Clinical trial NCT02725567
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-06-02; Completion date: 2022-06-28
Enrollment: 57 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the safety of ivacaftor treatment, and PK of ivacaftor and metabolites in participants with cystic fibrosis (CF) who are \<24 months of age at treatment initiation and have an ivacaftor-responsive CF transmembrane conductance regulator (CFTR) gene mutation.

Detailed description:

Arms: arm 1: Participants weighing 5 to less than (\<) 7 kilogram (kg) received 25 milligram (mg) IVA, 7 to \<14 kg received 50 mg IVA, and those weighing 14 to \<25 kg received 75 mg IVA administered every 12 hours (q12h) on Days 1 through 3 and 1 morning dose on Day 4. arm 2: Participants 4 to \<6 months of age and weighing greater than or equal to (≥) 5 kg received 25 mg IVA q12h. At 6 months of age and older, participants weighing 5 to \<7 kg received 25 mg IVA, 7 to \<14 kg received 50 mg IVA, and those weighing 14 to \<25 kg received 75 mg IVA q12h for 24 weeks on Part B. For Part A/B, participants 1 to \<4 months weighing 3 kg to \<5 kg received an initial low dose of 5.7 mg q12h IVA and those weighing ≥5 kg received 11.4 mg q12h IVA for the first 15 days of IVA treatment. Doses were maintained or adjusted upward at Day 15 and based on weight and/or age once they reached 4 months of age.
Interventions: intervention 1: IVA
Intervention descriptions: intervention 1: Granules in sachet for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 101 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, 2-Part, Open-label Study to Evaluate the 
Safety, Pharmacokinetics, and Pharmacodynamics 
of Ivacaftor in Subjects With Cystic Fibrosis Who Are 
Less Than 24 Months of Age at Treatment Initiation 
and Have an Ivacaftor-responsive CFTR Mutation 
Vertex Study Number: VX15-770-124  
 
EudraCT Number: 2015-001997-16 
Date of Protocol: 01 April 2021 (Version 4.0) 
Replaces Version 3.1, dated 29 June 2020 
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. 
 




Vertex Pharmaceuticals Incorporated 
Confidential Information 


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2 
PROTOCOL SYNOPSIS 
Title A Phase 3, 2-Part, Open-label Study to Evaluate the Safety, Pharmacokinetics, and 
Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis Who Are Less Than 
24 Months of Age at Treatment Initiation and Have an Ivacaftor-responsive CFTR 
Mutation 
  
Clinical Phase and 
Clinical Study Type  
Phase 3, safety, pharmacokinetics, and efficacy 
  
Part A Objectives  Primary: 
• 
To evaluate the safety of ivacaftor treatment in subjects with cystic fibrosis (CF) 
who are <24 months of age at treatment initiation and have a CF transmembrane 
conductance regulator (CFTR) gene gating mutation  
• 
To evaluate the pharmacokinetics (PK) of ivacaftor and metabolites 
hydroxymethyl-ivacaftor (M1) and ivacaftor carboxylate (M6) in subjects with 
CF who are <24 months of age at treatment initiation and have a CFTR gating 
mutation 
 
 
Part B Objectives  Primary: 
• 
To evaluate the safety of ivacaftor treatment in subjects with CF who are 
<24 months of age at treatment initiation and have a CFTR gating mutation 
Secondary: 
• 
To evaluate the PK of ivacaftor and metabolites M1 and M6 in subjects with CF 
who are <24 months of age at treatment initiation and have a CFTR gating 
mutation 
• 
To evaluate the pharmacodynamics (PD) of ivacaftor treatment in subjects with 
CF who are <24 months of age at treatment initiation and have a CFTR gating 
mutation  
  
Part A/B Objectives 
Cohort 8 
Primary: 
• 
To evaluate the safety of ivacaftor treatment in subjects with CF who are 1 to 
<4 months of age at treatment initiation and have an ivacaftor-responsive CFTR 
mutation (consistent with the approved mutations in the region)  
• 
To evaluate the PK of ivacaftor and the ivacaftor metabolites M1 and M6 in 
subjects with CF who are 1 to <4 months of age at treatment initiation and have 
an ivacaftor-responsive CFTR mutation (consistent with the approved mutations 
in the region)  


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Secondary: 
• 
To evaluate the PD of ivacaftor treatment in subjects with CF who are 1 to 
<4 months of age at treatment initiation and have an ivacaftor-responsive CFTR 
mutation (consistent with the approved mutations in the region)   
Part A Endpoints Primary: 
• 
Safety, as determined by adverse events, clinical laboratory values (serum 
chemistry and hematology), standard 12-lead electrocardiograms (ECGs), vital 
signs, and ophthalmologic examinations (OEs)  
• 
PK parameter estimates of ivacaftor and metabolites M1 and M6 after 4 days of 
ivacaftor treatment 
  
Part B Endpoints Primary: 
• 
Safety, as determined by adverse events, clinical laboratory values (serum 
chemistry and hematology), ECGs, vital signs, and OEs 
Secondary: 
• 
PK parameter estimates of ivacaftor and metabolites M1 and M6 
• 
Absolute change from baseline in sweat chloride  


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Part A/B Endpoints 
Cohort 8 
Primary: 
• 
Safety, as determined by adverse events, clinical laboratory values (serum 
chemistry and hematology), standard 12-lead ECGs, vital signs, and OEs 
• 
PK parameter estimates of ivacaftor and metabolites M1 and M6  
Secondary: 
• 
Absolute change from baseline in sweat chloride  
  
Number of Subjects in 
Part A 
A minimum of 15 subjects: 
• 
minimum of 5 subjects aged 12 to <24 months 
• 
minimum of 5 subjects aged 6 to <12 months 
• 
minimum of 5 subjects aged 3 to <6 months 
  
Number of Subjects in 
Part B 
A minimum of 15 subjects: 
• 
minimum of 5 subjects aged 12 to <24 months 
• 
minimum of 5 subjects aged 6 to <12 months 
• 
minimum of 5 subjects aged 4 to <6 months  
  
Number of Subjects in 
Part A/B Cohort 8 
• 
A minimum of 6 and up to approximately 10 subjects, aged 1 to <4 months, with 
at least 4 subjects evenly distributed in the age range 1 to <3 months 
  
Study Population Male and female subjects with CF who are <24 months of age at Day 1 (ivacaftor 
treatment initiation) and have a CFTR gating mutation (as listed below) on at least 
1 allele.  
Subjects who have 1 of the following 9 CFTR mutations on at least 1 allele will be 
considered eligible for enrollment in this study: G551D, G178R, S549N, S549R, 
G551S, G1244E, S1251N, S1255P, or G1349D. Subjects who have an R117H-CFTR 
mutation will be eligible in regions where ivacaftor is approved for use in subjects 
with an R117H-CFTR mutation. 


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Subjects who have an ivacaftor-responsive CFTR mutation on at least 1 allele will be 
considered eligible for enrollment in Part A/B Cohort 8 (consistent with the approved 
mutations in the region). 
  
Investigational Drug Active substance: ivacaftor 
 Activity: CFTR potentiator 
 Strengths and route of administration: 5.7 mg, 25 mg, 50 mg, and 75 mg; granules in 
sachet for oral administration  
Doses of 25, 50, and 75 mg every 12 hours (q12h) for study in Cohorts 1 through 7. 
Doses of 5.7, 11.4, 17.1, 22.8, 25, 50, and 75 mg, q12h, for study in Cohort 8; 
multiple sachets of 5.7 mg will be used to achieve doses of 11.4, 17.1, and 22.8 mg. 
Dosing in all cohorts will be based on safety, PK, age, and weight. 
  
Study Duration for 
Part A 
Excluding the Screening Period, Part A subjects will participate in the study for 
approximately 10 weeks (from Day 1 through the Part A Follow-up OE).  
  
Study Duration for 
Part B 
Excluding the Screening Period, subjects will participate in Part B for approximately 
24 weeks (from Day 1 through Week 24). 
  
Study Duration for 
Part A/B Cohort 8 
Excluding the Screening Period, subjects will participate in Part A/B Cohort 8 for 
approximately 24 weeks (from Day 1 through Week 24).  
  
Study Design This is a Phase 3, 2-part, open-label study designed to evaluate the safety, PK, PD, 
and efficacy of ivacaftor in subjects with CF who are <24 months of age at treatment 
initiation (Day 1) and have an ivacaftor-responsive CFTR mutation on at least 1 
allele. Part A is designed to evaluate the safety and PK of multiple-dose 
administration of ivacaftor in subjects <24 months of age over 4 days of dosing, and 
to confirm (or adjust if necessary) the doses for Part B. Part B is designed to evaluate 
the safety, PK, PD, and efficacy of ivacaftor in subjects <24 months of age over 
24 weeks. Part A/B Cohort 8 is designed to evaluate the safety, PK, PD, and efficacy 
of ivacaftor in subjects with CF who are 1 to <4 months of age, ≥38 weeks gestation, 
weigh at least 3 kg at the time of treatment initiation (Day 1), and have an ivacaftor-
responsive CFTR mutation (consistent with the approved mutations in the region) on 
at least 1 allele. Subjects will receive an initial low dose of ivacaftor (based on their 
Day 1 age and weight) and they will continue that dose up to Day 15, at which time 
the dose may be adjusted to better match the median adult exposure. Subjects are 
intended to remain on that dose until they are 4 months of age and at least 5 kg, after 
which the recommended age- and weight-appropriate dose(s) will be administered.  
Part A: 
Subjects will be enrolled in Part A sequentially in the following cohorts: 
• 
Cohort 1: subjects aged 12 to <24 months 
• 
Cohort 2: subjects aged 6 to <12 months 
• 
Cohort 3: subjects aged 3 to <6 months 
Enrollment in Part A will begin with subjects in Cohort 1. Enrollment for subjects in 
Cohort 2 will begin after an assessment of safety and PK data for subjects from 
Cohort 1. Enrollment for subjects in Cohort 3 will begin after an assessment of safety 
and PK data for subjects in Cohort 2.  
PK data from each completed cohort in Part A will be used to update the population 
PK model and inform dose selection for the subsequent cohort before that cohort 


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begins enrolling. If PK data from any cohort in Part A are insufficient to confirm the 
dose for that age group, additional subjects will be enrolled in the cohort until an 
appropriate dose is confirmed.  
Part A of this study includes: 
• 
Screening Period (Day -28 to Day -1) 
• 
Treatment Period (Day 1 to Day 5):  
• 
25-mg (for subjects 5 to <7 kg on Day 1), 50-mg (for subjects 7 to <14 kg on 
Day 1), or 75-mg (for subjects 14 to <25 kg on Day 1) ivacaftor will be 
administered q12h on Days 1 through 3 and 1 morning dose on Day 4. These 
doses may be amended at any time based on available PK data from previous 
cohorts and may result in additional doses or different weight strata. Data from 
each cohort in Part A will be used to update the population PK model and inform 
dose predictions for each subsequent (younger) cohort. 
• 
Study visits will occur on Days 1, 4, and 5. 
• 
PK samples will be collected before the morning dose on Day 4, between 2 and 
4 hours, between 6 to 8 hours, and between 24 and 60 hours after the Day 4 dose.  
• 
For subjects who prematurely discontinue treatment, a PK blood sample will be 
collected at the Early Termination of Treatment (ETT) Visit (within 5 days after 
the last dose of study drug). 
• 
Follow-up Telephone Call (Day 14) 
• 
Follow-up OE (within 8 weeks after the last dose of study drug). 
Subjects who prematurely discontinue treatment before their last scheduled dose in 
Part A will be required to complete the ETT Visit, Follow-up Telephone Call, and 
Follow-up OE. 
Part B: 
Subjects will be enrolled in Part B sequentially in the following cohorts based on age 
at Day 1 of Part B: 
• 
Cohort 5: subjects aged 12 to <24 months 
• 
Cohort 6: subjects aged 6 to <12 months 
• 
Cohort 7: subjects aged 4 to <6 months 
Enrollment of subjects in Cohort 5 will begin following an assessment of:  
• 
Safety and PK data from Part A for subjects from Cohort 1 and confirmation of 
dose for subjects aged 12 to <24 months. 
Enrollment of subjects in Cohort 6 will begin after an assessment of:  
• 
Safety and PK data from Part A for subjects from Cohort 2 and confirmation of 
dose for subjects aged 6 to <12 months. 
• 
Safety data from Week 12 of Part B for at least 5 subjects in Cohort 5.   
Enrollment of subjects in Cohort 7 will begin with enrollment of subjects aged 4 to 
<6 months following an assessment of: 
• 
Safety and PK data from Part A for subjects from Cohort 3 and confirmation of 
dose in subjects aged 3 to <6 months.  
• 
Safety data from Week 12 of Part B for at least 5 subjects in Cohort 6.  
Subjects from Cohorts 2 and 3 who will age out of the corresponding age cohort 
(Cohorts 6 or 7) in Part B at Day 1 may enroll in an older age cohort in Part B with 


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the Vertex medical monitor’s permission. Otherwise, those subjects who will age out 
of the corresponding age cohort may enroll in the Extension Study. 
Part B of this study includes: 
• 
Screening Period (Day -28 to Day -1) 
• 
Treatment Period (Day 1 to Week 24): 
• 
Starting doses in Cohorts 5 and 6 of 25-mg (for subjects 5 to <7 kg on Day 1), 
50-mg (for subjects 7 to <14 kg on Day 1), or 75-mg (for subjects 14 to <25 kg 
on Day 1) ivacaftor will be administered q12h for 24 weeks (or other suitable 
starting dose based on safety and PK data from Part A). At each study visit the 
ivacaftor dose for each subject will be reassessed based on body weight and 
adjusted if necessary.  
• 
All subjects enrolled in Cohort 7 will receive a 25 mg dose of ivacaftor q12h 
until the subject reaches the age of 6 months. At each study visit after the age of 
6 months, the ivacaftor dose for each subject will be reassessed based on body 
weight and adjusted, if necessary, as follows:  
o 
Subjects 5 to <7 kg will be dosed with 25 mg q12h  
o 
Subjects 7 to <14 kg will be dosed with 50 mg q12h  
o 
Subjects 14 to <25 kg will be dosed with 75 mg q12h  
• 
Study visits will occur on Day 1 and Weeks 2, 4, 8, 12, 18, and 24.  
• 
PK blood samples will be collected at the following time points:  
o 
Week 2: before the morning dose, between 2 and 4 hours and between 6 and 
8 hours after the morning dose 
o 
Week 8: before the morning dose and 1 and 4 hours after the morning dose 
o 
Week 24: before the morning dose and between 2 and 4 hours after the 
morning dose  
o 
For subjects who prematurely discontinue treatment, a PK blood sample will 
be collected at the ETT Visit. 
• 
OEs will be performed at screening, Week 12, and Week 24.  
All subjects who complete 24 weeks of study drug treatment will be eligible to enroll 
in the open-label treatment arm of an Extension Study. The Follow-up Visit will not 
be required for subjects who enroll in the treatment arm of this study. 
Subjects who complete 24 weeks of study drug treatment who elect not to enroll in 
the treatment arm of the Extension Study will be required to complete the Follow-up 
Visit and will be eligible to enroll in the observational arm of the Extension Study. 
The Follow-up Visit will not be required in the event that the subject initiates 
treatment with commercially available ivacaftor within 3 weeks of the Week 24 Visit.  
Subjects who prematurely discontinue treatment before their last scheduled dose will 
be required to complete the ETT Visit, Follow-up Visit, and Follow-up OE. The 
Follow-up Visit will not be required: 
• 
If the ETT Visit occurs 3 weeks or later after the last dose of study drug. 
• 
In the event that the subject initiates treatment with commercially available 
ivacaftor within 3 weeks of the ETT Visit.  
Subjects who prematurely discontinue study drug treatment will be eligible to enroll 
in the observational arm of the Extension Study. Subjects enrolling into the Extension 


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Study within 24 weeks after the last dose of study drug are not required to have the 
Follow-up OE (the OE will be performed in the Extension Study). 
Part A/B Cohort 8: 
Subjects 1 to <4 months of age, ≥38 weeks gestation, and weighing at least 3 kg at 
the time of treatment initiation (Day 1), will receive an initial low dose of ivacaftor 
(5.7 mg q12h or 11.4 mg q12h based on their Day 1 age and weight) from Day 1 up 
to Day 15. Subjects 3 months of age must weigh ≥5 kg on Day 1. This initial low 
dose is based on prior age- and weight-based simulations of exposure which accounts 
for potential variability in metabolic enzyme maturation affecting exposures. The 
initial dose is expected to result in exposures within or below the adult exposure 
range. On Day 4, PK samples from each subject will be collected before and after 
dosing and analyzed to determine the exposure and assess whether the initial dose 
needs to be adjusted to better match the median adult exposure.  
Part A/B Cohort 8 of this study includes: 
• 
Confirmed genotype; genotype testing is expected to be initiated prior to 
screening and results must be available prior to Day 1 
• 
Screening Period (Day -28 to Day -14) 
o 
Due to limitations in the volume of blood that should be collected from the 
1- to <4-month-old age group in a 28-day span, screening should be 
completed at least 14 days prior to Day 1 (treatment initiation) 
• 
Initial Treatment Period (Day 1 up to Day 15):  
o 
Subjects will receive an initial low dose of ivacaftor (5.7 mg q12h or 11.4 
mg q12h based on their Day 1 age and weight) from Day 1 up to Day 15, as 
follows:  
Age 
Weight Range 
Starting Dose 
1 month 
≥3 kg 
5.7 mg q12h 
2 months 
≥3 to <5 kg 
5.7 mg q12h 
2 months 
≥5 kg 
11.4 mg q12h 
3 months 
≥5 kg 
11.4 mg q12h 
All subjects must have gestational age ≥38 weeks and weigh ≥3 kg. 
Subjects 3 months of age must weigh ≥5 kg on Day 1. 
o 
Study visits will occur on Days 1, 4, and 15. 
o 
Follow-up Telephone Call (Day 1 evening) 
o 
PK samples will be collected before the morning dose on Day 4, between 2 
to 4 hours and between 6 to 8 hours after the Day 4 morning dose.  
o 
The subject’s Day 4 PK data will be used to calculate exposure to determine 
a dose that is expected to bring the exposure for the subject closest to the 
adult median. This potential dose adjustment will be communicated in 
writing to the principal investigator for administration to the subject on 
Day 15. 
o 
At the Day 15 Visit, a trough PK sample will be collected before the 
morning dose. The ivacaftor dose will be adjusted if necessary, to either 5.7, 
11.4, 17.1, 22.8, or 25 mg, and the adjusted dose will be administered q12h 
starting with the evening dose on Day 15. 
• 
Subsequent Treatment Period (Day 16 to Week 24):  


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o 
Follow-up Telephone Call (Day 17) 
o 
Study visits will occur on Weeks 4, 8, 12, 18, and 24. 
o 
The subject is intended to remain on the same dose from Day 15 until the 
subject is 4 months of age and at least 5 kg, after which the recommended 
age- and weight-appropriate dose(s) will be administered.  
o 
PK samples will be collected before the morning dose on Week 8, between 2 
to 4 hours and between 6 to 8 hours after the Week 8 morning dose. 
o 
Additional PK samples will be collected before the morning dose on the 
Week 4, 12, 18, and 24 Visits to characterize the longitudinal PK profile. 
• 
The entire treatment period of the study will be 24 weeks, after which subjects 
will be eligible to enroll in an Extension Study. 
• 
Subjects who do not enroll in the Extension Study will have a Follow-up Visit 
within 4 weeks ± 7 days after the last dose of study drug and a Follow-up OE 
within 12 weeks ± 14 days after the last dose of study drug. 
Subjects who prematurely discontinue treatment before their last scheduled dose will 
be required to complete the Early Termination of Treatment (ETT) Visit, Follow-up 
Visit, and Follow-up OE. A PK blood sample will be collected at the ETT Visit (if 
the ETT Visit occurs within 3 days after the last dose of study drug).  
  
Safety Assessments 
for Parts A, B, and 
A/B Cohort 8 
Adverse events, clinical laboratory values (serum chemistry and hematology), ECGs, 
vital signs, physical examinations, and OEs 
  
Pharmacodynamic 
Assessment for 
Parts B and A/B 
Cohort 8 
Sweat chloride test 
Statistical Analyses Details will be provided in the statistical analysis plan (SAP) for the final analysis, 
which will be finalized and approved before the clinical database lock. A detailed 
analysis plan for PK and PK/PD parameter estimations will be presented in a clinical 
pharmacology analysis plan (CPAP), which will be finalized and approved before 
database lock.  
The sample size of a minimum of 15 subjects in Part A and 15 subjects in Part B, and 
6 up to approximately 10 subjects in Part A/B Cohort 8 is determined to be 
appropriate based on PK considerations and feasibility assessments for CF subjects 
meeting the age and enrollment criteria. The study is not powered to detect a 
significant treatment effect. Relatively rich PK samples (4 samples at steady state) 
will be collected in Part A, in addition to PK samples collected from all subjects in 


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Part B through 24 weeks. PK evaluation will consist of a population PK approach, 
utilizing the current population PK model and existing data for subjects ≥24 months 
of age. Based on a review of model-based pediatric simulations, the variability 
estimate of ivacaftor from Study VX11-770-108, and the PK collection scheme, the 
number of subjects planned for enrollment is expected to provide reasonably precise 
estimates of key PK parameters using a population PK approach. For Part A/B 
Cohort 8, relatively rich PK samples will be collected at Day 4 of the Treatment 
Period, followed by additional sparse PK samples through 24 weeks. 
Safety analyses for Parts A, B, and A/B Cohort 8 will be conducted separately. 
Efficacy and PD analyses are applicable to Part B and Part A/B Cohort 8 only, and 
Part A/B Cohort 8 will be analyzed separately from other cohorts. Parts B and A/B 
Cohort 8 may also be pooled for analyses of safety, PD, and efficacy endpoints 
common to both parts. The Safety Set (defined as subjects who receive a dose of 
study drug) will be used for all safety analyses. The Full Analysis Set (FAS) (defined 
as subjects who are enrolled and dosed) will be used for all efficacy analyses in Part 
B and Part A/B Cohort 8. Data from all safety, efficacy, and PD endpoints will be 
analyzed using descriptive statistics, and presented by study visit and dose level for 
Parts A and B, and by study visit without separation by dose level for Part A/B 
Cohort 8. 
Nonlinear mixed effects modeling will be applied for the PK analysis of ivacaftor for 
comparison of ivacaftor disposition to that of adults. The primary exposure estimates 
of interest are ivacaftor area under the concentration versus time curve (AUC) and 
minimum observed concentration (Cmin). Exposure of metabolites M1 and M6 will be 
described by descriptive statistics. 
As noted above, preliminary analyses will be performed on the PK data obtained 
from each cohort in Part A. The PK analysis, along with safety data from Part A, will 
be used to appropriately confirm the dose selection for Part B (or adjust the doses if 
necessary) based on criteria that take into account both the Cmin and AUC relative to 
historical results in adult CF subjects. PK parameters other than Cmin and AUC may 
be considered if deemed appropriate.  
For Part A/B Cohort 8, preliminary analyses of individual PK data collected on Day 4 
will be used to inform subsequent dosing for that subject. 
  
IDMC Reviews Data will be reviewed by an independent data monitoring committee (IDMC) to 
ensure the safety of the subjects in the study. Procedural details of the IDMC's 
structure and function, frequency of meetings, and data planned for review will be 
included in the IDMC charter, which will be finalized before the first IDMC review 
meeting. 


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3 
SCHEDULE OF ASSESSMENTS 
Table 3-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of 
Treatment, and Follow-up Periods) 
Table 3-2 
Study VX15-770-124: Part B (Screening and Treatment Periods) 
Table 3-3 
Study VX15-770-124: Part B (Early Termination of Treatment Visit and Follow-
up Period)  
Table 3-4 
Study VX15-770-124: Part A/B Cohort 8 (Screening, Treatment, Early 
Termination of Treatment, and Follow-up Periods) 
 




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Table 3-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of Treatment, and Follow-up 
Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
Early 
Termination of 
Treatment 
Visit 
Follow-up Telephone Call 
Follow-up 
Ophthalmologic 
Examination 
Day -28 
to Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Within 5 Days 
After Last 
Dose of Study 
Drug 
Day 14 
( 2 Days) 
8 Weeks 
( 14 Days) 
After Last Dose 
of Study Drug 
12-lead ECGsf 
X 
 
 
 
 
X 
X 
 
 
Ophthalmologic 
examinationg 
X 
 
 
 
 
 
 
 
X 
Serum chemistry 
and hematologyh 
X 
 
 
 
X 
X 
 
 
PK blood collection 
 
 
 
 
Xi 
Xj 
X 
 
 
Sweat chloride testk 
X 
 
 
 
 
 
 
 
 
Study drug 
administrationl 
 
X 
X 
X 
X 
 
 
 
 
                                                 
f 
All 12-lead ECGs will be performed before the morning dose. The subject should rest for at least 5 minutes, if possible, before having the ECG performed. 
The ECG will be performed before any other procedures that may affect heart rate, such as blood draws.  
g 
The screening OE may be performed predose on Day 1. For subjects who have the Part A Follow-up OE within 6 months of enrolling in Part B, the 
screening OE for Part B is not required.  
h 
To minimize blood draws, the Screening Visit and Day 1 clinical laboratory assessments will be combined into a single blood draw taken up to 9 days before 
Day 1 dosing. The results must be received and reviewed before the first dose of study drug. All blood samples will be collected while subjects are in a 
seated or supine position. 
i 
PK samples will be collected before the morning dose and between 2 and 4 hours and between 6 and 8 hours after dosing on Day 4. 
j 
A PK sample will be collected between 24 and 60 hours after Day 4 morning dose (Day 5+1 day). 
k 
A sweat chloride test must be performed if the sweat chloride value is not available in the subject’s medical records and the value is needed to establish 
eligibility. For subjects with sweat chloride values documented in their medical records and for whom it is not needed to establish eligibility, the sweat 
chloride test at screening is not required. 
l 
Study drug will be administered q12h for 3 days and the last dose of study drug in Part A will be the morning dose on Day 4. The Day 1 and Day 4 morning 
doses will be administered in the clinic. Doses administered from the evening dose on Day 1 through the evening dose on Day 3 will be administered q12h at 
home. Each dose of granules will be mixed with approximately 1 teaspoon (5 mL) of appropriate liquid or soft food (as listed in the study manual). Details 


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Table 3-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of Treatment, and Follow-up 
Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
Early 
Termination of 
Treatment 
Visit 
Follow-up Telephone Call 
Follow-up 
Ophthalmologic 
Examination 
Day -28 
to Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Within 5 Days 
After Last 
Dose of Study 
Drug 
Day 14 
( 2 Days) 
8 Weeks 
( 14 Days) 
After Last Dose 
of Study Drug 
In-clinic observation 
for 4 hours after 
administration of the 
first dose of study 
drug 
 
X 
 
 
 
 
 
 
 
Study drug 
dispensing 
 
X 
 
 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through the Follow-up Telephone Call (Day 14 ± 2 days; see Section 14.1.1.3) 
Ocular adverse 
events only 
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit through the Follow-up Telephone Call (Day 14 ± 2 days) 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ECG: electrocardiogram; ETT: Early Termination of Treatment; ICF: informed 
consent form; OE: ophthalmologic examination; PK: pharmacokinetic; q12h: every 12 hours. 
 
                                                 
of dose preparation and dose administration will be provided in the study manual. The administration dates and times and whether doses were administered 
with food during the 3 days should be recorded in each subject’s dosing diary.  


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Table 3-2 
Study VX15-770-124: Part B (Screening and Treatment Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Day -28  
to Day -1 Day 1 
Day 3 
Week 2 
( 1 Day) 
Week 4 
( 5 Days) 
Week 8 
( 5 Days) 
Week 12 
( 5 Days) 
Week 18 
( 5 Days) 
Week 24a 
( 5 Days)  
Informed consentb 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
X 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
 
X 
X 
X 
X 
X 
X 
Telephone contact 
 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
CFTR genotypec 
X 
 
 
 
 
 
 
 
 
 weightd 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical examinatione 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECGsg 
X 
 
 
 
X 
 
X 
 
X 
Ophthalmologic 
examinationsh 
X 
 
 
 
 
 
X 
 
X 
Serum chemistry and 
hematologyi  
X 
 
chemistry 
only 
LFTs and 
hematology only 
X 
X 
X 
X 
PK blood collectionj 
 
 
 
X 
 
X 
 
  
Xk 
Sweat chloride testl 
X 
X 
 
X 
 
 
X 
 
X 
Study drug 
administrationq 
 
X 
 
X 
X  
X 
X 
X 
X 
                                                 
a 
Subjects who complete 24 weeks of study drug treatment in Part B will be eligible to enroll in the open-label treatment arm of the Extension Study. For 
subjects who enroll, the Week 24 visit can be the same visit as Day 1 in the treatment arm of the Extension Study, and these subjects do not need to complete 


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Confidential Information 
                                                 
the Follow-up Visit. All other subjects must complete the ETT and/or Follow-up Visits (as applicable) and will be eligible to enroll in an observational arm 
of the Extension Study. 
b 
Informed consent may be obtained before the Screening Visit and must be obtained before any screening assessment is performed.  
c 
Subjects who had CFTR genotyping completed in Part A of the study will not require repeat testing upon entry into Part B. For all other subjects, the 
genotype results must be available before the first dose of study drug. If a genotype test has been performed previously and is documented in the subject’s 
medical record, the subject's eligibility must be approved by the Vertex medical monitor. If a historic genotype result is not available at screening or if the 
historic genotype result is not approved by the Vertex medical monitor, subjects will be tested for CFTR genotype and the results must be reviewed before 
the first dose of study drug. 
d 
 weight must be measured with the subject in a dry diaper or dry underclothes only (see Section 12.5.1 for details). 
 weight 
measurements will be made before the morning dose on Day 1.  
e 
Full physical examinations will occur at the Screening and Week 24 Visits; abbreviated physical examinations will occur at all other study visits. 
f 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration rate, and pulse oximetry. The subject should rest for at least 5 
minutes, if possible, before having vital signs measured. Day 1 vital signs measurements will be collected before dosing. Temperature must be obtained by 
the same method throughout the study. 
g 
All 12-lead ECGs will be performed before the morning dose. The subject should rest for at least 5 minutes, if possible, before having the ECG performed. 
The ECG will be performed before any other procedures that may affect heart rate, such as blood draws. 
h 
The screening OE may be performed predose on Day 1. If an adequate slit-lamp examination cannot be conducted at the Part B screening, subjects will not 
be enrolled in Part B until an adequate repeat slit-lamp examination is completed (within 4 weeks of the Screening Period) and eligibility criteria regarding 
the ophthalmologic findings are met. If an adequate slit-lamp examination cannot be conducted at any visit where it is required, the subject will continue to 
receive study drug until an adequate repeat examination is completed (within 4 weeks of the study visit); if an adequate slit-lamp examination cannot be 
conducted at the second examination or a lens opacity or cataract is identified, study drug dosing will be discontinued. A screening OE will not need to be 
conducted for subjects who have the Part A Follow-up OE within 6 months of enrolling in Part B. 
i 
To minimize blood draws, the Screening Visit and Day 1 clinical laboratory assessments will be combined into a single blood draw taken up to 9 days before 
Day 1 dosing. The results must be received and reviewed before the first dose of study drug. All blood samples will be collected while subjects are in a 
seated or supine position. 
j 
PK samples will be collected before the morning dose and between 2 and 4 hours and between 6 and 8 hours after the morning dose on Week 2. PK samples 
will be collected before the morning dose and 1 hour and 4 hours after the morning dose on Week 8. PK samples will be collected before the morning dose 
and between 2 and 4 hours after the morning dose on Week 24.  
k 
PK sample collection is optional at Week 24 for subjects who undergo MBW. 
l 
At Screening a sweat chloride test must be performed if the sweat chloride value is not available in the subject’s medical records and the value is needed to 
establish eligibility. For subjects with sweat chloride values documented in their medical records and for whom it is not needed to establish eligibility, the 
sweat chloride test at screening is not required. Subjects who had a sweat chloride test during Screening for Part A will not require repeat testing during 
Screening for Part B. At the Day 1 Visit, the sweat chloride test must be performed before the morning dose. At the Week 2, 12, and 24 Visits, the sweat 
chloride test must be performed within a window of ± 2 hours relative to the morning dose of the study drug   


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Table 3-2 
Study VX15-770-124: Part B (Screening and Treatment Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Day -28  
to Day -1 Day 1 
Day 3 
Week 2 
( 1 Day) 
Week 4 
( 5 Days) 
Week 8 
( 5 Days) 
Week 12 
( 5 Days) 
Week 18 
( 5 Days) 
Week 24a 
( 5 Days)  
In-clinic observation for 
4 hours after 
administration of the 
first dose of study drug 
 
X 
 
 
 
 
 
 
 
Study drug count 
 
X 
 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
X 
 
X 
X 
X 
X 
X 
Xr 
Adverse events 
14.1.1.3  
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit through the ETT and Follow-up Visit (if required)  
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ECG: electrocardiogram; ICF: informed consent form; 
 
 LFT: liver function test; PK: pharmacokinetic; q12h: every 12 hours 
q 
Study drug will be administered q12h. Each dose of granules will be mixed with approximately 1 teaspoon (5 mL) of liquid appropriate liquid or soft food 
(as listed in the study manual). Details of dose preparation and dose administration will be provided in the study manual. The dose administration dates and 
times, occurrence and time of regurgitation within 1 hour after dosing, and their timing with respect to food intake, will be recorded for the 2 doses prior to 
each PK clinic visit in each subject’s dosing diary. 
r 
Study drug will only be dispensed to subjects enrolling in the open-label treatment arm of the Extension Study.  


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Table 3-3 
Study VX15-770-124: Part B (Early Termination of Treatment Visit and 
Follow-up Period) 
 
Early Termination of 
Treatment Visita 
Follow-up Visitb 
Follow-up Ophthalmologic 
Examinationc 
Event/Assessment 
As Soon as Possible After the 
Last Dose of Study Drug 
4 Weeks (± 7 Days) After the Last 
Dose of Study Drug 
24 Weeks (± 14 Days) 
After the Last Dose of 
Study Drug 
Clinic visit 
X 
X 
 
 
weightd 
X 
X 
 
Physical 
examinatione 
X 
X 
 
Vital signsf 
X 
X 
 
12-lead ECGsg 
X 
 
 
Serum chemistry 
and hematologyh 
X 
X 
 
Ophthalmologic 
examinationi 
X 
 
X 
PK blood 
collection 
X 
 
 
Study drug count 
X 
 
 
                                                 
a  Subjects who prematurely discontinue treatment before their last scheduled dose will be required to complete the 
ETT Visit as soon as possible after the last dose of study drug and the Follow-up Visit. All subjects who 
prematurely discontinue from study drug treatment in Part B will be eligible to enroll in an observational arm of 
the Extension Study. 
b  The Follow-up Visit is not required if the subject completes the Part B treatment period and enrolls in the 
treatment arm of the Extension Study. For all other subjects, the Follow-up Visit is not required if the ETT Visit 
occurs 3 weeks or later after the last dose of study drug (ivacaftor) or in the event that the subject initiates 
treatment with commercially available ivacaftor within 3 weeks of the final scheduled treatment visit or ETT 
Visit. 
c  Subjects who prematurely discontinue ivacaftor treatment in Part B and received at least 1 dose of ivacaftor 
treatment in Part B will have a Follow-up OE 24 weeks after the last dose of study drug. Subjects enrolling into 
the Extension Study within 24 weeks after the last dose of study drug are not required to have the Follow-up OE 
(the OE will be performed in the Extension Study instead). 
d  
 weight must be measured with the subject in a dry diaper or dry underclothes only (see 
Section 12.5.1 for details). 
e  Full physical examinations will be performed at the ETT Visit and Follow-up Visit. 
f  Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration rate, and pulse 
oximetry. The subject should rest for at least 5 minutes, if possible, before having vital signs measured. 
Temperature must be obtained by the same method throughout the study. 
g  The subject should rest for at least 5 minutes, if possible, before having the ECG performed. The ECG will be 
performed before any other procedures that may affect heart rate, such as blood draws.  
h  All blood samples will be collected while subjects are in a seated or supine position. 
i  The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue study drug dosing. If 
the ETT Visit occurs within 12 weeks of the subject's last OE, the OE at the ETT Visit will not be required. In 
addition, these subjects will be eligible to enroll in an observational arm of the Extension Study for long-term 
follow-up OE. 
 


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Table 3-3 
Study VX15-770-124: Part B (Early Termination of Treatment Visit and 
Follow-up Period) 
 
Early Termination of 
Treatment Visita 
Follow-up Visitb 
Follow-up Ophthalmologic 
Examinationc 
Event/Assessment 
As Soon as Possible After the 
Last Dose of Study Drug 
4 Weeks (± 7 Days) After the Last 
Dose of Study Drug 
24 Weeks (± 14 Days) 
After the Last Dose of 
Study Drug 
Adverse events 
Continuous from signing ICF through the ETT (if required) and 
Follow-up Visit (see Section 14.1.1.3)  
Ocular adverse events only 
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit through the ETT and Follow-up Visit (if 
required; see Section 10.3.1) 
ECG: electrocardiogram; ETT: Early Termination of Treatment; ICF: informed consent form; OE: ophthalmologic 
examination; PK: pharmacokinetic. 


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Table 3-4 
Study VX15-770-124: Part A/B Cohort 8 (Screening, Treatment, Early Termination of Treatment, and Follow-
up Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Early 
Termination of 
Treatment 
Visita 
Follow-up 
Visitb 
Follow-up 
Ophthalmologic 
Examinationc 
Day -28  
to Day -14 Day 1 
Day 4 
Day 15 
( 1 Day) 
Day 17 
( 1 Day) 
Week 4 
( 5 Days) 
Week 8 
( 5 Days) 
Weeks 12, 
18, and 24 
( 5 Days) 
As Soon as 
Possible After 
the Last Dose 
of Study Drug 
4 Weeks 
(± 7 Days) 
After Last Dose 
of  
Study Drug 
12 Weeks (± 14 Days) 
After Last Dose of  
Study Drug 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
X 
 
 
 
 
 
 
 
 
 
Clinic visit/ 
Assessment contact 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Telephone contact 
 
pm 
 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 weighte 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Physical examinationf 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Vital signsg 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
12-lead ECGsh 
X 
 
X 
 
 
X 
 
X 
X 
 
Ophthalmologic 
examinationsi 
X 
 
 
 
 
 
 
Xj 
X 
 
X 
Serum chemistryk 
X 
X 
X 
X  
 
X 
X 
X 
X 
X 
 
Hematologyk 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
PK blood collectionl 
 
 
Xm 
X 
 
X 
Xl 
X 
Xn 
 
 
Sweat chloride testo 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
Study drug 
administrationq 
 
X 
X 
X 
 
X  
X 
X 
 
 
 


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a 
Subjects who prematurely discontinue treatment before their last scheduled dose will be required to complete the ETT Visit as soon as possible after the last 
dose of study drug and the Follow-up Visit. All subjects who prematurely discontinue from study drug treatment in Part A/B Cohort 8 will be eligible to 
enroll in an observational arm of the Extension Study. 
b 
The Follow-up Visit is not required if the subject completes the Part A/B Cohort 8 treatment period and enrolls in the treatment arm of the Extension Study. 
For all other subjects, the Follow-up Visit is not required if the ETT Visit occurs 3 weeks or later after the last dose of study drug (ivacaftor) or in the event 
that the subject initiates treatment with commercially available ivacaftor within 3 weeks of the final scheduled treatment visit or ETT Visit. 
c 
Subjects who prematurely discontinue ivacaftor treatment in Part A/B Cohort 8 and received at least 1 dose of ivacaftor treatment in Part A/B Cohort 8 will 
have a Follow-up OE 12 weeks after the last dose of study drug. Subjects enrolling into the Extension Study within 12 weeks after the last dose of study drug 
are not required to have the Follow-up OE (the OE will be performed in the Extension Study instead). Subjects who initiate treatment with commercially 
available ivacaftor within 3 weeks of the ETT Visit will not have the Follow-up OE. 
d 
Informed consent may be obtained before the Screening Visit and must be obtained before any screening assessment is performed. 
e 
 weight must be measured with the subject in a dry diaper or dry underclothes only (see Section 12.5.1 for details). 
 weight 
measurements will be made before the morning dose on Day 1.  
f 
Full physical examinations will occur at the Screening, Week 24, and Early Termination of Treatment (ETT) Visits; abbreviated physical examinations will 
occur at all other study visits. 
g 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration rate, and pulse oximetry. The subject should rest for at least 
5 minutes, if possible, before having vital signs measured. Day 1 vital sign measurements will be collected before the morning dose. Temperature must be 
obtained by the same method throughout the study. 
h 
All 12-lead ECGs will be performed before the morning dose. The subject should rest for at least 5 minutes, if possible, before having the ECG performed. 
The ECG will be performed before any other procedures that may affect heart rate, such as blood draws. 
i 
The screening OE may be performed at any time from screening until before the first dose on Day 1. If an adequate slit-lamp examination cannot be 
conducted at screening, subjects will not be enrolled until an adequate repeat slit-lamp examination is completed (within 4 weeks of the Screening Period). 
Eligibility criteria regarding the ophthalmologic findings must be met prior to dosing. 
j 
OE to be performed at the Week 12 and Week 24 Visits. 
k 
To minimize the volume of blood drawn on Day 1, clinical laboratory assessments will be determined from a single blood draw taken during the Screening 
Period Day -28 to Day -14. The results must be received and reviewed before the first dose of study drug. All blood samples will be collected while subjects 
are in a seated or supine position. 
l 
PK samples will be collected before the morning dose and between 2 to 4 hours and between 6 to 8 hours after the morning dose on Day 4 and the Week 8 
Visit. PK samples will be collected before the morning dose on Day 15, and on the Week 4, 12, 18, and 24 Visits. 
m 
If all PK samples collected on Day 4 are missing or cannot be analyzed, PK samples collected on Day 15 will be used to assess whether the initial dose 
should be adjusted at the Week 4 Visit. 
n 
Assessment will be performed only if within 3 days of last dose of study drug. 
o 
At Screening a sweat chloride test must be performed if the sweat chloride value is not available in the subject’s medical records and the value is needed to 
establish eligibility. For subjects with sweat chloride values documented in their medical records and for whom it is not needed to establish eligibility, the 
sweat chloride test at screening is not required. At the Day 1 Visit, the sweat chloride test must be performed before the morning dose. At the Day 15 and 
Week 4, 8, 12, 18 and 24 Visits, the sweat chloride test must be performed within a window of ± 2 hours relative to the morning dose of the study drug. 


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Table 3-4 
Study VX15-770-124: Part A/B Cohort 8 (Screening, Treatment, Early Termination of Treatment, and Follow-
up Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Early 
Termination of 
Treatment 
Visita 
Follow-up 
Visitb 
Follow-up 
Ophthalmologic 
Examinationc 
Day -28  
to Day -14 Day 1 
Day 4 
Day 15 
( 1 Day) 
Day 17 
( 1 Day) 
Week 4 
( 5 Days) 
Week 8 
( 5 Days) 
Weeks 12, 
18, and 24 
( 5 Days) 
As Soon as 
Possible After 
the Last Dose 
of Study Drug 
4 Weeks 
(± 7 Days) 
After Last Dose 
of  
Study Drug 
12 Weeks (± 14 Days) 
After Last Dose of  
Study Drug 
In-clinic observation for 
4 hours after 
administration of the 
first dose of study drug 
 
X 
 
 
 
 
 
 
 
 
 
Study drug count 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Study drug dispensing 
 
X 
 
X 
 
X 
X 
Xr 
 
 
 
Adverse events 
Continuous from signing of ICF through ETT and Follow-up Visit (if required; see Section 14.1.1.3) 
Ocular adverse events 
only 
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit (or from birth, as relevant) through the ETT and Follow-up Visit (if required; see 
Section 10.3.1) 
CF: cystic fibrosis; ECG: electrocardiogram; ETT: early termination of treatment; ICF: informed consent form; 
; 
OE: ophthalmologic examination; PK: pharmacokinetic; q12h: every 12 hours 
                                                 
q 
Study drug will be administered q12h. Each dose of granules will be mixed with approximately 1 teaspoon (5 mL) of appropriate liquid or soft food (as 
listed in the study manual). Details of dose preparation and dose administration will be provided in the study manual. The dose administration dates and 
times, occurrence and time of regurgitation within 1 hour after dosing, and their timing with respect to food intake, will be recorded for the 2 doses prior to 
each PK clinic visit in each subject’s dosing diary. In addition, the time of administration of study drug and occurrence and time of regurgitation within 
1 hour after dosing in clinic on the day of the visit will be recorded. 
r 
Week 12 and Week 18 Visits only. Study drug will only be dispensed at Week 24 to subjects enrolling in the open-label treatment arm of the Extension 
Study. 


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4 
TABLE OF CONTENTS 
1 
Title page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments...................................................................................................... 13 
4 
Table of Contents ................................................................................................................. 25 
List of Tables............................................................................................................................ 28 
List of Figures .......................................................................................................................... 29 
List of Abbreviations................................................................................................................ 30 
Definition of Terms: ................................................................................................................. 31 
5 
Introduction.......................................................................................................................... 32 
5.1 
Overview of Cystic Fibrosis ........................................................................................... 32 
5.2 
Overview of Cystic Fibrosis in Infants and Young Children ......................................... 33 
5.3 
Overview of Ivacaftor ..................................................................................................... 34 
6 
Study Objectives .................................................................................................................. 35 
6.1 
Part A .............................................................................................................................. 35 
7 
Primary Objectives .............................................................................................................. 35 
7.1 
Part B .............................................................................................................................. 35 
7.1.1 
Primary Objective ................................................................................................... 35 
7.1.2 
Secondary Objectives ............................................................................................. 35 
7.2 
Part A/B Cohort 8 ........................................................................................................... 36 
7.2.1 
Primary Objectives ................................................................................................. 36 
7.2.2 
Secondary Objectives ............................................................................................. 36 
8 
Study Endpoints ................................................................................................................... 36 
8.1 
Part A .............................................................................................................................. 36 
8.1.1 
Primary Endpoints .................................................................................................. 36 
8.2 
Part B .............................................................................................................................. 36 
8.2.1 
Primary Endpoint .................................................................................................... 36 
8.2.2 
Secondary Endpoints .............................................................................................. 37 
 
8.3 
Part A/B Cohort 8 Endpoints .......................................................................................... 37 
8.3.1 
Primary Endpoints .................................................................................................. 37 
8 3 2 
Secondary Endpoints 
 37 
 
9 
Study Design ......................................................................................................................... 38 
9.1 
Overview of Study Design ............................................................................................. 38 
9.1.1 
Screening ................................................................................................................ 44 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 45 
9.1.1.2 
Rescreening ...................................................................................................... 45 
9.1.1.3 
Extension of Screening Window ...................................................................... 45 
9.1.2 
Treatment Period .................................................................................................... 45 
9.1.3 
Follow-up................................................................................................................ 46 
9.1.3.1 
Follow-up Ophthalmologic Examination ......................................................... 47 


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9.1.4 
Early Termination of Treatment ............................................................................. 47 
9.2 
Independent Data Monitoring Committee ...................................................................... 47 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 48 
9.3.1 
Study Design........................................................................................................... 48 
9.3.2 
Study Drug Dose and Duration .............................................................................. 49 
9.3.2.1 
Dose Selection .................................................................................................. 50 
9.3.3 
Rationale for Study Assessments ........................................................................... 51 
10 Study Population .................................................................................................................. 53 
10.1 Inclusion Criteria ............................................................................................................ 54 
10.2 Exclusion Criteria ........................................................................................................... 55 
10.3 Study Restrictions ........................................................................................................... 56 
10.3.1 
Prior and Concomitant Medications and Other Study Restrictions ........................ 56 
10.3.2 
Prohibited Medications ........................................................................................... 56 
10.4 Removal of Subjects ....................................................................................................... 57 
10.5 Replacement of Subjects ................................................................................................ 57 
11 Study Drug Administration and Management ................................................................. 58 
11.1 Preparation and Dispensing ............................................................................................ 58 
11.2 Administration ................................................................................................................ 58 
11.3 Method of Assigning Subjects to Treatment Groups ..................................................... 59 
11.4 Dose Modification for Toxicity ...................................................................................... 59 
11.5 Packaging and Labeling ................................................................................................. 59 
11.6 Study Drug Supply, Storage, and Handling ................................................................... 60 
11.7 Drug Accountability ....................................................................................................... 60 
11.8 Disposal, Return, or Retention of Unused Drug ............................................................. 60 
11.9 Compliance ..................................................................................................................... 60 
11.10 Blinding and Unblinding ................................................................................................ 60 
12 Assessments .......................................................................................................................... 60 
12.1 Timing of Assessments ................................................................................................... 60 
12.2 Subject and Disease Characteristics ............................................................................... 61 
12.3 Pharmacokinetics ............................................................................................................ 61 
12.3.1 
Blood Sampling ...................................................................................................... 61 
12.3.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 63 
12.3.3 
Bioanalysis.............................................................................................................. 64 
12.4 Pharmacodynamics ......................................................................................................... 64 
12.4.1 
Sweat Chloride ....................................................................................................... 64 
12.6 Safety .............................................................................................................................. 66 


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12.6.1 
Adverse Events ....................................................................................................... 66 
12.6.2 
Clinical Laboratory Assessments ........................................................................... 66 
12.6.3 
Physical Examinations and Vital Signs .................................................................. 69 
12.6.4 
Electrocardiograms ................................................................................................. 69 
12.6.5 
Ophthalmologic Examinations ............................................................................... 69 
12.6.6 
Contraception and Pregnancy ................................................................................. 70 
13 Statistical and Analytical Plans .......................................................................................... 70 
13.1 Sample Size and Power .................................................................................................. 71 
13.2 Part A Analyses .............................................................................................................. 72 
13.2.1 
Analysis Set ............................................................................................................ 72 
13.3 Part B Analyses .............................................................................................................. 72 
13.3.1 
Analysis Sets........................................................................................................... 72 
13.4 Part A/B Cohort 8 Analyses ........................................................................................... 72 
13.4.1 
Analysis Sets........................................................................................................... 72 
13.5 Statistical Analysis ......................................................................................................... 73 
13.5.1 
General Considerations ........................................................................................... 73 
13.5.2 
Background Characteristics .................................................................................... 73 
13.5.2.1 Subject Disposition .......................................................................................... 73 
13.5.2.2 Demographics and Baseline Characteristics .................................................... 74 
13.5.2.3 Prior and Concomitant Medications................................................................. 74 
13.5.2.4 Study Drug Exposure and Compliance ............................................................ 74 
13.5.3 
Efficacy Analysis (Part B) ...................................................................................... 75 
13.5.3.1 Analysis of Primary Variables ......................................................................... 75 
13 5 3 2 Analysis of Secondary Efficacy Variables 
 75 
13.5.4 
Efficacy Analysis (Part A/B Cohort 8) ................................................................... 76 
13.5.4.1 Analysis of Primary Variables ......................................................................... 76 
13.5.4.2 Analysis of Secondary Efficacy Variables ....................................................... 77 
13.5.5 
Safety Analysis ....................................................................................................... 78 
13.5.5.1 Adverse Events................................................................................................. 78 
13.5.5.2 Clinical Laboratory Assessments ..................................................................... 79 
13.5.5.3 Electrocardiogram ............................................................................................ 79 
13.5.5.4 Vital Signs ........................................................................................................ 79 
13.5.5.5 Physical Examination ....................................................................................... 79 
13 5 5 6
Ophthalmological Examination 
 79
13.5.6 
Interim and IDMC Analyses ................................................................................... 80 
13.5.6.1 Interim Analysis ............................................................................................... 80 
13.5.6.2 IDMC Analysis ................................................................................................ 80 
13.6 Clinical Pharmacology Analysis .................................................................................... 80 
13.6.1 
Pharmacokinetic Analysis (Part A and Part B) ...................................................... 80 
13.6.2 
Pharmacokinetic Analysis (Part A/B Cohort 8) ..................................................... 80 
14 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 81 
14.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 81 


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14.1.1 
Adverse Events ....................................................................................................... 81 
14.1.1.1 Definition of an Adverse Event........................................................................ 81 
14.1.1.2 Clinically Significant Assessments .................................................................. 81 
14.1.1.3 Documentation of Adverse Events................................................................... 81 
14.1.1.4 Adverse Event Severity .................................................................................... 83 
14.1.1.5 Adverse Event Causality .................................................................................. 83 
14.1.1.6 Study Drug Action Taken ................................................................................ 84 
14.1.1.7 Adverse Event Outcome .................................................................................. 84 
14.1.1.8 Treatment Given............................................................................................... 84 
14.1.2 
Serious Adverse Events .......................................................................................... 85 
14.1.2.1 Definition of a Serious Adverse Event............................................................. 85 
14.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 85 
14.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 86 
14.2 Administrative Requirements ......................................................................................... 86 
14.2.1 
Product Complaints ................................................................................................ 86 
14.2.2 
Ethical Considerations ............................................................................................ 86 
14.2.3 
Subject Information and Informed Consent ........................................................... 87 
14.2.4 
Investigator Compliance ......................................................................................... 87 
14.2.5 
Access to Records ................................................................................................... 87 
14.2.6 
Subject Privacy ....................................................................................................... 87 
14.2.7 
Record Retention .................................................................................................... 88 
14.2.8 
Study Termination .................................................................................................. 88 
14.2.9 
End of Study ........................................................................................................... 88 
14.3 Data Quality Assurance .................................................................................................. 88 
14.4 Monitoring ...................................................................................................................... 89 
14.5 Electronic Data Capture ................................................................................................. 89 
14.6 Confidentiality and Disclosure ....................................................................................... 89 
14.7 Publications and Clinical Study Report .......................................................................... 90 
14.7.2 
Clinical Study Report ............................................................................................. 90 
15 References ............................................................................................................................. 91 
16 Appendix A: CFTR Mutations Included in the Study ...................................................... 97 
17 Appendix B: Selection of Starting Dose from Different Models ..................................... 98 
18 Protocol Signature Pages .................................................................................................. 100 
18.1 Sponsor Signature Page ................................................................................................ 100 
18.2 Investigator Signature Page .......................................................................................... 101 
 
List of Tables 
Table 3-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of 
Treatment, and Follow-up Periods) ...................................................................... 14 
Table 3-2 
Study VX15-770-124: Part B (Screening and Treatment Periods) ....................... 17 
Table 3-3 
Study VX15-770-124: Part B (Early Termination of Treatment Visit and Follow-
up Period) .............................................................................................................. 20 
Table 3-4 
Study VX15-770-124: Part A/B Cohort 8 (Screening, Treatment, Early 
Termination of Treatment, and Follow-up Periods) ............................................. 22 
Table 12-1 
Expected Blood Volumes to be Collected at Each Study Visit ............................ 62 


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Table 12-2 
Acceptable Pharmacokinetic Sampling Windows ................................................ 63 
Table 12-3  
Safety Laboratory Test Panels .............................................................................. 67 
Table 14-1 
Grading of Adverse Event Severity ...................................................................... 83 
Table 14-2 
Classifications for Adverse Event Causality ......................................................... 83 
Table 14-3 
Classifications for Study Drug Action Taken With Regard to an Adverse Event 84 
Table 14-4 
Classifications for Outcome of an Adverse Event ................................................ 84 
Table 16-1 
List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to 
Ivacaftor ................................................................................................................ 97 
Table 17-1 
Starting Dose Table............................................................................................... 99 
List of Figures 
Figure 9-1 
Schematic of Study Design ................................................................................... 42 
Figure 9-2 
Schematic of Part A/B Cohort 8 Study Design ..................................................... 44 
Figure 17-1 
Selection of Starting Dose From Different Models .............................................. 98 
 
 


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List of Abbreviations 
Abbreviation 
Term 
ALT 
alanine transaminase or alanine aminotransferase 
AST 
aspartate transaminase or aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CF 
cystic fibrosis 
CFF 
Cystic Fibrosis Foundation 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator 
CI 
confidence intervals 
CL 
clearance 
Cmin 
minimum observed concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CSR 
clinical study report 
CYP 
cytochrome P450 
CYP3A4 
cytochrome P450 3A4 
ECGs 
electrocardiograms 
EDC 
electronic data capture 
EENT 
eyes/ears/nose/throat 
ETT 
Early Termination of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
G551D 
CFTR missense gene mutation that results in the replacement of a glycine residue at 
position 551 of CFTR with an aspartic acid residue 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act and associated regulations 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IECs 
independent ethics committees 
IQR 
interquartile range 
IRB 
institutional review board 


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Abbreviation 
Term 
IV 
intravenous 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
NCHS 
National Center for Health Statistics 
OEs 
ophthalmologic examinations 
PBPK 
physiologically-based pharmacokinetic 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
popPK 
population PK 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
R117H 
CFTR missense gene mutation that results in the replacement of an arginine residue at 
position 117 of CFTR with a histidine residue 
RVRTC 
raised volume rapid thoracoabdominal compression 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SI 
SI units (International System of Units) 
TEAEs 
treatment-emergent adverse events 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
 
Definition of Terms: 
Part A of this study includes Cohorts 1, 2, and 3 and Part B includes Cohorts 5, 6, and 7. 
Part A/B of the amended protocol includes Cohort 8. Cohort 4 has been dropped from the 
amended protocol as the age group within that cohort will be studied in Part A/B Cohort 8.


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5 
INTRODUCTION 
5.1 
Overview of Cystic Fibrosis 
Cystic fibrosis (CF) is a chronically debilitating autosomal, recessive disease with high 
morbidity and premature mortality that affects approximately 30,000 individuals in the United 
States1 and 36,000 in the European Union.2 The disease affects predominately Whites3 and is 
caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which results 
in absent or deficient function of the CFTR protein at the cell surface.4 CFTR is an epithelial 
chloride channel responsible for aiding in the regulation of salt and water absorption and 
secretion in various tissues. The failure to regulate chloride transport in these tissues results in 
the multisystem pathology associated with CF.5 In the lungs, obstruction of airways with thick 
mucus, establishment of a chronic bacterial infection in the airways, and damaging inflammatory 
responses are all thought to play a role in causing irreversible structural changes in the lungs and 
respiratory failure. Progressive loss of lung function is the leading cause of mortality.1, 3 
Currently, there is no cure for CF, and, despite adjunctive treatments with nutritional 
supplements, antibiotics, and mucolytics,6 the median predicted age of survival of individuals 
born today with CF is approximately 40 years of age.1, 7-9  
More than 1900 mutations in the CFTR gene have been identified.10 CFTR mutations result in 
reduced quantity of CFTR at the cell surface or reduced CFTR function, leading to a decrease in 
epithelial chloride transport.11, 12 Reduced CFTR function can be due to defects in channel gating 
(opening and closing of CFTR channel) or channel conductance (rate of chloride travel through 
the open channel).  
Gating refers to the amount of time in which the CFTR channel is open and can transport 
chloride. Ten CFTR mutations that lead to CFTR gating functional defects have been identified: 
G551D, G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, and G1349D. The 
G551D mutation is the most common mutation that causes CFTR gating defects worldwide and 
results in a severe CF clinical phenotype.13-15 While reports of individual cases and small cohorts 
of patients show variable phenotypes in patients carrying the G551D mutation16-18 the 3 largest 
genotype-phenotype association studies that evaluated patients from different geographical 
regions have classified the G551D mutation as being associated with a severe phenotype,14, 19-21 
with rates of lung disease progression15 and mortality13, 14 that are similar to other severe 
phenotypes. There are few published reports on the clinical features of patients with other 
non-G551D mutations that cause CFTR gating defects; however, an analysis of the US CF 
Foundation Patient Registry data revealed that the rates of lung disease progression in patients 
with these mutations are similar to that of patients with the G551D mutation.15 
Mutations that cause CFTR gating defects are present in about 5% of the CF patient population 
worldwide. Approximately 4% of patients (1032 patients with CF in the US, 1083 in the 
European Union (EU), and 2374 worldwide) have the G551D mutation and the remaining 1% 
(140 patients in the US, 205 in the EU, and 370 worldwide) have other mutations that cause a 
CFTR gating defect.15, 22 The R117H mutation causes defects in channel gating, but also in 
channel conductance.23 This mutation is present in about 700 people with CF in the US, 
including about 500 people age 6 years and older.1, 24 The R117H mutation is often associated 
with delayed onset of clinical symptoms, although CF patients with this mutation have 
progressive disease, with premature mortality and considerable morbidity.25-27  


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In May 2017, the FDA approved an additional 23 ivacaftor-responsive mutations based on 
clinical or in-vitro data focused on ivacaftor’s mechanism of action as a CFTR modulator. In the 
US, these 23 residual function mutations are present in over 1800 patients (US Cystic Fibrosis 
Foundation [CFF] Registry data 201224 and 20131; Vertex data on file). In August 2017, the 
FDA approved an additional 5 residual function mutations, present in over 600 patients in the 
US,1 that result in a splicing defect in the CFTR gene. The US CFF registry data show a clear 
progression of lung disease with age in these patients. Intervening early in the disease process 
can ameliorate this progression. The potential risks of providing ivacaftor to patients with these 
28 specific mutations are considered low.   
5.2 
Overview of Cystic Fibrosis in Infants and Young Children 
The diagnosis of CF is suggested by the presence of 1 or more characteristic clinical features, a 
history of CF in a sibling, or a positive newborn screening test result, and is confirmed by 
laboratory evidence of abnormal CFTR protein function (a positive sweat test) or by genotyping 
analysis.28 Since the introduction and continued advances of newborn screening, many patients 
with CF are identified through a positive screen test and subsequently diagnosed within the first 
neonatal year.28 In the US and the EU, more than 61% of people with CF who were diagnosed in 
2012 were found because of an abnormal newborn screen.1, 29 In the UK, 57% of people with CF 
who were diagnosed in 2012 were found because of an abnormal newborn screen.30 In the US, 
more than 80% of patients with CF are diagnosed by age 2; however, approximately 10% of 
newly diagnosed cases are 16 years of age or older.1 In the EU, approximately 60% of patients 
with CF are diagnosed by 1 year of age,29 and in the UK, approximately 83% of patients with CF 
are diagnosed by 1 year of age.31 Genotyping for mutations in the CFTR gene is now routine 
practice in many countries.  
In infants with CF, pancreatic insufficiency32 and poor nutritional status33-35 are the most 
significant clinical manifestations of the disease. These factors often lead to poor growth with 
subsequent growth delay,36, 37 poorer cognitive development,38 and other clinical comorbidities 
such as decreased lung function and survival.39, 40 Studies of subjects 1 month through 6 years of 
age also show the presence of lung disease41-44 and liver disease.45 High-resolution computed 
tomography studies including infants with CF that were diagnosed by newborn screening, but 
were considered clinically healthy, indicates that structural lung damage is common even very 
early in disease progression.44, 46, 47 In a cohort of 81 well-treated CF patients in Australia, by the 
age of 3 years, 10% had Pseudomonas aeruginosa infection and 84% had evidence of 
bronchiectasis.48 This is consistent with the results of inflammatory marker studies that have 
found that airway inflammation begins in infancy.42, 49, 50 The presence of airway inflammation in 
infancy signals the beginning of the destructive cycles of chronic inflammation, infection, and 
irreversible lung damage that are characteristic of CF lung disease.51 A study of the longitudinal 
development of P. aeruginosa infection in children with CF found that 29% of the infants 
followed developed nonmucoid infection in the first 6 months of life; overall, the median age for 
nonmucoid P. aeruginosa infection was 1.0 years and for the transition from nonmucoid to 
mucoid P. aeruginosa infection was 13.0 years.52 Mucoid P. aeruginosa infection is considered 
the major limiting factor in survival for patients with CF.53 
Poor somatic growth and poor nutritional status are common in patients with CF owing to a 
number of factors, including exocrine pancreatic insufficiency, increased energy expenditure and 
appetite suppression due to lung disease, as well as diabetes.54 Notably, 18% of children with CF 
fall below the US Centers for Disease Control and Prevention’s (CDC) fifth percentile for weight 


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and 16% of children fall below the CDC fifth percentile for height.55 Malnourishment is 
associated with worsening lung function in children with CF and is also an independent predictor 
of mortality in this population.56 
Compounds such as CFTR modulators may have the potential to preserve normal lung and 
pancreatic exocrine function. Data in the literature suggest that early therapeutic intervention is 
beneficial to young children with CF; studies have demonstrated benefits such as improved 
measures of growth, nutrition, and lung disease through early intervention in children diagnosed 
by newborn screening.57, 58 Moreover, treatments that target the underlying mechanisms of 
disease at a young age could postpone or even prevent the onset of clinical manifestation of CF 
such as CF lung disease.59  
5.3 
Overview of Ivacaftor 
Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical 
benefit in patients with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] and 
VX08-770-103 [Study 103]) showed that ivacaftor is effective in the treatment of subjects with 
CF 6 years of age and older who have the G551D-CFTR mutation, as evidenced by sustained 
improvements in CFTR channel function (measured by reduction in sweat chloride 
concentration) and corresponding substantial, durable improvements in lung function, pulmonary 
exacerbations, respiratory symptoms, and weight gain. Ivacaftor was also well tolerated, as 
evidenced by the rates and reasons for premature discontinuation and results of safety 
assessments.60 
Results from Part 1 (placebo-controlled, double-blind, crossover period) of Study VX12-770-111 
(Study 111), a Phase 3 clinical study that assessed efficacy and safety in subjects with CF who 
have non-G551D-CFTR gating mutations, showed that treatment with ivacaftor has systemic 
benefit, including substantial improvements in both pulmonary and extrapulmonary measures, 
with corresponding improvements in CFTR function. Ivacaftor produced consistent, clinically 
meaningful, and highly statistically significant improvements in percent predicted forced 
expiratory volume in 1 second (FEV1), body mass index (BMI)/weight, sweat chloride, and the 
Cystic Fibrosis Questionnaire–Revised (CFQ-R; respiratory domain). These results were 
comparable to those observed in the Phase 3 studies (Studies 102 and 103) in subjects with the 
G551D mutation in the CFTR gene.60 
Results from Study VX11-770-110 (Study 110), a Phase 3, randomized, double-blind, placebo-
controlled, parallel-group study in subjects aged 6 years and older with CF who have an R117H 
mutation, showed that in subjects 18 years of age or older treatment with ivacaftor resulted 
statistically significant improvements in 
, CFTR activity as measured by sweat chloride, 
and in respiratory symptoms as measured by the CFQ-R respiratory domain score, compared to 
placebo through 24 weeks of treatment. Although the 6- to 11-years-old subgroup showed a 
comparable sweat chloride response to the ≥18-years-old subgroup, the younger subgroup did 
not show any other meaningful response to ivacaftor.60 
All ivacaftor doses tested in VX06-770-101 (Study 101) showed a very robust improvement in 
CFTR function as measured by sweat chloride (Study 101 CSR, Figure 11-8). The lowest dose of 
25 mg, which is one-sixth the approved adult dose, yielded improvements in sweat chloride in 
the range of -30 to -40 mmol/L which would be expected to be associated with clinical benefit. 
This was accompanied by positive trends in relative change in ppFEV1 (Study 101 CSR, Figure 
11-6) and nasal potential difference (Study 101 CSR, Figure 11-7).  


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The starting doses for Part A/B Cohort 8 were selected to maintain exposures within a range that 
was safe (i.e., not exceeding the range observed with the 150 mg dose in adults) and efficacious 
(i.e., exposures above those observed with the 25 mg dose in adults as described) (Appendix B).  
Results from Study VX11-770-108 (Study 108), a Phase 3, open-label study of orally 
administered ivacaftor in subjects with CF who are 2 through 5 years of age and have a CFTR 
gating mutation in at least 1 allele, showed that subjects had rapid, substantial, persistent 
reductions in sweat chloride, improvements in nutritional status, and increases in fecal elastase-1. 
Additionally, the safety profile of ivacaftor was similar to that identified in the prior Phase 2b/3 
analyses for subjects 6 years of age and older with a CFTR mutation that causes gating defects.60 
Ivacaftor is now indicated in the US and the EU for the treatment of CF in patients 6 months of 
age and older who have at least 1 mutation in the CFTR gene that is responsive to ivacaftor 
potentiation based on clinical and/or in vitro assay data. The approved genotypes vary by 
country/region. 
Based on data from subjects in the 4 to <6 months of age cohort (Study 124, Cohort 7) and the 
demonstrated safety profile in subjects with a CFTR gating defect 6 to <24 months of age (Study 
124, Cohorts 5 and 6) and subjects 2 through 5 years of age with a CFTR gating defect (Study 
108); the demonstrated clinical efficacy in subjects 6 years of age and older with a G551D-CFTR 
mutation (Studies 102 and 103) or a non-G551D-CFTR mutation (Study 111); evidence of 
complications of CF by age 6, and evidence supporting the benefits of early therapeutic 
intervention, there is great potential for patients less than 24 months of age who have an 
ivacaftor-responsive CFTR mutation to benefit from ivacaftor treatment.60  
6 
STUDY OBJECTIVES 
6.1 
Part A 
7 
PRIMARY OBJECTIVES 
• To evaluate the safety of ivacaftor treatment in subjects with CF who are <24 months of age 
at treatment initiation and have a CFTR gating mutation  
• To evaluate the pharmacokinetics (PK) of ivacaftor and metabolites hydroxymethyl-ivacaftor 
(M1) and ivacaftor carboxylate (M6) in subjects with CF who are <24 months of age at 
treatment initiation and have a CFTR gating mutation 
7.1 
Part B 
7.1.1 
Primary Objective 
• To evaluate the safety of ivacaftor treatment in subjects with CF who are <24 months of age 
at treatment initiation and have a CFTR gating mutation 
7.1.2 
Secondary Objectives 
• To evaluate the PK of ivacaftor and metabolites M1 and M6 in subjects with CF who are 
<24 months of age at treatment initiation and have a CFTR gating mutation 
• To evaluate the pharmacodynamics (PD) of ivacaftor treatment in subjects with CF who are 
<24 months of age at treatment initiation and have a CFTR gating mutation 


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7.2 
Part A/B Cohort 8 
For subjects 1 to <4 months of age, Parts A and B will be carried out sequentially in each 
individual subject, rather than performing a cohort analysis of Part A before starting Part B. 
7.2.1 
Primary Objectives 
• To evaluate the safety of ivacaftor treatment in subjects with CF who are 1 to <4 months of 
age at treatment initiation and have an ivacaftor-responsive CFTR mutation (consistent with 
the approved mutations in the region)  
• To evaluate the PK of ivacaftor and the ivacaftor metabolites M1 and M6 in subjects with CF 
who are 1 to <4 months of age at treatment initiation and have an ivacaftor-responsive CFTR 
mutation (consistent with the approved mutations in the region) 
7.2.2 
Secondary Objectives 
• To evaluate the PD of ivacaftor treatment in subjects with CF who are 1 to <4 months of age 
at treatment initiation and have an ivacaftor-responsive CFTR mutation (consistent with the 
approved mutations in the region) 
8 
STUDY ENDPOINTS 
8.1 
Part A 
8.1.1 
Primary Endpoints 
• Safety, as determined by adverse events, clinical laboratory values (serum chemistry and 
hematology), standard 12-lead electrocardiograms (ECGs), vital signs, and ophthalmologic 
examinations (OEs)  
• PK parameter estimates of ivacaftor and metabolites M1 and M6 after 4 days of ivacaftor 
treatment 
8.2 
Part B 
8.2.1 
Primary Endpoint 
• Safety, as determined by adverse events, clinical laboratory values (serum chemistry and 
hematology), ECGs, vital signs, and OEs 


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8.2.2 
Secondary Endpoints 
• PK parameter estimates of ivacaftor and metabolites M1 and M6 
• Absolute change from baseline in sweat chloride 
8.3 
Part A/B Cohort 8 Endpoints 
8.3.1 
Primary Endpoints 
• Safety, as determined by adverse events, clinical laboratory values (serum chemistry and 
hematology), standard 12-lead ECGs, vital signs, and OEs 
• PK parameter estimates of ivacaftor and the ivacaftor metabolites M1 and M6 
8.3.2 
Secondary Endpoints 
• Absolute change from baseline in sweat chloride 


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9 
STUDY DESIGN 
9.1 
Overview of Study Design 
This is a Phase 3, 2-part, open-label study as depicted in Figure 9-1. This study is designed to 
evaluate the safety, PK, PD, and efficacy of ivacaftor in subjects with CF who are <24 months of 
age at the time of treatment initiation (Day 1) and have an ivacaftor-responsive CFTR mutation 
on at least 1 allele. Part A is designed to evaluate the safety and PK of multiple-dose 
administration of ivacaftor in subjects <24 months of age over 4 days of dosing, and to confirm 
(or adjust if necessary) the doses for Part B. Part B is designed to evaluate the safety, PK, PD, 
and efficacy of ivacaftor in subjects <24 months of age over 24 weeks. Part A/B Cohort 8 is 
designed to evaluate the safety, PK, PD, and efficacy of ivacaftor in subjects with CF who are 
1 to <4 months of age, ≥38 weeks gestation, weigh at least 3 kg at the time of treatment initiation 
(Day 1), and have an ivacaftor-responsive CFTR mutation (consistent with the approved 
mutations in the region) on at least 1 allele. Subjects will receive an initial low dose of ivacaftor 
(based on their Day 1 age and weight) up to Day 15, at which time the dose may be adjusted to 
better match the median adult exposure. Subjects are intended to remain on that dose until they 
are 4 months of age and at least 5 kg, after which the recommended age- and weight-appropriate 
dose(s) will be administered.   
Part A: 
Subjects will be enrolled in Part A sequentially in the following cohorts: 
• Cohort 1: subjects aged 12 to <24 months 
• Cohort 2: subjects aged 6 to <12 months 
• Cohort 3: subjects aged 3 to <6 months 
Enrollment in Part A will begin with subjects in Cohort 1. Enrollment for subjects in Cohort 2 
will begin after an assessment of safety and PK data for subjects from Cohort 1. Enrollment for 
subjects in Cohort 3 will begin after an assessment of safety and PK data for subjects in 
Cohort 2. 


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PK data from each completed cohort in Part A will be used to update the population PK model 
and inform dose selection for the subsequent cohort before that cohort begins enrolling. If PK 
data from any cohort in Part A are insufficient to confirm the dose for that age group, additional 
subjects will be enrolled in the cohort until an appropriate dose is confirmed.  
Part A of this study includes: 
• Screening Period (Day -28 to Day -1) 
• Treatment Period (Day 1 to Day 5):  
o 25-mg (for subjects 5 to <7 kg on Day 1), 50-mg (for subjects 7 to <14 kg on Day 1), or 
75-mg (for subjects 14 to <25 kg on Day 1) ivacaftor will be administered every 12 hours 
(q12h) on Days 1 through 3 and 1 morning dose on Day 4. These doses may be amended 
at any time, based on available PK data from previous cohorts, and may result in 
additional doses or different weight strata. Data from each cohort in Part A will be used 
to update the population PK model and inform dose predictions for each subsequent 
(younger) cohort. 
o Study visits will occur on Days 1, 4, and 5. 
o PK samples will be collected before the morning dose on Day 4, between 2 and 4 hours, 
between 6 to 8 hours, and between 24 to 60 hours after the Day 4 dose.  
o For subjects who prematurely discontinue treatment, a PK blood sample will be collected 
at the Early Termination of Treatment (ETT) Visit (within 5 days after the last dose of 
study drug). 
• Follow-up Telephone Call (Day 14) 
• Follow-up OE (within 8 weeks ± 14 days after the last dose of study drug, see Section 
9.1.3.1). 
Subjects who prematurely discontinue treatment before their last scheduled dose in Part A will 
be required to complete the ETT Visit, Follow-up Telephone Call, and Follow-up OE.  
Part B: 
Subjects will be enrolled in Part B sequentially in the following cohorts based on age at Day 1 of 
Part B: 
• Cohort 5: subjects aged 12 to <24 months 
• Cohort 6: subjects aged 6 to <12 months 
• Cohort 7: subjects aged 4 to <6 months 
Enrollment of subjects in Cohort 5 will begin following an assessment of: 
• Safety and PK data from Part A for subjects from Cohort 1 and confirmation of dose for 
subjects aged 12 to <24 months. 
Enrollment of subjects in Cohort 6 will begin after an assessment of:  
• Safety and PK data from Part A for subjects from Cohort 2 and confirmation of dose for 
subjects aged 6 to <12 months. 


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• Safety data from Week 12 of Part B for at least 5 subjects in Cohort 5.   
Enrollment of subjects in Cohort 7 will begin with enrollment of subjects aged 4 to <6 months 
following an assessment of: 
• Safety and PK data from Part A for subjects from Cohort 3 and confirmation of dose in 
subjects aged 3 to <6 months.  
• Safety data from Week 12 of Part B for at least 5 subjects in Cohort 6.  
Subjects from Cohorts 2 and 3 who age out of the corresponding age cohort (Cohorts 6 or 7) at 
Part B Day 1 may enroll in an older age cohort in Part B with the Vertex medical monitor’s 
permission. For example, subjects in Cohort 2 who will age out of Cohort 6 may enroll in 
Cohort 5; and subjects in Cohorts 3 or 4 who will age out of Cohort 7 may enroll in Cohort 6. 
Otherwise, subjects who will age out of the corresponding age cohort may enroll in the 
Extension Study. 
Part B of this study includes: 
• Screening Period (Day -28 to Day -1) 
• Treatment Period (Day 1 to Week 24): 
o Starting doses in Cohorts 5 and 6 of 25-mg (for subjects 5 to <7 kg on Day 1), 50-mg (for 
subjects 7 to <14 kg on Day 1), or 75-mg (for subjects 14 to <25 kg on Day 1) ivacaftor 
will be administered q12h for 24 weeks (or other suitable starting dose based on safety 
and PK data from Part A). At each study visit the ivacaftor dose for each subject will be 
reassessed based on body weight and adjusted if necessary.  
o All subjects enrolled in Cohort 7 will receive a 25 mg dose of ivacaftor q12h until the 
subject reaches the age of 6 months. At each study visit after the age of 6 months, the 
ivacaftor dose for each subject will be reassessed based on body weight and adjusted, if 
necessary, as follows:  
 Subjects 5 to <7 kg will be dosed with 25 mg q12h  
 Subjects 7 to <14 kg will be dosed with 50 mg q12h  
 Subjects 14 to <25 kg will be dosed with 75 mg q12h  
o Study visits will occur on Day 1 and Weeks 2, 4, 8, 12, 18, and 24.  
o PK blood samples will be collected at the following time points:  
 Week 2: before the morning dose, between 2 and 4 hours and between 6 and 8 hours 
after the morning dose 
 Week 8: before the morning dose and 1 and 4 hours after the morning dose 
 Week 24: before the morning dose and between 2 and 4 hours after the morning dose 
 PK blood sampling at Week 24 is optional for subjects who undergo MBW (due to 
fasting requirements)  
 For subjects who prematurely discontinue treatment, a PK blood sample will be 
collected at the ETT Visit. 


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o OEs will be performed at screening, Week 12, and Week 24.  
All subjects who complete 24 weeks of study drug treatment will be eligible to enroll in the 
open-label treatment arm of an Extension Study. The Follow-up Visit will not be required for 
subjects who enroll in the treatment arm of this study. 
Subjects who complete 24 weeks of study drug treatment who elect not to enroll in the treatment 
arm of the Extension Study will be required to complete the Follow-up Visit (4 weeks ± 7 days 
after the last dose of study drug) and will be eligible to enroll in the observational arm of the 
Extension Study. The Follow-up Visit will not be required in the event that the subject initiates 
treatment with commercially available ivacaftor within 3 weeks of the Week 24 Visit. 
Subjects who prematurely discontinue study drug treatment before their last scheduled dose will 
be required to complete the ETT Visit, Follow-up Visit, and Follow-up OE (see Section 9.1.3.1). 
The Follow-up Visit will not be required: 
• If the ETT Visit occurs 3 weeks or later after the last dose of study drug. 
• In the event that the subject initiates treatment with commercially available ivacaftor within 
3 weeks of the ETT Visit.  
Subjects who prematurely discontinue treatment will be eligible to enroll in the observational 
arm of the Extension Study. Subjects who are eligible will enroll in the Extension Study as soon 
as enrollment is open.  




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• Screening Period (Day -28 to Day -14) 
o Due to limitations in the volume of blood that should be collected from the 1- to 
<4-month-old age group in a 28-day span, screening should be completed at least 14 days 
prior to Day 1 (treatment initiation) 
• Initial Treatment Period (Day 1 up to Day 15):  
o Subjects will receive an initial low dose of ivacaftor (5.7 mg q12h or 11.4 mg q12h based 
on their Day 1 age and weight) from Day 1 up to Day 15, as follows:  
Age 
Weight Range 
Starting Dose 
1 month 
≥3 kg 
5.7 mg q12h 
2 months 
≥3 to <5 kg 
5.7 mg q12h 
2 months 
≥5 kg 
11.4 mg q12h 
3 months  
≥5 kg 
11.4 mg q12h 
All subjects must have gestational age ≥38 weeks and weigh ≥3 kg. Subjects 3 months of age must 
weigh ≥5 kg on Day 1. 
o Study visits will occur on Days 1, 4, and 15. 
o Follow-up Telephone Call (Day 1 evening) 
o PK samples will be collected before the morning dose on Day 4, and between 2 to 
4 hours and between 6 to 8 hours after the Day 4 morning dose.  
o The Day 4 PK data will be reviewed by the study team to determine the dose to be 
administered on Day 15. The subject’s Day 4 PK data will be used to calculate exposure 
to determine a dose that is expected to bring the exposure for the subject closest to the 
adult median. This potential dose adjustment will be communicated in writing to the 
principal investigator to administer to the subject on Day 15. If all PK samples collected 
on Day 4 are missing or cannot be analyzed, PK samples collected on Day 15 will be 
used to assess whether the initial dose should be adjusted at the Week 4 Visit. 
o At the Day 15 Visit, a trough PK sample will be collected before the morning dose. The 
ivacaftor dose will be adjusted (based on the Day 4 PK data) if necessary, to either 5.7, 
11.4, 17.1, 22.8, or 25 mg, and the adjusted dose will be administered q12h starting with 
the evening dose on Day 15. 
• Subsequent Treatment Period (Day 16 to Week 24):  
o Follow-up Telephone Call (Day 17) 
o Study visits will occur on Weeks 4, 8, 12, 18, and 24. 
o The subject is intended to remain on the same dose from Day 15 until the subject is 
4 months of age and at least 5 kg, after which the recommended age- and weight-
appropriate dose(s) will be administered.  
o PK samples will be collected before the morning dose on Week 8, between 2 to 4 hours, 
and between 6 to 8 hours after the Week 8 morning dose. 




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9.1.1.1 
Repetition of Screening Assessments 
Repetition of screening assessment(s) that do not meet eligibility criteria is not permitted, with 
the following exceptions:  
• There is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction. In this case, collection of a repeat sample for the appropriate laboratory test may 
be permitted after discussion with the Vertex medical monitor or authorized designee. 
• If a convincing alternative etiology is identified for elevated transaminases, exclusionary 
liver function test (LFT) levels may be retested within 2 weeks of the original Screening 
Visit date. 
• If an adequate slit-lamp examination could not be conducted (Section 12.6.5). 
If repeat values are within the eligibility criteria and completed within the screening window or 
extended screening window (Section 9.1.1.3), the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Rescreening may be considered only with approval of the Vertex medical monitor. The 
investigator (or an appropriate authorized designee at the study site) will confirm the assessments 
(e.g., number/type of blood sample assessments) required for rescreening with the Vertex 
medical monitor. CFTR genotyping and sweat chloride testing do not need to be repeated. If a 
subject has had an OE including an adequate slit-lamp examination within 12 weeks, the OE 
does not need to be repeated. If a subject is rescreened, the screening window will begin once the 
first rescreening assessment has been initiated. 
9.1.1.3 
Extension of Screening Window 
A subject may have the screening window extended by 2 weeks for the following reasons upon 
approval by the Vertex medical monitor: 
• Repetition of screening assessments (Section 9.1.1.1) 
• Unexpected operational or logistical delays (e.g., delayed drug shipment)  
• To meet the eligibility criteria 
• Scheduling of the OE (Section 12.6.5) 
• Availability of required equipment 
The screening window can be extended by 4 weeks if a slit-lamp examination must be repeated 
(Sections 9.1.1.1 and 12.6.5). 
9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-1, Table 3-2, Table 3-3, and Table 16-1. 
In Part A, subjects will be administered 25 mg, 50 mg, or 75 mg q12h, or other appropriate dose 
of ivacaftor based on emerging PK data (by weight, see Section 9.3.2), on Days 1 through 3, and 
1 morning dose on Day 4. Subjects will be outpatients during the study; visits will occur on 
Day 1, Day 4, and Day 5. Telephone contact will also occur in the evening of Day 1 and the 
morning of Day 2. 


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After preliminary analysis of PK and safety data from Part A is performed and dose selection for 
Part B is confirmed, subjects in Part B Cohorts 5 and 6 will be administered 25-mg, 50-mg, or 
75-mg ivacaftor (by weight, see Section 9.3.2) or other appropriate doses (to be determined 
based on PK data from Part A) administered q12h for 24 weeks. All subjects enrolled in Cohort 7 
will receive a 25 mg dose of ivacaftor q12h until the subject reaches the age of 6 months, at 
which time the ivacaftor dose for each subject will be reassessed and adjusted based on body 
weight (Section 9.3.2). For subjects who participated in Part A, the starting dose in Part B may 
be different than that of Part A based on body weight on Day 1. Subjects will be outpatients 
during the study; visits will occur on Day 1 and Weeks 2, 4, 8, 12, 18, and 24; and a telephone 
contact will occur on Day 3. 
In Part A/B Cohort 8, subjects will be administered an initial low dose of ivacaftor (5.7 mg q12h 
or 11.4 mg q12h based on their Day 1 age and weight) from Day 1 up to Day 15 (see 
Section 9.3.2). Subjects will be outpatients during the study; visits will occur on Day 1, Day 4, 
Day 15, Week 4, Week 8, Week 12, Week 18, and Week 24. On Day 4, PK samples will be 
collected before the morning dose, between 2 to 4 hours and between 6 to 8 hours after the 
morning dose. The subject’s Day 4 PK data will be used to calculate exposure to determine a 
dose that is expected to bring the exposure for the subject closest to the adult median. This dose 
or potential dose adjustment will be communicated in writing to the principal investigator to 
administer to the subject on Day 15. At the Day 15 Visit, a trough PK sample will be collected 
before the morning dose. The ivacaftor dose will be adjusted based on the Day 4 PK data if 
necessary, to either 5.7, 11.4, 17.1, 22.8, or 25 mg, and the adjusted dose will be administered 
q12h starting with the evening dose on Day 15. The subject is intended to remain on the same 
dose from Day 15 until the subject is 4 months of age and at least 5 kg at which time the 
recommended age- and weight-appropriate dose(s) will be administered. At the Week 8 Visit, 
PK samples will be collected before the morning dose, and between 2 to 4 hours and between 
6 to 8 hours after the morning dose. The subject’s Week 8 pre- and post-dose PK data will be 
used to more fully characterize the PK profile. Additional PK samples will be collected before 
the morning dose on the Week 4, 12, 18, and 24 Visits to characterize the longitudinal PK 
profile. The entire treatment period of the study will be 24 weeks, after which subjects will be 
eligible to enroll in an Extension Study. 
9.1.3 
Follow-up 
Follow-up assessments are listed in Part A Table 3-1, Part B Table 3-3, and Part A/B Cohort 8 
Table 16-1. 
In Part A, there will be a Follow-up Telephone Call (Day 14 ± 2 days) and a Follow-up OE (see 
Section 9.1.3.1) for all subjects. 
In Part B and in Part A/B Cohort 8, there will be a Follow-up Visit 4 weeks ± 7 days after the 
last dose of study drug.  
All subjects who complete 24 weeks of study drug treatment in Part B or Part A/B Cohort 8 will 
be eligible to enroll in the open-label treatment arm of the Extension Study. The Follow-up Visit 
will not be required for subjects who enroll in the treatment arm of Extension Study.   
Subjects who prematurely discontinue study drug treatment in Part B or in Part A/B Cohort 8, 
and subjects who complete 24 weeks of study drug treatment in Part B or Part A/B Cohort 8, but 


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do not enroll in the treatment arm of the Extension Study, will be required to complete the 
Follow-up Visit. The Follow-up Visit will not be required: 
• If the ETT Visit occurs 3 weeks or later after the last dose of study drug. 
• In the event that the subject initiates treatment with commercially available ivacaftor within 
3 weeks of the final scheduled treatment visit in Part B or Part A/B Cohort 8, or the ETT 
Visit. 
Subjects who prematurely discontinue study drug treatment and subjects who complete 24 weeks 
of study drug treatment in Part B or Part A/B Cohort 8, but do not enroll in the treatment arm of 
the Extension Study, will be eligible to enroll in the observational arm of the Extension Study. 
Subjects who are eligible will enroll in the Extension Study as soon as enrollment is open. 
9.1.3.1 
Follow-up Ophthalmologic Examination 
In Part A, there will be a Follow-up OE 8 weeks ± 14 days after the last dose of study drug. For 
subjects who have the Part A Follow-up OE within 6 months of enrolling in Part B, a screening 
OE for Part B is not required.  
In Part B, subjects who prematurely discontinue study drug treatment and received at least 1 dose 
of ivacaftor treatment in Part B will have a Follow-up OE 24 weeks ± 14 days after the last dose 
of study drug. Subjects enrolling into the Extension Study within 24 weeks after the last dose of 
study drug are not required to have the Part B Follow-up OE (the OE will be performed in the 
Extension Study instead). 
In Part A/B Cohort 8, subjects who prematurely discontinue study drug treatment and received at 
least 1 dose of ivacaftor treatment in Part A/B Cohort 8 will have a Follow-up OE 12 weeks ± 
14 days after the last dose of study drug. Subjects enrolling into the Extension Study within 
12 weeks after the last dose of study drug are not required to have the Part A/B Cohort 8 Follow-
up OE (the OE will be performed in the Extension Study instead). 
Subjects who initiate treatment with commercially available ivacaftor within 3 weeks of the ETT 
Visit will not have the Part B or Part A/B Cohort 8 Follow-up OE. 
9.1.4 
Early Termination of Treatment 
ETT assessments are listed in Part A Table 3-1, Part B Table 3-3, and Part A/B Cohort 8 
Table 16-1. 
In Part A, subjects who prematurely discontinue treatment before their last scheduled dose will 
be required to complete the ETT Visit (within 5 days after the last dose of study drug), 
Follow-up Telephone Call (Day 14).  
In Part B, and Part A/B Cohort 8, subjects who prematurely discontinue treatment before their 
last scheduled dose will be required to complete the ETT Visit (as soon as possible after the last 
dose of study drug).  
9.2 
Independent Data Monitoring Committee 
Data will be reviewed by an independent data monitoring committee (IDMC) to ensure the safety 
of the subjects in the study (Section 13.5.6). Procedural details of the IDMC's structure and 
function, frequency of meetings, and data planned for review will be included in the IDMC 
charter. The IDMC charter will be finalized before the first IDMC review meeting.  


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9.3 
Rationale for Study Design and Study Drug Regimens 
Part A of this study is designed to evaluate the safety and characterize the PK of ivacaftor in 
subjects <24 months of age at the time of treatment initiation. The plasma PK data obtained in 
Part A will be used for the confirmation (or adjustment if necessary) of planned doses for Part B, 
as described in Section 13.6.1. The ivacaftor doses identified for the initiation of Part A (25 mg, 
50 mg, and 75 mg) are based on modeling and simulation results, as described in Section 9.3.2. 
Based on emerging data from Part A, these doses may be amended for ongoing cohorts or for 
future cohorts in Part A and Part B. Subjects may receive higher or lower doses and dosing may 
be amended to different weight strata as appropriate based on emerging data. If PK data from the 
initial 5 subjects enrolled in a cohort in Part A are insufficient to determine the appropriate dose 
for that age group, additional subjects may be enrolled and receive the same or a different dose. 
Dosing will not proceed in a particular age group in Part B until confirmation of the dose for that 
age group in Part A. 
Part A/B Cohort 8 of this study is designed to evaluate the safety and characterize the PK of 
ivacaftor in subjects aged 1 to <4 months old who are ≥38 weeks gestation and weigh at least 
3 kg at the time of treatment initiation (Day 1). Given the rapid change and uncertainty in CYP 
maturation in this young age range, an initial lower dose and adjustment of dosing based on a PK 
evaluation will help ensure appropriate exposures for these patients during the study conduct. 
Thus, an alternative study design will be used to study the cohort of patients aged 1 month to 
<4 months. At the end of study, a comprehensive evaluation using all of the data will be used to 
determine the optimal dose and regimen for this patient population. 
9.3.1 
Study Design 
This open-label study is designed to evaluate the safety, PK, PD, and efficacy of ivacaftor in 
subjects with CF who are <24 months of age at the time of treatment initiation and have an 
ivacaftor-responsive CFTR mutation on at least 1 allele. Part A is designed to evaluate the safety 
and PK of multiple-dose administration of ivacaftor in subjects <24 months of age and to 
confirm (or adjust if necessary) the doses for Part B. Part B is designed to evaluate the safety, 
PK, PD, and efficacy of ivacaftor in subjects <24 months of age over a 24-week treatment 
period. Subjects who complete 24 weeks of study drug treatment in Part B will be eligible to 
enroll in an Extension Study and receive open-label ivacaftor treatment. All other subjects will 
be eligible to enroll in an observational arm of the Extension Study. The Extension Study is 
designed to evaluate the long-term safety, PD, and efficacy of ivacaftor.  
Part A/B Cohort 8 is designed to evaluate the safety, PK, PD, and efficacy of multiple-dose 
administration of ivacaftor in subjects 1 to <4 months of age starting with an initial relatively low 
dose of ivacaftor. Subjects will receive this initial low dose of ivacaftor (5.7 mg q12h or 11.4 mg 
q12h based on their Day 1 age and weight) from Day 1 up to Day 15. On Day 4, PK samples 
from each subject will be collected before and after dosing and analyzed to determine the 
exposure and assess whether the initial dose needs to be adjusted to better match the median 
adult exposure. Safety laboratory test results, ECGs, and any adverse events will also be 
evaluated when determining whether to dose subjects. The ivacaftor dose will be adjusted (based 
on the Day 4 PK data) if necessary, to either 5.7, 11.4, 17.1, 22.8, or 25 mg, and the adjusted 
dose will be administered q12h starting with the evening dose on Day 15. The subject is intended 
to then remain on the same dose of ivacaftor from Day 15 until the subject is 4 months of age 


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and at least 5 kg, after which the recommended age- and weight-appropriate dose(s) will be 
administered.  
The entire treatment period of the study will be 24 weeks, after which subjects will be eligible to 
enroll in an Extension Study and receive open-label ivacaftor treatment. The 24-week treatment 
period will provide subject data at least through the age of 7 months. Vertex plans to enroll a 
minimum of 6 and up to approximately 10 subjects to have adequate data to assess the PK and 
safety in this age range.  
Due to the lack of equipoise for a placebo-controlled study based upon the robust efficacy results 
demonstrated in subjects with CF 6 years of age and older who have a CFTR gating mutation 
(Studies 102, 103, and 111) and supportive results demonstrated in subjects with CF 2 to 5 years 
of age who have a CFTR gating mutation (Study 108), combined with the ethical consequence of 
withholding a known effective treatment in the study of young children, an open-label design has 
been selected for this study. 
9.3.2 
Study Drug Dose and Duration 
In Part A, subjects weighing 5 to <7 kg on Day 1 will be administered 25-mg ivacaftor q12h, 
subjects weighing 7 to <14 kg on Day 1 will be administered 50-mg ivacaftor q12h, and subjects 
weighing 14 to <25 kg on Day 1 will be administered 75-mg ivacaftor q12h. Doses of ivacaftor 
will be administered q12h for 3 days with the last dose of study drug administered the morning 
dose on Day 4 (7 total doses) to obtain steady-state concentrations of ivacaftor. These doses may 
be amended at any time based on available PK data from previous cohorts and may result in 
additional doses or different weight strata. Sites will receive a memorandum entitled 
“Justification for Dose Selection” as notification of updates to study drug dose, or changes to age 
strata or weight bounds. 
In Part B Cohorts 5 and 6, subjects weighing 5 to <7 kg on Day 1 will be administered 25-mg 
ivacaftor q12h, subjects weighing 7 to <14 kg on Day 1 will be administered 50-mg ivacaftor 
q12h, and subjects weighing 14 to <25 kg on Day 1 will be administered 75-mg ivacaftor q12h 
(or other suitable starting dose based on PK data from Part A). At each study visit the ivacaftor 
dose for each subject will be reassessed based on body weight and adjusted if necessary. 
All subjects enrolled in Cohort 7 will receive a 25 mg dose of ivacaftor q12h until the subject 
reaches the age of 6 months. At each study visit after the age of 6 months, the ivacaftor dose for 
each subject will be reassessed based on body weight and adjusted, if necessary, as follows: 
• Subjects 5 to <7 kg will be dosed with 25 mg q12h  
• Subjects 7 to <14 kg will be dosed with 50 mg q12h  
• Subjects 14 to <25 kg will be dosed with 75 mg q12h  
The treatment duration will be 24 weeks for Part B. A 24-week treatment duration was utilized in 
the primary analysis of Study 108, a safety, PK, and PD study conducted in subjects age 2 to <6 
years of age. Thus, the 24-week duration of treatment will provide a similar period for evaluation 
of safety, PK, and PD response in subjects <24 months of age.  
In Part A/B Cohort 8, subjects will receive an initial low dose of ivacaftor (5.7 mg q12h or 
11.4 mg q12h based on their Day 1 age and weight) from Day 1 up to Day 15, as follows:  


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Age 
Weight Range 
Starting Dose 
1 month 
≥3 kg 
5.7 mg q12h 
2 months 
≥3 to <5 kg 
5.7 mg q12h 
2 months 
≥5 kg 
11.4 mg q12h 
3 months  
≥5 kg 
11.4 mg q12h 
All subjects must have gestational age ≥38 weeks and weigh ≥3 kg. Subjects 3 months of age must 
weigh ≥5 kg on Day 1. 
On Day 4, PK samples from each subject will be collected before and after dosing and analyzed 
to determine the exposure and assess whether the initial dose needs to be adjusted to better match 
the median adult exposure. The ivacaftor dose will be adjusted (if necessary) to either 5.7, 11.4, 
17.1, 22.8, or 25 mg, and the adjusted dose will be communicated in writing to the principal 
investigator to administer to the subject on Day 15. The subject should then remain on the same 
dose of ivacaftor from Day 15 until the subject is 4 months of age and at least 5 kg, after which 
the recommended age- and weight-appropriate dose(s) will be administered.  
If all PK samples collected on Day 4 are missing or cannot be analyzed, PK samples collected on 
Day 15 will be used to assess whether the initial dose should be adjusted at the Week 4 Visit. 
The entire treatment period of the study will be 24 weeks, after which subjects will be eligible to 
enroll in an Extension Study and receive open-label ivacaftor treatment. The 24-week treatment 
period will provide subject data at least through the age of 7 months. 
9.3.2.1 
Dose Selection 
The population PK approach used for selection of doses in subjects 2 to <6 years of age in Study 
108 was implemented for dose selection in subjects <24 months of age with the addition of a 
CYP maturation component to the model. In the population PK model from Study 108, body 
weight represents changes in ivacaftor PK as a function of body size by incorporation of an 
allometric model. At the conclusion of Study 108, PK data obtained from subjects 2 to <6 years 
of age was included in the most recent population PK model.  
Dose Selection for Subjects 3 to <24 Months of Age 
Using the current model, simulations were performed to predict ivacaftor exposure in 3 weight 
groups of patients <24 months of age: 4.5 to <7 kg, 7 to <14 kg, and 14 to <25 kg. Target 
exposure parameters are minimum observed concentration (Cmin) and area under the 
concentration versus time curve (AUC) values observed in adult CF patients. The simulations 
incorporated a maturation function to determine the range of likely exposures given maturational 
changes in clearance (CL). Since the maturation characteristics of CL for ivacaftor are unknown, 
a range of values was assumed for simulation purposes. Extent of the change was allowed to 
vary between 0 to 80% from adult values for a newborn, and CL reached a mature value between 
12 and 18 months. Maximum change in CL (80% difference from adults) and maturation rate are 
consistent with differences in cytochrome P450 3A4 (CYP3A4) expression in infants.61-63 
Maturation of ivacaftor clearance was described as follows:64 
FCL = 1 – (1– βCL) · exp(– Age · (0.693/TCL)) 
CL = ΘCL · (WT/70kg)0.75 · FCL 


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Where, FCL = fraction of mature CL, β = fractional CL at birth (0.2 - 1), TCL = maturation 
half-life (2.4 - 3.6 months), ΘCL = population mean CL 
The simulations support selection of the following doses for CF subjects <24 months of age: 
25 mg for 5 to <7 kg, 50 mg for 7 to <14 kg, and 75 mg for 14 to <25 kg. 
Dose Selection for Subjects 1 to <4 Months of Age 
To select doses for Part A/B Cohort 8, population PK models were updated to include all 
available data from pediatric subjects 3 months of age and older to account for potential 
maturation effects. For a more comprehensive estimate of the range of potential exposures, the 
updated population PK (popPK) models and a physiologically-based pharmacokinetic (PBPK) 
model were used to predict potential variability in CYP3A4 maturation for the 1 to <4-month-old 
age group. While these models adequately described the available data from subjects 3 months to 
1 year of age (noting that only 2 subjects were <4 months of age), they yielded a range of 
exposure predictions (AUC0-12) for the 1 to <4-months of age population due to the different 
predicted CYP3A4 maturation effects. Initial low doses of ivacaftor (5.7 mg q12h or 11.4 mg 
q12h based on their Day 1 age and weight) were selected using simulations from these models. 
These initial doses are predicted to yield exposures within or below the adult exposure range and 
to provide a degree of clinical benefit.  
9.3.3 
Rationale for Study Assessments 
The safety and PK assessments are standard parameters for clinical studies in drug development. 
The scope of the assessments is considered appropriate for safety monitoring in the context of 
this study.  
The following assessments are widely accepted and generally recognized as reliable, accurate, 
and relevant to the study of patients with CF. 
Sweat chloride test: The sweat chloride test (quantitative pilocarpine iontophoresis) is a direct 
measure of CFTR activity in vivo and is the most commonly used diagnostic tool for CF. Sweat 
in normal individuals is hypotonic with respect to plasma chloride and sodium due to the 
absorption of chloride by CFTR and sodium by the epithelial sodium channel from sweat prior to 
the sweat reaching the surface of the skin. Because patients with CF have diminished CFTR 
activity, chloride ions are poorly reabsorbed, leading to elevated sweat chloride concentration.65, 
66 Sweat chloride can be measured in patients with CF of all ages, although levels do increase 
throughout the first 6 months of life.67 For infants up to and including 6 months of age, 
interpretation of sweat chloride levels is as follows:  
• <30 mmol/L indicates that diagnosis of CF is very unlikely; 
• 30 to 59 mmol/L indicates that that CF is possible; and 
• ≥60 mmol/L indicates that CF is likely to be diagnosed.68,69 
In the Phase 3 trials of ivacaftor in subjects 6 years of age and older with CF and the 
G551D-CFTR mutation (Studies 102 and 103) or a non-G551D-CFTR mutation (Study 111), 
treatment with ivacaftor led to a substantial and statistically significant improvement in CFTR 
function compared with placebo as measured by sweat chloride concentration. In these trials, 
treatment with ivacaftor resulted in substantial, durable, and statistically significant 
improvements in FEV1, respiratory symptoms, weight, and time-to-first pulmonary 


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exacerbation.60 In another Phase 3 study of ivacaftor in subjects 2 through 5 years of age with a 
mutation that causes CFTR gating defects (Study 108), results showed that treatment with 
ivacaftor for 24 weeks improved CFTR function, as evidenced by improvements in sweat 
chloride levels. These improvements were also consistent with improvements in subjects greater 
than 6 years of age with a mutation that causes CFTR gating defects.60 
Based on the mechanism of action of ivacaftor, and the results of the previous Phase 3 studies of 
ivacaftor, the sweat chloride test is included in this study as a PD measure of the effect of 
ivacaftor on CFTR activity.  


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10 
STUDY POPULATION 
Eligibility should be reviewed and documented by an appropriately qualified member of the 
investigator's team before subjects are enrolled in Part A, Part B, and Part A/B Cohort 8.  


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10.1 
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible. 
1. Male or female with confirmed diagnosis of CF, defined as a sweat chloride value 
≥60 mmol/L by quantitative pilocarpine iontophoresis OR 2 CF-causing mutations.  
• A sweat chloride test must be performed if the sweat chloride value is not available in the 
subject’s medical records and the value is needed to establish eligibility. For subjects with 
sweat chloride values documented in their medical records and for whom it is not needed to 
establish eligibility, the sweat chloride test at screening is optional.  
2. Have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, 
S549R, G551S, G1244E, S1251N, S1255P, or G1349D. Subjects who have an R117H-CFTR 
mutation will be eligible in regions where ivacaftor is approved for use in subjects with an 
R117H-CFTR mutation. Subjects eligible for Part A/B Cohort 8 may also have other 
ivacaftor-responsive mutations (see Appendix A). 
• If a genotype test has been performed previously and is documented in the subject’s medical 
record, the subject's eligibility must be approved by the Vertex medical monitor (see Section 
12.6.2). If a historic genotype result is not available at screening or if the historic genotype 
result is not approved by the Vertex medical monitor, the subject will be tested for CFTR 
genotype at screening and the results must be reviewed before the first dose of ivacaftor. 
Subjects who have been enrolled and whose screening genotype does not confirm study 
eligibility will not receive study drug. 
• Subjects who have an ivacaftor-responsive mutation on at least 1 allele will be eligible to 
enroll in Part A/B Cohort 8 in regions where ivacaftor is approved (consistent with the 
approved mutations in the region; see Appendix A). 
o Subjects must be ≥1  to <4 months of age, ≥38 weeks gestation, and weigh ≥3 kg at 
Day 1 (treatment initiation); subjects 3 months of age must weigh ≥5 kg on Day 1 
(Section 9.3.2) 
o Subjects must have a documented genotype test (performed to applicable national 
standards). Genotype testing is expected to be initiated prior to screening. Results of the 
genotype test are to be reviewed and approved by the Vertex medical monitor prior to 
Day 1. 
 Subjects with the R117H genotype should have the 5T variant or a sweat chloride 
value ≥60 mmol/L by quantitative pilocarpine iontophoresis. 
3. Aged 0 to <24 months at Day 1; subjects who completed Part A who are ≥24 months of age 
on Day 1 in Part B are not eligible to enroll in Part B.  
4. For Cohorts 7 and 8 only, gestational age ≥38 weeks. 
5. Hematology, serum chemistry, and vital signs results at screening with no clinically 
significant abnormalities that would interfere with the study assessments, as judged by the 
investigator. 
6. Weight at screening must be within the weight limits as defined for the study drug dose 
levels (Section 9.3.2). 


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7. As judged by the investigator, the individual (i.e., parent or legal guardian) signing the 
informed consent on behalf of the subject must be able to understand the protocol 
requirements, restrictions, and instructions and should be able to ensure the subject’s 
compliance with study requirements and the subject’s likelihood for completing the study as 
planned. 
8. Parent or legal guardian must sign the informed consent form (ICF). 
10.2 
Exclusion Criteria  
Subjects who meet any of the following exclusion criteria will not be eligible.  
1. History of any illness or condition that, in the opinion of the investigator, might confound the 
results of the study or pose an additional risk in administering study drug to the subject.  
2. An acute upper or lower respiratory infection, or pulmonary exacerbation, or changes in 
therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 
3. This exclusion criterion is waived for subjects enrolling in Part A/B Cohort 8. 
Colonization with organisms associated with a more rapid decline in pulmonary status (e.g., 
Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at 
screening. The investigator could be guided by the following suggested criteria for a subject 
to be considered free of colonization:  
• The subject should have had 2 respiratory tract cultures negative for these organisms within 
the past 12 months, with no subsequent positive cultures. 
• These 2 respiratory tract cultures should have been separated by at least 3 months. 
• One of these 2 respiratory tract cultures should have been obtained within the past 6 months.   
4. Abnormal liver function at screening or any prior history of clinically relevant elevated 
(>2 × upper limit of normal [ULN]) serum aspartate transaminase (AST), serum alanine 
transaminase (ALT), or bilirubin (excluding newborn hyperbilirubinemia) 
5. History of solid organ or hematological transplantation 
6. Any clinically significant "non-CF-related" illness within 2 weeks before Day 1. "Illness" is 
defined as an acute (serious or nonserious) condition (e.g., gastroenteritis) 
7. Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 
2 weeks before Day 1 
8. Participation in a clinical study involving administration of either an investigational or a 
marketed drug within 30 days or 5 terminal half-lives (whichever is longer or as determined 
by the local requirements) before screening  
9. Hemoglobin <9.5 g/dL at screening 
10. Chronic kidney disease of Stage 3 or above 
11. An adequate slit-lamp examination could not be conducted at the screening OE  
12. Presence of a lens opacity or cataract identified at the screening OE (excluding those 
considered congenital and nonprogressive, such as a suture cataract)  


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10.3 
Study Restrictions 
10.3.1 
Prior and Concomitant Medications and Other Study Restrictions 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies (including drug name, 
dose, and dose regimen) administered during the following periods will be collected:  
• For subjects who are enrolled in Part A: from 28 days before the Part A Screening Visit 
through the Follow-up Telephone Call (Day 14 ± 2 days) in Part A 
• For subjects who are enrolled in Part B: from 28 days before the Part B Screening Visit 
through: 
• the Week 24 Visit for subjects who complete the study and enter the treatment arm of the 
Extension Study,  
• the Follow-up Visit (if required) for subjects who complete the study and do not enter the 
treatment arm of the Extension Study, and 
• the ETT or Follow-up Visit (if required) for subjects who prematurely discontinue from 
treatment. 
• For subjects who are enrolled in Part A/B Cohort 8: from 28 days before (or from birth, as 
relevant) the Part A/B Cohort 8 Screening Visit through: 
• the Week 24 Visit for subjects who complete the study and enter the treatment arm of the 
Extension Study,  
• the Follow-up Visit (if required) for subjects who complete the study and do not enter the 
treatment arm of the Extension Study, and 
• the ETT or Follow-up Visit (if required) for subjects who prematurely discontinue from 
treatment. 
For any subjects in Part A, Part B, or Part A/B Cohort 8 who are screened but are not 
subsequently enrolled in the study, details of prior and concomitant medications will only be 
documented in the subject's source documents. 
For all subjects enrolled in the study, it is recommended that subjects remain on current 
medication regimens for their CF from 28 days before Day 1 through the end of study 
participation. 
10.3.2 
Prohibited Medications 
Subjects must have ended use of moderate and strong inducers and inhibitors of CYP3A, 
including certain herbal medications and food containing grapefruit or Seville oranges at least 
14 days before Day 1 in Part A, Part B, or Part A/B Cohort 8 as applicable. 
In Part A, subjects may not consume these items until the end of the Day 5 Visit or, if applicable, 
the ETT Visit. 
In Part B and Part A/B Cohort 8, subjects may not consume these items while on study drug. If a 
subject discontinues from study drug prematurely, the subject may consume these items after the 
ETT Visit.   


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A more comprehensive list of restricted medications will be provided in the study manual. 
Noncompliance with these restrictions will be addressed on a case-by-case basis with the Vertex 
medical monitor.  
10.4 
Removal of Subjects 
Subjects may withdraw from the study at any time at the request of the parent or legal guardian. 
Subjects may be withdrawn from study drug treatment at any time at the discretion of the 
investigator or Vertex for safety, behavior, noncompliance with study procedures, or 
administrative reasons. If a subject has been withdrawn from study drug treatment, the subject 
should continue to be followed through the ETT, Follow-up Visit, Follow-up Call, and Follow-
up OEs, as indicated in Sections 9.1.3, 9.1.3.1, and 9.1.4, provided the subject’s parent or legal 
guardian 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 a Follow-up Visit, if applicable (see Section 9.1.3), and follow up with 
the subject’s parent or legal guardian regarding any unresolved adverse events.  
If the subject’s parent or legal guardian 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. 
A subject will be discontinued from study treatment for any of the following reasons:  
• Vertex, regulatory authorities, or the site's institutional review board (IRB) or ethics 
committee (EC) closes the study. 
• A subject is noncompliant with study protocol requirements, restrictions, and instructions. 
• A subject participates in another therapeutic clinical study. 
• A subject develops a new lens opacity or cataract (see Section 12.6.5).  
• The assessment of benefit-risk is no longer favorable. 
A subject may be discontinued from the study treatment, after discussion between the 
investigator and the Vertex medical monitor, for any of the following reasons: 
• A subject develops a medical condition that requires prolonged concomitant therapy with a 
prohibited medication or prolonged interruption of ivacaftor. 
• A subject develops a life-threatening adverse event, or a serious adverse event (SAE) that 
places them at immediate risk. 
• A subject experiences an increase in liver function test levels (LFTs; e.g., AST or ALT 
levels) as described in Section 12.6.2.  
• An adequate repeat slit-lamp examination cannot be performed (see Section 12.6.5). 
10.5 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
periods may be replaced at Vertex's discretion.  


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11 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
11.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
11.2 
Administration 
On Day 1 of Part A, subjects who meet all inclusion and exclusion criteria will receive a single 
dose of 25-mg, 50-mg, or 75-mg ivacaftor (or other dose, based on emerging PK data; dose by 
weight, see Section 9.3.2) in the clinic. Each dose of granules will be mixed with approximately 
1 teaspoon (5 mL) of appropriate liquid or soft food (as listed in the study manual) and 
administered with an age-appropriate fat-containing meal or snack. All subjects will be observed 
for 4 hours after administration of the first dose of study drug.  
In Part A, doses administered from the evening dose on Day 1 through the evening dose on 
Day 3 will be administered q12h at home, and the Day 1 and Day 4 morning dose will be 
administered in the clinic. Parents will be instructed on how to empty the packet and administer 
ivacaftor with food or liquid. Details of dose preparation and dose administration will be 
provided in the study manual. A diary of the dose administration dates and times, occurrence and 
time of regurgitation within 1 hour after dosing, and whether doses were administered with food 
during the 3 days will be kept by the subject's parents/caregivers.  
On Day 1 of Part B, subjects who meet all inclusion and exclusion criteria will receive a single 
dose of 25-mg, 50-mg, or 75-mg ivacaftor, or other suitable starting dose based on PK data from 
Part A (by weight, see Section 9.3.2) in the clinic; all subjects will be observed for 4 hours after 
administration of the first dose of study drug. Each dose of granules will be mixed with 
approximately 1 teaspoon (5 mL) of appropriate liquid or soft food (as listed in the study 
manual) and administered orally q12h with an age-appropriate fat-containing meal or snack from 
Day 1 through Week 24. Details of dose preparation and dose administration will be provided in 
the study manual.  
At the Part B Week 2, Week 8, and Week 24 Visits, the administration dates and timing with 
respect to food intake and occurrence and time of regurgitation within 1 hour after dosing for the 
2 doses of study drug administered immediately prior to the study visit should be recorded in 
each subject's dosing diary. In addition, the time of administration of study drug and occurrence 
and time of regurgitation within 1 hour after dosing in clinic on the day of the visit will be 
recorded. 
On Day 1 of Part A/B Cohort 8, subjects who meet all inclusion and no exclusion criteria will 
receive a single dose of 5.7 mg or 11.4 mg ivacaftor based on Day 1 age and weight (see 
Section 9.3.2) in the clinic. Each dose of granules will be mixed with approximately 1 teaspoon 
(5 mL) of appropriate liquid or soft food (as listed in the study manual) and administered with an 
age-appropriate fat-containing meal or snack. All subjects will be observed for 4 hours after 
administration of the first dose of study drug.  
In Part A/B Cohort 8, doses from the evening dose on Day 1 through the evening dose on Day 14 
will be administered q12h at home, except for the Day 4 morning dose, which will be 
administered in the clinic. Parents will be instructed on how to empty the packet and administer 
ivacaftor with food or liquid. Details of dose preparation and dose administration will be 


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provided in the study manual. A diary of the dose administration dates and times, occurrence and 
time of regurgitation within 1 hour after dosing, and whether doses were administered with 
food/liquid during the 3 days prior to the Day 4 Visit, will be kept by the subject's 
parents/caregivers. If regurgitation of a dose should occur, the subject should not be re-dosed  
At the Day 15 Visit of Part A/B Cohort 8, the ivacaftor dose will be adjusted, if necessary, to 5.7, 
11.4, 17.1, 22.8, or 25 mg based on PK data from Day 4 (see Section 9.3.2), and the adjusted 
dose will be administered starting with the evening dose on Day 15. The subject should then 
remain on the same dose from Day 15 until the subject is 4 months of age and at least 5 kg, after 
which the recommended age- and weight-appropriate dose(s) will be administered.  
Each dose of granules will be mixed with approximately 1 teaspoon (5 mL) of appropriate liquid 
or soft food (as listed in the study manual) and administered orally q12h with an age-appropriate 
fat-containing meal or snack from the evening dose on Day 15 through Week 24. Aside from 
doses administered during scheduled clinic visits, doses from the evening dose on Day 15 
through Week 24 will be administered q12h at home. Details of dose preparation and dose 
administration will be provided in the study manual.  
At the Part A/B Cohort 8 Week 4, 8, 12, 18, and 24 Visits, the dose administration dates and 
times, occurrence and time of regurgitation within 1 hour after dosing, and whether doses were 
administered with food/liquid will be recorded for the 2 doses of study drug administered 
immediately prior to each PK clinic visit in each subject's dosing diary. In addition, the time of 
administration of study drug and occurrence and time of regurgitation within 1 hour after dosing 
in clinic on the day of the visit will be recorded. 
When possible, subjects should take the dose of ivacaftor at the same time each day. If the 
caregiver of the subject forgets to administer a dose and remembers within 0 to 6 hours (before 
the halfway point of the dosing interval), the subject should be given the dose at that time and 
resume their normal schedule for the following dose. If caregiver of the subject forgets to give a 
dose and remembers within 6 to 12 hours after the missed dose, they should skip that dose and 
resume their normal schedule for the following dose. 
11.3 
Method of Assigning Subjects to Treatment Groups 
This study is open-labeled and all subjects will receive ivacaftor.  
11.4 
Dose Modification for Toxicity 
The investigator may interrupt study drug dosing if medically necessary. If study drug dosing 
must be interrupted for more than 72 hours, the Vertex medical monitor must be notified. In 
these instances, study drug dosing may only resume after approval by the Vertex medical 
monitor. Specific instructions for interruption for elevated LFT levels are provided in 
Section 12.6.2.  
11.5 
Packaging and Labeling 
Ivacaftor granules in a foil-laminated sachet/packet will be supplied by Vertex in kits. Study 
drug labeling will be in compliance with applicable local and national regulations. Additional 
details regarding packaging, labeling, and dispensing for ivacaftor will be included in the 
pharmacy manual. 


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11.6 
Study Drug Supply, Storage, and Handling 
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, all study drugs 
will be accounted for as described in Section 11.7. Study drug must be stored at temperatures of 
≤25°C (77°F) with excursions to 30°C (86°F). Additional storage and handling conditions will 
be provided in the pharmacy manual.  
11.7 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received, (2) study drug dispensed to the subjects, and (3) study drug 
returned by the subjects' parent or legal guardian. Subjects’ parent or legal guardian will be 
instructed to return all used and unused materials associated with the study drug to the site. 
These materials will be retained at the site according to instructions provided by Vertex or its 
designee until inventoried by the study monitor. The study monitor will review study drug 
records and inventory throughout the study. 
11.8 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects’ 
parent or legal guardian 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. 
11.9 
Compliance 
Study drug accountability should be assessed at each visit by counting returned dosage units 
(sachets/packets).   
If there is continued non-compliance with study requirements, restrictions, instructions, and 
study drug dosing despite educational efforts, the investigator should contact the Vertex medical 
monitor to discuss noncompliance and discontinuation of the subject from the study.   
11.10 
Blinding and Unblinding 
This will be an open-label study. 
12 
ASSESSMENTS 
12.1 
Timing of Assessments 
The timing of assessments is shown in: 
• Table 3-1 for Part A (Screening, Treatment, ETT, and Follow-up Periods) 
• Table 3-2 for Part B (Screening and Treatment Periods) 
• Table 3-3 for Part B (ETT Visit and Follow-up Periods) 
• Table 16-1 for Part A/B Cohort 8 (Screening, Treatment, ETT, and Follow-up Periods) 


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12.2 
Subject and Disease Characteristics 
Subject and disease characteristics include demographics and medical history. In addition, the 
following historical data will be collected for each Part B and Part A/B Cohort 8 subject from 
birth to screening: age at CF diagnosis, 
 pulmonary 
exacerbations, LFTs, and CF-related medications-of-interest. The following historical data from 
birth to screening will also be collected:  
• Maternal/pregnancy history: complications in pregnancy, gestational age at delivery, method 
of delivery 
• Quarterly (approximately every 12 weeks) 
  
• The dates and reasons for all 
  
• Any use (yes or no) of the following medications will be assessed: inhaled tobramycin, 
inhaled aztreonam, inhaled colimycin, inhaled hypertonic saline, dornase alfa, ibuprofen, 
azithromycin, and pancreatic enzyme replacement therapy.  
• Historical pancreatic status measurements 
12.3 
Pharmacokinetics 
12.3.1 
Blood Sampling 
At visits indicated in Part A Table 3-1, Part B Table 3-2 and Table 3-3, and Part A/B Cohort 8 
Table 16-1, blood samples will be collected for the determination of the concentrations of 
ivacaftor and metabolites M1 and M6 in plasma. Approximately 0.25 mL of blood will be 
collected at each PK time point.  
PK blood sampling time points are relative to the morning dose of study drug. The sampling 
schedule is as follows: 
Part A 
• Day 4: before the morning dose; between 2 and 4 hours and between 6 and 8 hours after the 
Day 4 morning dose 
• Day 5: between 24 and 60 hours after the Day 4 morning dose.  
• For subjects who prematurely discontinue treatment, a PK blood sample will be collected at 
the ETT Visit.  
• The administration dates and times and their timing with respect to food intake of all study 
drug doses administered outside the clinic should be recorded in each subject's dosing diary. 
Part B 
• Week 2: before the morning dose, between 2 and 4 hours and between 6 and 8 hours after the 
morning dose 
• Week 8: before the morning dose and 1 and 4 hours after the morning dose 
• Week 24: before the morning dose and between 2 and 4 hours after the morning dose  
o PK blood sampling at Week 24 is optional for subjects who undergo MBW (due to 
fasting requirements) 


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• For subjects who prematurely discontinue treatment, a PK blood sample will be collected at 
the ETT Visit. 
• The dose administration dates and times, and their timing with respect to food intake, will be 
recorded for the 2 doses prior to each PK clinic visit in each subject’s dosing diary.  
Part A/B Cohort 8 
• Day 4: before the morning dose; between 2 to 4 hours and between 6 to 8 hours after the 
Day 4 morning dose 
• Day 15: before the morning dose 
• Weeks 4, 12, 18 and 24: before the morning dose 
• Week 8: before the morning dose; between 2 to 4 hours and between 6 to 8 hours after the 
Week 8 morning dose 
• For subjects who prematurely discontinue treatment, a PK blood sample will be collected at 
the ETT Visit only if within 3 days of last dose of study drug. 
• The dose administration dates and times, occurrence and time of regurgitation within 1 hour 
after dosing, and whether doses were administered with food/liquid will be recorded for the 
2 doses of study drug administered immediately prior to each PK clinic visit in each subject’s 
dosing diary.  
The total anticipated blood volume collected at each study visit is presented in Table 12-1. 
Cumulatively, each subject is expected to have 27.0 mL of blood collected over the course of the 
study (from Screening to Week 24), excluding the ETT. The total blood volume collected at any 
single study visit is not expected to exceed about 1% of a subject’s estimated total blood volume 
(based on body weight) and the total blood volume collected over the course of any 4 weeks is 
not expected to exceed about 3% of a subject’s estimated blood volume. Total blood volume was 
estimated based on the expectation of total volume being at least 80 mL blood/kg body weight 
(240 mL at Day 1 for a subject weighing 3 kg).93 
Table 12-1 
Expected Blood Volumes to be Collected at Each Study Visit 
Study Visit 
Assessments Requiring Blood Collection 
Total Blood Volume (mL) 
Screening (Day -28 to -14) 
Serum chemistry, Hematology 
2.3 
Day 1 
Serum chemistry, IRT 
2.2 
Day 4 
Serum chemistry, PKa 
2.6 
Day 15 
Serum chemistry, Hematology, PKa 
2.8 
Week 4 
Serum chemistry, Hematology, PKa 
2.8 
Week 8 
Serum chemistry, PKa 
2.6 
Weeks 12, 18, and 24 
Serum chemistry, Hematology, PKa, IRT 
3 × 3.9 = 11.7 
ETT 
Serum chemistry, Hematology, PKb 
2.8 
ETT: Early Termination of Treatment; IRT: immunoreactive trypsin and/or trypsinogen; PK: pharmacokinetic 
a 
PK samples will be collected before the morning dose and between 2 to 4 hours and between 6 to 8 hours 
after the morning dose on Day 4 and Week 8. PK samples will be collected before the morning dose on 
Day 15, and on Weeks 4, 12, 18, and 24. 
b 
PK sample will be collected only if within 3 days of last dose of study drug. 


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The acceptable windows for the PK sampling time points are listed in Table 12-2. Samples 
collected outside these acceptable windows will be considered protocol deviations. All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Table 12-2 
Acceptable Pharmacokinetic Sampling Windows 
Study Part 
Nominal Sampling Times 
Acceptable Window 
Part A 
ETT Visit 
at the time of the ETT Visit 
 
Day 4: 0 (before morning dose) 
within 60 minutes before dosing 
 
Day 4: between 2 and 4 hours after the 
Day 4 morning dose 
within the time window of 2 to 4 hours after 
the Day 4 morning dose 
 
Day 4: between 6 and 8 hours after the 
Day 4 morning dose 
within the time window of 6 to 8 hours after 
the Day 4 morning dose 
 
Day 5: 24 and 60 hours after the Day 4 
morning dose 
within the time window of 24 to 60 hours 
after the Day 4 morning dose 
Part B 
ETT Visit 
at the time of the ETT Visit 
 
Week 2: 0 (before morning dose) 
within 60 minutes before dosing 
Week 2: between 2 and 4 hours after the 
morning dose 
within the time window of 2 and 4 hours 
after the morning dose 
Week 2: between 6 and 8 hours after the 
morning dose  
within the time window of 6 and 8 hours 
after the morning dose 
Week 8: 0 (before morning dose) 
within 60 minutes before dosing 
Week 8: 1 and 4 hours after the morning 
dose  
± 15 minutes  
Week 24: 0 (before morning dose) 
within 60 minutes before dosing 
Week 24: between 2 and 4 hours after the 
morning dose 
within the time window of 2 to 4 hours after 
the morning dose 
Part A/B  
Cohort 8 
ETT Visita 
at the time of the ETT Visit 
Day 4: 0 (before morning dose) 
within 60 minutes before dosing 
Day 4: between 2 and 4 hours after the 
Day 4 morning dose 
within the time window of 2 to 4 hours after 
the Day 4 morning dose 
Day 4: between 6 and 8 hours after the 
Day 4 morning dose 
within the time window of 6 to 8 hours after 
the Day 4 morning dose 
Day 15, Weeks 4, 12, 18, and 24: 0 (before 
morning dose) 
within 60 minutes before dosing 
Week 8: 0 (before morning dose) 
within 60 minutes before dosing 
Week 8: between 2 and 4 hours after the 
Week 8 morning dose 
within the time window of 2 to 4 hours after 
the Week 8 morning dose 
Week 8: between 6 and 8 hours after the 
Week 8 morning dose 
within the time window of 6 to 8 hours after 
the Week 8 morning dose 
a 
Assessment will be performed only if within 3 days of last dose of study drug. 
12.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the Sample Handling Guideline. The 
shipment address and assay laboratory contact information will be provided to the investigational 
site before initiation of the study. 


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12.3.3 
Bioanalysis 
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. 
12.4 
Pharmacodynamics 
12.4.1 
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 qualified study sites using an approved 
Macroduct® (Wescor, Logan, UT) collection device. Sweat samples will be sent to a central 
laboratory for testing and interpretation of results. Individual sweat 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.  
Sweat collection will be completed at visits as indicated in Part A Table 3-1, Part B Table 3-2, 
and Part A/B Cohort 8 Table 16-1. In Part B and in Part A/B Cohort 8, the sweat chloride test at 
the Day 1 Visit must be performed before the morning dose. At subsequent visits, the sweat 
chloride test must be performed within a window of ± 2 hours relative to the morning dose of the 
study drug. Change from baseline in sweat chloride will be analyzed as a secondary endpoint of 
Part B and Part A/B Cohort 8 in this study  


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12.6 
Safety 
Safety evaluations will include adverse events, clinical laboratory assessments (serum chemistry 
and hematology), vital signs, ECGs, physical examinations (with clinically significant 
abnormalities recorded as medical history or adverse events), and OEs.  
12.6.1 
Adverse Events 
All adverse events will be assessed, documented, and reported in accordance with ICH GCP 
guidelines. Section 14.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting adverse events. A separate document that details adverse 
event case report form (CRF) completion guidelines for investigators as well as training will be 
provided. 
12.6.2 
Clinical Laboratory Assessments 
Blood samples will be collected at times specified in Part A Table 3-1, Part B Table 3-2 and 
Table 3-3, and Part A/B Cohort 8 Table 16-1. If, under exceptional circumstances, these blood 
samples must be drawn and/or analyzed at a local laboratory, approval must be first obtained 


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from the Vertex medical monitor. All blood samples will be collected while subjects are in a 
seated or supine position. Specific instructions for the collection, processing, and shipment of 
samples will be provided in a separate Laboratory Manual. Laboratory test results that are 
abnormal and considered clinically significant must be reported as adverse events (see 
Section 14.1). 
The safety laboratory test panels are shown in Table 12-3:  
Table 12-3  
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Glucose  
Blood urea nitrogen  
Creatinine 
Sodium 
Potassium 
Calcium 
Phosphate 
Bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate transaminase (=SGOT) 
Alanine transaminase (=SGPT) 
Lactate dehydrogenase 
Gamma-glutamyl transferase 
Protein 
Albumin 
Amylase 
Lipase 
Hemoglobin  
Hematocrit 
Red blood cell count 
Platelet count 
White blood cell count 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Monocytes 
 
 
CFTR Genotype:  
Subjects must have a CFTR ivacaftor-responsive mutation on at least 1 allele to meet inclusion 
criteria (see Appendix A: CFTR Mutations Included in the Study). For all Parts, the genotype 
results must be available before the first dose of study drug. Subjects who had CFTR genotyping 
completed in Part A of the study will not require repeat testing upon entry into Part B. 
If a genotype test has been performed previously and is documented in the subject’s medical 
record, the subject's eligibility must be approved by the Vertex medical monitor, including an 
assessment whether the genotyping meets applicable standards.  
For Parts A and B, if a historic genotype result is not available at screening or if the historic 
genotype result is not approved by the Vertex medical monitor, subjects will be tested for CFTR 
genotype at screening and the results must be reviewed before the first dose of study drug.  
Subjects will not receive the study drug if CFTR genotype is not confirmed by either an 
approved historic genotype and approval of Vertex medical monitor result OR by genotype 
testing at screening. 
For Part A/B Cohort 8, subjects must have documented genotype test results reviewed and 
approved by the Vertex medical monitor prior to Day 1. Genotype testing is expected to be 
initiated prior to screening and results must be available prior to Day 1. 


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Instruction for collecting a sample for CFTR genotyping will be included in the Laboratory 
Manual. 
Elevation of LFT Parameters:  
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN must 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. In addition, if ALT or AST are >5 × ULN, repeat follow-up levels must be 
obtained within 7 ± 2 days and followed up 7 days later. All reasonable efforts should be made to 
repeat confirmatory analysis by the central laboratory. If, under exceptional circumstances, these 
blood samples must be drawn and/or analyzed at a local laboratory, approval must be first 
obtained from the Vertex medical monitor. Elevations in LFTs measured by the local laboratory 
must be reported immediately to the Vertex 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).  
LFT Elevations Leading to Study Drug Interruption: 
Study drug administration must be interrupted immediately, and the Vertex medical monitor 
must be notified if any of the following criteria is met: 
• ALT or AST >8 × ULN, or 
• ALT or AST >5 × ULN for 2 weeks or more, or 
• ALT or AST >3 × ULN in association with elevation of bilirubin >2 × ULN and/or clinical 
jaundice 
Repeat testing should be performed within 48 to 72 hours to confirm the initial elevation. 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression.  
If no convincing alternative etiology (e.g., concurrent infections) for the elevated transaminases 
is identified, regardless of whether ALT or AST levels have improved, the subject must be 
discontinued from the study in consultation with the Vertex medical monitor (Section 10.4). 
Subjects in whom treatment is discontinued for elevated transaminases should have their 
transaminases monitored closely until levels normalize or return to baseline. 
If a convincing alternative cause of transaminase elevation has been identified, study drug may 
be resumed once transaminases return to ≤2 × ULN. Approval of the Vertex medical monitor is 
required before resumption of study drug. Upon resumption of study drug, transaminases should 
be assessed weekly for 4 weeks. If a protocol-defined transaminase elevation occurs within 4 
weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology.  
Additional Evaluations:  
Additional clinical laboratory evaluations will be performed at other times if judged to be 
clinically appropriate or if the ongoing review of the data suggests a more detailed assessment of 
clinical laboratory safety evaluations is required. Any changes to the scheduled times of clinical 
laboratory determination will be agreed between the investigator and Vertex and documented in 
the study master files. 


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12.6.3 
Physical Examinations and Vital Signs 
A physical examination of all body systems and vital signs assessment will be performed at 
screening and select study visits as shown in Part A Table 3-1, Part B Table 3-2 and Table 3-3, 
and Part A/B Cohort 8 Table 16-1. At other visits, symptom-directed physical examinations and 
symptom-directed vital signs assessments can be performed at the discretion of the investigator 
or healthcare provider. 
A physical examination includes a review of the following systems: head/neck/thyroid; 
eyes/ears/nose/throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. After screening, any clinically significant abnormal findings 
in physical examinations will be reported as adverse events. 
The abbreviated physical examination will include an assessment of the following body systems: 
head/neck/thyroid, EENT, cardiovascular system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration 
rate, and pulse oximetry. The subject should rest for at least 5 minutes, if possible, before having 
vital signs measured. Temperature must be obtained by the same method throughout the study. 
12.6.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout at the time points listed 
in Part A Table 3-1, Part B Table 3-2 and Table 3-3, and Part A/B Cohort 8 Table 16-1. 
Additional standard 12-lead ECGs will be performed at any other time if clinically indicated. 
The performance of all ECGs will adhere to the following guidelines: 
• The subject should rest 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. 
The ECG traces will be manually read at the study site at the Screening and Follow-up Visits. A 
printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. All traces will be centrally evaluated by a qualified pediatric 
cardiologist. Clinically significant ECG abnormalities occurring during the study through the 
Follow-up Visit will be recorded as adverse events.  
To ensure safety of the subjects, the investigator will make comparisons of the ECG findings to 
baseline measurements. Repeat ECGs will be performed as deemed appropriate. Subject 
eligibility to continue in the study will be evaluated. 
12.6.5 
Ophthalmologic Examinations 
Subjects will undergo an OE at the time points in Part A Table 3-1, Part B Table 3-2 and Table 
3-3, and Part A/B Cohort 8 Table 16-1. The OE must be conducted by a licensed 
ophthalmologist, preferably a pediatric ophthalmologist. The OE will include:  
• examination of the lens with a slit-lamp (portable or otherwise; pharmacologically-dilated 
examination). Details of the slit-lamp examination will be documented. 
• assessment of the red reflex (pharmacologically-dilated examination) 
• Screening OEs only: examination of the fundus (retina, optic nerve, and vessels), pupils, and 
eye movements 


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In addition, at screening, relevant medical history will be obtained for all subjects, including the 
following: 
• history of steroid use 
• history of trauma to the eye 
• any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
At screening for all Parts, the subject is not eligible for enrollment if:  
• an adequate slit-lamp examination cannot be conducted  
• a lens opacity/cataract is identified (excluding those considered congenital and 
nonprogressive, such as a suture cataract) 
During the screening period, if an adequate slit-lamp examination cannot be conducted, the slit-
lamp examination may be repeated until an adequate repeat slit-lamp examination is completed 
(Sections 9.1.1.1 and 9.1.1.3) and eligibility criteria regarding the ophthalmologic findings are 
met.  
For Part A, the Follow-up OE will be performed 8 weeks after the last dose of study drug 
(Section 9.1.3.1).  
During the Part B and Part A/B Cohort 8 treatment periods, if a new lens opacity or cataract is 
identified at any OE, the Vertex medical monitor must be notified and study drug dosing must be 
discontinued. If an adequate slit-lamp examination cannot be conducted at any visit where it is 
required in Part B (Table 3-2) or Part A/B Cohort 8 (Table 16-1), the subject will continue 
receiving study drug until an adequate repeat examination is completed (within 4 weeks of the 
study visit). If an adequate slit-lamp examination cannot be conducted within 4 weeks of the 
study visit, study drug dosing may be discontinued.  
For Part B (Table 3-3) and Part A/B Cohort 8 (Table 16-1), the OE for the ETT Visit will be 
conducted for all subjects who prematurely discontinue study drug dosing, regardless of the 
reason for discontinuation. If the ETT Visit occurs within 12 weeks of the subject's last OE, the 
OE at the ETT Visit will not be required. A Follow-up OE will also be performed 
(Section 9.1.3.1). 
Lastly, all Part B and Part A/B Cohort 8 subjects who do not continue ivacaftor in the open-label 
treatment arm of the Extension Study will be eligible to enroll in the observational arm of the 
Extension Study for long-term follow-up OEs.  
12.6.6 
Contraception and Pregnancy 
Not applicable. 
13 
STATISTICAL AND ANALYTICAL PLANS 
Analysis of all data, including safety, efficacy, PK, PD, and exploratory data, will be performed 
by Vertex (or designee). The results of the study will be reported in the clinical study report 
(CSR). 
Details will be provided in the statistical analysis plan (SAP) for the final analysis, which will be 
finalized and approved before the clinical database lock. A detailed analysis plan for PK and 


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PK/PD parameter estimations will be presented in a clinical pharmacology analysis plan (CPAP), 
which will be finalized and approved before the database lock. As the study design is open-label, 
a draft SAP for the final analysis will be available before the first subject is dosed.  
13.1 
Sample Size and Power 
The sample size of a minimum of 15 subjects in Part A, 15 subjects in Part B, and 6 up to 
approximately 10 subjects in Part A/B Cohort 8 is based on the availability of the subject 
population and PK analysis considerations, and not on any statistical consideration. Therefore, 
the study is not powered to detect a significant treatment effect.  
Part A: A minimum of 15 subjects: 
• minimum of 5 subjects aged 12 to <24 months  
• minimum of 5 subjects aged 6 to <12 months 
• minimum of 5 subjects aged 3 to <6 months 
Part B: A minimum of 15 subjects: 
• minimum of 5 subjects aged 12 to <24 months 
• minimum of 5 subjects aged 6 to <12 months 
• minimum of 5 subjects aged 4 to <6 months  
Note: Subjects who have an R117H-CFTR mutation will only be enrolled in regions where 
ivacaftor is approved for use in subjects 2 through 5 years of age with an R117H-CFTR 
mutation.  
Part A/B Cohort 8:  
• A minimum of 6 up to approximately 10 subjects aged 1 to <4 months, ≥38 weeks gestation, 
and at least 3 kg at the time of treatment initiation (Day 1) (see Section 9.3.2) 
• Subjects who have an ivacaftor-responsive mutation on at least 1 allele (see Appendix A) 
will be eligible to enroll in regions where ivacaftor is approved (consistent with the approved 
mutations in the region). 
There are estimated to be approximately 1800 CF births per year worldwide29, 30, 95. If it is 
assumed that 61% of these cases are detected by newborn screening 29, 30, 95 and 5% carry a 
gating mutation22, 95 there will be approximately 50 patients available for enrollment in this study 
each year from NBS (1800 × 0.6 × 0.05). There are estimated to be approximately 70 children 
between 0 to 2 years of age with a gating mutation not diagnosed by NBS who are available for 
enrollment in this study each year (1800 × 0.4 × 0.05). If 15% to 20% of the entire available 
global patient population is enrolled, this would allow enrollment of approximately 20 subjects 
per year. There is often a delay in the time it takes for patients to be referred to and evaluated at a 
CF center following diagnosis, as well as time needed for parents to process the CF diagnosis 
and to become informed about the disease. Thus, feedback from CF pediatricians indicates there 
will be some difficulty in enrolling this CF population of <2-year-olds, particularly those <2 to 
4 months of age.  
Relatively rich PK samples (4 samples at steady-state) will be collected in Part A, which will 
provide sufficient PK data to inform the population PK model, while accounting for blood 


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volume restrictions in this vulnerable age range. In addition to evaluation of PK in Part A, this 
study will collect PK samples from all subjects in Part B through 24 weeks. PK evaluation will 
consist of a population PK approach, utilizing the current population PK model and existing data 
for patients ≥24 months of age. The between-subject variability estimate for ivacaftor in subjects 
with CF 2 through 5 years of age from Study 108 is a coefficient of variation (CV) of 34% to 
41% for area under the concentration versus time curve (AUC). Based on a review of model-
based pediatric simulations with a range of variability, the variability estimate of ivacaftor from 
Study 108, and the PK collection scheme, the number of subjects planned for enrollment is 
expected to provide reasonably precise estimates of key PK parameters using a population PK 
approach.96, 97 The inclusion of data from pediatric patients ≥24 months of age with the 
population PK approach is expected to reduce the required sample size.97  
Given the above feasibility assessment and PK considerations, a minimum of 15 subjects in 
Part A, 15 subjects in Part B, and 6 up to approximately 10 subjects in Part A/B Cohort 8 is 
considered an appropriate sample size for evaluation of the PK and safety of ivacaftor in subjects 
<24 months of age. 
For Part A/B Cohort 8, PK samples (3 samples) will be collected on the Day 4 and Week 8 Visits 
to provide sufficient PK data to assess exposure, while accounting for blood volume restrictions 
in this vulnerable age range. In addition to evaluation of PK on Day 4, trough PK samples will be 
collected from all subjects in Part A/B at each visit through 24 weeks.  
13.2 
Part A Analyses 
A preliminary PK analysis will take place after all samples have been collected and bioanalysis 
is complete for each cohort in Part A. The available data will be used to confirm dose(s) for use 
in Part B.  
13.2.1 
Analysis Set 
Safety Set: The Safety Set for Part A includes all subjects who received at least 1 dose of study 
drug (i.e., ivacaftor). The dose assignment for the Safety Set will be as treated. 
13.3 
Part B Analyses 
The analyses of safety and efficacy will be based on the 24-week data.  
13.3.1 
Analysis Sets 
The Safety Set for Part B is defined as subjects who received at least 1 dose of study drug (i.e., 
ivacaftor). The Safety Set is to be used for all safety summaries. The dose assignment for the 
Safety Set will be as treated. 
Full Analysis Set (FAS): The FAS for Part B includes all subjects who are enrolled and receive 
at least 1 dose of study drug (i.e., ivacaftor). 
13.4 
Part A/B Cohort 8 Analyses 
The analyses of safety and efficacy will be based on the 24-week data.  
13.4.1 
Analysis Sets 
The Safety Set for Part A/B Cohort 8 is defined as subjects who received at least 1 dose of study 
drug (i.e., ivacaftor). The Safety Set is to be used for all safety summaries. The dose assignment 
for the Safety Set will be as treated. 


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The FAS for Part A/B Cohort 8 includes all subjects who are enrolled and receive at least 1 dose 
of study drug (i.e., ivacaftor). 
13.5 
Statistical Analysis 
Safety analyses for Part A, Part B, and Part A/B Cohort 8 will be conducted separately. Efficacy 
and PD analyses are applicable to Parts B and Part A/B Cohort 8 only., and Part A/B Cohort 8 
will be analyzed separately from other cohorts. Parts B and A/B Cohort 8 may also be pooled for 
analyses of safety, PD, and efficacy endpoints common to both parts. 
13.5.1 
General Considerations 
All individual subject data, including derived variables, will be presented in the data listings, 
which will include data for all subjects included in the study from all of the analysis sets. All 
analyses will be performed using SAS® (SAS Institute, Cary, North Carolina, USA).  
Continuous data will be summarized by means of descriptive statistics (number of subjects [n], 
mean, standard deviation [SD], standard error [SE], median, minimum value [min], maximum 
value [max], and 95% confidence intervals [CI], as appropriate).  
Categorical data will be summarized by contingency tables (n, percentage, and 95% CI).  
Additionally, all subject data, including derived variables, will be presented in subject data 
listings; listings will display all subjects who were enrolled or dosed. 
For safety analyses, only descriptive analyses will be carried out (i.e., no statistical hypothesis 
testing will be performed).  
Annualized event rates will be normalized to annualized event rates for the final analysis; 
however, in the event of data being used for a regulatory submission, event rates will be 
normalized to a 24-week period. 
Definition of the baseline value: The baseline value will be defined separately for Parts A, B, and 
A/B Cohort 8 as the most recent non-missing measurement collected before the initial 
administration of study drug in the respective study part. Note that this definition applies to both 
scheduled and unscheduled measurements; if an unscheduled value is the most recent non-
missing measurement, it will be taken as baseline. The absolute change from baseline value will 
be defined as postbaseline value minus baseline value. The definitions will apply to all analysis 
variables: demographics, background, baseline characteristics, safety, and efficacy (Part B and 
Part A/B Cohort 8), unless otherwise specified. 
13.5.2 
Background Characteristics 
13.5.2.1 
Subject Disposition 
Number and percentage of subjects in the following categories will be summarized as 
appropriate: 
• Enrolled 
• Enrolled and dosed (Safety Set) 
• Last Treatment Period Visit Completed (Day 1, Day 2, Day 3, Day 4, and Day 5 in Part A; 
Day 1, Week 2, Week 4, Week 8, Week 12, Week 18, and Week 24 in Part B; and Day 1, 
Day 4, Day 15, Week 4, Week 8, Week 12, Week 18, and Week 24 in Part A/B Cohort 8). 


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• Prematurely discontinued the study drug treatment during the Treatment Period and the 
reasons for discontinuation 
The disposition summary will be based on all subjects and will be provided for the interim and 
final analysis. 
13.5.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized. Protocol deviations/violations will be provided as a subject data listing only. No 
statistical tests will be carried out to evaluate any baseline imbalance between dose groups. 
13.5.2.3 
Prior and Concomitant Medications 
All medications will be coded using the World Health Organization-Drug Dictionary Enhanced 
(WHO-DDE). 
Medications used in the study will be identified as prior, concomitant, or both, according to the 
rules given below. 
Medications used in the study will be summarized by preferred name in frequency tables in 
2 parts: 
• Prior medication: any medication that started before the first dose of study drug, regardless 
of when it ended. 
• Concomitant medication: medication received at or after dosing of study drug, or 
medication that was received before dosing with study drug and continued after dosing of 
study drug. 
If medication start date is at or after date of first dosing of study drug, then medication will be 
summarized as concomitant medication regardless of whether the medication end date is missing 
or not. If the medication end date is before the date of first dosing of study drug, then the 
medication will be summarized as prior medication regardless of whether the medication start 
date is missing or not. Note that medication that started before first dosing of study drug and 
continued after dosing will be summarized as prior medication and separately as concomitant 
medication. 
Both prior and concomitant medications will be based on the Safety Set, with concomitant 
medications provided for the final analysis. 
For the final analysis, medications received during the period from the first dose of study drug 
through the end of Part A participation will be summarized as concomitant medications in Part 
A. A similar rationale will be adopted for concomitant medications in Part B and Part A/B 
Cohort 8.  
If the data contain missing or partial medication start and stop dates which do not allow 
definitive classification as either prior medication, concomitant medication, or both, a 
conservative rule will be implemented and will be provided in the SAP. 
13.5.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug (i.e., duration of treatment) will be summarized for the Safety Set in 
terms of duration of treatment a subject received (in days). 


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Dosing compliance will be summarized for the Safety Set, and is calculated as the actual number 
of dosing occasions at which study drug was administered, as a percentage of the planned 
number of dosing occasions. 
Duration of treatment and dosing compliance will be summarized by means of descriptive 
summary statistics. 
13.5.3 
Efficacy Analysis (Part B) 
Statistical methodology will be restricted to descriptive statistics only. All efficacy analyses will 
be based on the FAS.  
13.5.3.1 
Analysis of Primary Variables 
Not applicable. 
13.5.3.2 
Analysis of Secondary Efficacy Variables   
13.5.3.2.1 
Change from Baseline in Sweat Chloride 
Sweat chloride results (including changes from baseline) will be analyzed as a continuous 
variable using descriptive summary statistics and presented by visit and treatment (dose level). In 
addition, data summaries excluding subjects who have an R117H-CFTR mutation will be carried 
out separately. 


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13.5.4 
Efficacy Analysis (Part A/B Cohort 8) 
13.5.4.1 
Analysis of Primary Variables 
Not applicable. 


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13.5.4.2 
Analysis of Secondary Efficacy Variables   
13.5.4.2.1 
Change from Baseline in Sweat Chloride 
Sweat chloride results (including changes from baseline) will be analyzed as a continuous 
variable using descriptive summary statistics and presented by visit.  


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13.5.5 
Safety Analysis 
Evaluating safety is the primary objective of this study. The overall safety profile of ivacaftor 
will be assessed in terms of the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory results (serum chemistry and hematology) 
• Standard 12-lead ECG outcomes 
• Vital signs 
• Physical examinations 
• OEs 
TEAEs are the key safety assessment. Descriptive analysis of safety will be performed; raw 
values, changes from baseline, shifts-from-baseline, and clinical abnormalities will be 
summarized, where applicable. 
All safety analyses will be based on the Safety Set.  
13.5.5.1 
Adverse Events 
TEAEs, defined as adverse events with start date or increased severity on or after the first dose of 
study drug through the end of participation (as applicable), will be summarized by treatment 
(dose level). TEAEs will hereafter be referred to as adverse events. Adverse event summary 
tables will include the following analyses presented by treatment (dose level):  
• All adverse events 
• Related (defined as possibly related or related) adverse events 
• Adverse events leading to treatment discontinuation 
• SAEs 
• Adverse events by severity 
• Adverse events by relationship 


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Summaries will be presented by MedDRA system organ class and preferred term using 
frequency counts and percentages. A subject with multiple occurrences of the same adverse 
event or a continuing adverse event will be counted only once, with the highest severity or 
relationship. 
For Part A/B safety results will be summarized by visit only and not by treatment (dose level). 
In addition, a table containing individual subject adverse event data for all deaths and other 
serious and significant adverse events will be provided.  
13.5.5.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using SI units. Continuous serum 
chemistry and hematology results will be summarized at each visit and presented by treatment 
(dose level). For Part A/B safety results will be summarized by visit only and not by treatment 
(dose level). Changes from baseline will also be summarized. The number and percentage of 
subjects with shift changes from baseline based on the laboratory normal ranges will be 
tabulated. 
In addition, a listing containing individual subject serum chemistry and hematology values 
outside the reference ranges will be provided. These listings will include data from scheduled 
and unscheduled time points.  
Clinically significant abnormal findings will be reported as adverse events.  
13.5.5.3 
Electrocardiogram 
Continuous ECG measurements will be summarized by visit and treatment (dose level). For Part 
A/B safety results will be summarized by visit only and not by treatment (dose level). Changes 
from baseline will also be summarized. In addition, the number and percentage of subjects by 
maximum and minimum on-treatment value and by maximum and minimum on-treatment 
increase from baseline in QT/QTc intervals will be presented. A shift table for ECG complexes 
analyzed and a listing of abnormal ECG complexes from the ambulatory recordings will also be 
presented. 
13.5.5.4 
Vital Signs 
The following vital signs will be summarized by visit and treatment (dose level): systolic and 
diastolic blood pressure (mmHg), temperature (°C), pulse oximetry (%), heart rate (beats per 
minute), and respiration rate (breaths per minute). For Part A/B safety results will be summarized 
by visit only and not by treatment (dose level). Changes from baseline will also be summarized. 
Clinically significant findings in vital signs will be reported as adverse events. 
13.5.5.5 
Physical Examination 
Physical examination results will be presented in individual subject data listings only. Clinically 
relevant results identified after screening will be reported as adverse events.  
13.5.5.6 
Ophthalmological Examination 
The ocular safety profile of ivacaftor will be assessed in terms of the following analyses: 
• Incidence of cataracts or lens opacities based on results from dilated slit-lamp examination 
• Red reflex 


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Results of OEs (incidence of cataracts or lens opacities) will be summarized as a categorical 
variable and results will be presented by treatment (dose level). For Part A/B safety results will 
be summarized by visit only and not by treatment (dose level).  
Lens refracting power and red reflex will be listed as appropriate.  
13.5.6 
Interim and IDMC Analyses 
13.5.6.1 
Interim Analysis 
An interim analysis (IA) of safety, PK, and PD data from subjects in Cohorts 1 and 5 can be 
conducted after either of the following: 
• a sufficient number of subjects in Cohort 5 have completed their Week 12 Visit  
• a sufficient number of subjects in Cohort 5 have completed their Week 24 Visit  
Additional interim analyses for regulatory, safety, or operational purposes may also be 
performed. 
13.5.6.2 
IDMC Analysis 
See Section 9.2.  
13.6 
Clinical Pharmacology Analysis 
13.6.1 
Pharmacokinetic Analysis (Part A and Part B) 
Nonlinear mixed effects modeling will be applied for the PK analysis of ivacaftor for comparison 
of ivacaftor disposition to that of adults. The primary exposure estimates of interest are ivacaftor 
AUC and Cmin. Exposure of metabolites M1 and M6 will be described by descriptive statistics.  
Preliminary analyses will be performed on the PK data obtained from a minimum of 5 subjects 
from each cohort in Part A. The PK analysis, along with safety data from Part A, will be used to 
appropriately confirm the dose selection for Part B (or adjust the doses if necessary) based on 
criteria that take into account both the Cmin and AUC relative to historical results in adult CF 
subjects. At least 4 samples per subject are needed. If PK data from a completed cohort in Part A 
are insufficient to confirm the appropriate dose for that age group, additional subjects may be 
enrolled in Part A until a dose can be confirmed. PK parameters other than Cmin and AUC may be 
considered if deemed appropriate.  
A detailed plan of the quantitative methods used to derive PK parameter estimations for Parts A 
and B will be presented in the CPAP. 
13.6.2 
Pharmacokinetic Analysis (Part A/B Cohort 8) 
The primary exposure estimates of interest are the AUC and Cmin of ivacaftor and its metabolites 
(M1 and M6). These exposures will be described by descriptive statistics. Preliminary analyses 
will be performed on Day 4 PK data obtained from individual subjects in Part A/B Cohort 8 to 
assist in the Day 15 dose adjustment. Details of this dose adjustment are further described in 
Report P292. 


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A detailed plan of the noncompartmental analyses used to derive PK parameter estimations of 
ivacaftor and its M1 and M6 metabolites for Part A/B Cohort 8 will be presented in the CPAP. 
PK analysis of ivacaftor may be performed using nonlinear mixed effects modeling, as data 
allow. 
14 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
14.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
14.1.1 
Adverse Events 
14.1.1.1 
Definition of an Adverse Event 
An adverse event 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 informed consent form (ICF) is signed.  
An adverse event is considered serious if it meets the definition in Section 14.1.2.1.  
14.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, physical examinations, vital signs, and 
ophthalmologic examinations will be assessed and those deemed to have clinically significant 
worsening from baseline will be documented as an adverse event. 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 adverse event (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the clinical status of the subject indicates a life-threatening adverse event. 
14.1.1.3 
Documentation of Adverse Events 
In each study part, all adverse events will be collected from the time ICF is signed until the 
following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 


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• For subjects enrolled in Part A: through Day 14, with the exception of ocular adverse events 
noted during the Follow-up OE in Part A  
• For subjects enrolled in Part B who complete the study and enter the treatment arm of the 
Extension Study: through the Week 24 Visit 
• For subjects who enrolled in Part B who complete the study and do not enter the treatment 
arm of the Extension Study: the Follow-up Visit (if required), with the exception of ocular 
adverse events noted during the Follow-up OE in Part A 
• For subjects who enrolled in Part B who prematurely discontinue from treatment: the ETT or 
Follow-up Visit (if required) 
• For subjects enrolled in Part A/B Cohort 8 who complete the study and enter the treatment 
arm of the Extension Study: through the Week 24 Visit 
• For subjects who enrolled in Part A/B Cohort 8 who complete the study and do not enter the 
treatment arm of the Extension Study: the Follow-up Visit (if required), with the exception of 
ocular adverse events noted during the Follow-up OE 
• For subjects who enrolled in Part A/B Cohort 8 who prematurely discontinue from treatment: 
the ETT or Follow-up Visit (if required) 
Ocular adverse events will continue to be collected as follows: 
• In Part A, from the Follow-up Telephone Call (Day 14) through the Follow-up OE (8 weeks 
after the last dose of study drug) 
• In Part B, from the Follow-up Visit (4 weeks after the last dose of study drug) through the 
Follow-up OE (24 weeks after the last dose of study drug) 
• In Part A/B Cohort 8, from the Follow-up Visit (4 weeks after the last dose of study drug) 
through the Follow-up OE (12 weeks after the last dose of study drug) 
All subjects' parents or legal guardians will be queried, using non-leading questions, about the 
occurrence of adverse events at each study visit. When possible, a constellation of signs and/or 
symptoms will be identified as 1 overall event or diagnosis. All adverse events for enrolled 
subjects will be recorded in the CRF and source document. Adverse events 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 adverse event: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug 
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 


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For the purposes of study analysis, if the adverse event has not resolved at the end of the study 
reporting period (the Follow-up Visit), it will be documented as ongoing. For subjects who enroll 
in the Extension Study, adverse events that are ongoing at the time of the last visit in Study 124 
will be monitored in the Extension Study. For purposes of safety monitoring, the investigator is 
required to follow the adverse event to symptom resolution or until the condition stabilizes. 
14.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious adverse 
events.  
The guidance available at the following website will be consulted: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007, Center for Biologics Evaluation and Research, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/Vaccines/ucm074775.htm (accessed September 2019). When 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 in the vaccine scale. The severity of an adverse 
event that does not appear in this scale will be determined according to the definitions in 
Table 14-1.  
Table 14-1 
Grading of Adverse Event Severity 
Classification 
Definition 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Grade 4 (Life-threatening) 
Life-threatening consequences; urgent intervention indicated  
Grade 5 (Death) 
Death related to adverse event 
 
14.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the adverse event, if 
any, to the study drug. Causality will be classified using the categories presented in Table 14-2. 
Table 14-2 
Classifications for Adverse Event 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. 


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Table 14-2 
Classifications for Adverse Event Causality 
Classification 
Definition 
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). 
 
14.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the adverse event. The 
action taken will be classified according to the categories shown in Table 14-3.  
Table 14-3 
Classifications for Study Drug Action Taken With Regard to an Adverse 
Event 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an adverse event 
Dose reduced 
Study drug dose reduced in response to an adverse event 
Drug interrupted 
Study drug administration interrupted in response to an adverse event  
Drug withdrawn 
Study drug administration permanently discontinued in response to an adverse 
event 
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 adverse event began and no opportunity to 
decide whether to continue, interrupt, or withdraw treatment is possible. 
 
14.1.1.7 
Adverse Event Outcome 
An adverse event 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 14-4. 
Table 14-4 
Classifications for Outcome of an Adverse Event 
Classification 
Definition 
Recovered/Resolved 
Resolution of an adverse event with no residual signs or symptoms 
Recovered/Resolved 
With Sequelae 
Resolution of an adverse event with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an adverse event, such that it 
remains ongoing 
Fatal 
Outcome of an adverse event is death. “Fatal” will be used when death is at least 
possibly related to the adverse event. 
Unknown 
Outcome of an adverse event is not known (e.g., a subject lost to follow-up) 
 
14.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any adverse event, 
including clinically significant laboratory values related to study drug. In addition, the 


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investigator will describe whether any treatment was given for the adverse event. “Yes” is used if 
any treatment was given in response to an adverse event, and may include treatments such as 
other medications, hospitalization, surgery, or physical therapy. “No” indicates the absence of 
any kind of treatment for an adverse event. 
14.1.2 
Serious Adverse Events 
14.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any adverse event that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person's ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject’s parent or legal guardian signed the ICF, and the hospitalization or 
procedure was planned before the subject’s parent or legal guardian signed the ICF, the 
hospitalization or procedure should not be considered to indicate an SAE, unless an adverse 
event 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 adverse 
event (e.g., social hospitalization for purposes of respite care) should not be considered to 
indicate an SAE. 
Clarification will be made between the terms “serious” and "severe,” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject's life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
14.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through the Follow-up Visit or ETT Visit 
(if Follow-up Visit is not required; see Section 9.1.3), regardless of causality, will be reported by 
the investigator to Vertex Global Patient Safety (GPS) within 24 hours of identification. In 


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addition, all SAEs that occur after the study has concluded and are considered related to study 
drug will be reported to Vertex GPS within 24 hours of identification. 
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, 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: 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial 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. 
14.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug 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. 
14.2 
Administrative Requirements 
14.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint.   
Product complaints are to be reported to Vertex. 
14.2.2 
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 


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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. 
14.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject’s parent or legal guardian before study participation. The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with current 
ICH E6 GCP Guidelines and all applicable laws and regulations and will be subject to approval 
by Vertex or its designee. 
14.2.4 
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 protocol will be 
fully documented in the source documentation and in a protocol deviation log.  
14.2.5 
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.  
14.2.6 
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. 


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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. 
14.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 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. 
14.2.8 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
14.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
14.3 
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 per the 
current ICH E6 GCP Guidelines. 
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 


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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. 
14.4 
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. 
14.5 
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, adverse events, other 
observations, and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a CD or other electronic media will be placed in the investigator's study file. 
14.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 


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The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
14.7 
Publications and Clinical Study Report 
14.7.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations.  


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Beker LT, Russek-Cohen E, Fink RJ. Stature as a prognostic factor in cystic fibrosis 
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Konstan MW, Butler SM, Wohl MEB, Stoddard M, Matousek R, Wagener JS, et al. 
Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. 
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Mott LS, Park J, Murray CP, Gangell CL, de Klerk NH, Robinson PJ, et al. Progression 
of early structural lung disease in young children with cystic fibrosis assessed using CT. 
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Pillarisetti N, Williamson E, Linnane B, Skoric B, Robertson CF, Robinson P, et al. 
Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am J 
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Ramsey KA, Ranganathan S. Interpretation of lung function in infants and young 
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Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, et 
al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after 
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Leeuwen L, Fitzgerald DA, Gaskin KJ. Liver disease in cystic fibrosis. Paediatr Respir 
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Long FR, Williams RS, Castile RG. Structural airway abnormalities in infants and young 
children with cystic fibrosis. J Pedia. 2004;144(2):154-61. 
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Martínez TM, Llapur CJ, Williams TH, Coates C, Gunderman R, Cohen MD, et al. High-
resolution computed tomography imaging of airway disease in infants with cystic 
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Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, et al. Risk factors for 
bronchiectasis in children with cystic fibrosis. N Engl J Med. 2013;368(21):1963-70. 
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Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW. Early pulmonary 
inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med. 
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Sly PD, Brennan S, Gangell C, de Klerk N, Murray C, Mott L, et al. Lung disease at 
diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Respir Crit 
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Starner TD, McCray PB, Jr., American College of P, American Physiological S. 
Pathogenesis of early lung disease in cystic fibrosis: a window of opportunity to eradicate 
bacteria. Ann Intern Med. 2005;143(11):816-22. 
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Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, et al. Longitudinal 
development of mucoid Pseudomonas aeruginosa infection and lung disease progression 
in children with cystic fibrosis. JAMA. 2005;293(5):581-8. 
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Koch C. Early infection and progression of cystic fibrosis lung disease. Pediatr Pulmonol. 
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Pencharz PB, Durie PR. Pathogenesis of malnutrition in cystic fibrosis, and its treatment. 
Clin Nutr. 2000;19(6):387-94. 
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Peterson ML, Jacobs DR, Milla CE. Longitudinal changes in growth parameters are 
correlated with changes in pulmonary function in children with cystic fibrosis. Pediatrics. 
2003;112(3):588-92. 
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Sharma R, Florea VG, Bolger AP, Doehner W, Florea ND, Coats AJ, et al. Wasting as an 
independent predictor of mortality in patients with cystic fibrosis. Thorax. 
2001;56(10):746-50. 
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Döring G, Hoiby N. Early intervention and prevention of lung disease in cystic fibrosis: a 
European consensus. J Cystic Fibros. 2004;3(2):67-91. 
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Sims EJ, Clark A, McCormick J, Mehta G, Connett G, Mehta A. Cystic fibrosis 
diagnosed after 2 months of age leads to worse outcomes and requires more therapy. 
Pediatrics. 2007;119(1):19-28. 
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Grasemann H, Ratjen F. Early lung disease in cystic fibrosis. Lancet Respir Med. 
2013;1(2):148-57. 
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Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator's Brochure 
Investigator's Brochure, Version 12.0. Report date: 08 May 2015. 
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Metrum Research Group. Report K199. Population pharmacokinetics of ivacaftor in 
pediatric subjects with cystic fibrosis and a CFTR gating mutation. Report date: 20 
August 2014. 
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Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling 
of clearance in children. Clin Pharmacokinet. 2006;45(7):683-704. 
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Developmental pharmacology--drug disposition, action, and therapy in infants and 
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modelling covariate effects. Eur J Pediatr. 2006;165(12):819-29. 
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Rowe SM, Accurso F, Clancy JP. Detection of cystic fibrosis transmembrane 
conductance regulator activity in early-phase clinical trials. Proc Am Thorac Soc. 
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Wilschanski M, Zielenski J, Markiewicz D, Tsui L-C, Corey M, Levison H, et al. 
Correlation of sweat chloride concentration with classes of the cystic fibrosis 
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age in cystic fibrosis and normal populations: further investigations in equivocal cases. 
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Cystic Fibrosis Foundation. Sweat Test. Available at: https://www.cff.org/What-is-
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Farrell PM, White TB, Ren CL, Hempstead SE, Accurso FJ, Derichs N. Diagnosis of 
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weight and length predict growth faltering better than velocity measures in infants with 
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Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, et al. 
Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl 
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Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. 
Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas 
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Tramper-Stranders GA, Wolfs TFW, Fleer A, Kimpen JLL, van der Ent CK. 
Maintenance azithromycin treatment in pediatric patients with cystic fibrosis. Pediatr 
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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  
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Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
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Davis SD, Brody AS, Emond MJ, Brumback LC, Rosenfeld M. Endpoints for clinical 
trials in young children with cystic fibrosis. Proc Am Thorac Soc. 2007;4(4):418-30. 
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Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: Pseudomonas 
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Kalish LA, Waltz DA, Dovey M, Potter-Bynoe G, McAdam AJ, LiPuma JJ, et al. Impact 
of Burkholderia dolosa on lung function and survival in cystic fibrosis. Am J Respir Crit 
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West SE, Zeng L, Lee BL, Kosorok MR, Laxova A, Rock MJ, et al. Respiratory 
infections with Pseudomonas aeruginosa in children with cystic fibrosis. JAMA. 
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Weintraub A, Blau H, Mussaffi H, Picard E, Bentur L, Kerem E, et al. Exocrine 
pancreatic function testing in patients with cystic fibrosis and pancreatic sufficiency: A 
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Bruzzese E, Raia V, Gaudiello G, Polito G, Buccigrossi V, Formicola V, et al. Intestinal 
inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic 
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Filbrun AG, Lumeng CN, Nasr SZ. Infant pulmonary function testing guides therapy in 
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Ranganathan SC, Stocks J, Dezateux C, Bush A, Wade A, Carr S, et al. The evolution of 
airway function in early childhood following clinical diagnosis of cystic fibrosis. Am J 
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Frey U. Clinical applications of infant lung function testing: does it contribute to clinical 
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Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, et al. 
Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected 
with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2010;303(17):1707-
15. 
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Cystic Fibrosis Foundation. 2013 Patient Registry Annual Data Report. Bethesda, MD: 
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Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 
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Lala M WY, Jadhav P, Gobburu J. Implementation of a pharmacokinetic quality standard 
to improve pediatric trial design. . Presented at: America Conference on Pharmacometrics 
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Centers for Disease Control and Prevention. Growth charts. Available at: 
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Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
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Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 
 


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16 
APPENDIX A: CFTR MUTATIONS INCLUDED IN THE STUDY 
Subjects who have 1 of the following ivacaftor-responsive CFTR mutations on at least 1 allele 
will be considered eligible for enrollment in this study in regions where ivacaftor is approved for 
use in subjects 4 months of age and older with an ivacaftor-responsive mutation per Inclusion 
Criterion 2:  
The list below represents acceptable mutations, which are detectable by a genotyping assay or 
other method (e.g., sequencing) performed to applicable national standards; however, this list 
may not include every eligible mutation, and investigators should refer to the currently approved 
regional/local label or contact the medical monitor regarding other mutations that may also meet 
study eligibility criteria. 
Table 16-1 
List of CFTR Gene Mutations that Produce CFTR Protein and are 
Responsive to Ivacaftor 
711+3A→G 
F311del 
I148T 
R75Q 
S589N 
2789+5G→A 
F311L 
I175V 
R117C 
S737F 
3272-26A→G 
F508C 
I807M 
R117G 
S945L 
3849+10kbC→T 
F508C; S1251N
a 
I1027T 
R117H 
S977F 
A120T 
F1052V 
I1139V 
R117L 
S1159F 
A234D 
F1074L 
K1060T 
R117P 
S1159P 
A349V 
G178E 
L206W 
R170H 
S1251N 
A455E 
G178R 
L320V 
R347H 
S1255P 
A1067T 
G194R 
L967S 
R347L 
T338I 
D110E 
G314E 
L997F 
R352Q 
T1053I 
D110H 
G551D 
L1480P 
R553Q 
V232D 
D192G 
G551S 
M152V 
R668C 
V562I 
D579G 
G576A 
M952I 
R792G 
V754M 
D924N 
G970D 
M952T 
R933G 
V1293G 
D1152H 
G1069R 
P67L 
R1070Q 
W1282R 
D1270N 
G1244E 
Q237E 
R1070W 
Y1014C 
E56K 
G1249R 
Q237H 
R1162L 
Y1032C 
E193K 
G1349D 
Q359R 
R1283M 
 
E822K 
H939R 
Q1291R 
S549N 
 
E831X 
H1375P 
R74W 
S549R 
 
a 
Complex/compound mutation where a single allele of the CFTR gene has multiple mutations; these exist 
independent of the presence of mutations on the other allele. 
Subjects with the R117H genotype should have the 5T variant or a sweat chloride value 
≥60 mmol/L by quantitative pilocarpine iontophoresis. 


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17 
APPENDIX B: SELECTION OF STARTING DOSE FROM DIFFERENT 
MODELS 
Steady-state AUC0-12 exposures for different weight and age groups were simulated to select the 
starting ivacaftor doses from the available ivacaftor doses of 5.7, 11.4, 17.1, 22.8, and 25 mg 
q12h. These simulations used 4 different models to account for uncertainty in CYP3A maturation 
possibilities, which impacts the exposures for this age range as shown in Figure 17-1 (Report 
P292). The ivacaftor starting doses presented in Table 17-1 were selected to ensure that the 
highest predicted exposures from the 4 models were within the range previously shown to be 
safe and efficacious in adults. The majority of predicted exposures for all models exceeds the 
mean AUC0-12 exposure for the adult 25 mg dose of 955.6 ng-h/mL (Study 101 CSR, Table 
14.4.2.1), which provided efficacy as evidenced by improvement in sweat chloride. 
Figure 17-1 
Selection of Starting Dose From Different Models 
 
5.7 mg q12h 
 
11.4 mg q12h 
 
 
 
Source: Report P292 
AUC0-12: area under the concentration versus time curve from the time of dosing to 12 hours; PBPK: 
physiologically-based pharmacokinetic; q12h: every 12 hours; yr: year 
Note: Marker lines: Green line indicates the median of the adult values. Orange lines indicate 5th and 95th percentiles 
of the adult values. Red line is the 95th percentile of 6- to 11-year-old values from Study VX08-770-103 (Report 
K199 2014). Boxplots: the median is represented by a horizontal line, and the interquartile range (IQR) is 
represented by a box. The whiskers represent the largest and smallest values within 1.5 × IQR. 


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Table 17-1 
Starting Dose Table 
Age 
Weight Range 
Starting Dose 
1 month 
>3 kg 
5.7 mg q12h  
2 months 
>3 to <5 kg 
5.7 mg q12h  
2 months 
>5 kg 
11.4 mg q12h 
3 months 
>5 kg 
11.4 mg q12h 
Source: Report P292 
Note: All subjects must have gestational age ≥38 weeks and weigh ≥3 kg. Subjects 3 months of age must weigh 
≥5 kg on Day 1. 




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18.2 
Investigator Signature Page 
Protocol #: 
VX15-770-124 
Version #: 
4.0 
Version Date: 
01 April 2021 
Study Title: A Phase 3, 2-Part, Open-label Study to Evaluate the Safety, Pharmacokinetics, 
and Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis Who Are Less Than 
24 Months of Age at Treatment Initiation and Have an Ivacaftor-responsive CFTR Mutation 
 
I have read Protocol VX15-770-124, Version 4.0, and agree to conduct the study according to its 
terms. I understand that all information concerning ivacaftor and this protocol supplied to me by 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential.   
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 




Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
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Summary of Changes to Cystic Fibrosis Clinical Study Protocols 
Vertex is currently evaluating several CFTR modulators in clinical studies for the treatment of 
cystic fibrosis (CF), a serious and life-threatening disease. In completed studies, treatment with 
these CFTR modulators has generally resulted in rapid, robust, clinically meaningful, and 
statistically significant improvements in clinical measures, and are generally safe and well 
tolerated. Adverse events (AEs) seen with these treatments are mostly consistent with common 
manifestations of CF disease or with common illnesses in CF subjects.  
During this COVID-19 pandemic, the safety of the subjects, investigators, and site personnel 
participating in these clinical studies is Vertex’s first priority, thus it is important to minimize 
any unnecessary risk to COVID-19 exposure through travel to study sites. This addendum 
summarizes the measures taken for ongoing CF clinical studies. These operational adjustments 
were implemented to align with Health Authority guidance ensuring the protection of subjects, 
investigators, and site personnel while maintaining compliance with GCP and minimizing impact 
to the integrity of the studies. Overall, the benefit-risk of these studies remains favorable. 
Vertex recommends that subjects and sites refer to local guidance regarding travel restrictions. 
There are no operational changes to the study protocols for subjects who can travel to the study 
sites for their visits. However, to ensure continued safety of subjects who cannot travel to the 
study sites for their visits (for any reason due to COVID-19), specific alternative measures are 
being implemented to minimize the risk of exposure to COVID-19 (see table below). As the 
COVID-19 pandemic evolves, Vertex will continue to assess the need for additional actions to 
ensure the safety of all involved in these clinical studies. 
Addendum Version 3.0 summarizes additional measures taken for these ongoing CF clinical 
studies (see table below) to ensure continued safety. 
 













SAP_001.pdf: 
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VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX15-770-124 
(Final Analysis) 
 
A Phase 3, 2-Part, Open-label Study to Evaluate the Safety, 
Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Subjects 
With Cystic Fibrosis Who Are Less Than 24 Months of Age at 
Treatment Initiation and Have an Ivacaftor-responsive CFTR Mutation 
 
Author of SAP: 
 
 
 
Version: Version 3.0 
Version Date of SAP: 07 December 2022 
 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
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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1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 2 
3 
Introduction ...................................................................................................................... 6 
4 
Study Objectives .............................................................................................................. 6 
4.1 
Primary Objectives ..................................................................................................... 6 
4.2 
Secondary Objectives ................................................................................................. 7 
5 
Study Endpoints ............................................................................................................... 7 
5.1 
Efficacy Endpoint (Part B and Part A/B Cohort 8) .................................................... 7 
5.1.1 
Primary Efficacy Endpoint ................................................................................. 7 
5.1.2 
Secondary Efficacy Endpoint ............................................................................. 7 
5.2 
Safety Endpoints ......................................................................................................... 9 
6 
Study Design ..................................................................................................................... 9 
6.1 
Overall Design ............................................................................................................ 9 
6.2 
Sample Size and Power ............................................................................................ 15 
6.3 
Randomization .......................................................................................................... 17 
6.4 
Blinding and Unblinding .......................................................................................... 17 
7 
Analysis Sets ................................................................................................................... 17 
7.1 
All Subjects Set ........................................................................................................ 17 
7.2 
Full Analysis Set (Combined Part B and Part A/B Cohort 8 only) .......................... 17 
7.3 
Safety Set .................................................................................................................. 17 
8 
Statistical Analysis ......................................................................................................... 17 
8.1 
General Considerations ............................................................................................ 17 
8.2 
Background Characteristics ...................................................................................... 19 
8.2.1 
Subject Disposition ........................................................................................... 19 
8.2.2 
Demographics and Baseline Characteristics ..................................................... 20 
8.2.3 
Prior and Concomitant Medications ................................................................. 21 
8.2.4 
Study Drug Exposure ........................................................................................ 22 
8.2.5 
Study Drug Compliance (Combined Part B and Part A/B Cohort 8 only) ....... 22 
8.2.6 
Important Protocol Deviations/Violations ........................................................ 23 
8.3 
Efficacy Analysis (Combined Part B and Part A/B Cohort 8 only) ......................... 23 
8.3.1 
Analysis of Primary Efficacy Variable ............................................................. 23 
8.3.2 
Analysis of Secondary Efficacy Variable ......................................................... 23 
8.3.3.1 
Definition of Variables ............................................................................... 24 
8.4 
Safety Analysis ......................................................................................................... 26 


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8.4.1 
Adverse Events ................................................................................................. 26 
8.4.2 
Clinical Laboratory ........................................................................................... 27 
8.4.3 
Electrocardiogram ............................................................................................ 27 
8.4.4 
Vital Signs ........................................................................................................ 27 
8.4.5 
Physical Examination ....................................................................................... 28 
8.4.6 
Ophthalmological Examination ........................................................................ 28 
8.4.7 
Other Safety Analysis ....................................................................................... 28 
9 
Summary of Interim and IDMC Analyses .................................................................. 28 
9.1 
Interim Analysis ....................................................................................................... 28 
9.2 
IDMC Analysis ......................................................................................................... 28 
10 References ....................................................................................................................... 29 
11 List of Appendices .......................................................................................................... 30 
Appendix A: Schedule of Assessments.............................................................................. 30 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ........... 42 
Appendix C: Imputation Rules for Missing AE dates ....................................................... 43 
Appendix D: Analysis Visit Window Mapping Rules for Safety and Efficacy Assessments
 .................................................................................................................................. 44 
 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) Methods for the final analysis of Study VX15-770-124 is 
based on the approved clinical study protocol (CSP), Version 4.0, dated 01 April 2021, final 
electronic case report form (eCRF) completion guidelines, Version 7.0, dated 18 April 2022, 
and approved eCRF, Version 10.0, dated 28 March 2022. 
Study VX15-770-124 is a Phase 3, 2-Part, Open-label Study to evaluate the safety, 
pharmacokinetics, and pharmacodynamics of ivacaftor in subjects with cystic fibrosis who 
are less than 24 months of age at treatment initiation and have an Ivacaftor (IVA)-responsive 
CFTR mutation. This SAP (Methods) documents the planned final statistical analysis of 
efficacy and safety endpoints defined in the study protocol of VX15-770-124.  
The Vertex Biometrics Department will perform the final statistical analysis of the efficacy 
and safety data; SAS® Version 9.4 Software (SAS Institute, Cary, North Carolina, USA) or 
higher will be used to generate all statistical outputs (tables, figures, listings, and datasets).   
The SAP (Methods) for the final analysis will be finalized and approved before the database 
lock for the final analysis. Any changes made to the SAP Methods after the clinical database 
lock has occurred will be documented in the clinical study report for this study. 
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). 
4 
STUDY OBJECTIVES  
4.1 
Primary Objectives 
                        
Part A: 
 
 
 
 
 
 
 
 
 
Part B:  
 
 
Part A/B: 
  
 
• To evaluate the safety of ivacaftor treatment in subjects with cystic fibrosis 
(CF) who are <24 months of age at treatment initiation and have a CF 
transmembrane conductance regulator (CFTR) gene gating mutation  
• To evaluate the pharmacokinetics (PK) of ivacaftor and metabolites 
hydroxymethyl-ivacaftor (M1) and ivacaftor carboxylate (M6) in subjects 
with CF who are <24 months of age at treatment initiation and have a 
CFTR gating mutation 
 
• 
To evaluate the safety of ivacaftor treatment in subjects with CF who are 
<24 months of age at treatment initiation and have a CFTR gating mutation 
 
• To evaluate the safety of ivacaftor treatment in subjects with CF who are 1 
to <4 months of age at treatment initiation and have an ivacaftor-responsive 
CFTR mutation (consistent with the approved mutations in the region)  
• 
To evaluate the PK of ivacaftor and the ivacaftor metabolites M1 and M6 
in subjects with CF who are 1 to <4 months of age at treatment initiation 


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and have an ivacaftor-responsive CFTR mutation (consistent with the 
approved mutations in the region) 
4.2 
Secondary Objectives  
 
Part B: 
• To evaluate the PK of ivacaftor and metabolites M1 and M6 in subjects 
with CF who are <24 months of age at treatment initiation and have a 
CFTR gating mutation 
• 
To evaluate the pharmacodynamics (PD) of ivacaftor treatment in subjects 
with CF who are <24 months of age at treatment initiation and have a 
CFTR gating mutation  
Part A/B 
Cohort 8:  
• To evaluate the PD of ivacaftor treatment in subjects with CF who are 1 to 
<4 months of age at treatment initiation and have an ivacaftor-responsive 
CFTR mutation (consistent with the approved mutations in the region)   
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoint (Part B and Part A/B Cohort 8) 
5.1.1 
Primary Efficacy Endpoint  
Not applicable 
5.1.2 
Secondary Efficacy Endpoint  
Absolute change from baseline in sweat chloride  


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5.2 
Safety Endpoints 
Primary 
Endpoint for 
Part A 
 
• Safety, as determined by adverse events, clinical laboratory values 
(serum chemistry and hematology), standard 12-lead 
electrocardiograms (ECGs), vital signs, and ophthalmologic 
examinations (OEs) 
Primary 
Endpoint for 
Part B 
• Safety, as determined by adverse events, clinical laboratory values 
(serum chemistry and hematology), ECGs, vital signs, and OEs 
Primary 
Endpoint for 
Part A/B 
Cohort 8 
• Safety, as determined by adverse events, clinical laboratory values 
(serum chemistry and hematology), standard 12-lead ECGs, vital 
signs, and OEs 
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 3, 2-part, open-label study as depicted in Figure 6-1. This study is 
designed to evaluate the safety, PK, PD, and efficacy of ivacaftor in subjects with CF 
who are <24 months of age at treatment initiation (Day 1) and have an ivacaftor-
responsive CFTR mutation on at least 1 allele. Part A is designed to evaluate the safety 
and PK of multiple-dose administration of ivacaftor in subjects <24 months of age over 4 
days of dosing, and to confirm (or adjust if necessary) the doses for Part B. Part B is 
designed to evaluate the safety, PK, PD, and efficacy of ivacaftor in subjects <24 months 
of age over 24 weeks. Part A/B Cohort 8 is designed to evaluate the safety, PK, PD, and 
efficacy of ivacaftor in subjects with CF who are 1 to <4 months of age, ≥38 weeks 
gestation, weigh at least 3 kg at the time of treatment initiation (Day 1), and have an 
ivacaftor-responsive CFTR mutation (consistent with the approved mutations in the 
region) on at least 1 allele. Subjects will receive an initial low dose of ivacaftor (based on 
their Day 1 age and weight) up to Day 15, at which time the dose may be adjusted to 
better match the median adult exposure. Subjects are intended to remain on that dose until 
they are 4 months of age and at least 5 kg, after which the recommended age- and weight-
appropriate dose(s) will be administrated.  


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Part A: 
Subjects will be enrolled in Part A sequentially in the following cohorts: 
• Cohort 1: subjects aged 12 to <24 months 
• Cohort 2: subjects aged 6 to <12 months 
• Cohort 3: subjects aged 3 to <6 months 
 
Enrollment in Part A will begin with subjects in Cohort 1. Enrollment for subjects in 
Cohort 2 will begin after a review of safety and PK data for subjects from Cohort 1. 
Enrollment for subjects in Cohort 3 will begin after a review of safety and PK data for 
subjects in Cohort 2.   
PK data from each completed cohort in Part A will be used to update the population PK 
model and inform dose selection for the subsequent cohort before that cohort begins 
enrolling. If PK data from any cohort in Part A are insufficient to confirm the dose for that 
age group, additional subjects will be enrolled in the cohort until an appropriate dose is 
confirmed.  
Part A of this study includes: 
• Screening Period (Day -28 to Day -1) 
• Treatment Period (Day 1 to Day 5):  
o 25-mg (for subjects 5 to <7 kg on Day 1), 50-mg (for subjects 7 to <14 kg on Day 1), 
and 75-mg (for subjects 14 to <25 kg on Day 1) ivacaftor will be administered every 
12 hours (q12h) on Days 1 through 3 and 1 morning dose on Day 4. These doses may 
be amended at any time based on available PK data from previous cohorts, and may 
result in additional doses or different weight strata. Data from each cohort in Part A will 
be used to update the population PK model and inform dose predictions for each 
subsequent (younger) cohort. 
o Study visits will occur on Days 1, 4, and 5. 
o PK samples will be collected before the morning dose on Day 4, between 2 and 4 hours, 
between 6 to 8 hours, and between 24 and 60 hours after the Day 4 dose.  
o For subjects who prematurely discontinue treatment, a PK blood sample will be 
collected at the Early Termination of Treatment (ETT) Visit (within 5 days after the last 
dose of study drug). 
• Follow-up Telephone Call (Day 14) 
• Follow-up OE (within 8 weeks after the last dose of study drug). 
 
Subjects who prematurely discontinue treatment before their last scheduled dose in Part A 
will be required to complete the ETT Visit, Follow-up Telephone Call, and Follow-up OE.  
 
Part B: 
Subjects will be enrolled in Part B sequentially in the following cohorts based on age at 
Day 1 of Part B: 


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• Cohort 5: subjects aged 12 to <24 months 
• Cohort 6: subjects aged 6 to <12 months 
• Cohort 7: subjects aged 4 to <6 months 
 
Enrollment of subjects in Cohort 5 will begin following an assessment of: 
• Safety and PK data from Part A for subjects from Cohort 1 and confirmation of dose for 
subjects aged 12 to <24 months. 
 
Enrollment of subjects in Cohort 6 will begin after an assessment of:  
• Safety and PK data from Part A for subjects from Cohort 2 and confirmation of dose for 
subjects aged 6 to <12 months. 
• Safety data from Week 12 of Part B for at least 5 subjects in Cohort 5.  
 
Enrollment of subjects in Cohort 7 will begin with enrollment of subjects aged 4 to 
<6 months following an assessment of: 
• Safety and PK data from Part A for subjects from Cohort 3 and confirmation of dose in 
subjects aged 3 to <6 months.  
• Safety data from Week 12 of Part B for at least 5 subjects in Cohort 6.   
Subjects from Cohorts 2 or 3 who age out of the corresponding age cohort (Cohorts 6 or 7) in 
Part B at Day 1 may enroll in an older age cohort in Part B with the Vertex medical monitor’s 
permission. Otherwise, subjects who will age out of the corresponding age cohort may enroll in 
the Extension Study. 
 
Part B of this study includes: 
• Screening Period (Day -28 to Day -1) 
• Treatment Period (Day 1 to Week 24): 
o Starting doses in Cohorts 5 and 6 of 25-mg (for subjects 5 to <7 kg on Day 1), 50-mg 
(for subjects 7 to <14 kg on Day 1), and 75-mg (for subjects 14 to <25 kg on Day 1) 
ivacaftor will be administered q12h for 24 weeks (or other suitable starting dose based 
on safety and PK data from Part A). At each study visit the ivacaftor dose for each 
subject will be reassessed based on body weight and adjusted if necessary.  
o All subjects enrolled in Cohort 7 will receive a 25 mg dose of ivacaftor q12h until the 
subject reaches the age of 6 months. At each study visit after the age of 6 months, the 
ivacaftor dose for each subject will be reassessed based on body weight and adjusted, if 
necessary as above for Cohorts 5 and 6. 
o Study visits will occur on Day 1 and Weeks 2, 4, 8, 12, 18, and 24.  
o PK blood samples will be collected at the following time points:  
• Week 2: before the morning dose, between 2 and 4 hours and between 6 and 
8 hours after the morning dose 
• Week 8: before the morning dose and 1 and 4 hours after the morning dose 


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• Week 24: before the morning dose and between 2 and 4 hours after the 
morning dose  
 PK blood sampling at Week 24 is optional for subjects who undergo 
MBW (due to fasting requirements) 
• For subjects who prematurely discontinue treatment, a PK blood sample will 
be collected at the ETT Visit. 
o OEs will be performed at screening, Week 12, and Week 24.  
 
All subjects who complete 24 weeks of study drug treatment will be eligible to enroll in the 
open-label treatment arm of an Extension Study. In this study, subjects will receive 96 
additional weeks of ivacaftor treatment. The Follow-up Visit will not be required for subjects 
who enroll in the treatment arm of this study. 
Subjects who complete 24 weeks of study drug treatment who elect not to enroll in the 
treatment arm of the Extension Study will be required to complete the Follow-up Visit 
(4 weeks ± 7 days after the last dose of study drug) and will be eligible to enroll in the 
observational arm of the Extension Study. The Follow-up Visit will not be required in the 
event that the subject initiates treatment with commercially available ivacaftor within 
3 weeks of the Week 24 Visit.  
Subjects who prematurely discontinue treatment before their last scheduled dose will be 
required to complete the ETT Visit, Follow-up Visit, and Follow-up OE. The Follow-up visit 
will not be required: 
o If the ETT Visit occurs 3 weeks or later after the last dose of study drug. 
o In the event that the subject initiates treatment with commercially available ivacaftor 
within 3 weeks of the ETT Visit.  
Subjects who prematurely discontinue study drug treatment will be eligible to enroll in the 
observational arm of the Extension Study. Subjects who are eligible will enroll in the 
Extension Study as soon as enrollment is open. Subjects enrolling into the Extension Study 
within 24 weeks after the last dose of study drug are not required to have the Follow-up OE 
(the OE will be performed in the Extension Study). 


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Figure 6-1 
Schematic of Study Design 
 
 
Part A/B Cohort 8: 
Subjects 1 to <4 months of age, ≥38 weeks gestation, and weighing at least 3 kg at the time 
of treatment initiation (Day 1), will receive an initial low dose of ivacaftor (5.7 mg q12h or 
11.4 mg q12h based on their Day 1 age and weight) from Day 1 up to Day 15 (Figure 6-2). 
Subjects 3 months of age must weigh ≥5 kg on Day 1. This initial low dose is based on prior 
age- and weight-based simulations of exposure which accounts for potential variability in 
metabolic enzyme maturation affecting exposures. The initial dose is expected to result in 
exposures within or below the adult exposure range. On Day 4, PK samples from each 
subject will be collected before and after dosing and analyzed to determine the exposure and 
assess whether the initial dose needs to be adjusted to better match the median adult 
exposure.  
Part A/B Cohort 8 of this study includes: 
• Confirmed genotype; genotype testing is expected to be initiated prior to screening and 
results must be available prior to Day 1 
• Screening Period (Day -28 to Day -14) 


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o Due to limitations in the volume of blood that should be collected from the 1- to 
<4-month-old age group in a 28-day span, screening should be completed at least 
14 days prior to Day 1 (treatment initiation) 
• Initial Treatment Period (Day 1 up to Day 15):  
o Subjects will receive an initial low dose of ivacaftor (5.7 mg q12h or 11.4 mg q12h 
based on their Day 1 age and weight) from Day 1 up to Day 15, as follows:  
Age 
Weight Range 
Starting Dose 
1 month 
≥3 kg 
5.7 mg q12h 
2 months 
≥3 to <5 kg 
5.7 mg q12h 
2 months 
≥5 kg 
11.4 mg q12h 
3 months 
≥5 kg 
11.4 mg q12h 
All subjects must have gestational age ≥38 weeks and 
weigh ≥3 kg. Subjects 3 months of age must weigh 
≥5 kg on Day 1. 
o Study visits will occur on Days 1, 4, and 15. 
o Follow-up Telephone Call (Day 1 evening) 
o PK samples will be collected before the morning dose on Day 4, between 2 to 4 hours 
and between 6 to 8 hours after the Day 4 morning dose.  
o The subject’s Day 4 PK data will be used to calculate exposure to determine a dose 
that is expected to bring the exposure for the subject closest to the adult median. This 
potential dose adjustment will be communicated in writing to the principal 
investigator for administration to the subject on Day 15. 
o At the Day 15 Visit, a trough PK sample will be collected before the morning dose. 
The ivacaftor dose will be adjusted if necessary, to either 5.7, 11.4, 17.1, 22.8, or 
25 mg, and the adjusted dose will be administered q12h starting with the evening dose 
on Day 15. 
o If all PK samples collected on Day 4 are missing or cannot be analyzed, PK samples 
collected on Day 15 will be used to assess whether the initial dose should be adjusted 
at the Week 4 Visit. 
• Subsequent Treatment Period (Day 16 to Week 24):  
o Follow-up Telephone Call (Day 17) 
o Study visits will occur on Weeks 4, 8, 12, 18, and 24. 
o The subject is intended to remain on the same dose from Day 15 until the subject is 
4 months of age and at least 5 kg, after which the recommended age- and weight-
appropriate dose(s) will be administered.  




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Part B: A minimum of 15 subjects: 
• minimum of 5 subjects aged 12 to <24 months 
• minimum of 5 subjects aged 6 to <12 months 
• minimum of 5 subjects aged 4 to <6 months  
Note: Subjects who have an R117H-CFTR mutation will only be enrolled in regions where 
ivacaftor is approved for use in subjects 2 through 5 years of age with an R117H-CFTR 
mutation. 
Part A/B Cohort 8:  
• A minimum of 6 up to approximately 10 subjects aged 1 to <4 months, ≥38 weeks 
gestation, and at least 3 kg at the time of treatment initiation (Day 1)  
• Subjects who have an ivacaftor-responsive mutation on at least 1 allele will be eligible to 
enroll in regions where ivacaftor is approved (consistent with the approved mutations in 
the region). 
There are estimated to be approximately 1800 CF births per year worldwide. If it is assumed 
that 61% of these cases are detected by newborn screening (NBS) and 5% carry a gating 
mutation, then there will be approximately 50 patients available for enrollment in this study 
each year from NBS (1800 × 0.6 × 0.05). There are estimated to be approximately 70 children 
between 0 to 2 years of age with a gating mutation not diagnosed by NBS who are available 
for enrollment in this study each year (1800 × 2 × 0.4 × 0.05). If 15% to 20% of the entire 
available global patient population is enrolled, this would allow enrollment of approximately 
20 subjects per year. There is often a delay in the time it takes for patients to be referred to and 
evaluated at a CF center following diagnosis, as well as time needed for parents to process the 
CF diagnosis and to become informed about the disease. Thus, feedback from CF pediatricians 
indicates there will be some difficulty in enrolling this CF population of <2 year-olds, 
particularly those <2 to 3 months of age.  
Relatively rich PK samples (4 samples at steady-state) will be collected in Part A, which will 
provide sufficient PK data to inform the population PK model, while accounting for blood 
volume restrictions in this vulnerable age range. In addition to evaluation of PK in Part A, this 
study will collect PK samples from all subjects in Part B through 24 weeks. PK evaluation will 
consist of a population PK approach, utilizing the current population PK model and existing 
data for patients ≥24 months of age. The between-subject variability estimate for ivacaftor in 
subjects with CF 2 through 5 years of age from Study 108 is a coefficient of variation (CV) of 
34% to 41% for area under the concentration versus time curve (AUC). Based on a review of 
model-based pediatric simulations with a range of variability, the variability estimate of 
ivacaftor from Study 108, and the PK collection scheme, the number of subjects planned for 
enrollment is expected to provide reasonably precise estimates of key PK parameters using a 
population PK approach. The inclusion of data from pediatric patients ≥24 months of age with 
the population PK approach is expected to reduce the required sample size.  
Given the above feasibility assessment and PK considerations, a minimum of 15 subjects in 
Part A and 15 subjects in Part B, and 6 up to approximately 10 subjects in Part A/B Cohort 8 


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is considered an appropriate sample size for evaluation of the PK and safety of ivacaftor in 
subjects <24 months of age. 
 
For Part A/B Cohort 8, PK samples (3 samples) will be collected on the Day 4 and Week 8 
Visits to provide sufficient PK data to assess exposure, while accounting for blood volume 
restrictions in this vulnerable age range. In addition to evaluation of PK on Day 4, trough PK 
samples will be collected from all subjects in Part A/B at each visit through 24 weeks.  
 
6.3 
Randomization 
This study is an open-label study. Randomization is not required because all subjects will be 
treated identically within a single cohort. 
6.4 
Blinding and Unblinding 
This study is open-labeled and all subjects will receive ivacaftor.  
 
7 
ANALYSIS SETS 
7.1 
All Subjects Set 
The All Subjects Set will be defined separately for Part A, and for the combined Part B and 
Part A/B Cohort 8 as all subjects who are eligible for study enrollment or received at least 
1 dose of study drug. This analysis set will be used for all individual subject data listings and 
the disposition summary table, unless specified otherwise. 
7.2 
Full Analysis Set (Combined Part B and Part A/B Cohort 8 only) 
The Full Analysis Set (FAS) for combined Part B and Part A/B Cohort 8 will be defined as 
all subjects who are eligible for study enrollment and receive at least 1 dose of study drug in 
Part B or Part A/B cohort 8. 
7.3 
Safety Set 
The Safety Set will be defined separately for Part A, and for the combined Part B and Part 
A/B Cohort 8 as all subjects who received at least 1 dose of study drug. The Safety Set will 
be used for all safety analyses with subjects from Part A, and subjects from combined Part B 
and Part A/B Cohort 8, unless specified otherwise. 
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The Schedule of Assessments is provided in Appendix A. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables. 
All individual subject data for subjects who were eligible for study enrollment or received at 
least 1 dose of study drug will be presented in individual subject data listings. 


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Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum value (min), and maximum value (max), and 95% confidence intervals 
[CI], as appropriate. 
Categorical variables will be summarized using counts, percentages, and 95% CI (as 
appropriate). 
Baseline value, unless specified otherwise, will be defined separately for Parts A, and 
combined Part B and Part A/B Cohort 8 as the most recent non-missing measurement 
(scheduled or unscheduled) collected before the first dose of study drug in the respective 
study part.  
Change (absolute change) from baseline will be calculated as 
Postbaseline value − Baseline value. 
Treatment-emergent (TE) Period  
For Part A the TE period will include the time period starting from the first dose date of the 
study drug to the Follow-up Telephone Call, or the last dose date + 28 days for subjects who 
do not have a Follow-up Telephone Call. The TE period will be used for safety analyses 
unless specified otherwise. 
For the combined Part B and Part A/B Cohort 8 the TE period will include the time period 
starting from the first dose date of the study drug to the Follow-up Visit, or to the end of 
study date for subjects who roll over into the Extension Study and for whom the Follow-up 
Visit is not required.  The last dose date + 28 days will be used as the TE period end date for 
subjects who do not have a Follow-up Visit or an end of study date. The TE period will be 
used for safety analyses unless specified otherwise. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules (Combined Part B 
and Part A/B Cohort 8 only). 
• In the derivation of baseline measurements. 
• In the derivation of maximum/minimum on-treatment values and 
maximum/minimum change from baseline values for safety analyses. 
• In individual subject data listings as appropriate. 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided 
in Appendix D.  The windows will be applied using the following rules for both scheduled 
and unscheduled visits. If no measurement is available within a visit window, the assessment 
will be considered missing for the visit. If there is more than one measurement available 
within the same visit window, the following rules will be used:  
• For all safety parameters, if there are multiple measurements within a visit window, then 
1) the record closest to the target day will be used, with the exception of the threshold 
analysis in which the worst record will be used; 2) if there are multiple records within the 
same distance of the target day, the latest record will be used; or 3) the Safety Follow-Up 
(SFU) visit will not be windowed; instead, the nominal visit will be used in relevant 


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analyses; 4) the Follow-Up OE visit will not be windowed; instead, the nominal visit will 
be used in relevant analyses. 
• For all efficacy parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used. Otherwise, 
− if there are no measurements at the scheduled visit, then the record closest to the 
target day will be used;  
− if there are multiple records with the same distance to the target day, the latest record 
will be used.   
− assessments at the ETT visit will follow the windowing rules for regular visits.  
− assessments at SFU visit will follow the windowing rules for regular visits if they fall 
within the upper boundary of the window for the last scheduled visit; it will remain as 
the SFU if it goes beyond the upper boundary of the window for the last scheduled 
visit. 
 
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 for hypothesis testing. 
All analyses will be done separately for Part A, and combined Part B and Part A/B Cohort 8, 
as applicable. Unless otherwise specified, summary tables will be presented by cohort and 
overall. 
8.2 
Background Characteristics  
Background characteristics will be summarized separately for Part A, and for the combined 
Part B and Part A/B Cohort 8. Summary tables will be presented by cohort and overall. 
8.2.1 
Subject Disposition 
Part A: 
The number of subjects in the following categories will be summarized:  
• Enrolled  
• Enrolled and dosed (Safety Set) 
The number and percentage (based on the Safety Set) of subjects in each of the following 
disposition categories will be summarized: 
• Last Treatment Visit completed (Day 1, Day 2, Day 3, Day 4, and Day 5). 
• Completed treatment 
• Prematurely discontinued the treatment and the reason for discontinuation  
• Completed study  


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• Prematurely discontinued the study and the reason for discontinuation  
Combined Part B and Part A/B Cohort 8: 
The number of subjects in the following categories will be summarized:  
• Enrolled 
• Enrolled and dosed (Safety Set) 
• FAS 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized: 
• Last Treatment visit completed (Day 1, Day 4, Day15/Week 2, Week 4, Week 8, 
Week 12, Week 18 and Week 24). 
• Completed treatment 
• Prematurely discontinued the treatment and the reason for discontinuation  
• Completed study  
• Prematurely discontinued the study and the reason for discontinuation  
• Enrolled in a rollover extension study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation.  
  
8.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized for Part A, 
and combined Part B and Part A/B Cohort 8, respectively, based on the Safety Set. 
Demographic data will include the following: 
• Age (in months) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• 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: 


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For the combined Part B and Part A/B Cohort 8 only, the following disease characteristics 
will also be summarized: 
• Age at CF diagnosis 
• Maternal/pregnancy history: complications in pregnancy, gestational age at delivery, 
method of delivery 
• Does subject have abnormal liver function tests documented since birth? 
• Any use (yes or no) of the following medications from birth to screening will be 
assessed: inhaled tobramycin, inhaled aztreonam, inhaled colimycin, inhaled 
hypertonic saline, dornase alfa, ibuprofen, azithromycin, and pancreatic enzyme 
replacement therapy.  
• Historical pancreatic test measurements  
Medical history will be summarized by MedDRA system organ class (SOC) and preferred 
term (PT).  
No statistical tests will be carried out to evaluate any baseline imbalance between dose 
groups. 
8.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and categorized as the following: 
Prior medication: any medication that started before the first dose date of study drug, 
regardless of when the medication ended. 
Concomitant medication: medication continued or newly received on or after the first dose 
date of study drug through the end of TE period. 
Post-treatment medication (combined Part B and Part A/B Cohort 8 only): medication 
continued or newly received after the TE period. 


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A given medication may be classified as follows: prior, concomitant, post-treatment, both 
prior and concomitant, both concomitant and post-treatment, or prior, concomitant, and 
post-treatment.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date, concomitantly, or after the TE 
period, it will be classified as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by preferred name.  
For the final analysis, medications received during the period from the first dose of study 
drug through the end of Part A participation will be summarized as concomitant medications 
in Part A. A similar rationale will be adopted for concomitant medications in the combined 
Part B and Part A/B Cohort 8.  
Summaries of medications will be based on the Safety Set.  
Post-treatment medications will be listed by subject.  
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix B. 
8.2.4 
Study Drug Exposure  
Duration of study drug exposure (in days) will be calculated as: last dose date – first dose 
date + 1 day, regardless of study drug interruption.  
Exposure summaries will be based on the Safety Set. 
8.2.5 
Study Drug Compliance (Combined Part B and Part A/B Cohort 8 
only)  
Study drug compliance based on the number of sachets taken will be calculated as: 
100 × [(total number of sachets dispensed) – (total number of sachets returned)]/ (total 
number of sachets planned to be taken per day × duration of study drug exposure in days). 
The maximum percentage of sachets taken will be 100%. 
 
Note: For Part A/B Cohort 8 only, multiple sachets of 5.7 mg will be used to achieve doses of 
11.4, 17.1, and 22.8 mg. Total number of sachets planned to be taken per day to achieve each 
dose is: 
 
Doses (q12h)  Total number of sachets of planned to be taken per day 
5.7mg              2 
11.4mg            4 
17.1mg            6 
22.8mg            8 


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Study drug compliance based on study drug exposure will be calculated as: 100 × [1 − (total 
number of days of any study drug interruption) / (duration of study drug exposure in days)].  
Study drug compliance will be summarized descriptively by the number of subjects (n), 
mean, SD, SE, median, min, and max. They will also be summarized in categories: <80% 
and ≥80% using frequency tables. 
Study drug compliance summaries will be based on the Safety Set. 
8.2.6 
Important Protocol Deviations/Violations 
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of key study data or that may 
significantly affect a subject's rights, safety, or well-being. IPD rules will be developed and 
finalized before database lock. 
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
• 
Violation of subjects rights, safety or well-being 
• 
Subject entered the study despite violation of any inclusion or exclusion criteria 
• 
Subject was less than 80% compliant with study medications 
• 
Subject received excluded concomitant medications 
• 
Subject received the wrong treatment or incorrect doses 
• 
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.  
IPDs will be presented as an individual subject data listing only. 
8.3 
Efficacy Analysis (Combined Part B and Part A/B Cohort 8 only) 
Statistical methodology will be restricted to descriptive statistics only. All efficacy analyses 
described in this section will be based on the FAS, unless specified otherwise. Summary 
tables will be presented by visit for each cohort and overall, for combined Part B and Part 
A/B Cohort 8 based on the FAS. 
 
8.3.1 
Analysis of Primary Efficacy Variable 
Not applicable. 
8.3.2 
Analysis of Secondary Efficacy Variable 
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 qualified study sites using an 
approved Macroduct® (Wescor, Logan, UT) collection device. Sweat samples will be sent to 
a central laboratory for testing and interpretation of results. Individual sweat test results will 


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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. 
Sweat chloride will be collected at visits as indicated in Appendix A. Absolute change from 
baseline in sweat chloride will be calculated as: 
Base
Right
Left
SW
SW
SW
mean
−
)
,
(
, where SWLeft 
and SWRight are the measurements obtained on the left and right arms, respectively, at a 
particular visit and SWbase is the mean of right and left baseline measurements. If 1 of the 2 
measurements at a time point is missing, the other will be used as the mean. If both are 
missing, then sweat chloride is missing for that visit.  
Note:  A volume of ≥15 μL is required for an accurate determination                                     
of sweat chloride.  Any results reported having volume <15 μL will not be included in 
analysis. In addition, sweat chloride with concentration >160 mmol/L will not be included in 
analysis.  
Definition of Baseline: Only results obtained from sample collections completed prior to the 
first administration of study drug will be considered as baseline results. If sweat chloride 
collection was completed for 1 arm prior to the first dose and completed for the other arm 
after the first dose, the baseline will consist of a single measurement. If both sweat 
collections were completed after the first dose, the baseline sweat chloride result will be 
considered missing for analysis purposes.  
Sweat chloride results (including changes from baseline) will be analyzed as a continuous 
variable using descriptive summary statistics and presented by visit.  


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8.4 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Adverse events 
• Clinical laboratory values (hematology and serum chemistry) 
•  OEs 
• Physical examinations 
• Standard 12-lead electrocardiograms 
• Vital signs 
Safety endpoints will be analyzed based on the Safety Set, separately for Part A and for the 
combined Part B and Part A/B Cohort 8. Only a descriptive analysis of safety will be 
performed. Summary tables will be presented by visit for each cohort, and overall. All safety 
data will be presented in individual subject data listings. No statistical hypothesis testing will 
be conducted. 
8.4.1 
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, defined as 
follows:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose date of study drug through the end of the TE period  
Post-treatment AE (Combined Part B and Part A/B Cohort 8): any AE that worsened 
(either in severity or seriousness) or that was newly developed beyond the TE period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in 
Appendix C. 


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AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by severity 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• Related (defined as possibly related or related) TEAEs. 
Summaries will be presented by MedDRA system organ class and preferred term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event). 
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 strongest 
relationship level will be presented in the relationship summaries.  
In addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation, SAEs and deaths will be provided separately. All AEs, including 
pre- and post-treatment AEs, will be presented in an individual subject data listing. 
8.4.2 
Clinical Laboratory 
For treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous hematology and chemistry results will be summarized in SI units by 
visit.  
For all LFT results, the maximum on-treatment LFTs will be summarized.  
In addition, a listing containing individual subject hematology and chemistry values outside 
the normal reference ranges will be provided. This listing will include data from both 
scheduled and unscheduled visits. 
Clinically significant abnormal findings will be reported as AEs.  
8.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from 
baseline values will be provided by visit. In addition, the number and percentage of subjects 
by maximum on-treatment value and by maximum on-treatment increase from baseline in 
QTc intervals will be presented.  A listing of abnormal ECG complexes from the ambulatory 
recordings will be presented. 
8.4.4 
Vital Signs 
For treatment-emergent vital sign measurements, the raw values and change from baseline 
values will be summarized by visit: systolic and diastolic blood pressure (mmHg), oral body 
temperature (°C), pulse oximetry (%), heart rate (beats per minute), and respiration rate 
(breaths per minute). 
Clinically significant findings in vital signs will be reported as AEs. 


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8.4.5 
Physical Examination  
Physical examination findings will be presented as an individual subject data listing only. 
8.4.6 
Ophthalmological Examination 
The ocular safety profile of ivacaftor will be assessed in terms of the following analyses: 
• Incidence of cataracts or lens opacities based on results from dilated slit-lamp 
examination 
• Red reflex 
Results of OEs (incidence of cataracts or lens opacities) will be summarized as a categorical 
variable and results will be presented by visit. 
Lens refracting power and red reflex will be listed as appropriate.  
8.4.7 
Other Safety Analysis 
Not applicable. 
9 
SUMMARY OF INTERIM AND IDMC ANALYSES 
9.1 
Interim Analysis 
An interim analysis (IA) of safety, PK, and PD data from subjects in Cohorts 1 and 5 was 
conducted after either of the following:  
• All subjects in Cohort 5 have completed their Week 12 Visit and 5 subjects in Cohort 
5 have completed their Week 24 Visit 
• All subjects in Cohort 5 have completed their Week 24 Visit  
An IA of safety, PK, and PD data from subjects in Cohorts 2 and 6 was conducted after: 
• All subjects in Cohort 6 have completed their Week 24 Visit 
An IA of safety, PK, and PD data from subjects in Cohorts 3 and 7 was conducted after: 
• All subjects aged 4 to <6 months in Cohort 7 have completed their Week 24 Visit  
An IA of safety, PK, and PD data from subjects in Cohorts 8 was conducted after: 
• All subjects aged 1 to <4 months in Cohort 8 have completed their study participation  
 
9.2 
IDMC Analysis 
Data will be reviewed by an independent data monitoring committee (IDMC) to ensure the 
safety of the subjects in the study. Procedural details of the IDMC's structure and function, 
frequency of meetings, and data planned for review will be included in the IDMC charter. 
The IDMC charter will be finalized before the first IDMC review meeting.  


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10 
REFERENCES 
 


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11 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
Table 11-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of 
Treatment, and Follow-up Periods) 
Table 11-2 
Study VX15-770-124: Part B (Screening and Treatment Periods) 
Table 11-3 
Study VX15-770-124: Part B (Early Termination of Treatment Visit and 
Follow-up Period)  
Table 11-4 
Study VX15-770-124: Part A/B Cohort 8 (Screening, Treatment, Early 
Termination of Treatment, and Follow-up Periods)  


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Table 11-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of Treatment, and Follow-up 
Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
Early 
Termination of 
Treatment 
Visit 
Follow-up Telephone Call 
Follow-up 
Ophthalmologic 
Examination 
Day -28 
to Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Within 5 Days 
After Last 
Dose of Study 
Drug 
Day 14 
(± 2 Days) 
8 Weeks 
(± 14 Days) 
After Last Dose 
of Study Drug 
Informed consenta  
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
X 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
 
 
X 
X 
X 
 
 
Telephone contact       
 
evening 
morning 
 
 
 
 
X 
 
Study drug count 
 
X 
 
 
X 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
CFTR genotypeb 
X 
 
 
 
 
 
 
 
 
 weightc 
X 
X 
 
 
 
X 
X 
 
 
Physical 
examinationd 
X 
X 
 
 
 
X 
X 
 
 
 
a 
Informed consent may be obtained before the Screening Visit and must be obtained before any screening assessment is performed. 
b 
The CFTR genotype results must be available before the first dose of study drug. If a genotype test has been performed previously and is documented in the 
subject’s medical record, the subject's eligibility must be approved by the Vertex medical monitor. If a historic genotype result is not available at screening 
or if the historic genotype result is not approved by the Vertex medical monitor, subjects will be tested for CFTR genotype and the results must be reviewed 
before the first dose of study drug. 
c 
 weight must be measured with the subject in a dry diaper or dry underclothes only. 
 weight measurements will be made before the 
morning dose on Day 1. 
.  
d 
Full physical examinations will occur at the Screening Visit and the Early Termination of Treatment (ETT) Visit; abbreviated physical examinations will 
occur at the Day 1 and Day 5 Visits. 


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Table 11-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of Treatment, and Follow-up 
Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
Early 
Termination of 
Treatment 
Visit 
Follow-up Telephone Call 
Follow-up 
Ophthalmologic 
Examination 
Day -28 
to Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Within 5 Days 
After Last 
Dose of Study 
Drug 
Day 14 
(± 2 Days) 
8 Weeks 
(± 14 Days) 
After Last Dose 
of Study Drug 
Vital signse 
X 
X 
 
 
 
X 
X 
 
 
12-lead ECGsf 
X 
 
 
 
 
X 
X 
 
 
Ophthalmologic 
examinationg 
X 
 
 
 
 
 
 
 
X 
Serum chemistry 
and hematologyh 
X 
 
 
 
X 
X 
 
 
PK blood collection 
 
 
 
 
Xi 
Xj 
X 
 
 
Sweat chloride testk 
X 
 
 
 
 
 
 
 
 
 
e 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration rate, and pulse oximetry. The subject should rest for at least 
5 minutes, if possible, before having vital signs measured. Day 1 vital signs measurements will be collected before the morning dose. Temperature must be 
obtained by the same method throughout the study. 
f 
All 12-lead ECGs will be performed before the morning dose. The subject should rest for at least 5 minutes, if possible, before having the ECG performed. 
The ECG will be performed before any other procedures that may affect heart rate, such as blood draws.  
g      The screening OE may be performed predose on Day 1. For subjects who have the Part A Follow-up OE within 6 months of enrolling in Part B, the 
screening OE for Part B is not required.  
h 
To minimize blood draws, the Screening Visit and Day 1 clinical laboratory assessments will be combined into a single blood draw taken up to 9 days before 
Day 1 dosing. The results must be received and reviewed before the first dose of study drug. All blood samples will be collected while subjects are in a 
seated or supine position. 
i 
PK samples will be collected before the morning dose and between 2 and 4 hours and between 6 and 8 hours after dosing on Day 4. 
j 
A PK sample will be collected between 24 and 60 hours after Day 4 morning dose (Day 5+1 day). 
k 
A sweat chloride test must be performed if the sweat chloride value is not available in the subject’s medical records and the value is needed to establish 
eligibility. For subjects with sweat chloride values documented in their medical records and for whom it is not needed to establish eligibility, the sweat 
chloride test at screening is not required. 


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Table 11-1 
Study VX15-770-124: Part A (Screening, Treatment, Early Termination of Treatment, and Follow-up 
Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
Early 
Termination of 
Treatment 
Visit 
Follow-up Telephone Call 
Follow-up 
Ophthalmologic 
Examination 
Day -28 
to Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Within 5 Days 
After Last 
Dose of Study 
Drug 
Day 14 
(± 2 Days) 
8 Weeks 
(± 14 Days) 
After Last Dose 
of Study Drug 
Study drug 
administrationl 
 
X 
X 
X 
X 
 
 
 
 
In-clinic observation 
for 4 hours after 
administration of the 
first dose of study 
drug 
 
X 
 
 
 
 
 
 
 
Study drug 
dispensing 
 
X 
 
 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through the Follow-up Telephone Call (Day 14 ± 2 days; see Section 14.1.1.3 of 
the Clinical Study Protocol)  
Ocular adverse 
events only 
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit through the Follow-up Telephone Call (Day 14 ± 2 days) 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ECG: electrocardiogram; ETT: Early Termination of Treatment; ICF: informed 
consent form; OE: ophthalmologic examination; PK: pharmacokinetic; q12h: every 12 hours. 
 
l 
Study drug will be administered q12h for 3 days and the last dose of study drug in Part A will be the morning dose on Day 4. The Day 1 and Day 4 morning 
doses will be administered in the clinic. Doses administered from the evening dose on Day 1 through the evening dose on Day 3 will be administered q12h at 
home. Each dose of granules will be mixed with approximately 1 teaspoon (5 mL) of appropriate liquid or soft food (as listed in the study manual). Details of 
dose preparation and dose administration will be provided in the study manual. The administration dates and times and whether doses were administered 
with food during the 3 days should be recorded in each subject’s dosing diary.  


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Table 11-2 
Study VX15-770-124: Part B (Screening and Treatment Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Day -28  
to Day -1 Day 1 
Day 3 
Week 2 
(± 1 Day) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days) 
Week 12 
(± 5 Days) 
Week 18 
(± 5 Days) 
Week 24a 
(± 5 Days)  
Informed consentb 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
X 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
 
X 
X 
X 
X 
X 
X 
Telephone contact 
 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
CFTR genotypec 
X 
 
 
 
 
 
 
 
 
 weightd 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical examinatione 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECGsg 
X 
 
 
 
X 
 
X 
 
X 
Ophthalmologic 
examinationsh 
X 
 
 
 
 
 
X 
 
X 
Serum chemistry and 
hematologyi  
X 
 
chemistry 
only 
LFTs and 
hematology only 
X 
X 
X 
X 
PK blood collectionj 
 
 
 
X 
 
X 
 
  
Xk 
Sweat chloride testl 
X 
X 
 
X 
 
 
X 
 
X 
Study drug 
administrationq 
 
X 
 
X 
X  
X 
X 
X 
X 


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a 
Subjects who complete 24 weeks of study drug treatment in Part B will be eligible to enroll in the open-label treatment arm of the Extension Study. For subjects who enroll, 
the Week 24 visit can be the same visit as Day 1 in the treatment arm of the Extension Study, and these subjects do not need to complete the Follow-up Visit. All other 
subjects must complete the ETT and/or Follow-up Visits (as applicable) and will be eligible to enroll in an observational arm of the Extension Study. 
b 
Informed consent may be obtained before the Screening Visit and must be obtained before any screening assessment is performed.  
c 
Subjects who had CFTR genotyping completed in Part A of the study will not require repeat testing upon entry into Part B. For all other subjects, the genotype results must be 
available before the first dose of study drug. If a genotype test has been performed previously and is documented in the subject’s medical record, the subject's eligibility must 
be approved by the Vertex medical monitor. If a historic genotype result is not available at screening or if the historic genotype result is not approved by the Vertex medical 
monitor, subjects will be tested for CFTR genotype and the results must be reviewed before the first dose of study drug. 
d 
 weight must be measured with the subject in a dry diaper or dry underclothes only. 
 weight measurements will be made before the morning dose on 
Day 1.  
e 
Full physical examinations will occur at the Screening and Week 24 Visits; abbreviated physical examinations will occur at all other study visits. 
f 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration rate, and pulse oximetry. The subject should rest for at least 5 minutes, if 
possible, before having vital signs measured. Day 1 vital signs measurements will be collected before dosing. Temperature must be obtained by the same method throughout 
the study. 
g 
All 12-lead ECGs will be performed before the morning dose. The subject should rest for at least 5 minutes, if possible, before having the ECG performed. The ECG will be 
performed before any other procedures that may affect heart rate, such as blood draws. 
h 
The screening OE may be performed predose on Day 1. If an adequate slit-lamp examination cannot be conducted at the Part B screening, subjects will not be enrolled in 
Part B until an adequate repeat slit-lamp examination is completed (within 4 weeks of the Screening Period) and eligibility criteria regarding the ophthalmologic findings are 
met. If an adequate slit-lamp examination cannot be conducted at any visit where it is required, the subject will continue to receive study drug until an adequate repeat 
examination is completed (within 4 weeks of the study visit); if an adequate slit-lamp examination cannot be conducted at the second examination or a lens opacity or cataract 
is identified, study drug dosing will be discontinued. A screening OE will not need to be conducted for subjects who have the Part A Follow-up OE within 6 months of 
enrolling in Part B. 
i 
To minimize blood draws, the Screening Visit and Day 1 clinical laboratory assessments will be combined into a single blood draw taken up to 9 days before Day 1 dosing. 
The results must be received and reviewed before the first dose of study drug. All blood samples will be collected while subjects are in a seated or supine position. 
j 
PK samples will be collected before the morning dose and between 2 and 4 hours and between 6 and 8 hours after the morning dose on Week 2. PK samples will be collected 
before the morning dose and 1 hour and 4 hours after the morning dose on Week 8. PK samples will be collected before the morning dose and between 2 and 4 hours after the 
morning dose on Week 24.  
k 
 PK sample collection is optional at Week 24 for subjects who undergo 
 
l 
At Screening a sweat chloride test must be performed if the sweat chloride value is not available in the subject’s medical records and the value is needed to establish 
eligibility. For subjects with sweat chloride values documented in their medical records and for whom it is not needed to establish eligibility, the sweat chloride test at 
screening is not required. Subjects who had a sweat chloride test during Screening for Part A will not require repeat testing during Screening for Part B. At the Day 1 Visit, 
the sweat chloride test must be performed before the morning dose. At the Week 2, 12, and 24 Visits, the sweat chloride test must be performed within a window of ± 2 hours 
relative to the morning dose of the study drug.  


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Table 11-2 
Study VX15-770-124: Part B (Screening and Treatment Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Day -28  
to Day -1 Day 1 
Day 3 
Week 2 
(± 1 Day) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days) 
Week 12 
(± 5 Days) 
Week 18 
(± 5 Days) 
Week 24a 
(± 5 Days)  
In-clinic observation for 
4 hours after 
administration of the 
first dose of study drug 
 
X 
 
 
 
 
 
 
 
Study drug count 
 
X 
 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
X 
 
X 
X 
X 
X 
X 
Xr 
Adverse events 
Continuous from signing of ICF through ETT and Follow-up Visit (if required; see Section 14.1.1.3 of the Clinical Study Protocol)  
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit through the ETT and Follow-up Visit (if required)  
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ECG: electrocardiogram; ICF: informed consent form; 
 
IRT: immunoreactive trypsin and/or trypsinogen; 
 LFT: liver function test; PK: pharmacokinetic; q12h: every 12 hours 
 
Study drug will be administered q12h. Each dose of granules will be mixed with approximately 1 teaspoon (5 mL) of liquid appropriate liquid or soft food (as listed in the 
study manual). Details of dose preparation and dose administration will be provided in the study manual. The dose administration dates and times, occurrence and time of 
regurgitation within 1 hour after dosing, and their timing with respect to food intake, will be recorded for the 2 doses prior to each PK clinic visit in each subject’s dosing 
diary. 
r 
Study drug will only be dispensed to subjects enrolling in the open-label treatment arm of the Extension Study.  


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Table 11-3 
Study VX15-770-124: Part B (Early Termination of Treatment Visit 
and Follow-up Period) 
 
Early Termination of 
Treatment Visita 
Follow-up Visitb 
Follow-up Ophthalmologic 
Examinationc 
Event/Assessment 
As Soon as Possible After the 
Last Dose of Study Drug 
4 Weeks (± 7 Days) After 
the Last Dose of 
Study Drug 
24 Weeks (± 14 Days) After 
the Last Dose of Study Drug 
Clinic visit 
X 
X 
 
 weightd 
X 
X 
 
Physical 
examinatione 
X 
X 
 
Vital signsf 
X 
X 
 
12-lead ECGsg 
X 
 
 
Serum chemistry 
and hematologyh 
X 
X 
 
Ophthalmologic 
examinationi 
X 
 
X 
PK blood collection 
X 
 
 
Study drug count 
X 
 
 
Adverse events 
Continuous from signing ICF through the ETT (if required) 
and Follow-up Visit 
Ocular adverse events only 
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit through the ETT and Follow-up Visit (if 
required) 
ECG: electrocardiogram; ETT: Early Termination of Treatment; ICF: informed consent form; OE: ophthalmologic 
examination; PK: pharmacokinetic. 
 
a  Subjects who prematurely discontinue treatment before their last scheduled dose will be required to complete the ETT 
Visit as soon as possible after the last dose of study drug and the Follow-up Visit. All subjects who prematurely 
discontinue from study drug treatment in Part B will be eligible to enroll in an observational arm of the Extension Study. 
b  The Follow-up Visit is not required if the subject completes the Part B treatment period and enrolls in the treatment arm 
of the Extension Study. For all other subjects, the Follow-up Visit is not required if the ETT Visit occurs 3 weeks or later 
after the last dose of study drug (ivacaftor) or in the event that the subject initiates treatment with commercially available 
ivacaftor within 3 weeks of the Week 24 or ETT Visit. 
c  Subjects who prematurely discontinue ivacaftor treatment in Part B and received at least 1 dose of ivacaftor treatment in 
Part B will have a Follow-up OE 24 weeks after the last dose of study drug. Subjects enrolling into the Extension Study 
within 24 weeks after the last dose of study drug are not required to have the Follow-up OE (the OE will be performed in 
the Extension Study instead). 
d  
 weight must be measured with the subject in a dry diaper or dry underclothes only. 
e  Full physical examinations will be performed at the ETT Visit and Follow-up Visit. 
f  Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration rate, and pulse oximetry. 
The subject should rest for at least 5 minutes, if possible, before having vital signs measured. Temperature must be 
obtained by the same method throughout the study. 
g  The subject should rest for at least 5 minutes, if possible, before having the ECG performed. The ECG will be performed 
before any other procedures that may affect heart rate, such as blood draws.  
h  All blood samples will be collected while subjects are in a seated or supine position. 
i  
The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue study drug dosing. If the ETT 
Visit occurs within 12 weeks of the subject's last OE, the OE at the ETT Visit will not be required. In addition, these 
subjects will be eligible to enroll in an observational arm of the Extension Study for long-term follow-up OE. 


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Table 12-4 
Study VX15-770-124: Part A/B Cohort 8 (Screening, Treatment, Early Termination of Treatment, and 
Follow-up Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Early 
Termination of 
Treatment 
Visita 
Follow-up 
Visitb 
Follow-up 
Ophthalmologic 
Examinationc 
Day -28  
to Day -14 Day 1 
Day 4 
Day 15 
(± 1 Day) 
Day 17 
(± 1 Day) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days) 
Weeks 12, 
18, and 
24 
(± 5 Days) 
As Soon as 
Possible After 
the Last Dose 
of Study Drug 
4 Weeks 
(± 7 Days) 
After Last 
Dose of  
Study Drug 
12 Weeks 
(± 14 Days) After 
Last Dose of  
Study Drug 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
X 
 
 
 
 
 
 
 
 
 
Clinic visit/ 
Assessment contact 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Telephone contact 
 
pm 
 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 weighte 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Physical examinationf 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Vital signsg 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
12-lead ECGsh 
X 
 
X 
 
 
X 
 
X 
X 
 
Ophthalmologic 
examinationsi 
X 
 
 
 
 
 
 
Xj 
X 
 
X 
Serum chemistryk 
X 
X 
X 
X  
 
X 
X 
X 
X 
X 
 
Hematologyk 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
PK blood collectionl 
 
 
Xm 
X 
 
X 
Xl 
X 
Xn 
 
 
Sweat chloride testo 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 


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a 
Subjects who prematurely discontinue treatment before their last scheduled dose will be required to complete the ETT Visit as soon as possible after the 
last dose of study drug and the Follow-up Visit. All subjects who prematurely discontinue from study drug treatment in Part A/B Cohort 8 will be 
eligible to enroll in an observational arm of the Extension Study. 
b 
The Follow-up Visit is not required if the subject completes the Part A/B Cohort 8 treatment period and enrolls in the treatment arm of the Extension 
Study. For all other subjects, the Follow-up Visit is not required if the ETT Visit occurs 3 weeks or later after the last dose of study drug (ivacaftor) or in 
the event that the subject initiates treatment with commercially available ivacaftor within 3 weeks of the final scheduled treatment visit or ETT Visit. 
c 
Subjects who prematurely discontinue ivacaftor treatment in Part A/B Cohort 8 and received at least 1 dose of ivacaftor treatment in Part A/B Cohort 8 
will have a Follow-up OE 12 weeks after the last dose of study drug. Subjects enrolling into the Extension Study within 12 weeks after the last dose of 
study drug are not required to have the Follow-up OE (the OE will be performed in the Extension Study instead). Subjects who initiate treatment with 
commercially available ivacaftor within 3 weeks of the ETT Visit will not have the Follow-up OE. 
d 
Informed consent may be obtained before the Screening Visit and must be obtained before any screening assessment is performed. 
e 
 weight must be measured with the subject in a dry diaper or dry underclothes only. 
 weight measurements will be made before 
the morning dose on Day 1.  
f 
Full physical examinations will occur at the Screening, Week 24, and Early Termination of Treatment (ETT) Visits; abbreviated physical examinations 
will occur at all other study visits. 
g 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiration rate, and pulse oximetry. The subject should rest for at 
least 5 minutes, if possible, before having vital signs measured. Day 1 vital sign measurements will be collected before the morning dose. Temperature 
must be obtained by the same method throughout the study. 
h 
All 12-lead ECGs will be performed before the morning dose. The subject should rest for at least 5 minutes, if possible, before having the ECG 
performed. The ECG will be performed before any other procedures that may affect heart rate, such as blood draws. 
i 
The screening OE may be performed at any time from screening until before the first dose on Day 1. If an adequate slit-lamp examination cannot be 
conducted at screening, subjects will not be enrolled until an adequate repeat slit-lamp examination is completed (within 4 weeks of the Screening 
Period). Eligibility criteria regarding the ophthalmologic findings must be met prior to dosing. 
j 
OE to be performed at the Week 12 and Week 24 Visits. 
k 
To minimize the volume of blood drawn on Day 1, clinical laboratory assessments will be determined from a single blood draw taken during the 
Screening Period Day -28 to Day -14. The results must be received and reviewed before the first dose of study drug. All blood samples will be collected 
while subjects are in a seated or supine position. 
l 
PK samples will be collected before the morning dose and between 2 to 4 hours and between 6 to 8 hours after the morning dose on Day 4 and the 
Week 8 Visit. PK samples will be collected before the morning dose on Day 15, and on the Week 4, 12, 18, and 24 Visits. 
m 
If all PK samples collected on Day 4 are missing or cannot be analyzed, PK samples collected on Day 15 will be used to assess whether the initial dose 
should be adjusted at the Week 4 Visit. 
n 
Assessment will be performed only if within 3 days of last dose of study drug. 
o 
At Screening a sweat chloride test must be performed if the sweat chloride value is not available in the subject’s medical records and the value is needed 
to establish eligibility. For subjects with sweat chloride values documented in their medical records and for whom it is not needed to establish eligibility, 
the sweat chloride test at screening is not required. At the Day 1 Visit, the sweat chloride test must be performed before the morning dose. At the Day 15 
and Week 4, 8, 12, 18 and 24 Visits, the sweat chloride test must be performed within a window of ± 2 hours relative to the morning dose of the study 
drug. 


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Table 12-4 
Study VX15-770-124: Part A/B Cohort 8 (Screening, Treatment, Early Termination of Treatment, and 
Follow-up Periods) 
Event/Assessment 
Screening 
Period 
Treatment Period 
(Day 1 to Week 24) 
Early 
Termination of 
Treatment 
Visita 
Follow-up 
Visitb 
Follow-up 
Ophthalmologic 
Examinationc 
Day -28  
to Day -14 Day 1 
Day 4 
Day 15 
(± 1 Day) 
Day 17 
(± 1 Day) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days) 
Weeks 12, 
18, and 
24 
(± 5 Days) 
As Soon as 
Possible After 
the Last Dose 
of Study Drug 
4 Weeks 
(± 7 Days) 
After Last 
Dose of  
Study Drug 
12 Weeks 
(± 14 Days) After 
Last Dose of  
Study Drug 
Study drug 
administrationq 
 
X 
X 
X 
 
X  
X 
X 
 
 
 
In-clinic observation 
for 4 hours after 
administration of the 
first dose of study drug 
 
X 
 
 
 
 
 
 
 
 
 
Study drug count 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Study drug dispensing 
 
X 
 
X 
 
X 
X 
Xr 
 
 
 
Adverse events 
Continuous from signing of ICF through ETT and Follow-up Visit (if required; see Section 14.1.1.3 of the 
Clinical Study Protocol) 
Ocular adverse 
events only 
Medications and 
procedures review 
Continuous from 28 days before the Screening Visit (or from birth, as relevant) through the ETT and Follow-up Visit (if required) 
CF: cystic fibrosis; ECG: electrocardiogram; ETT: early termination of treatment; ICF: informed consent form; 
 
 OE: ophthalmologic examination; PK: pharmacokinetic; q12h: every 12 hours 
 
q 
Study drug will be administered q12h. Each dose of granules will be mixed with approximately 1 teaspoon (5 mL) of appropriate liquid or soft food (as 
listed in the study manual). Details of dose preparation and dose administration will be provided in the study manual. The dose administration dates and 
times, occurrence and time of regurgitation within 1 hour after dosing, and their timing with respect to food intake, will be recorded for the 2 doses prior 
to each PK clinic visit in each subject’s dosing diary. In addition, the time of administration of study drug and occurrence and time of regurgitation 
within 1 hour after dosing in clinic on the day of the visit will be recorded. 
r 
Week 12 and Week 18 Visits only. Study drug will only be dispensed at Week 24 to subjects enrolling in the open-label treatment arm of the Extension 
Study. 


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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 11-4 
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 
TE Period 
> End Date of TE 
Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE 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: 
• If the full (or  partial) AE end date is NOT before the first dose date or AE end date is missing, then impute the AE start 
day as the day of first dose date; otherwise, impute the AE start day as 1. 
• Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is pretreatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
• If the full (or partial) AE end date is NOT before the first dose date or AE end date is missing, then impute the AE start 
Month and Day as the Month and Day of first dose date; otherwise, impute the AE start Month as January and the Day as 
1. 
• Otherwise, impute the AE start MONTH as January and the DAY as 1. 
Compare the imputed AE start date with TE 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: Analysis Visit Window Mapping Rules for Safety and Efficacy Assessments 
Table 11-4 Analysis Visit Windows for Safety Assessments for Part B 
Safety Assessment 
Visita 
Target Study Day 
Analysis Visit Window 
(in study days) 
Serum Chemistry 
 
Baseline 
1 
≤1 
Week 2 
14 
[2,35] 
Week 8 
56 
[36,70] 
Week 12 
84 
[71,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
Follow-up Visit 
NA 
Use nominal visit 
LFTs 
Baseline 
1 
≤1 
Week 2 
14 
[2,21] 
Week 4 
28 
[22,42] 
Week 8 
56 
[43,70] 
Week 12 
84 
[71,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
Follow-up Visit 
NA 
Use nominal visit 
Hematology 
Baseline 
1 
≤1 
Week 4 
28 
[2,42] 
Week 8 
56 
[43,70] 
Week 12 
84 
[71,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
Follow-up Visit 
NA 
Use nominal visit 
Standard 12-Lead ECG 
Baseline 
1 
≤1 
Week 4 
28 
[2,56] 
Week 12 
84 
[57,126] 
Week 24 
168 
[127, Date of Week 24 Visit] 
Vital Signs 
Baseline 
1 
≤1 


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Week 2 
14 
[2,21] 
Week 4 
28 
[22,42] 
Week 8 
56 
[43,70] 
Week 12 
84 
[71,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
Follow-up Visit 
NA 
Use nominal visit 
Ophthalmologic Exam 
Baseline 
1 
≤1 
Week 12 
84 
[2,126] 
Week 24 
168 
[127, Date of Week 24 Visit] 
Follow-up OE visit 
NA 
Use nominal visit  
When a subject is lost to follow up and last dose date is unknown, impute last dose date of all study drugs as last on-treatment visit date. 
aVisit name is used to report data in tables, listings and figures.  
 


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Table 11-5 Analysis Visit Windows for Efficacy Assessments for Part B 
Safety Assessment 
Visita 
Target Study Day 
Analysis Visit Window 
(in study days) 
Follow-up Visit 
NA 
Use nominal visit 
Sweat Chloride 
 
Baseline 
1 
≤1 
Week 2 
14 
[2,49] 
Week 12 
84 
[50,126] 
Week 24 
168 
[127, Date of Week 24 Visit] 


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When a subject is lost to follow up and last dose date is unknown, impute last dose date of all study drugs as last on-treatment visit date. 
aVisit name is used to report data in tables, listings and figures.  
 
 
 


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Table 11-6 Analysis Visit Windows for Safety Assessments for Part A/B Cohort 8 
Safety Assessment 
Visita 
Target Study Day 
Analysis Visit Window 
(in study days) 
Serum Chemistry 
 
Baseline 
1 
≤1 
Day 4 
4 
[2,9] 
Day 15 
15 
[10,21] 
Week 4 
28 
[22,42] 
Week 8 
56 
[43,70] 
Week 12 
84 
[71,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
Follow-up Visit 
NA 
Use nominal visit 
Hematology 
Baseline 
1 
≤1 
Day 15 
15 
[2,21] 
Week 4 
28 
[22,56] 
Week 12 
84 
[57,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
Follow-up Visit 
NA 
Use nominal visit 
Standard 12-Lead ECG 
Baseline 
1 
≤1 
Day4 
4 
[2,16] 
Week 4 
28 
[17,56] 
Week 12 
84 
[57,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
Vital Signs 
Baseline 
1 
≤1 
Day 4 
4 
[2,9] 
Day 15 
15 
[10,21] 
Week 4 
28 
[22,42] 
Week 8 
56 
[43,70] 
Week 12 
84 
[71,105] 
Week 18 
126 
[106,147] 


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Week 24 
168 
[148, Date of Week 24 Visit] 
Follow-up Visit 
NA 
Use nominal visit 
Ophthalmologic Exam 
Baseline 
1 
≤1 
Week 12 
84 
[2,126] 
Week 24 
168 
[127, Date of Week 24 Visit] 
Follow-up OE visit 
NA 
Use nominal visit  
When a subject is lost to follow up and last dose date is unknown, impute last dose date of all study drugs as last on-treatment visit date. 
a Visit name is used to report data in tables, listings and figures.  
 
Table 12-7 Analysis Visit Windows for Efficacy Assessments for Part A/B Cohort 8 
Safety Assessment 
Visita 
Target Study Day 
Analysis Visit Window 
(in study days) 
Sweat Chloride 
 
Baseline 
1 
≤1 
Day 15 
15 
[2,21] 
Week 4 
28 
[22,42] 
Week 8 
56 
[43,70] 


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Week 12 
84 
[71,105] 
Week 18 
126 
[106,147] 
Week 24 
168 
[148, Date of Week 24 Visit] 
When a subject is lost to follow up and last dose date is unknown, impute last dose date of all study drugs as last on-treatment visit date. 
a Visit name is used to report data in tables, listings and figures.