The LCI assessment (subjects t3 years of age at screening who consent/assent to the optional LCI Substudy) may be 
performed pre- or post-bronchodilator. The assessment will be performed in multiple replicates and before the 
spirometry assessment. Refer to Section 11.4.2 for details. 
i 
Spirometry (subjects t3 years of age at screening only) may be performed pre- or post-bronchodilator. Refer to 
Section 11.6.7 for details.  
j 
Refer to Section 9.4.2 for details.  








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TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
2 
Protocol Synopsis ............................................................................................................. 3 
3 
Schedule of Assessments.................................................................................................. 7 
4 
Table of Contents ........................................................................................................... 15 
List of Tables...................................................................................................................... 19 
List of Figures .................................................................................................................... 19 
5 
Introduction.................................................................................................................... 20 
5.1 
Background ............................................................................................................... 20 
5.2 
Study Rationale ........................................................................................................ 21 
6 
Study Objectives ............................................................................................................ 21 
6.1 
Primary Objectives ................................................................................................... 21 
6.2 
Secondary Objectives ............................................................................................... 21 
7 
Study Endpoints ............................................................................................................. 22 
7.1 
Primary Endpoints .................................................................................................... 22 
7.2 
Secondary Endpoints ................................................................................................ 22 
8 
Study Design ................................................................................................................... 23 
8.1 
Overview of Study Design ....................................................................................... 23 
8.1.1 
Part A ................................................................................................................ 23 
8.1.2 
Part B ................................................................................................................ 24 
8.1.3 
Screening .......................................................................................................... 25 
8.1.4 
Repetition of Screening Assessments ............................................................... 26 
8.1.5 
Rescreening ...................................................................................................... 26 
8.1.6 
Extension of Screening Period Window ........................................................... 26 
8.1.7 
Treatment Period .............................................................................................. 26 
8.1.7.1 
Part A ......................................................................................................... 27 
8.1.7.2 
Part B .......................................................................................................... 27 
8.1.8 
Washout Period................................................................................................. 27 
8.1.8.1 
Part A ......................................................................................................... 27 
8.1.8.2 
Part B .......................................................................................................... 27 
8.1.9 
Follow-up.......................................................................................................... 27 
8.1.9.1 
Part A ......................................................................................................... 27 
8.1.9.2 
Part B .......................................................................................................... 27 
8.1.10 
Early Discontinuation/Early Termination of Treatment ................................... 28 
8.1.10.1 Part A ......................................................................................................... 28 
8.1.10.2 Part B .......................................................................................................... 28 
8.2 
Independent Data Monitoring Committee ................................................................ 28 
8.3 
Rationale for Study Design and Study Drug Regimens ........................................... 28 
8.3.1 
Study Design..................................................................................................... 28 
8.3.2 
Study Drug Dose and Duration ........................................................................ 29 
8.3.3 
Rationale for Study Assessments ..................................................................... 31 
9 
Study Population ............................................................................................................ 33 
9.1 
Inclusion Criteria ...................................................................................................... 33 


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9.2 
Exclusion Criteria ..................................................................................................... 34 
9.3 
Study Restrictions ..................................................................................................... 35 
9.4 
Prior and Concomitant Medications ......................................................................... 36 
9.4.1 
Prohibited Medications ..................................................................................... 36 
9.4.2 
Prior and Concomitant Medications ................................................................. 37 
9.5 
Removal of Subjects ................................................................................................. 37 
9.6 
Replacement of Subjects .......................................................................................... 38 
10 Study Drug Administration and Management ........................................................... 38 
10.1 Preparation and Dispensing ...................................................................................... 38 
10.2 Administration .......................................................................................................... 38 
10.2.1 
Part A ................................................................................................................ 38 
10.2.2 
Part B ................................................................................................................ 39 
10.3 Method of Assigning Subjects to Treatment Groups ............................................... 41 
10.4 Dose Modification for Toxicity ................................................................................ 41 
10.5 Packaging and Labeling ........................................................................................... 41 
10.6 Study Drug Supply, Storage, and Handling ............................................................. 41 
10.7 Drug Accountability ................................................................................................. 41 
10.8 Disposal, Return, or Retention of Unused Drug ....................................................... 42 
10.9 Compliance ............................................................................................................... 42 
10.10 Blinding and Unblinding .......................................................................................... 42 
11 Assessments .................................................................................................................... 42 
11.1 Timing of Assessments ............................................................................................. 42 
11.2 Subject and Disease Characteristics ......................................................................... 43 
11.3 Pharmacokinetics ...................................................................................................... 43 
11.3.1 
Blood Sampling ................................................................................................ 43 
11.3.2 
Processing and Handling of Pharmacokinetic Samples ................................... 44 
11.3.3 
Bioanalysis........................................................................................................ 44 
11.4 Pharmacodynamics ................................................................................................... 44 
11.4.1 
Sweat Chloride ................................................................................................. 44 
11.4.2 
Lung Clearance Index ....................................................................................... 44 
11.4.3 
Weight, Stature, and BMI ................................................................................. 45 
11.4.4 
Other Events Related to Outcome .................................................................... 46 
11.4.4.1 Antibiotic Therapy for Sinopulmonary Sign/Symptoms ........................... 46 
11.4.4.2 Hospitalization for CF ................................................................................ 47 
11.4.5 
Fecal Elastase-1 ................................................................................................ 47 
11.4.6 
Immunoreactive Trypsinogen ........................................................................... 47 
11.4.7 
Microbiology Cultures ...................................................................................... 47 
11.4.8 
Spirometry ........................................................................................................ 47 
11.4.9 
Acceptability/Palatability Assessment ............................................................. 48 
11.5 Efficacy ..................................................................................................................... 48 
11.6 Safety ........................................................................................................................ 48 
11.6.1 
Adverse Events ................................................................................................. 48 
11.6.2 
Clinical Laboratory Assessments ..................................................................... 48 
11.6.3 
Elevation of Liver Function Test Parameters ................................................... 49 
11.6.4 
Physical Examinations and Vital Signs ............................................................ 51 


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11.6.5 
Electrocardiograms ........................................................................................... 51 
11.6.6 
Ophthalmologic Examination ........................................................................... 52 
11.6.7 
Spirometry ........................................................................................................ 53 
11.6.8 
Contraception and Pregnancy ........................................................................... 54 
12 Statistical and Analytical Plans .................................................................................... 54 
12.1 Sample Size and Power ............................................................................................ 54 
12.2 Analysis Sets ............................................................................................................ 55 
12.3 Statistical Analysis ................................................................................................... 56 
12.3.1 
General Considerations ..................................................................................... 56 
12.3.2 
Background Characteristics .............................................................................. 57 
12.3.2.1 Subject Disposition .................................................................................... 57 
12.3.2.2 Demographics and Baseline Characteristics .............................................. 58 
12.3.2.3 Prior and Concomitant Medications........................................................... 58 
12.3.2.4 Study Drug Exposure ................................................................................. 58 
12.3.2.5 Study Drug Compliance ............................................................................. 59 
12.3.3 
Pharmacodynamics Analysis (Part B Only) ..................................................... 59 
12.3.3.1 Analysis of Primary Endpoints .................................................................. 59 
12.3.3.2 Analysis of Secondary Pharmacodynamic Endpoints ............................... 60 
12.3.4 
Safety Analysis ................................................................................................. 63 
12.3.4.1 Adverse Events........................................................................................... 63 
12.3.4.2 Clinical Laboratory Assessments ............................................................... 64 
12.3.4.3 Electrocardiogram ...................................................................................... 65 
12.3.4.4 Vital Signs .................................................................................................. 65 
12.3.4.5 Pulse Oximetry ........................................................................................... 65 
12.3.4.6 Ophthalmological Examinations ................................................................ 65 
12.3.4.7 Spirometry .................................................................................................. 65 
12.3.4.8 Physical Examination ................................................................................. 65 
12.3.5 
Interim and IDMC Analyses ............................................................................. 66 
12.3.5.1 Interim Analysis ......................................................................................... 66 
12.3.5.2 IDMC Analysis .......................................................................................... 66 
12.4 Clinical Pharmacology Analysis .............................................................................. 66 
12.4.1 
Pharmacokinetic Analysis ................................................................................ 66 
12.4.2 
Pharmacodynamic Analysis ............................................................................. 66 
12.4.3 
Pharmacokinetic/Pharmacodynamic Analyses ................................................. 66 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ..................... 67 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting .................................................................................................................. 67 
13.1.1 
Adverse Events ................................................................................................. 67 
13.1.1.1 Definition of an Adverse Event.................................................................. 67 
13.1.1.2 Clinically Significant Assessments ............................................................ 67 
13.1.1.3 Documentation of Adverse Events............................................................. 67 
13.1.1.4 Adverse Event Severity .............................................................................. 68 
13.1.1.5 Adverse Event Causality ............................................................................ 68 
13.1.1.6 Study Drug Action Taken .......................................................................... 69 
13.1.1.7 Adverse Event Outcome ............................................................................ 69 


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13.1.1.8 Treatment Given......................................................................................... 70 
13.1.2 
Serious Adverse Events .................................................................................... 70 
13.1.2.1 Definition of a Serious Adverse Event....................................................... 70 
13.1.2.2 Documentation of Serious Adverse Events................................................ 71 
13.1.2.3 Reporting Serious Adverse Events............................................................. 71 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ................................ 71 
13.2 Administrative Requirements ................................................................................... 72 
13.2.1 
Ethical Considerations ...................................................................................... 72 
13.2.2 
Subject Information and Informed Consent ..................................................... 72 
13.2.3 
Investigator Compliance ................................................................................... 72 
13.2.4 
Access to Records ............................................................................................. 72 
13.2.5 
Subject Privacy ................................................................................................. 73 
13.2.6 
Record Retention .............................................................................................. 73 
13.2.7 
Study Termination ............................................................................................ 73 
13.3 Data Quality Assurance ............................................................................................ 74 
13.4 Monitoring ................................................................................................................ 74 
13.5 Electronic Data Capture ........................................................................................... 74 
14 References ....................................................................................................................... 76 
15 Protocol Signature Pages .............................................................................................. 80 
15.1 Sponsor Signature Page ............................................................................................ 80 
15.2 Investigator Signature Page ...................................................................................... 81 


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List of Tables 
Table 3-1 
Study VX15-809-115: Part A Screening .......................................................... 8 
Table 3-2 
Study VX15-809-115: Part A Treatment Period and Safety Follow-up Visit .. 9 
Table 3-3 
Study VX15-809-115: Part B Screening......................................................... 11 
Table 3-4 
Study VX15-809-115: Part B Treatment Period and Safety Follow-up Visit 12 
Table 8-1 
Summary of LUM and IVA Exposures in Subjects With CF Who Are 6 Years 
of Age and Older ............................................................................................. 30 
Table 9-1 
Study Restrictions – Part A ............................................................................. 35 
Table 9-2 
Study Restrictions – Part B ............................................................................. 36 
Table 10-1 
Study Drug Administration – Part A .............................................................. 38 
Table 10-2 
Study Drug Administration – Planned Doses for Part B ................................ 39 
Table 10-3 
Study Drug – Part A and Part B ...................................................................... 41 
Table 11-1 
Safety Laboratory Test Panels ........................................................................ 49 
Table 12-1 
Probability of Observing Adverse Events in At Least 1 Subject if the Adverse 
Event Incidence (T) is 5% and 10% ................................................................ 55 
Table 13-1 
Grading of AE Severity .................................................................................. 68 
Table 13-2 
Classifications for AE Causality ..................................................................... 69 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ............ 69 
Table 13-4 
Classifications for Outcome of an AE ............................................................ 69 
List of Figures 
Figure 8-1 
Schematic of Study Design for Part A ............................................................ 24 
Figure 8-2 
Schematic of Study Design for Part B ............................................................ 25 


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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 
United States (US),1,2 32,000 individuals in the European Union (EU),3 4,100 individuals in 
Canada,4 and 3,200 individuals in Australia.5 The incidence and prevalence of CF varies 
between racial groups. For example, CF is considerably more common in the Caucasian 
populations of North America and Europe than in Asian and African populations.2,3 Based on 
the size of the population, CF qualifies as an orphan disease.6,7 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.2,8,9 Although the disease affects multiple organs, 
progressive loss of lung function is the leading cause of mortality.10
Cystic fibrosis is caused by a defect in the gene encoding the cystic fibrosis transmembrane 
conductance regulator (CFTR), an epithelial chloride (Cl-) ion channel activated by cyclic 
AMP-dependent protein kinase A that is responsible for aiding in the regulation of salt and 
water absorption and secretion in various tissues.11 This function is defective in patients with 
CF due to a loss of either cell surface expression and/or function of CFTR. 
More than 2000 mutations in the CFTR gene have been identified.12 The most prevalent 
mutation is an in-frame deletion in the CFTR gene resulting in a loss of phenylalanine at 
position 508 in the wild-type CFTR protein (F508del-CFTR).13 The proportion of patients 
with CF who are homozygous for the F508del-CFTR mutation is similar across geographic 
regions: approximately 47% in the US2, 44% in the EU3, 50% in Canada4, and 51% in 
Australia.5 The F508del-CFTR mutation interferes with the ability of the CFTR protein to 
reach and remain at the cell surface, as well as to open and close, resulting in decreased Cl−
transport.14,15 Because of the near-complete loss of CFTR chloride transport, the 
F508del/F508del mutation is typically associated with a severe form of CF, characterized by 
a rapid rate of lung function decline, colonization with Pseudomonas aeruginosa, a high 
incidence of pancreatic insufficiency, and reduced life expectancy.
16,17,18,19
Based on the understanding of the molecular defects caused by CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. The first 
approach is to increase the quantity of CFTR delivered to the cell surface using small 
molecules known as CFTR correctors. The second approach is to increase the channel gating 
activity of CFTR at the cell surface using small molecules known as CFTR potentiators. One 
or both of these mechanisms may be necessary, depending on the specific mutation. Because 
the channel gating activity of CFTR delivered to the cell surface by CFTR correctors can be 
enhanced by CFTR potentiators, together, CFTR correctors and potentiators provide 
complementary therapeutic approaches to improve chloride transport.  


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Lumacaftor (LUM) is a CFTR corrector that improves the processing and trafficking of the 
F508del-CFTR protein, resulting in an increase in the quantity of F508del-CFTR protein at 
the cell surface. Ivacaftor (IVA) increases the channel open probability of the F508del-CFTR 
protein delivered to the cell surface by LUM, thereby enhancing total chloride transport. In 
the absence of LUM, there is very little F508del-CFTR protein at the cell surface for IVA to 
potentiate. The combined effect of LUM and IVA is increased quantity and function of 
F508del-CFTR at the cell surface. 
LUM and IVA in combination is the first medicine designed to treat the underlying 
molecular defect and enhance the function of CFTR in patients homozygous for F508del.
The LUM/IVA development program targets patients with CF who have the F508del
mutation, the most common mutation in the CFTR gene.  
Details about the LUM/IVA development program can be found in the Investigator’s 
Brochure.20
5.2
Study Rationale 
CF greatly affects the pediatric population, as approximately half of the total CF population 
is less than 18 years of age.21 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 present study is designed to obtain 
pharmacokinetic (PK) and safety information to support a proposed indication expansion of 
LUM/IVA in subjects 2 through 5 years of age, homozygous for F508del. 
6
STUDY OBJECTIVES 
6.1
Primary Objectives 
Part A 
To evaluate the PK of LUM and IVA and their respective metabolites in subjects aged 
2 through 5 years with CF, homozygous for F508del
Part B 
To evaluate the safety of LUM/IVA combination therapy in subjects aged 2 through 5 years 
with CF, homozygous for F508del
6.2
Secondary Objectives 
Part A 
To evaluate the safety of LUM/IVA combination therapy in subjects aged 2 through 5 years 
with CF, homozygous for F508del
Part B 
x
To evaluate the pharmacodynamics (PD) of LUM/IVA combination therapy in subjects 
aged 2 through 5 years with CF, homozygous for F508del


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x
To evaluate the off-drug PD response after the Washout Period 
x
To evaluate the PK of LUM and IVA and their respective metabolites in subjects aged 
2 through 5 years with CF, homozygous for F508del
7
STUDY ENDPOINTS 
7.1
Primary Endpoints 
Part A 
PK parameters of LUM and IVA 
Part B  
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values 
(serum chemistry, hematology, coagulation studies, and urinalysis), standard 12-lead 
electrocardiograms (ECGs), vital signs, pulse oximetry, ophthalmological examinations, and 
spirometry 
7.2
Secondary Endpoints 
Part A 
x
PK parameters of the metabolites of LUM and IVA 
x
Safety and tolerability assessments based on AEs, clinical laboratory values (serum 
chemistry, hematology, coagulation studies, and urinalysis), standard 12-lead 
electrocardiograms (ECGs), vital signs, pulse oximetry, and spirometry
Part B 
x
Absolute change from baseline in sweat chloride at Week 24
x
Absolute change from baseline in body mass index (BMI) and BMI-for-age z-score at 
Week 24
x
Absolute change from baseline in weight and weight-for-age z-score at Week 24
x
Absolute change from baseline in stature and stature-for-age z-score at Week 24
x
Time-to-first pulmonary exacerbation through Week 24
x
Number of pulmonary exacerbations through Week 24
x
Number of CF-related hospitalizations through Week 24 
x
Absolute change in fecal elastase-1 (FE-1) levels from baseline at Week 24 
x
Absolute change in serum levels of immunoreactive trypsinogen (IRT) from baseline 
through Week 24  
x
Change in microbiology cultures from baseline at Week 24  
x
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) at Week 24  


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x
Absolute change in sweat chloride from Week 24 at Week 26 
x
Acceptability/palatability of LUM/IVA granules at Day 1 
x
Absolute change from baseline in lung clearance index (LCI)2.5 at Week 24 
x
Absolute change from baseline in LCI5.0 at Week 24 
x
PK parameters of LUM, IVA, and their respective metabolites 
8
STUDY DESIGN  
8.1
Overview of Study Design 
This is a Phase 3, 2-part, open-label, multicenter study evaluating the PK, safety, tolerability, 
and PD of multiple doses of LUM/IVA in subjects 2 through 5 years of age (inclusive) with 
CF, homozygous for F508del. Subjects who participate in Part A may participate in Part B, if 
they meet the eligibility criteria.  
8.1.1
Part A 
Approximately 12 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 10 subjects should complete Part A. Approximately half of the subjects should 
complete the study in each of the following weight groups: <14 kg and ≥14 kg at screening.  
Part A includes the following: 
x
Screening Period (Day -28 through Day -1) 
x
Treatment Period (Day 1 through Day 15 ± 2 days) 
x
Safety Follow-up Visit (10 ± 3 days after the last dose of LUM/IVA) 
Figure 8-1 depicts the schematic for the Part A study design. Procedural details are described 
in the following sections:  
x
Section 10.2.1 for dose administration; 
x
Section 8.1.3 for the Screening Period; 
x
Section 8.1.7.1 for the Treatment Period; 
x
Section 8.1.9.1 for the Safety Follow-up; and 
x
Section 8.1.10.1 for early discontinuation. 
A review of safety, tolerability, and available PK data will be completed by an internal 
Vertex Pharmaceuticals Incorporated (Vertex) team after Part A to determine the dose(s) to 
be evaluated in Part B. Additional subjects or treatment cohorts may be enrolled, if data from 
the initial, planned, 12 subjects are inadequate to make a determination of the dose(s) to be 
evaluated in Part B. 






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For Parts A and B, the Screening Period will occur within 28 days before the first dose of 
LUM/IVA to confirm that subjects meet the selection criteria for the corresponding part in 
the study. To participate in either part of the study, the subject's parent or legal guardian must 
sign and date a study-specific informed consent form (ICF) and the subject must sign an 
assent form (if applicable) before any study-specific procedures can be performed. The ICF 
(and assent form, if applicable) will comply with all applicable regulations governing the 
protection of human subjects and will be approved by Vertex and the site's institutional 
review board (IRB). 
To prepare for study participation, subjects/caregivers will be instructed on the study 
restrictions (Section 9.3).  
8.1.4
Repetition of Screening Assessments 
Repetition of any individual Screening Visit assessment(s) that did not meet eligibility 
criteria is not permitted, with the following exceptions:  
x
If there is clear evidence of a laboratory error (e.g., hemolyzed sample), equipment 
malfunction, or technician error, collection of a repeat sample for the appropriate 
laboratory test may be permitted after discussion with the Vertex medical monitor or 
authorized designee. 
x
Exclusionary liver function test (LFT) levels, which may be retested within 14 days of 
the original Screening Visit date. 
If repeat values of the individual assessment(s) are within the eligibility criteria and 
completed within the Screening Period window, then the subject is eligible for the study. 
8.1.5
Rescreening 
Subjects may be rescreened after discussion with the Vertex medical monitor or authorized 
designee; all rescreening requires Vertex approval. If a subject is rescreened, all Screening 
Visit assessments will be repeated except for CF genotyping and the ophthalmologic 
examination (if performed within the last 3 months before the Screening Visit). Subjects may 
only be rescreened once per study part. If a subject is rescreened, the new screening window 
date will begin once the first rescreening assessment has been initiated. 
8.1.6
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 1 week after approval by the 
medical monitor or authorized designee for the following reasons: 
x
Repetition of the Screening Period assessments (Section 8.1.4)
x
Scheduling of the ophthalmologic examination (Section 11.6.6)
x
Availability or malfunction of required equipment or technician error. 
8.1.7
Treatment Period 
Treatment Period assessments are listed in Table 3-2 for Part A and Table 3-4 for Part B.


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8.1.7.1
Part A 
The Part A Treatment Period is 15 days; LUM/IVA will be administered every 12 hours 
(q12h) from Day 1 through Day 15. The morning LUM/IVA dose on Day 15 will be the last 
dose in Part A. LUM/IVA administration and management details are provided in Section 10.
Study visits during the Treatment Period will occur as shown in Table 3-2. Subjects will be 
outpatients during the Treatment Period. All visits should occur within the windows 
specified. 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled visit, the Vertex medical monitor or authorized designee will be notified, and the 
investigator will make every effort to arrange follow-up evaluations at appropriate intervals 
to document the course of the abnormalities. 
Procedures for subjects who prematurely discontinue LUM/IVA treatment are described in 
Section 8.1.10.1.
8.1.7.2
Part B 
The Part B Treatment Period is 24 weeks; LUM/IVA will be administered q12h from Day 1 
through Week 24. The evening LUM/IVA dose before the Week 24 Visit will be the last 
dose in Part B. LUM/IVA administration and management details are provided in Section 10.
Study visits during the Treatment Period will occur as shown in Table 3-4. Subjects will be 
outpatients during the Treatment Period. All visits should occur within the windows 
specified. 
Procedures for subjects who prematurely discontinue LUM/IVA treatment are described in 
Section 8.1.10.2.
8.1.8
Washout Period 
8.1.8.1
Part A 
Not applicable 
8.1.8.2
Part B 
A 2-week Washout Period (Week 24 to Week 26 ± 4 days) will be included in order to 
evaluate the off-drug PD response. 
8.1.9
Follow-up 
8.1.9.1
Part A 
Table 3-2 lists the Safety Follow-up Visit assessments for Part A. Subjects will have a Safety 
Follow-up Visit 10 (± 3) days after the last dose of LUM/IVA.  
8.1.9.2
Part B 
Table 3-4 lists the Safety Follow-up Visit assessments for Part B. The Safety Follow-up Visit 
is scheduled to occur 2 weeks (± 4 days) after the last dose of LUM/IVA.  
The Safety Follow-up Visit, if applicable is the last visit for Part B, and should also be the 
Day 1 Visit in the Extension Study. 


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The Safety Follow-up Visit is not required for subjects who continue onto 
commercially-available LUM/IVA by prescription of a physician within 2 weeks (± 4 days) 
of completing LUM/IVA treatment at Week 24 or at the ETT Visit. 
The Safety Follow-up Visit is not required for subjects who permanently discontinue 
LUM/IVA treatment before or at the Week 16 Visit if they return for the Week 24 Visit. 
8.1.10
Early Discontinuation/Early Termination of Treatment 
8.1.10.1
Part A 
Subjects who permanently discontinue LUM/IVA treatment for any reason (except 
withdrawal of consent) will be asked to return to the clinical site 10 (± 3) days after their last 
dose of LUM/IVA. The assessments to be performed at this visit will be the same as those for 
the Safety Follow-up Visit (Table 3-2).
8.1.10.2
Part B 
Subjects who prematurely discontinue LUM/IVA treatment will be asked to complete the 
ETT Visit as soon as possible after their last dose, to remain on study, and to complete the 
study assessments from the time of LUM/IVA treatment discontinuation through the 
Week 24 Visit and the Safety Follow-up Visit, if applicable. The assessments to be 
completed are shown in Table 3-4. 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, if applicable 
(i.e., the assessments performed will be those specified for the ETT Visit), and a Safety 
Follow-up Visit will not be required.  
Subjects who become eligible to receive commercially-available LUM/IVA by prescription 
of a physician, and who choose to continue onto commercially-available LUM/IVA before 
completion of Part B, must remain on study-supplied LUM/IVA through the ETT Visit, and 
may only initiate treatment with commercially-available LUM/IVA after completion of this 
visit. 
8.2
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) is planned for Part B only. Before the 
start of Part B, the IDMC may be consulted at the discretion of the sponsor. The IDMC 
objectives and operational details will be defined in a separate document (the IDMC 
Charter), which will be finalized before the first subject is enrolled in Part B. The IDMC will 
conduct regular planned reviews of study data for the purpose of safety monitoring as 
outlined in the IDMC Charter. 
8.3
Rationale for Study Design and Study Drug Regimens 
8.3.1
Study Design 
This is a Phase 3, 2-part, open-label, multicenter study in subjects 2 through 5 years of age 
(inclusive) with CF who are homozygous for F508del.
Part A will evaluate the PK and safety of LUM/IVA over 15 days of dosing. The evaluation 
of LUM/IVA as multiple doses allows for the assessment of the time-dependent induction 
effect of LUM on IVA. The duration of dosing in Part A was selected to evaluate the PK and 
safety endpoints when the induction effect of LUM on the metabolism of IVA was 


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anticipated to have reached steady-state. Part B is designed to evaluate the safety of 
LUM/IVA dosing over 24 weeks in this pediatric CF population. In addition, the PD effects 
and PK of multiple doses of LUM/IVA over 24 weeks of dosing will be evaluated.  
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.22
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]). The present study is 
designed to obtain PK and safety information to support a proposed indication expansion of 
LUM/IVA in subjects 2 through 5 years of age, homozygous for F508del. The open-label 
design is considered adequate to evaluate the PK and safety of LUM/IVA in this pediatric 
population. 
This design is consistent with ICH guidelines for the study of human subjects, especially 
children, and balances safety concerns with potential benefits for the individual. 
8.3.2
Study Drug Dose and Duration 
Rationale for Dose 
Part A of this study 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 Part A is 
intended to inform the appropriateness or necessary adjustment of planned doses for Part B. 
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 the study 
population. The IVA model was coupled to the LUM model to account for the induction of 
cytochrome P450 (CYP)3A by LUM, which increases the metabolism of IVA. Thus, the IVA 
clearance is impacted by the weight dependence for the clearance of IVA alone and LUM 
exposure dependence induction effect. The population PK model is based on data obtained 
from subjects 6 years of age and older across the LUM and IVA combination development 
program.  
In the combination program, the dose regimen of LUM 400 mg/IVA 250 mg q12h was used 
in the Phase 3 studies (Studies 103 and 104) for subjects 12 years of age and older. In the 
Phase 3 Study 011, the dose regimen of LUM 200 mg/IVA 250 mg q12h was used for 
subjects 6 through 11 years of age. The LUM and IVA exposures from these studies are 
summarized in Table 8-1. For subjects 2 through 5 years of age who weigh less than 14 kg, 
oral administration of 100 mg LUM is projected to yield a mean area under the 
concentration-time curve as steady state (AUCss) of 201 μg/mL*h. For subjects 2 through 
5 years of age who weigh 14 kg or greater, oral administration of 150 mg LUM is projected 
to yield a mean AUCss of 238 μg/mL*h. Based on simulations for subjects 2 through 5 years 
of age, the LUM doses selected for Part A are expected to yield exposures that are 
comparable to those of subjects 6 years of age and older, which has been shown to be safe 
and well-tolerated in combination with IVA. 


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IVA as a single agent was previously investigated and approved for use in pediatric patients 
with CF 2 to less than 6 years of age with select mutations. In the Phase 3 study for this 
population, pediatric subjects who weighed less than 14 kg received oral administration of 
IVA granules, 50 mg q12h, and had a mean AUCss of 10.5 μg/mL*h; pediatric subjects 2 to 
less than 6 years of age who weighed 14 kg or greater received IVA granules, 75 mg q12h, 
and had a mean AUCss of 11.3 μg/mL*h. In the combination program, due to the induction 
effect of LUM on the metabolism of IVA, the IVA exposures are lower than that of the IVA 
monotherapy. The IVA AUCss for subjects 6 years of age and older in the combination 
program are summarized in Table 8-1. For subjects 2 through 5 years of age who weigh less 
than 14 kg, oral administration of 125 mg IVA in combination with LUM is projected to 
yield a mean AUCss of 5.49 μg/mL*h. For subjects 2 through 5 years of age who weigh 14 kg 
or greater, oral administration of 188 mg IVA in combination with LUM is projected to yield 
a mean AUCss of 5.71 μg/mL*h. Based on simulations for subjects 2 through 5 years of age, 
the IVA doses selected for Part A are expected to yield IVA exposures that are comparable to 
subjects 6 years of age and older and within prior clinical experience with IVA alone and 
IVA given in combination with LUM. 
Table 8-1 
Summary of LUM and IVA Exposures in Subjects With CF Who Are 
6 Years of Age and Older  
LUM AUC0-12h
(hr∙μg/mL)
IVA AUC0-12h
(hr∙μg/mL)
Age Group
N
Mean (SD)
Mean (SD)
6 through 11 years 
(pediatrics)
62
203 (57.4)
5.26 (3.08)
12 through 17 years 
(adolescents)
98
241 (61.4)
3.90 (1.56)
18 years and older 
(adults)
265
216 (47.9)
3.80 (1.94)
AUC0-12h: area under the concentration-time curve from 0 to12 hours; IVA: ivacaftor; LUM: lumacaftor; 
PK: pharmacokinetic; q12h: every 12 hours; SD: standard deviation
Note: PK data are from Study 011 Part B (6 through 11 years of age) and Studies 103 and 104 (12 through 
17 years of age; 18 years of age and older). Subjects in Study 011 received LUM 200 mg/IVA 250 mg q12h 
for 24 weeks and subjects in Studies 103 and 104 received LUM 400 mg/IVA 250 mg q12h for 24 weeks.
No safety issues were identified in prior clinical or nonclinical studies that would preclude 
the dosing regimen proposed for the current protocol.  
Rationale for the Duration of Dosing 
The concentration-time course of LUM in combination with IVA was studied in prior drug-
drug interaction studies (Studies VX08-809-005 and VX10-809-006). When given in 
combination, LUM is expected to cause time-dependent induction of IVA metabolism. The 
duration of 15 days was selected for Part A to evaluate PK, safety, and tolerability when the 
induction effect of LUM on the metabolism of IVA is anticipated to have reached steady-
state. 


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The duration of 24 weeks for Part B will provide an adequate assessment of safety in this 
population. 
8.3.3
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. Ophthalmologic examinations and spirometry assessments were added to 
the standard safety assessments. In addition, assessments were added to evaluate the PD 
effects of LUM/IVA and the acceptability/palatability of LUM/IVA granules. 
Ophthalmologic Examinations: A juvenile rat toxicity study performed to support dosing of 
IVA in subjects <2 years of age demonstrated lens opacities in some animals.20 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 ophthalmologic examinations 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, the spirometry 
testing will only be performed on subjects who are ≥3 years of age at screening. Even with 
this age stipulation, it is anticipated that reproducible spirometry will be obtained in a 
minority of the study population. 
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.23,24
Studies have shown that 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.25,26 Furthermore, 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.27 Therefore, only subjects who are ≥3 years of 
age at screening and who consent/assent to the optional LCI Substudy will undergo the LCI 
assessments, and LCI will only be done at selected sites that have the capability to perform 
these assessments. 
Weight, Stature, and BMI: Malnutrition is common in patients with CF because of increased 
energy expenditures due to lung disease and fat malabsorption. Given that LUM/IVA is a 
systemic therapy, it has the potential to improve extrapulmonary manifestations of CF, 
including those in the gastrointestinal system. Improved nutritional status, defined as an 
increase in weight and/or BMI, is considered an appropriate endpoint for therapies targeting 
exocrine pancreatic manifestation of CF and was explored in previous clinical studies of 
CFTR-targeted therapies (Studies 103 and 104).  
As children gain weight and stature as part of normal growth, adjustment for age and sex is 
necessary to assess changes in nutritional status in a population of boys and girls in varying 


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stages of growth. To evaluate the effect of LUM/IVA on growth and nutrition adjusted for 
age and sex, respective weight, stature, and BMI z-scores will be determined. Stature and 
weight will be collected at the study visits indicated in the Schedule of Assessments.  
Sweat Chloride: In patients with CF, the underlying CFTR ion transport defect results in 
elevated sweat electrolyte levels.28,29 The sweat chloride test (quantitative pilocarpine 
iontophoresis) is the most common diagnostic tool for CF. A sweat chloride concentration of 
t60 mmol/L is considered to be diagnostic of CF, whereas <40 mmol/L is considered 
normal. Based on the mechanism of action of LUM and IVA, the sweat chloride test was 
included in this study as a measure of the PD effect of LUM/IVA on CFTR activity. 
Other Events Related to Outcome: These assessments (pulmonary exacerbations, 
administration of antibiotic therapy for sinopulmonary signs and symptoms, and 
hospitalizations) are other outcomes used to assess efficacy in therapies targeting 
improvement in CF disease. CF pulmonary exacerbations are a compilation of patient signs 
and symptoms that often result in the need for aggressive treatment, including the use of 
intravenous (IV) antibiotics that may require hospitalization. To date, there is no generally 
accepted objective definition of a pulmonary exacerbation,30 and large multicenter CF 
clinical studies have used many variations of physician-derived definitions.31,32,33,34 Despite 
the lack of a standard definition, reduction in pulmonary exacerbation rate has served as a 
key clinical efficacy measure in definitive CF clinical studies, supporting the registration of 
2 chronic CF pulmonary therapies (inhaled recombinant human DNase and inhaled 
tobramycin).30 To evaluate the potential effect of LUM/IVA on pulmonary exacerbations, 
count, duration, and time-to-first event of hospitalizations and count and time-to-first event 
of IV courses of antibiotics for pulmonary exacerbations will be derived. For data 
consistency, this protocol specifies 1 definition of pulmonary exacerbation, which is based on 
the definition used for the other studies including the IVA monotherapy initial registration
studies (Section 11.4.4.1). Because signs and symptoms in the definition may occur without 
meeting the overall definition of a pulmonary exacerbation, the number and timing of 
outpatient sick visits to the clinic or hospital for CF that are unrelated to the study protocol 
will also be collected. 
Exocrine Pancreatic Function: The pancreas is 1 of the earliest and most seriously affected 
organs in patients with CF who have 2 copies of the F508del mutation, a high fraction of 
which develop pancreatic insufficiency (PI). 
x
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.35 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. 
x
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 


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collected at multiple time points during the study for evaluations of 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 2 through 5 years of age do not expectorate spontaneously, 
oropharyngeal swabs will be used to obtain airway cultures in this study. 
Acceptability/palatability measures: All subjects in Part B will have their acceptance of the 
dose administered recorded. The reaction of the subject will be assessed by the investigator 
or authorized designee as described in Section 11.4.9.
9
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled.
9.1
Inclusion Criteria 
Part A and Part B 
Subjects who meet all of the following inclusion criteria will be eligible. 
1. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) 
will sign and date an ICF and the subject will sign and date an assent form (if applicable). 
2. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) 
is willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, and other study procedures. 
3. Subjects (males and females) will be between 2 and 5 years of age, inclusive, on the date 
of informed consent (and assent, if applicable) for the relevant study part. 
4. Subjects who weigh t8 kg without shoes and wearing light clothing at the Screening 
Visit.  
5. Subjects with confirmed diagnosis of CF36 at the Screening Visit. CF is defined as: 
x
2 CF-causing mutations (all as documented in the subject's medical record) AND
x
chronic sinopulmonary disease OR gastrointestinal/nutritional abnormalities; OR
x
Part B only: a sweat chloride value ≥60 mmol/L by quantitative pilocarpine 
iontophoresis as documented in the subject’s medical record OR from the sweat 
chloride test result obtained at the Screening Visit. If an eligible historical sweat 
chloride result is documented in the subject’s medical record, that result alone [and 
not the Screening Visit result] may be used to determine eligibility.  


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6. Subjects who are homozygous for F508del (genotype to be confirmed at the Screening 
Visit). If the CFTR screening genotype result is not received before Day -1, a previous 
CFTR genotype laboratory report may be used to establish eligibility. Note:  
x
Subjects who have been enrolled and whose screening genotype does not confirm 
study eligibility must be discontinued from the study, as described in Section 9.5.
x
This assessment does not need to be repeated for confirmed subjects in Part A who 
may participate in Part B.  
7. Subjects with stable CF disease as deemed by the investigator at the Screening Visit. 
8. Subjects who are willing to remain on a stable CF medication regimen through Day 15 
(Part A) or through the Safety Follow-up Visit (Part B), if applicable. 
9.2
Exclusion Criteria 
Part A and Part B 
Subjects who meet any of the following exclusion criteria will not be eligible.  
1. History of any comorbidity reviewed at the Screening Visit 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. For example, a history of cirrhosis with portal 
hypertension. 
2. Any clinically significant laboratory abnormalities at the Screening Visit that would 
interfere with the study assessments or pose an undue risk for the subject (as deemed by 
the investigator). 
3. Any of the following abnormal laboratory values at the Screening Visit: 
x
Hemoglobin <10 g/dL 
x
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin 
>2 × upper limit of normal (ULN) 
x
Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2
(calculated by the Bedside Schwartz equation)37
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in 
therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first 
dose of LUM/IVA). 
5. A standard 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. If QTc 
exceeds 450 msec at the Screening Visit, the ECG should be repeated 2 more times 
during the Screening Period, and the average of the 3 QTc values should be used to 
determine the subject's eligibility. 
6. History of solid organ or hematological transplantation. 


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7. Ongoing or prior participation in an investigational drug study (including studies 
investigating LUM and/or IVA) within 30 days of the Screening Visit.  
x
A washout period of 5 terminal half-lives of the previous investigational study drug,
or 30 days, whichever is longer, must elapse before the Screening Visit.  
x
The duration of the elapsed time may be longer if required by local regulations.  
Note: Ongoing participation in a noninterventional study (including observational 
studies) is permitted. 
8. Use of restricted medication or food within specified duration before the first dose of 
LUM/IVA as defined in Section 9.3.
9. History of cataract/lens opacity or evidence of cataract/lens opacity determined to be 
clinically significant by a licensed ophthalmologist during the ophthalmologic 
examination at the Screening Visit. The Screening Visit ophthalmologic examination 
does not need to be repeated if there is documentation of an examination meeting 
protocol criteria that was conducted within 3 months before the Screening Visit 
(Section 11.6.6). Subjects with documentation of bilateral lens removal do not need the 
ophthalmologic examination and this criterion does not apply. 
10. The subject or a close relative of the subject is the investigator or a subinvestigator, 
research assistant, pharmacist, study coordinator, or other staff directly involved with the 
conduct of the study. 
9.3
Study Restrictions 
Part A  
Prohibited medications and certain foods are not allowed during the time periods summarized 
in Table 9-1.
A nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided in the study reference manual. 
Table 9-1 
Study Restrictions – Part A 
Restricted Medication/Fooda
Study Period
Screening Period
Treatment Period
Moderate and strong CYP3A 
inhibitors and inducers
None allowed within 14 days before 
the first dose of LUM/IVA
None allowed until after the Safety 
Follow-up Visit
Grapefruit/grapefruit juice, 
pomelos, star fruit, Seville 
oranges
None allowed within 14 days before 
the first dose of LUM/IVA
None allowed until last PK sample 
is taken
CYP: cytochrome P450; IVA: ivacaftor; LUM: lumacaftor; PK: pharmacokinetics
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.
a
See Section 9.4 for guidance for concomitant medications.


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Part B  
Prohibited medications and certain foods are not allowed (Screening Period through Week 24 
of Part B) as summarized in Table 9-2.
A nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided in the study reference manual. 
Table 9-2 
Study Restrictions – Part B 
Restricted Medication/Fooda
Study Period
Screening Period
Treatment Period
Strong CYP3A inducers
None allowed within 14 days before 
the first dose of LUM/IVA
None allowed
Strong CYP3A inhibitors
None allowed within 14 days before 
the first dose of LUM/IVA
Use with caution
CYP: cytochrome P450; IVA: ivacaftor; LUM: lumacaftor
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.
a
See Section 9.4 for guidance for concomitant medications.
9.4
Prior and Concomitant Medications 
9.4.1
Prohibited Medications 
Part A and Part B 
The prohibited medications that are described for Part A and Part B in Section 9.3 are not 
allowed in this study while subjects are receiving LUM/IVA. 
The use of CYP3A substrates is not prohibited in this study, but investigators need to be 
aware that LUM appears to be a strong inducer of this CYP isoenzyme. Therefore, the 
efficacy of drugs extensively metabolized by this isoenzyme may be affected. Each 
investigator should evaluate the benefit/risk ratio of using such drugs with LUM during this 
study. Investigators should discuss any concerns regarding the use of CYP3A substrates 
during this study with the Vertex medical monitor or authorized designee. 
The use of CYP2C and 2B6 substrates are not prohibited in this study, 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 such drugs with LUM and 
IVA during this study and discuss the use of these substrates during this study with the 
medical monitor or authorized designee. 
A nonexhaustive list of study prohibitions and cautions for food and medications will be 
provided in the study reference manual. 


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9.4.2
Prior and Concomitant Medications 
Part A and Part B 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered from
28 days before the first dose through the Safety Follow-up Visit will be recorded in each 
subject's source documents. In addition, concomitant medication dose(s) may be collected. 
x
It is recommended that subjects remain on a stable medication regimen for their CF from 
28 days before Day 1 through Day 15 (Part A), through the Safety Follow-up Visit 
(Part B), if applicable. 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. 
x
While the etiology of respiratory events associated with LUM/IVA is not yet known, data 
from healthy subjects in Study VX12-809-009 Cohort 4 suggest that treatment with 
short-acting bronchodilators may reverse the initial transient decline in ppFEV1 when 
dosed with LUM/IVA. Subjects in Part B will be prescribed a short-acting 
bronchodilator (if not already prescribed) to ensure constant availability during the study. 
x
Information about bronchodilator use during the study will be collected and documented 
in the subject's source documents. Subjects who are using a bronchodilator should have 
their spirometry assessments performed according to the guidelines provided in 
Section 11.6.7.
9.5
Removal of Subjects 
Part A and Part B 
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 LUM/IVA 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 LUM/IVA treatment in Part B, the subject will 
continue to be followed and should continue to return for study assessments as noted in 
Section 8.1.10, 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 or Safety Follow-up Visit, as applicable (see 
Sections 8.1.8 and 8.1.10), and follow up with the subject regarding any unresolved AEs.  
If a subject/caregiver withdraws consent, 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. 
Part A and Part B: Removal of subjects due to CFTR genotype 
Subjects who are enrolled on the basis of a historical genotype result (see Section 9.1,
Inclusion Criterion # 6), and whose screening genotype does not confirm study eligibility, 


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will be discontinued from LUM/IVA treatment, undergo the ETT and/or Safety Follow-up 
Visits, as per Sections 8.1.8 and 8.1.10, and will then be discontinued from the study. After 
LUM/IVA treatment discontinuation, these subjects will not undergo any further assessments 
other than those performed at the ETT and/or Safety Follow-up Visit(s). 
9.6
Replacement of Subjects 
Part A 
Subjects who withdraw or are withdrawn for non-safety reasons during the Treatment Period 
may be replaced in order to have an adequate number of subjects complete the study.  
Part B 
Subjects who withdraw or are withdrawn during the Treatment Period will not be replaced. 
10
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
10.1
Preparation and Dispensing 
Part A and Part B 
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) for administration to the study subject. 
10.2
Administration 
10.2.1
Part A 
On Day 1 through the morning dose on Day 15 (last dose of LUM/IVA), LUM/IVA granules 
will be orally administered with the approved foods and liquids listed in the study manual 
(e.g., apple sauce), as shown in Table 10-1.
Table 10-1 
Study Drug Administration – Part A 
Dose
Time
LUM/IVA
(Number of capsules)
Subject screening weight <14 kga
LUM 100 mg/IVA 125 mg q12h
AM
1 capsule
PM
1 capsule
Subject screening weight ≥14 kga
LUM 150 mg/IVA 188 mg q12h
AM
2 capsules
PM
2 capsules
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours
a
Doses are based on the subject’s weight at screening; no dose adjustments will be made across the duration of study 
treatment.
LUM/IVA will be administered approximately 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:  


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1. The morning LUM/IVA dose will be administered at the clinical site on Days 1, 8, 
and 15.
2. In the event that a subject’s scheduled visit occurs in the afternoon, all assessments will 
be collected relative to the evening dose. 
3. LUM/IVA will be administered after all predose safety and PK assessments have been 
performed. 
4. All LUM/IVA doses (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 1 hour) on each dosing occasion (e.g., if the morning 
dose is administered at 08:00 on Day 1, all subsequent morning doses should be 
administered between 07:00 and 09:00).  
5. The granule formulation will be dispensed by opening the capsules containing the 
granules and mixing the granules with the approved foods and liquids listed in the study
manual (e.g., apple sauce). Each dose (LUM 100 mg/IVA 125 mg or LUM 150 mg/IVA 
188 mg) will be comprised of the approved food or liquids into which the granules from 
the capsules are mixed. Details on preparing LUM/IVA will be provided in the pharmacy 
manual. 
6. At the Day 1 Visit, all subjects will be observed for 4 hours after the morning LUM/IVA 
dose. 
7. The morning dose on Day 15 will be the last LUM/IVA dose. 
10.2.2
Part B 
A review of safety, tolerability, and available PK data will be completed by an internal 
Vertex team after Part A to determine the dose(s) chosen for evaluation in Part B 
(Section 8.3.2). The planned doses are listed in Table 10-2. However, depending on the 
results from Part A, a single dose from Part A may be selected for all Part B subjects or a 
previously unspecified dose or doses may be selected for Part B. 
On Day 1 through the evening dose before the Week 24 Visit (last dose of LUM/IVA), 
LUM/IVA granules will be orally administered with the approved foods and liquids listed in 
the study manual (e.g., apple sauce), as shown in Table 10-2.
Table 10-2 
Study Drug Administration – Planned Doses for Part B 
Proposed Dosesa
Time
LUM/IVA
(Number of stick packs)
Subject screening weight <14 kgb
LUM 100 mg/IVA 125 mg q12h
AM
1 stick pack
PM
1 stick pack
Subject screening weight ≥14 kgb
LUM 150 mg/IVA 188 mg q12h
AM
1 stick pack
PM
1 stick pack
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours
a
The doses listed above are the planned doses for Part B. Depending on the results from Part A, a single dose from Part A 
may be selected for all Part B subjects or a previously unspecified dose or doses may be selected for Part B.
b
Doses are based on the subject’s weight at screening; no dose adjustments will be made across the duration of study 
treatment.


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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. All doses of LUM/IVA (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 2 hours) on each dosing occasion (e.g., if the morning 
dose is administered at 08:00 on Day 1, all subsequent morning doses should be 
administered between 06:00 and 10:00). 
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 
manual (e.g., apple sauce). Each dose (LUM 100 mg/IVA 125 mg or LUM 150 mg/IVA 
188 mg) 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 Day 1 Visit, all subjects will be observed for 4 hours after the morning LUM/IVA 
dose. 
4. The date, amount taken, and time of LUM/IVA administration, including whether food 
was taken with each dose, will be recorded for 1 day before PK sample collection and on 
the days of PK sample collection. 
5. On days of scheduled visits (Day 1, Day 15, and during Weeks 4, 8, and 16), 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.  
6. 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: 
x
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. 
x
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. 
7. 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. 
8. At the Week 24 Visit, the morning LUM/IVA dose will NOT be administered. The last 
LUM/IVA dose in Part B will be the evening dose administered the day before the 
Week 24 Visit.  


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10.3
Method of Assigning Subjects to Treatment Groups 
This is an open-label study with weight-based treatment. Randomization is not required in 
Part A or Part B.  
10.4
Dose Modification for Toxicity 
Part A and Part B 
Modifications of the LUM/IVA dose are prohibited. Should any unacceptable toxicity arise, 
individual subjects will be withdrawn from the study treatment. 
10.5
Packaging and Labeling 
Part A and Part B
Vertex will supply the LUM/IVA granules in capsules in bottles for Part A and in stick packs 
in kits for Part B. 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. 
10.6
Study Drug Supply, Storage, and Handling 
Part A and Part B 
Table 10-3 provides LUM/IVA 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 
requirements. To ensure adequate records, LUM/IVA will be accounted for as described in 
Section 10.7. Detailed instructions regarding the storage, handling, and dispensation of 
LUM/IVA will be provided in the pharmacy manual. 
Table 10-3 
Study Drug – Part A and Part B 
Drug 
Name
Formulation/
Route
Packaging (Formulation Strength)
Storage
Condition
LUM/IVA
Granules/
Oral
Part A:
Supplied as 
100-mg LUM/125-mg IVA 
granules in 1 capsule 
Part B:
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
Part A:
Supplied as 
150-mg LUM/188-mg IVA 
granules in 2 capsules 
Part B:
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)
IVA: ivacaftor; LUM: lumacaftor
10.7
Drug Accountability 
Part A and Part B
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 


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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. 
10.8
Disposal, Return, or Retention of Unused Drug 
Part A and Part B
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. 
10.9
Compliance 
Part A and Part B
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.  
10.10
Blinding and Unblinding 
Part A and Part B 
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 (Part A and Part B, subjects ≥3 years of age at corresponding part’s screening), 
sweat chloride (Part B only), and LCI results (Part B only, subjects ≥3 years of age at 
screening who consent/assent to the optional LCI Substudy) during the study, regardless if 
the subject permanently discontinues treatment. 
11
ASSESSMENTS 
11.1
Timing of Assessments 
The timing of assessments is shown in: 
x
Table 3-1 and Table 3-2 for Part A, and  
x
Table 3-3 and Table 3-4 for Part B.  
The following assessments must be performed in the order specified below when more than 
1 assessment is required at a particular time point: 


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1. Predose ECGs and vital signs should be performed before any other procedures that may 
affect heart rate (e.g., blood draws including PK). 
2. PK sampling and spirometry may be performed in either order. 
3. For Part B only, the LCI assessment (if applicable) should be performed before 
spirometry. 
4. For Part B only, the FE-1 sample may be collected at the study center during the study 
visit or may be collected by the subject up to 24 hours before the study visit at home and 
brought to the study visit. The sample may be collected pre- or postdose. 
11.2
Subject and Disease Characteristics 
Part A and Part B 
Subject and disease characteristics include the following: demographics, medical history, 
stature, and weight. 
Medical history will be elicited from each subject's caregiver during screening. Based on the 
medical history, the subject will be assessed for any disqualifying medical conditions as 
specified in the inclusion and exclusion criteria. The medical history should include a 
complete review of systems, past medical and surgical histories, and any known allergies. 
11.3
Pharmacokinetics 
11.3.1
Blood Sampling 
Part A and Part B
For the evaluation of plasma concentrations of LUM, IVA, and their respective metabolites, 
PK blood samples will be collected from all subjects as noted in Table 3-2 (Part A) and 
Table 3-4 (Part B).
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard 
operating procedures. 
The actual times may change upon agreement of the clinical pharmacologist and investigator, 
but the number of samples will remain the same (Part A only). All efforts will be made to 
obtain the PK samples at the exact nominal time relative to dosing. Samples collected outside 
of the acceptable windows will be considered protocol deviations. For each PK blood draw, a 
record of LUM/IVA administration will be collected as described in Section 10.7. The 
collection date and time that each PK blood sample is drawn will also be recorded.
If appropriate, these samples may also be used for the evaluation of metabolites that arise 
during treatment, for further evaluation of the bioanalytical method, and/or for analyses that 
provide information on the metabolic pathways used by, or impacted by, LUM or IVA. 
These data will be used for exploratory purposes and may not be included in the clinical 
study report.  
Details on sample collection, processing, and shipping will be provided in a separate 
guideline. 


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11.3.2
Processing and Handling of Pharmacokinetic Samples 
Part A and Part B
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in a separate guideline. The 
shipment address and assay laboratory contact information will be provided to the 
investigational site before initiation of the study.  
11.3.3
Bioanalysis 
Part A and Part B
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will 
be provided in separate reports. 
11.4
Pharmacodynamics 
Part A 
Not applicable. 
Part B  
The PD assessments described in Section 11.4.1 through Section 11.4.9 will be performed in 
Part B.
11.4.1
Sweat Chloride 
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Collection of sweat samples will be performed at visits specified in Table 3-3 and 
Table 3-4 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 must be conducted predose relative to the morning dose of LUM/IVA 
during the Treatment Period (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 regardless if the subject has prematurely discontinued 
treatment. 
11.4.2
Lung Clearance Index 
The optional LCI assessments derived from N2-multiple-breath washout (MBW) testing will 
be conducted at visits specified in Table 3-3 and Table 3-4 to evaluate the effect of 
LUM/IVA on LCI and for evaluation of correlations between LCI and sweat chloride, and 
correlations between LCI and spirometry parameters. LCI will only be performed on subjects 
who are ≥3 years of age at Part B screening and who consent/assent to the optional LCI 
Substudy.   


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LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas 
concentration to 1/40th of its starting value, whereas LCI5.0 represents the number of lung 
turnovers required to reduce the end tidal inert gas concentration to 1/20th of its starting 
value.38
Each MBW will be performed in multiple replicates for each visit and the final LCI value 
will be calculated from the technically acceptable washout replicates. The time for 
performing this test (in multiple replicates) during the study is approximately 1 hour at each 
study visit.  
Pre-bronchodilator MBW testing is defined as MBW testing performed for subjects who 
have 
x
withheld their short-acting bronchodilator (e.g., albuterol) or anticholinergic 
(e.g., Atrovent®) for more than 4 hours before the MBW testing; 
x
withheld their long-acting bronchodilator (e.g., salmeterol) more than 12 hours before the 
MBW testing; and 
x
withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva®]) for more than 24 hours before the MBW testing. 
During the Screening Period, the MBW testing may be performed pre- or 
post-bronchodilator. At all other visits, all MBW testing should be performed 
“pre-bronchodilator.” During the Treatment Period, MBW testing must be performed before 
dosing, unless noted otherwise. In the event that a subject forgets to withhold 
bronchodilator(s), MBW testing should be performed according to the following: 
x
If a subject's Day 1 MBW testing is pre-bronchodilator, but on a subsequent visit, the 
subject forgets to withhold bronchodilator use, post-bronchodilator MBW testing will be 
obtained for that visit only, and the visit will not be rescheduled. 
x
If on Day 1, the subject forgets to withhold his/her dose of bronchodilator, MBW testing 
should be performed post-bronchodilator and all subsequent MBW testing (according to 
the Schedule of Assessments detailed for LCI in Table 3-4) should be performed 
post-bronchodilator. 
x
Each MBW test will be recorded in the source documents as pre-bronchodilator or 
post-bronchodilator. 
The MBW testing should be performed before the spirometry assessment (Section 11.6.7).
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 regardless if the subject has prematurely discontinued treatment. 
11.4.3
Weight, Stature, and BMI 
Refer to Section 11.6.4.


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11.4.4
Other Events Related to Outcome 
11.4.4.1
Antibiotic Therapy for Sinopulmonary Sign/Symptoms 
New or changed antibiotic therapy (IV, inhaled, or oral) for the following sinopulmonary 
signs/symptoms will be determined and documented at visits as indicated in Table 3-3 and 
Table 3-4:
For this study, given the absence of a consensus definition for pulmonary exacerbation in 
clinical trials in this population, the definition appearing below will be applied to the signs 
and symptoms shown below for the analysis of pulmonary exacerbations.  
Definition: New or changed treatment with oral, inhaled, or IV antibiotics AND fulfillment 
of 1 criterion from List A or 2 criteria from List B, within the period 3 days before antibiotic 
start date through antibiotic stop date.39
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:  
x
Decrease in FEV1 ≥10% change from highest value in the past 6 months before the first 
dose, unresponsive to albuterol (if applicable)  
x
Oxygen saturation <90% on room air or ≥5% decrease from baseline  
x
New lobar infiltrate(s) or atelectasis on chest x-ray 
x
Hemoptysis (more than streaks on more than 1 occasion in past week) 
List B:
x
Increased work of breathing or respiratory rate (duration ≥3 days)
x
New or increased adventitial sounds on lung examination (duration ≥3 days)
x
Weight loss ≥5% decrease from highest value or decrease across 1 major percentile for 
age in past 6 months  
x
Increased cough (duration ≥3 days) 
x
Worked harder to breathe during physical activity (duration ≥3 days) 
x
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: 
x
Number of pulmonary exacerbations 
x
Number of days with pulmonary exacerbations 
x
Time-to-first pulmonary exacerbation 
x
Number of pulmonary exacerbations requiring hospitalizations 


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x
Number of days hospitalized for pulmonary exacerbations 
x
Time-to-first hospitalization for pulmonary exacerbation 
x
Number of pulmonary exacerbations requiring IV antibiotic therapy 
x
Number of days on IV antibiotic therapy for pulmonary exacerbations 
x
Time-to-first IV antibiotic therapy for pulmonary exacerbations 
11.4.4.2
Hospitalization for CF 
At visits indicated in Table 3-3 and Table 3-4, 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: 
x
Number of planned hospitalizations for CF (i.e., prophylactic antibiotic therapy) 
x
Number of all unplanned hospitalizations 
x
Number of days of all unplanned hospitalizations 
x
Time-to-first unplanned hospitalization 
11.4.5
Fecal Elastase-1 
Stool samples for assessment of FE-1 will be collected at the time points noted in Table 3-4.
Samples 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. Specific instructions for the collection, processing, and shipment of 
samples will be provided in a separate laboratory manual. 
11.4.6
Immunoreactive Trypsinogen 
Blood samples will be collected for IRT at the time points noted in Table 3-4. Specific 
instructions for the collection, processing, and shipment of samples will be provided in a 
separate laboratory manual.  
11.4.7
Microbiology Cultures 
At the time points noted in Table 3-4, a cotton-tipped swab will be used to collect the 
specimen from the posterior oropharyngeal wall and tonsillar pillars. Specific instructions for 
the collection, processing, and shipment of samples will be provided in a separate laboratory 
manual. 
11.4.8
Spirometry 
Refer to Section 11.6.7.


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11.4.9
Acceptability/Palatability Assessment 
At the time point noted in Table 3-4, the acceptability/palatability of LUM/IVA granules will 
be assessed by the investigator or authorized designee. The assessment will be conducted in 
2 steps. First the acceptability/palatability of only the approved food/liquid will be assessed. 
Next, the acceptability/palatability of the approved food/liquid with the LUM/IVA granules 
mixed in will be assessed. All subjects will have their acceptance of the administrations and 
the volumes consumed recorded. The facial expressions of all subjects will also be observed 
and any spontaneous comments in regards to likes or dislikes will be noted. Immediately 
after receiving each administration (the approved food/liquid and the approved food/liquid 
with the LUM/IVA granules mixed in), subjects will be asked to rate 
acceptability/palatability using the visual analog scale that incorporates a 5-point facial 
hedonic scale.40 All interviews will be conducted on a one-on-one basis in the clinic setting. 
Subjects will be familiarized with the scale using hypothetical situations before taste testing 
is conducted.  
11.5
Efficacy 
Part B Only 
All efficacy-related assessments are listed in Section 11.4, Pharmacodynamics. 
11.6
Safety 
Part A and Part B  
Safety evaluations will include AEs, clinical laboratory assessments (hematology, chemistry, 
coagulation studies, and urinalysis), clinical evaluation of vital signs, pulse oximetry, ECGs, 
physical examinations (PEs), spirometry, and ophthalmologic examinations (Part B). 
11.6.1
Adverse Events 
Part A and Part B
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 
Part A and Part B 
Blood and urine samples will be analyzed at a central laboratory. Although blood samples are 
to be collected and analyzed at a central laboratory, a local laboratory may be used if a 
subject cannot return to the clinical study site for the mandatory liver function testing 
(Section 11.6.3).
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1, Table 3-2, Table 3-3, and Table 3-4. Laboratory test results that are abnormal and 
considered clinically significant will be reported as AEs (see Section 13.1).  
The safety laboratory test panels are shown in Table 11-1.


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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.
Clinical laboratory assessments from screening will have no clinically significant findings 
that preclude participation in the study, as judged by the investigator, for a subject to receive 
LUM/IVA on Day 1. 
CF genotype (Screening Period only): CF genotyping will be performed on all subjects to 
confirm the subject is homozygous for the F508del-CFTR mutation. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be 
used. Local laboratories may be used at the discretion of the local investigator for 
management of urgent medical issues. 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 
Part A and Part B
It is strongly recommended that subjects with new ALT or AST elevations of ≥3 × ULN and 
clinical symptoms be followed closely, including repeat confirmatory testing performed by 


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the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT and AST levels, as clinically indicated. 
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: 
x
ALT or AST ≥8 × ULN 
x
ALT or AST ≥5 × ULN for more than 2 weeks 
x
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. 
If no plausible 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, in consultation 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. 
Resumption of Study Drug 
If a convincing alternative etiology is identified for the elevated transaminases (ALT, AST, 
GGT, alkaline phosphatase, and total bilirubin), LUM/IVA may be resumed when 
transaminases 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 transaminase elevation occurs within 4 weeks of rechallenge with 
LUM/IVA, then LUM/IVA must be discontinued, regardless of the presumed etiology. 
Mandatory Liver Function Testing 
Liver function testing (ALT, AST, GGT, alkaline phosphatase, and total bilirubin) must be 
performed while subjects are receiving LUM/IVA treatment (see Table 3-2 and Table 3-4).
These blood samples should be processed and shipped immediately per the laboratory 
manual. 
It is strongly recommended that subjects with new treatment-emergent ALT or AST 
elevations of >3 × ULN and clinical symptoms 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 (as indicated above) at the local laboratory must be reported immediately 
to the medical monitor AND the subject must have the tests repeated and sent to the central 
laboratory as soon as possible (ideally within 48 to 72 hours). 


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11.6.4
Physical Examinations and Vital Signs 
Part A and Part B
A PE of all body systems and vital signs assessment will be performed at screening and 
select study visits (see Table 3-1, Table 3-2, Table 3-3, and Table 3-4). At other visits, 
symptom-directed PEs and symptom-directed vital sign assessments can be performed at any 
time if triggered by AEs or if deemed necessary by the investigator or healthcare provider.
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/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. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, respiration 
rate, and pulse oximetry. The subject should rest for at least 5 minutes before having 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. Weight and stature will be 
measured at the time points noted in Table 3-1, Table 3-2, Table 3-3, and Table 3-4. If 
children 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).
Part B 
An abbreviated PE will be performed according to the Schedule of Assessments 
(see Table 3-4).
The abbreviated PE will include an assessment of the following body systems: 
head/neck/thyroid, EENT, cardiovascular system, respiratory system, skin, and abdomen. 
11.6.5
Electrocardiograms 
Part A and Part B  
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (see Table 3-1, Table 3-2, Table 3-3, and Table 3-4). 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: 
x
The subject will be instructed to rest in the supine position for at least 5 minutes, if 
possible, before having an ECG performed. 
x
The ECG will be performed before any other procedures that may affect heart rate, such 
as blood draws. 


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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. 
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. 
The PR, QT, and QT corrected for HR (QTc) intervals (including Fridericia's correction 
[QTcF = QT/RR1/3]), QRS duration, and HR will be captured in the ECG database. The 
central ECG diagnostic service's standard reference ranges will be used throughout the study. 
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 in whom treatment is discontinued for increased QTcF should have their QTcF 
monitored closely until it normalizes or returns to baseline. 
11.6.6
Ophthalmologic Examination 
Part A and Part B 
In Part A, subjects will undergo an ophthalmologic examination at the Screening Visit 
(Table 3-1).  
In Part B, subjects will undergo an ophthalmologic examination at the Screening Visit 
(Table 3-3) and at the Week 24 Visit OR the ETT Visit OR the Safety Follow-up Visit, as 
applicable (Table 3-4).
The ophthalmologic examination includes: 
x
measurement of best corrected distance visual acuity of each eye 
x
pharmacologically dilated examination of the lens with a slit lamp 


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These examinations must be conducted by a licensed ophthalmologist. The Part A and Part B
screening ophthalmologic examination must be completed and the results reviewed before 
enrollment. If cataract/lens opacity is identified and determined to be clinically significant by 
the licensed ophthalmologist at the screening examination, the subject must not be enrolled. 
The screening ophthalmologic examination does not need to be repeated if there is 
documentation of an examination meeting protocol criteria that was conducted within 
3 months before the Screening Visit. Subjects with documentation of bilateral lens removal 
do not need the ophthalmologic examination. 
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 8.1.10. If the subject continues, more frequent 
ophthalmologic monitoring should be considered. 
In addition, at the Screening Visit, the following history will be obtained for all subjects: 
x
history of steroid use 
x
history of trauma to the eye 
x
any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
Additional ophthalmologic examinations may be conducted at the discretion of the 
investigator. The Vertex medical monitor or designee should be notified of any additional 
ophthalmologic examinations. 
11.6.7
Spirometry 
Part A and Part B
Spirometry will be performed according to the American Thoracic Society Guidelines41 at 
the time points noted in Table 3-1, Table 3-2, Table 3-3, and Table 3-4, according to the 
additional guidelines that follow. In Part A and Part B, spirometry will only be performed on 
subjects who are ≥3 years of age at screening of the corresponding part.   
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who 
have 
x
withheld their short-acting bronchodilator (e.g., albuterol) or anticholinergic 
(e.g., Atrovent®) for more than 4 hours before the spirometry assessment; 
x
withheld their long-acting bronchodilator (e.g., salmeterol) more than 12 hours before the 
spirometry assessment; and 
x
withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva®]) for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
“pre-bronchodilator.” During the Treatment Period, spirometry assessments must be 


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performed before dosing, unless noted otherwise. In the event that a subject forgets to 
withhold bronchodilator(s), spirometry should be performed according to the following: 
x
If a subject's Day 1 spirometry is pre-bronchodilator, but on a subsequent visit, the 
subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry will be 
obtained for that visit only, and the visit will not be rescheduled. 
x
If on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator and all subsequent spirometric measurements 
(according to the Schedule of Assessments detailed in Table 3-2 and Table 3-4) should be 
performed post-bronchodilator. 
x
Each spirometry assessment will be recorded in the source documents as 
pre-bronchodilator or post-bronchodilator. 
The parameters listed below will be normalized using the standards of GLI.42
x
FEV1 (L) 
x
Forced vital capacity (FVC) (L) 
x
FEV1/FVC (ratio) 
x
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 regardless if the subject has prematurely discontinued treatment. 
11.6.8
Contraception and Pregnancy 
Not applicable. 
12
STATISTICAL AND ANALYTICAL PLANS 
Analysis of all data, including safety, PD and PK profiles, will be performed by Vertex or its 
designee. Two detailed analysis plans, 1 for the analysis of safety data in Part A, 1 for the 
analysis of safety and PD in Part B, will be presented in corresponding statistical analysis 
plans (SAPs), and a detailed analysis plan for PK profiles will be presented in a clinical 
pharmacology analysis plan (CPAP) before the data cut/lock for each part. 
12.1
Sample Size and Power 
Part A 
No formal sample size calculations have been performed. The number of subjects 
participating is common in early clinical pharmacology studies and is considered sufficient to 
achieve the PK objectives of Part A. 


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Part B 
No formal sample size calculations have been performed. The number of subjects in Part B is 
deemed adequate to meet the primary safety objective. Given approximately 56 subjects are 
planned for enrollment and assuming a 10% dropout rate, approximately 50 subjects will 
complete Part B. Table 12-1 displays estimates of the probability for observing AEs in at 
least 1 subject for the given incidence (T) and sample size. With a total sample size of 
50 subjects (completers), there is a 92.3% chance of observing AEs in at least 1 subject if the 
true incidence is 5%, and a 99.5% chance of observing AEs in at least 1 subject if the true 
incidence is 10%. The probabilities are the binomial probabilities calculated using S-PLUS ®.  
Table 12-1 
Probability of Observing Adverse Events in At Least 1 Subject if the 
Adverse Event Incidence (T) is 5% and 10%
Sample Size
T = 5%
T = 10%
50a
92.3%
99.5%
a
50 reflects the sample size of the completers.
Additional subjects may be enrolled at the sponsor’s discretion to achieve up to 30 subjects 
in the LCI Substudy. This sample size is consistent with prior exploratory studies conducting 
LCI assessments.43,44
12.2
Analysis Sets 
Part A 
All Subjects Set is defined as all subjects who have signed informed consent (and assent, if 
applicable) and enrolled or dosed in Part A.  
Safety Set will include all subjects who received at least 1 dose of study drug in Part A. The 
safety analyses will be based on the Safety Set overall, unless otherwise specified. In 
addition, the summary by the dosing groups (LUM 100 mg/IVA 125 mg q12h and 
LUM 150 mg/IVA 188 mg q12h) at enrollment determined by weight at the Screening Visit 
will be provided as supplementary information. 


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Part B 
All Subjects Set is defined as all subjects who have signed informed consent (and assent, if 
applicable) and enrolled or dosed in Part B.  
Safety Set will include all subjects who received at least 1 dose of study drug in Part B. The 
safety analyses will be based on the Safety Set overall, unless otherwise specified. If the 
weight-based 2 doses are used in Part B, the summary by the dosing groups 
(LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/IVA 188 mg q12h) at enrollment 
determined by weight at Screening Visit will be provided as supplementary information.  
Full Analysis Set (FAS) will include all enrolled subjects in Part B who are exposed to any 
amount of study drug in Part B. PD analyses (except LCI) will be based on the FAS. 
LCI Substudy Set will include all subjects who have signed informed consent (and assent, if 
applicable) to the optional LCI Substudy in Part B and enrolled and dosed in Part B. 
LCI-related analysis will be based on the LCI Substudy Set. 
Subject data listings for both Part A and Part B will be the referenced using the All Subjects 
Set in the corresponding part, unless otherwise specified. 
12.3
Statistical Analysis 
This section presents a summary of the planned statistical analyses of safety for Part A and 
the planned statistical analysis of safety and PD for Part B. The Vertex Biometrics 
Department, or designee, will analyze the data derived from this study. 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 SAPs for the 
corresponding parts. Details of additional supportive safety (Part A and Part B), and PD 
(Part B only) analyses not included in the protocol will be provided in the SAPs. The SAPs 
will be finalized before the data cut/lock for each part.  
12.3.1
General Considerations 
This section applies to Part A and Part B, unless otherwise specified. 
For Part A and Part B, all individual subject data based on All Subjects Set of the 
corresponding part will be presented in data listings.  
Continuous variables will be summarized using the following descriptive summary 
statistics: number of subjects (n), mean, SD, standard error (SE), median, minimum, and 
maximum.  
Categorical variables will be summarized using counts and percentages.  
Baseline value: For Part A and Part B, unless otherwise specified, the baseline value will be 
defined as the most recent non-missing measurement (scheduled or unscheduled) collected 
before the initial administration of study drug.  
x
For ECG, the baseline will be defined as the average of the 3 pretreatment measurements 
on Day 1.  


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For Part B only: 
x
For LCI-related parameters, the values at each visit will be calculated from the 
technically acceptable washout replicates as detailed in Section 12.3.3.2.12. 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. 
x
For sweat chloride, the values at each visit will be based on the averaged measurements 
from left and right arms as specified in Section 12.3.3.2.1. The baseline will be defined as 
the average of the values at screening and the pretreatment measurement on Day 1. 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 postbaseline value - baseline 
value. 
Relative change from baseline: will be calculated and presented in percentage as 
100 × (postbaseline value - baseline value)/baseline value. 
12.3.2
Background Characteristics 
Unless otherwise specified, this section applies to both Parts A and B. All summaries will be 
based on the Safety Set of the corresponding part overall. For Part A, and Part B if the 
weight-based 2 doses are used, the summary by the dosing groups (LUM 100 mg/IVA 
125 mg q12h and LUM 150 mg/IVA 188 mg q12h) at enrollment determined by weight at 
the Screening Visit will be provided as supplementary information, unless otherwise 
specified. No statistical hypothesis testing will be performed.  
12.3.2.1
Subject Disposition 
Number and percentage of subjects in the following categories will be summarized as 
appropriate. 
Numbers of the following categories will be provided: 
x
All Subjects Set  
x
Dosed (Safety Set) 
x
Enrolled and dosed (FAS, Part B only) 
Both numbers and percentages of subjects in the following categories will be provided. The 
percentage will be based on the number in Safety Set of the corresponding part. 
x
Completed study drug treatment 
x
Prematurely discontinued the treatment and the reasons for discontinuations 
x
Completed study 
x
Prematurely discontinued the study and the reasons for discontinuations 
For Part B, similar disposition tables will be provided based on the LCI Substudy Set. 


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12.3.2.2
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized. Important protocol deviations/violations will be provided as a subject data 
listing only. The rules used to define the important protocol deviations/violations will be 
provided in the SAPs.
The demographics, baseline characteristics, and medical history summary will be presented 
for the Safety Set of the corresponding part to allow review of the characteristics of those 
included in safety analyses, which will be based on this analysis set. 
For Part B, similar tables for demographics and baseline characteristics will be provided 
based on the LCI Substudy Set. 
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:  
x
Prior medication: any medication that started before initial dosing of study drug in each 
part, regardless of when it ended. 
x
Concomitant medication: medication continued or newly received at or after initial 
dosing of study drug in each part to 14 days after the last dose of study drug in the 
corresponding part. 
x
Post-treatment medication: medication continued or newly received after 14 days after 
the last dose of study drug in each part.  
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or 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 after 14 days after the last dose of study drug, it will be considered as prior, 
concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively based on 
the Safety Set. Post-treatment medications will be listed for each subject.  
12.3.2.4
Study Drug Exposure 
Duration of study drug exposure is defined as follows: last dose date −first dose 
date + 1 day, regardless of any interruptions in dosing. If the last dose date of study drug is 
missing, the subject's last exposure date will be used for analysis purposes. 
Part A 
Study drug exposure will be summarized overall based on Part A Safety Set. In addition, the 
summary by the dosing group (LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/ 
IVA 188 mg q12h) at enrollment determined by weight at the Screening Visit will be 
provided as supplementary information.  


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Study drug exposure will be presented in an individual subject data listing to indicate 
whether the study drug was taken or not. 
Part B 
Duration of study drug exposure will be summarized overall based on Part B Safety Set and 
descriptively as a quantitative variable (number, mean, SD, SE, median, minimum, and 
maximum). If the weight-based 2 doses are used in Part B, summary by dosing groups 
(LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/IVA 188 mg q12h) at enrollment 
determined by weight at the Screening Visit will be provided as supplementary information. 
Additionally, the cumulative 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. 
12.3.2.5
Study Drug Compliance 
Part A 
Compliance will be presented in an individual subject data listing. 
Part B 
Study drug compliance will be assessed by calculating as follows: 100 × (1 − [total number 
of days of study drug interruption] / [duration of study drug exposure + total number of days 
study drug interrupted after last dose, 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), 
where number of days of each study drug interruption is defined as the interruption 
end date −the corresponding interruption start date + 1. 
Percent of stick packs taken will be calculated as follows: 100 × (total number of stick packs 
administered) / (2 × [duration of study drug exposure in days + total number of days study
drug interrupted after last dose, if any]). Subjects who have a calculated percent of stick 
packs taken >100% will be considered as having taken 100% of stick packs. 
Treatment compliance percentages and percent of stick packs taken will be summarized 
descriptively as quantitative variables (number, mean, SD, SE, median, minimum, and 
maximum). The number and percentage of subjects whose compliance is <80% or ≥80% and 
the number and percentage of subjects whose percent of stick packs taken is <80% or ≥80% 
will be summarized. 
Study drug compliance will be based on Part B Safety Set overall. If the weight-based 
2 doses are used in Part B, supplementary information will be provided for study drug 
compliance by the dosing group (LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/ 
IVA 188 mg q12h) at enrollment determined by weight at the Screening Visit. 
12.3.3
Pharmacodynamics Analysis (Part B Only) 
12.3.3.1
Analysis of Primary Endpoints 
Not applicable. 


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12.3.3.2
Analysis of Secondary Pharmacodynamic Endpoints 
Analyses for secondary PD endpoints are described in Sections 12.3.3.2.1 through 
12.3.3.2.13. Analyses for other secondary endpoints and sensitivity analysis, supportive 
analysis, subgroup analysis of secondary variables, and analyses for other endpoints will be 
described in the SAP. 
12.3.3.2.1
Absolute Change From Baseline in Sweat Chloride at Week 24 
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., values 
from samples with volumes <15 μL will be considered missing for analysis purposes). If a 
subject has replicated measurements at a postbaseline time point, then the median of the 
values will be used in data analyses. 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. Note: Any sweat 
chloride concentration values reported as <10 mmol/L or >160 mmol/L will be considered 
missing. 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with the 95% confidence interval and within-group P value based on Normal approximation, 
will be provided for absolute change from baseline in sweat chloride at Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval based on 
Normal approximation, will be provided for all other visits.  
Additional analysis of the primary endpoint will be described in the SAP. 
12.3.3.2.2
Absolute Change From Baseline in BMI/BMI-for-Age Z-score at 
Week 24 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with the 95% confidence interval and within-group P value based on Normal approximation, 
will be provided for absolute change from baseline in BMI and BMI-for-age z-score at 
Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval based on 
Normal approximation, will be provided at all other visits.  
12.3.3.2.3
Absolute Change From Baseline in Weight/Weight-for-Age 
Z-Score at Week 24 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in weight and weight-for-age z-score at 
Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval based on 
Normal approximation, will be provided at all other visits.  


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12.3.3.2.4
Absolute Change From Baseline in Stature/Stature-for-Age 
Z-score at Week 24 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in stature and stature-for-age z-score at 
Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval based on 
Normal approximation, will be provided at all other visits.  
12.3.3.2.5
Analysis of Pulmonary Exacerbation-related Other Secondary 
Pharmacodynamic Variables 
x
Time-to-first pulmonary exacerbation through Week 24: Time-to-first pulmonary 
exacerbation will be analyzed using Kaplan-Meier method. Cumulative incidence of 
pulmonary exacerbation will be summarized and plotted. Subjects without an 
exacerbation by Week 24 Visit will be censored at Week 24 Visit or at the last visit 
before the Safety Follow-up Visit for subjects with missing Week 24 Visit.  
x
Number of pulmonary exacerbations through Week 24: The number of pulmonary 
exacerbations through Week 24 [inclusive] (including both on-treatment events and 
events after treatment discontinuation), normalized by the time spent in the study 
(Week 24 date – first dose date +1), will be summarized. 
x
Number of CF-related hospitalizations through Week 24: For the number of 
CF-related hospitalizations through Week 24 [inclusive], the analysis will be similar to 
the analysis of the number of pulmonary exacerbations through Week 24.  
12.3.3.2.6
Absolute Change in FE-1 Levels From Baseline at Week 24 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in FE-1 levels at Week 24. In addition, 
descriptive summary statistics, along with 95% confidence interval based on Normal 
approximation, will be provided at all other visits.  
Number and percentage of subjects with pancreatic insufficiency, defined as having FE-1 
level <200 μg/g, will be provided at Week 24 and at baseline. The within-group shift will be 
tested based on McNemar’s test. 
12.3.3.2.7
Absolute Change in Serum Levels of IRT From Baseline Through 
Week 24 
For each subject, the serum levels of IRT through Week 24 for each subject will be derived 
as the simple arithmetic mean at each visit (Day 15, Weeks 4, 8, 16, and 24), regardless of 
on-treatment measurement or measurement after treatment discontinuation. As long as there 
is at least 1 measurement available, the average will be calculated based on all available 
measurements. If all measurements are missing, then the average through Week 24 will be 
missing and the subject will not be included in the summary for the average through 
Week 24. The absolute change in serum levels of IRT from baseline through Week 24 will be 


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derived similarly as the simple arithmetic mean of the absolute change in serum levels of IRT 
from baseline at each visit. 
Summary statistics, along with 95% confidence interval and within-group P values based on 
Normal approximation, for absolute change from baseline in serum levels of IRT through 
Week 24 will be provided.  
In additional, summary statistics, along with 95% confidence interval based on Normal 
approximation, will be provided at each visit.  
12.3.3.2.8
Change in Microbiology Culture From Baseline at Week 24 
Raw values and change in microbiology from baseline at Week 24 will be summarized 
descriptively. The summary will be separated for each possibly-detected organism.  
12.3.3.2.9
Absolute Change From Baseline in ppFEV1 at Week 24 
Summary statistics, along with 95% confidence interval and within-group P values based on 
Normal approximation, for absolute change from baseline in ppFEV1 will be provided at 
Week 24.  
In addition, summary statistics, along with 95% confidence interval based on Normal 
approximation, will be provided at all other visits.  
12.3.3.2.10
Absolute Change in Sweat Chloride From Week 24 at Week 26 
Summary statistics, along with 95% CI and within-group P values based on Normal 
approximation, for absolute change from Week 24 will be provided at Week 26.  
12.3.3.2.11
Acceptability/Palatability of LUM/IVA Granules at Day 1 
Summary statistics will be provided for the acceptability/palatability data. 
12.3.3.2.12
Absolute Change From Baseline in LCI2.5 at Week 24 
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 be 
considered missing; 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. 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in LCI2.5 at Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval based on 
Normal approximation, will be provided at all other visits.  


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12.3.3.2.13
Absolute Change From Baseline in LCI5.0 at Week 24 
Analysis of absolute change in LCI5.0 from baseline at Week 24 will be similar to the analysis 
of absolute change in LCI2.5 from baseline at Week 24.  
12.3.4
Safety Analysis 
Unless otherwise specified, this section applies to Part A and Part B. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
x
Incidence of treatment-emergent adverse events (TEAEs) 
x
Clinical laboratory values (serum chemistry, hematology, coagulation studies, and 
urinalysis) 
x
ECGs (standard 12-lead) 
x
Vital signs 
x
Pulse oximetry 
x
Ophthalmological examinations (Part B only) 
x
Spirometry (subjects ≥3 years age at screening)
For Parts A and B, safety endpoints will be analyzed based on the Safety Set for the 
corresponding part overall. For Part A, and Part B if the weight-based 2 doses are used, the 
summary by the dosing groups (LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/ 
IVA 188 mg q12h) at each part’s enrollment determined by weight at the Screening Visit will 
be provided as the supplementary information.  
12.3.4.1
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or 
post-treatment AEs.  
x
Pretreatment AE: any AE that started before initial dosing of study drug in each part. 
x
TEAE: any AE that increased in severity or that was newly developed during the 
Treatment Period which is defined as being the period from initial dosing of study drug in 
each part to 14 days after the last dose of study drug in the corresponding part. 
x
Post-treatment AE: any AE that increased in severity or that developed after 14 days 
after the last dose of study drug in each part. 
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. 
For Part A and Part B, TEAE summaries will be presented using number and percentages of 
subjects.  
An overview of TEAE profile will be provided, including total number of TEAEs, with 
number and percentage of subjects for the following categories: (1) All TEAEs, 
(2) Grades 3/4 TEAEs, (3) TEAEs by relationship to study drug, (4) TEAEs by maximum 


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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: 
x
All TEAEs  
x
Grades 3/4 TEAEs 
x
TEAEs by relationship to study drug  
x
TEAEs by maximum severity 
x
TEAEs leading to treatment interruption 
x
TEAEs leading to treatment discontinuation 
x
Serious TEAEs 
x
Serious TEAEs related to study drug 
x
TEAEs leading to death 
x
Frequently reported TEAEs (Part B only)
Summaries will be presented by MedDRA system organ class (SOC) and preferred term (PT) 
using frequency counts and percentages. 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. 
In addition, listings that contain individual subject data for all TEAEs leading to treatment 
interruption, TEAEs leading to treatment discontinuation, deaths, and serious AEs will be 
provided separately. All AEs, including pre- and post-treatment AEs, will be presented in 
individual subject data listings. 
12.3.4.2
Clinical Laboratory Assessments 
For the laboratory measurements, the raw values and change from baseline values of the 
continuous hematology and chemistry results will be summarized in SI units at each 
scheduled time point. 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 will be summarized. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event (i.e., categorical change) during the Treatment Period will be summarized. The 
PCS/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. 


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12.3.4.3
Electrocardiogram 
For the ECG measurements, a summary of raw values and change from baseline values will 
be provided at each scheduled time point 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 PCS ECG reading (i.e., categorical 
change) during the Treatment Period will be summarized. The PCS/categorical criteria will 
be provided in the SAP. 
The number and percentage of subjects with shift changes from baseline (normal/missing, 
not clinically significant, and potentially clinically significant according to overall ECG 
evaluation) to the worst ECG evaluation during the Treatment Period will be summarized. 
12.3.4.4
Vital Signs 
For the vital signs measurements, the raw values and change from baseline values will be 
summarized at each scheduled time point: 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 PCS vital sign event (i.e., categorical 
change) during the Treatment Period will be summarized. The PCS/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 baseline 
values will be provided at each scheduled time point for the percent of oxygen saturation by 
pulse oximetry.  
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
Treatment Period will be provided.  
12.3.4.6
Ophthalmological Examinations 
Ophthalmological examination findings will be presented as a data listing for Part A 
(screening only) and Part B.  
12.3.4.7
Spirometry 
Spirometry data, including their raw values, absolute change from baseline and relative 
change from baseline, will be summarized descriptively at each visit.  
12.3.4.8
Physical Examination 
PE findings will be presented as a data listing only. 


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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 8.2) analysis will be provided in the IDMC Analysis Plan. 
12.4
Clinical Pharmacology Analysis 
12.4.1
Pharmacokinetic Analysis 
Nonlinear mixed effects modeling will be applied for the PK analysis of LUM and IVA. 
Covariates (e.g., body weight) will be evaluated and included in the final population PK 
model if including them significantly improves the overall model fit and the accuracy and 
precision of population estimates of PK parameters.  
Preliminary analysis will be performed on the PK data obtained from Part A of the current 
study. The PK analysis, along with safety and tolerability data from Part A, will be used to 
appropriately confirm the dose selection for Part B of the study (or adjust the doses if 
necessary before the start of Part B) based on PK parameters relative to historical results in 
the clinical development program. An interim PK analysis of data collected in Parts A and B 
may be performed to inform future development of LUM and IVA. This interim analysis, if 
performed, will not affect the conduct of the present study. Plasma concentrations for LUM, 
IVA, and their metabolites will be summarized using descriptive statistics by visits and time 
points. 
12.4.2
Pharmacodynamic Analysis 
12.4.3
Pharmacokinetic/Pharmacodynamic Analyses 
The relationship between the outcome measures (e.g., sweat chloride) and drug 
concentrations may be used in exploratory analysis.  
An interim PK/PD analysis of data collected in Part B (e.g., sweat chloride) may be 
performed to inform future development of LUM and IVA. This interim analysis, if 
performed, will not affect the conduct of the present study.  
Details of methods used will be provided in the CPAP.


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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.  
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:
x
Concomitant signs or symptoms related to the abnormal study assessment 
x
Further diagnostic testing or medical/surgical intervention 
x
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 a serious adverse event (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 ICF is signed until the following time points: 
x
For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
x
For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit 


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x
For enrolled subjects who do not have a Safety Follow-up Visit: through the end of study 
participation 
All subject's caregivers 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: 
x
Description of the event 
x
Classification of “serious” or “nonserious”
x
Date of first occurrence and date of resolution (if applicable) 
x
Severity  
x
Causal relationship to study drug(s) 
x
Action taken  
x
Outcome  
x
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 
August 2015). 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. Causality will be classified using the categories presented in Table 13-2.


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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).
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.


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Table 13-4 
Classifications for Outcome of an AE 
Classification
Definition
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. 
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: 
x
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) 
x
Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred  
x
Inpatient hospitalization or prolongation of hospitalization 
x
Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions) 
x
Congenital anomaly or birth defect 
x
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 


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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 GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug 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 and possible etiologies. On the SAE Form, relationship to study 
drug will be assessed only as related (includes possibly related) or not related (includes 
unlikely related), and 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 IRB/local 
IEC of all unexpected serious adverse drug reactions involving risk to human subjects. 


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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 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.  


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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 and associated regulations (“HIPAA”) 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 
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: 
x
Subject or investigator noncompliance 
x
Unsatisfactory subject enrollment 
x
Lack of adherence to protocol procedures 
x
Lack of evaluable and/or complete data 
x
Potentially unacceptable risk to study subjects 
x
Decision to modify drug development plan 
x
Decision by the FDA or other regulatory authority 


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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. 
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.  


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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. 


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14
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
http://www.cff.org/AboutCF/. Accessed 17 June 2016. 
2 
Cystic Fibrosis Foundation Patient Registry. 2013 Annual Data Report. Bethesda, 
MD: Cystic Fibrosis Foundation; 2014. 
3 
European Cystic Fibrosis Society. ECFS Patient Registry: 2010 Annual Report. 
Karup, Denmark: 2014. 
4 
The Canadian Cystic Fibrosis Registry. 2013 Annual Report. Toronto, Ontario: 
Cystic Fibrosis Canada; 2015. 
5 
Australian Cystic Fibrosis Data Registry. Cystic fibrosis in Australia 2013: 16th 
annual report. Baulkham Hills, New South Wales, Australia: Cystic Fibrosis 
Australia; 2015. 
6 
FDA Office of Orphan Products Development. Developing Products for Rare 
Diseases & Conditions. Available at: http://www.fda.gov/ForIndustry/ 
DevelopingProductsforRareDiseasesConditions/default.htm. Accessed 17 June 2016. 
7 
European Medicines Agency. Committee for Orphan Medicinal Products (COMP). 
Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/ 
general/general_content_000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC
0b01ac0580028e30. Accessed 17 June 2016. 
8 
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. 
9 
Cystic Fibrosis Trust. Cystic Fibrosis Trust annual review 2010. London, UK: Cystic 
Fibrosis Trust; 2012. 
10  
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
11  
Kriendler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new 
therapies. Pharmacol Ther. 2010;125:219-29. 
12 
Cystic Fibrosis Mutation Database (CFTR1). Cystic Fibrosis Centre at the Hospital 
for Sick Children in Toronto Web Site [Internet]. Available from: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed: 17 June 2016. 
13  
McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype 
and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 
2003;361(9370):1671-6. 
14 
Cheng SH, Gregory RJ, Marshall J, Sucharita P, Souza DW, White GA, et al. 
Defective intracellular transport and processing of CFTR is the molecular basis of 
most cystic fibrosis. Cell. 1990;63:827-34. 


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15 
Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, et al. Altered 
chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. 
Nature. 1991;354:526-8. 
16  
Kerem E, Kerem B. Genotype-phenotype correlations in cystic fibrosis. Pediatr 
Pulmonol. 1996;22:387-95.
17  
Johansen HK, Nir M, Hoiby N, Koch C, Schwartz M. Severity of cystic fibrosis in 
patients homozygous and heterozygous for delta F508 mutation. Lancet.
1991;337:631-4. 
18  
Kerem E, Corey M, Kerem BS, Rommens J, Markiewicz D, Levison H, et al. The 
relation between genotype and phenotype in cystic fibrosis—analysis of the most 
common mutation (delta F508). N Engl J Med. 1990;323:1517-22.
19  
McKone EF, Goss CH, Aitken ML. CFTR genotype as a predictor of prognosis in 
cystic fibrosis. Chest 2006;130:1441-7.
20  
Vertex Pharmaceuticals Incorporated. Lumacaftor/Ivacaftor Investigator's Brochure, 
Version 2.0. Report date: 11 July 2016. 
21  
Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, 
et al. Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST 
CF). Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis 
after newborn screening. J Pediatr. 2009 Nov;155(5):623-8.
22  
ICH E11. Clinical Investigation of Medicinal Products in the Pediatric Population. 
20 July 2000. 
23 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103:793-9. 
24 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple 
breath washout indices in unsedated preterm neonate. Pediatr Pulmonol. 
2010;45:62-70. 
25
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas 
washout and spirometry versus structural lung disease in cystic fibrosis. Thorax. 
2008;63(2):129-34 
26 
Lum S, Gustafsson P, Ljungberg H, Hülskamp G, Bush A, Carr SB, et al. London 
Cystic Fibrosis Collaboration. Early detection of cystic fibrosis lung disease: 
multiple-breath washout versus raised volume tests. Thorax. 2007;62(4):341-7.
27  
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. Journal of CF. 
2014;13:123–38. 
28 
Wilschanski M, Zielenski J, Markiewicz D, Tsui LC, Corey M, Levison H, et al. 
Correlation of sweat chloride concentration with classes of the cystic fibrosis 
transmembrane conductance regulator gene mutations. J Pediatr. 1995;127:705-10.


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29 
Rowe S, Accurso F, Clancy JP. Detection of cystic fibrosis transmembrane 
conductance regulator activity in early-phase clinical trials. Proc Am Thorac Soc. 
2007;4:387-98. 
30 
Mayer-Hamblett N, Ramsey BW, Kronmal RA. Advancing outcome measures for the 
new era of drug development in cystic fibrosis. Proc Am Thorac Soc. 
2007;4(4):370-7. 
31 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331:637-42. 
32 
Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgomery AB, 
et al. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr. 
2001;139(3):359-65. 
33 
Rabin HR, Butler SM, Johnson CA, Colin AA, FitzSimmons SC, Geller DE, et al. 
Pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol. 2004;37(5):400-6.
34 
Blumer JL, Saiman L, Konstan MW, Melnick D. The efficacy and safety of 
meropenem and tobramycin vs. ceftazidime and tobramycin in the treatment of acute 
pulmonary exacerbations in patients with cystic fibrosis. Chest. 2005;128(4):2336-46.
35 
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;145:322-6. 
36 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
37 
Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in 
children with CKD. J Am Soc Nephrol. 2009; 20: 629-637.
38  
Stanojevic S, Jensen R, Sundaralingam D, Salazar JG, Yammine S, Singer F, et al. 
Alternative outcomes for the multiple breath washout in children with CF. J Cyst 
Fibros. 2015; http://dx.doi.org/10.1016/j.jcf.2014.12.008. 
39  
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 5;303(17):1707-15. 
40  
Davies EH, Tuleu C. Medicines for children: a matter of taste. J Pediatr. 
2008;153(5):599-604. 
41 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38.


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42  
Quanjer 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.
43 
Amin R, Subbarao P, Jabar A , Balkovec S, Jensen R, Kerrigan S, et al. Hypertonic 
saline improves the LCI in paediatric patients with CF with normal lung function. 
Thorax. 2010;65:379-383.
44 
Davies J, Sheridan H, Bell N, Cunningham S, Davis S, Elborn J, et al. Assessment of 
clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with 
a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. 
Lancet. Early online publication, 10 September 2013 (doi:10.1016/S2213-
2600(13)70182-6).  




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15.2
Investigator Signature Page 
Protocol #:
VX15-809-115
Version #:
3.0
Version Date:
13APR2017
A Phase 3, 2-Part, Open-label Study to Evaluate the Safety and Pharmacokinetics of 
Lumacaftor/Ivacaftor Combination Therapy in Subjects Aged 2 Through 5 Years With 
Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation
I have read Protocol VX15-809-115 Version 3.0, and agree to conduct the study according to 
its terms. I understand that all information concerning lumacaftor/ivacaftor and this protocol 
supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
Printed Name
Signature
Date

SAP_001.pdf: 
Page 1 of 26
Vertex Pharmaceuticals Incorporated 
1
TITLE PAGE 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods) 
Protocol Number: VX15-809-115
(Final Analysis - Part A) 
A Phase 3, 2-Part, Open-label Study to Evaluate the Safety and 
Pharmacokinetics of Lumacaftor/Ivacaftor Combination Therapy in 
Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous 
for the F508del-CFTR Mutation.
Author of SAP:
  
Version: 1.0 
Version Date of SAP: 23 September 2016 
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. 


Statistical Analysis Plan Methods, Version 1.0 23 SEP 2016 
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Protocol VX15-809-115, (Version 2.0, 01 AUG 2016)
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2
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
2 
Table of Contents ............................................................................................................. 2 
4 
Introduction...................................................................................................................... 5 
5 
Study Objectives .............................................................................................................. 5 
5.1 
Primary Objective ....................................................................................................... 5 
5.2 
Secondary Objectives ................................................................................................. 5 
5.3 
Other Objectives ......................................................................................................... 6 
6 
Study Endpoints ............................................................................................................... 6 
6.1 
Primary Endpoint ........................................................................................................ 6 
6.2 
Secondary Endpoints .................................................................................................. 6 
7 
Study Design ..................................................................................................................... 7 
7.1 
Overall Design ............................................................................................................ 7 
7.2 
Sample Size and Power ............................................................................................ 10 
7.3 
Randomization .......................................................................................................... 10 
7.4 
Blinding and Unblinding .......................................................................................... 10 
8 
Analysis Sets ................................................................................................................... 10 
8.1 
All Subjects Set ........................................................................................................ 10 
8.2 
Safety Set .................................................................................................................. 10 
9 
Statistical Analysis ......................................................................................................... 10 
9.1 
General Considerations ............................................................................................ 10 
9.2 
Background Characteristics ...................................................................................... 11 
9.2.1 
Subject Disposition ........................................................................................... 11 
9.2.2 
Demographics and Baseline Characteristics ..................................................... 12 
9.2.3 
Prior and Concomitant Medications ................................................................. 12 
9.2.4 
Study Drug Exposure........................................................................................ 13 
9.3 
Efficacy Analysis ...................................................................................................... 13 
9.4 
Safety Analysis ......................................................................................................... 13 
9.4.1 
Adverse Events ................................................................................................. 14 
9.4.2 
Clinical Laboratory ........................................................................................... 15 
9.4.3 
Electrocardiogram ............................................................................................ 15 
9.4.4 
Vital Signs ........................................................................................................ 16 
9.4.5 
Pulse Oximetry ................................................................................................. 16 
9.4.6 
Ophthalmological Examinations ...................................................................... 16 
9.4.7 
Spirometry ........................................................................................................ 16 
9.4.8 
Physical Examination ....................................................................................... 16 
9.4.9 
Other Safety Analysis ....................................................................................... 16 
10 Summary of Interim and IDMC Analyses .................................................................. 16 
10.1 Interim Analysis ....................................................................................................... 16 
10.2 IDMC Analysis ......................................................................................................... 16 


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11 References ....................................................................................................................... 16 
12 List of Appendices.......................................................................................................... 17 
Appendix A: Schedule of Assessments.............................................................................. 17 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ........... 21 
Appendix C: Imputation Rules for Missing AE dates ....................................................... 22 
Appendix D: Criteria for Potentially Clinically Significant Events................................... 23 
Appendix E: Details of Statistical Methodology ............................................................... 26 




Statistical Analysis Plan Methods, Version 1.0 23 SEP 2016 
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4
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of study VX15-809-115 Part A 
only and is based on the  
x
approved clinical study protocol, dated 01 August 2016, Version 2.0,  
x
approved eCRF, dated 08 June 2016, Version 2.0.
Study VX15-809-115 is a phase 3, 2-part, open-label study to evaluate the safety and 
pharmacokinetics of lumacaftor/ivacaftor combination therapy in subjects aged 2 through 5 
years with cystic fibrosis, homozygous for the F508del-CFTR mutation. 
This SAP (Methods) documents the planned final safety analysis and data presentation for 
Part A of VX15-809-115. 
SAS® Version 9.2 Software (SAS Institute, Cary, North Carolina, USA) or higher will be 
used to generate all statistical outputs (tables, figures, listings and datasets).  
The SAP will be finalized and approved before the end of Part A with CRFs locked on 
individual subject basis for the final analysis of Part A. Any changes made to the SAP 
Methods after the above end of Part A activity has occurred will be documented in the 
clinical study report for this study. 
The analysis addressing the pharmacokinetic (PK) objective of the study will be described in 
the Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the 
Clinical Pharmacology department at Vertex Pharmaceuticals Incorporated (Vertex). 
5
STUDY OBJECTIVES  
5.1
Primary Objective 
Part A 
To evaluate the PK of lumacaftor (LUM) and ivacaftor (IVA) and their respective 
metabolites in subjects aged 2 through 5 years with cystic fibrosis (CF), homozygous for 
F508del 
Part B 
To evaluate the safety of LUM/IVA combination therapy in subjects aged 2 through 5 years
with CF, homozygous for F508del
5.2
Secondary Objectives 
Part A 
To evaluate the safety of LUM/IVA combination therapy in subjects aged 2 through 5 years 
with CF, homozygous for F508del 


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Part B 
x
To evaluate the pharmacodynamics (PD) of LUM/IVA combination therapy in subjects 
aged 2 through 5 years with CF, homozygous for F508del
x
To evaluate the off-drug PD response after the Washout Period 
x
To evaluate the PK of LUM and IVA and their respective metabolites in subjects aged 
2 through 5 years with CF, homozygous for F508del
5.3
Other Objectives 
Not Applicable 
6
STUDY ENDPOINTS 
6.1
Primary Endpoint 
Part A 
PK parameters of LUM and IVA 
Part B 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values 
(serum chemistry, hematology, coagulation studies, and urinalysis), standard 12-lead 
electrocardiograms (ECGs), vital signs, pulse oximetry, ophthalmological examinations, and 
spirometry 
6.2
Secondary Endpoints 
Part A 
x
PK parameters of the metabolites of LUM and IVA 
x
Safety and tolerability assessments based on AEs, clinical laboratory values (serum 
chemistry, hematology, coagulation studies, and urinalysis), ECGs, vital signs, pulse 
oximetry, and spirometry
Part B 
x
Absolute change from baseline in sweat chloride at Week 24
x
Absolute change from baseline in body mass index (BMI) and BMI-for-age z-score at 
Week 24
x
Absolute change from baseline in weight and weight-for-age z-score at Week 24
x
Absolute change from baseline in stature and stature-for-age z-score at Week 24
x
Time-to-first pulmonary exacerbation through Week 24
x
Number of pulmonary exacerbations through Week 24
x
Number of CF-related hospitalizations through Week 24 


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x
Absolute change in fecal elastase-1 (FE-1) levels from baseline at Week 24 
x
Absolute change in serum levels of immunoreactive trypsinogen (IRT) from baseline 
through Week 24  
x
Change in microbiology cultures from baseline at Week 24  
x
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) at Week 24  
x
Absolute change in sweat chloride from Week 24 at Week 26
x
Acceptability/palatability of LUM/IVA granules at Day 1 
x
Absolute change from baseline in lung clearance index (LCI)2.5 at Week 24 
x
Absolute change from baseline in LCI5.0 at Week 24
x
PK parameters of LUM, IVA, and their respective metabolite 
7
STUDY DESIGN  
7.1
Overall Design  
This is a Phase 3, 2-part, open-label, multicenter study evaluating the PK, safety, tolerability, 
and PD of multiple doses of LUM/IVA in subjects 2 through 5 years of age (inclusive) with 
CF, homozygous for F508del. Part A is designed to evaluate the PK of LUM and IVA and 
their respective metabolites and the safety of LUM/IVA combination therapy. Part B is 
designed to evaluate the safety and PD of LUM/IVA combination therapy and also to 
evaluate the PK of LUM and IVA and their respective metabolites.
Subjects who participate in Part A may participate in Part B, if they meet the eligibility 
criteria.  
Part A 
Approximately 12 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 10 subjects should complete Part A. Approximately half of the subjects should 
complete the study in each of the following weight groups: <14 kg and ≥14 kg at screening.  
Part A includes the following:
x
Screening Period (Day -28 through Day -1) 
x
Treatment Period (Day 1 through Day 15 ± 2 days) 
x
Safety Follow-up Visit (10 ± 3 days after the last dose of LUM/IVA) 
Figure 7-1 depicts the schematic for the Part A study design.  
A review of safety, tolerability, and available PK data will be completed by an internal 
Vertex team after Part A to determine the dose(s) to be evaluated in Part B. Additional 
subjects or treatment cohorts may be enrolled, if data from the initial, planned, 12 subjects 
are inadequate to make a determination of the dose(s) to be evaluated in Part B. 
In the later sections, all discussions and analyses plans will be limited to Part A only.






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7.2
Sample Size and Power 
No formal sample size calculations have been performed for Part A. The number of subjects 
participating is common in early clinical pharmacology studies and is considered sufficient to 
achieve the PK objectives of Part A. 
7.3
Randomization 
Part A is an open-label study with weight-based treatment group assignment. Randomization 
is not required in this Part.  
7.4
Blinding and Unblinding 
This is an open-label study. However for Part A, subjects and their legally appointed and 
authorized representative (e.g., parent or legal guardian) should not be informed of their 
study-related spirometry (subjects ≥3 years of age at corresponding part’s screening) during 
the study, regardless if the subject permanently discontinues treatment. 
8
ANALYSIS SETS 
8.1
All Subjects Set 
All Subjects Set is defined as all subjects who have signed informed consent (and assent, if 
applicable) and enrolled or dosed in Part A. This analysis set will be used for all individual 
subject data listings and the disposition summary table, unless specified otherwise. 
8.2
Safety Set 
Safety Set will include all subjects who received at least 1 dose of study drug in Part A. The 
Safety Set will be used for all safety analyses, with subjects analyzed according to the 
treatment they received, unless specified otherwise. In addition, the summary by the dosing 
groups (LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/IVA 188 mg q12h) at enrollment 
determined by weight at the Screening Visit will be provided as supplementary information. 
9
STATISTICAL ANALYSIS 
9.1
General Considerations 
The Schedule of Assessments is provided in Appendix A. The precision standards for 
reporting safety variables are provided in an internal Biometrics document that specifies the 
programming rules including the precision for derived variables. 
All individual subject data based on All Subjects Set of the corresponding part will be 
presented in data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum (min), and maximum (max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For 


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ECGs, the baseline value will be defined as the average of the pretreatment measurements on 
Day 1. 
Change (absolute change) from baseline will be calculated as postbaseline value - baseline 
value. 
Relative change from baseline: will be calculated and presented in percentage as 
100 × (postbaseline value - baseline value)/baseline value. 
Treatment-emergent Period for Part A will include the time period starting from the first 
dose date of the study drug through 14 days after last dose of study drug. The Treatment-
Emergent period will be used for safety analyses unless specified otherwise.
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
x
In the derivation of baseline measurements. 
x
In individual subject data listings as appropriate. 
Visit windowing rules: The majority of assessments are anticipated to be on schedule. Visit 
windowing will not add significant value to the analysis and will not be applied. Nominal 
visit will be used for all assessments. 
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. 
Unless otherwise specified, the analysis will be performed using descriptive summary 
statistics by dosing groups (LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/IVA 
188 mg q12h) and overall. All summaries will be based on the Safety Set. No statistical 
hypothesis testing will be performed.  
9.2
Background Characteristics  
9.2.1
Subject Disposition 
The number of subjects in the following categories will be summarized by dosing group and 
overall:
x
All Subjects Set 
x
Dosed (Safety Set) 
The numbers and percentages (based on the Safety Set) of subjects in the following 
disposition categories will be summarized by dosing group and overall 
x
Completed study drug treatment 
x
Prematurely discontinued the treatment and the reasons for discontinuations 
x
Completed study 
x
Prematurely discontinued the study and the reasons for discontinuations 


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A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. 
9.2.2
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized overall and 
by dosing group based on the Safety Set. 
Demographic data will include the following: 
x
Age at baseline  
x
Sex (female and male) 
x
Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
x
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
x
Weight (kg) 
x
Stature (cm) 
x
BMI (kg/m2) 
Medical history will be summarized by MedDRA system organ class (SOC) and preferred 
term (PT).  
9.2.3
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHODDE) and categorized as the following: 
x
Prior medication: any medication that started before initial dosing of study drug in each 
part, regardless of when it ended. 
x
Concomitant medication: medication continued or newly received at or after initial 
dosing of study drug in each part to 14 days after the last dose of study drug in the 
corresponding part. 
x
Post-treatment medication: medication continued or newly received after 14 days after 
the last dose of study drug in each part.  
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or 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 after 14 days after 
the last dose of study drug, it will be considered as prior, concomitant, and post-treatment. 


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Prior medications and concomitant medications will be summarized descriptively by 1) 
preferred names; 2) anatomic class (ATC) level 1, ATC level 2, and preferred names based 
on the Safety Set.  
Summaries of medications will be based on the Safety Set.  
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix B.
9.2.4
Study Drug Exposure  
Duration of study drug exposure is defined as follows: last dose date − first dose 
date + 1 day, regardless of any interruptions in dosing. If the last dose date of study drug is 
missing, the subject's last date from the dosing panel (excluding PK dosing) will be used for 
analysis purposes.
Study drug exposure will be summarized descriptively (n, mean, SD, SE, median, min, and 
max in days) by dosing group and overall based on Safety Set. In addition, the summary by 
the dosing group (LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/IVA 188 mg q12h) at 
enrollment determined by weight at the Screening Visit will be provided as supplementary 
information. 
Study drug exposure will be presented in an individual subject data listing to indicate 
whether the study drug was taken or not. 
9.3
Efficacy Analysis  
Not Applicable 
9.4
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
x
Incidence of treatment-emergent adverse events (TEAEs) 
x
Clinical laboratory values (serum chemistry, hematology, coagulation studies, and 
urinalysis) 
x
ECGs (standard 12-lead) 
x
Vital signs 
x
Pulse oximetry 
x
Spirometry (subjects ≥3 years age at screening)
Safety analyses will be performed by dosing group and overall. Safety analyses will be 
conducted for the Safety Set. Safety data will be presented in the individual subject data 
listings based on the All Subjects Set. Only descriptive summary statistics of safety data will 
be provided (i.e., no statistical hypothesis testing will be performed). 
The summary by the dosing groups (LUM 100 mg/IVA 125 mg q12h and 
LUM 150 mg/IVA 188 mg q12h) at each part’s enrollment determined by weight at the 
Screening Visit will be provided as the supplementary information. 


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9.4.1
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs. 
x
Pretreatment AE: any AE that started before initial dosing of study drug in each part. 
x
TEAE: any AE that increased in severity or that was newly developed during the 
Treatment Period which is defined as being the period from initial dosing of study drug in 
each part to 14 days after the last dose of study drug in the corresponding part. 
x
Post-treatment AE: any AE that increased in severity or that developed after 14 days 
after the last dose of study drug in each part. 
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 adverse events are described in 
Appendix C. 
TEAE summaries will be presented using number and percentages of subjects. 
An overview of TEAE profile will be provided, including total number of TEAEs, with 
number and percentage of subjects for the following categories: (1) All TEAEs, (2) 
Grades  3/4 TEAEs, (3) TEAEs by relationship to study drug, (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: 
x
All TEAEs  
x
Grades 3/4 TEAEs 
x
TEAEs by relationship to study drug  
x
TEAEs by maximum severity 
x
TEAEs leading to treatment interruption 
x
TEAEs leading to treatment discontinuation 
x
Serious TEAEs 
x
Serious TEAEs related to study drug 
x
TEAEs leading to death 
Summaries will be presented by MedDRA system organ class (SOC) and preferred term (PT) 
using frequency counts and percentages. 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. 


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Separate tables will be provided summarizing the number of subjects, the number of events 
and the number of related events for the following by SOC and PT as per EudraCT 
requirement: 
x
Treatment-emergent Serious AEs 
x
Treatment-emergent Non-Serious AEs 
Note if an event increases in its severity, it will be reported as a separate event in the clinical 
database and thus may be counted more than once. 
In addition, listings that contain individual subject data for all TEAEs leading to treatment 
interruption, TEAEs leading to treatment discontinuation, deaths, and serious AEs will be 
provided separately. All AEs, including pre- and post-treatment AEs, will be presented in 
individual subject data listings. 
9.4.2
Clinical Laboratory 
For laboratory measurements, the raw values and change from baseline values of the 
continuous hematology/coagulation and chemistry results will be summarized by dosing 
group and overall in SI units at each scheduled time point. 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 will be 
summarized. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
laboratory event (i.e., categorical change) during the Treatment-Emergent period will be 
summarized. The PCS/categorical criteria are provided in Appendix D.
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 normal reference ranges will be provided. This listing will include data 
from both scheduled and unscheduled visits.
9.4.3
Electrocardiogram 
For ECG measurements, a summary of raw values and change from baseline values will be 
provided by dosing group and overall at each scheduled time point for the following standard 
12-lead ECG measurements: RR (ms), HR (bpm), PR (ms), QRS duration (ms), QT (ms), 
and QT corrected for HR intervals [Fridericia's correction QTcF (ms) =QT/RR1/3]. In 
addition, the mean value at each time point will be plotted for QTcF. 
The number and percentage of subjects with at least 1 PCS ECG event (i.e., categorical 
change) during the Treatment-Emergent period will be summarized. The PCS/categorical 
criteria are provided in Appendix D. 
The number and percentage of subjects with shift changes from baseline (normal/missing, 
not clinically significant, and potentially clinically significant according to overall ECG 
evaluation) to the worst ECG evaluation during the Treatment Period will be summarized. 


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9.4.4
Vital Signs 
For vital signs measurements, the raw values and change from baseline values will be 
summarized by dosing group and overall at each scheduled time point: systolic and diastolic 
blood pressure (mm Hg), body temperature (°C), pulse rate (beats per minute), and 
respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 PCS vital sign event (i.e., categorical 
change) during the Treatment period will be summarized. The PCS/categorical criteria are 
provided in Appendix D.
9.4.5
Pulse Oximetry 
For the pulse oximetry measurements, a summary of raw values and change from baseline 
values will be provided at each scheduled time point for the percent of oxygen saturation by 
pulse oximetry.  
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
Treatment Period will be provided. 
9.4.6
Ophthalmological Examinations 
Ophthalmological examination findings (Screening only) will be presented as a data listing. 
9.4.7
Spirometry 
Spirometry data will be presented as a data listing only. 
9.4.8
Physical Examination 
Physical examination findings will be presented as a data listing only.  
9.4.9
Other Safety Analysis 
Not applicable. 
10
SUMMARY OF INTERIM AND IDMC ANALYSES 
10.1
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. 
10.2
IDMC Analysis 
Details of the IDMC (Section 8.2 of the protocol) analysis will be provided in the IDMC 
Analysis Plan. There is no IDMC analysis for Part A. 
11
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.
 


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12
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 


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Table 12-1 
Study VX15-809-115: Part A Screening 
Assessment
Screening Visit
Day -28 through Day -1
Informed consent/assent
X
Demographics
X
Medical and ophthalmological history
X
Stature, weight, and vital signsa,b
X
Pulse oximetryb
X
Ophthalmologic examinationc
X
Full physical examination
X
Standard 12-lead ECGd
X
Spirometrye
X
CFTR genotypef
X
Serum chemistryg
X
Hematologyg
X
Coagulation studiesg
X
Urinalysisg
X
Medications reviewh
Continuous from signing of ICF through Safety Follow-up Visit
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit
BMI: 
body 
mass 
index;
CFTR:
cystic 
fibrosis 
transmembrane 
conductance 
regulator 
gene;
ECG: electrocardiogram; ICF: informed consent form.
                                                
a
If children 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. Refer to Section 11.4.3 of the protocol for details. 
b
The subject should rest for at least 5 minutes before having vital signs and pulse oximetry measured. Refer 
to Section 11.6.4 of the protocol for details.
c 
An ophthalmologic examination will be conducted by a licensed ophthalmologist. The examination does 
not need to be repeated if there is documentation of an examination meeting protocol criteria that was 
conducted within 3 months before the Screening Visit. Subjects with documentation of bilateral lens 
removal do not need the ophthalmologic examination. Refer to Section 11.6.6 of the protocol for details. 
d 
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. Refer to Section 11.6.5 of the protocol for 
details.  
e 
Spirometry (subjects t3 years of age at screening only) may be performed pre- or post-bronchodilator. 
Refer to Section 11.6.7 of the protocol for details.  
f  
All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype 
laboratory report. Refer to Section 11.6.2 of the protocol for details.  
g 
Refer to Section 11.6.2 of the protocol for details.  
h 
Refer to Section 9.4.2 of the protocol for details. 






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Appendix B: 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 12-3 
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
 


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Appendix C: 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: 
x
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. 
x
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: 
x
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. 
x
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 D: Criteria for Potentially Clinically Significant Events 
Table 12-4 
Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter
PCS
Comments
Clinical Chemistry
ALT
≤3xULN*(Not a PCS criterion)
>3x - ≤ 5xULN
>5x - ≤ 8xULN
>3xULN
>5xULN
>8xULN
FDA DILI Guidance Jul 2009. 
AST
≤3xULN*(Not a PCS criterion)
>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
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
Potassium
<3 mmol/L
≥5.5 mmol/L
FDA Feb 2005.


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Table 12-4 
Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter
PCS
Comments
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.
Table 12-5 
Criteria for Potentially Clinically Significant ECGs 
Parameter
PCS
Comments
HR
≤50 bpm and decrease from baseline ≥20 bpm
≥120 bpm and increase from baseline ≥20 bpm
PR
≥220 ms and increase from baseline ≥20 ms
QRS
≥120 ms


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Table 12-5 
Criteria for Potentially Clinically Significant ECGs 
Parameter
PCS
Comments
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 12-6 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter
PCS
Comments
HR
≤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.
SBP
≤95 mmHg and decrease from baseline 
≥20mmHg
≥160 mmHg and increase from baseline ≥20 
mmHg
To be applied for all positions (including 
missing) except STANDING.
DBP
≤45 mmHg and decrease from baseline ≥10 
mmHg
≥110 mmHg and increase from baseline ≥10 
mmHg
To be applied for all positions (including 
missing) except STANDING.
Weight
≥5% increase from baseline 
≥5% decrease from baseline
FDA criteria Feb 2007.
 


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Appendix E: Details of Statistical Methodology 
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.
 


 
Page 1 of 41 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
1 
TITLE PAGE
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods)
Protocol Number:  VX15-809-115
(Final Analysis - Part B) 
A Phase 3, 2-Part, Open-label Study to Evaluate the Safety and 
Pharmacokinetics of Lumacaftor/Ivacaftor Combination Therapy in 
Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous 
for the F508del-CFTR Mutation. 
 
Author of SAP:  
  
 
Version: 2.0 
Version Date of SAP: 07 September 2017 
 
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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2
TABLE OF CONTENTS 
1
Title Page .......................................................................................................................... 1
2
Table of Contents ............................................................................................................. 2
4
Introduction ...................................................................................................................... 5
5
Study Objectives .............................................................................................................. 5
5.1
Primary Objective ....................................................................................................... 5
5.2
Secondary Objectives ................................................................................................. 5
5.3
Other Objectives ......................................................................................................... 6
6
Study Endpoints ............................................................................................................... 6
6.1
Primary Endpoint ........................................................................................................ 6
6.2
Secondary Endpoints .................................................................................................. 6
7
Study Design ..................................................................................................................... 7
7.1
Overall Design ............................................................................................................ 7
7.2
Randomization .......................................................................................................... 10
7.3
Blinding and Unblinding .......................................................................................... 10
8
Analysis Sets ................................................................................................................... 10
8.1
All Subjects Set ........................................................................................................ 10
8.2
Safety Set .................................................................................................................. 10
8.3
Full Analysis Set ....................................................................................................... 10
8.4
LCI Substudy Set ...................................................................................................... 10
9
Statistical Analysis ......................................................................................................... 11
9.1
General Considerations ............................................................................................ 11
9.2
Background Characteristics ...................................................................................... 12
9.2.1
Subject Disposition ........................................................................................... 12
9.2.2
Demographics and Baseline Characteristics ..................................................... 13
9.2.3
Prior and Concomitant Medications ................................................................. 14
9.2.4
Study Drug Exposure ........................................................................................ 14
9.2.5
Study Drug Compliance ................................................................................... 15
9.2.6
Important Protocol Deviations .......................................................................... 15
9.3
Efficacy Analysis ...................................................................................................... 15
9.4
Safety Analysis ......................................................................................................... 15
9.4.1
Adverse Events ................................................................................................. 16
9.4.2
Clinical Laboratory ........................................................................................... 18
9.4.3
Electrocardiogram ............................................................................................ 19
9.4.4
Vital Signs ........................................................................................................ 19
9.4.5
Pulse Oximetry ................................................................................................. 20
9.4.6
Ophthalmological Examinations ...................................................................... 20
9.4.7
Spirometry ........................................................................................................ 20
9.4.8
Physical Examination ....................................................................................... 21
9.4.9
Other Safety Analysis ....................................................................................... 21


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9.5
Pharmacodynamic Analysis ..................................................................................... 21
9.5.1
Analysis of Primary Endpoints ......................................................................... 21
9.5.2
Analysis of Secondary Pharmacodynamic Endpoints ...................................... 21
9.5.2.1
Absolute Change From Baseline in Sweat Chloride at Week 24............... 21
9.5.2.2
Absolute Change From Baseline in BMI/BMI-for-Age Z-score at 
Week 24 ..................................................................................................... 22
9.5.2.3
Absolute Change From Baseline in Weight/Weight-for-Age Z-Score at 
Week 24 ..................................................................................................... 22
9.5.2.4
Absolute Change From Baseline in Stature/Stature-for-Age Z-score at 
Week 24 ..................................................................................................... 23
9.5.2.5
Analysis of Pulmonary Exacerbation-related Other Secondary 
Pharmacodynamic Variables ...................................................................... 23
9.5.2.6
Absolute Change in FE-1 Levels From Baseline at Week 24 .................... 23
9.5.2.7
Absolute Change in Serum Levels of IRT From Baseline Through 
Week 24 ..................................................................................................... 24
9.5.2.8
Change in Microbiology Culture From Baseline at Week 24 .................... 24
9.5.2.9
Absolute Change From Baseline in ppFEV1 at Week 24 .......................... 24
9.5.2.10 Absolute Change in Sweat Chloride From Week 24 at Week 26 .............. 24
9.5.2.11 Acceptability/Palatability of LUM/IVA Granules at Day 1 ...................... 25
9.5.2.12 Absolute Change From Baseline in LCI2.5 at Week 24 ............................ 25
9.5.2.13 Absolute Change From Baseline in LCI5.0 at Week 24 ............................ 25
9.6
Narratives Listings .................................................................................................... 25
10 Summary of Interim and IDMC Analyses .................................................................. 25
10.1 Interim Analysis ....................................................................................................... 25
10.2 IDMC Analysis ......................................................................................................... 26
11 References ....................................................................................................................... 26
12 List of Appendices .......................................................................................................... 26
Appendix A: Schedule of Assessments.............................................................................. 26
Appendix B: Analysis Visit Window Mapping Rules for Safety and Pharmacodynamic 
Measurements ........................................................................................................... 31
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ........... 32
Appendix D: Imputation Rules for Missing AE dates ....................................................... 33
Appendix E: Criteria for Potentially Clinically Significant Events ................................... 34
Appendix F: Details of Statistical Methodology ................................................................ 37
Appendix G:  Blood Pressure Normal Levels for Boys and Girls by Age and Height 
Percentile .................................................................................................................. 38
Appendix H: Important Protocol Deviation Programming Rules (Based on the Clinical 
Database) .................................................................................................................. 39
 




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4 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of study VX15-809-115 Part B 
only and is based on the  
x
approved clinical study protocol, dated 13 April 2017, Version 3.0,  
x
approved eCRF, dated 16 December 2016, Version 4.0. 
Study VX15-809-115 is a phase 3, 2-part, open-label study to evaluate the safety and 
pharmacokinetics (PK) of lumacaftor/ivacaftor combination therapy in subjects aged 2 
through 5 years with cystic fibrosis, homozygous for the F508del-CFTR mutation. 
This SAP (Methods) documents the planned final safety and pharmacodynamics analysis and 
data presentation for Part B of VX15-809-115.  
SAS® Version 9.3 Software (SAS Institute, Cary, North Carolina, USA) or higher will be 
used to generate all statistical outputs (tables, figures, listings and datasets).   
The SAP will be finalized and approved before the database lock for the final analysis for 
Part B. Any changes made to the SAP Methods after the above end of Part B activity has 
occurred will be documented in the clinical study report. 
The analysis addressing the PK objective of the study will be described in the Clinical 
Pharmacology Analysis Plan (CPAP), which will be developed separately by the Clinical 
Pharmacology department at Vertex Pharmaceuticals Incorporated (Vertex). 
5
STUDY OBJECTIVES
5.1 
Primary Objective 
Part A 
To evaluate the PK of lumacaftor (LUM) and ivacaftor (IVA) and their respective 
metabolites in subjects aged 2 through 5 years with cystic fibrosis (CF), homozygous for 
F508del
Part B 
To evaluate the safety of LUM/IVA combination therapy in subjects aged 2 through 5 years 
with CF, homozygous for F508del 
 
5.2 
Secondary Objectives 
Part A 
To evaluate the safety of LUM/IVA combination therapy in subjects aged 2 through 5 years 
with CF, homozygous for F508del
 
 


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Part B 
x
To evaluate the pharmacodynamics (PD) of LUM/IVA combination therapy in subjects 
aged 2 through 5 years with CF, homozygous for F508del  
x
 To evaluate the off-drug PD response after the Washout Period 
x
To evaluate the PK of LUM and IVA and their respective metabolites in subjects aged 
2 through 5 years with CF, homozygous for F508del 
 
5.3 
Other Objectives 
Not Applicable 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Part A 
PK parameters of LUM and IVA 
Part B 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values 
(serum chemistry, hematology, coagulation studies, and urinalysis), standard 12-lead 
electrocardiograms (ECGs), vital signs, pulse oximetry, ophthalmological examinations, and 
spirometry 
 
6.2 
Secondary Endpoints 
Part A 
x
PK parameters of the metabolites of LUM and IVA 
x
Safety and tolerability assessments based on AEs, clinical laboratory values (serum 
chemistry, hematology, coagulation studies, and urinalysis), standard 12-lead ECGs, vital 
signs, pulse oximetry, and spirometry 
Part B 
x
Absolute change from baseline in sweat chloride at Week 24  
x
Absolute change from baseline in body mass index (BMI) and BMI-for-age z-score at 
Week 24 
x
Absolute change from baseline in weight and weight-for-age z-score at Week 24 
x
Absolute change from baseline in stature and stature-for-age z-score at Week 24 
x
Time-to-first pulmonary exacerbation through Week 24 
x
Number of pulmonary exacerbations through Week 24 
x
Number of CF-related hospitalizations through Week 24 


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x
Absolute change in fecal elastase-1 (FE-1) levels from baseline at Week 24 
x
Absolute change in serum levels of immunoreactive trypsinogen (IRT) from baseline 
through Week 24  
x
Change in microbiology cultures from baseline at Week 24  
x
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) at Week 24  
x
Absolute change in sweat chloride from Week 24 at Week 26 
x
Acceptability/palatability of LUM/IVA granules at Day 1 
x
Absolute change from baseline in lung clearance index (LCI)2.5 at Week 24 
x
Absolute change from baseline in LCI5.0 at Week 24 
x
PK parameters of LUM, IVA, and their respective metabolites 
7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3, 2-part, open-label, multicenter study evaluating the PK, safety, tolerability, 
and PD of multiple doses of LUM/IVA in subjects 2 through 5 years of age (inclusive) with 
CF, homozygous for F508del. Part A is designed to evaluate the PK of LUM and IVA and 
their respective metabolites and the safety of LUM/IVA combination therapy. Part B is 
designed to evaluate the safety and PD of LUM/IVA combination therapy and also to 
evaluate the PK of LUM and IVA and their respective metabolites. 
Subjects who participate in Part A may participate in Part B, if they meet the eligibility 
criteria.  
Part A 
Approximately 12 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 10 subjects should complete Part A. Approximately half of the subjects should 
complete the study in each of the following weight groups: <14 kg and 14 kg at screening.  
Part A includes the following: 
x
Screening Period (Day -28 through Day -1) 
x
Treatment Period (Day 1 through Day 15 ± 2 days) 
x
Safety Follow-up Visit (10 ± 3 days after the last dose of LUM/IVA) 
Figure 7-1 depicts the schematic for the Part A study design.  
A review of safety, tolerability, and available PK data will be completed by an internal 
Vertex team after Part A to determine the dose(s) to be evaluated in Part B. Additional 
subjects or treatment cohorts may be enrolled, if data from the initial, planned, 12 subjects 
are inadequate to make a determination of the dose(s) to be evaluated in Part B. 






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Table 7-1 
Probability of Observing Adverse Events in At Least 1 Subject if the 
Adverse Event Incidence (T) is 5% and 10% 
Sample Size 
T = 5% 
T = 10% 
50a 
92.3% 
99.5% 
a 
50 reflects the sample size of the completers. 
Additional subjects may be enrolled at the sponsor’s discretion to achieve up to 30 subjects 
in the LCI Substudy. This sample size is consistent with prior exploratory studies conducting 
LCI assessments. 
7.2 
Randomization 
This is an open-label study with weight-based treatment group assignment. Randomization is 
not applicable.  
7.3 
Blinding and Unblinding 
This is an open-label study. However for Part B, subjects and their legally appointed and 
authorized representative (e.g., parent or legal guardian) should not be informed of their 
study-related spirometry (subjects 3 years of age at screening), sweat chloride, and LCI 
results (subjects 3 years of age at screening who consent/assent to the optional LCI 
Substudy) during the study, regardless if the subject permanently discontinues treatment. 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
All Subjects Set is defined as all subjects who have signed informed consent (and assent, if 
applicable) and enrolled, or dosed in Part B. This analysis set will be used for all individual 
subject data listings, unless specified otherwise. 
8.2 
Safety Set 
Safety Set will include all subjects who received at least 1 dose of study drug in Part B. The 
Safety Set will be used for all safety analyses, with subjects analyzed according to the 
treatment they received, unless specified otherwise. In addition, the summary by the dosing 
groups (LUM 100 mg/IVA 125 mg q12h and LUM 150 mg/IVA 188 mg q12h) at enrollment 
determined by weight at the Screening Visit will be provided as supplementary information. 
8.3 
Full Analysis Set 
Full Analysis Set (FAS) will include all enrolled subjects in Part B who are exposed to any 
amount of study drug in Part B. PD analyses (except LCI) will be based on the FAS. 
8.4 
LCI Substudy Set 
LCI Substudy Set will include all subjects who have signed informed consent (and assent, if 
applicable) to the optional LCI Substudy in Part B and enrolled and dosed in Part B. LCI 
related analysis will be based on the LCI Substudy Set. 
 


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9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Part B Schedule of Assessments is provided in Appendix A. The precision standards for 
reporting safety variables are provided in an internal Biometrics document that specifies the 
programming rules including the precision for derived variables. 
All individual subject data based on All Subjects Set will be presented in data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum (min), and maximum (max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of Part B study drug.  
For ECGs, the Part B baseline value will be defined as the average of the pretreatment 
measurements on Day 1.  
For LCI-related parameters, the values at each visit will be calculated from the technically 
acceptable washout replicates. The Part B baseline of LCI will be the most recent non-
missing value calculated from the technically acceptable replicates before the initial 
administration of study drug. 
For sweat chloride, the values at each visit will be based on the averaged measurements from 
left and right arms. The Part B baseline will be defined as the average of the values at 
screening of Part B and the pretreatment measurement on Day 1 of Part B. If only 1 pre-first 
dose measurement of sweat chloride is available, that measurement will be considered the 
Part B baseline. 
Change (absolute change) from baseline will be calculated as postbaseline value - Part B 
baseline value. 
Relative change from baseline: will be calculated and presented in percentage as 
100 × (postbaseline value - Part B baseline value)/ Part B baseline value. 
Treatment-emergent Period for Part B will include the time period starting from the first 
dose date of the Part B study drug through 14 days after last dose of Part B study drug. The 
Treatment-Emergent period of Part B will be used for safety analyses unless specified 
otherwise. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
x
In scheduled visit windows per specified visit windowing rules 
x
In the derivation of baseline measurements/last on-treatment visit 
x
In the derivation of maximum/minimum values and maximum/minimum changes 
from baseline values 
x
In individual subject data listings as appropriate 


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Visit windowing rules: Appendix B defines the visit window mapping rules to derive the 
analysis visits for Part B. 
Repeated observations within the same visits window: 
x
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.   
x
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 analysis 
visit 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. 
Unless otherwise specified, the analysis will be performed using descriptive summary 
statistics overall and by dosing groups (LUM 100 mg/IVA 125 mg q12h and LUM 150 
mg/IVA 188 mg q12h). No statistical hypothesis testing will be performed.  
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized overall and by dosing 
group:  
x
All Subjects Set 
x
Dosed (Safety Set) 
x
Enrolled and dosed (FAS) 
The numbers and percentages (based on the Safety Set) of subjects in the following 
disposition categories will be summarized overall and by dosing group: 
x
Completed Part B study drug treatment 
x
Prematurely discontinued the Part B treatment  
o
Reasons for discontinuations 
o
Last completed scheduled on-treatment visit 


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x
Completed Part B of study 
x
Prematurely discontinued the Part B of study and the reasons for discontinuations 
x
Rollover to extension study 
o
Yes (Observational Cohort versus Treatment Cohort) 
o
No 
The above disposition summary will also be provided based on the LCI Substudy Set. 
A listing will be provided for subjects who discontinued Part B treatment or who 
discontinued Part B of study with reasons for discontinuation. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics of Part B will be summarized 
overall and by dosing group based on the Safety Set. 
Demographic data will include the following: 
x
Age at Part B baseline 
x
Age Group (< 3 and  3 years) 
x
Sex (female and male) 
x
Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
x
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: 
x
Weight (kg) 
x
Weight Group (<14 kg and 14 kg) 
x
Stature (cm) 
x
BMI (kg/m2) 
x
Weight-for-age z-score   
x
Stature-for-age z-score   
x
BMI-for-age z-score  
x
Sweat Chloride 
x
Spirometry (Subjects 3 years age at screening): FEV1 (L), Percent Predicted FEV1 
(percentage points), FVC (L), Percent Predicted FVC(percentage points), FEF25-75% 
(L/s), Percent Predicted FEF25-75% (percentage points), FEV1/FVC, Percent Predicted 
FEV1/FVC (percentage points) 


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Similar tables for demographics and baseline characteristics will be provided based on the 
LCI Substudy Set. For that table, LCI2.5 and LCI5.0 summaries will also be summarized. 
Medical history will be summarized by MedDRA system organ class (SOC) and preferred 
term (PT).  
9.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHODDE) and categorized as the following: 
x
Prior medication: any medication that started before initial dosing of study drug in Part 
B, regardless of when it ended. 
x
Concomitant medication: medication continued or newly received at or after initial 
dosing of study drug in Part B to 14 days after the last dose of study drug in Part B. 
x
Post-treatment medication: medication continued or newly received after 14 days after 
the last dose of study drug in Part B.  
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or 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 after 14 days after 
the last dose of study drug, it will be considered as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively by 1) 
preferred names; 2) anatomic class (ATC) level 1, ATC level 2, and preferred names based 
on the Safety Set.  
Summaries of medications will be based on the Safety Set.  
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 
9.2.4 
Study Drug Exposure  
Duration of Part B study drug exposure is defined as follows: Part B last dose date í Part B 
first dose date + 1 day, regardless of any interruptions in dosing. If the last dose date of Part 
B study drug is missing, the subject's last date in Part B will be used for analysis purposes. 
Study drug exposure will be summarized descriptively (n, mean, SD, SE, median, min, and 
max in days) overall and by dosing group based on Safety Set.  
Additionally, the cumulative duration of Part B 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 (>0 to 2 weeks, >2 
to 4 weeks, >4 to 8 weeks, >8 to 16 weeks, >16 to 24 weeks, and >24 weeks). 
Exposure summaries will be based on the Safety Set.  


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9.2.5 
Study Drug Compliance  
Part B study drug compliance will be assessed by calculating as follows:  
100 × (1 í [total number of days of Part B study drug interruption] / [duration of Part B study 
drug exposure + total number of days Part B study drug interrupted after last dose, 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), where number of days of each study drug interruption is 
defined as the interruption end date í the corresponding interruption start date + 1. 
In calculating the total number of days of Part B 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. 
Percent of stick packs taken will be calculated as follows:  
100 × (total number of stick packs administered) / (2 × [duration of study drug exposure in 
days + total number of days study drug interrupted after last dose, if any]).  
Subjects who have a calculated percent of stick packs taken >100% will be considered as 
having taken 100% of stick packs. 
Treatment compliance percentages and percent of stick packs taken will be summarized 
descriptively as quantitative variables (n, mean, SD, SE, median, minimum, and maximum) 
overall and by dosing group based on Safety Set. The number and percentage of subjects 
whose compliance is <80% or 80% and the number and percentage of subjects whose 
percent of stick packs taken is <80% or 80% will be summarized. 
9.2.6 
Important Protocol Deviations 
An important protocol deviation and violation (IPD) is a protocol deviation that has the 
potential to affect the interpretation of study results. IPD will be identified from the clinical 
database and/or site deviation log.  
The rules for identifying important protocol deviations based on the clinical database are 
defined in Appendix H. 
All IPDs will be presented in an individual subject data listing only. 
9.3 
Efficacy Analysis  
Not Applicable 
9.4 
Safety Analysis 
The overall safety profile of Part B study drug will be assessed in terms of the following 
safety and tolerability endpoints:  
x
Treatment-emergent adverse events (TEAEs) 
x
Clinical laboratory values (serum chemistry, hematology, coagulation studies, and 
urinalysis) 
x
ECGs (standard 12-lead) 


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x
Vital signs 
x
Pulse oximetry 
x
Ophthalmological examinations 
x
Spirometry (Subjects 3 years age at screening) 
Safety analyses will be performed overall and by dosing group. Safety analyses will be 
conducted for the Safety Set. Safety data will be presented in the individual subject data 
listings based on the All Subjects Set. Only descriptive summary statistics of safety data will 
be provided (i.e., no statistical hypothesis testing will be performed). 
9.4.1 
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs. 
x
Pretreatment AE: any AE that started before initial dosing of study drug in Part B.  
x
TEAE: any AE that increased in severity or that was newly developed during the 
Treatment Period which is defined as being the period from initial dosing of study drug in 
Part B to 14 days after the last dose of study drug in Part B. 
x
Post-treatment AE: any AE that increased in severity or that developed after 14 days 
after the last dose of study drug in Part B. 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after Part B study treatment, then the AEs will be classified as TEAEs for Part B. 
Details for imputing missing or partial start dates of adverse events are described in 
Appendix D. 
TEAE summaries will be presented using number and percentages of subjects. 
An overview of TEAE profile will be provided, including total number of TEAEs, with 
number and percentage of subjects for the following categories: (1) All TEAEs, (2) 
Grades  3/4 TEAEs, (3) TEAEs by relationship to study drug, (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: 
x
All TEAEs  
x
Grades 3/4 TEAEs 
x
TEAEs by relationship to study drug  
x
TEAEs by maximum severity 
x
TEAEs leading to treatment interruption 
x
TEAEs leading to treatment discontinuation 
x
Serious TEAEs 


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x
Serious TEAEs related to study drug 
x
TEAEs leading to death 
x
Frequently reported TEAEs (5% at the preferred term level) 
Summaries will be presented by MedDRA system organ class (SOC) and preferred term (PT) 
using frequency counts and percentages. 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. 
Separate tables will be provided summarizing the number of subjects, the number of events 
and the number of related events for the following by SOC and PT as per EudraCT 
requirement: 
x
Treatment-emergent Serious AEs 
x
Treatment-emergent Non-Serious AEs 
Analysis of AEs of special interest (AESI) categories:  
The following AESIs are defined: 
1.  Elevated Transaminases 
The AESI of elevated transaminases is defined by the AEs whose PTs fall into any of the 
following:  
x
Alanine aminotransferase abnormal  
x
Alanine aminotransferase increased  
x
Aspartate aminotransferase abnormal 
x
Aspartate aminotransferase increased 
x
Transaminases abnormal 
x
Transaminases increased 
x
Liver function test abnormal 
x
Liver function test increased 
x
Hypertransaminasaemia 
x
Hepatic enzyme increased 
x
Hepatic enzyme abnormal 
2. Respiratory Symptom AESI 
The respiratory symptoms AESI is defined by the AEs whose PTs fall into any of the 
following: 
x
Chest Discomfort 


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x
Dyspnoea 
x
Respiration abnormal 
3. Respiratory Event AESI (including respiratory symptoms or reactive airways) 
The respiratory AESI of respiratory symptoms or reactive airways is defined by the AEs 
whose PTs fall into any of the following: 
x
Asthma 
x
Bronchial hyperreactivity 
x
Bronchospasm  
x
Chest Discomfort 
x
Dyspnoea 
x
Respiration abnormal 
x
Wheezing 
Treatment-emergent AESIs will also be summarized  
1. Showing number and percentage of subjects by PT; 
2. Showing number and percentage of subjects by maximum severity; 
3. Summary of duration of events (days) with descriptive statistics; 
4. Summary of time-to-onset of the first event in days (relative to first dose date).  
5. Showing number and percentage of subjects with TEAE leading to treatment 
discontinuation; with TEAE leading to treatment interruption; with serious TEAEs; with 
related serious TEAEs; and with TEAE leading to death. 
In addition, listings that contain individual subject data for all TEAEs leading to treatment 
interruption, TEAEs leading to treatment discontinuation, deaths, and serious AEs will be 
provided separately. All AEs, including pre- and post-treatment AEs, will be presented in 
individual subject data listings. 
9.4.2 
Clinical Laboratory 
For laboratory measurements, the raw values and change from Part B baseline values of the 
continuous hematology/coagulation and chemistry results will be summarized overall and by 
dosing group in SI units at each scheduled time point. 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 will be summarized. 
The number and percentage of subjects with at least 1 categorical change during the Part B 
Treatment-Emergent period will be summarized. The categorical criteria are provided in 
Appendix E. 
For each of the LFTs, mean (±SD) will be plotted at each timepoint. 
Results of urinalysis will be listed in individual subject data listings only.  


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In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the normal reference ranges will be provided. This listing will include data 
from both scheduled and unscheduled visits. 
9.4.3 
Electrocardiogram 
For ECG measurements, a summary of raw values and change from Part B baseline values 
will be provided overall and by dosing group at each scheduled time point for the following 
standard 12-lead ECG measurements: RR (ms), HR (bpm), PR (ms), QRS duration (ms), QT 
(ms), and QT corrected for HR intervals [Fridericia's correction QTcF (ms) =QT/RR1/3]. 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 Part B 
Treatment-Emergent period will be summarized. The categorical criteria are provided in 
Appendix E. 
The number and percentage of subjects with shift changes from baseline (normal/missing, 
not clinically significant, and potentially clinically significant according to overall ECG 
evaluation) to the worst ECG evaluation during the Treatment Period will be summarized. 
9.4.4 
Vital Signs 
For vital signs measurements, the raw values and change from Part B baseline values will be 
summarized overall and by dosing group at each scheduled time point: systolic and diastolic 
blood pressure (mm Hg), body temperature (°C), pulse rate (beats per minute), and 
respiratory rate (breaths per minute). 
In addition, respiratiory rate at each predose and the corresponding postdose timepoints will 
be summarized (1 hour, 2 hours, 4 hours, worse value of 1, 2 or 4 hours), absolute change 
from predose to the corresponding postdose (1 hour, 2 hours, 4 hours, worse value of 1, 2 or 
4 hours) will also be summarized. 
The number and percentage of subjects with at least 1 categorical change during the 
Treatment period will be summarized. The categorical criteria are provided in Appendix E. 
Potentially abnormal SBP and DBP by their percentiles adjusted for sex, age and stature will 
be provided, including 
x
Number and percentage of subjects with categories 90%-<95%, 95%-<99% + 5 
mmHg and 99% + 5 mmHg)  
x
Number and percentage of subjects with SBP and DBP percentiles 95% once and twice 
during the treatment-emergent period will be provided. 
x
Number and percentage of subjects with SBP and DBP percentiles 95% at each visit 
will also be provided.  
 
 


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The stature adjustment will be based on stature-for-age z-scores and their corresponding 
percentiles using the standard normal distribution (Appendix G). The stature percentiles will 
be further mapped per the following rules: 
Table 9-1 
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 
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). 
9.4.5 
Pulse Oximetry 
For the pulse oximetry measurements, a summary of raw values and change from Part B 
baseline values will be provided at each scheduled time point for the percent of oxygen 
saturation by pulse oximetry.  
In addition, oxygen saturation at each predose and the corresponding postdose timepoints 
will be summarized (1 hour, 2 hours, 4 hours, worse value of 1, 2 or 4 hours), absolute 
change from predose to the corresponding postdose (1 hour, 2 hours, 4 hours, worse value of 
1, 2 or 4 hours) will also be summarized. 
The number and percentage of subjects with shift changes from Part B baseline 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the Treatment Period will be provided. 
9.4.6 
Ophthalmological Examinations 
Ophthalmological examination findings will be presented as a data listing. 
9.4.7 
Spirometry 
Spirometry data will be summarized descriptively at each visit.  
The following parameters of forced expiratory volume in 1 second (FEV1 (L)) and percent 
predicted FEV1 (ppFEV1),  forced vital capacity (FVC) (L) and percent predicted FVC 
(ppFVC), FEV1/FVC (ratio) and ppFEV1/FVC as well as forced expiratory flow (FEF25%-75%) 
(L/s) and percent predicted FEF (ppFEF25%-75%) will be summarized using descriptive 
statistics1. The percent predicted values ppFEV1, ppFVC, ppFEV1/FVC and ppFEF25%-75% 
will be calculated using the standards of Global Lungs Initiative (GLI) as described in 


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Appendix F. In addition, the mean value (95% CI) at each time point will be plotted for the 
absolute change from Part B baseline in ppFEV1. 
In addition, ppFEV1 at each predose and the corresponding postdose timepoints will be 
summarized (2 hours, 4 hours, worse value of 2 or 4 hours), absolute change from predose to 
the corresponding postdose (2 hours, 4 hours, worse value of 2 or 4 hours) will also be 
summarized. 
In addition, a listing containing individual subject data will be provided. 
9.4.8 
Physical Examination 
Physical examination findings will be presented as a data listing only. 
9.4.9 
Other Safety Analysis 
Not applicable. 
9.5 
Pharmacodynamic Analysis 
PD analyses (except LCI) will be based on the FAS. LCI related analysis will be based on the 
LCI Substudy Set. 
9.5.1 
Analysis of Primary Endpoints 
Not applicable. 
9.5.2 
Analysis of Secondary Pharmacodynamic Endpoints 
9.5.2.1 
Absolute Change From Baseline in Sweat Chloride at Week 24 
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. If a subject has replicated measurements at a postbaseline time 
point, then the median of the values will be used in data analyses. 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with the 95% confidence interval and within-group P value based on Normal approximation, 
will be provided for absolute change from baseline in sweat chloride at Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval and within-
group P values based on Normal approximation, will be provided for all other visits. Mean 
(95% CI) at each visit, overall and by dosing groups will be plotted. 


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9.5.2.2 
Absolute Change From Baseline in BMI/BMI-for-Age Z-score at 
Week 24 
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: 
°
°
°
°
¯
°°
°
°
®
­
 
¸
¹
·
¨
©
§
z

¸
¹
·
¨
©
§
 
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). 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with the 95% confidence interval and within-group P value based on Normal approximation, 
will be provided for absolute change from baseline in BMI and BMI-for-age z-score at 
Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval and within-
group P values based on Normal approximation, will be provided at all other visits. Mean 
(95% CI) at each visit, overall and by dosing groups will be plotted. 
9.5.2.3 
Absolute Change From Baseline in Weight/Weight-for-Age 
Z-Score at Week 24 
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).   
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in weight and weight-for-age z-score at 
Week 24.  


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In addition, descriptive summary statistics, along with 95% confidence interval and within-
group P values based on Normal approximation, will be provided at all other visits. Mean 
(95% CI) at each visit, overall and by dosing groups will be plotted. 
9.5.2.4 
Absolute Change From Baseline in Stature/Stature-for-Age 
Z-score at Week 24 
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). 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in stature and stature-for-age z-score at 
Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval and within-
group P values based on Normal approximation, will be provided at all other visits. Mean 
(95% CI) at each visit, overall and by dosing groups will be plotted. 
9.5.2.5 
Analysis of Pulmonary Exacerbation-related Other Secondary 
Pharmacodynamic Variables 
x
Time-to-first pulmonary exacerbation through Week 24: Time-to-first pulmonary 
exacerbation will be analyzed using Kaplan-Meier method. Cumulative incidence of 
pulmonary exacerbation will be summarized and plotted. Subjects without an 
exacerbation by Week 24 Visit will be censored at Week 24 Visit or at the last visit 
before the Safety Follow-up Visit for subjects with missing Week 24 Visit.  
x
Number of pulmonary exacerbations through Week 24: The number of pulmonary 
exacerbations through Week 24 [inclusive] (including both on-treatment events and 
events after treatment discontinuation), normalized by the time spent in the study 
(Week 24 date – first dose date +1), will be summarized. For subjects with missing Week 
24 visit, the last visit before Safety Follow-up Visit will be used instead of the Week 24 
date. 
x
Number of CF-related hospitalizations through Week 24: For the number of 
CF-related hospitalizations through Week 24 [inclusive], the analysis will be similar to 
the analysis of the number of pulmonary exacerbations through Week 24.  
9.5.2.6 
Absolute Change in FE-1 Levels From Baseline at Week 24 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in FE-1 levels at Week 24.  


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In addition, descriptive summary statistics, along with 95% confidence interval based on 
Normal approximation, will be provided at all other visits.  
In addition, a summary of FE-1 values (<15 μg/g  and >=15 μg/g) shift from baseline to 
Week 24 will be displayed. A spaghetti plot of the FE-1 values will also be plotted. 
Number and percentage of subjects with pancreatic insufficiency, defined as having FE-1 
level <200 μg/g, will be provided at Week 24 and at baseline. The within-group shift will be 
tested based on McNemar’s test.  
9.5.2.7 
Absolute Change in Serum Levels of IRT From Baseline Through 
Week 24 
For each subject, the serum levels of IRT through Week 24 for each subject will be derived 
as the simple arithmetic mean at each visit (Day 15, Weeks 4, 8, 16, and 24), regardless of 
on-treatment measurement or measurement after treatment discontinuation. As long as there 
is at least 1 measurement available for a specific visit, the average of the corresponding visit 
will be calculated based on all available measurements. If all measurements are missing, then 
the average through Week 24 will be missing and the subject will not be included in the 
summary for the average through Week 24. The absolute change in serum levels of IRT from 
baseline through Week 24 will be derived similarly as the simple arithmetic mean of the 
absolute change in serum levels of IRT from baseline at each visit. 
Summary statistics, along with 95% confidence interval and within-group P values based on 
Normal approximation, for absolute change from baseline in serum levels of IRT through 
Week 24 will be provided.  
In additional, summary statistics, along with 95% confidence interval and within-group 
P values based on Normal approximation, will be provided at each visit.  
In addition, a summary of IRT values (<14 ng/mL  and >=14 ng/mL ) shift from baseline to 
Week 24 will be displayed. A spaghetti plot of the IRT values will also be plotted. 
9.5.2.8 
Change in Microbiology Culture From Baseline at Week 24 
The presence of bacteria will be descriptively summarized by subject counts and percentages 
by visit and dosing group. 
9.5.2.9 
Absolute Change From Baseline in ppFEV1 at Week 24 
Summary statistics, along with 95% confidence interval and within-group P values based on 
Normal approximation, for absolute change from baseline in ppFEV1 will be provided at 
Week 24 [1].  
In addition, summary statistics, along with 95% confidence interval and within-group 
P values based on Normal approximation, will be provided at all other visits. Mean (95% CI) 
at each visit, overall and by dosing groups will be plotted. 
9.5.2.10 
Absolute Change in Sweat Chloride From Week 24 at Week 26 
Summary statistics, along with 95% CI and within-group P values based on Normal 
approximation, for absolute change from Week 24 will be provided at Week 26.  


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9.5.2.11 
Acceptability/Palatability of LUM/IVA Granules at Day 1 
Summary statistics will be provided for the acceptability/palatability data. 
9.5.2.12 
Absolute Change From Baseline in LCI2.5 at Week 24 
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. 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along 
with 95% confidence interval and within-group P values based on Normal approximation, 
will be provided for absolute change from baseline in LCI2.5 at Week 24.  
In addition, descriptive summary statistics, along with 95% confidence interval and within-
group P values based on Normal approximation, will be provided at all other visits. Mean 
(95% CI) at each visit, overall and by dosing groups will be plotted. 
9.5.2.13 
Absolute Change From Baseline in LCI5.0 at Week 24 
Analysis of absolute change in LCI5.0 from baseline at Week 24 will be similar to the analysis 
of absolute change in LCI2.5 from baseline at Week 24.  
9.6 
Narratives Listings 
Narratives listings will be provided for subjects with any of the following events that 
occurred by the study cutoff date: 
x
Death 
x
Serious AEs 
x
TEAEs leading to treatment discontinuation  
x
LFT elevations meeting at least 1 of the following criteria: 
o
ALT or AST > 5xULN, or  
o
ALT>3xULN and total bilirubin>2xULN, or  
o
AST>3xULN and total bilirubin>2xULN  
during the treatment-emergent period 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis 
Details of the Interim Analysis (IA) analysis will be provided in the IA/DMC Analysis Plan. 


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10.2 
IDMC Analysis 
Details of the IDMC (Section 8.2 of the protocol) analysis will be provided in the IA/DMC 
Analysis Plan. 
11 
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. 
12 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
 
 


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Table 12-1 
Study VX15-809-115: Part B Screening 
Assessment 
Screening Visit 
Day -28 through Day -1 
Informed consent/assent 
X 
Demographics 
X 
Medical and ophthalmological history 
X 
Stature, weight, and vital signsa,b 
X 
Pulse oximetryb 
X 
Ophthalmologic examinationc 
X 
Full physical examination 
X 
Standard 12-lead ECGd 
X 
CFTR genotypee 
X 
Serum chemistryf 
X 
Hematologyf 
X 
Coagulation studiesf 
X 
Urinalysisf 
X 
Sweat chlorideg 
X 
LCI (optional)h 
X 
Spirometryi 
X 
Medications reviewj 
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) 
BMI: body mass index; CFTR: cystic fibrosis transmembrane conductance regulator gene; ECG: electrocardiogram; 
ICF: informed consent form; LCI: lung clearance index 
 
                                                 
a 
If children 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. Refer to Section 11.4.3 of the protocol for details. 
b 
The subject should rest for at least 5 minutes before having vital signs and pulse oximetry measured. Refer to 
Section 11.6.4 of the protocol for details. 
c 
An ophthalmologic examination will be conducted by a licensed ophthalmologist. The examination does not need to be 
repeated if there is documentation of an examination meeting protocol criteria that was conducted within 3 months 
before the Screening Visit. Subjects with documentation of bilateral lens removal do not need the ophthalmologic 
examination. Refer to Section 11.6.6 of the protocol for details. 
d 
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. Refer to Section 11.6.5 of the protocol for details. 
e  
All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype laboratory 
report. Refer to Section 11.6.2 of the protocol for details. However, this assessment does not need to be repeated for 
confirmed subjects in Part A who may participate in Part B. 
f 
Refer to Section 11.6.2 of the protcol for details. 
g 
If an eligible historical sweat chloride result is documented in the subject’s medical record, that result alone (and not 
the Screening Visit result) may be used to determine eligibility. For subjects using an historical sweat chloride value 
documented in their medical record to determine eligibility, the sweat chloride test at the Screening Visit is still 
required. At screening, 2 samples may be collected, 1 sample from each arm (left and right). 
h 
The LCI assessment (subjects t3 years of age at screening who consent/assent to the optional LCI Substudy) may be 
performed pre- or post-bronchodilator. The assessment will be performed in multiple replicates and before the 
spirometry assessment. Refer to Section 11.4.2 of the protocol for details. 
i 
Spirometry (subjects t3 years of age at screening only) may be performed pre- or post-bronchodilator. Refer to 
Section 11.6.7 of the protocol for details.  
j 
Refer to Section 9.4.2 of the protocol for details.  








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Appendix B: Analysis Visit Window Mapping Rules for Safety and 
Pharmacodynamic Measurements 
Table 12-3 Visit Window Mapping Rules for Safety and Pharmacodynamic 
Measurements 
Assessments 
Visit 
Target Study Day 
Visit Window  
(in study days) 
x Spirometry 
x Weight and stature 
x Labs 
o Chemistry  
o Hematology 
x Vital signs 
x Pulse oximetry 
x Standard digital ECG 
x Fecal elastase -1 
x Immunoreactive 
trypsinogen 
 
Day 15 
15 
(1, 22] 
Week 4 
29 
[23, 43] 
Week 8 
57 
[44, 85] 
Week 16 
Week 24 
113 
169 
[86, 141] 
[142, 176] 
 
 
 
x Labs 
o Coagulation 
x Ophthalmologic exam 
 
Week 24 
 
169 
 
(1, 176] 
 
 
 
 
x Sweat chloride                       Week 4                                                    29                               (1, 99] 
x LCI                                        Week 24                                                  169                             [100, 176]
                                              
                                                   
 
Special handling for Spirometry (for the change from predose to postdose analysis 
only): 
For the change from predose to postdose spirometry analysis only, no windowing rules are 
used. 
1. Predose spirometry: analysis visit = nominal visit;  
2. Postdose 2-hour/4-hour spirometry: analysis visit = nominal visit. 
Special handling for VS/ECG (for the change from predose to postdose analysis only): 
For the change from predose to postdose VS/ECG analysis only, no windowing rules are 
used. 
1. Day 1 predose VS/ECG: analysis visit = nominal visit for Day 1, Predose. 
2. Day 1 post-dose VS/ECG by hour: analysis visit = nominal visit. 
Special handling for Follow-up: 
Follow-up will use the nominal visit and will not follow the visit window rule. 
 


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Appendix C: 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 12-4 
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 
 


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Appendix D: 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: 
x
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. 
x
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: 
x
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. 
x
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 E: Criteria for Potentially Clinically Significant Events 
Table 12-5 
Criteria for Potentially Clinically Significant 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 ȝmol/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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Table 12-5 
Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter 
Categorical change 
Comments 
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. 
 
 
Table 12-6 
Criteria for Potentially Clinically Significant 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 
 


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Table 12-6 
Criteria for Potentially Clinically Significant ECGs 
Parameter 
Categorical change 
Comments 
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 12-7 
Criteria for Potentially Clinically Significant 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. 
 
 


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Appendix F: Details of Statistical Methodology 
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.  
 
 
 
 


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Appendix G:  Blood Pressure Normal Levels for Boys and Girls by Age and 
Height Percentile 


Blood Pressure Levels for Boys by Age and Height Percentile 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
Í Percentile of Height Î
Í Percentile of Height Î
Age 
(Year)
BP
Percentile
Ð
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
50th 
 
80 
81 
83 
85 
87 
88 
89 
 
34 
35 
36 
37 
38 
39 
39 
 
90th 
 
94 
95 
97 
99 
100 
102 
103 
 
49 
50 
51 
52 
53 
53 
54 
 
95th 
 
98 
99 
101 
103 
104 
106 
106 
 
54 
54 
55 
56 
57 
58 
58 
 
99th 
 
105 
106 
108 
110 
112 
113 
114 
 
61 
62 
63 
64 
65 
66 
66 
2 
50th 
 
84 
85 
87 
88 
90 
92 
92 
 
39 
40 
41 
42 
43 
44 
44 
 
90th 
 
97 
99 
100 
102 
104 
105 
106 
 
54 
55 
56 
57 
58 
58 
59 
 
95th 
 
101 
102 
104 
106 
108 
109 
110 
 
59 
59 
60 
61 
62 
63 
63 
 
99th 
 
109 
110 
111 
113 
115 
117 
117 
 
66 
67 
68 
69 
70 
71 
71 
3 
50th 
 
86 
87 
89 
91 
93 
94 
95 
 
44 
44 
45 
46 
47 
48 
48 
 
90th 
 
100 
101 
103 
105 
107 
108 
109 
 
59 
59 
60 
61 
62 
63 
63 
 
95th 
 
104 
105 
107 
109 
110 
112 
113 
 
63 
63 
64 
65 
66 
67 
67 
 
99th 
 
111 
112 
114 
116 
118 
119 
120 
 
71 
71 
72 
73 
74 
75 
75 
4 
50th 
 
88 
89 
91 
93 
95 
96 
97 
 
47 
48 
49 
50 
51 
51 
52 
 
90th 
 
102 
103 
105 
107 
109 
110 
111 
 
62 
63 
64 
65 
66 
66 
67 
 
95th 
 
106 
107 
109 
111 
112 
114 
115 
 
66 
67 
68 
69 
70 
71 
71 
 
99th 
 
113 
114 
116 
118 
120 
121 
122 
 
74 
75 
76 
77 
78 
78 
79 
5 
50th 
 
90 
91 
93 
95 
96 
98 
98 
 
50 
51 
52 
53  
54 
55 
55 
 
90th 
 
104 
105 
106 
108 
110 
111 
112 
 
65 
66 
67 
68  
69 
69 
70 
 
95th 
 
108 
109 
110 
112 
114 
115 
116 
 
69 
70 
71 
72 
73 
74 
74 
 
99th 
 
115 
116 
118 
120 
121 
123 
123 
 
77 
78 
79 
80 
81 
81 
82 
6 
50th 
 
91 
92 
94 
96 
98 
99 
100 
 
53 
53 
54 
55 
56 
57 
57 
 
90th 
 
105 
106 
108 
110 
111 
113 
113 
 
68 
68 
69 
70 
71 
72 
72 
 
95th 
 
109 
110 
112 
114 
115 
117 
117 
 
72 
72 
73 
74 
75 
76 
76 
 
99th 
 
116 
117 
119 
121 
123 
124 
125 
 
80 
80 
81 
82 
83 
84 
84 
7 
50th 
 
92 
94 
95 
97 
99 
100 
101 
 
55 
55 
56 
57 
58 
59 
59 
 
90th 
 
106 
107 
109 
111 
113 
114 
115 
 
70 
70 
71 
72 
73 
74 
74 
 
95th 
 
110 
111 
113 
115 
117 
118 
119 
 
74 
74 
75 
76 
77 
78 
78 
 
99th 
 
117 
118 
120 
122 
124 
125 
126 
 
82 
82 
83 
84 
85 
86 
86 
8 
50th 
 
94 
95 
97 
99 
100 
102 
102 
 
56 
57 
58 
59 
60 
60 
61 
 
90th 
 
107 
109 
110 
112 
114 
115 
116 
 
71 
72 
72 
73 
74 
75 
76 
 
95th 
 
111 
112 
114 
116 
118 
119 
120 
 
75 
76 
77 
78 
79 
79 
80 
 
99th 
 
119 
120 
122 
123 
125 
127 
127 
 
83 
84 
85 
86 
87 
87 
88 
9 
50th 
 
95 
96 
98 
100 
102 
103 
104 
 
57 
58 
59 
60 
61 
61 
62 
 
90th 
 
109 
110 
112 
114 
115 
117 
118 
 
72 
73 
74 
75 
76 
76 
77 
 
95th 
 
113 
114 
116 
118 
119 
121 
121 
 
76 
77 
78 
79 
80 
81 
81 
 
99th 
 
120 
121 
123 
125 
127 
128 
129 
 
84 
85 
86 
87 
88 
88 
89 
10 
50th 
 
97 
98 
100 
102 
103 
105 
106 
 
58 
59 
60 
61 
61 
62 
63 
 
90th 
 
111 
112 
114 
115 
117 
119 
119 
 
73 
73 
74 
75 
76 
77 
78 
 
95th 
 
115 
116 
117 
119 
121 
122 
123 
 
77 
78 
79 
80 
81 
81 
82 
 
99th 
 
122 
123 
125 
127 
128 
130 
130 
 
85 
86 
86 
88 
88 
89 
90 


Blood Pressure Levels for Boys by Age and Height Percentile (Continued) 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
Í Percentile of Height Î
Í Percentile of Height Î
Age 
(Year)
BP
Percentile
Ð
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
11 
50th 
 
99 
100 
102 
104 
105 
107 
107 
 
59 
59 
60 
61 
62 
63 
63 
 
90th 
 
113 
114 
115 
117 
119 
120 
121 
 
74 
74 
75 
76 
77 
78 
78 
 
95th 
 
117 
118 
119 
121 
123 
124 
125 
 
78 
78 
79 
80 
81 
82 
82 
 
99th 
 
124 
125 
127 
129 
130 
132 
132 
 
86 
86 
87 
88 
89 
90 
90 
12 
50th 
 
101 
102 
104 
106 
108 
109 
110 
 
59 
60 
61 
62 
63 
63 
64 
 
90th 
 
115 
116 
118 
120 
121 
123 
123 
 
74 
75 
75 
76 
77 
78 
79 
 
95th 
 
119 
120 
122 
123 
125 
127 
127 
 
78 
79 
80 
81 
82 
82 
83 
 
99th 
 
126 
127 
129 
131 
133 
134 
135 
 
86 
87 
88 
89 
90 
90 
91 
13 
50th 
 
104 
105 
106 
108 
110 
111 
112 
 
60 
60 
61 
62 
63 
64 
64 
 
90th 
 
117 
118 
120 
122 
124 
125 
126 
 
75 
75 
76 
77 
78 
79 
79 
 
95th 
 
121 
122 
124 
126 
128 
129 
130 
 
79 
79 
80  
81 
82 
83 
83 
 
99th 
 
128 
130 
131 
133 
135 
136 
137 
 
87 
87 
88 
89 
90 
91 
91 
14 
50th 
 
106 
107 
109 
111 
113 
114 
115 
 
60 
61 
62 
63 
64 
65 
65 
 
90th 
 
120 
121 
123 
125 
126 
128 
128 
 
75 
76 
77 
78 
79 
79 
80 
 
95th 
 
124 
125 
127 
128 
130 
132 
132 
 
80 
80 
81 
82 
83 
84 
84 
 
99th 
 
131 
132 
134 
136 
138 
139 
140 
 
87 
88 
89 
90 
91 
92 
92 
15 
50th 
 
109 
110 
112 
113 
115 
117 
117 
 
61 
62 
63 
64 
65 
66 
66 
 
90th 
 
122 
124 
125 
127 
129 
130 
131 
 
76 
77 
78 
79 
80 
80 
81 
 
95th 
 
126 
127 
129 
131 
133 
134 
135 
 
81 
81 
82 
83 
84 
85 
85 
 
99th 
 
134 
135 
136 
138 
140 
142 
142 
 
88 
89 
90 
91 
92 
93 
93 
16 
50th 
 
111 
112 
114 
116 
118 
119 
120 
 
63 
63 
64 
65 
66 
67 
67 
 
90th 
 
125 
126 
128 
130 
131 
133 
134 
 
78 
78 
79 
80 
81 
82 
82 
 
95th 
 
129 
130 
132 
134 
135 
137 
137 
 
82 
83 
83 
84 
85 
86 
87 
 
99th 
 
136 
137 
139 
141 
143 
144 
145 
 
90 
90 
91 
92 
93 
94 
94 
17 
50th 
 
114 
115 
116 
118 
120 
121 
122 
 
65 
66 
66 
67 
68 
69 
70 
 
90th 
 
127 
128 
130 
132 
134 
135 
136 
 
80 
80 
81 
82 
83 
84 
84 
 
95th 
 
131 
132 
134 
136 
138 
139 
140 
 
84 
85 
86 
87 
87 
88 
89 
 
99th 
 
139 
140 
141 
143 
145 
146 
147 
 
92 
93 
93 
94 
95 
96 
97 
BP, blood pressure 
* The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. 
For research purposes, the standard deviations in Appendix Table B–1 allow one to compute BP Z-scores and percentiles for boys 
with height percentiles given in Table 3 (i.e., the 5th,10th, 25th, 50th, 75th, 90th, and 95th percentiles).  These height percentiles
must be converted to height Z-scores given by (5% = -1.645; 10% = -1.28; 25% = -0.68; 50% = 0; 75% = 0.68; 90% = 1.28%; 
95% = 1.645) and then computed according to the methodology in steps 2–4 described in Appendix B.  For children with height 
percentiles other than these, follow steps 1–4 as described in Appendix B. 


Blood Pressure Levels for Girls by Age and Height Percentile 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
Í Percentile of Height Î
Í Percentile of Height Î
Age 
(Year)
BP
Percentile
Ð
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
l 
50th 
 
83 
84 
85 
86 
88 
89 
90 
 
38 
39 
39 
40 
41 
41 
42 
 
90th 
 
97 
97 
98 
100 
101 
102 
103 
 
52 
53 
53 
54 
55 
55 
56 
 
95th 
 
100 
101 
102 
104 
105 
106 
107 
 
56 
57 
57 
58 
59 
59 
60 
 
99th 
 
108 
108 
109 
111 
112 
113 
114 
 
64 
64 
65 
65 
66 
67 
67 
2 
50th 
 
85 
85 
87 
88 
89 
91 
91 
 
43 
44 
44 
45 
46 
46 
47 
 
90th 
 
98 
99 
100 
101 
103 
104 
105 
 
57 
58 
58 
59 
60 
61 
61 
 
95th 
 
102 
103 
104 
105 
107 
108 
109 
 
61 
62 
62 
63 
64 
65 
65 
 
99th 
 
109 
110 
111 
112 
114 
115 
116 
 
69 
69 
70 
70 
71 
72 
72 
3 
50th 
 
86 
87 
88 
89 
91 
92 
93 
 
47 
48 
48 
49 
50 
50 
51 
 
90th 
 
100 
100 
102 
103 
104 
106 
106 
 
61 
62 
62 
63 
64 
64 
65 
 
95th 
 
104 
104 
105 
107 
108 
109 
110 
 
65 
66 
66 
67 
68 
68 
69 
 
99th 
 
111 
111 
113 
114 
115 
116 
117 
 
73 
73 
74 
74 
75 
76 
76 
4 
50th 
 
88 
88 
90 
91 
92 
94 
94 
 
50 
50 
51 
52 
52 
53 
54 
 
90th 
 
101 
102 
103 
104 
106 
107 
108 
 
64 
64 
65 
66 
67 
67 
68 
 
95th 
 
105 
106 
107 
108 
110 
111 
112 
 
68 
68 
69 
70 
71 
71 
72 
 
99th 
 
112 
113 
114 
115 
117 
118 
119 
 
76 
76 
76 
77 
78 
79 
79 
5 
50th 
 
89 
90 
91 
93 
94 
95 
96 
 
52 
53 
53 
54 
55 
55 
56 
 
90th 
 
103 
103 
105 
106 
107 
109 
109 
 
66 
67 
67 
68 
69 
69 
70 
 
95th 
 
107 
107 
108 
110 
111 
112 
113 
 
70 
71 
71 
72 
73 
73 
74 
 
99th 
 
114 
114 
116 
117 
118 
120 
120 
 
78 
78 
79 
79 
80 
81 
81 
6 
50th 
 
91 
92 
93 
94 
96 
97 
98 
 
54 
54 
55 
56 
56 
57 
58 
 
90th 
 
104 
105 
106 
108 
109 
110 
111 
 
68 
68 
69 
70 
70 
71 
72 
 
95th 
 
108 
109 
110 
111 
113 
114 
115 
 
72 
72 
73 
74 
74 
75 
76 
 
99th 
 
115 
116 
117 
119 
120 
121 
122 
 
80 
80 
80 
81 
82 
83 
83 
7 
50th 
 
93 
93 
95 
96 
97 
99 
99 
 
55 
56 
56 
57 
58 
58 
59 
 
90th 
 
106 
107 
108 
109 
111 
112 
113 
 
69 
70 
70 
71 
72 
72 
73 
 
95th 
 
110 
111 
112 
113 
115 
116 
116 
 
73 
74 
74 
75 
76 
76 
77 
 
99th 
 
117 
118 
119 
120 
122 
123 
124 
 
81 
81 
82 
82 
83 
84 
84 
8 
50th 
 
95 
95 
96 
98 
99 
100 
101 
 
57 
57 
57 
58 
59 
60 
60 
 
90th 
 
108 
109 
110 
111 
113 
114 
114 
 
71 
71 
71 
72 
73 
74 
74 
 
95th 
 
112 
112 
114 
115 
116 
118 
118 
 
75 
75 
75 
76 
77 
78 
78 
 
99th 
 
119 
120 
121 
122 
123 
125 
125 
 
82 
82 
83 
83 
84 
85 
86 
9 
50th 
 
96 
97 
98 
100 
101 
102 
103 
 
58 
58 
58 
59 
60 
61 
61 
 
90th 
 
110 
110 
112 
113 
114 
116 
116 
 
72 
72 
72 
73 
74 
75 
75 
 
95th 
 
114 
114 
115 
117 
118 
119 
120 
 
76 
76 
76 
77 
78 
79 
79 
 
99th 
 
121 
121 
123 
124 
125 
127 
127 
 
83 
83 
84 
84 
85 
86 
87 
10 
50th 
 
98 
99 
100 
102 
103 
104 
105 
 
59 
59 
59 
60 
61 
62 
62 
 
90th 
 
112 
112 
114 
115 
116 
118 
118 
 
73 
73 
73 
74 
75 
76 
76 
 
95th 
 
116 
116 
117 
119 
120 
121 
122 
 
77 
77 
77 
78 
79 
80 
80 
 
99th 
 
123 
123 
125 
126 
127 
129 
129 
 
84 
84 
85 
86 
86 
87 
88 


Blood Pressure Levels for Girls by Age and Height Percentile (Continued) 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
Í Percentile of Height Î
Í Percentile of Height Î
Age 
(Year)
BP
Percentile
Ð
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
11 
50th 
 
100 
101 
102 
103 
105 
106 
107 
 
60 
60 
60 
61 
62 
63 
63 
 
90th 
 
114 
114 
116 
117 
118 
119 
120 
 
74 
74 
74 
75 
76 
77 
77 
 
95th 
 
118 
118 
119 
121 
122 
123 
124 
 
78 
78 
78 
79 
80 
81 
81 
 
99th 
 
125 
125 
126 
128 
129 
130 
131 
 
85 
85 
86 
87 
87 
88 
89 
12 
50th 
 
102 
103 
104 
105 
107 
108 
109 
 
61 
61 
61 
62 
63 
64 
64 
 
90th 
 
116 
116 
117 
119 
120 
121 
122 
 
75 
75 
75 
76 
77 
78 
78 
 
95th 
 
119 
120 
121 
123 
124 
125 
126 
 
79 
79 
79 
80 
81 
82 
82 
 
99th 
 
127 
127 
128 
130 
131 
132 
133 
 
86 
86 
87 
88 
88 
89 
90 
13 
50th 
 
104 
105 
106 
107 
109 
110 
110 
 
62 
62 
62 
63 
64 
65 
65 
 
90th 
 
117 
118 
119 
121 
122 
123 
124 
 
76 
76 
76 
77 
78 
79 
79 
 
95th 
 
121 
122 
123 
124 
126 
127 
128 
 
80 
80 
80 
81 
82 
83 
83 
 
99th 
 
128 
129 
130 
132 
133 
134 
135 
 
87 
87 
88 
89 
89 
90 
91 
14 
50th 
 
106 
106 
107 
109 
110 
111 
112 
 
63 
63 
63 
64 
65 
66 
66 
 
90th 
 
119 
120 
121 
122 
124 
125 
125 
 
77 
77 
77 
78 
79 
80 
80 
 
95th 
 
123 
123 
125 
126 
127 
129 
129 
 
81 
81 
81 
82 
83 
84 
84 
 
99th 
 
130 
131 
132 
133 
135 
136 
136 
 
88 
88 
89 
90 
90 
91 
92 
15 
50th 
 
107 
108 
109 
110 
111 
113 
113 
 
64 
64 
64 
65 
66 
67 
67 
 
90th 
 
120 
121 
122 
123 
125 
126 
127 
 
78 
78 
78 
79 
80 
81 
81 
 
95th 
 
124 
125 
126 
127 
129 
130 
131 
 
82 
82 
82 
83 
84 
85 
85 
 
99th 
 
131 
132 
133 
134 
136 
137 
138 
 
89 
89 
90 
91 
91 
92 
93 
16 
50th 
 
108 
108 
110 
111 
112 
114 
114 
 
64 
64 
65 
66 
66 
67 
68 
 
90th 
 
121 
122 
123 
124 
126 
127 
128 
 
78 
78 
79 
80 
81 
81 
82 
 
95th 
 
125 
126 
127 
128 
130 
131 
132 
 
82 
82 
83 
84 
85 
85 
86 
 
99th 
 
132 
133 
134 
135 
137 
138 
139 
 
90 
90 
90 
91 
92 
93 
93 
17 
50th 
 
108 
109 
110 
111 
113 
114 
115 
 
64 
65 
65 
66 
67 
67 
68 
 
90th 
 
122 
122 
123 
125 
126 
127 
128 
 
78 
79 
79 
80 
81 
81 
82 
 
95th 
 
125 
126 
127 
129 
130 
131 
132 
 
82 
83 
83 
84 
85 
85 
86 
 
99th 
 
133 
133 
134 
136 
137 
138 
139 
 
90 
90 
91 
91 
92 
93 
93 
BP, blood pressure 
* The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. 
For research purposes, the standard deviations in Appendix Table B–1 allow one to compute BP Z-scores and percentiles for girls
with height percentiles given in Table 4 (i.e., the 5th,10th, 25th, 50th, 75th, 90th, and 95th percentiles).  These height percentiles
must be converted to height Z-scores given by (5% = -1.645; 10% = -1.28; 25% = -0.68; 50% = 0; 75% = 0.68; 90% = 1.28%; 
95% = 1.645) and then computed according to the methodology in steps 2–4 described in Appendix B.  For children with height 
percentiles other than these, follow steps 1–4 as described in Appendix B. 


Statistical Analysis Plan Methods, Version 2.0 07 SEP 2017 
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Protocol VX15-809-115, (Version 3.0, 13 April 2017)  
 
Vertex Pharmaceuticals Incorporated 
 
 
Appendix H: Important Protocol Deviation Programming Rules (Based on the 
Clinical Database) 
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
x
Subject entered the study despite violation of an inclusion or exclusion criteria 
x
Subject received the wrong treatment or incorrect doses  
x
Subject received excluded concomitant medications 
x
Subject remained in study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but the blinded 
team should categorize them as IPDs only if they have the potential to affect interpretation of 
study results.  The team should construct rules for identifying IPDs rather than identifying 
individual subjects with IPDs.  
Important protocol deviations before first dose 
1. Inclusion criteria: 
a.
I3: Subjects (males and females) will be between the ages of 2 and 5 years, inclusive, 
on the date of informed consent (and assent, if applicable) for the relevant study part. 
b. I4: Subjects who weigh t8 kg without shoes and wearing light clothing at the 
Screening Visit. 
c.
I6: Subjects who are homozygous for F508del (genotype to be confirmed at the 
Screening Visit). If the CFTR screening genotype result is not received before Day -1, 
a previous CFTR genotype laboratory report may be used to establish eligibility. 
Note:  
o
Subjects who have been enrolled and whose screening genotype does not 
confirm study eligibility must be discontinued from the study, as described 
in Protocol Section 9.5. 
o
This assessment does not need to be repeated for confirmed subjects in 
Part A who may participate in Part B.  
 


Statistical Analysis Plan Methods, Version 2.0 07 SEP 2017 
Page 40 of 41 
Protocol VX15-809-115, (Version 3.0, 13 April 2017)  
 
Vertex Pharmaceuticals Incorporated 
 
 
2. Exclusion criteria: 
a.
E3: Any of the following abnormal laboratory values at the Screening Visit: 
o
Hemoglobin <10 g/dL 
o
ALT, AST or Total bilirubin >2× ULN  
o
Abnormal renal function defined as glomerular filtration rate 
45 mL/min/1.73 m2 (calculated by the Bedside Schwartz equation) 
b. E5: A standard 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. If 
QTc exceeds 450 msec at the Screening Visit, the ECG should be repeated 2 more 
times during the Screening Period, and the average of the 3 QTc values should be 
used to determine the subject's eligibility. 
Programming notes: 
o
Check if screening QTcF>450 msec at screening, if yes, 
o
Check whether ECG was repeated 2 more times during the screening 
period, if no, report as important protocol deviation. If yes,  
o
Check whether the average of the 3 QTcF values 450msec, if no, report 
as important protocol deviation. 
c.
E6: History of solid organ or hematological transplantation. 


Statistical Analysis Plan Methods, Version 2.0 07 SEP 2017 
Page 41 of 41 
Protocol VX15-809-115, (Version 3.0, 13 April 2017)  
 
Vertex Pharmaceuticals Incorporated 
 
 
Important protocol deviations during the treatment period 
1. Compliance < 80%. 
2. Prohibited medication not happened during study drug interruption period (prohibited 
medication treatment period overlaps with study drug treatment period) 
Programming notes: 
o
Prohibited medication and study drug should not be taken at the same 
time/day. 
 
3. Nominal Post dose ECGs on Day 1 or Day 15 that are collected before the dosing time on 
the same visit. 
Programming note:  
o
If the ECG is labeled as post-dose but the actual timing is pre-dose, then it 
should be reported as important protocol deviation. 
 
4. Eye exam is not completed at either Week 24 or the Safety Follow-Up Visit (Week 26). 
5. Subject received the wrong treatment or incorrect doses.