Conditions: Cystic Fibrosis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 86
Healthy volunteers: no

Brief summary:
This is a Phase 3, 2-arm, multicenter study with an open-label ivacaftor arm and an observational arm to evaluate the safety and efficacy of long-term ivacaftor treatment in participants with cystic fibrosis (CF) who are \<24 months of age at treatment initiation and have an approved Ivacaftor-Responsive mutation.

Detailed description:

Arms:
arm 1: Participants less than (\<) 24 months of age and weighing 5 to less than (\<) 7 kilogram (kg) received 25 mg IVA every 12 hours (q12h), 7 to \<14 kg received 50 mg IVA q12h, and those weighing 14 to \<25 kg received 75 mg IVA q12h.

Participants more than or equal (\>=) 24 months of age and weighing \<14 kg received 50 mg IVA q12h, and those weighing more than or equal to (\>=)14 kg received 75 mg IVA q12h in the treatment period for up to 96 weeks.

Doses were determined based on safety and pharmacokinetic (PK) data from parent study, age and weight. arm 2: None

Interventions: intervention 1: IVA
Intervention descriptions: intervention 1: Granules for oral administration.

Protocol document:
Prot_000.pdf: 
 
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1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, 2-Arm, Open-label Study to Evaluate the 
Safety and Pharmacodynamics of Long-term 
Ivacaftor Treatment in Subjects With Cystic Fibrosis 
Who Are Less Than 24 Months of Age at Treatment 
Initiation and Have an Approved 
Ivacaftor-Responsive Mutation 
Vertex Study Number: VX15-770-126 
IND Number: 74,633 
EudraCT Number: 2017-001379-21 
Date of Protocol: 05 October 2017 (Version 2.0)  
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


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Summary of Changes to the Protocol  
The previous version of this protocol (Version 1.0, 13 April 2017) was amended to create the 
current version (Version 2.0, 05 October 2017). The protocol history is provided below.  
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 13 April 2017 
Original version 
Version 2.0, 05 October 2017 
Current version 
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
Major revisions 
 
For subjects not from Study 124 Part B, revised inclusion criterion #5 
to change lower weight bound at screening to comply with request 
from Regulatory Health Authority. Revised text to inform that future 
changes to study drug dose, age strata, or weight bounds will be 
communicated to site personnel through a memorandum entitled 
“Justification for Dose Selection” to ensure clarity and consistency in 
study conduct. 
Sections 8.2.1, 9.2.2 
For subjects not from Study 124 Part B, revised study population and 
inclusion criteria #3 to include subjects with CF <24 months of age 
who have an ivacaftor-responsive CFTR mutation on at least 1 allele. 
Subjects will be eligible in countries/regions where ivacaftor is 
approved for use in subjects 2 years of age and older to align with 
newly approved indication. 
Sections 1, 2, 6.1.1, 6.1.2, 6.1.3, 6.2.1, 8, 
8.2.1, 11.6.2, 15.1, and 15.2 
Added text to alert investigators that the study manual and the 
approved ivacaftor label in their country/region should be consulted 
to confirm the approved mutations for subject eligibility. 
Sections 2, 8, and 11.6.2 
Added paragraph to introduce ivacaftor-responsive mutations. 
Section 5.1 
Added paragraph to indicate that a list of approved ivacaftor-
responsive CFTR mutations is included in the study manual, and that 
any updates to approved mutations will be communicated to 
investigative sites through a memorandum. 
Section 8 
Added text to indicate that dosing, age or weight strata may be 
modified based on available PK data and how this information will 
be communicated to investigational sites. 
Section 9.2.2 
Removed Study Visit at Week 104, as the 2-year treatment period 
concludes at Week 96. 
Table 3-1, Table 3-2, Table 3-3, Table 3-4, 
Figure 2-1, Figure 9-1 and Sections 2, 
7.1.2, 7.1.3, 9.1, 9.1.1.2, 9.1.4.1, 9.2.1, 9.4,  
Other revisions affecting study implementation 
 
Revised footnotes and appropriate sections to allow subjects, after 
their Week 24 Visit, to receive their morning dose at home prior to 
that day’s clinic visit, to allow assessments to be done postdose, and 
to allow sweat chloride to be assessed outside the ± 2 hour window to 
allow for flexibility in scheduling the time of a subject’s visit. 
Clarified that time of dose administration need not be recorded after 
Week 24. The 24-week Follow-up OE window changed to 
(+ 14 Days) rather than (± 14 Days) to ensure adequate follow-up 
period.  
Table 3-1, Table 3-2, and Table 3-3; 
Sections 2, 9.1.1.4, 9.4, 11.2, 11.4.1, and 
11.6.4 


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Change and Rationale 
Affected Sections  
Deleted ‘Demographics’, and footnote ‘c’ because neither were 
needed. Added collection of medical history for Gap Transition 
subjects who have new conditions that start after the Study 124 
Safety Follow-up Visit and prior to the Study 126 Screening Visit.  
Table 3-2 
Added a 1 day window around the Day 3 Visit. Added footnote “a” 
and text in appropriate sections to clarify when enrollment in 
Study 126 will be open for a particular age group. Added footnote 
“d” to ensure historical CF data are collected at screening or at Day 1. 
Deleted footnote “j” (OE performed at Week 12 and Week 24) 
because it is already explained in the table. Added 4-hour observation 
period after administration of first dose. Deleted study drug count on 
Day 1. Clarified in footnote “l” and in appropriate section, that if an 
OE was conducted in Study 124 Part A within 12 weeks of the Day 1 
Visit, the Day 1 Visit OE does not need to be repeated. Added to 
footnote “r” that an additional MBW will be performed on the Week 
72 Visit. 
Table 3-3; Sections 8.2 and 9.1.1.1 
Added a 7-day window around the telephone contacts at Weeks 48 
and 96 for subjects in the Observational Arm to allow flexibility in 
contacting subjects. 
Table 3-4; Sections 2 and 9.1.4.1 
Revisions to clarify text 
 
Clarified in footnote ‘p’ that baseline sweat chloride test is not 
required at Day 1 if it was completed at screening. 
Table 3-2 and Table 3-3; Section 11.4.1 
Clarified that enrollment of subjects in Study 126 age cohorts is 
closely linked to Study 124 and will be based on available PK data. 
Section 9.1 
Clarified when screening serum chemistry and hematology 
assessments need to be performed with respect to first dose.  
Sections 9.1.1.1, 9.1.1.1.3, and 9.1.1.2.1 
Clarified when rescreening OE needs to be repeated. 
Section 9.1.1.1.2 
Revised text to indicate the IDMC charter will be finalized before the 
1st subject is screened. 
Sections 2 and 9.1.5 
Text was changed to clarify how blood samples from local 
laboratories should be handled. 
Section 11.6.2 
Added that subjects who did not participate in Study 124 Part B 
should have an additional OE exam at Week 12. Simplified text 
requiring that study drug be discontinued if a new lens opacity or 
cataract is identified at any OE in the ivacaftor arm. 
Section 11.6.5 
Removed reference to presentation of various analyses by treatment 
(dose levels), as these will be addressed in the statistical analysis plan 
(SAP). 
Section 12.3 
Removed reference to diary cards as they will not be used in the 
study. 
Section 13.2.1 
Deleted Appendices A and B since they were not needed. 
Sections 15 and 16 
 
Typographical and administrative changes were also made to improve the clarity of the document. 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, 2-Arm, Open-label Study to Evaluate the Safety and Pharmacodynamics 
of Long-term Ivacaftor Treatment in Subjects With Cystic Fibrosis Who Are Less 
Than 24 Months of Age at Treatment Initiation and Have an Approved 
Ivacaftor-Responsive Mutation 
Brief Title 
A Study to Evaluate the Safety of Long-term Ivacaftor Treatment in Subjects with 
Cystic Fibrosis Who Are Less Than 24 Months of Age at Treatment Initiation and 
Have an Approved Ivacaftor-Responsive Mutation 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3, safety, pharmacodynamics (PD), and efficacy 
 
 
Ivacaftor Arm 
Objectives 
Primary  
To evaluate the safety of long-term ivacaftor treatment in subjects with cystic fibrosis 
(CF) who are <24 months of age at treatment initiation and have an approved 
ivacaftor-responsive mutation 
Secondary  
To evaluate the PD of long-term ivacaftor treatment in subjects with CF who are 
<24 months of age at treatment initiation and have an approved ivacaftor-responsive 
mutation  
Tertiary  
To evaluate the efficacy of long-term ivacaftor treatment in subjects with CF who are 
<24 months of age at treatment initiation and have an approved ivacaftor-responsive 
mutation  
Observational Arm 
Objective 
To evaluate long-term safety after discontinuation of ivacaftor treatment in subjects 
with CF who were <24 months of age at treatment initiation and have an approved 
ivacaftor-responsive mutation 
 
 
Ivacaftor Arm 
Endpoints 
Primary  
Safety, as determined by: 
 
Adverse events 
 
Laboratory values (serum chemistry and hematology)  
 
12-lead ECGs and vital signs  
 
Ophthalmologic examinations (OEs) 
Secondary  
Absolute change from baseline in sweat chloride through Week 96  
Tertiary  
 
Absolute change from baseline through Week 96 for the following 
endpoints: 
o 
Weight  
o 
Length (assessed as height, as age appropriate) 
o 
Weight-for-length  
o 
Weight-for-age z-score 
o 
Length-for-age z-score  
o 
Weight-for-length-for-age z-score 
o 
Body mass index (BMI) 
o 
BMI-for-age z-score 
o 
Lung clearance index (LCI) at qualified study sites  
o 
Fecal elastase-1 


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o 
Markers of intestinal inflammation  
o 
Qualitative microbiology cultures 
 
Annualized rate of pulmonary exacerbations  
 
Rate of CF-related hospitalizations 
Observational Arm 
Endpoint 
Safety after stopping ivacaftor treatment in Study VX15-770-124 (Study 124) Part B 
as determined by serious adverse events (SAEs) and results from an OE 
approximately 24 weeks after the last dose of ivacaftor in Study 124 Part B. 
 
 
Number of Subjects 
Approximately 75 subjects will be enrolled.  
 
 
Study Population 
Subjects with CF <24 months of age at treatment initiation who have an 
ivacaftor-responsive CFTR mutation on at least 1 allele.  
 Subjects will be eligible in countries/regions where ivacaftor is approved for use 
in subjects 2 years of age and older.  
 Investigators should consult the approved ivacaftor label in their country/region 
to confirm approved mutations for subject eligibility.  
Source of Subjects Enrolled in the Ivacaftor Arm 
 Subjects who completed ivacaftor treatment in Study 124 Part B 
 Subjects who did not participate in Study 124 Part B (e.g., subjects who 
participated in Study 124 Part A only and subjects who did not participate in 
Study 124 Part A or B) and are <24 months of age at Day 1 of 
Study VX15-770-126 (Study 126)  
Source of Subjects Enrolled in the Observational Arm 
 Subjects who completed ivacaftor treatment in Study 124 Part B and elected not 
to enroll in the ivacaftor arm of Study 126 
 Subjects who received at least 1 dose of ivacaftor and prematurely discontinued 
ivacaftor treatment in Study 124 Part B 
 
 
Investigational Drug 
Active substance: ivacaftor 
 
Activity: CFTR potentiator 
 
Strength and route of administration: 25 mg, 50 mg, 75 mg, and others (to be 
determined based on safety and PK data from Study 124, age, and weight); granules 
for oral administration 
 
 
Study Duration 
Ivacaftor Arm: Subjects will participate for approximately 128 weeks (from Day 1 
through the Follow-up OE).  
Observational Arm: Subjects will participate for approximately 96 weeks (from 
Day 1 through the Week 96 Follow-up Telephone Contact). 
 
 


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Study Design 
This is a Phase 3, 2-arm, multicenter study with an open-label ivacaftor arm and an 
observational arm. The study design is shown in Figure 2-1. 
Figure 2-1 
VX15-770-126 Study Design 
 
a 
For subjects who have a Same-day Transition, the Week 24 Visit of Study 124 Part B will 
be the same day as the Day 1 Visit of Study 126. For subjects who have a Gap Transition, 
the last study visit of Study 124 Part B will not be the same day as the Day 1 Visit of 
Study 126 (see Section 9.1.1.2.1).  
b 
Day 1 for subjects in the observational arm can be the last study visit of Study 124 Part B 
(see Section 9.1.3). 
c 
The Follow-up OE in the observational arm can be performed in Study 124. 
d 
Only for subjects who received at least 4 weeks of study drug in Study 124 Part B. 
Study Overview for Subjects in the Ivacaftor Arm 
This arm will include the following: 
 
Screening Period (for subjects not from Study 124 Part B only): Day -28 
to Day -1  
 
Treatment Period: Day 1 to Week 96  
o 
Appropriate doses will be based on Study 124 Parts A and B findings  
 
Safety Follow-up Visit: 4 weeks (± 7 days) after the last dose of ivacaftor 
 
Early Termination of Treatment (ETT) Visit (if applicable): as soon as 
possible after the last dose of ivacaftor  
 
Follow-up OE: 24 weeks (+ 14 days) after the last dose of ivacaftor  
Subjects who receive commercially available ivacaftor will be discontinued from 
study drug dosing and will complete the ETT Visit and the Follow-up OE; the Safety 
Follow-up Visit will not be required. 
Study Overview for Subjects in the Observational Arm 
The observational arm will include the following:  
 
Day 1 Visit 
 
OE: 24 weeks (+ 14 days) after the last dose of ivacaftor in Study 124 


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Part B, unless the Follow-up OE was performed in Study 124  
 
Follow-up Telephone Contacts: Week 48 [± 7 Days] and Week 96 
[± 7 Days] (only for subjects who received ≥4 weeks of ivacaftor in Study 
124 Part B) 
Subjects who receive commercially available ivacaftor will be discontinued from the 
observational arm after completing the OE.  
 
 
Assessments 
Safety (ivacaftor and observational arms) 
Adverse events, clinical laboratory values (serum chemistry and hematology), ECGs, 
vital signs, physical examinations (PEs), and OEs 
Pharmacodynamic (ivacaftor arm only) 
Sweat chloride 
Efficacy (ivacaftor arm only) 
Weight, length, weight-for-length, weight-for-age z-score, length-for-age z-score, 
weight-for-length-for-age z-score, BMI, BMI-for-age z-score, multiple breath 
washout (MBW), qualitative microbiology cultures, annualized rate of pulmonary 
exacerbations, rate of CF-related hospitalizations, fecal elastase-1, and markers of 
intestinal inflammation 
 
 
Statistical Analyses 
The study is not powered to detect a significant treatment effect. The Safety Set 
(defined as enrolled subjects who receive at least 1 dose of ivacaftor in Study 126) 
will be used for all safety analyses. The Full Analysis Set (FAS) (defined as enrolled 
subjects who have at least 1 postbaseline efficacy assessment in Study 126) will be 
used for all efficacy analyses. Data from all safety and efficacy endpoints will be 
analyzed using descriptive statistics. For efficacy endpoints, separate tables will be 
presented for subjects in the ivacaftor arm. 
Details will be provided in the statistical analysis plan (SAP), which will be finalized 
and approved before the clinical database lock. 
 
 
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 subject is 
screened. 


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3 
SCHEDULE OF ASSESSMENTS 
Table 3-1 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Same-day 
Transition Subjects From Study 124 Part B) 
Table 3-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition 
Subjects From Study 124 Part B) 
Table 3-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A 
Only Subjects or Subjects Not From Study 124) 
Table 3-4 
Schedule of Assessments for VX15-770-126 (Observational Arm) 
 


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Table 3-1 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Same-day Transition Subjects From 
Study 124 Part B) 
 
Treatment Period 
(Day 1 Through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE 
Event/Assessment 
Day 1c 
Weeks 12, 36, 
60, and 84 
(± 7 Days) 
Weeks 24, 48, 72, 
and 96 
(± 7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks (± 7 Days) 
After the Last Dose 
24 Weeks 
(+ 14 Days) After 
the Last Dose 
Informed consent 
X 
 
 
 
 
 
Confirm eligibility 
X 
 
 
 
 
 
Clinic visit 
X 
X 
X 
X 
X 
 
Study drug dose determinationd 
X 
X 
X 
 
 
 
Length and weighte 
X 
X 
X 
X 
X 
 
Physical examinationf 
X 
X 
X 
X 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
 
12-lead ECGsg, h 
X 
 
X 
X 
X 
 
Serum chemistry and hematology 
X 
X 
X 
X 
X 
 
Ophthalmologic examinationi 
X 
 
X 
Xj 
  
X 
 
a 
The ETT Visit is to be scheduled as soon as possible after the last dose of ivacaftor. If the ETT Visit occurs 3 weeks or later after the last dose of ivacaftor, 
the Safety Follow-up Visit will not be required. Subjects who elect to receive commercially available ivacaftor will be discontinued from ivacaftor dosing and 
will complete the ETT Visit and Follow-up OE. 
b 
For subjects who elect to receive commercially available ivacaftor, the Safety Follow-up Visit will not be required. 
c The Day 1 Visit will be the same day as the Week 24 Visit of Study 124 Part B. Any Study 126 Day 1 assessments performed at the Week 24 Visit of 
Study 124 Part B do not need to be repeated. Day 1 results should be taken from the Week 24 Visit in Study 124 (if applicable) on which these data are 
available (including demographics and medical history), except for the signing of informed consent, confirmation of eligibility, and IVRS/IWRS contact. 
d The ivacaftor dose for each subject will be reassessed based on body weight and adjusted if necessary (see Section 9.4).  
e 
Length and weight measurements will be performed predose through the Week 24 Visit (see Section 11.5.1). 
f 
Full physical examinations will be performed at the ETT and Safety Follow-up Visits; abbreviated physical examinations will be performed at all other study 
visits. 
g Vital signs and ECGs will be taken predose through the Week 24 Visit. Following the Week 24 Visit, vital signs and ECGs may be taken pre- or post-dose. 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiratory rate, and pulse oximetry (see Section 11.6.3). 
h All 12-lead ECGs will be taken predose at the Day 1, Week 12 and Week 24 Clinic Visits. At all visits, ECGs will be taken before any other procedures that 
may affect heart rate, such as blood draws (see Section 11.6.4).  
i 
The OE will be conducted by a licensed ophthalmologist, preferably a pediatric ophthalmologist. The OE may be performed at the study visit or ± 14 days of 
the clinic visit. 
j 
The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue ivacaftor dosing (for any reason) unless performed in the last 
12 weeks.  


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Table 3-1 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Same-day Transition Subjects From 
Study 124 Part B) 
 
Treatment Period 
(Day 1 Through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE 
Event/Assessment 
Day 1c 
Weeks 12, 36, 
60, and 84 
(± 7 Days) 
Weeks 24, 48, 72, 
and 96 
(± 7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks (± 7 Days) 
After the Last Dose 
24 Weeks 
(+ 14 Days) After 
the Last Dose 
Fecal sample collectionk  
X 
 
X 
X 
 
 
Sweat chloride testl 
X 
 
X 
 
 
 
Qualitative microbiology cultures 
X 
 
X 
 
 
 
Multiple breath washout (optional)m  
X 
 
Xn 
 
 
 
Study drug administrationo 
X 
X 
X 
 
 
 
Study drug count 
X 
X 
X 
X 
 
 
Pulmonary exacerbations, CF-related 
hospitalizations 
Continuous from signing of ICF through the last 
dose of study drug 
 
 
 
Adverse events 
Continuous from signing ICF through the Safety Follow-up Visit (see Section 13.1.1.3) 
Ocular adverse 
events only 
Medications and procedures review 
Continuous from signing of ICF through the Safety Follow-up Visit 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ETT: Early Termination of Treatment; ICF: informed consent form; MBW: multiple 
breath washout; LFT: liver function test; OE: ophthalmologic examination; q12h: every 12 hours. 
 
k  Samples will be analyzed for fecal elastase-1 and other markers of intestinal inflammation, including fecal calprotectin. Samples may be collected up to 
24 hours before the study visit (e.g., at home) and brought to the clinic. If the sample is collected in the clinic, the sample may be collected pre- or postdose. 
l 
The sweat chloride test must be performed on Day 1 before the ivacaftor dose. At all other visits up to the Week 24 Visit, the sweat chloride test must be 
performed within ± 2 hours of the ivacaftor dose. After the Week 24 Visit, the sweat chloride test may be performed at any time during the visit. 
m MBW will be performed on subjects for whom additional or separate informed consent was obtained for the procedures, and only at sites that are adequately 
trained and qualified to perform MBW (see Section 11.5.6). The Day 1 MBW must be performed within 1 week before the Day 1 Visit. The Week 96 MBW 
must be performed within 1 week before the last dose. Detailed procedures will be supplied in a separate study manual. 
n  MBW will be performed at the Week 24 and 48 Visits (± 7 days). 
o The morning dose of study drug will be administered at the Day 1, Week 12 and Week 24 Clinic Visits. After the Week 24 Visit, the morning dose need not 
be administered at the Clinic Visit. Additional guidance for preparation and administration of study drug is provided in Section 9.4 and the study manual. 


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Table 3-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition Subjects From Study 124 Part B) 
 
Treatment Period 
(Day 1 through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE 
Event/Assessment 
Day -28 
to 
Day -1 
Day 1c 
Weeks 12, 36, 
60, and 84 
(±7 Days) 
Weeks 24, 48, 
72, and 96 
(±7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks 
(±7 Days) After 
the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Informed consentd 
X 
X 
 
 
 
 
 
Reconfirm eligibility 
X 
X 
 
 
 
 
 
Medical historye 
X 
 
 
 
 
 
 
Clinic visit 
X 
X 
X 
X 
X 
X 
 
Study drug dose determinationf 
 
X 
X 
X 
 
 
 
Length and weightg 
 
X 
X 
X 
X 
X 
 
Physical examinationh 
 
X 
X 
X 
X 
X 
 
Vital signsi 
 
X 
X 
X 
X 
X 
 
12-lead ECGsi, j 
 
X 
 
X 
X 
X 
 
Serum chemistry and hematology 
Xk  
X 
X 
X 
X 
 
 
a 
The ETT Visit is to be scheduled as soon as possible after the last dose of ivacaftor. If the ETT Visit occurs 3 weeks or later after the last dose of ivacaftor, 
the Safety Follow-up Visit will not be required. Subjects who elect to receive commercially available ivacaftor will be discontinued from ivacaftor dosing and 
will complete the ETT Visit and Follow-up OE. 
b For subjects who elect to receive commercially available ivacaftor, the Safety Follow-up Visit will not be required. 
c The Day 1 Visit will not be the same day as the last study visit of Study 124 Part B. All Day 1 assessments will be conducted on Day 1 with the possible 
exception of the serum and hematology assessments and the OE, as detailed in footnotes k and m. If the Day 1 Visit is ≤9 days after the last study visit of 
Study 124 Part B, the subjects must sign the ICF and confirm eligibility before dosing on Day 1.  
d  Subjects must sign the ICF before undergoing any study-related assessments. 
e  Medical history only applies to subjects that complete a Study 124 Safety Follow-up Visit and only for new conditions that start after the Study 124 Safety 
Follow-up Visit and prior to the Study 126 Screening Visit. 
f  The ivacaftor dose for each subject will be reassessed based on body weight and adjusted if necessary (see Section 9.4). 
g 
Length and weight measurements will be performed predose through the Week 24 Visit (see Section 11.5.1). 
h Full physical examinations will be performed at the ETT and Safety Follow-up Visits; abbreviated physical examinations will be performed at all other study 
visits. 
i 
Vital signs and ECGs will be taken predose through the Week 24 Visit. Following the Week 24 Visit, vital signs and ECGs may be taken pre- or post-dose. 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiratory rate, and pulse oximetry (see Section 11.6.3). 
j 
All 12-lead ECGs will be taken predose at the Day 1, Week 12 and Week 24 Clinic Visits. At all visits, ECGs will be taken before any other procedures that 
may affect heart rate, such as blood draws (see Section 11.6.4).  


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Table 3-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition Subjects From Study 124 Part B) 
 
Treatment Period 
(Day 1 through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE 
Event/Assessment 
Day -28 
to 
Day -1 
Day 1c 
Weeks 12, 36, 
60, and 84 
(±7 Days) 
Weeks 24, 48, 
72, and 96 
(±7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks 
(±7 Days) After 
the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Ophthalmologic examinationl 
 
Xm 
 
X 
Xn 
 
X 
Fecal sample collectiono  
 
X 
 
X 
X 
 
 
Sweat chloride testp 
 
X 
 
X 
 
 
 
Qualitative microbiology cultures 
 
X 
 
X 
 
 
 
Multiple breath washout (optional)q  
 
X 
 
Xr 
 
 
 
 
k 
If the Day 1 Visit is conducted ≤9 days after the last study visit of Study 124 Part B, the serum chemistry and hematology assessments performed at the last 
study visit of Study 124 Part B will not need to be repeated. If the Day 1 Visit is conducted >9 days after the last study visit of Study 124 Part B, the serum 
chemistry and hematology assessments can be obtained up to 9 days before or at the Day 1 Visit. The results must be reviewed before the first dose of study 
drug. 
l 
The OE will be conducted by a licensed ophthalmologist, preferably a pediatric ophthalmologist. The OE may be performed at the study visit or ± 14 days of 
the clinic visit. 
m  The OE does not need to be repeated if the subject had an OE in Study 124 Part B within 24 weeks of the Day 1 Visit. Otherwise, an OE must be conducted 
within 14 days of the Day 1 Visit. Throughout this study, these subjects should have OEs approximately every 24 weeks (± 14 days) from the last OE in 
Study 124. 
n The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue ivacaftor dosing (for any reason) unless performed in the last 
12 weeks.  
o  Samples will be analyzed for fecal elastase-1 and other markers of intestinal inflammation, including fecal calprotectin. Samples may be collected (e.g., at 
home) up to 24 hours before the study visit (e.g., at home) and brought to the clinic. If the sample is collected in the clinic, the sample may be collected pre- 
or postdose. 
p 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. For all subjects, except those that completed a baseline sweat chloride test at screening, the Day 1 sweat 
chloride test will be performed predose. At all other visits up to the Week 24 Visit, the test must be performed within ± 2 hours of the ivacaftor dose. After the 
Week 24 Visit, the sweat chloride test may be performed at any time during the visit. 
q MBW will be performed on subjects for whom additional or separate informed consent was obtained for the procedures, and only at sites that are adequately 
trained and qualified to perform MBW (see Section 11.5.6). If MBW was performed in Study 124 within 28 days of the Day 1 Visit in Study 126, MBW will 
not need to be repeated on Day 1. If a Day 1 MBW is needed, the MBW must be performed within 1 week before the Day 1 Visit. The Week 96 MBW must 
be performed within 1 week before the last dose. Detailed procedures will be supplied in a separate study manual. 
r 
MBW will be performed at the Week 24 and 48 Visits (± 7 days).  


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Table 3-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition Subjects From Study 124 Part B) 
 
Treatment Period 
(Day 1 through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE 
Event/Assessment 
Day -28 
to 
Day -1 
Day 1c 
Weeks 12, 36, 
60, and 84 
(±7 Days) 
Weeks 24, 48, 
72, and 96 
(±7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks 
(±7 Days) After 
the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Study drug administrations 
 
X 
X 
X 
 
 
 
Study drug count 
 
X 
X 
X 
X 
 
 
Pulmonary exacerbations,  
CF-related hospitalizations 
Continuous from signing of ICF through the last dose of 
study drug 
 
 
 
Adverse events 
Continuous from signing ICF through the Safety Follow-up Visit (see Section 13.1.1.3) 
Ocular adverse 
events only 
Medications and procedures review 
Continuous from signing of ICF through the Safety Follow-up Visit 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ETT: Early Termination of Treatment; ICF: informed consent form; MBW: multiple 
breath washout; LFT: liver function test; OE: ophthalmologic examination; q12h: every 12 hours. 
 
s 
The morning dose of study drug will be administered at the Day 1, Week 12 and Week 24 Clinic Visits. After the Week 24 Visit, the morning dose need not 
be administered at the Clinic Visit. Additional guidance for preparation and administration of study drug is provided in Section 9.4 and the study manual. 


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Table 3-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects Not 
From Study 124) 
 
Screening 
Perioda 
Treatment Period 
(Day 1 through Week 96) 
ETT Visitb 
Safety 
Follow-up 
Visitc 
24-Week 
Follow-up 
OE 
Event/Assessment 
Day -28 to 
Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as Possible 
After the 
Last Dose 
4 Weeks 
(± 7 Days) 
After the 
Last Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
X 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone contact 
 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Historical data 
Xd 
 
 
 
 
 
 
 
 
 
 
 
CFTR genotypee 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug dose 
determination 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Length and weightf 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a 
Subjects will only be allowed to enroll in Study 126 after an adequate number of subjects have completed the corresponding age cohort in Study 124, in 
conjunction with feedback from regulatory authorities.  
b 
The ETT Visit is to be scheduled as soon as possible after the last dose of ivacaftor. If the ETT Visit occurs 3 weeks or later after the last dose of ivacaftor, 
the Safety Follow-up Visit will not be required. Subjects who elect to receive commercially available ivacaftor will be discontinued from ivacaftor dosing 
and will complete the ETT Visit. 
c 
For subjects who elect to receive commercially available ivacaftor, the Safety Follow-up Visit will not be required. 
d 
Historical data from birth to screening will also be collected before (i.e., at screening) or at Day 1 (see Section 11.2). 
e 
For subjects who participated in Study 124 Part A, the CFTR genotype result can be taken from Study 124. 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. 
f 
Length and weight measurements will be performed predose through the Week 24 Visit (see Section 11.5.1). 


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Table 3-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects Not 
From Study 124) 
 
Screening 
Perioda 
Treatment Period 
(Day 1 through Week 96) 
ETT Visitb 
Safety 
Follow-up 
Visitc 
24-Week 
Follow-up 
OE 
Event/Assessment 
Day -28 to 
Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as Possible 
After the 
Last Dose 
4 Weeks 
(± 7 Days) 
After the 
Last Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Physical 
examinationg 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGsh, i 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Serum chemistry 
and hematologyj 
X 
 
Chem-
istry 
only 
LFTs 
and 
hema-
tology 
only 
X 
X 
X 
X 
X 
X 
 
Ophthalmologic 
examinationk 
Xl 
 
 
 
 
 
X 
 
X 
Xm 
 
X 
Fecal sample 
collection n 
Xo 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
g 
Full physical examinations will be performed at the Screening, ETT, and Safety Follow-up Visits; abbreviated physical examinations will be performed at all 
other study visits. 
h 
Vital signs and ECGs will be taken predose through the Week 24 Visit. Following the Week 24 Visit, vital signs and ECGs may be taken pre- or post-dose. 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiratory rate, and pulse oximetry (see Section 11.6.3). 
i 
All 12-lead ECGs will be performed predose at the Day 1, Week 12 and Week 24 Clinic Visits. At all visits, ECGs will be taken before any other procedures 
that may affect heart rate, such as blood draws (see Section 11.6.4). 
j 
To minimize blood draws, the Screening Visit and Day 1 clinical laboratory assessments can be combined into a single blood draw taken up to 9 days before 
the Day 1 dosing. The results must be received and reviewed before the first dose of study drug. 
k 
The OE will be conducted by a licensed ophthalmologist, preferably a pediatric ophthalmologist. The OE may be performed at the study visit or ± 14 days of 
the clinic visit. 
l 
If an OE was conducted in Study 124 Part A within 12 weeks of the Day 1 Visit, the Day 1 Visit OE does not need to be repeated. 
m 
The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue ivacaftor dosing in the ivacaftor arm, 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. 


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Table 3-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects Not 
From Study 124) 
 
Screening 
Perioda 
Treatment Period 
(Day 1 through Week 96) 
ETT Visitb 
Safety 
Follow-up 
Visitc 
24-Week 
Follow-up 
OE 
Event/Assessment 
Day -28 to 
Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as Possible 
After the 
Last Dose 
4 Weeks 
(± 7 Days) 
After the 
Last Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Sweat chloride 
testp 
X 
X 
 
X 
 
 
X 
 
X 
 
 
 
Qualitative 
microbiology 
cultures 
 
X 
 
 
 
 
X 
 
X 
 
 
 
Multiple breath 
washout (optional)q  
 
X 
 
 
 
 
X 
 
Xr 
 
 
 
Study drug 
administrations  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
n 
Samples will be analyzed for fecal elastase-1 and other markers of intestinal inflammation, including fecal calprotectin. Samples may be collected (e.g., at 
home) up to 24 hours before the study visit (e.g., at home) and brought to the clinic. If the sample is collected in the clinic, the sample may be collected pre- 
or postdose. 
o 
The fecal sample may be collected at any time during screening.  
p 
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. For all subjects, except those that completed a baseline sweat chloride test at screening, a Day 1 sweat 
chloride test will be performed predose. At all other visits up to the Week 24 Visit, the test must be performed within a window of ± 2 hours relative to the 
ivacaftor dose. After the Week 24 Visit, the sweat chloride test may be performed at any time during the visit. 
q 
MBW will be performed on subjects for whom additional or separate informed consent was obtained for the procedures, and only at sites that are adequately 
trained and qualified to perform this assessment (Section 11.5.6). The Day 1 MBW must be performed within 1 week before the first dose, not postdose. The 
Week 96 MBW must be performed within 1 week before the last dose, not after the last dose. Detailed procedures will be supplied in a separate study 
manual. 
r 
MBW will be performed at the Week 48 and Week 72 Visits (± 7 days).  
s 
The morning dose of study drug will be administered at the Day 1, and 2-, 4-, 8-, 12-, 18-, and 24-Week Clinic Visits. After the Week 24 Visit, the morning 
dose need not be administered at the Clinic Visit. Additional guidance for preparation and administration of study drug is provided in Section 9.4 and the 
study manual. 


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Table 3-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects Not 
From Study 124) 
 
Screening 
Perioda 
Treatment Period 
(Day 1 through Week 96) 
ETT Visitb 
Safety 
Follow-up 
Visitc 
24-Week 
Follow-up 
OE 
Event/Assessment 
Day -28 to 
Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as Possible 
After the 
Last Dose 
4 Weeks 
(± 7 Days) 
After the 
Last Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
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 
 
 
Pulmonary 
exacerbations, 
CF-related 
hospitalizations 
Continuous from signing of ICF through the last dose of study drug 
 
 
 
Adverse events 
Continuous from signing ICF through the Safety Follow-up Visit (see Section 13.1.1.3) 
Ocular 
adverse 
events only 
Medications and 
procedures review 
Continuous from signing of ICF through the Safety Follow-up Visit 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ETT: Early Termination of Treatment; ICF: informed consent form; MBW: 
multiple breath washout; LFT: liver function test; OE: ophthalmologic examination; q12h: every 12 hours. 
 
 


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Table 3-4 
Schedule of Assessments for VX15-770-126 (Observational Arm) 
Event/Assessment 
Day 1a 
Ophthalmologic 
Examination 
(Week 24 [± 14 Days] 
After the Last Dose)b 
Long-term Follow-up 
Telephone Contact 
(Week 48 [± 7 Days] 
and Week 96 [± 7 Days])c 
Clinic visit 
X 
 
 
Informed consent 
X 
 
 
Inclusion/exclusion criteria review 
X 
 
 
Ophthalmologic examination 
 
X 
 
Telephone contact 
 
 
X 
Serious adverse events 
Continuous from Day 1 through the Long-term Follow-up Telephone 
Contact at Week 96 
OE: ophthalmologic examination 
 
a  
The Day 1 Visit can be the same day as the last study visit of Study 124 Part B. If the Day 1 Visit is not the 
same day as the last study visit of Study 124 Part B, a clinic visit will be required for signing of the ICF and 
inclusion/exclusion criteria review.   
b  
Subjects in the observational arm will complete the OE approximately 24 weeks after the last dose of ivacaftor. 
This OE will be performed in Study 126 unless already completed in Study 124 Part B. 
c  
Only for subjects who received ≥4 weeks of ivacaftor treatment in Study 124 Part B. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 19 
List of Tables............................................................................................................................ 23 
List of Figures .......................................................................................................................... 23 
List of Abbreviations................................................................................................................ 24 
5 
Introduction.......................................................................................................................... 26 
5.1 
Overview of Cystic Fibrosis ........................................................................................... 26 
5.2 
Overview of Cystic Fibrosis in Infants and Young Children ......................................... 26 
5.3 
Overview of Ivacaftor ..................................................................................................... 27 
6 
Study Objectives .................................................................................................................. 28 
6.1 
Ivacaftor Arm ................................................................................................................. 28 
6.1.1 
Primary Objective ................................................................................................... 28 
6.1.2 
Secondary Objective ............................................................................................... 28 
6.1.3 
Tertiary Objective ................................................................................................... 28 
6.2 
Observational Arm ......................................................................................................... 28 
6.2.1 
Primary Objective ................................................................................................... 28 
7 
Study Endpoints ................................................................................................................... 29 
7.1 
Ivacaftor Arm ................................................................................................................. 29 
7.1.1 
Primary Endpoint .................................................................................................... 29 
7.1.2 
Secondary Endpoint ................................................................................................ 29 
7.1.3 
Tertiary Endpoints .................................................................................................. 29 
7.2 
Observational Arm Endpoint .......................................................................................... 29 
8 
Study Population .................................................................................................................. 30 
8.1 
Ivacaftor Arm: Subjects From Study 124 Part B ............................................................ 30 
8.1.1 
Inclusion Criteria .................................................................................................... 30 
8.1.2 
Exclusion Criteria ................................................................................................... 31 
8.2 
Ivacaftor Arm: Subjects Not From Study 124 Part B ..................................................... 31 
8.2.1 
Inclusion Criteria .................................................................................................... 31 
8.2.2 
Exclusion Criteria ................................................................................................... 32 
8.3 
Observational Arm ......................................................................................................... 32 
8.3.1 
Inclusion Criterion .................................................................................................. 32 
8.3.2 
Exclusion Criterion ................................................................................................. 32 
9 
Study Implementation ......................................................................................................... 32 
9.1 
Overview of Study Design ............................................................................................. 32 
9.1.1 
Ivacaftor Arm ......................................................................................................... 33 
9.1.1.1 
Ivacaftor Arm: Screening (Subjects Not From Study 124 Part B)................... 33 
9.1.1.1.1 Repetition of Screening Assessments ......................................................... 34 
9.1.1.1.2 Rescreening ................................................................................................. 34 
9.1.1.1.3 Extension of Screening Window ................................................................. 35 
9.1.1.2 
Ivacaftor Arm Treatment Period (All Subjects) ............................................... 35 
9.1.1.2.1 Transition from Study 124 Part B to Day 1 of Study 126 ........................... 35 


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9.1.1.3 
Ivacaftor Arm Safety Follow-up Visit (All Subjects) ...................................... 36 
9.1.1.4 
Ivacaftor Arm Follow-up Ophthalmologic Examination (All Subjects).......... 36 
9.1.1.5 
Ivacaftor Arm Early Termination of Treatment (All Subjects) ....................... 36 
9.1.2 
Observational Arm ................................................................................................. 36 
9.1.3 
Observational Arm Day 1 Visit .............................................................................. 36 
9.1.4 
Observational Arm Ophthalmologic Examination ................................................. 36 
9.1.4.1 
Observational Arm Long-term Follow-up ....................................................... 37 
9.1.4.2 
Observational Arm Early Discontinuation ....................................................... 37 
9.1.5 
Independent Data Monitoring Committee .............................................................. 37 
9.2 
Rationale for Study Design and Study Drug Regimens ................................................. 37 
9.2.1 
Study Design........................................................................................................... 37 
9.2.2 
Study Drug Dose and Duration .............................................................................. 37 
9.2.3 
Rationale for Study Assessments ........................................................................... 38 
9.3 
Study Restrictions ........................................................................................................... 40 
9.3.1 
Prior and Concomitant Medications ....................................................................... 40 
9.3.2 
Prohibited Medications/Dietary Restrictions.......................................................... 40 
9.4 
Study Drug Dosage and Administration ......................................................................... 41 
9.5 
Dose Modification for Toxicity ...................................................................................... 41 
9.6 
Study Drug Interruptions ................................................................................................ 41 
9.7 
Removal of Subjects ....................................................................................................... 41 
9.8 
Replacement of Subjects ................................................................................................ 43 
10 Study Drug Information and Management ....................................................................... 43 
10.1 Preparation and Dispensing ............................................................................................ 43 
10.2 Packaging and Labeling ................................................................................................. 43 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 43 
10.4 Drug Accountability ....................................................................................................... 43 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 43 
10.6 Compliance ..................................................................................................................... 43 
10.7 Blinding and Unblinding ................................................................................................ 44 
11 Assessments .......................................................................................................................... 44 
11.1 Timing of Assessments ................................................................................................... 44 
11.2 Subject and Disease Characteristics ............................................................................... 44 
11.3 Pharmacokinetics ............................................................................................................ 44 
11.4 Pharmacodynamics (Ivacaftor Arm Only) ..................................................................... 44 
11.4.1 
Sweat Chloride ....................................................................................................... 44 
11.5 Efficacy and Exploratory Assessments (Ivacaftor Arm Only) ....................................... 45 
11.5.1 
Measures of Nutritional Status ............................................................................... 45 
11.5.2 
Qualitative Microbiology Cultures ......................................................................... 45 
11.5.3 
Pulmonary Exacerbations ....................................................................................... 45 
11.5.4 
CF-related Hospitalizations .................................................................................... 46 
11.5.5 
Markers of Intestinal Inflammation ........................................................................ 46 
11.5.6 
Multiple Breath Washout........................................................................................ 46 
11.6 Safety .............................................................................................................................. 46 
11.6.1 
Adverse Events ....................................................................................................... 46 
11.6.2 
Clinical Laboratory Assessments (Ivacaftor Arm Only) ........................................ 46 
11.6.3 
Physical Examinations and Vital Signs (Ivacaftor Arm Only) ............................... 48 


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11.6.4 
Electrocardiograms (Ivacaftor Arm Only) ............................................................. 49 
11.6.5 
Ophthalmologic Examinations ............................................................................... 49 
12 Statistical and Analytical Plans .......................................................................................... 50 
12.1 Sample Size and Power .................................................................................................. 50 
12.2 Analysis Sets .................................................................................................................. 50 
12.3 Statistical Analysis ......................................................................................................... 50 
12.3.1 
General Considerations ........................................................................................... 50 
12.3.2 
Background Characteristics .................................................................................... 51 
12.3.2.1 Subject Disposition .......................................................................................... 51 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 51 
12.3.2.3 Prior and Concomitant Medications (Ivacaftor Arm Only) ............................. 52 
12.3.2.4 Study Drug Exposure and Compliance (Ivacaftor Arm Only)......................... 52 
12.3.3 
Efficacy Analysis (Ivacaftor Arm Only) ................................................................ 52 
12.3.3.1 Analysis of Primary Variables ......................................................................... 52 
12.3.3.2 Analysis of Secondary Variables ..................................................................... 53 
12.3.3.3 Analysis of Tertiary Variables ......................................................................... 53 
12.3.4 
Safety Analysis ....................................................................................................... 54 
12.3.4.1 Adverse Events................................................................................................. 54 
12.3.4.2 Clinical Laboratory Assessments (Ivacaftor Arm Only) ................................. 55 
12.3.4.3 Electrocardiogram (Ivacaftor Arm Only)......................................................... 55 
12.3.4.4 Vital Signs (Ivacaftor Arm Only) .................................................................... 55 
12.3.4.5 Physical Examination (Ivacaftor Arm Only) ................................................... 56 
12.3.4.6 Ophthalmological Examination ....................................................................... 56 
12.3.5 
Interim and IDMC Analyses ................................................................................... 56 
12.3.5.1 Interim Analysis ............................................................................................... 56 
12.3.5.2 IDMC Analysis ................................................................................................ 56 
12.3.6 
Pharmacokinetic Analysis ...................................................................................... 56 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 56 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 56 
13.1.1 
Adverse Events ....................................................................................................... 56 
13.1.1.1 Definition of an Adverse Event........................................................................ 56 
13.1.1.2 Clinically Significant Assessments .................................................................. 56 
13.1.1.3 Documentation of Adverse Events................................................................... 57 
13.1.1.4 Adverse Event Severity .................................................................................... 58 
13.1.1.5 Adverse Event Causality .................................................................................. 58 
13.1.1.6 Study Drug Action Taken ................................................................................ 59 
13.1.1.7 Adverse Event Outcome .................................................................................. 59 
13.1.1.8 Treatment Given............................................................................................... 59 
13.1.2 
Serious Adverse Events .......................................................................................... 59 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 59 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 60 
13.1.2.3 Reporting Serious Adverse Events................................................................... 61 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 61 
13.2 Administrative Requirements ......................................................................................... 61 
13.2.1 
Ethical Considerations ............................................................................................ 61 


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13.2.2 
Subject Information and Informed Consent ........................................................... 61 
13.2.3 
Investigator Compliance ......................................................................................... 61 
13.2.4 
Access to Records ................................................................................................... 62 
13.2.5 
Subject Privacy ....................................................................................................... 62 
13.2.6 
Record Retention .................................................................................................... 62 
13.2.7 
Study Termination .................................................................................................. 62 
13.3 Data Quality Assurance .................................................................................................. 63 
13.4 Monitoring ...................................................................................................................... 63 
13.5 Electronic Data Capture ................................................................................................. 63 
13.6 Publications and Clinical Study Report .......................................................................... 64 
13.6.1 
Publication of Study Results ................................................................................... 64 
13.6.2 
Clinical Study Report ............................................................................................. 64 
14 References ............................................................................................................................. 65 
15 Protocol Signature Pages .................................................................................................... 70 
15.1 Sponsor Signature Page .................................................................................................. 70 
15.2 Investigator Signature Page ............................................................................................ 71 
 


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List of Tables 
Table 3-1 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Same-day 
Transition Subjects From Study 124 Part B) .......................................................... 9 
Table 3-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition 
Subjects From Study 124 Part B).......................................................................... 11 
Table 3-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A 
Only Subjects or Subjects Not From Study 124) .................................................. 14 
Table 3-4 
Schedule of Assessments for VX15-770-126 (Observational Arm) ..................... 18 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 47 
Table 13-1 
Grading of AE Severity ........................................................................................ 58 
Table 13-2 
Classifications for AE Causality ........................................................................... 58 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 59 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 59 
List of Figures 
Figure 2-1 
VX15-770-126 Study Design ................................................................................. 6 
Figure 9-1 
VX15-770-126 Study Design ............................................................................... 33 
 


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List of Abbreviations  
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
CL 
clearance 
CL/F 
apparent clearance 
CRF 
case report form 
EC 
ethics committee 
ECG 
electrocardiogram 
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 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
intravenous 
LCI 
lung clearance index 
LFT 
liver function test 
MBW 
multiple breath washout 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCHS 
Nutrition Examination Survey 
OE 
ophthalmologic examination 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic, pharmacokinetics 
PND 
postnatal day 
q12h 
every 12 hours 


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Abbreviation 
Definition 
QTc 
QT interval corrected 
QTcB 
QT interval corrected by Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected, unexpected, serious adverse reaction 
TEAE 
treatment-emergent adverse event 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
Vertex 
Vertex Pharmaceuticals Incorporated 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
 


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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 70,000 individuals worldwide, 
with 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 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, 6 
Currently, there is no cure for CF, and despite adjunctive treatments with nutritional 
supplements, antibiotics, and mucolytics,7 the median predicted age of survival of individuals 
born today with CF is approximately 40 years of age.1, 8-10  
More than 2000 mutations in the CFTR gene have been identified.11 CFTR mutations result in 
reduced quantity of CFTR at the cell surface or reduced CFTR function, leading to a decrease in 
epithelial chloride transport.12, 13 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).  
Mutations that cause CFTR gating defects are present in about 5% of the CF patient population 
worldwide. Approximately 4% of patients have the G551D mutation, and the remaining 1% have 
other mutations that cause a CFTR gating defect.14,15 The R117H mutation causes defects not 
only in channel gating but also in channel conductance.16 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.17-19 
Based on clinical and/or in vitro data, 28 additional ivacaftor-responsive mutations were 
approved in the US in 2017; approval for these additional mutations may be requested in other 
countries/regions.  
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) and/or by 
genotyping analysis.20 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. In the US, more than 80% of patients with CF are diagnosed by age 
2.1 In the EU, approximately 60% of patients with CF are diagnosed by 1 year of age,21 and in 
the UK, approximately 83% of patients with CF are diagnosed by 1 year of age.22 Genotyping for 
mutations in the CFTR gene is now routine practice in many countries.  
In infants with CF, pancreatic insufficiency23 and poor nutritional status24-26 are the most 
significant clinical manifestations of the disease. These factors often lead to poor growth with 


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subsequent growth delay,27, 28 poorer cognitive development,29  and other clinical comorbidities 
such as decreased lung function and survival.30, 31 Studies of subjects 1 month through 6 years of 
age also show the presence of lung disease21, 32-34 and liver disease35. High-resolution computed 
tomography studies including infants with CF that were diagnosed by newborn screening, but 
were considered clinically healthy, indicate that structural lung damage is common even very 
early in disease progression.21, 36, 37 In a cohort of 81 well-treated CF patients in Australia, by 
3 years, 10% had Pseudomonas aeruginosa infection and 84% had evidence of bronchiectasis.38 
This is consistent with the results of inflammatory marker studies that have found that airway 
inflammation begins in infancy.33, 39, 40 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.41 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.42 Mucoid P. aeruginosa infection is considered the 
major limiting factor in survival for patients with CF.43 
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.44 Notably, 18% of children with CF 
fall below the US Centers for Disease Control and Prevention’s (CDC) fifth percentile for 
weight, and 16% of children fall below the CDC fifth percentile for height.45 Malnourishment is 
associated with worsening lung function in children with CF and is also an independent predictor 
of mortality in this population.46 
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.47, 48 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.49  
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 showed that ivacaftor is effective in the treatment of subjects with 
CF 6 years of age and older who have gating mutations. Ivacaftor treatment produced 
improvements in CFTR function, as evidenced by improvements in lung function, sweat 
chloride, body mass index (BMI)/weight, pulmonary exacerbations, respiratory symptoms, and 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R; respiratory domain) in subjects who have a 
G551D gating mutations (Studies VX08-770-102 [Study 102] and VX08-770-103 [Study 103]) 
and in subjects who have non-G551D gating mutations (Study VX12-770-111 [Study 111]).50 
Results from Study VX11-770-110 (Study 110) showed that ivacaftor treatment in subjects aged 
6 years and older with CF who have an R117H mutation resulted in statistically significant 
improvements in sweat chloride response, but these subjects did not show any other meaningful 


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response. The safety profiles of ivacaftor from Studies 102, 103, 111, and 110 were all similar 
and demonstrated that ivacaftor was well tolerated.50  
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.50 Results from Study VX11-770-109 (Study 109), a Phase 3, open-label rollover 
study to evaluate the safety and pharmacodynamics (PD) of long-term ivacaftor in subjects from 
Study 108, showed that the overall safety profile was durable and remained favorable over an 
additional 84 weeks of treatment.51 
Based on the demonstrated safety profile in subjects 2 through 5 years of age with a CFTR gating 
defect (Studies 108 and 109), 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),50 evidence of complications of CF by age 6, and evidence supporting the benefits of 
early therapeutic intervention, there is great potential for patients <24 months of age who have an 
ivacaftor-responsive CFTR mutation to benefit from ivacaftor treatment.  
6 
STUDY OBJECTIVES 
6.1 
Ivacaftor Arm 
6.1.1 
Primary Objective 
To evaluate the safety of long-term ivacaftor treatment in subjects with CF who are <24 months 
of age at treatment initiation and have an approved ivacaftor-responsive mutation  
6.1.2 
Secondary Objective 
To evaluate the pharmacodynamics (PD) of long-term ivacaftor treatment in subjects with CF 
who are <24 months of age at treatment initiation and have an approved ivacaftor-responsive 
mutation  
6.1.3 
Tertiary Objective 
To evaluate the efficacy of long-term ivacaftor treatment in subjects with CF who are 
<24 months of age at treatment initiation and have an approved ivacaftor-responsive mutation  
6.2 
Observational Arm 
6.2.1 
Primary Objective 
To evaluate the long-term safety after discontinuation of ivacaftor treatment in subjects with CF 
who were <24 months of age at treatment initiation and have an approved ivacaftor-responsive 
mutation. 


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7 
STUDY ENDPOINTS 
7.1 
Ivacaftor Arm 
7.1.1 
Primary Endpoint 
Safety, as determined by: 
 Adverse events 
 Laboratory values (serum chemistry and hematology)  
 12-Lead ECGs and vital signs 
 Ophthalmologic examinations (OEs) 
7.1.2 
Secondary Endpoint 
Absolute change from baseline in sweat chloride through Week 96  
7.1.3 
Tertiary Endpoints 
 Absolute change from baseline through Week 96 for the following endpoints: 
o Weight  
o Length (assessed as height, as age appropriate) 
o Weight-for-length  
o Weight-for-age z-score 
o Length-for-age z-score 
o Weight-for-length-for-age z-score 
o BMI 
o BMI-for-age z-score 
o Lung clearance index (LCI) at qualified study sites  
o Fecal elastase-1 
o Markers of intestinal inflammation  
o Qualitative microbiology cultures 
 Annualized rate of pulmonary exacerbations  
 Rate of CF-related hospitalizations  
7.2 
Observational Arm Endpoint 
Safety after stopping ivacaftor treatment in Study VX15-770-124 (Study 124) Part B as 
determined by serious adverse events (SAEs) and results from an OE approximately 24 weeks 
after the last dose of ivacaftor in Study 124 Part B. 


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8 
STUDY POPULATION 
Subjects with CF <24 months of age at treatment initiation who have an ivacaftor-responsive 
CFTR mutation on at least 1 allele.  
 Subjects will be eligible in countries/regions where ivacaftor is approved for use in 
subjects 2 years of age and older. A list of approved ivacaftor-responsive CFTR 
mutations is included in the study manual. If ivacaftor is approved for additional 
mutations in any country/region, a memorandum will be sent to investigative sites in that 
country/region and subjects with the newly approved mutations will also be eligible.  
 Investigators should consult the approved ivacaftor label in their country/region to 
confirm approved mutations for subject eligibility. 
The study is open to subjects who meet all inclusion and exclusion criteria. Subjects will be 
drawn from 2 sources:  
 Subjects who completed Study 124 Part B and elect to enroll in Study VX15-770-126 
(Study 126) 
 Subjects who did not participate in Study 124 Part B, which includes  
o subjects who participated in Study 124 Part A only  
o subjects who did not participate in Study 124 Part A or B 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
8.1 
Ivacaftor Arm: Subjects From Study 124 Part B 
8.1.1 
Inclusion Criteria 
1. Subjects transitioning from Study 124 Part B must have completed the last study visit of 
Study 124 Part B 
Added guidance: 
 Subjects who had a study drug interruption at the last scheduled visit of Study 124 Part B, 
subjects who required study drug interruption that was to be continued or initiated at 
Day 1 in Study 126, or subjects who resumed study drug in Study 124 Part B after a 
study drug interruption due to elevated transaminases but who did not complete at least 
4 weeks of rechallenge with study drug (due to the timing of the rechallenge versus the 
time remaining in Study 124 Part B) must meet eligibility criteria and have received 
approval from the Vertex medical monitor. 
2. For Gap Transition subjects: hematology and serum chemistry results at baseline with no 
clinically significant abnormalities that would confound the study assessments or pose an 
additional risk to administering ivacaftor to the study subject, as judged by the investigator. 
3. As judged by the investigator, parent or legal guardian must be able to understand protocol 
requirements, restrictions, and instructions; and must sign the informed consent form (ICF).  


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8.1.2 
Exclusion Criteria 
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 ivacaftor to the subject. 
Examples of subjects who may not be eligible include  
 subjects with a history of allergy or hypersensitivity to the study drug; and 
 subjects with severe or life-threatening reactions to the study drug in Study 124.  
2. Subjects receiving commercially available ivacaftor treatment  
8.2 
Ivacaftor Arm: Subjects Not From Study 124 Part B  
Subjects not from Study 124 Part B will only be allowed to enroll in Study 126 after an adequate 
number of subjects have completed the corresponding age cohort in Study 124, in conjunction 
with feedback from regulatory authorities. 
8.2.1 
Inclusion Criteria 
1. Age <24 months at the Day 1 Visit 
2. Confirmed diagnosis of CF, defined as a sweat chloride value ≥60 mmol/L by quantitative 
pilocarpine iontophoresis or 2 CF-causing mutations  
 If the results of the sweat chloride and/or the genotype test are documented in the 
subject’s medical record, and the historic genotype result is approved by the Vertex 
medical monitor, the tests do not need to be performed 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.  
3. An ivacaftor-responsive CFTR mutation on at least 1 allele. Subjects will be eligible in 
countries/regions where ivacaftor is approved for use in subjects 2 years of age and older. 
 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, the subject will undergo CFTR genotype 
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.  
4. Hematology, serum chemistry, and vital signs results have no clinically significant 
abnormalities that would confound the study assessments, as judged by the investigator. 
5. Weight at screening must be within the weight limits as defined for the study drug dose 
levels (Section 9.2.2) or according to the dosing guidelines identified in the “Justification for 
Dose Selection” memorandum effective at the time a subject is screened. 
6. For subjects <3 months of age only, gestational age ≥38 weeks. 
7. As judged by the investigator, parent or legal guardian must be able to understand protocol 
requirements, restrictions, and instructions; and must sign the ICF. 


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8.2.2 
Exclusion Criteria 
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 ivacaftor 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 of Day 1 
3. Known colonization with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). A 
subject is excluded if they have a positive culture of one of these organisms.  
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, e.g., physiologic 
jaundice or breastmilk jaundice of the newborn)  
5. Hemoglobin <9.5 g/dL at screening 
6. History of solid organ or hematological transplantation 
7. Any clinically significant “non-CF-related” illness within 2 weeks of Day 1. “Illness” is 
defined as an acute (serious or nonserious) condition (e.g., gastroenteritis) 
8. Use of any moderate or strong inducers or inhibitors of cCYP3A within 2 weeks of Day 1 
9. 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. Note: Participation in a noninterventional study 
(including observational studies, registry studies, and studies requiring blood collections 
without administration of study drug) is permitted.  
10. Chronic kidney disease of Stage 3 or above 
11. Unable to undergo an adequate slit-lamp examination at screening 
12. Presence of a lens opacity or cataract identified at the screening OE (excluding those 
considered congenital and nonprogressive, such as a suture cataract)  
8.3 
Observational Arm 
8.3.1 
Inclusion Criterion 
1. Completed ivacaftor treatment in Study 124 Part B and elected not to enroll in the ivacaftor 
arm of Study 126, or received at least 1 dose of ivacaftor and prematurely discontinued 
ivacaftor treatment in Study 124 Part B and received at least 1 dose of ivacaftor treatment in 
Study 124 Part B  
8.3.2 
Exclusion Criterion 
1. Receiving ivacaftor treatment 
9 
STUDY IMPLEMENTATION 
9.1 
Overview of Study Design 
This is a Phase 3, 2-arm, multicenter study.  


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Enrollment in Study 126 is closely linked to Study 124 which will enroll subjects according to 
defined age cohorts, starting with ages 12 to <24 months, followed sequentially by appropriately 
grouped descending age cohorts based on available PK data. 
This study includes an ivacaftor arm (open-label, 96-week treatment period) and an 
observational arm. The study design is shown in Figure 9-1. 
Figure 9-1 
VX15-770-126 Study Design 
a 
For subjects who have a Same-day Transition, the Week 24 visit of Study 124 Part B will be the same day as 
the Day 1 Visit of Study 126. For subjects who have a Gap Transition, the last study visit of Study 124 Part B 
will not be the same day as the Day 1 Visit of Study 126 (see Section 9.1.1.2.1).  
b 
Day 1 for subjects in the observational arm can be the last study visit of Study 124 Part B (see Section 9.1.3). 
c 
The Follow-up OE in the observational arm can be performed in Study 124. 
d 
Only for subjects who received at least 4 weeks of study drug in Study 124 Part B. 
9.1.1 
Ivacaftor Arm 
9.1.1.1 
Ivacaftor Arm: Screening (Subjects Not From Study 124 Part B) 
Subjects not from Study 124 Part B will only be allowed to enroll in Study 126 after an adequate 
number of subjects have completed the corresponding age cohort in Study 124, in conjunction 
with feedback from regulatory authorities. 


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Subjects who participated only in Study 124 Part A and subjects who did not participate in 
Study 124 will have a Screening Period. CFTR genotyping does not need to be repeated for 
subjects from Study 124 Part A or for subjects whose genotype is adequately documented in 
their medical record and who receives approval from the Vertex medical monitor 
(Section 11.6.2).  
The investigator (or an appropriate authorized designee at the study site) will obtain informed 
consent from the subject’s parent or legal guardian before any study specific procedures are 
performed. Screening will occur within 28 days before administration of study drug.  
 If serum chemistry and hematology assessments are performed >9 days before Day 1, 
they must be repeated on Day 1, and the results must be reviewed and eligibility 
confirmed before the first dose of study drug.  
 If an OE was conducted in Study 124 Part A within 12 weeks of the Day 1 Visit, the 
Day 1 Visit OE does not need to be repeated. 
Screening Visit assessments are listed in Table 3-4. 
To prepare for study participation, the subject's parent or legal guardian will be instructed on the 
study restrictions (Section 9.3). 
9.1.1.1.1 
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 with approval of the Vertex medical monitor. 
 An adequate slit-lamp examination could not be conducted (Section 11.6.5). 
If repeat values are within the eligibility criteria and completed within the screening window or 
extended screening window (Section 9.1.1.1.3), the subject is eligible for the study. 
9.1.1.1.2 
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 and the 
OE only needs to be repeated if it has been >12 weeks since the last adequate slit-lamp 
examination. 
If a subject is rescreened, the rescreening window (28 days) will begin once the first rescreening 
assessment has been initiated.  


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9.1.1.1.3 
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 9.1.1.1.1) 
 Unexpected operational or logistical delays (e.g., delayed drug shipment)  
 Scheduling of the OE (Section 11.6.5) 
 Availability of required equipment 
A subject may have the screening window extended by 4 weeks upon approval by the Vertex 
medical monitor for a repeat slit-lamp examination (Sections 9.1.1.1.1 and 11.6.5). 
Regardless of approved extensions in the screening window, all subjects to be enrolled in the 
ivacaftor arm must have Day 1 serum chemistry and hematology assessments performed and 
reviewed for eligibility within 9 days before dosing on Day 1. 
9.1.1.2 
Ivacaftor Arm Treatment Period (All Subjects) 
Ivacaftor will be administered every 12 hours (q12h) from Day 1 through the morning dose of 
the Week 96 Visit. At each visit, except the final treatment period visit, the ivacaftor dose for 
each subject will be reassessed and adjusted if necessary. See Section 9.2.2 for information about 
ivacaftor doses.  
Subjects will be outpatients; study visits will occur as follows: 
 For subjects from Study 124 Part B: Day 1 and Weeks 12, 24, 36, 48, 60, 72, 84, and 96. 
 For subjects not from Study 124 Part B: Day 1 and Weeks 2, 4, 8, 12, 18, 24, 36, 48, 60, 
72, 84, and 96; a telephone contact will occur at Day 3. 
Treatment Period assessments are listed in Table 3-1 and Table 3-2 for subjects from Study 124 
Part B and in Table 3-3 for subjects not from Study 124 Part B. 
9.1.1.2.1 
Transition from Study 124 Part B to Day 1 of Study 126  
All subjects must sign the ICF before any Study 126-related assessments. Subjects from 
Study 124 Part B can transition into Study 126 as follows: 
 Same-day Transition: If the Day 1 Visit is the same day as the Week 24 Visit of 
Study 124 Part B, the subject will not have to perform any Day 1 assessments that were 
performed at the Week 24 Visit of Study 124 Part B (Table 3-1).  
 Gap Transition: If the Day 1 Visit is NOT the same day as the last study visit of 
Study 124 Part B, all Day 1 assessments will need to be performed (Table 3-2), with the 
possible exception of the following: 
o Clinical laboratory assessments: Results must be reviewed and eligibility 
confirmed before dosing on Day 1.  
 If the Day 1 Visit is conducted ≤9 days after the last study visit of 
Study 124 Part B, the serum chemistry and hematology assessments 
performed at the last study visit of Study 124 Part B will not need to be 
repeated. 


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 If the Day 1 Visit is conducted >9 days after the last study visit of 
Study 124 Part B, the serum chemistry and hematology assessments must 
be repeated on Day 1, and the results must be reviewed and eligibility 
confirmed before the first dose of study drug.  
o OE: If an OE was conducted in Study 124 Part B within 24 weeks of the Day 1 
Visit, the Day 1 Visit OE does not need to be repeated. Otherwise, an OE must be 
conducted within 14 days of the Day 1 Visit. Throughout this study, these 
subjects should have OEs approximately every 24 weeks (± 14 days) from the last 
OE in Study 124. 
9.1.1.3 
Ivacaftor Arm Safety Follow-up Visit (All Subjects) 
There will be a Safety Follow-up Visit 4 weeks ± 7 days after the last dose of ivacaftor. The 
Safety Follow-up Visit is not required if the Early Termination of Treatment (ETT) Visit occurs 
3 weeks or later after the last dose of ivacaftor or if the subject begins treatment with 
commercially available ivacaftor. 
Safety Follow-up assessments are listed in Table 3-1 and Table 3-2 for subjects from Study 124 
Part B and Table 3-3 for subjects not from Study 124 Part B. 
9.1.1.4 
Ivacaftor Arm Follow-up Ophthalmologic Examination (All Subjects) 
There will be a Follow-up OE 24 weeks + 14 days after the last dose of ivacaftor for all subjects. 
9.1.1.5 
Ivacaftor Arm Early Termination of Treatment (All Subjects) 
Subjects who prematurely discontinue treatment before their last scheduled dose will be required 
to complete the ETT Visit, Safety Follow-up Visit, and Follow-up OE. The ETT Visit must be 
completed as soon as possible after the last dose of ivacaftor. If the ETT Visit occurs 3 weeks or 
later after the last dose of ivacaftor, the Safety Follow-up Visit will not be required.  
Subjects who receive commercially available ivacaftor will be discontinued from ivacaftor 
dosing and will complete the ETT Visit and Follow-up OE; the Safety Follow-up Visit will not 
be required. 
If the subject withdraws consent for the study, no further evaluations should be performed and no 
additional data should be collected. Vertex may retain and continue to use any data collected 
before such withdrawal of consent. 
ETT assessments are listed in Table 3-1 and Table 3-2 for subjects from Study 124 Part B and 
Table 3-3 for subjects not from Study 124 Part B. 
9.1.2 
Observational Arm 
9.1.3 
Observational Arm Day 1 Visit 
The Day 1 Visit can be on the same day as the last study visit of Study 124 Part B (see 
Table 3-4). Demographics and baseline characteristics will be taken from the most recent 
Study 124 Part B visit from which these data are available.  
9.1.4 
Observational Arm Ophthalmologic Examination 
An OE will be conducted approximately 24 weeks after the last dose of ivacaftor in Study 124 
Part B, unless an OE was already conducted approximately 24 weeks after the last dose of 
ivacaftor in Study 124 Part B. 


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9.1.4.1 
Observational Arm Long-term Follow-up 
Subjects who received at least 4 weeks of study drug in Study 124 Part B will be followed for 
96 weeks; telephone contact will be made at Week 48 (± 7 Days) and Week 96 (± 7 Days). 
9.1.4.2 
Observational Arm Early Discontinuation 
Subjects who receive commercially available ivacaftor will be discontinued from the 
observational arm after completing the observational arm OE (Section 9.1.4). 
9.1.5 
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 12.3.5). 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 subject is screened. 
9.2 
Rationale for Study Design and Study Drug Regimens 
9.2.1 
Study Design 
Based on the mechanism of action of ivacaftor and available data indicating that the 
CFTR-potentiating effects of ivacaftor stop when ivacaftor treatment is discontinued, it is likely 
that ivacaftor will be a chronic treatment for patients with CF. Given the study objectives of 
generating data about long-term safety and providing data to complement existing efficacy 
studies in subjects having CFTR gating mutations, an open-label study of extended duration 
provides the best way to provide as many patients as possible potentially beneficial therapy while 
providing necessary monitoring to ensure safety. The 96-week duration of the ivacaftor arm of 
this study allows for the evaluation of the long-term safety and PD of ivacaftor treatment, as well 
as an exploration of the efficacy of long-term ivacaftor treatment in subjects <24 months of age 
at treatment initiation. 
Subjects who completed Study 124 Part B will be eligible for enrollment. To increase the study 
sample size, subjects who did not participate in Study 124 Part B (subjects who participated in 
Study 124 Part A only, or subjects who did not participate in Study 124) and are <24 months of 
age at the Day 1 Visit in Study 126 are also eligible for enrollment. 
The Observational Arm will evaluate the ocular safety following ivacaftor treatment and the 
potential for long-term, off-treatment effects in subjects who received ≥4 weeks of ivacaftor in 
Study 124 Part B.  
9.2.2 
Study Drug Dose and Duration 
The same population pharmacokinetic (PK) approach used for selection of doses in subjects 2 to 
<6 years of age in Study VX11-770-108 (Study 108) was used for dose selection in subjects 
<24 months of age. In the population PK model, body weight represents changes in ivacaftor PK 
as a function of body size by incorporation of an allometric model. Simulations performed using 
the population PK model supported a dose of 50 mg q12h for subjects with a body weight 
<14 kg and 75 mg q12h for subjects with a body weight ≥14 kg in Study 108. At the conclusion 
of Study 108, PK data obtained from subjects 2 to <6 years of age were included in the most 
recent population PK model. Body weight is the most important predictor of ivacaftor 
disposition, with an ivacaftor apparent clearance (CL/F) of 39% and 131% of the reference 70-kg 
subject for the typical 20-kg and 100-kg subjects, respectively.52  


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Using the current model, simulations were performed to provide different weight strata for doses 
of ivacaftor. The simulations incorporated a maturation function to determine the range of likely 
exposures given the maturational changes in clearance (CL). Because 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% and 80% from adult values for a 
newborn, and CL reached a mature value between 12 and 18 months. The maximum changes in 
CL and maturation rate are consistent with the differences in CYP3A4 expression in infants.53, 54 
The simulations support selection of the following doses for CF subjects <24 months of age: 
25 mg for ≥5.0 to <7 kg, 50 mg for ≥7 to <14 kg, and 75 mg for ≥14 to <25 kg. These doses may 
be modified in the future based on available PK data and may result in additional doses or 
different age and/or weight strata. 
Data from Studies 124 and 126 and any updated modeling approaches resulting from such data 
may result in updated dose recommendations. Changes to study drug dose, age strata or weight 
bounds will be communicated to site personnel through a memorandum entitled “Justification for 
Dose Selection” to ensure clarity and consistency in study conduct. 
Once a subject reaches 24 months of age, ivacaftor will be dosed at 50 mg q12h for subjects 
<14 kg and 75 mg q12h for subjects ≥14 kg, in accordance with the approved recommended 
dosages for commercially available ivacaftor. 
9.2.3 
Rationale for Study Assessments 
The safety 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.  
OEs are included in this study because a juvenile toxicity study conducted in albino rats to 
support clinical studies of ivacaftor in children <2 years of age demonstrated the presence of 
cataracts (lens opacities) when newborn rats were dosed with ivacaftor beginning at postnatal 
day (PND) 7 through PND 35, particularly at the highest dose tested. The results of chronic 
toxicity studies in the rat and dog did not reveal a cataractogenic potential. Although the 
relevance of this finding to humans is unknown, subjects will undergo an OE at the time points 
indicated in Table 3-1, Table 3-2, Table 3-3, and Table 3-4 to monitor the potential risk of 
cataracts (lens opacities). 
The efficacy assessments were evaluated in Study 124 and are included in this study to evaluate 
the long-term effects of ivacaftor treatment. The efficacy assessments are widely accepted and 
are 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 before 
the sweat reaches the surface of the skin. Because patients with CF have diminished CFTR 
activity, chloride ions are poorly reabsorbed, leading to elevated sweat chloride concentration.55, 
56 Sweat chloride can be measured in patients with CF of all ages, although levels do increase 
throughout the first 6 months of life.57 


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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.  
Measures of nutritional status: Poor somatic growth and poor nutritional status are common in 
patients with CF owing to a number of factors, including increased energy expenditures and 
appetite suppression due to lung disease as well as diabetes and pancreatic insufficiency-related 
fat malabsorption.44 Growth deficiencies in children as young as 2 years of age are associated 
with worsening lung function and are also independent predictors of mortality in children with 
CF.58 Furthermore, growth deficiencies at 4 months of age are most predictive of later growth 
deficiencies.29 
While it is unknown if poor weight gain predicts clinical lung disease or whether progressive 
lung disease leads to poor weight gain, change in weight is a clinically relevant endpoint. Given 
that ivacaftor is a systemic therapy, it has the potential to improve extrapulmonary 
manifestations of CF. Modulation of CFTR function in the pancreas and gastrointestinal tract 
may lead to improvements in digestion and, consequently, weight gain. 
In Phase 3 Studies 102 and 103, the improvement in mean weight gain after 24 weeks of 
ivacaftor versus placebo treatment was substantial, clinically meaningful, and statistically 
significant in subjects ≥12 years of age (Study 102) and 6 to 11 years of age, inclusive 
(Study 103). In open-label Phase 3 Study 108, conducted in subjects 2 through 5 years of age, 
substantial improvements in nutritional status with ivacaftor treatment were observed for weight, 
weight-for-age z-scores, BMI, and BMI-for-age z-scores; these improvements continued to 
Week 24.  
As children gain weight as part of normal growth, adjustment for age and sex is necessary to 
assess changes in nutritional status in a population of boys and girls in varying stages of growth. 
To evaluate the effect of ivacaftor on growth and nutrition adjusted for age and sex, 
weight-for-age, length-for-age, weight-for-length-for-age, and BMI-for-age z-scores will be 
determined.  
Qualitative microbiology cultures: Microbiological endpoints, such as bacterial colony counts 
and selection of resistant bacterial strains, are well-established endpoints used to evaluate 
antimicrobial therapies in CF.35, 59, 60 Because compounds such as ivacaftor that restore CFTR 
function may increase hydration of airway secretions and lead to a decrease in acquisition of 
bacteria in the CF airway, acquisition of bacteria is included as a tertiary endpoint in this study. 
Because the majority of subjects <24 months of age do not expectorate spontaneously, 
oropharyngeal swabs will be used to obtain airway cultures in this study.   
Pulmonary exacerbations and CF-related hospitalizations: Pulmonary exacerbations are used to 
assess efficacy in therapies targeting improvement in CF disease.61, 62 These events have been 
associated with the severity and rate of progression of lung disease in patients with CF. To date, 
however, there is no generally accepted objective definition of an exacerbation,63 and large 
multicenter CF clinical studies have used many variations of physician-derived definitions64-68 in 
patients 6 years of age and older. Despite the lack of a standard definition, reduction in 
exacerbation rate has served as a key clinical efficacy measure in definitive CF clinical studies, 
supporting the registration of 2 chronic CF pulmonary therapies.65, 67 Definitions for pulmonary 
exacerbation in subjects <24 months of age are being evaluated in ongoing studies of CF 
therapies,69 but they have not yet been validated for use in clinical studies involving subjects of 


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this age. In this study, pulmonary exacerbation has been defined based on modification of criteria 
used in previous and ongoing trials in young children with CF, and occurrence will be derived 
based on both primary and alternative definitions. In addition, data on CF-related hospital 
admissions will be collected to assess the rate of these clinically significant events. 
Measures of pancreatic function: Fecal elastase-1 is used clinically to diagnose pancreatic 
exocrine insufficiency in patients with CF. The increasing use of fecal elastase-1 in the clinic is a 
result of the relative ease of collecting samples for its assessment and the establishment of 
diagnostic cut-offs for pancreatic exocrine function.70-73 Therefore, fecal elastase-1 represents a 
feasible measure to evaluate exocrine pancreatic function after treatment in this study. In 
open-label Phase 3 Study 108 conducted in subjects 2 through 5 years of age, substantial 
increases from baseline in fecal elastase-1 were observed at Week 24.50 These results suggest an 
improvement in pancreatic function with ivacaftor treatment. 
Markers of intestinal inflammation: Fecal samples will be collected to investigate biomarkers 
related to intestinal inflammation in CF patients, including but not limited to fecal calprotectin. 
Fecal calprotectin has been shown to be increased in pediatric patients with CF.74 These data 
support the concept that intestinal inflammation is a feature of CF, and that intestinal 
inflammation can be monitored by measuring noninvasive biomarkers such as fecal calprotectin 
in clinical studies with CF patients. 
Multiple breath washout (MBW) for LCI values: LCI is a measure of ventilation inhomogeneity 
derived from MBW assessment that is based on tidal breathing techniques that have been 
evaluated in patients as young as infants.75, 76 This assessment will explore the value of MBW in 
the diagnosis of early changes in lung function in infants with CF (see Section 11.5.6). 
9.3 
Study Restrictions 
9.3.1 
Prior and Concomitant Medications 
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 from Study 124 Part B: from Day 1 through the Safety Follow-up Visit 
(Section 9.1.1.3) 
 For subjects not from Study 124 Part B: from 28 days before the Screening Visit through 
the Safety Follow-up Visit (Section 9.1.1.3) 
For any subjects who are screened but are not enrolled in the study, details of prior and 
concomitant medications will only be documented in the subject’s source documents.  
For subjects in the ivacaftor arm, 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. 
9.3.2 
Prohibited Medications/Dietary Restrictions 
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. 
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 or authorized designee.  
9.4 
Study Drug Dosage and Administration 
The starting dose will be 25, 50, or 75 mg ivacaftor granules, or another suitable dose (to be 
determined based on safety and PK data from Study 124 Parts A and B, age, and weight; see 
Section 9.2.2). At each clinic visit, the ivacaftor dose for each subject will be reassessed based on 
body weight and adjusted if necessary. 
Once a subject reaches 24 months of age, ivacaftor will be dosed at 50 mg q12h for subjects with 
a body weight <14 kg and 75 mg q12h for subjects with a body weight ≥14 kg, in accordance 
with the approved recommended dosages for commercially available ivacaftor. 
For subjects not from Study 124 Part B, the first dose of ivacaftor will be administered in the 
clinic, and subjects will be observed for 4 hours after dose administration.  
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 from Day 1 through Week 96. Details of dose preparation and dose 
administration will be provided in the study manual. 
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 the 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. 
At the Day 1 and Week 2, 4, 8, 12, 18, and 24 Visits, the time of administration of ivacaftor in 
the clinic on the day of the visit will be recorded. 
9.5 
Dose Modification for Toxicity 
The investigator must not adjust the study drug dose for toxicity.  
9.6 
Study Drug Interruptions 
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 on interruption for elevated LFT levels are provided in 
Section 11.6.2.  
9.7 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. 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, Safety Follow-up, and OE Follow-up Visits, as indicated in Sections 9.1.1.3 
and 9.1.1.5, provided the subject’s parent or legal guardian has not withdrawn consent.  


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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 Safety Follow-up Visit, if applicable (see Section 9.1.1.5), and 
follow up with the subject’s parent or legal guardian regarding any unresolved adverse events 
(AEs). 
If the subject’s parent or legal guardian withdraws consent for the study, no further evaluations 
will be performed and no additional data will be collected. Vertex may retain and continue to use 
any data collected before such withdrawal of consent. 
A subject will be discontinued from study treatment for any of the following reasons:  
 Vertex, regulatory authorities, or the site's IRB or ethics committee (EC) closes the study. 
 A subject is noncompliant with study protocol requirements, restrictions, and instructions 
to an extent that is considered unacceptable by the investigator or Vertex medical 
monitor. 
 A subject participates in another interventional clinical study. 
 A subject develops a new lens opacity or cataract (see Section 11.6.5).  
A subject may be discontinued from 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 has an increase in liver function test levels (LFTs; e.g., AST or ALT levels) as 
described in Section 11.6.2. 
 Clinically significant findings are observed in the slit-lamp examination. 
During the course of the study, if ivacaftor is approved and available for the treatment of CF in 
populations enrolled in this study, subjects may be discontinued at the discretion of the sponsor. 
If a subject is switching to commercially available ivacaftor, the ETT Visit (Section 9.1.1.5) will 
be completed before dosing with commercial drug begins, and the Safety Follow-up Visit will 
not be required.  
Alternatively, if local health authorities decline to approve ivacaftor, or if ivacaftor cannot be 
given to patients within a given age cohort (e.g., an appropriate dose cannot be determined), then 
subjects of the relevant populations may be discontinued after communication to investigators 
and IRBs/IECs of the benefits/risks for the relevant subject population. If subjects are 
discontinued from the study, an ETT Visit should occur as soon as possible after the last dose of 
study drug and a Safety Follow-up Visit should occur within 4 weeks (± 7 days) after the last 
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9.8 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex's discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
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. 
10.2 
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. 
10.3 
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 10.4. 
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.  
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects' parent or legal guardian. Subjects’ parents or legal guardians will be 
instructed to return all used and unused materials associated with the study drug to the site. 
These materials will be retained at the site according to instructions provided by Vertex or its 
designee until inventoried by the study monitor. The study monitor will review study drug 
records and inventory throughout the study. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects’ 
parents or legal guardians until the study monitor has performed drug accountability. At the end 
of the study, the study monitor will provide instructions as to the disposition of any unused 
investigational product. If the study monitor authorizes destruction at the study site, the 
investigator will ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by Vertex. 
Destruction will be adequately documented. 
10.6 
Compliance  
Study drug accountability should be assessed at each visit by counting returned dosage units 
(sachets/packets). 


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If there is continued noncompliance with study requirements, restrictions, instructions, and study 
drug dosing despite educational efforts, the investigator should contact the Vertex medical 
monitor or authorized designee to discuss noncompliance and discontinuation of the subject from 
the study.  
10.7 
Blinding and Unblinding 
This will be an open-label study. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments for the ivacaftor arm is shown in:  
 Table 3-1: subjects from Study 124 Part B who have a Same-day Transition 
(Section 9.1.1.2.1) 
 Table 3-2: subjects from Study 124 Part B who have a Gap Transition (Section 9.1.1.2.1)  
 Table 3-3: subjects from Study 124 Part A or subjects not from Study 124 Parts A or B 
The timing of assessments for the observational arm is shown in Table 3-4.  
11.2 
Subject and Disease Characteristics 
For subjects transitioning from Study 124 Part B, demographics, medical history, and historical 
data will be taken from Study 124. For all other subjects, demographics, medical history, length, 
weight, and the additional historical data described below will be collected before (e.g., at 
screening) or at Day 1. 
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) length and weight measurements  
 The dates and reasons for all CF-related hospitalizations  
 Any use (yes or no) of the following medications: inhaled tobramycin, inhaled 
aztreonam, inhaled colimycin, inhaled hypertonic saline, dornase alfa, ibuprofen, 
azithromycin, and pancreatic enzyme replacement therapy  
 Historical pancreatic status measurements (prior fecal elastase-1 assessments) 
11.3 
Pharmacokinetics 
Not applicable. 
11.4 
Pharmacodynamics (Ivacaftor Arm Only) 
11.4.1 
Sweat Chloride 
Collection of sweat chloride samples will be performed at qualified study sites using an approved 
Macroduct® (Wescor, Logan, UT) collection device. Sweat chloride samples will be sent to a 
central laboratory for testing and interpretation of results. Individual sweat chloride test results 
will not be disclosed to the study sites. Specific instructions for the collection, handling, 


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processing, and shipping of sweat chloride samples to the central laboratory will be provided 
separately.  
The sweat chloride test at the Day 1 Visit must be performed before the ivacaftor dose. Baseline 
sweat chloride test is not required at Day 1 if it was completed at screening. At subsequent visits 
through Week 24, the sweat chloride test must be performed within a window of ± 2 hours 
relative to the ivacaftor dose. After the Week 24 Visit, the sweat chloride test may be performed 
at any time during the visit. Change from baseline in sweat chloride will be analyzed as a 
secondary endpoint in this study. 
11.5 
Efficacy and Exploratory Assessments (Ivacaftor Arm Only) 
11.5.1 
Measures of Nutritional Status 
Length and weight must be measured with the subject in a dry diaper or dry underclothes only. 
Length should be measured throughout the study while the subject is lying supine by measuring 
from the crown of the head to the bottom of the feet with the hips and legs straightened. Change 
from baseline in weight, length, weight-for-length, weight-for-age z-score, length-for-age 
z-score, weight-for-length-for-age z-score, BMI, and BMI-for-age z-score will be analyzed as a 
tertiary endpoint in this study.  
11.5.2 
Qualitative Microbiology Cultures 
A cotton-tipped swab will be used to collect the microbiology specimen from the posterior 
oropharyngeal wall and tonsillar pillars. Specific instructions for the collection, processing, and 
shipment of samples will be provided in a separate Laboratory Manual.  
11.5.3 
Pulmonary Exacerbations 
The incidence of pulmonary exacerbations will be recorded. For this study, given the absence of 
a consensus definition for pulmonary exacerbation in clinical studies in this population, 
2 definitions will be applied to the signs and symptoms shown below for analyses of pulmonary 
exacerbations: 
Definition 1: Treatment with oral, inhaled, or intravenous (IV) antibiotics AND fulfillment of 
1 or more of the criteria from List A or List B, within 3 days before antibiotic start date through 
antibiotic stop date.  
Definition 2: Treatment with oral, inhaled, or IV antibiotics AND fulfillment of 1 criterion from 
List A or 2 criteria from List B, within the period 3 days before antibiotic start date through 
antibiotic stop date.77 
The occurrence of any new or changed antibiotic therapy (IV, inhaled, oral) and the presence of 
the following signs and symptoms will be collected:  
List A: 
 Oxygen saturation <90% on room air or ≥5% decrease from baseline  
 New lobar infiltrate(s) or atelectasis on chest x-ray 
 Hemoptysis (more than streaks on more than 1 occasion in the past week) 
List B: 
 Increased work of breathing or respiratory rate (duration ≥3 days) 


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 New or increased adventitial sounds on lung exam (duration ≥3 days) 
 Weight loss of ≥5% from the highest value or decrease across 1 major percentile for age 
in the past 6 months  
 Increased cough (duration ≥3 days) 
 Worked harder to breathe during physical activity (duration ≥3 days) 
 Increased chest congestion or change in sputum (duration ≥3 days) 
11.5.4 
CF-related Hospitalizations 
Subject’s parents/caregivers will be queried about CF-related hospitalizations. The dates and 
reasons for the CF-related hospitalizations will be collected.  
11.5.5 
Markers of Intestinal Inflammation 
Fecal samples for assessment of fecal elastase-1, fecal calprotectin, and other markers of 
intestinal inflammation will be collected.  
11.5.6 
Multiple Breath Washout 
MBW is optional and will only be performed on subjects for whom additional or separate 
informed consent was obtained. Also, MBW will only be performed at sites that are adequately 
trained and qualified and are equipped with a mass spectrometry MBW system. Therefore, only a 
subset of subjects will undergo MBW assessment. However, subjects from other sites may be 
referred to the sites that have capability to perform MBW. Detailed procedures for the MBW will 
be supplied in a separate study manual. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, 12-lead ECGs, physical examinations (PEs; with clinically significant abnormalities 
recorded as medical history or adverse events), and OEs. 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions; collection periods; criteria; and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments (Ivacaftor Arm Only) 
Blood samples for clinical laboratory assessments will be analyzed at a central laboratory. Local 
laboratories may be used at the discretion of the local investigator for management of urgent 
medical issues. If a local laboratory test value is found to be abnormal and clinically significant, 
it will be verified by the central laboratory as soon as possible after the investigator becomes 
aware of the abnormal result. The Vertex medical monitor or authorized designee should be 
notified. 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 will be reported as AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-1. 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Glucose  
Blood urea nitrogen  
Creatinine 
Sodium 
Potassium 
Calcium 
Phosphate 
Bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate transaminase  
Alanine transaminase  
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 
  
Note: Screening Visit blood draws will be done after a minimum 4-hour fast. All subsequent blood draws do not 
require fasting.  
CFTR Genotype:  
Subjects must have an approved ivacaftor-responsive mutation on at least 1 allele to meet 
inclusion criteria (see study manual and approved country/region ivacaftor label). The genotype 
results must be available before the first dose of study drug is administered to the subject. 
Subjects who had CFTR genotyping completed in Study 124 will not require repeat testing upon 
entry into this study. 
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.  
Subjects will not receive the study drug if CFTR genotype is not confirmed by a historic 
genotype result OR by genotype testing at screening. 
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 levels 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 for repeat confirmatory analysis by the central laboratory. If, under exceptional 


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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 9.7). 
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 any 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. 
11.6.3 
Physical Examinations and Vital Signs (Ivacaftor Arm Only) 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital sign assessments 
can be performed at the discretion of the investigator or health care provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat 
(EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 


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neurological. Anorectal and genital examinations will be performed when medically indicated. 
After screening, any clinically significant abnormal findings in PEs will be reported as AEs. 
The abbreviated PE will include an assessment of the following body systems: 
head/neck/thyroid, EENT, cardiovascular system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiratory 
rate, and pulse oximetry. The subject will be instructed to rest in the supine position (if possible) 
for at least 5 minutes before vital signs are assessed. The temperature must be obtained by the 
same method throughout the study. 
11.6.4 
Electrocardiograms (Ivacaftor Arm Only) 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
 The subject will rest in the supine position for at least 5 minutes, if possible, before 
having an ECG performed. 
 The ECG will be performed predose through the Week 24 Visit before any other 
procedures that may affect heart rate, such as blood draws. Following the Week 24 Visit, 
ECGs may be taken pre- or post-dose. 
The ECG traces will be manually read at the study site at the Screening Visit and Safety 
Follow-up Visit. A printout of the ECG traces will be made for safety review by the investigator 
and maintained with source documentation. Clinically significant ECG abnormalities occurring 
during the study through the Safety Follow-up Visit will be recorded as AEs. 
Study sites should use QTcF unless they receive approval in advance from the Vertex medical 
monitor or authorized designee to use QTcB. 
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 
11.6.5 
Ophthalmologic Examinations 
All subjects should have an OE approximately every 24 weeks while on ivacaftor treatment in 
this study. Subjects who did not participate in Study 124 Part B should have an additional OE 
exam at Week 12. The OE must be conducted by a licensed ophthalmologist, preferably a 
pediatric ophthalmologist. Whenever possible, the same ophthalmologist should perform the OEs 
throughout the study. The OE will include the following: 
 Examination of the lens with a slit-lamp (portable or otherwise; pharmacologically 
dilated examination) 
 Assessment of the red reflex (pharmacologically dilated examination)  


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 Screening OEs (subjects not from Study 124 Part B only): examination of the fundus 
(retina, optic nerve, and vessels), pupils, and eye movements 
For subjects not from Study 124, relevant medical history (e.g., history of steroid use; history of 
trauma to the eye; and family history of glaucoma, congenital cataracts, or cataracts arising later 
in life) will be collected at screening. For subjects from Study 124 Part B with a Same-day 
Transition, the above relevant ophthalmological medical history will be collected in Study 124. 
For subjects from Study 124 Part B with a Gap Transition, the above relevant ophthalmological 
history will be collected before or at the Day 1 Visit. 
During the screening period, if an adequate slit-lamp examination cannot be conducted, subjects 
will not be enrolled until an adequate repeat slit-lamp examination is completed 
(Sections 9.1.1.1.1 and 9.1.1.1.3) and eligibility criteria regarding the ophthalmologic findings 
are met.  
If a new lens opacity or cataract is identified at any OE in subjects in the ivacaftor arm, study 
drug dosing must be discontinued. The Vertex medical monitor should also be notified.  
12 
STATISTICAL AND ANALYTICAL PLANS 
Analysis of all data will be performed by Vertex (or designee).  
A detailed analysis plan for the analysis of safety and efficacy data will be presented in a 
statistical analysis plan (SAP). As the study design is open label, a draft SAP for the final 
analysis will be available before the first subject is dosed; the SAP will be approved before data 
lock. 
12.1 
Sample Size and Power 
The study is not powered to detect a significant treatment effect. The study will enroll 
approximately 75 subjects. 
12.2 
Analysis Sets 
The All Subjects Set (defined as all enrolled subjects) will be used to summarize the disposition 
table and listings. The Safety Set (defined as enrolled subjects who receive at least 1 dose of 
ivacaftor in Study 126) will be used for all safety analyses. The Full Analysis Set (FAS) (defined 
as enrolled subjects who have at least 1 postbaseline efficacy assessment in Study 126) will be 
used for all efficacy analyses. 
12.3 
Statistical Analysis 
Data from all endpoints will be summarized using descriptive statistics and presented by subjects 
from Study 124 Part B/subjects not from Study 124 Part B, and by study visit. No inferential 
analyses are planned. 
12.3.1 
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 using descriptive statistics.  
Categorical data will be summarized by contingency tables (n, percentage, and 95% CI).  


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Listings will display all subjects who were enrolled or dosed. 
Definition of the baseline value: There are 2 baselines, the baseline from Study 124 Part B and 
the baseline in the current study.  
The Study 124 Part B baseline value will be defined as the baseline measurement from 
Study 124 Part B. That is, the most recent non-missing measurement collected on or before the 
initial administration of study drug in Study 124 Part B will be the Study 124 Part B baseline. 
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 Study 126 baseline value will be defined as the most recent non-missing measurement 
collected on or before the initial administration of study drug or enrollment in the observational 
arm, including both the scheduled and unscheduled measurements.  
The absolute change from baseline value will be defined as the postbaseline value minus the 
baseline value.  
For subjects from Study 124 Part B with a Same-day Transition (Section 9.1.1.2.1), absolute 
change will be determined from Study 124 Part B baseline and Study 126 baseline. For subjects 
from Study 124 Part B with a Gap Transition (Section 9.1.1.2.1), absolute change will be 
determined from Study 126 baseline. 
For subjects who did not participate in Study 124 Part B (e.g., subjects from Study 124 Part A or 
subjects not from Study 124), absolute change will be determined from Study 126 baseline.  
The definitions will apply to all analysis variables: demographics, medical history (including 
prior and concomitant medications), baseline characteristics, efficacy, and safety, unless 
otherwise specified. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in the following categories will be summarized as 
appropriate: 
 Enrolled 
 Enrolled and dosed (Safety Set) 
 Observational arm 
 Last treatment visit completed 
 Prematurely discontinued the study during the Treatment Period and the reasons for 
discontinuations 
The disposition summary will be based on all subjects and will be provided for the final analysis. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic background (e.g., medical history) and baseline characteristics (Study 124 Part B 
baseline or current study baseline) will be summarized. No statistical tests will be carried out to 
evaluate any baseline imbalance between dose groups. 


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For subjects from Study 124 Part B with a Same-day Transition, medical history (including prior 
and concomitant medications) will be taken from Study 124. For subjects from Study 124 Part B 
with a Gap Transition and subjects not from Study 124 Part B, medical history (including prior 
and concomitant medications) will be taken before (e.g., during screening) or at Day 1. 
12.3.2.3 
Prior and Concomitant Medications (Ivacaftor Arm Only) 
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 as frequency tables in 2 parts: 
 Prior medication: any medication that started before the first dose of ivacaftor, 
regardless of when it ended 
 Concomitant medication: medication received at or after dosing of ivacaftor, or 
medication that was received before dosing with ivacaftor and continued after dosing of 
ivacaftor 
If medication start date is at or after the date of the first dosing of ivacaftor in Study 126, 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 the first dosing of 
ivacaftor in Study 126, then the medication will be summarized as prior medication regardless of 
whether the medication start date is missing or not. Note that medication that is started before the 
first dosing of ivacaftor in Study 126 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.  
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. 
12.3.2.4 
Study Drug Exposure and Compliance (Ivacaftor Arm Only) 
Exposure to ivacaftor (i.e., duration of treatment) will be summarized for the Safety Set in terms 
of duration of treatment a subject received (in days). 
Dosing compliance will be summarized for the Safety Set and is calculated as the actual number 
of dosing occasions at which ivacaftor 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. 
12.3.3 
Efficacy Analysis (Ivacaftor Arm Only) 
12.3.3.1 
Analysis of Primary Variables 
Not applicable (see Section 12.3.4). 


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12.3.3.2 
Analysis of Secondary Variables 
Sweat chloride results (including changes from baseline) will be summarized by either treatment 
duration or time on study and presented by treatment group (subjects from Study 124 Part B and 
subjects not from Study 124 Part B). 
12.3.3.3 
Analysis of Tertiary Variables 
 Weight 
 Length 
 Weight-for-length 
 Weight-for-age z-score 
 Length-for-age z-score 
 Weight-for-length-for-age z-score 
 BMI 
 BMI-for-age z-score 
Data (including changes from baseline) will be summarized by either treatment duration or time 
on study and presented by treatment group (subjects from Study 124 Part B and subjects not 
from Study 124 Part B). 
Weight, length, and weight-for-length, adjusted for sex and age, will be summarized as 
weight-for-age z-score, length-for-age z-score, and weight-for-length z-score, respectively. 
Z-scores will be calculated using the Nutrition Examination Survey (NCHS) Growth Chart 
Equations for children and adolescents 0 to 48 months of age.78  
 LCI (including changes from baseline) will be summarized by either treatment duration 
or time on study and presented by treatment for subjects who had their LCIs evaluated. 
 Measure of pancreatic function (fecal elastase-1): This parameter will be summarized 
descriptively as a continuous parameter, and results (including changes from baseline) 
will be summarized by either treatment duration or time on study and presented by 
treatment. 
 Markers of intestinal inflammation (e.g., fecal calprotectin): This parameter will be 
summarized descriptively as a continuous parameter, and results (including changes from 
baseline) will be summarized by either treatment duration or time on study and presented 
by treatment. 
 Qualitative microbiology cultures: The presence of bacteria will be descriptively 
summarized by subject counts and percentages by visit and treatment. Shifts from 
baseline may be presented, as appropriate. 
 Pulmonary exacerbations: Pulmonary exacerbations will be identified using the 
definitions provided in Section 11.5.3 and will be analyzed in 3 ways:  
o The number of pulmonary exacerbations will be normalized to an annual period to 
adjust for differences in time spent on study and summarized as a continuous variable 
using descriptive summary statistics and presented by treatment.  


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o The number of days with pulmonary exacerbations (cumulative duration) will be 
normalized to an annual period to adjust for differences in time spent on study and 
summarized as a continuous variable using descriptive summary statistics and 
presented by treatment. 
o The time-to-first pulmonary exacerbation will be analyzed using the Kaplan-Meier 
method (provided the number of subjects with events observed is adequate) and the 
event-free rate presented by treatment. 
 CF-related hospitalizations will be analyzed in 3 ways: 
o The number of CF-related hospitalizations will be normalized to an annual period to 
adjust for differences in time spent on study and analyzed as a continuous variable 
using descriptive summary statistics and presented by treatment. 
o The number of days hospitalized (cumulative duration) will be normalized to an 
annual period to adjust for differences in time spent on study and summarized as a 
continuous variable using descriptive summary statistics and presented by treatment. 
o The time-to-first hospitalization will be analyzed using the Kaplan-Meier method 
(provided the number of subjects with events observed is adequate) and the event-free 
rate presented by treatment. 
12.3.4 
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: 
 Treatment-emergent adverse event (TEAEs) 
 Clinical laboratory results (serum chemistry and hematology) 
 ECG outcomes 
 PEs (clinically significant abnormalities recorded as medical history or adverse events) 
 Vital signs (systolic blood pressure, diastolic blood pressure, temperature, pulse rate, and 
respiratory rate) 
 OEs 
TEAEs are the key safety assessment and will be assessed overall. Descriptive analysis of other 
safety endpoints will be performed; raw values, changes from baseline, shifts-from-baseline, and 
clinical abnormalities will be summarized for other endpoints. 
12.3.4.1 
Adverse Events 
TEAEs, defined as adverse events with start date or increased severity on or after the first dose of 
ivacaftor through the end of participation (as applicable) in this study, will be summarized by 
treatment. TEAEs will hereafter be referred to as adverse events. Adverse event summary tables 
will include the following analyses presented by treatment:  
 All adverse events 
 Related (defined as possibly related or related) adverse events 
 Adverse events leading to treatment discontinuation 


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 SAEs 
 Adverse events by severity 
 Adverse events by relationship 
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. 
In addition, a table containing individual subject adverse event data for all deaths and other 
serious and significant adverse events will be provided. 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF up 
to the start of study drug dosing. 
Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
start of study drug dosing through the the end of participation (as applicable) in this study. 
Only TEAEs will be summarized in tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study drug. Some rules that will apply to the 
summarization of AEs are as follows: (1) a subject with multiple occurrences of the same AE or 
a continuing AE will only be counted once; (2) only the maximum severity level will be 
presented in the severity summary; and (3) only the worst relationship level will be presented in 
the relationship summary. 
AEs leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the Safety Follow-up Visit will be listed in an individual subject data 
listing, including pretreatment AEs.  
12.3.4.2 
Clinical Laboratory Assessments (Ivacaftor Arm Only) 
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. 
Changes from baseline will also be summarized. 
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.  
12.3.4.3 
Electrocardiogram (Ivacaftor Arm Only) 
Continuous ECG measurements will be summarized by visit and treatment. 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 QTcF intervals will be presented.  
12.3.4.4 
Vital Signs (Ivacaftor Arm Only) 
The following vital signs will be summarized by visit and treatment: systolic and diastolic blood 
pressure (mm Hg), temperature (°C), pulse oximetry (%), heart rate (beats per minute), and 
respiratory rate (breaths per minute). Changes from baseline will also be summarized. 


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Clinically significant findings in vital signs will be reported as adverse events. 
12.3.4.5 
Physical Examination (Ivacaftor Arm Only) 
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 
12.3.4.6 
Ophthalmological Examination 
The ocular safety profile of ivacaftor will be assessed in terms of the following analyses: 
 Incidence of cataracts (lens opacities) based on results from dilated slit-lamp examination 
 Red reflex 
Results of OEs (incidence of cataracts) will be summarized as a categorical variable and 
presented by treatment. 
Red reflex will be analyzed as continuous variables using descriptive summary statistics and 
presented by visit and treatment. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
Interim analyses for regulatory or operational purposes may be performed. 
12.3.5.2 
IDMC Analysis 
Details of the IDMC (Section 9.1.5) analyses will be provided in the IDMC Analysis Plan. 
12.3.6 
Pharmacokinetic Analysis 
Not applicable. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed, and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 


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the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time 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) 
 For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit, with the exception of ocular adverse events noted during the Follow-up OE 
 For enrolled subjects who do not have a Safety Follow-up Visit: the earliest of 4 weeks 
± 7 days after the last dose of study drug, or the ETT Visit, if that visit is 3 weeks or later 
following the last dose of study drug (see Section 9.1.1.5) 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject's source documents. The following data will be documented 
for each AE: 
 Description of the event 
 Classification of “serious” or “nonserious” 
 Date of first occurrence and date of resolution (if applicable) 
 Severity  
 Causal relationship to study drug(s)  
 Action taken  
 Outcome  
 Concomitant medication or other treatment given 


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For the purposes of study analysis, if the event has not resolved at the end of the study reporting 
period (the Safety Follow-up Visit), it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the adverse event to symptom 
resolution or until the condition stabilizes.  
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: 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 August 2015). In considering the severity of an AE in 
a pediatric subject, the investigator will consider that reference ranges for pediatric clinical 
laboratory parameters may differ from those given in the vaccine scale. The severity of an AE 
that does not appear in this scale will be determined according to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug, and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject's medical record). 
 


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13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved With 
Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up). 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation in the study and is suspected of being a delayed toxicity due to 
administration of the study drug) 


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


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13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: globalpatientsafety@vrtx.com (preferred choice) 
Fax: + 1-617-341-6159  
Contact Telephone: + 1-617-341-6677 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. In addition, Vertex, or authorized designee, will be responsible for the submission of 
safety letters to central 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. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator's 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects, 
safety updates, annual progress reports, and any revisions to these documents will be provided to 
the IRB/IEC by the investigator or Vertex, as allowable by local applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject’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 ICH GCP 
and all applicable laws and regulations and will be subject to approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 


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When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”), an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility, and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 


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 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 
 Lack of evaluable and/or complete data 
 Potentially unacceptable risk to study subjects 
 Decision to modify drug development plan 
 Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator's responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject's 
CRF. Source documentation supporting the CRF data will indicate the subject's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 


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The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a CD or other electronic media will be placed in the investigator's study file. 
13.6 
Publications and Clinical Study Report 
13.6.1 
Publication of Study Results 
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. 
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. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between Vertex and the investigator and/or the 
investigator's institution. 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


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69 
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. 
70 
Borowitz D, Baker SS, Duffy L, Baker RD, Fitzpatrick L, Gyamfi J, et al. Use of fecal 
elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr. 
2004;145(3):322-26. 
71 
Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: Pseudomonas 
aeruginosa infection. J Clin Epidemiol. 1995;48(8):1041-49. 
72 
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 
Care Med. 2006;173(4):421-25. 
73 
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. 
2002;287(22):2958. 
74 
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 
administration. Aliment Pharmacol Ther. 2004;20(7):813-19. 
75 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99. 
76 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70. 
77 
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. 
78 
Centers for Disease Control and Prevention. Growth charts. Available at: 
http://www.cdc.gov/growthcharts. Accessed 02 June 2014. 
 


Protocol VX15-770-126, Version 2.0 
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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX15-770-126 
Version #: 
2.0 
Version Date: 
05 October 2017 
Study Title: A Phase 3, 2-Arm, Open-label Study to Evaluate the Safety and Pharmacodynamics 
of Long-term Ivacaftor Treatment in Subjects With Cystic Fibrosis Who Are Less Than 
24 Months of Age at Treatment Initiation and Have an Approved Ivacaftor-Responsive Mutation 
This Clinical Study Protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


Protocol VX15-770-126, Version 2.0 
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15.2 
Investigator Signature Page 
Protocol #:  
VX15-770-126 
Version #: 
2.0 
Version Date: 
05 October 2017 
Study Title: A Phase 3, 2-Arm, Open-label Study to Evaluate the Safety and Pharmacodynamics 
of Long-term Ivacaftor Treatment in Subjects With Cystic Fibrosis Who Are Less Than 
24 Months of Age at Treatment Initiation and Have an Approved Ivacaftor-Responsive Mutation 
 
 
I have read Protocol VX15-770-126, Version 2.0, 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 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods)  
Page 1 of 40 
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Vertex Pharmaceuticals Incorporated 
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VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX15-770-126 
Final Analysis 
 
A Phase 3, 2-Arm, Open-label Study to Evaluate the Safety and 
Pharmacodynamics of Long-term Ivacaftor Treatment in Subjects 
With Cystic Fibrosis Who Are Less Than 24 Months of Age at 
Treatment Initiation and Have an Approved Ivacaftor-Responsive 
Mutation 
 
 
 
 
Version: 1.0  
Version Date of SAP: 25 APR 2023 
 
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 
2 
Modifications .................................................................................................................... 4 
2.1 
Modifications to the Approved Clinical Study Protocol ............................................ 4 
2.2 
Modifications to the Approved Statistical Analysis Plan ........................................... 5 
3 
Introduction...................................................................................................................... 6 
4 
Study Objectives .............................................................................................................. 6 
4.1 
Primary Objective ....................................................................................................... 7 
4.2 
Secondary Objectives ................................................................................................. 7 
4.3 
Tertiary Objectives ..................................................................................................... 7 
5 
Study Endpoints ............................................................................................................... 7 
5.1 
Efficacy Endpoint ....................................................................................................... 7 
5.1.1 
Primary Efficacy Endpoint ................................................................................. 7 
5.1.2 
Secondary Efficacy/Pharmacodynamic Endpoints ............................................. 7 
5.1.3 
Tertiary Endpoints .............................................................................................. 7 
5.2 
Safety Endpoints ......................................................................................................... 8 
6 
Study Design ..................................................................................................................... 8 
6.1 
Overall Design ............................................................................................................ 8 
6.2 
Sample Size and Power .............................................................................................. 9 
6.3 
Randomization ............................................................................................................ 9 
6.4 
Blinding and Unblinding ............................................................................................ 9 
7 
Analysis Sets ................................................................................................................... 10 
7.1 
Ivacaftor Arm Analysis Set ...................................................................................... 10 
7.1.1 
All Subjects Set ................................................................................................ 10 
7.1.2 
Full Analysis Set ............................................................................................... 10 
7.1.3 
Safety Set .......................................................................................................... 10 
7.2 
Observational Arm Analysis Set .............................................................................. 10 
8 
As no subjects enrolled in the Observational Arm, the Observational Arm 
Analysis Set will not be defined. Statistical Analysis .................................................. 10 
8.1 
General Considerations ............................................................................................ 10 
8.2 
Background Characteristics  ..................................................................................... 12 
8.2.1 
Subject Disposition ........................................................................................... 12 
8.2.2 
Demographics and Baseline Characteristics ..................................................... 12 
8.2.3 
Prior and Concomitant Medications ................................................................. 13 
8.2.4 
Study Drug Exposure........................................................................................ 14 
8.2.5 
Study Drug Compliance ................................................................................... 14 
8.2.6 
Important Protocol Deviations .......................................................................... 15 
8.3 
Efficacy Analysis ...................................................................................................... 15 
8.3.1 
Analysis of Primary Efficacy Variable ............................................................. 15 
8.3.2 
Analysis of Secondary Efficacy/Pharmacodynamic Variable .......................... 16 
8.3.3 
Analysis of Tertiary Efficacy Variables ........................................................... 16 
8.3.3.1 
Definition of Variables ............................................................................... 16 
8.3.3.2 
Tertiary Analysis ........................................................................................ 17 


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8.4 
Safety Analysis ......................................................................................................... 18 
8.4.1 
Adverse Events ................................................................................................. 18 
8.4.2 
Clinical Laboratory ........................................................................................... 19 
8.4.3 
Electrocardiogram ............................................................................................ 19 
8.4.4 
Vital Signs ........................................................................................................ 20 
8.4.5 
Physical Examination ....................................................................................... 20 
8.4.6 
Ophthalmological Examination ........................................................................ 20 
9 
Summary of Interim and IDMC Analyses. ................................................................. 20 
9.1 
Interim Analysis ....................................................................................................... 20 
9.2 
IDMC Analysis ......................................................................................................... 20 
10 References ....................................................................................................................... 21 
11 List of Appendices.......................................................................................................... 22 
Appendix A: Schedule of Assessments.............................................................................. 22 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................... 33 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ........... 38 
Appendix D: Imputation Rules for Missing AE dates ....................................................... 39 
Appendix E: Criteria for Threshold Analysis .................................................................... 40 
 


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2 
MODIFICATIONS  
2.1 
Modifications to the Approved Clinical Study Protocol 
In calculating normalized measures of growth (weight-for-age z-scores, length-for-age z-
scores, and weight-for-length-for-age z-scores), WHO reference standards are used instead of 
CDC reference standards, per CDC recommendations.  The reference for z-scores has been 
updated accordingly. 
Per Administrative Letter dated 31 October 2017, in the Schedule of Assessments tables for 
same-day and gap-transition subjects from Study 124 Part B, an ‘X’ was inadvertently 
omitted from the row “12-lead ECGs” for the column “Weeks 12, 36, 60, and 84 (+/- 7 
Days)” under “Treatment Period (Day 1 through Week 96).”  Data from 12-lead ECGs at 
these visits will be presented. 
Per Administrative Letter dated 07 October 2022, text identified below is revised to clarify 
that the Follow-up Ophthalmologic Examination (OE) is not required for subjects who rolled 
over from Study VX15-770-124 and who initiate treatment with commercially available 
ivacaftor, because safety information for these patients will be collected and reported as part 
of the post-marketing process. This clarification is being provided to maintain consistency 
with the Safety Follow-up visit for these subjects, which is not required for the same reason. 
Text identified below is copied from the indicated section of the protocol with clarifying text 
provided in italics and deleted text in strikethrough font. 
Section 2      Protocol Synopsis Study Design 
Subjects who receive commercially available ivacaftor will be discontinued f rom study drug 
dosing and will complete the ETT Visit and the Follow up OE; the Safety Follow-up Visit 
and 24-Week Follow-up OE will not be required 
 
Section 9.1.1.4       Ivacaftor Arm Follow-up Ophthalmologic Examination (All Subjects) 
There will be a Follow-up OE 24 weeks + 14 days after the last dose of ivacaftor f or all 
subjects except for subjects who initiate treatment with commercially available ivacaftor 
within 3 weeks of the final scheduled treatment visit or ETT Visit. 
Section 9.1.1.5      Ivacaftor Arm Early Termination of Treatment (All Subjects) 
 
Subjects who receive commercially available ivacaftor will be discontinued f rom ivacaftor 
dosing and will complete the ETT Visit and Follow-up OE; the Saf ety Follow up Visit and 
Follow-up OE will not be required. 
Section 9.7             Removal of Subjects 
 
During the course of study conduct, if ivacaftor is approved and available for the treatment of 
CF in populations enrolled in this study, and if a subject chooses to move onto commercially 
available ivacaftor, the ETT Visit (Section 9.1.1.5) will be completed before dosing with 
commercial drug begins, and the Safety Follow-up Visit and Follow-up OE will not be 
required. 
Table 3-1    Footnote “a” 
 


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The ETT Visit is to be scheduled as soon as possible after the last dose of ivacaftor. If the 
ETT Visit occurs 3 weeks or later aft er the last dose of ivacaftor, the Safety Follow up Visit 
will not be required. Subjects who elect to receive commercially available ivacaftor will be 
discontinued from ivacaftor dosing and will complete the ETT Visit and Follow up OE. 
Table 3-1    Footnote “b” 
 
For subjects who elect to receive commercially available ivacaftor, the Saf ety Follow -up 
Visit and Follow-up OE will not be required. 
Additional Clarifications 
 
The following are provided to correct minor inconsistencies: 
Table 3-1            Footnote “d” 
 
Study Drug Dose Determination is not to be performed at the Week 96 Visit because it is the 
final visit of the treatment period. 
Tertiary Endpoint “weight-for-length-for-age z-score” 
 
The term “weight-for-length-f or-age z-score” is not the appropriate name for this endpoint. 
The correct name is “weight-for-length z-score” in the following sections of the protocol: 
Sections 2 Synopsis (Assessments); 7.1.3 Tertiary Endpoints; 9.2.3 Rationale f or Study 
Assessments (Measures of Nutritional Status); 11.5.1 Measures of Nutritional Status; and 
12.3.3.3 Analysis of Tertiary Variables. 
In addition, the final analysis will be based on the combined subjects from Study 124 Parts B 
and A/B, and subjects not from Study 124 Parts B and A/B.  
 
2.2 
Modifications to the Approved Statistical Analysis Plan 
Not applicable. 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) Methods is for the final analysis for the VX15-770-126 
study and is based on the approved clinical study protocol (CSP), dated 05 October 2017, 
version 2.0. 
Study VX15-770-126 is a phase 3, 2-arm, open-label study to evaluate the safety and 
pharmacodynamics of long-term ivacaftor treatment in subjects with cystic fibrosis who are 
less than 24 months of age at treatment initiation and have an approved ivacaftor-responsive 
mutation. 
This SAP (Methods) documents the planned final statistical analysis of efficacy and safety 
endpoints defined in the study protocol of VX15-770-126.  
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 database lock has 
occurred will be documented in the clinical study report for the final analysis.  


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4 
OBJECTIVES 
4.1 
Primary Objective 
Ivacaftor Arm: 
To evaluate the safety of long-term ivacaftor treatment in subjects with CF who are <24 months 
of age at treatment initiation and have an approved ivacaftor-responsive mutation. 
Observational Arm: 
To evaluate the long-term safety after discontinuation of ivacaftor treatment in subjects with CF 
who were <24 months of age at treatment initiation and have an approved ivacaftor-responsive 
mutation. 
4.2 
Secondary Objectives  
Ivacaftor Arm: 
To evaluate the pharmacodynamics (PD) of long-term ivacaftor treatment in subjects with CF 
who are <24 months of age at treatment initiation and have an approved ivacaftor-responsive 
mutation. 
Observational Arm: 
Not applicable. 
4.3 
Tertiary Objectives 
Ivacaftor Arm: 
To evaluate the efficacy of long-term ivacaftor treatment in subjects with CF who are <24 
months of age at treatment initiation and have an approved ivacaftor-responsive mutation. 
Observational Arm: 
Not applicable. 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoint 
5.1.1 
Primary Efficacy Endpoint 
Not applicable. 
5.1.2 
Secondary Efficacy/Pharmacodynamic Endpoints 
Ivacaftor Arm: 
Absolute change from baseline in sweat chloride through Week 96 
Observational Arm:  
Not applicable. 
5.1.3 
Tertiary Endpoints 
Ivacaftor Arm: 


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• 
Absolute change from baseline through Week 96 for the following endpoints:  
o Weight  
o Length (assessed as height, as age appropriate)  
o Weight-for-length  
o Weight-for-age z-score  
o Length-for-age z-score  
o Weight-for-length z-score  
o BMI  
o BMI-for-age z-score  
o Lung clearance index (LCI) at qualified study sites  
o Fecal elastase-1  
o Markers of intestinal inflammation  
o Qualitative microbiology cultures  
• 
Annualized rate of pulmonary exacerbations  
• 
Rate of CF-related hospitalizations  
 
Observational Arm: 
Not applicable 
5.2 
Safety Endpoints 
Ivacaftor Arm: 
Safety, as determined by adverse events (AEs), laboratory values (serum chemistry and 
hematology), 12-lead ECGs and vital signs, and ophthalmologic examinations (OEs) 
 
Observational Arm: 
Safety after stopping ivacaftor treatment in Study VX15-770-124 (Study 124) Part B as 
determined by serious adverse events (SAEs) and results from an OE approximately 24 weeks 
after the last dose of ivacaftor in Study 124 Part B 
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 3, 2-arm, multicenter study with an open-label ivacaftor arm and an 
observational arm. The study design is shown in Figure 6-1. 


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Figure 6-1:  VX15-770-126 Study Design 
 
a 
For subjects who have a Same-day Transition, the Week 24 Visit of Study 124 Part B or Part A/B will be the same day 
as the Day 1 Visit of Study 126. For subjects who have a Gap Transition, the last study visit of Study 124 Part B or Part 
A/B will not be the same day as the Day 1 Visit of Study 126.  
b 
Day 1 for subjects in the observational arm can be the last study visit of Study 124 Part B. 
c 
The Follow-up OE in the observational arm can be performed in Study 124. 
d 
Only for subjects who received at least 4 weeks of study drug in Study 124 Part B. 
6.2 
Sample Size and Power 
The study is not powered to detect a significant treatment effect. The study will enroll 
approximately 75 subjects. 
6.3 
Randomization 
Not applicable; treatment dose assignments in this study are determined by age and weight. 
6.4 
Blinding and Unblinding 
Not applicable; this is an open-label study. 


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7 
ANALYSIS SETS 
7.1 
Ivacaftor Arm Analysis Set 
7.1.1 
All Subjects Set 
The All Subjects Set will be defined as all subjects who are enrolled in the current study. 
This analysis set will be used for all individual subject data listings and the disposition 
summary table, unless specified otherwise. 
7.1.2 
Full Analysis Set  
The Full Analysis Set (FAS) will be defined as all subjects who are enrolled and receive at 
least 1 postbaseline efficacy assessment in the current study. The FAS will be used for all 
efficacy analyses, unless specified otherwise. 
7.1.3 
Safety Set 
The Safety Set will be defined as all subjects who receive at least 1 dose of study drug in the 
current study. The Safety Set will be used for all safety analyses, unless specified otherwise. 
7.2 
Observational Arm Analysis Set 
As no subjects enrolled in the Observational Arm, the Observational Arm Analysis Set will 
not be defined. Statistical Analysis 
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 are enrolled in the current study will be 
presented in individual subject data listings. 
As no subjects are enrolled in the Observation Arm, all analyses will be done for subjects 
from the Ivacaftor Arm only. All analysis will be performed for the Ivacaftor Arm overall, 
unless otherwise specified.  
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). 95% confidence intervals (CI) 
may be provided as appropriate. 
Categorical variables will be summarized using counts and percentages. 95% CI may be 
provided as appropriate. 
Baseline value is defined in two different ways: 
Study 124 baseline: the baseline value for rollover subjects (who participated in Study 124 
Part B or Part A/B) is defined as the baseline measurement from Study 124 Part B or Part 
A/B. That is, the most recent non-missing measurement collected on or before the initial 


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administration of study drug in Study 124 Part B or Part A/B. Note that this definition is 
consistent with the definition of baseline in Study 124 and applies to both scheduled and 
unscheduled measurements; if an unscheduled value is the most recent non-missing 
measurement, it will be used as baseline. 
Study 126 baseline: the baseline value for IVA-naïve subjects (who did not participate in 
Study 124 Part B or Part A/B) is defined as the most recent non-missing measurement 
collected on or before the initial administration of study drug in the current study, including 
both the scheduled and unscheduled measurements. 
Change (absolute change) from baseline will be calculated as 
Postbaseline value − Baseline value. 
Relative change from baseline will be calculated and expressed in percentage as 
100% × (Postbaseline value − Baseline value)/Baseline value. 
Treatment-emergent (TE) Period  
For the Ivacaftor Arm, the TE period will include the time period starting from the first dose 
date of the study drug in the current study to the Safety Follow-up Visit, or the last dose 
date + 28 days for subjects who do not have a Safety Follow-up Visit. 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  
• In the derivation of baseline/last on-treatment 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 in the 
Ivacaftor Arm are provided in Appendix B.  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 
analyses. 
• For all efficacy parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used. Otherwise, 
o If there are no measurements at the scheduled visit, then the record closest to the 
target day will be used; 


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o If there are multiple records with the same distance to the target day, the latest record 
will be used. 
o Assessments at the early treatment termination (ETT) visit will follow the windowing 
rules for regular visits, with the exception of the ETT visit occurs 21 days or later 
after the last dose, which will be treated as SFU visit.  
o Assessments at the 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. 
Visit windowing rules will not be used for the Observational Arm as they will not add value. 
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. 
8.2 
Background Characteristics  
Background characteristics will be analyzed for the total subjects in the Ivacaftor Arm. 
8.2.1 
Subject Disposition 
Ivacaftor Arm: 
The number of subjects in the following categories will be summarized:  
• Enrolled (All Subjects Set) 
• Enrolled and Dosed (Safety Set) 
•  Enrolled and having at least 1 post baseline efficacy assessment (FAS) 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation  
• Completed study 
• Prematurely discontinued study and the reason for discontinuation  
• Last treatment visit completed (Day 1, Week 2, Week 4, Week 8, Week 12, Week 18, 
Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96) 
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 based on the 
Safety Set. For rollover subjects, the demographics and baseline characteristics from the 
Study 124 will be used.   
Demographic data will include the following: 


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• 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: 
• Weight (kg) 
• Length (cm) 
• Weight-for-length 
• BMI (kg/m2) 
• Weight-for-age z-score 
• Length-for-age z-score 
• Weight-for-length z-score 
Disease characteristics will include the following: 
• Age at CF diagnosis 
• Maternal/pregnancy history: complications in pregnancy, gestational age at delivery, 
method of delivery 
• Number of CF-related hospitalizations from birth to screening 
• Number of pulmonary exacerbations requiring antibiotics that occurred from birth to 
screening 
• Number of pulmonary exacerbations requiring IV antibiotics that occurred from birth to 
screening 
• Does subject have abnormal liver function tests (LFTs) 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  
 
8.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary Enhanced 
(WHO-DDE). 


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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 classified as follows: 
• Prior medication: any medication that started before the first dose of ivacaftor in the 
current study, regardless of when it ended 
• Concomitant medication: medication received at or after dosing of ivacaftor in the 
current study, or medication that was received before dosing with ivacaftor in the 
current study and continued after dosing of ivacaftor 
• Post‑treatment medication: medication continued or newly received after the TE 
period. 
 
If medication start date is on or after the date of the first dosing of ivacaftor in the current 
study, the 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 the 
first dosing of ivacaftor in the current study, then the medication will be summarized as prior 
medication regardless of whether the medication start date is missing or not. If medication 
started before the first dosing of ivacaftor in the current study and continued after dosing of 
ivacaftor, the medication will be summarized as prior medication and separately as 
concomitant medication.  
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by Preferred Name.  
Both prior and concomitant medications will be based on the Safety Set, with concomitant 
medications provided for the final analysis.  
Post-treatment medications will be provided in data listings only. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 
Note that for rollover subjects from Study 124 Part B or Part A/B, only medications entered 
in the current study will be summarized.  
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  
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 in 
the current study). The maximum percentage of sachets taken will be 100%. 


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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, 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 FAS. 
8.2.6 
Important Protocol Deviations  
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the 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 may 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 may be considered as potential IPDs, but the study team 
will categorize them as IPDs if they have the potential to affect interpretation of study results 
or a subject's rights, safety, or well-being. .  
IPDs will be presented as an individual subject data listing only. 
8.2.7 
COVID-19 Impacted Visits 
A listing containing subjects’ visits impacted due to COVID-19 will be provided.  
8.3 
Efficacy Analysis  
Statistical methodology will be restricted to descriptive statistics only. Unless specified 
otherwise, all efficacy analyses described in this section will be based on the FAS, for the 
Ivacaftor Arm overall. 
The analysis will include all available measurements per the visit windowing rules described 
in Appendix B. 
8.3.1 
Analysis of Primary Efficacy Variable 
Not applicable. 


Statistical Analysis Plan (Methods)  
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8.3.2 
Analysis of Secondary Efficacy/Pharmacodynamic Variable 
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. 
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 at baseline. If 
1 of the 2 measurements at a time point is missing, the other will be used as the mean.  
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. 
Defintion of Baseline: Only results obtained from sample collections completed prior to the 
first administration of study drug (in Study 124 for Study 124 baseline, and in Study 126 for 
Study 126 baseline) 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. 
If sweat chloride was not performed at baseline or if the volume of sweat obtained from both 
arms was insufficient for analysis (<15 μL), or if the concentration of sweat chloride from 
both arms was >160 mmol/L, the most recent historical sweat chloride result may be used to 
impute the missing baseline value. 
Sweat chloride results (including changes from baseline) will be analyzed as a continuous 
variable using descriptive summary statistics by visit.  
8.3.3 
Analysis of Tertiary Efficacy Variables 
8.3.3.1 
Definition of Variables 
For the normalization of annual period the following formula will be used: Normalized 
Variable = Variable x 365.25 / (date of last dose – date of first dose +1). 
The time-to-first pulmonary exacerbation (in days) is calculated as: first pulmonary 
exacerbation date (postdose in the current study) – first dose date + 1. 
The time-to-first CF-related hospitalization (in days) is calculated as: first CF-related 
hospitalization date (postdose in the current study) – first dose date + 1. 
Weight-for-age z-scores, length-for-age z-scores, weight-for-length z-scores, and BMI-for-
age z-scores will be derived from weight, length, and BMI values using the WHO Child 
Growth Standards for infants and children1, for whom population norms are available from 0 
to 60 months of age.  The same growth standards will be used to calculate percentiles for 
each measure. 


Statistical Analysis Plan (Methods)  
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8.3.3.2 
Tertiary Analysis 
• The following growth parameters will be summarized descriptively as continuous 
variables by visit (including change from baseline).   
o Weight 
o Length 
o Weight-for-length (expressed as a percentile) 
o BMI 
o Weight-for-age z-score 
o Length-for-age z-score 
o Weight-for-length z-score 
o BMI-for-age z-score 
Summary statistics for weight-for-age, length-for-age, and BMI-for-age percentiles 
may also be provided to aid interpretation of z-scores. 
• LCI2.5 will be analyzed as a continuous variable using descriptive summary statistics 
and results (including changes from baseline) presented by visit. In the event that 
fewer than 3 subjects have these optional assessments available, listings of results 
may be provided instead of summary statistics.  
• Markers of pancreatic inflammation (fecal elastase-1): These parameters will be 
summarized descriptively as a continuous parameter and results (including changes 
from baseline) presented by visit. Shifts from baseline will be summarized by visit. 
• Marker of intestinal inflammation (fecal calprotectin). This parameter will be 
summarized descriptively as a continuous parameter and results (including changes 
from baseline) presented by visit. 
• Qualitative microbiology cultures: the presence of bacteria will be descriptively 
summarized by subject counts and percentages by visit. Shifts from baseline may be 
presented, as appropriate. 
• Pulmonary exacerbations: Pulmonary exacerbations (PEx) will be identified using the 
definitions provided in Section 11.5.3 of the protocol, and will be analyzed in 3 ways, 
as follows:  
o The number of pulmonary exacerbations will be normalized to an annual 
period to adjust for differences in time spent on study and summarized as a 
continuous variable using descriptive summary statistics. 
o The number of days with pulmonary exacerbations (cumulative duration) will 
be normalized to an annual period to adjust for differences in time spent on 
study and summarized as a continuous variable using descriptive summary 
statistics. 


Statistical Analysis Plan (Methods)  
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o The time-to-first pulmonary exacerbation in 96 weeks, total treatment 
duration will be analyzed using the Kaplan-Meier method (provided the 
number of subjects with events observed is adequate) and the event-free rate.  
• Rate of CF-related hospitalizations will be analyzed in 3 ways, as follows: 
o The number of CF-related hospitalizations will be normalized to an annual 
period to adjust for differences in time spent on study and analyzed as a 
continuous variable using descriptive summary statistics. 
o The number of days hospitalized (cumulative duration) will be normalized to 
an annual period to adjust for differences in time spent on study and 
summarized as a continuous variable using descriptive summary statistics. 
o The time-to-first CF-related hospitalization in 96 weeks, total treatment 
duration will be analyzed using the Kaplan-Meier method (provided the 
number of subjects with events observed is adequate) and the event-free rate.  
8.4 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (hematology and serum chemistry) 
• Standard 12-lead electrocardiograms 
• PEs (clinically significant abnormalities recorded as medical history or adverse events) 
• Vital signs (systolic blood pressure, diastolic blood pressure, temperature, pulse rates, 
and respiratory rate) 
• Ophthalmologic examinations 
Unless specified otherwise, safety endpoints will be analyzed based on the Safety Set, for the 
total subjects in the Ivacaftor arm. Only a descriptive analysis of safety will be performed. 
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 in Study 126 
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 in the current 
study.  
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed beyond the TE period 


Statistical Analysis Plan (Methods)  
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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 AEs are described in Appendix D. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation. 
• Serious TEAEs  
• Related (defined as missing, possibly related, or related) TEAEs 
• Serious 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 AE data for TEAEs leading to treatment 
interruption, TEAEs leading to 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 selected LFT parameters, the number and percentage of subjects meeting at least 1 
threshold analysis criterion event, during the TE period, will be summarized. The threshold 
analysis criteria are provided in Appendix E.  
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. 
8.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from 
baseline values will be provided by visit for the following standard 12-lead ECG 
measurements: RR (ms), HR (bpm), PR (ms), QRS duration (ms), QRS axis (degrees), QT 
(ms), and QT corrected for HR intervals [QTcF (ms)].  


Statistical Analysis Plan (Methods)  
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The number and percentage of subjects meeting at least 1 threshold analysis criterion during 
the TE period for the Treatment Period will be summarized. The threshold analysis criteria 
are provided in Appendix E. 
 
8.4.4 
Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized by visit: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), heart rate (beats per minute), respiratory rate (breaths per minute) and 
oxygen saturation (%). 
Clinically significant findings in vital signs will be reported as AEs. 
8.4.5 
Physical Examination  
PE 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 ophthalmologic examinations (incidence of cataracts or lens opacities) will be 
summarized as a categorical variable and results will be presented. 
Lens refracting power and red reflex will be listed as appropriate.  
9 
SUMMARY OF INTERIM AND IDMC ANALYSES.  
9.1 
Interim Analysis 
Not applicable. 
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.  


Statistical Analysis Plan (Methods)  
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10 
REFERENCES 
1.    World Health Organization Growth Standards.  Growth charts available at:  
 https://www.cdc.gov/growthcharts/who_charts.htm 


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11 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
Table 11-1 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Same-day Transition Subjects From 
Study 124 Part B) 
 
Treatment Period 
(Day 1 Through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE 
Event/Assessment 
Day 1c 
Weeks 12, 36, 
60, and 84 
(± 7 Days) 
Weeks 24, 48, 
72, and 96 
(± 7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks (± 7 Days) 
After the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Informed consent 
X 
 
 
 
 
 
Confirm eligibility 
X 
 
 
 
 
 
Clinic visit 
X 
X 
X 
X 
X 
 
Study drug dose determinationd 
X 
X 
X 
 
 
 
Length and weighte 
X 
X 
X 
X 
X 
 
Physical examinationf 
X 
X 
X 
X 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
 
                                                 
a 
The ETT Visit is to be scheduled as soon as possible after the last dose of ivacaftor. If the ETT Visit occurs 3 weeks or later after the last dose of ivacaftor, 
the Safety Follow-up Visit will not be required. Subjects who elect to receive commercially available ivacaftor will be discontinued from ivacaftor dosing and 
will complete the ETT Visit and Follow-up OE. 
b 
For subjects who elect to receive commercially available ivacaftor, the Safety Follow-up Visit will not be required. 
c The Day 1 Visit will be the same day as the Week 24 Visit of Study 124 Part B. Any Study 126 Day 1 assessments performed at the Week 24 Visit of 
Study 124 Part B do not need to be repeated. Day 1 results should be taken from the Week 24 Visit in Study 124 (if applicable) on which these data are 
available (including demographics and medical history), except for the signing of informed consent, confirmation of eligibility, and IVRS/IWRS contact. 
d The ivacaftor dose for each subject will be reassessed based on body weight and adjusted if necessary (see CSP Section 9.4).  
e 
Length and weight measurements will be performed predose through the Week 24 Visit (see CSP Section 11.5.1). 
f 
Full physical examinations will be performed at the ETT and Safety Follow-up Visits; abbreviated physical examinations will be performed at all other study 
visits. 
g Vital signs and ECGs will be taken predose through the Week 24 Visit. Following the Week 24 Visit, vital signs and ECGs may be taken pre- or post-dose. 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiratory rate, and pulse oximetry (see CSP Section 11.6.3). 
1 


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Table 11-1 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Same-day Transition Subjects From 
Study 124 Part B) 
Treatment Period 
(Day 1 Through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE
Event/Assessment 
Day 1c 
Weeks 12, 36, 
60, and 84 
(± 7 Days) 
Weeks 24, 48, 
72, and 96 
(± 7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks (± 7 Days) 
After the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
12-lead ECGsg, h
X 
X 
X 
X 
Serum chemistry and hematology 
X 
X 
X 
X 
X 
Ophthalmologic examinationi 
X 
X 
Xj 
X 
Fecal sample collectionk  
X 
X 
X 
Sweat chloride testl 
X 
X 
Qualitative microbiology cultures 
X 
X 
Multiple breath washout (optional)m 
X 
Xn 
Study drug administrationo 
X 
X 
X 
Study drug count 
X 
X 
X 
X 
Pulmonary exacerbations, CF-
related hospitalizations 
Continuous from signing of ICF through the last 
dose of study drug 
h
All 12-lead ECGs will be taken predose at the Day 1, Week 12 and Week 24 Clinic Visits. At all visits, ECGs will be taken before any other procedures that 
may affect heart rate, such as blood draws (see CSP Section 11.6.4).  
i
The OE will be conducted by a licensed ophthalmologist, preferably a pediatric ophthalmologist. The OE may be performed at the study visit or ± 14 days of 
the clinic visit. 
j
The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue ivacaftor dosing (for any reason) unless performed in the last 
12 weeks.  
k
Samples will be analyzed for fecal elastase-1 and other markers of intestinal inflammation, including fecal calprotectin. Samples may be collected up to 
24 hours before the study visit (e.g., at home) and brought to the clinic. If the sample is collected in the clinic, the sample may be collected pre- or postdose. 
l
The sweat chloride test must be performed on Day 1 before the ivacaftor dose. At all other visits up to the Week 24 Visit, the sweat chloride test must be
performed within ± 2 hours of the ivacaftor dose. After the Week 24 Visit, the sweat chloride test may be performed at any time during the visit.
m MBW will be performed on subjects for whom additional or separate informed consent was obtained for the procedures, and only at sites that are adequately 
trained and qualified to perform MBW (see CSP Section 11.5.6). The Day 1 MBW must be performed within 1 week before the Day 1 Visit. The Week 96 
MBW must be performed within 1 week before the last dose. Detailed procedures will be supplied in a separate study manual. 
n  MBW will be performed at the Week 24 and 48 Visits (± 7 days). 
o
The morning dose of study drug will be administered at the Day 1, Week 12 and Week 24 Clinic Visits. After the Week 24 Visit, the morning dose need not
be administered at the Clinic Visit. Additional guidance for preparation and administration of study drug is provided in CSP Section 9.4 and the study manual.


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Table 11-1 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Same-day Transition Subjects From 
Study 124 Part B) 
 
Treatment Period 
(Day 1 Through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week Follow-
up OE 
Event/Assessment 
Day 1c 
Weeks 12, 36, 
60, and 84 
(± 7 Days) 
Weeks 24, 48, 
72, and 96 
(± 7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks (± 7 Days) 
After the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Adverse events 
Continuous from signing ICF through the Safety Follow-up Visit (see CSP Section 13.1.1.3) 
Ocular adverse 
events only 
Medications and procedures review 
Continuous from signing of ICF through the Safety Follow-up Visit 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ETT: Early Termination of Treatment; ICF: informed consent form; MBW: 
multiple breath washout; LFT: liver function test; OE: ophthalmologic examination; q12h: every 12 hours. 


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Table 11-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition Subjects From Study 124 Part B) 
 
Treatment Period 
(Day 1 through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week 
Follow-up OE 
Event/Assessment 
Day -
28 to 
Day -1 
Day 1c 
Weeks 12, 36, 
60, and 84 
(±7 Days) 
Weeks 24, 48, 
72, and 96 
(±7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks 
(±7 Days) After 
the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Informed consentd 
X 
X 
 
 
 
 
 
Reconfirm eligibility 
X 
X 
 
 
 
 
 
Medical historye 
X 
 
 
 
 
 
 
Clinic visit 
X 
X 
X 
X 
X 
X 
 
Study drug dose determinationf 
 
X 
X 
X 
 
 
 
Length and weightg 
 
X 
X 
X 
X 
X 
 
Physical examinationh 
 
X 
X 
X 
X 
X 
 
Vital signsi 
 
X 
X 
X 
X 
X 
 
12-lead ECGsi, j 
 
X 
 
X 
X 
X 
 
                                                 
a 
The ETT Visit is to be scheduled as soon as possible after the last dose of ivacaftor. If the ETT Visit occurs 3 weeks or later after the last dose of ivacaftor, 
the Safety Follow-up Visit will not be required. Subjects who elect to receive commercially available ivacaftor will be discontinued from ivacaftor dosing and 
will complete the ETT Visit and Follow-up OE. 
b For subjects who elect to receive commercially available ivacaftor, the Safety Follow-up Visit will not be required. 
c The Day 1 Visit will not be the same day as the last study visit of Study 124 Part B. All Day 1 assessments will be conducted on Day 1 with the possible 
exception of the serum and hematology assessments and the OE, as detailed in footnotes k and m. If the Day 1 Visit is ≤9 days after the last study visit of 
Study 124 Part B, the subjects must sign the ICF and confirm eligibility before dosing on Day 1.  
d  Subjects must sign the ICF before undergoing any study-related assessments. 
e  Medical history only applies to subjects that complete a Study 124 Safety Follow-up Visit and only for new conditions that start after the Study 124 Safety 
Follow-up Visit and prior to the Study 126 Screening Visit. 
f  The ivacaftor dose for each subject will be reassessed based on body weight and adjusted if necessary (see CSP Section 9.4). 
g 
Length and weight measurements will be performed predose through the Week 24 Visit (see CSP Section 11.5.1). 
h Full physical examinations will be performed at the ETT and Safety Follow-up Visits; abbreviated physical examinations will be performed at all other study 
visits. 
i 
Vital signs and ECGs will be taken predose through the Week 24 Visit. Following the Week 24 Visit, vital signs and ECGs may be taken pre- or post-dose. 
Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiratory rate, and pulse oximetry (see CSP Section 11.6.3). 
j 
All 12-lead ECGs will be taken predose at the Day 1, Week 12 and Week 24 Clinic Visits. At all visits, ECGs will be taken before any other procedures that 
may affect heart rate, such as blood draws (see CSP Section 11.6.4).  
1 


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Table 11-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition Subjects From Study 124 Part B) 
 
Treatment Period 
(Day 1 through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week 
Follow-up OE 
Event/Assessment 
Day -
28 to 
Day -1 
Day 1c 
Weeks 12, 36, 
60, and 84 
(±7 Days) 
Weeks 24, 48, 
72, and 96 
(±7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks 
(±7 Days) After 
the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Serum chemistry and hematology 
Xk  
X 
X 
X 
X 
 
Ophthalmologic examinationl 
 
Xm 
 
X 
Xn 
 
X 
Fecal sample collectiono  
 
X 
 
X 
X 
 
 
Sweat chloride testp 
 
X 
 
X 
 
 
 
Qualitative microbiology cultures 
 
X 
 
X 
 
 
 
                                                 
k 
If the Day 1 Visit is conducted ≤9 days after the last study visit of Study 124 Part B, the serum chemistry and hematology assessments performed at the last 
study visit of Study 124 Part B will not need to be repeated. If the Day 1 Visit is conducted >9 days after the last study visit of Study 124 Part B, the serum 
chemistry and hematology assessments can be obtained up to 9 days before or at the Day 1 Visit. The results must be reviewed before the first dose of study 
drug. 
l 
The OE will be conducted by a licensed ophthalmologist, preferably a pediatric ophthalmologist. The OE may be performed at the study visit or ± 14 days of 
the clinic visit. 
m  The OE does not need to be repeated if the subject had an OE in Study 124 Part B within 24 weeks of the Day 1 Visit. Otherwise, an OE must be conducted 
within 14 days of the Day 1 Visit. Throughout this study, these subjects should have OEs approximately every 24 weeks (± 14 days) from the last OE in 
Study 124. 
n The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue ivacaftor dosing (for any reason) unless performed in the last 
12 weeks.  
o  Samples will be analyzed for fecal elastase-1 and other markers of intestinal inflammation, including fecal calprotectin. Samples may be collected (e.g., at 
home) up to 24 hours before the study visit (e.g., at home) and brought to the clinic. If the sample is collected in the clinic, the sample may be collected pre- 
or postdose. 
p 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. For all subjects, except those that completed a baseline sweat chloride test at screening, the Day 1 sweat 
chloride test will be performed predose. At all other visits up to the Week 24 Visit, the test must be performed within ± 2 hours of the ivacaftor dose. After the 
Week 24 Visit, the sweat chloride test may be performed at any time during the visit. 
1 


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Table 11-2 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Gap Transition Subjects From Study 124 Part B) 
 
Treatment Period 
(Day 1 through Week 96) 
ETT Visita 
Safety 
Follow-up Visitb 
24-Week 
Follow-up OE 
Event/Assessment 
Day -
28 to 
Day -1 
Day 1c 
Weeks 12, 36, 
60, and 84 
(±7 Days) 
Weeks 24, 48, 
72, and 96 
(±7 Days) 
As Soon as 
Possible After 
the Last Dose 
4 Weeks 
(±7 Days) After 
the Last Dose 
24 Weeks 
(+ 14 Days) 
After the Last 
Dose 
Multiple breath washout (optional)q  
 
X 
 
Xr 
 
 
 
Study drug administrations 
 
X 
X 
X 
 
 
 
Study drug count 
 
X 
X 
X 
X 
 
 
Pulmonary exacerbations,  
CF-related hospitalizations 
Continuous from signing of ICF through the last dose 
of study drug 
 
 
 
Adverse events 
Continuous from signing ICF through the Safety Follow-up Visit (see CSP Section 13.1.1.3) 
Ocular adverse 
events only 
Medications and procedures review 
Continuous from signing of ICF through the Safety Follow-up Visit 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ETT: Early Termination of Treatment; ICF: informed consent form; MBW: 
multiple breath washout; LFT: liver function test; OE: ophthalmologic examination; q12h: every 12 hours. 
                                                 
q MBW will be performed on subjects for whom additional or separate informed consent was obtained for the procedures, and only at sites that are adequately 
trained and qualified to perform MBW (see CSP Section 11.5.6). If MBW was performed in Study 124 within 28 days of the Day 1 Visit in Study 126, MBW 
will not need to be repeated on Day 1. If a Day 1 MBW is needed, the MBW must be performed within 1 week before the Day 1 Visit. The Week 96 MBW 
must be performed within 1 week before the last dose. Detailed procedures will be supplied in a separate study manual. 
r 
MBW will be performed at the Week 24 and 48 Visits (± 7 days).  
s 
The morning dose of study drug will be administered at the Day 1, Week 12 and Week 24 Clinic Visits. After the Week 24 Visit, the morning dose need not 
be administered at the Clinic Visit. Additional guidance for preparation and administration of study drug is provided in CSP Section 9.4 and the study manual. 


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Table 11-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects 
Not From Study 124) 
 
Screenin
g 
Period35 
Treatment Period 
(Day 1 through Week 96) 
ETT 
Visit36 
Safety 
Follow-
up Visit37 
24-Week 
Follow-up 
OE 
Event/Assessmen
t 
Day -28 
to Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 
2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as 
Possible 
After the 
Last Dose 
4 Weeks 
(± 7 
Days) 
After the 
Last 
Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusio
n criteria review 
X 
X 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone contact 
 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Historical data 
X38 
 
 
 
 
 
 
 
 
 
 
 
CFTR genotype39 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug dose 
determination 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
                                                 
35 
Subjects will only be allowed to enroll in Study 126 after an adequate number of subjects have completed the corresponding age cohort in Study 124, in 
conjunction with feedback from regulatory authorities.  
36 
The ETT Visit is to be scheduled as soon as possible after the last dose of ivacaftor. If the ETT Visit occurs 3 weeks or later after the last dose of 
ivacaftor, the Safety Follow-up Visit will not be required. Subjects who elect to receive commercially available ivacaftor will be discontinued from 
ivacaftor dosing and will complete the ETT Visit. 
37 
For subjects who elect to receive commercially available ivacaftor, the Safety Follow-up Visit will not be required. 
38 
Historical data from birth to screening will also be collected before (i.e., at screening) or at Day 1 (see CSP Section 11.2). 
39 
For subjects who participated in Study 124 Part A, the CFTR genotype result can be taken from Study 124. 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 
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Table 11-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects 
Not From Study 124) 
 
Screenin
g 
Period35 
Treatment Period 
(Day 1 through Week 96) 
ETT 
Visit36 
Safety 
Follow-
up Visit37 
24-Week 
Follow-up 
OE 
Event/Assessmen
t 
Day -28 
to Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 
2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as 
Possible 
After the 
Last Dose 
4 Weeks 
(± 7 
Days) 
After the 
Last 
Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Length and 
weight40 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
examination41 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs42 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGs42, 43 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Serum chemistry 
and hematology44 
X 
 
Chem-
istry 
only 
LFTs 
and 
hema-
tology 
only 
X 
X 
X 
X 
X 
X 
 
                                                 
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. 
40 
Length and weight measurements will be performed predose through the Week 24 Visit (see CSP Section 11.5.1). 
41 
Full physical examinations will be performed at the Screening, ETT, and Safety Follow-up Visits; abbreviated physical examinations will be performed 
at all other study visits. 
42 
Vital signs and ECGs will be taken predose through the Week 24 Visit. Following the Week 24 Visit, vital signs and ECGs may be taken pre- or post-
dose. Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, respiratory rate, and pulse oximetry (see CSP Section 11.6.3). 
43 
All 12-lead ECGs will be performed predose at the Day 1, Week 12 and Week 24 Clinic Visits. At all visits, ECGs will be taken before any other 
procedures that may affect heart rate, such as blood draws (see CSP Section 11.6.4). 
44 
To minimize blood draws, the Screening Visit and Day 1 clinical laboratory assessments can be combined into a single blood draw taken up to 9 days 
before the Day 1 dosing. The results must be received and reviewed before the first dose of study drug. 
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Table 11-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects 
Not From Study 124) 
 
Screenin
g 
Period35 
Treatment Period 
(Day 1 through Week 96) 
ETT 
Visit36 
Safety 
Follow-
up Visit37 
24-Week 
Follow-up 
OE 
Event/Assessmen
t 
Day -28 
to Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 
2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as 
Possible 
After the 
Last Dose 
4 Weeks 
(± 7 
Days) 
After the 
Last 
Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Ophthalmologic 
examination45 
X46 
 
 
 
 
 
X 
 
X 
X47 
 
X 
Fecal sample 
collection 48 
X49 
 
X 
X 
X 
X 
 
X 
X 
 
 
Sweat chloride 
test50 
X 
X 
 
X 
 
 
X 
 
X 
 
 
 
Qualitative 
microbiology 
cultures 
 
X 
 
 
 
 
X 
 
X 
 
 
 
                                                 
45 
The OE will be conducted by a licensed ophthalmologist, preferably a pediatric ophthalmologist. The OE may be performed at the study visit or ± 14 
days of the clinic visit. 
46 
If an OE was conducted in Study 124 Part A within 12 weeks of the Day 1 Visit, the Day 1 Visit OE does not need to be repeated. 
47 
The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue ivacaftor dosing in the ivacaftor arm, 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. 
48 
Samples will be analyzed for fecal elastase-1 and other markers of intestinal inflammation, including fecal calprotectin. Samples may be collected (e.g., 
at home) up to 24 hours before the study visit (e.g., at home) and brought to the clinic. If the sample is collected in the clinic, the sample may be 
collected pre- or postdose. 
49 
The fecal sample may be collected at any time during screening.  
50 
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. For all subjects, except those that completed a baseline sweat chloride test at screening, a 
Day 1 sweat chloride test will be performed predose. At all other visits up to the Week 24 Visit, the test must be performed within a window of 
± 2 hours relative to the ivacaftor dose. After the Week 24 Visit, the sweat chloride test may be performed at any time during the visit. 
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Table 11-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects 
Not From Study 124) 
 
Screenin
g 
Period35 
Treatment Period 
(Day 1 through Week 96) 
ETT 
Visit36 
Safety 
Follow-
up Visit37 
24-Week 
Follow-up 
OE 
Event/Assessmen
t 
Day -28 
to Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 
2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as 
Possible 
After the 
Last Dose 
4 Weeks 
(± 7 
Days) 
After the 
Last 
Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Multiple breath 
washout 
(optional)51  
 
X 
 
 
 
 
X 
 
X52 
 
 
 
Study drug 
administration53  
 
X 
 
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 
X 
 
 
Pulmonary 
exacerbations, 
CF-related 
hospitalizations 
Continuous from signing of ICF through the last dose of study drug 
 
 
 
                                                 
51 
MBW will be performed on subjects for whom additional or separate informed consent was obtained for the procedures, and only at sites that are 
adequately trained and qualified to perform this assessment (CSP Section 11.5.6). The Day 1 MBW must be performed within 1 week before the first 
dose, not postdose. The Week 96 MBW must be performed within 1 week before the last dose, not after the last dose. Detailed procedures will be 
supplied in a separate study manual. 
52 
MBW will be performed at the Week 48 and Week 72 Visits (± 7 days).  
53 
The morning dose of study drug will be administered at the Day 1, and 2-, 4-, 8-, 12-, 18-, and 24-Week Clinic Visits. After the Week 24 Visit, the 
morning dose need not be administered at the Clinic Visit. Additional guidance for preparation and administration of study drug is provided in CSP 
Section 9.4 and the study manual. 


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Table 11-3 
Schedule of Assessments for VX15-770-126 (Ivacaftor Arm: Study 124 Part A Only Subjects or Subjects 
Not From Study 124) 
 
Screenin
g 
Period35 
Treatment Period 
(Day 1 through Week 96) 
ETT 
Visit36 
Safety 
Follow-
up Visit37 
24-Week 
Follow-up 
OE 
Event/Assessmen
t 
Day -28 
to Day -1 
Day 1 
Day 3 
(± 1 
Day) 
Week 
2 
(± 1 
Day) 
Week 
4 
(± 5 
Days) 
Weeks 
8 and 
18  
(± 7 
Days) 
Weeks 
12 and 
24 
(± 7 
Days) 
Weeks 
36, 60, 
and 84 
(± 7 
Days) 
Weeks 
48, 72, 
and 96 
(± 7 
Days) 
As Soon 
as 
Possible 
After the 
Last Dose 
4 Weeks 
(± 7 
Days) 
After the 
Last 
Dose 
24 Weeks 
(+ 14 
Days) 
After the 
Last Dose 
Adverse events 
Continuous from signing ICF through the Safety Follow-up Visit (see CSP Section 13.1.1.3) 
Ocular 
adverse 
events 
only 
Medications and 
procedures review 
Continuous from signing of ICF through the Safety Follow-up Visit 
 
CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ETT: Early Termination of Treatment; ICF: informed consent form; MBW: 
multiple breath washout; LFT: liver function test; OE: ophthalmologic examination; q12h: every 12 hours. 
 
 
 
 
 


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Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments - Rollover 
Subjects From Study 124 Part B or Part A/B 
Assessment 
Visita 
Target Study 
Day 
Analysis Visit Window 
(in study days) 
Safety Assessments 
Serum Chemistry 
Hematology 
Vital Signs 
 
Baseline 
Not applicable 
parent study baseline 
Week 12 
84 
[2, 126] 
Week 24 
168 
[127, 210] 
Week 36 
252 
[211, 294] 
Week 48 
336 
[295, 378] 
Week 60 
420 
[379, 462] 
Week 72 
504 
[463, 546] 
Week 84 
588 
[547, 630] 
Week 96 
672 
[631, max(686, Date of Week 
96 + 14)] 
Safety Follow-up Visit 
NA 
Use nominal visit 
Standard 12-Lead ECG 
 
Baseline 
Not applicable 
parent study baseline 
Week 24 
168 
[2, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421,588] 
Week 96 
672 
[589, max(686, Date of Week 
96 + 14)] 
Safety Follow-up Visit 
NA 
Use nominal visit 
Ophthalmologic Exam 
Baseline 
Not applicable 
parent study baseline 
Week 24 
168 
[2, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421, 588] 
Week 96 
672 
[589, max(686, Date of Week 
96 + 14)] 
24-Week Follow-up OE 
NA 
Use nominal visit 
Efficacy Assessments 
Weight 
Length 
Weight-for-length 
BMI 
Weight-for-age z-score 
Length-for-age z-score 
Weight-for-length z-score  
BMI-for-age z score 
Baseline 
Not applicable 
parent study baseline 
Week 12 
84 
[2, 126] 
Week 24 
168 
[127, 210] 
Week 36 
252 
[211, 294] 
Week 48 
336 
[295, 378] 
Week 60 
420 
[379, 462] 
Week 72 
504 
[463, 546] 
Week 84 
588 
[547, 630] 
Week 96 
672 
[631, max(686, Date of Week 
96 + 14)] 
Safety Follow-up Visit 
NA 
Use nominal visitc 
                                                 
 


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Fecal elastase-1 
Fecal calprotectin 
Sweat chloride 
Qualitative Microbiology 
Multiple Breath Washout 
 
Baseline 
Not applicable 
parent study baseline 
Week 24 
168 
[2, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421, 588] 
Week 96 
672 
[589, max(686, Date of Week 
96 + 14)] 
a Visit name is used to report data in tables, listings and figures. 
b Target day time point per protocol is predose, except for ECG measurements. 
c  Per section 8.1, it will remain as the SFU if it goes beyond the upper boundary of the window for the last 
scheduled visit. 
 
 
Table 11-5 
Analysis Visit Windows for Safety and Efficacy Assessments – IVA-naïve 
subjects (Subjects Not From Study 124 Part B or Part A/B) 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Safety Assessments 
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, 210] 
Week 36 
252 
[211, 294] 
Week 48 
336 
[295, 378] 
Week 60 
420 
[379, 462] 
Week 72 
504 
[463, 546] 
Week 84 
588 
[547, 630] 
Week 96 
672 
[631, max(686, Date of Week 
96 + 14)] 
Safety 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, 210] 
Week 36 
252 
[211, 294] 
Week 48 
336 
[295, 378] 
Week 60 
420 
[379, 462] 
Week 72 
504 
[463, 546] 
Week 84 
588 
[547, 630] 
                                                 
 
 


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Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Week 96 
672 
[631, max(686, Date of Week 
96 + 14)] 
Safety 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, 210] 
Week 36 
252 
[211, 294] 
Week 48 
336 
[295, 378] 
Week 60 
420 
[379, 462] 
Week 72 
504 
[463, 546] 
Week 84 
588 
[547, 630] 
Week 96 
672 
[631, max(686, Date of Week 
96 + 14)] 
Safety Follow-up Visit 
NA 
Use nominal visit 
 
Liver Function Tests 
Vital Signs 
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, 210] 
Week 36 
252 
[211, 294] 
Week 48 
336 
[295, 378] 
Week 60 
420 
[379, 462] 
Week 72 
504 
[463, 546] 
Week 84 
588 
[547, 630] 
Week 96 
672 
[631, max(686, Date of Week 
96 + 14)] 
Safety Follow-up Visit 
NA 
Use nominal visit 
Ophthalmologic Exam 
Baseline 
1 
1 
Week 12 
84 
[2, 126] 
Week 24 
168 
[127, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421, 588] 
Week 96 
672 
[589, max(686, Date of Week 
96 + 14)] 
24-Week Follow-up OE 
NA 
Use nominal visit 
Efficacy Assessments 
Weight 
Length 
Weight-for-length 
BMI 
Weight-for-age z-score 
Length-for-age z-score 
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] 


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Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Weight-for-length z-score  
BMI-for-age z score 
Week 24 
168 
[148, 210] 
Week 36 
252 
[211, 294] 
Week 48 
336 
[295, 378] 
Week 60 
420 
[379, 462] 
Week 72 
504 
[463, 546] 
Week 84 
588 
[547, 630] 
Week 96 
672 
[631, max(686, Date of Week 
96 + 14)] 
Safety Follow-up Visit 
NA 
Use nominal visitc 
Fecal elastase-1 
Fecal calprotectin 
 
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, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421, 588] 
Week 96 
672 
[589, max(686, Date of Week 
96 + 14)] 
Sweat Chloride 
Baseline 
1 
1 
Week 2 
14 
[2, 49] 
Week 12 
84 
[50, 126] 
Week 24 
168 
[127, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421, 588] 
Week 96 
672 
[589, max(686, Date of Week 
96 + 14)] 
Qualitative Microbiology 
 
Baseline 
1 
1 
Week 12 
84 
[2, 126] 
Week 24 
168 
[127, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421, 588] 
Week 96 
672 
[589, max(686, Date of Week 
96 + 14)] 
Multiple Breath Washout 
Baseline 
1 
1 
Week 12 
84 
[2, 126] 
Week 24 
168 
[127, 252] 
Week 48 
336 
[253, 420] 
Week 72 
504 
[421, 588] 
Week 96 
672 
[589, max(686, Date of Week 
96 +14)] 
a Visit name is used to report data in tables, listings and figures. 
b Target day time point per protocol is predose, except for ECG measurements. 
c  Per section 8.1, it will remain as the SFU if it goes beyond the upper boundary of the window for the last 
scheduled visit. 


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Notes:  
The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit. 
2. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  
a. 
For efficacy parameters: if there are multiple measurements within a visit window, the 
measurement at the scheduled visit will be used. Otherwise, 
i. If there are no measurements at the scheduled visit, then the measurement closest to the target 
day will be used; or 
ii. If there are multiple measurements with the same distance to the target day, the latest 
measurement will be used.   
b. For safety parameters: if there are multiple measurements within a visit window,   
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements within the same distance from the target day, the latest 
measurement will be used. 
iii. For tables of the extreme lab measurement based on ULN or LLN, convert the lab 
measurements into times of ULN or LLN first, and then select the extreme measurement 
 
 


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Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use the informed consent date for 
non-rollovers and the first dose date for rollovers. 
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, use End of Study date. 
In summary, the prior, concomitant or post categorization of a medication is described below. 
Table 11-5 
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 D: Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
• 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 E: Criteria for Threshold Analysis 
Table 11-6 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
≤ULN 
>ULN - ≤2xULN 
>2xULN - ≤3xULN 
>3xULN - ≤ 5xULN 
>5xULN- ≤ 8xULN 
>8xULN  
FDA DILI Guidance  
AST 
≤ULN 
>ULN - ≤2xULN 
>2xULN - ≤3xULN 
>3xULN - ≤ 5xULN 
>5xULN- ≤ 8xULN 
>8xULN 
FDA DILI Guidance 
ALT or AST 
≤ULN 
>ULN - ≤2xULN 
>2xULN - ≤3xULN 
>3xULN - ≤ 5xULN 
>5xULN- ≤ 8xULN 
>8xULN 
FDA DILI Guidance 
Total Bilirubin 
≤ULN 
>ULN - ≤2xULN 
>2xULN - ≤3xULN 
>3xULN - ≤ 5xULN 
>5xULN- ≤ 8xULN 
>8xULN 
FDA DILI Guidance 
(ALT or AST) and Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance 
  
Table 11-7 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
QT interval 
corrected by 
Fridericia’s 
formula  
<=450 msec 
>450 to <=480 msec 
>480 to <=500 msec 
>500 msec