Clinical trial NCT04235140
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2020-02-24; Completion date: 2023-08-22
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, multicenter, open-label and roll-over study in participants who are 12 to \<24 months of age at initiation of Lumacaftor/Ivacaftor (LUM/IVA) treatment.

Detailed description:

Arms: arm 1: Participants weighing 7 to less than (\<) 9 kilograms (kg) received LUM 75 milligrams (mg)/IVA 94 mg fixed-dose combination (FDC) every 12 hours (q12h) and those weighing 9 to \<14 kg received LUM 100 mg/IVA 125 mg q12h in the treatment period of 96 weeks. Participants weighing greater than or equal to (\>=)14 kg received LUM 150 mg/IVA 188 mg FDC q12h in the treatment period of 96 weeks.
Interventions: intervention 1: LUM/IVA
Intervention descriptions: intervention 1: LUM/IVA granules for oral administration

Protocol documents:
Prot_000.pdf: 
Page 1 of 57 
 
 
1 
TITLE PAGE 
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
 
 
 
 
Clinical Study Protocol 
A Phase 3, Open-label, and Rollover Study to 
Evaluate the Long-term Safety and Tolerability of 
Lumacaftor/Ivacaftor Treatment in Subjects With 
Cystic Fibrosis Who Are Homozygous for F508del 
and 12 to <24 Months of Age at Treatment Initiation 
Vertex Study Number: VX19-809-124 
IND Number: 79521 
 
Date of Protocol: 12 February 2021 (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. 


Protocol VX19-809-124, Version 2.0 
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Confidential Information 
 
 
Summary of Changes to the Protocol 
The previous version of this protocol (Version 1.0, 13 August 2019) was amended to create the 
current version (Version 2.0, 12 February 2021). The protocol history is below. 
 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 13 August 2019 
Original version 
Version 2.0, 12 February 2021 
Added the new dose of LUM 75 mg/IVA 94 mg and adjusted the lower 
weight bound for the LUM 100 mg/IVA 125 mg dose. 
 
Key changes in the current version of the protocol are summarized below. 
 
Change and Rationale 
Affected Sections 
Updated the planned dosing regimen based on PK results from 
Study 122 as follows: 
• Added a lower dose of LUM 75 mg/IVA 94 mg for subjects 
who weigh 7 to <9 kg at Day 1 for the Rollover Subjects 
and at screening for LUM/IVA-naïve subjects. 
• Updated the lower weight bound from 10 kg to 9 kg for the 
LUM 100 mg/IVA 125 mg dose 
The planned dosing regimen was also added to the study 
design figure. 
Sections 2 (Figure 2-1), 9.1 (Figure 9-1), 9.6 
(Table 9-2), and 10.3 (Table 10-1) 
Added text to clarify the use of an assessment of Study 122B 
safety data before starting the enrollment of LUM/IVA-naïve 
subjects in each age group. Before initiating enrollment of 
LUM/IVA-naïve subjects 18 to <24 months of age, this safety 
assessment was performed in addition to meeting the minimum 
enrollment criteria in Study 122B. 
Sections 2 (including Figure 2-1) and 9.1 
(including Figure 9-1) 
Removed footnote “c” from the “Follow-up OE” in the study 
design figure, as the footnote does not apply to the 
ophthalmologic examination. 
Figure 2-1 and Figure 9-1 
Added a ±30-minute window to the abbreviated physical 
examination performed postdose on Day 1 for the LUM/IVA- 
naïve subjects. 
Table 3-2 
Added a new section to describe the use of remote measures in 
extenuating circumstances, such as the COVID-19 pandemic. 
Section 9.1.6; Table 3-1 and Table 3-2 
Added clarification that screening sweat chloride results may 
be reviewed if needed to confirm eligibility. 
Section 10.7 
Removed the limitation that only central laboratory results for 
clinical laboratory assessments may be used for data analysis to 
allow for the use of local laboratories in extenuating 
circumstances, as described in new Section 9.1.6. 
Section 11.4.2 
Updated the analysis definitions for “Prior Medication” and 
“Pretreatment Adverse Event (AE)” to capture medications 
taken and AEs during Study 122 for the Rollover subjects. 
Sections 12.3.2.3 and 12.3.5.1 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 


Protocol VX19-809-124, Version 2.0 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Open-label, and Rollover Study to Evaluate the Long-term Safety and 
Tolerability of Lumacaftor/Ivacaftor Treatment in Subjects With Cystic Fibrosis 
Who Are Homozygous for F508del and 12 to <24 Months of Age at Treatment 
Initiation 
 
Brief Title 
Long-term Safety of Lumacaftor/Ivacaftor in Subjects With Cystic Fibrosis Who 
Are Homozygous for F508del and 12 to <24 Months of Age at Treatment Initiation 
 
Clinical Phase and 
Clinical Study Type 
Phase 3, safety 
 
Objectives 
Primary Objective 
To evaluate the safety and tolerability of long-term lumacaftor/ivacaftor (LUM/IVA) 
treatment in subjects with cystic fibrosis (CF), who are homozygous for F508del 
and 12 to <24 months of age at treatment initiation 
Secondary Objective 
To evaluate the pharmacodynamics (PD) of long-term LUM/IVA treatment in 
subjects with CF, who are homozygous for F508del and 12 to <24 months of age at 
treatment initiation 
 
Endpoints 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory (serum chemistry and hematology), standard 12-lead ECGs, vital signs, 
pulse oximetry, and ophthalmological examinations (OEs) 
Secondary Endpoint 
Absolute change from baseline in sweat chloride 
Exploratory Endpoints 
• Absolute change from baseline in the following growth parameters: 
o Body mass index (BMI)-for-age z-score and BMI 
o Weight-for-age z-score and weight 
o Length/height-for-age z-score and length/height 
o Weight-for-length z-score 
• Absolute change from baseline in the following markers of pancreatic function: 
o Fecal elastase-1 (FE-1) levels 
o Serum immunoreactive trypsin and trypsinogen (IRT) levels 
• Absolute change from baseline in fecal calprotectin, a marker of intestinal 
inflammation 
 
Number of Subjects 
Approximately 50 subjects 
 
Study Population 
Male and female subjects with CF, homozygous for F508del, and who are 12 to 
<24 months of age at LUM/IVA treatment initiation 


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Rollover Subjects: Subjects who completed LUM/IVA treatment and the Safety 
Follow-up Visit in Study VX16-809-122 Part B (Study 122B) 
 
LUM/IVA-naïve Subjects: Subjects who did not participate in in Study 122B and 
are 12 to <24 months of age at Study 124 Day 1. 
 
Investigational Drug 
Active substance: LUM/IVA fixed-dose combination 
Activity: CFTR corrector and potentiator 
Strength and route of administration: 
• 
LUM 75-mg/IVA 94-mg granules for oral administration 
• 
LUM 100-mg/IVA 125-mg granules for oral administration 
• 
LUM 150-mg/IVA 188-mg granules for oral administration 
 
Study Duration 
Rollover Subjects: The total duration is up to 120 weeks (96 weeks for the 
Treatment Period and 24 weeks for the Follow-up OE) 
LUM/IVA-naïve Subjects: The total duration is up to 124 weeks (up to 28 days for 
the Screening Period, 96 weeks for the Treatment Period, and 24 weeks for the 
Follow-up OE) 
 
Study Design 
This is a Phase 3, multicenter, open-label study in subjects who are 12 to 
<24 months of age at initiation of LUM/IVA treatment (Figure 2-1). 
Figure 2-1 
Study 124 Design 
 
IVA: ivacaftor; LUM: lumacaftor; OE: ophthalmological examination; q12h: every 12 hours; 
wks: weeks 
a 
LUM/IVA-naïve subjects (by age group: 18 to <24 months and 12 to <18 months) will 
be able to enroll in Study 124 once minimum enrollment has been met in Study 122B 
(n = 10 subjects in each age group), and after an assessment of safety data from Study 
122B through Week 12 for ≥5 subjects in each age group. 
b 
For Rollover Subjects, the Day 1 Visit should be the same day as the Safety Follow-up 
Visit in Study 122B. 
c 
The Safety Follow-up Visit will not be required for subjects transitioning to commercial 
LUM/IVA. 
d 
For LUM/IVA-naïve subjects, doses will be determined by weight at screening. 
 
The subjects enrolled in this study include: 
Rollover Subjects: Subjects who participated in Study 122B and completed the 
Study 122B Safety Follow-up Visit. 


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LUM/IVA-naïve Subjects: Subjects who did not participate in Study 122B and are 
12 to <24 months of age at Study 124 Day 1. These subjects will enroll by age group 
as follows: 
• Subjects who are 18 to <24 months of age can enroll in Study 124 after a 
minimum of 10 subjects (aged 18 to <24 months) have enrolled in Study 122B, 
and after an assessment of safety data from Study 122B through Week 12 for 
≥5 subjects aged 18 to <24 months. 
• Subjects who are 12 to <18 months of age can enroll in Study 124 after a 
minimum of 10 subjects (aged 12 to <18 months) have enrolled in Study 122B, 
and after an assessment of safety data from Study 122B through Week 12 for 
≥5 subjects aged 12 to <18 months. 
Note: Subjects who are 18 to <24 months of age will start enrolling in Study 124 
before any subjects who are 12 to <18 months of age enroll as a result of the study 
design in Study 122, which includes sequential age cohorts. 
Rollover and LUM/IVA-naïve subjects will receive LUM/IVA every 12 hours 
(q12h), according to a weight-based dosing regimen determined in Study 122, for up 
to 96 weeks. 
Dose(s) and/or weight bounds may be adjusted after review of safety, tolerability, 
available pharmacokinetic (PK) data from Study 122, as well as any updated 
modeling approaches resulting from such data. Changes to study drug dose(s) and/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. 
During the treatment period, doses may also be adjusted upward based on consistent 
weight gain; however, no downward dose adjustments will be made if a subject’s 
weight decreases. 
 
Assessments 
Safety: AEs, clinical laboratory (serum chemistry and hematology), standard 
12-lead ECGs, vital signs, pulse oximetry, physical examinations, and OEs 
Pharmacodynamic: Sweat chloride 
Exploratory: BMI, BMI-for-age z-score, weight, weight-for-age z-score, 
length/height, length/height-for-age z-score, weight-for-length-for-age z-score, 
FE-1, IRT, and fecal calprotectin 
 
Statistical Analyses 
No formal sample size calculations have been performed. The study will enroll 
approximately 50 subjects to provide data for the assessment of long-term safety in 
the target patient population, as requested by a regulatory agency. 
Data from all safety, pharmacodynamic (PD), and exploratory endpoints will be 
analyzed using descriptive statistics. Raw and change from baseline values will be 
summarized descriptively for the continuous endpoints; number of subjects and 
percentages will be summarized for the categorical endpoints. 
 
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 
enrolled. 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 and Table 3-2. 
Table 3-1 
Study VX19-809-124: Rollover Subjects 
 
Event/ 
Assessmenta 
Treatment Period 
(Day 1 Through Week 96) 
ETT Visitb 
SFU Visit c 
Follow-up 
OE 
Comments 
Day 1d 
Day 3 
(± 1 Day) 
Day 15 
(± 3 
Days) 
Weeks 12, 
24, 36, 48, 
60, 72, and 
84 
(± 7 Days) 
Week 96 
(± 7 Days) 
As Soon As 
Possible 
After Last 
Dose 
2 Weeks 
(± 4 Days) 
After Last 
Dose 
24 Weeks 
(± 14 Days 
) After 
Last Dose 
Informed consent 
X 
Inclusion/exclusion 
criteria 
confirmation 
X 
Telephone contact 
X 
Assessment of subject’s status, any AEs, concomitant 
medications, treatments, and procedures. 
Clinic visit 
X 
X 
X 
X 
X 
X 
See Section 9.1.6 for use of remote measures in 
extenuating circumstances. 
Length/height and 
weight 
X 
X 
X 
X 
X 
X 
Measured with the subject in a dry diaper or dry 
underclothes. If the subject is >2 years of age and can stand 
unassisted and follow directions, standing height should be 
measured; otherwise recumbent length should be measured. 
(Section 11.3.1). 
Vital signs 
X 
X 
X 
X 
X 
X 
The subject should rest for at least 5 minutes, if possible, 
before having vital signs measured. (Section 11.4.4) 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
The subject should rest for at least 5 minutes, if possible, 
before having pulse oximetry measured. (Section 11.4.4) 
a 
Assessments will be performed before dosing unless noted otherwise. 
b 
If the ETT Visit occurs ≥10 days after the last dose of LUM/IVA, SFU Visit will not be required (Section 9.1.4). Subjects who prematurely discontinue LUM/IVA treatment for AEs should be 
followed until the AE is considered resolved. 
c 
The SFU Visit is required for 1) subjects who complete their ETT Visit <10 days after the last dose of LUM/IVA (footnote b and Section 9.1.4); and 2) subjects who interrupt LUM/IVA 
treatment and complete their Week 96 Visit <10 days after the last dose of LUM/IVA; it is not required for subjects who continue onto commercially available, physician-prescribed LUM/IVA 
within 2 weeks (± 4 days) of completing LUM/IVA treatment at the Week 96 or ETT Visit. 
d 
For subjects at sites activated by the time of their Study 122B SFU Visit, their Study 124 Day 1 Visit will be on the same day as their Study 122B SFU Visit, and any Study 124 Day 1 
assessments that were specified to be performed at the Study 122B SFU Visit do not need to be repeated. If the Study 124 Day 1 Visit does not coincide with the subject’s Study 122B SFU Visit, 
and if Study 124 Day 1 is ≤9 days after the Study 122B SFU Visit, the Study 124 Day 1 assessments do not need to be repeated. If Study 124 Day 1 is >9 days after the Study 122B SFU Visit, the 
subject will complete all Study 124 Day 1 assessments (except the OE if it was performed ≤12 weeks before the Study 124 Day 1 Visit). See Section 9.1 for details. 


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Table 3-1 
Study VX19-809-124: Rollover Subjects 
 
Event/ 
Assessmenta 
Treatment Period 
(Day 1 Through Week 96) 
ETT Visitb 
SFU Visit c 
Follow-up 
OE 
Comments 
Day 1d 
Day 3 
(± 1 Day) 
Day 15 
(± 3 
Days) 
Weeks 12, 
24, 36, 48, 
60, 72, and 
84 
(± 7 Days) 
Week 96 
(± 7 Days) 
As Soon As 
Possible 
After Last 
Dose 
2 Weeks 
(± 4 Days) 
After Last 
Dose 
24 Weeks 
(± 14 Days 
) After 
Last Dose 
Ophthalmological 
examination 
X 
Weeks 24, 
48, 72 
X 
Xe 
X 
To be performed by a licensed ophthalmologist, preferably 
a pediatric ophthalmologist. May be completed ± 2 weeks 
of the scheduled visit. (Section 11.4.6) 
Physical 
examination 
X 
X 
X 
X 
X 
Section 11.4.4 
12-lead ECGs 
X 
Weeks 24, 
48 
X 
X 
X 
The subject should rest for at least 5 minutes, if possible, 
before having ECGs measured. To be performed before 
any other procedures that may affect heart rate, such as 
blood draws. (Section 11.4.5) 
Serum chemistry 
and hematology 
X 
X (LFTs 
only) 
X 
X 
X 
X 
Section 11.4.2 
IRT 
X 
X 
X 
X 
X 
Section 11.3.2.2 
Sweat chloride 
X 
Weeks 24, 
48 
X 
X 
At each time point, 2 samples will be collected, 1 sample 
from each arm (left and right) (Section 11.2.1). 
Fecal sample 
collection 
X 
Weeks 24, 
48 
X 
X 
May be collected during the clinic visit or by the subject’s 
caregiver up to 48 hours before the clinic visit and brought 
to the clinic visit (Section 11.3.2.1). 
LUM/IVA dosing 
LUM/IVA q12h 
Administered q12h (± 2 hours) within 30 minutes of 
consuming fat-containing food according to the guidelines 
in Section 9.6. The last dose will be the previous dose (e.g., 
evening dose) administered before the Week 96 Visit. See 
Section 9.6 for dose determination details. 
Study drug count 
X 
X 
X 
X 
Medications, 
treatments, and 
procedures review 
Continuous from signing of ICF through the SFU Visit 
Section 9.5 
AEs 
Continuous from signing ICF through the SFU Visit 
Ocular 
AEs only 
Section 11.4.1 
AE: adverse event; ETT: Early Termination of Treatment; ICF: informed consent form; IRT: immunoreactive trypsinogen and trypsin; IVA: ivacaftor; LFT: liver function test; LUM: lumacaftor; 
OE: ophthalmological examination; q12h: every 12 hours; SFU: Safety Follow-up 
 
e 
The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue LUM/IVA dosing (for any reason) unless performed in the 12 weeks before the ETT Visit. 


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Table 3-2 
Study VX19-809-124: LUM/IVA-naïve Subjects 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
 
 
Event/Assessmenta 
Screening 
Treatment Period 
(Day 1 Through Week 96) 
ETT 
Visitb 
SFU Visitc 
Follow-up 
OE 
Comments 
Days -28 
Through 
-1 
Day 
1 
Day 3 
(± 1 
Day) 
Day 15 
(± 3 
Days) 
Weeks 
4, 8, 12, and 
16 
(± 5 Days) 
Week 20 
(± 5 Days) 
Weeks 24, 
36, 48, 60, 
72, and 
84 
(± 7 Days) 
Week 96 
(± 7 Days) 
As Soon 
As 
Possible 
After 
Last Dose 
2 Weeks 
(± 4 Days) 
After Last 
Dose 
24 Weeks 
(± 14 Days) 
After Last 
Dose 
Informed consent 
X 
Inclusion/exclusion 
criteria 
confirmation 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 9.1.6for use of remote measures in 
extenuating circumstances. 
Telephone contact 
X 
X 
Assessment of subject’s status, any AEs, 
concomitant medications, treatments, and 
procedures. 
Demographics 
X 
Medical history 
X 
CFTR genotype 
X 
Retesting is not required for subjects who have 
acceptable documentation of a genotype test as 
described in Section 11.4.2. 
Length/height and 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
Measured with the subject in a dry diaper or 
dry underclothes. If the subject is >2 years of 
age and can stand unassisted and follow 
directions, standing height should be 
measured; otherwise recumbent length should 
be measured. (Section 11.3.1). 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
The subject should rest for at least 5 minutes, 
if possible, before having vital signs measured. 
Days 1 and 15: Predose and 1 to 2 hours and 4 
to 6 hours postdose (Section 11.4.4) 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
The subject should rest for at least 5 minutes, 
if possible, before having pulse oximetry 
measured. 
a 
All assessments may be performed pre- or postdose unless noted otherwise. When repeats of an assessment are required postdose at a given visit, the assessment will be collected only once at that visit 
if LUM/IVA is not administered on the day of the visit (i.e., LUM/IVA interruption or permanent LUM/IVA discontinuation). 
b 
If the ETT Visit occurs ≥10 days after the last dose of LUM/IVA, the SFU Visit will not be required (Section 9.1.3). Subjects who prematurely discontinue LUM/IVA treatment for AEs should be 
followed until the AE is considered resolved. 
c 
The SFU Visit is required for 1) subjects who complete their ETT Visit <10 days after the last dose of LUM/IVA (footnote b and Section 9.1.4); and 2) subjects who interrupt LUM/IVA treatment and 
complete their Week 96 Visit <10 days after the last dose of LUM/IVA; it is not required for subjects who continue onto commercially available, physician-prescribed LUM/IVA within 2 weeks 
(± 4 days) of completing LUM/IVA treatment at the Week 96 or ETT Visit. 


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Table 3-2 
Study VX19-809-124: LUM/IVA-naïve Subjects 
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Confidential Information 
 
 
 
Event/Assessmenta 
Screening 
Treatment Period 
(Day 1 Through Week 96) 
ETT 
Visitb 
SFU Visitc 
Follow-up 
OE 
Comments 
Days -28 
Through 
-1 
Day 
1 
Day 3 
(± 1 
Day) 
Day 15 
(± 3 
Days) 
Weeks 
4, 8, 12, and 
16 
(± 5 Days) 
Week 20 
(± 5 Days) 
Weeks 24, 
36, 48, 60, 
72, and 
84 
(± 7 Days) 
Week 96 
(± 7 Days) 
As Soon 
As 
Possible 
After 
Last Dose 
2 Weeks 
(± 4 Days) 
After Last 
Dose 
24 Weeks 
(± 14 Days) 
After Last 
Dose 
Days 1 and 15: Predose and 1 to 2 hours and 4 
to 6 hours postdose (Section 11.4.4 ) 
Ophthalmological 
examination 
X 
Weeks 24, 
48, 72 
X 
Xd 
X 
To be performed by a licensed 
ophthalmologist, preferably a pediatric 
ophthalmologist. May be completed ± 2 weeks 
of the scheduled visit. (Section 11.4.6) 
Physical 
examination (PE) 
X 
X 
Abbrev 
Week 12 
X 
X 
X 
X 
Day 1: Full PE predose and an abbreviated PE 
4 hours (±30 minutes) postdose (Section 
11.4.4). 
Standard 12-lead 
ECG 
X 
Weeks 4, 12 
Weeks 24, 
48 
X 
X 
X 
The subject should rest for at least 5 minutes, 
if possible, before having ECGs measured. To 
be performed before any other procedures that 
may affect heart rate, such as blood draws. 
(Section 11.4.5) 
Serum chemistry 
and hematology 
X 
X 
X 
(LFTs 
only) 
X 
X 
X 
X 
X 
If the screening blood draw for chemistry and 
hematology was collected ≤9 days before 
Day 1, then a Day 1 blood sample does not 
need to be collected. 
Weeks 4 and 12: Serum chemistry and 
hematology are collected 
Day 15, Weeks 8 and 16: LFTs only 
(Sections 11.4.2 and 11.4.3) 
IRT 
X 
Weeks 4, 12 
X 
X 
X 
X 
Section 11.3.2.2 
Sweat chloride 
X 
X 
Weeks 4, 12 
Weeks 24, 
48 
X 
X 
Day 1 test is not required for subjects who 
have a valid sweat sample at screening. At 
each time point, 2 samples will be collected, 1 
sample from each arm (left and right) 
(Section 11.2.1). 
d 
The OE for the ETT Visit will be conducted for all subjects who prematurely discontinue LUM/IVA dosing (for any reason) unless performed in the 12 weeks before the ETT Visit. 


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Table 3-2 
Study VX19-809-124: LUM/IVA-naïve Subjects 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
 
 
Event/Assessmenta 
Screening 
Treatment Period 
(Day 1 Through Week 96) 
ETT 
Visitb 
SFU Visitc 
Follow-up 
OE 
Comments 
Days -28 
Through 
-1 
Day 
1 
Day 3 
(± 1 
Day) 
Day 15 
(± 3 
Days) 
Weeks 
4, 8, 12, and 
16 
(± 5 Days) 
Week 20 
(± 5 Days) 
Weeks 24, 
36, 48, 60, 
72, and 
84 
(± 7 Days) 
Week 96 
(± 7 Days) 
As Soon 
As 
Possible 
After 
Last Dose 
2 Weeks 
(± 4 Days) 
After Last 
Dose 
24 Weeks 
(± 14 Days) 
After Last 
Dose 
Fecal sample 
collection 
X 
Weeks 4, 12 
Weeks 24, 
48 
X 
X 
Sample collected before first dose of study 
drug may be collected either at screening OR 
up to 48 hours before the Day 1 Visit. All 
other samples may be collected during the 
clinic visit or by the subject’s caregiver up to 
48 hours before the clinic visit and brought to 
the clinic visit (Section 11.3.2.1). 
LUM/IVA dosing 
LUM/IVA q12h 
Administered q12h (± 2 hours) within 
30 minutes of consuming fat-containing food 
according to the guidelines in Section 9.6. The 
last dose will be the previous dose (e.g., 
evening dose) administered before the 
Week 96 Visit. See Section 9.6 for dose 
determination details. 
Observation 4 hours 
after the first dose 
X 
Study drug count 
X 
X 
X 
X 
X 
Medications, 
treatments, and 
procedures review 
Continuous from signing of ICF through the SFU Visit 
Section 9.5 
AEs 
Continuous from signing of ICF through the SFU Visit 
Ocular AEs 
only 
Section 11.4.1 
Abbrev: abbreviated; AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; ETT: Early Termination of Treatment; ICF: informed 
consent form; IRT: immunoreactive trypsin and trypsinogen; IVA: ivacaftor; LFT: liver function test; LUM: lumacaftor; OE: ophthalmological examination; PE: physical examination; q12h: every 
12 hours; SFU: Safety Follow-up 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................. 1 
Summary of Changes to the Protocol .......................................................................................... 2 
2 
Protocol Synopsis .................................................................................................................... 3 
3 
Schedule of Assessments ......................................................................................................... 6 
4 
Table of Contents .................................................................................................................. 11 
List of Tables ............................................................................................................................. 14 
List of Figures ........................................................................................................................... 14 
List of Abbreviations ................................................................................................................. 15 
Definitions of Terms ................................................................................................................. 16 
5 
Introduction ........................................................................................................................... 17 
5.1 
Background ...................................................................................................................... 17 
5.2 
Study Rationale ................................................................................................................ 17 
6 
Study Objectives .................................................................................................................... 17 
6.1 
Primary Objective ............................................................................................................ 17 
6.2 
Secondary Objective ........................................................................................................ 18 
7 
Study Endpoints .................................................................................................................... 18 
7.1 
Primary Endpoint ............................................................................................................. 18 
7.2 
Secondary Endpoint ......................................................................................................... 18 
7.3 
Exploratory Endpoints ..................................................................................................... 18 
8 
Study Population ................................................................................................................... 18 
8.1 
Rollover Subjects ............................................................................................................. 18 
8.1.1 
Inclusion Criteria ..................................................................................................... 18 
8.1.2 
Exclusion Criteria .................................................................................................... 19 
8.2 
LUM/IVA-naïve Subjects ................................................................................................ 19 
8.2.1 
Inclusion Criteria ..................................................................................................... 19 
8.2.2 
Exclusion Criteria .................................................................................................... 20 
9 
Study Implementation .......................................................................................................... 21 
9.1 
Study Design .................................................................................................................... 21 
9.1.1 
Screening (LUM/IVA-naïve Subjects Only) ........................................................... 23 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................. 23 
9.1.1.2 
Extension of Screening Period Window ........................................................... 24 
9.1.1.3 
Rescreening ....................................................................................................... 24 
9.1.2 
Treatment Period ...................................................................................................... 24 
9.1.3 
Follow-up ................................................................................................................. 24 
9.1.4 
Early Termination of Treatment OR Early Discontinuation .................................... 25 
9.1.5 
Independent Data Monitoring Committee ............................................................... 25 
9.1.6 
Use of Remote Measures in Extenuating Circumstances ........................................ 25 
9.2 
Method of Assigning Subjects to Treatment Groups ....................................................... 26 
9.3 
Rationale for Study Elements .......................................................................................... 26 
9.3.1 
Study Design ............................................................................................................ 26 
9.3.2 
Study Drug Dose and Duration ................................................................................ 26 
9.3.3 
Study Assessments ................................................................................................... 27 
9.4 
Study Restrictions ............................................................................................................ 28 
9.5 
Prior and Concomitant Medications ................................................................................ 28 


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9.6 
Administration ................................................................................................................. 29 
9.7 
Dose Modification for Toxicity ....................................................................................... 30 
9.8 
Study Drug Interruptions ................................................................................................. 30 
9.9 
Removal of Subjects ........................................................................................................ 30 
9.10 Replacement of Subjects .................................................................................................. 31 
10 Study Drug Information and Management ........................................................................ 31 
10.1 Preparation and Dispensing ............................................................................................. 31 
10.2 Packaging and Labeling ................................................................................................... 31 
10.3 Study Drug Supply, Storage, and Handling ..................................................................... 31 
10.4 Drug Accountability ......................................................................................................... 31 
10.5 Disposal, Return, or Retention of Unused Drug .............................................................. 32 
10.6 Compliance ...................................................................................................................... 32 
10.7 Blinding and Unblinding.................................................................................................. 32 
11 Assessments ............................................................................................................................ 32 
11.1 Subject and Disease Characteristics ................................................................................. 32 
11.2 Pharmacodynamics .......................................................................................................... 33 
11.2.1 
Sweat Chloride ......................................................................................................... 33 
11.3 Exploratory Assessments ................................................................................................. 33 
11.3.1 
Growth Parameters ................................................................................................... 33 
11.3.2 
Measures of Pancreatic Function ............................................................................. 33 
11.3.2.1 Fecal Elastase-1 ................................................................................................. 33 
11.3.2.2 Immunoreactive Trypsin and Trypsinogen ........................................................ 34 
11.3.3 
Markers of Intestinal Inflammation ......................................................................... 34 
11.4 Safety ............................................................................................................................... 34 
11.4.1 
Adverse Events ........................................................................................................ 34 
11.4.2 
Clinical Laboratory Assessments ............................................................................. 34 
11.4.3 
Elevation of Liver Function Test Parameters .......................................................... 35 
11.4.4 
Physical Examinations and Vital Signs ................................................................... 37 
11.4.5 
Electrocardiograms .................................................................................................. 37 
11.4.6 
Ophthalmological Examination ............................................................................... 37 
11.4.7 
Contraception and Pregnancy .................................................................................. 38 
12 Statistical and Analytical Plans............................................................................................ 38 
12.1 Sample Size and Power .................................................................................................... 38 
12.2 Analysis Sets .................................................................................................................... 38 
12.3 Statistical Analysis ........................................................................................................... 38 
12.3.1 
General Considerations ............................................................................................ 38 
12.3.2 
Background Characteristics ..................................................................................... 39 
12.3.2.1 Subject Disposition ............................................................................................ 39 
12.3.2.2 Demographics and Baseline Characteristics ...................................................... 39 
12.3.2.3 Prior and Concomitant Medications .................................................................. 39 
12.3.2.4 Study Drug Exposure and Compliance ............................................................. 40 
12.3.3 
Secondary Endpoint Analysis .................................................................................. 40 
12.3.3.1 Absolute Change From Baseline in Sweat Chloride ......................................... 40 
12.3.4 
Exploratory Endpoint Analysis ................................................................................ 40 
12.3.4.1 Absolute Change From Baseline in Growth Parameters ................................... 40 
12.3.4.2 Absolute Change From Baseline in Markers of Pancreatic Function ............... 41 


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12.3.4.3 Absolute Change From Baseline in Fecal Calprotectin .................................... 41 
12.3.5 
Safety Analysis ....................................................................................................... 41 
12.3.5.1 Adverse Events ................................................................................................. 41 
12.3.5.2 Clinical Laboratory Assessments ..................................................................... 42 
12.3.5.3 Electrocardiogram............................................................................................. 43 
12.3.5.4 Vital Signs ........................................................................................................ 43 
12.3.5.5 Physical Examination ....................................................................................... 43 
12.3.5.6 Pulse Oximetry ................................................................................................. 43 
12.3.5.7 Ophthalmological Examinations ...................................................................... 43 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses ........................... 43 
12.3.6.1 Interim Analysis ............................................................................................... 43 
12.3.6.2 IDMC Analysis ................................................................................................. 43 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ............................ 44 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 44 
13.1.1 
Adverse Events ....................................................................................................... 44 
13.1.1.1 Definition of an Adverse Event ........................................................................ 44 
13.1.1.2 Clinically Significant Assessments .................................................................. 44 
13.1.1.3 Documentation of Adverse Events ................................................................... 44 
13.1.1.4 Adverse Event Severity .................................................................................... 45 
13.1.1.5 Adverse Event Causality .................................................................................. 46 
13.1.1.6 Study Drug Action Taken ................................................................................. 46 
13.1.1.7 Adverse Event Outcome ................................................................................... 47 
13.1.1.8 Treatment Given ............................................................................................... 47 
13.1.2 
Serious Adverse Events .......................................................................................... 47 
13.1.2.1 Definition of a Serious Adverse Event ............................................................. 47 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 48 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ....................................... 48 
13.2 Administrative Requirements ......................................................................................... 49 
13.2.1 
Ethical Considerations ............................................................................................ 49 
13.2.2 
Subject Information and Informed Consent ............................................................ 49 
13.2.3 
Investigator Compliance ......................................................................................... 49 
13.2.4 
Access to Records ................................................................................................... 49 
13.2.5 
Subject Privacy ....................................................................................................... 49 
13.2.6 
Record Retention .................................................................................................... 50 
13.2.7 
Study Termination................................................................................................... 50 
13.2.8 
End of Study ........................................................................................................... 50 
13.3 Data Quality Assurance .................................................................................................. 51 
13.4 Electronic Data Capture .................................................................................................. 51 
13.5 Confidentiality and Disclosure ....................................................................................... 51 
13.6 Publications and Clinical Study Report .......................................................................... 52 
13.6.1 
Publication of Study Results ................................................................................... 52 
13.6.2 
Clinical Study Report .............................................................................................. 53 
14 References ............................................................................................................................. 54 
15 Protocol Signature Pages ..................................................................................................... 56 
15.1 Sponsor Signature Page .................................................................................................. 56 


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15.2 Investigator Signature Page ............................................................................................. 57 
 
List of Tables 
Table 3-1 
Study VX19-809-124: Rollover Subjects ............................................................... 6 
Table 3-2 
Study VX19-809-124: LUM/IVA-naïve Subjects .................................................. 8 
Table 9-1 
Study Restrictions .................................................................................................. 28 
Table 9-2 
Study Drug Administration: Planned Doses ......................................................... 29 
Table 10-1 
Study Drug ............................................................................................................. 31 
Table 11-1 
Safety Laboratory Test Panels ................................................................................ 35 
Table 13-1 
Grading of AE Severity .......................................................................................... 46 
Table 13-2 
Classifications for AE Causality ............................................................................ 46 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................... 46 
Table 13-4 
Classifications for Outcome of an AE ................................................................... 47 
List of Figures 
Figure 2-1 
Study 124 Design .................................................................................................... 4 
Figure 9-1 
Study 124 Design .................................................................................................. 22 


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List of Abbreviations 
 
Abbreviation 
Definition 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Cl- 
chloride ion 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
eGFR 
estimated glomerular filtration rate 
ETT 
Early Termination of Treatment 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the 
wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FE-1 
fecal elastase-1 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GPP3 
Good Publication Practices 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
immunoreactive trypsinogen 
IV 
intravenous 
IVA 
ivacaftor 
LFT 
liver function test 
LLN 
lower limit of normal 


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Abbreviation 
Definition 
LUM 
lumacaftor 
MedDRA 
Medical Dictionary for Regulatory Activities 
OE 
ophthalmological examination 
PC 
publication committee 
PD 
pharmacodynamics, pharmacodynamics 
PERT 
pancreatic enzyme replacement therapy 
PEx 
pulmonary exacerbation 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SE 
standard error 
SFU 
Safety Follow-up 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WHO-DD 
World Health Organization-Drug Dictionary 
 
Definitions of Terms 
Abbreviated study numbers: In the body of the text, study numbers are abbreviated to the last 
3 digits and the study part letter (if applicable) for lumacaftor/ivacaftor studies 
(e.g., Study VX16-809-122 Part B is Study 122B). 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality, and at present, there is no cure. CF is caused by a 
defect in the gene encoding CFTR, an epithelial chloride ion channel that is responsible for 
aiding in the regulation of salt and water absorption and secretion in various tissues.1 This 
function is abnormal in patients with CF due to a loss of cell surface expression and/or function 
of CFTR. CF affects more than 78,000 individuals worldwide.2, 3 Despite progress in the 
treatment of CF with antibiotics and mucolytics, the predicted median age of survival for a 
person with CF is approximately 40 years.4, 5 Although the disease affects multiple organs, 
progressive loss of lung function is the leading cause of mortality.6 
Approximately half of the total CF patient population is <18 years of age.2, 3, 7, 8 In the US, 58.4% 
of all new diagnoses are detected by newborn screening.2 Early diagnosis has been associated 
with better outcomes later in life.9 Pancreatic destruction leading to pancreatic exocrine 
insufficiency begins in utero, with over 90% of homozygous F508del infants demonstrating 
pancreatic insufficiency requiring pancreatic enzyme replacement therapy (PERT). Lung 
involvement is primarily manifested by changes in airway surface liquid height leading to 
impaired mucociliary clearance and subsequent neutrophilic airway inflammation, bacterial 
colonization, and infection leading to structural lung damage that begins shortly after birth.10, 11 
CFTR modulators, such as lumacaftor (LUM; VX-809)/ivacaftor (IVA; VX-770) combination 
therapy (Orkambi™), target the underlying cause of CF and have the potential to alter the course 
of the disease. LUM/IVA is the first medicine designed to treat the underlying molecular defect 
and enhance the function of CFTR in patients homozygous for F508del. The LUM/IVA 
development program is designed to support the hypothesis that an oral chronic treatment 
restoring CFTR function can lead to improved pulmonary and extrapulmonary manifestations of 
CF, prevent progressive lung damage, and ultimately prolong survival. 
Details about the LUM/IVA development program can be found in the Investigator’s Brochure. 
5.2 
Study Rationale 
The primary objectives of Study VX16-809-122 (Study 122) are to obtain pharmacokinetic (PK) 
and safety information to support a proposed indication expansion of LUM/IVA in subjects 12 to 
<24 months of age with CF, homozygous for F508del. The primary objective of 
Study VX19-809-124 (Study 124, the current study) is to evaluate the long-term safety of 
LUM/IVA in subjects 12 to <24 months of age with CF, homozygous for F508del, at the time of 
treatment initiation. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the safety and tolerability of long-term LUM/IVA treatment in subjects with CF, 
who are homozygous for F508del and 12 to <24 months of age at treatment initiation 


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6.2 
Secondary Objective 
To evaluate the pharmacodynamics (PD) of long-term LUM/IVA treatment in subjects with CF, 
who are homozygous for F508del and 12 to <24 months of age at treatment initiation 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory (serum 
chemistry and hematology), standard 12‑lead ECGs, vital signs, pulse oximetry, and 
ophthalmological examinations (OEs) 
7.2 
Secondary Endpoint 
Absolute change from baseline in sweat chloride 
7.3 
Exploratory Endpoints 
• 
Absolute change from baseline in the following growth parameters: 
o Body mass index (BMI)-for-age z-score and BMI 
o Weight-for-age z-score and weight 
o Length/height-for-age z-score and length/height 
o Weight-for-length z-score 
• 
Absolute change from baseline in the following markers of pancreatic function: 
o Fecal elastase-1 (FE-1) levels 
o Serum immunoreactive trypsin and trypsinogen (IRT) levels 
• 
Absolute change from baseline in fecal calprotectin, a marker of intestinal inflammation 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Rollover Subjects 
8.1.1 
Inclusion Criteria 
1. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) will 
sign and date an informed consent form (ICF). 
2. Completed the 24-week Treatment Period and the Safety Follow-up Visit in Study 122B. 
Note: Subjects who had study drug interruptions during Study 122B are eligible for 
Study 124 if they completed the study visits in the Treatment Period and the Safety Follow- 
up Visit. Subjects who had a study drug interruption at Week 24 of Study 122B or subjects 
who resumed study drug in Study 122B after a study drug interruption due to elevated 
transaminases but who did not complete at least 4 weeks of rechallenge with study drug (due 


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to <4 weeks remaining in the Study 122B Treatment Period) must meet eligibility criteria and 
receive approval from the Vertex medical monitor. 
3. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) are 
willing to have the subject remain on a stable CF medication regimen through the Safety 
Follow-up Visit. 
8.1.2 
Exclusion Criteria 
1. Prematurely discontinued LUM/IVA treatment in Study 122B. 
2. History of any comorbidity or laboratory abnormality that, in the opinion of the investigator, 
might confound the results of the study or pose an additional risk in administering LUM/IVA 
to the subject (e.g., cirrhosis with portal hypertension). 
3. History of drug intolerance or other serious reactions to LUM/IVA in Study 122B that would 
pose an additional risk to the subject in the opinion of investigator and which should be 
discussed with the Vertex medical monitor. 
4. Subjects with a history of allergy or hypersensitivity to LUM/IVA. 
5. Liver function test (LFT) abnormality meeting criteria for LUM/IVA treatment interruption 
at the completion of Study 122B, for which no convincing alternative etiology is identified. 
6. QTc value at the completion of Study 122B that would pose an additional risk to the subject 
in the opinion of investigator, and should be discussed with the Vertex medical monitor 
(e.g., remained above the threshold value [>45 msec from baseline or >500 msec] on 
repeated measurement or was noted on 2 or more occasions with no identified alternative 
etiology for the increased QTc). 
7. History of poor compliance with LUM/IVA and/or procedures in Study 122B as deemed by 
the investigator. 
8. Participation in an investigational drug study (including studies investigating LUM and/or 
IVA) other than Study 122B. NOTE: Participation in a non-interventional study is permitted 
(including observational studies, registry studies, and studies requiring blood collections 
without administration of study drug). 
8.2 
LUM/IVA-naïve Subjects 
8.2.1 
Inclusion Criteria 
1. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) will 
sign and date an informed consent form (ICF). 
2. As deemed by the investigator, the subject’s legally appointed and authorized representative 
(e.g., parent or legal guardian) must be able to understand protocol requirements, restrictions, 
and instructions. The subject’s legally appointed and authorized representative should be able 
to ensure that the subject will comply with, and is likely to complete, the study as planned. 
3. Subjects (male and female) will be 12 to <24 months of age on Day 1. 
4. Weight at screening must be within the weight limits as defined for the study drug dose 
levels (see Section 9.6) or according to the dosing guidelines identified in the “Justification 
for Dose Selection” memorandum effective at the time a subject is screened. 


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5. Subjects with confirmed diagnosis of CF12 at screening. CF is defined as: 
• 2 CF-causing mutations (all as documented in the subject’s medical record) 
o Subjects must be homozygous for F508del (genotype to be confirmed at screening): 
If a genotype test has been performed previously and is documented in the subject’s 
medical record, the subject is not required to be tested for CFTR genotype at 
screening, but 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 be 
tested for CFTR genotype at screening, and the results must be reviewed before the 
first dose. Note: Newborn screening genotype results are not sufficient for eligibility. 
AND (1 of the 2 criteria below) 
• chronic sinopulmonary disease OR gastrointestinal/nutritional abnormalities 
OR 
• a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis as 
documented in the subject’s medical record OR from the sweat chloride test result 
obtained at screening. If an eligible historical sweat chloride result is documented in the 
subject’s medical record, that result alone (and not the screening result) may be used to 
determine eligibility. 
6. Subjects with stable CF disease as deemed by the investigator at screening. 
7. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) are 
willing to have the subject remain on a stable CF medication regimen through the Safety 
Follow-up Visit. 
8.2.2 
Exclusion Criteria 
1. History of any comorbidity reviewed at screening that, in the opinion of the investigator, 
might confound the results of the study or pose an additional risk in administering LUM/IVA 
to the subject. For example, a history of cirrhosis with portal hypertension. 
2. Any clinically significant laboratory abnormalities at screening that would interfere with the 
study assessments or pose an undue risk for the subject (as deemed by the investigator). 
3. Any of the following abnormal laboratory values at screening: 
• Hemoglobin <9.5 g/dL 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin 
>2 × upper limit of normal (ULN) 
• Chronic kidney disease of Stage 3 (estimated glomerular filtration rate [eGFR] 
<60 mL/min/1.73 m2 calculated by the Bedside Schwartz equation13) based on the normal 
range for eGFR in this age group (62 to 191) 
4. An acute upper or lower respiratory infection, pulmonary exacerbation (PEx), or changes in 
therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose 
of LUM/IVA). 


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5. A standard 12-lead ECG demonstrating QTc >450 msec at screening. If QTc exceeds 
450 msec at the Screening Visit, the ECG should be repeated 2 more times during the 
Screening Period, and the average of the 3 QTc values should be used to determine the 
subject’s eligibility. 
6. History of solid organ or hematological transplantation. 
7. Ongoing or prior participation in an investigational drug study (including studies 
investigating LUM and/or IVA) within 30 days of screening. 
• A washout period of 5 terminal half-lives of the previous investigational study drug, or 
30 days, whichever is longer, must elapse before the Screening Visit. 
• The duration of the elapsed time may be longer if required by local regulations. 
Note: Ongoing participation in a noninterventional study (including observational studies) is 
permitted. 
8. Use of restricted medication or food within specified duration before the first dose of 
LUM/IVA as defined in Section 9.4. 
9. An adequate slit-lamp examination could not be conducted at the Screening OE. 
10. History of cataract/lens opacity or evidence of cataract/lens opacity determined to be 
clinically significant by a licensed ophthalmologist during the OE at screening. The 
screening OE does not need to be repeated if there is documentation of an examination 
meeting protocol criteria that was conducted within 12 weeks before screening. 
11. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, multicenter, open-label study in subjects who are 12 to <24 months of age at 
initiation of LUM/IVA treatment (Figure 9-1). The study will enroll approximately 50 subjects. 


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Figure 9-1 
Study 124 Design 
 
 
IVA: ivacaftor; LUM: lumacaftor; OE: ophthalmological examination; q12h: every 12 hours; wks: weeks 
a 
LUM/IVA naïve subjects (by age group: 18 to <24 months and 12 to <18 months) will be able to enroll in 
Study 124 once minimum enrollment has been met for Study 122B (n = 10 subjects in each age group) and 
after an assessment of safety data from Study 122B through Week 12 for ≥5 subjects in each age group. 
b 
For Rollover Subjects, the Day 1 Visit should be the same day as the Safety Follow-up Visit in Study 122B. 
c 
The Safety Follow-up Visit will not be required for subjects transitioning to commercial LUM/IVA 
(Section 9.1.3). 
d 
For LUM/IVA-naïve subjects, doses will be determined by weight at screening. 
 
Rollover Subjects 
Subjects who participated in Study 122B and meet all eligibility requirements will rollover into 
Study 124. 
Timing of Day 1 Visit 
For rollover subjects at sites activated by the Study 122B Safety Follow-up Visit, their Study 124 
Day 1 Visit will be on the same day as their Study 122B Safety Follow-up Visit. Any Study 124 
Day 1 assessments that are specified to be performed at the Study 122B Safety Follow-up Visit 
do not need to be repeated. 
If the Study 124 Day 1 Visit does not coincide with the Study 122B Safety Follow-up Visit, and 
if Study 124 Day 1 is ≤9 days after the Study 122B Safety Follow-up Visit, the Study 124 Day 1 
assessments do not need to be repeated. If Study 124 Day 1 is >9 days after the Study 122B 
Safety Follow-up Visit, the subject will complete all Study 124 Day 1 assessments (except the 
OE if it was performed ≤12 weeks before the Study 124 Day 1 Visit). 


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LUM/IVA-naïve Subjects 
Subjects who did not participate in Study 122B and are 12 to <24 months of age at Study 124 
Day 1 can enroll by age group: 
• 
Subjects who are 18 to <24 months of age can enroll in Study 124 after a minimum of 
10 subjects (aged 18 to <24 months) have enrolled in Study 122B, and after an assessment of 
safety data from Study 122B through Week 12 for ≥5 subjects aged 18 to <24 months. 
• 
Subjects who are 12 to <18 months of age can enroll in Study 124 after a minimum of 
10 subjects (aged 12 to <18 months) have enrolled in Study 122B, and after an assessment of 
safety data from Study 122B through Week 12 for ≥5 subjects aged 12 to <18 months. 
Note: Subjects 18 to <24 months of age will start enrolling in Study 124 before any subjects 
12 to <18 months of age enroll as a result of the staggered timing as a result of the study design 
in Study 122, which includes sequential age cohorts. 
9.1.1 
Screening (LUM/IVA-naïve Subjects Only) 
Screening Visit assessments are listed in Table 3-2. 
Screening will occur within 28 days before administration of LUM/IVA. The investigator (or an 
appropriate authorized designee at the study site) will obtain informed consent from each 
subject’s parent or legal guardian. 
To prepare for study participation, subject’s parent or legal guardian will be instructed on the 
study restrictions (Section 9.4). 
9.1.1.1 
Repetition of Screening Assessment(s) 
Repetition of any screening assessment that did not meet eligibility criteria is not permitted, with 
the following exceptions: 
• If there is clear evidence of a laboratory error (e.g., hemolyzed sample), equipment 
malfunction, or technician error, collection of a repeat sample for the appropriate laboratory 
test may be permitted after discussion with the Vertex medical monitor or authorized 
designee. 
• Exclusionary LFT levels, which may be retested within 14 days of the original Screening 
Visit date. 
• If an adequate slit-lamp examination could not be conducted (Section 11.4.6). 
• If QTc exceeds 450 msec at screening (see Section 8.2.2, exclusion criterion 5), the ECG 
should be repeated 2 more times during the Screening Period, and the average of the 3 QTc 
values should be used to determine the subject’s eligibility. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed 
within the Screening Period window or extended screening window (Section 9.1.1.2), then the 
subject is eligible for the study. 


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9.1.1.2 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks after approval by the 
medical monitor or authorized designee for the following reasons: 
• 
Repetition of the Screening Period assessments (Section 9.1.1.1) 
• 
Unexpected operational or logistical delays (e.g., delayed drug shipment) 
• 
To account for exclusionary events that may not reflect the subject’s true baseline due to an 
acute event, which may resolve 
• 
Scheduling of the OE (Section 11.4.6) 
• 
Availability or malfunction of required equipment or technician error 
The screening window can be extended by 4 weeks if a slit-lamp examination must be repeated 
(Section 9.1.1.1 and Section 11.4.6). 
9.1.1.3 
Rescreening 
Subjects may be rescreened after discussion with the Vertex medical monitor or authorized 
designee; all rescreening requires Vertex approval. If a subject is rescreened, all Screening Visit 
assessments will be repeated except for CFTR genotyping, sweat chloride testing, and the OE (if 
performed within the last 3 months before the Screening Visit). Subjects may only be rescreened 
once. If a subject is rescreened, the new screening window date will begin once the first 
rescreening assessment has been initiated. 
9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-1 for Rollover Subjects and Error! 
Reference source not found. for LUM/IVA-naïve Subjects. Subjects will be outpatients during 
the Treatment Period. All visits and telephone contacts should occur within the windows 
specified. 
The Treatment Period is 96 weeks; LUM/IVA will be administered every 12 hours (q12h) from 
Day 1 up to Week 96. LUM/IVA dose and administration details are provided in Section 9.6. 
Procedures for subjects who prematurely discontinue LUM/IVA treatment are described in 
Section 9.1.4. 
9.1.3 
Follow-up 
Safety Follow-up Visit 
Subjects will have a Safety Follow-up Visit 2 weeks (± 4 days) after the last dose of study drug. 
Safety Follow-up Visit assessments are listed in Table 3-1 for the Rollover Subjects and Error! 
Reference source not found. for the LUM/IVA-naïve Subjects. 
The Safety Follow-up Visit is required for: 
• 
Subjects who complete their Early Termination of Treatment (ETT) Visit <10 days after the 
last dose of LUM/IVA (Section 9.1.4) 
• 
Subjects who interrupt LUM/IVA treatment and complete their Week 96 Visit <10 days after 
the last dose of LUM/IVA 


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The Safety Follow-up Visit is not required for subjects who continue onto commercially 
available, physician-prescribed LUM/IVA within 2 weeks (± 4 days) of completing LUM/IVA 
treatment at the Week 96 or ETT Visit. 
Follow-up Ophthalmological Examination 
Subjects will have a Follow-up OE 24 weeks (± 14 days) after the last dose of study drug. 
9.1.4 
Early Termination of Treatment OR Early Discontinuation 
Subjects who prematurely discontinue LUM/IVA treatment will be asked to complete the ETT 
Visit as soon as possible after their last dose, to remain on study, and to complete the study 
assessments from the time of LUM/IVA treatment discontinuation through the Week 96 Visit 
and the Safety Follow-up Visit, if applicable. The assessments to be completed are shown in 
Table 3-1 and Table 3-2. If the ETT Visit occurs ≥10 days after the last dose of LUM/IVA, then 
a Safety Follow-up Visit will not be required. Additional safety assessments may also be 
performed at the discretion of the investigator, including possible consultation with a specialist 
consultant. The Vertex medical monitor will be informed about these additional assessments, and 
any additional data collected (e.g., as the result of an outside consultation) will be considered 
part of the study record to provide the most complete safety profile of the study drug. 
Subjects who become eligible to receive commercially available LUM/IVA by prescription from 
a physician and who choose to continue onto commercially available LUM/IVA before 
completion of the study must remain on study-supplied LUM/IVA through the ETT Visit and 
may only initiate treatment with commercially available LUM/IVA after completion of this visit. 
Subjects who continue onto commercially available LUM/IVA will complete the Follow-up OE 
24 weeks (± 14 days) after the last dose of study drug. 
9.1.5 
Independent Data Monitoring Committee 
Safety and tolerability data will be reviewed by an independent data monitoring committee 
(IDMC) to ensure the safety of the subjects (Section 12.3.6.2). Procedural details of the IDMC’s 
structure and function, frequency of meetings, and data planned for review will be in the IDMC 
charter. The IDMC charter will be finalized before the first subject is enrolled. 
9.1.6 
Use of Remote Measures in Extenuating Circumstances 
Study visits should be performed in the clinic as specified in Table 3-1 or Table 3-2, if at all 
possible. However, under extenuating circumstances, remote measures may be implemented 
(e.g., if a subject is unable to travel to the study site due to safety concerns and/or local 
restrictions related to COVID-19 or other emerging events). The decision whether to conduct 
study visits remotely or in clinic will be at the discretion of the investigator. 
Whenever local regulations or site practice do not allow remote measures, visits will be 
conducted at the site. 
Remote measures that may be implemented include, but are not limited to: 
• 
Consent or reconsent may be obtained remotely in writing (or verbally, with follow-up 
written confirmation), as allowed by local regulations. 
• 
Study drug may be shipped directly from the site to the subject, as applicable and as allowed 
by local regulations. 


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• 
Study visits may be conducted as in-home visits by qualified personnel. 
• 
Study assessments may be performed or overseen by qualified personnel conducting the 
in-home visits. 
• 
Remote monitoring visits may be implemented as applicable (including remote source data 
verification) and as allowed per local regulations 
• 
Blood samples for safety assessments may be collected and analyzed by local laboratories. 
• 
Weight and stature may be assessed by the subject’s caregivers using medical grade scales 
and stadiometers. 
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. 
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
Vertex has established efficacy, safety, and PK profiles for LUM/IVA in subjects 2 years of age 
and older with CF, homozygous for F508del (Studies 103, 104, 109, and 115). Because the 
underlying genetic and molecular etiology of the disease is identical between younger and older 
patients, and the impact of CFTR protein dysfunction is likely to be comparable, extrapolation of 
efficacy from older to younger patients is appropriate, and PK studies in younger patients, 
together with safety studies, can provide adequate information for use.14 
Safety and PK profiles for LUM/IVA have been established in subjects aged 2 years and older 
with CF, homozygous for F508del (Study 115). Study 122, a Phase 3, 2-part open-label study, 
which includes a 24-week Treatment Period in Part B, is designed to obtain PK and safety 
information to support a proposed indication expansion of LUM/IVA in subjects who are 12 to 
<24 months of age with CF, homozygous for F508del. 
Long-term safety and efficacy was established in subjects aged 6 years and older with CF, 
homozygous for F508del, in Study 110, the open-label rollover study for parent Studies 109 and 
011B. Evaluation of long-term safety in subjects aged 2 years and older with CF, homozygous 
for F508del, is currently ongoing in Study 116, the open-label rollover study for parent 
Study 115. 
Study 124 is a Phase 3, open-label, multicenter study in subjects with CF, homozygous for 
F508del, who are 12 to <24 months of age when LUM/IVA treatment is initiated. This study, 
which includes a 96-week Treatment Period, is designed to evaluate the long-term safety of 
LUM/IVA when treatment is initiated between 12 and 24 months of age. 
9.3.2 
Study Drug Dose and Duration 
Dose of LUM/IVA 
Study 122 Part A (Study 122A) was designed to characterize the safety and PK of LUM and IVA 
in subjects 12 through <24 months of age. The plasma concentration versus time data from 
Study 122A is intended to inform the appropriateness or necessary adjustment of planned doses 
for Studies 122B and 124. As data from Study 122B become available, the doses may be 
modified for subjects in Study 124. A population PK model with allometric scaling of clearance 
and volume of distribution as a function of weight was used to project exposures of LUM and 


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IVA for comparison with clinical experiences with both drugs and to select doses to be evaluated 
in this study population. No safety issues were identified in prior clinical or nonclinical studies 
that would preclude the dosing regimen proposed for Study 124. 
Duration of Dosing 
Subjects who receive LUM/IVA in Study 124 may receive treatment for up to 120 weeks (for 
Rollover Subjects: 24 weeks in Study 122B and 96 weeks in Study 124; for LUM/IVA-naïve 
Subjects: 96 weeks in Study 124), thus providing information on the long-term safety of 
LUM/IVA in subjects aged 1 year and older with CF, homozygous for F508del. 
9.3.3 
Study Assessments 
The safety assessments are standard parameters for clinical studies in drug development and are 
generally recognized as reliable, accurate, and relevant to the study of subjects with CF. OEs 
were added as part of safety monitoring. Assessments were added to evaluate the PD effects of 
LUM/IVA. The following PD and efficacy-related assessments are standard assessments used in 
studies in the LUM/IVA development program: sweat chloride and growth parameters, including 
weight, length, and BMI. Rationale is provided below for OEs and additional assessments 
(exocrine pancreatic function and markers of intestinal inflammation). 
Ophthalmological Examinations: A juvenile rat toxicity study performed to support dosing of 
IVA in subjects <2 years of age demonstrated lens opacities in some animals.15 Prior studies in 
rats and dogs of older age did not demonstrate similar findings. Given substantial differences 
between human and rat lens development, the finding is of unlikely relevance to humans. 
Periodic OEs for pediatric subjects receiving IVA or IVA in combination with a CFTR corrector 
are being performed to confirm this interpretation. The overall data acquired to date does not 
suggest an association between IVA treatment and cataract development. 
Exocrine Pancreatic Function: The pancreas is 1 of the earliest and most seriously affected 
organs in patients with CF who are homozygous for F508del, the vast majority of whom develop 
pancreatic insufficiency. 
• 
FE-1: FE-1 is a diagnostic measure of pancreatic exocrine sufficiency, with levels <200 µg/g 
considered consistent with pancreatic insufficiency. The increasing use of FE-1 in the clinic 
is a result of the ease of collecting samples (relative to other methods, e.g. 24-hour fecal fat) 
for its assessment and the establishment of diagnostic cutoffs for pancreatic exocrine 
function.16 FE-1 represents a feasible measure to evaluate exocrine pancreatic function 
during the study, with the hypothesis that treatment with LUM/IVA may rescue a degree of 
pancreatic function, resulting in increased FE-1 levels over the course of the study. 
• 
IRT: Trypsin and trypsinogen are proteins produced by the pancreas that can be detected in 
the blood via the IRT assay. Evaluation of IRT is used in clinical practice as the basis of 
newborn screening for CF, wherein elevated levels at birth are associated with disease. Over 
time, however, patients with CF show a longitudinal decline in IRT with nondetectable levels 
observed around 5 years of age, indicating a loss of pancreatic function.17 Blood samples for 
IRT testing will be collected at multiple time points to evaluate potential changes in exocrine 
pancreatic function. 
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.18 These data 


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support the concept that intestinal inflammation is a feature of CF and that intestinal 
inflammation can be monitored by measuring non-invasive biomarkers such as fecal calprotectin 
in clinical studies with CF patients. 
9.4 
Study Restrictions 
Prohibited medications and certain foods are not allowed as summarized in Table 9-1. 
A non-exhaustive list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. 
Table 9-1 
Study Restrictions 
Study Period 
 
 
Restricted Medication/Food 
Screening Period 
Treatment Period 
Strong CYP3A inducers 
None allowed within 14 days before 
the first dose of LUM/IVA 
Strong CYP3A inhibitors 
None allowed within 14 days before 
the first dose of LUM/IVA 
None allowed 
Use with caution 
IVA: ivacaftor; LUM: lumacaftor 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee. 
 
Use of CYP3A substrates is not prohibited, but investigators need to be aware that LUM appears 
to be a strong inducer of CYP3A. Therefore, the efficacy of drugs extensively metabolized by 
CYP3A may be affected. 
Use of CYP2C and CYP2B6 substrates is not prohibited, but investigators need to be aware that 
LUM has been shown in vitro to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition 
of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest 
that IVA may inhibit CYP2C9. Therefore, concomitant use of LUM/IVA with CYP2B6, 
CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates. 
Each investigator should evaluate the benefit-risk ratio of using CYP3A, CYP2B6, CYP2C8, 
CYP2C9, and CYP2C19 substrates with LUM and IVA and discuss their use with the medical 
monitor or authorized designee. 
9.5 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the first dose through the Safety Follow-up Visit, if applicable, will be recorded in each 
subject’s source documents. In addition, concomitant medication dose(s) may be collected. 
• 
It is recommended that subjects remain on a stable medication regimen for their CF from 
28 days before Day 1 through the Safety Follow-up Visit, if applicable. Stable medication 
regimen is defined as the current medication regimen for CF that subjects have been 
following for at least 28 days before Day 1. Note: PERT doses may be adjusted during this 
study. 
• 
While the etiology of respiratory events associated with LUM/IVA is not yet known, data 
from healthy subjects in Study 009 Cohort 4 suggest that treatment with short-acting 


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bronchodilators may reverse the initial transient decline in percent predicted forced 
expiratory volume in 1 second (ppFEV1) when dosed with LUM/IVA. Subjects may be 
prescribed a short-acting bronchodilator in accordance with local drug labeling (if not already 
prescribed) to ensure constant availability during the study. 
• 
Information about bronchodilator use during the study will be collected and documented in 
the subject’s source documents. 
9.6 
Administration 
LUM/IVA will be administered orally according to the planned doses and weight bounds shown 
in Table 9-2. Changes to study drug dose(s) and/or weight bounds based on results from 
Study 122 may be communicated to site personnel through a memorandum entitled “Justification 
for Dose Selection.” 
Table 9-2 
Study Drug Administration: Planned Doses 
 
Dose 
Subject’s Weighta 
Time 
LUM/IVA 
(Number of Stick Packs) 
 
LUM 75 mg/IVA 94 mg q12h 
7 to <9kg 
AM 
1 stick pack 
PM 
1 stick pack 
LUM 100 mg/IVA 125 mg q12h 
9 to <14 kg 
AM 
1 stick pack 
PM 
1 stick pack 
LUM 150 mg/IVA 188 mg q12h 
≥14 kg 
AM 
1 stick pack 
PM 
1 stick pack 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
a 
Doses may be adjusted upward based on weight gain; however, no downward dose adjustments will be made if 
a subject’s weight decreases. For example, if a subject weighs <14 kg at screening and subsequently weighs 
≥14 kg at 2 consecutive study visits, the dose will be adjusted to LUM 150 mg/IVA 188 mg q12h at the second 
study visit when weight ≥14 kg. 
 
LUM/IVA will be administered within 30 minutes from the start of consuming fat-containing 
food such as a standard “CF” high-fat, high-calorie meal or snack according to the following 
guidelines: 
1. All doses of LUM/IVA (morning and evening, as applicable) should be administered at 
approximately q12h (± 2 hours) on each dosing occasion (e.g., if the morning dose is 
administered at 08:00 on Day 1, all subsequent morning doses should be administered 
between 06:00 and 10:00). 
2. The granule formulation will be dispensed by opening the stick packs containing the granules 
and mixing the granules with the approved foods and liquids listed in the Study Reference 
Manual. Each dose will be composed of the approved food or liquids into which the granules 
from the stick packs are mixed. Details on preparing LUM/IVA will be provided in the 
Pharmacy Manual. 
3. At the Day 1 Visit, all LUM/IVA-naïve subjects will be observed for 4 hours after the 
LUM/IVA dose. 


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4. On days of scheduled visits, with the exception of afternoon visits addressed below, the 
morning LUM/IVA dose will be administered at the site after any predose assessments have 
been completed. 
5. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used for administering either the morning or evening dose: 
• If the dose in the clinic will be within 6 hours of the subject’s scheduled morning 
LUM/IVA dose, the subject should withhold their morning dose and the morning dose 
will be administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
LUM/IVA dose, the subject should take the morning dose at home and the evening dose 
will be administered in the clinic. In this event, all assessments will be collected relative 
to the evening dose. 
6. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused 
LUM/IVA materials to the site; LUM/IVA will be dispensed at each visit, as appropriate. 
At the Week 96 Visit, the LUM/IVA dose will NOT be administered. The last LUM/IVA dose 
will be the previous dose (e.g., evening dose) administered before the Week 96 Visit. 
9.7 
Dose Modification for Toxicity 
Modifications of the LUM/IVA dose are prohibited. Should any unacceptable toxicity arise, 
individual subjects will be withdrawn from the study treatment. 
9.8 
Study Drug Interruptions 
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 resume only after approval by the 
Vertex medical monitor. Specific instructions on interruption for elevated LFT levels are 
provided in Section 11.4.3. 
9.9 
Removal of Subjects 
Subjects may withdraw from the study at any time at the request of the parent or legal guardian. 
Subjects may be withdrawn from study drug treatment at any time at the discretion of the 
investigator or Vertex for safety, behavior, noncompliance with study procedures, or 
administrative reasons. If a subject has been withdrawn from study drug treatment, the subject 
will continue to be followed as described in Section 9.1.4, provided that the subject’s parent or 
legal guardian has not withdrawn consent. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject’s parent or legal guardian. In any circumstance, reasonable effort will be made to 
document subject outcome. The investigator will inquire about the reason for withdrawal, request 
that the subject’s parent or legal guardian return all unused investigational product(s), request 
that the subject return for a Safety Follow-up Visit, if applicable (see Section 9.1.3), and 
follow up with the subject’s parent or legal guardian regarding any unresolved AEs. 
If the subject’s parent or legal guardian withdraws consent for the study, no further evaluations 
should be performed, and no additional data should be collected. Vertex may retain and continue 
using the study data and samples after the study is over and may use the samples and information 
in the development of the study compound, and for other drugs and diagnostics, in publications 


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and presentations, and for education purposes. If the subject’s parent or legal guardian withdraws 
the subject from the study, the study data and samples collected will remain part of the study. A 
subject’s parent or legal guardian will not be able to request the withdrawal of the subject’s 
information from the study data. A subject’s parent or legal guardian may request destruction of 
the samples collected from the subject during the study as long as those samples can be identified 
as the subject’s samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug Treatment Period will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
LUM/IVA may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Vertex will supply the LUM/IVA granules in stick packs. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details about packaging, 
labeling, and dispensing for LUM/IVA will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs will be accounted for as described in 
Section 10.4. Detailed instructions regarding the storage, handling, and dispensation of 
LUM/IVA will be provided in the Pharmacy Manual. 
Table 10-1 
Study Drug 
 
Drug Name 
Formulation/ 
Route 
Packaging (Formulation Strength) 
How Supplied 
LUM/IVA 
Granules/ 
oral 
75-mg LUM/94-mg IVA granules 
Supplied in 1 stick pack 
LUM/IVA 
Granules/ 
oral 
100-mg LUM/125-mg IVA granules 
Supplied in 1 stick pack 
LUM/IVA 
Granules/ 
oral 
150-mg LUM/188-mg IVA granules 
Supplied in 1 stick pack 
IVA: ivacaftor; LUM: lumacaftor 
 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subject’s parent or legal guardian. The subject’s parent or legal guardian will be 
instructed to return all used and unused materials associated with the study drug to the site. 
These materials will be retained at the site according to instructions provided by Vertex or its 


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designee. The study monitor will review study drug records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subject’s 
parent or legal guardian until the study monitor has performed drug accountability. The 
investigator will ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by Vertex. 
Destruction will be adequately documented. 
10.6 
Compliance 
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject’s parent or legal guardian of study drug dosing 
requirements. Compliance will also be assessed by ongoing study drug count. 
If there is continued noncompliance of study drug dosing despite educational efforts, the 
investigator should contact the medical monitor to discuss discontinuation of the subject from the 
study treatment. 
10.7 
Blinding and Unblinding 
This is an open-label study. 
However, the site and the subject’s parent or legal guardian should not be informed of a subject’s 
study-related sweat chloride (except if needed to confirm eligibility), IRT, FE-1, and markers of 
intestinal inflammation results during the study even if the subject permanently discontinued 
treatment. 
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 for Rollover Subjects and Table 3-2 for 
LUM/IVA-naïve Subjects. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
For Rollover Subjects, medical history will be taken from Study 122B. For LUM/IVA-naive 
Subjects, medical history will be elicited from each subject’s parent or legal guardian during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history 
should include a complete review of systems, past medical and surgical histories, and any known 
allergies. 


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In addition, the following historical data will be collected from birth to screening (for all 
subjects): 
• 
Maternal/pregnancy history: complications in pregnancy, gestational age at delivery, method 
of delivery, and presence of meconium ileus (if documented in subject’s clinical chart) 
• 
Routine/quarterly CF clinic visit measurements for length/height and weight. Note: 
Measurements taken during sick visits or hospitalizations will not be collected. 
• 
The dates and indications for all CF-related hospitalizations 
• 
Any use (yes or no) of the following medications: 
o Inhaled antibiotics (e.g., tobramycin, aztreonam, or colimycin) 
o Nebulized hypertonic saline (any %) 
o Nebulized dornase alfa 
o Oral azithromycin (anti-inflammatory dosing M/W/F) 
• 
Historical pancreatic status measurements (e.g., prior FE-1 levels) 
In addition, the subject’s parent or legal guardian will be asked during screening to provide the 
height of the subject’s biological parents. 
11.2 
Pharmacodynamics 
11.2.1 
Sweat Chloride 
Collection of sweat samples will be performed using an approved collection device. Sweat 
samples will be sent to a central laboratory for testing and interpretation of results. Specific 
instructions for collection, handling, processing, and shipping of sweat chloride samples to the 
central laboratory will be provided separately. At each time point, 2 samples will be collected, 
1 sample from each arm (left and right). 
11.3 
Exploratory Assessments 
11.3.1 
Growth Parameters 
Weight and length/height will be assessed and BMI will be derived. Length/height and weight 
must be measured with the subject in a dry diaper or dry underclothes only. If the subject is 
>2 years of age and can stand unassisted and follow directions, standing height should be 
measured; otherwise recumbent length should be measured. Length should be measured while 
the subject is supine by measuring from the crown of the head to the bottom of the feet, with the 
hips and legs straightened. BMI will be calculated using the following equation: 
BMI (kg/m2) = body weight (kg) ÷ stature2 (m2). Z-scores adjusting for age and sex in weight, 
length/height, and BMI, as well as weight-for-length z-score will be derived. Formulas for 
calculating z-scores will be provided in the statistical analysis plan (SAP). 
11.3.2 
Measures of Pancreatic Function 
11.3.2.1 
Fecal Elastase-1 
Fecal samples for assessment of FE-1 may be collected at the study site during the study visit or 
by the subject’s caregiver up to 48 hours before the study visit (e.g., at home) and brought to the 
study visit. For the LUM/IVA-naïve subjects, the sample collected before the first dose of study 


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drug can either be collected at screening or up to 48 hours before the Day 1 study visit (as 
described in Table 3-2). Specific instructions for the collection, processing, and shipment of 
samples will be provided in a separate Laboratory Manual. 
11.3.2.2 
Immunoreactive Trypsin and Trypsinogen 
Specific instructions for the collection, processing, and shipment of blood samples for 
assessment of IRT will be provided in a separate Laboratory Manual. 
11.3.3 
Markers of Intestinal Inflammation 
Fecal samples for assessment of fecal calprotectin (and other markers of intestinal inflammation, 
if applicable) may be collected at the study site during the study visit or by the subject’s 
caregiver up to 48 hours before the study visit (e.g., at home) and brought to the study visit. For 
the LUM/IVA-naïve subjects, the sample collected before the first dose of study drug can either 
be collected at screening or up to 48 hours before the Day 1 study visit (as described in 
Table 3-2). Specific instructions for the collection, processing, and shipment of samples will be 
provided in a separate Laboratory Manual. 
11.4 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments (serum chemistry and 
hematology), clinical evaluation of vital signs, pulse oximetry, standard 12-lead ECGs, physical 
examinations, and OEs. 
11.4.1 
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. 
11.4.2 
Clinical Laboratory Assessments 
Blood samples will be analyzed at a central laboratory. Although blood samples are to be 
analyzed at a central laboratory, a local laboratory may be used if a subject cannot return to the 
clinical study site for the mandatory liver function testing (Section 11.4.3). 
Blood samples for clinical laboratory assessments will be collected as shown in Table 3-1 and 
Table 3-2. Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs (Section 13.1). 


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The safety laboratory test panels are shown in Table 11-1. 
Table 11-1 
Safety Laboratory Test Panels 
 
Serum Chemistry 
Hematology 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Total bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Lactate dehydrogenase 
Gamma glutamyl transferase (GGT) 
Total protein 
Albumin 
Creatine kinase 
Amylase 
Lipase 
Hemoglobin 
Platelets 
Total white blood cell count 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Monocytes 
 
Clinical laboratory assessments from screening (for LUM/IVA-naïve subjects) will have no 
clinically significant findings that preclude participation in the study, as judged by the 
investigator, for a subject to receive LUM/IVA on Day 1. 
CF Genotype (Screening Period for LUM/IVA-naïve subjects only): If a historic genotype result 
is not available at screening or if the historic genotype result is not approved by the Vertex 
medical monitor, CF genotyping will be performed on a subject to confirm the subject is 
homozygous for F508del. Note: Newborn screening genotype results are not sufficient for 
eligibility. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
11.4.3 
Elevation of Liver Function Test Parameters 
Mandatory Liver Function Testing 
Liver function testing (ALT, AST, gamma-glutamyl transferase [GGT], alkaline phosphatase 
[ALP], and total bilirubin) must be performed while subjects are receiving LUM/IVA treatment 
(see Table 3-2 and Section 11.4.2). These blood samples should be processed and shipped 
immediately as per the Laboratory Manual. 


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Rollover subjects who had a study drug interruption at the Week 24 Visit of Study 122B or 
subjects who resumed study drug in Study 122B after a study drug interruption due to elevated 
transaminases but who did not complete the required 4 weeks of rechallenge with LUM/IVA 
(due to <4 weeks remaining in the Study 122B Treatment Period) will be reviewed by the Vertex 
medical monitor and should continue to be monitored based on the guidance for study drug 
interruption and resumption provided below. For example, 4 weeks of rechallenge with 
LUM/IVA should be completed, and any other assessments deemed necessary by the 
investigator in conjunction with the Vertex medical monitor may be performed. If a subject has a 
study drug interruption that spans the time period between Week 24 of Study 122B and Day 1 of 
Study 124, approval from the Vertex medical monitor or designee is required before resumption 
of LUM/IVA in Study 124. 
Subjects with new ALT or AST elevations of ≥3 × ULN and clinical symptoms will be followed 
closely, including repeat confirmatory testing performed by the central laboratory within 48 to 
72 hours of the initial finding and subsequent close monitoring of ALT and AST levels, as 
clinically indicated. If a subject cannot return to the site for liver function testing, a local 
laboratory may be used. Elevations in LFTs (ALT or AST ≥3 × ULN) at the local laboratory 
must be reported immediately to the Vertex medical monitor or designee, AND the subject must 
have the tests repeated and sent to the central laboratory as soon as possible (ideally within 48 to 
72 hours). 
Study Drug Interruption 
LUM/IVA administration must be interrupted immediately, and the Vertex medical monitor or 
designee must be notified if any of the following criteria is met: 
• 
ALT or AST ≥8 × ULN 
• 
ALT or AST ≥5 × ULN for more than 2 weeks 
• 
ALT or AST ≥3 × ULN in association with total bilirubin ≥2 × ULN and/or clinical jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Resumption of Study Drug 
If a convincing alternative etiology is identified for the elevated liver tests (ALT, AST, and total 
bilirubin), LUM/IVA may be resumed when levels return to baseline or are ≤2 × ULN, 
whichever is higher. Approval of the Vertex medical monitor or designee is required before 
resumption of LUM/IVA. Upon resumption of LUM/IVA, transaminases should be assessed 
weekly for 4 weeks. If a protocol-defined liver test elevation occurs within 4 weeks of 
rechallenge with LUM/IVA, then LUM/IVA must be discontinued, regardless of the presumed 
etiology. 
Discontinuation of Study Drug 
If no convincing alternative etiology (e.g., acetaminophen use or viral hepatitis) for the elevated 
transaminases is identified, regardless of whether ALT or AST levels have improved, LUM/IVA 
treatment must be discontinued, after consulting with the Vertex medical monitor or authorized 
designee. Subjects in whom treatment is discontinued for elevated transaminases should have 
their transaminases monitored closely until levels normalize or return to baseline. 


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11.4.4 
Physical Examinations and Vital Signs 
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 signs assessments 
can be performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
An abbreviated PE will be performed at select study visits. 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 (any clinically acceptable 
method may be used, however, the same method should be used at each visit), pulse rate, 
respiration rate, and pulse oximetry. The subject should rest for at least 5 minutes, if possible, 
before vital signs are measured. 
Weight and length/height will be assessed and BMI will be derived. Length/height and weight 
must be measured with the subject in a dry diaper or dry underclothes only. Recumbent length 
should be measured for subjects ≤2 years, or until the subject is comfortable with having 
standing height measured. Recumbent length should be measured while the subject is supine by 
measuring from the crown of the head to the bottom of the feet, with the hips and legs 
straightened. Standing height should be measured for subjects >2 years of age or once the subject 
is comfortable with the procedure. 
11.4.5 
Electrocardiograms 
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 ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
• 
The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• 
The test should be performed in the supine position 
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. 
To ensure safety of the subjects, the investigator will make comparisons of the ECG findings to 
baseline measurements. Repeat ECGs will be performed as deemed appropriate. Subject 
eligibility to continue in the study will be evaluated. 
11.4.6 
Ophthalmological Examination 
OEs must be conducted by a licensed ophthalmologist, preferably a pediatric ophthalmologist. 
The OE includes an examination of the lens with a slit lamp. 


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For the LUM/IVA-naïve subjects, the screening OE must be completed and the results reviewed 
before enrollment. If cataract/lens opacity is identified and determined to be clinically significant 
by the licensed ophthalmologist at the screening OE, the subject must not be enrolled. The 
screening OE does not need to be repeated if there is documentation of an examination meeting 
protocol criteria that was conducted within 12 weeks before the Screening Visit. 
A Follow-up OE will be performed approximately 24 weeks after the last dose of LUM/IVA. 
11.4.7 
Contraception and Pregnancy 
Not applicable 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
Sample Size and Power 
No formal sample size calculations have been performed for this study. The study will enroll 
approximately 50 subjects to provide data for the assessment of long-term safety in the target 
patient population, as requested by a regulatory agency. 
12.2 
Analysis Sets 
124 All Subjects Set: All subjects who are enrolled or dosed in Study 124 
124 Safety Set: All subjects who are exposed to any amount of study drug in Study 124 
124 Full Analysis Set (124 FAS): All subjects who are enrolled and dosed in Study 124 
12.3 
Statistical Analysis 
Statistical Analysis System Version 9.2 or higher will be used to generate all statistical outputs 
(tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the SAP that will be finalized 
before the data cut/lock. Additional analysis deemed necessary but not specified in the protocol 
will be defined in the SAP. 
12.3.1 
General Considerations 
All individual subject data will be presented in data listings based on the 124 All Subjects Set. 
Continuous variables will be summarized using the following descriptive summary statistics: 
number of subjects, mean, SD, SE, median, minimum value (min), and maximum value (max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value will be defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected on or before the first dose of LUM/IVA in Study 124. 
For sweat chloride, values at each visit will be based on averaged measurements from left and 
right arms as specified in Section 11.2.1. For Rollover Subjects, baseline will be defined as the 
most recent non-missing measurement (scheduled or unscheduled) collected on or before the first 
dose of LUM/IVA in Study 124. For LUM/IVA-naïve Subjects, baseline will be defined as the 
average of the values at screening and the pretreatment measurement on Day 1 of Study 124. If 
only 1 pre-first dose measurement of sweat chloride is available, that measurement will be 
considered the baseline. 


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Change (Absolute Change) from baseline will be calculated as postbaseline value − baseline 
value. 
Current Study Period starts from the first dose of study drug in Study 124 to the last day in 
Study 124. 
The Treatment-emergent (TE) Period for the Current Study Period starts on or after the first 
dose date of study drug in Study 124 to 14 days (inclusive) after the last dose of study drug in 
Study 124 or up to the last day in Study 124, whichever occurs first. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
Number of subjects in the following categories for the population will be provided: 
• 
124 All Subjects Set 
• 
124 Safety Set 
• 
124 FAS 
Number and percentage (based on the 124 Safety Set) of subjects in each of the following 
categories will also be provided: 
• 
Enrolled but never dosed (number of subjects only) 
• 
Completed treatment 
• 
Prematurely discontinued treatment and the reason for discontinuation 
• 
Last scheduled on-treatment visit completed for subjects who discontinued treatment 
• 
Completed study (i.e., completed the Safety Follow-up Visit) 
• 
Prematurely discontinued the study and reason for discontinuation 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographics, baseline characteristics, and medical history will be summarized for the 
124 Safety Set. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). 
12.3.2.3 
Prior and Concomitant Medications 
Medications used will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and categorized as the following: 
Prior medication: Any medication that started before the date of the first dose of study drug in 
Study 124 
Concomitant medication: Medication continued or newly received during the TE Period of the 
Current Study Period 
Post-treatment medication: Any medication continued or newly received after the end of the 
TE Period of the Current Study Period 


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A given medication may be classified as prior; concomitant; post-treatment; both prior and 
concomitant; both concomitant and post-treatment; and prior, concomitant, and post-treatment. 
Incidence of prior medication will be summarized based on the 124 Safety Set by (1) Preferred 
Name; (2) anatomical therapeutic chemical (ATC) level 1; ATC level 2; and Preferred Name. 
Incidence of concomitant medication will be summarized based on the 124 Safety Set for the 
Current Study Period by (1) Preferred Name; (2) ATC level 1; ATC level 2; and Preferred Name. 
Details for imputing missing or partial start and/or stop dates of medication will be in the SAP. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study Drug Exposure 
Duration of study drug exposure is defined as follows: last dose date of the Current Study 
Period − first dose date of the Current Study Period + 1 day, regardless of any dose interruptions. 
Duration of study drug exposure as well as number of sticks administered, defined as (total 
number of sticks dispensed) − (total number of sticks returned), will be summarized descriptively 
overall based on the 124 Safety Set for the Current Study Period. Additionally, the total duration 
of treatment exposure, defined as the sum of the subject’s duration of treatment exposure and 
expressed in patient-years (1 patient-year is defined as 1 patient with 48 weeks of treatment), will 
be provided. Duration of exposure will also be summarized as a categorical variable. 
Study Drug Compliance 
Study drug compliance will be calculated as follows: 100 × (1 − [total number of days of study 
drug interruption in the Current Study Period] / [duration of study drug exposure in the Current 
Study Period]). The total number of days of study drug interruption is defined as the sum of 
(number of days of each study drug interruption in the Current Study Period), where number of 
days of each study drug interruption is defined as the interruption end date − the corresponding 
interruption start date + 1. 
Treatment compliance percentages will be summarized descriptively (number, mean, SD, 
median, min, and max) overall based on the 124 Safety Set for the Current Study Period. The 
number and percentage of subjects whose compliance is <80% or ≥80% will be summarized. 
12.3.3 
Secondary Endpoint Analysis 
12.3.3.1 
Absolute Change From Baseline in Sweat Chloride 
Raw values and absolute change from baseline in sweat chloride at each visit of the Current 
Study Period will be summarized descriptively based on the 124 FAS overall. Descriptive 
statistics, including number of subjects, mean, SD, median, min, and max, along with the 95% CI 
based on Normal approximation, will be provided for the absolute change from baseline values. 
The mean (95% CI) of the absolute change from baseline values will be plotted. 
12.3.4 
Exploratory Endpoint Analysis 
12.3.4.1 
Absolute Change From Baseline in Growth Parameters 
Raw values and absolute change from baseline in the following endpoints at each visit of the 
Current Study Period will be summarized descriptively based on the 124 FAS overall. In 
addition, 95% CI of the absolute change from baseline values will be provided. 
• 
BMI-for-age z-score and BMI 


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• 
Weight-for-age z-score and weight 
• 
Length/height-for-age z-score and length/height 
• 
Weight-for-length z-score 
12.3.4.2 
Absolute Change From Baseline in Markers of Pancreatic Function 
Raw values and absolute change from baseline in the following endpoints at each visit of the 
Current Study Period will be summarized descriptively based on the 124 FAS overall: 
• 
FE-1 levels 
• 
Serum IRT levels 
In addition, number and percentage of subjects with FE-1 levels consistent with pancreatic 
insufficiency, defined as FE-1 value <200 μg/g, will be provided at baseline and at each visit of 
the Current Study Period. The number and percentage of subjects with shift changes from 
baseline at each visit of the Current Study Period will be summarized as well. 
12.3.4.3 
Absolute Change From Baseline in Fecal Calprotectin 
Raw values and absolute change from baseline in fecal calprotectin levels at each visit of the 
Current Study Period will be summarized descriptively based on 124 FAS overall. 
12.3.5 
Safety Analysis 
The overall safety profile of LUM/IVA will be assessed in terms of the following safety and 
tolerability endpoints: 
• 
AEs 
• 
Clinical laboratory measurements (serum chemistry and hematology) 
• 
Standard 12-lead ECGs 
• 
Vital signs 
• 
Pulse oximetry 
• 
OEs 
Safety endpoints will be summarized descriptively based on the 124 Safety Set. 
All listings will be provided based on the 124 All Subjects Set. 
12.3.5.1 
Adverse Events 
AEs will be classified as pretreatment AEs or treatment-emergent adverse events (TEAEs), 
defined as follows: 
Pretreatment AE: Any AE that started before the first dose date of study drug in Study 124 
TEAE: Any AE that worsened (either in severity or seriousness) or that was newly developed on 
or after the first dose date of study drug through the end of the TE Period of the Current Study 
Period 
Post-treatment AE: Any AE that increased in severity or that newly developed after the 
TE Period of the Current Study Period 


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For AEs with missing or partial 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 will be described in the SAP. 
TEAE summaries will be presented using number and percentages of subjects for the Current 
Study Period based on the 124 Safety Set overall. 
An overview of the TEAE profile will be provided, including total number of TEAEs, with 
number and percentage of subjects for the following categories: (1) all TEAEs; (2) Grade 3/4 
TEAEs; (3) TEAEs by relationship; (4) TEAEs by maximum severity; (5) TEAEs leading to 
treatment interruption; (6) TEAEs leading to treatment discontinuation; (7) serious TEAEs; 
(8) related serious TEAEs; and (9) TEAEs leading to death. 
AE summary tables will be presented for TEAEs only and will include the following: 
• 
All TEAEs 
• 
Grade 3/4 TEAEs 
• 
TEAEs by relationship 
• 
TEAEs by maximal severity 
• 
TEAEs leading to treatment interruption 
• 
TEAEs leading to treatment discontinuation 
• 
Serious TEAEs 
• 
Related serious TEAEs 
• 
TEAEs leading to death 
• 
Frequently reported TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with any 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 worst/highest relationship level in the relationship summaries. 
In addition, listings containing individual subject data for all TEAEs leading to treatment 
interruption, TEAEs leading to treatment discontinuation, deaths, and serious adverse events 
(SAEs) will be provided separately. All AEs, including pre- and post-treatment AEs, will be 
presented in individual subject data listings. 
12.3.5.2 
Clinical Laboratory Assessments 
For the laboratory measurements, the raw values and change from baseline of the continuous 
hematology and chemistry results will be summarized in SI units at each visit of the Current 
Study Period overall. 
The number and percentage of subjects meeting the threshold analysis criterion during the 
TE Period of the Current Study Period will be summarized based on the 124 Safety Set overall. 
The threshold analysis criteria will be provided in the SAP. 


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In addition, a listing containing individual subject hematology and chemistry values outside the 
reference ranges will be provided. This listing will include data from scheduled and unscheduled 
visits. 
12.3.5.3 
Electrocardiogram 
For the ECG measurements, the raw values and change from baseline values will be summarized 
at each visit of the Current Study Period overall, for the following standard digital ECG 
measurements: PR, QT, and QT corrected for HR (QTc) intervals (Fridericia's correction), QRS 
duration, and HR. In addition, the mean value (95% CI) at each visit will be plotted for QTcF. 
The number and percentage of subjects meeting the threshold analysis criterion during the 
TE Period of the Current Study Period will be summarized based on the 124 Safety Set overall. 
The threshold analysis criteria will be provided in the SAP. 
12.3.5.4 
Vital Signs 
For the vital signs measurements, the raw values and change from baseline values will be 
summarized at each visit of the Current Study Period overall, for the following parameters: 
systolic and diastolic blood pressure (mm Hg), temperature (C), pulse rate (beats per minute), 
respiratory rate (breaths per minute), weight, length/height, and BMI. 
The number and percentage of subjects meeting the threshold analysis criterion during the 
TE Period of the Current Study Period will be summarized based on the 124 Safety Set overall. 
The threshold analysis criteria will be provided in the SAP. 
12.3.5.5 
Physical Examination 
PE findings will be presented in individual subject data listings only. 
12.3.5.6 
Pulse Oximetry 
For the pulse oximetry measurements, a summary of raw values and change from baseline values 
will be provided at each visit of the Current Study Period overall, for the percent of oxygen 
saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period of the Current Study Period will be summarized based on the 124 Safety Set overall. 
12.3.5.7 
Ophthalmological Examinations 
OE findings will be presented as a data listing. 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses 
12.3.6.1 
Interim Analysis 
Interim analyses may take place at any time during the study if warranted by the ongoing data, 
and/or deemed necessary by the internal Vertex team. 
12.3.6.2 
IDMC Analysis 
Details of the IDMC (Section 9.1.5) analysis will be provided in the IDMC Analysis Plan. 


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13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed. 
An AE is considered serious if it meets the definition in Section 13.1.2.1. 
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• 
Concomitant signs or symptoms related to the abnormal study assessment 
• 
Further diagnostic testing or medical/surgical intervention 
• 
A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• 
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 AEs noted during the Follow-up OE. 


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• 
For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 14 days after the last dose of study drug, or 
o the ETT Visit, if that visit is >10 days following the last dose of study drug (see 
Section 9.1.4) 
All subject’s parents or legal guardians 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 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 
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 AE 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, 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor 
mation/Guidances/Vaccines/UCM091977.pdf (Accessed July 2018). When considering the 
severity of an AE in a pediatric subject, the investigator will consider that reference ranges for 
pediatric clinical laboratory parameters may differ from those in the vaccine scale. The severity 
of an AE described by a term that does not appear in this scale will be determined according to 
the definitions in Table 13-1. 


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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 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 subject’s medical record). 
 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories 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. 


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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 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 
Not recovered/not 
resolved (continuing) 
Resolution of an AE with residual signs or symptoms 
 
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 followup) 
 
 
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, 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 and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• 
Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred 
• 
Inpatient hospitalization or prolongation of hospitalization 
• 
Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• 
Congenital anomaly or birth defect 
• 
Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home) 
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 


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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 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
Global Patient Safety (GPS) within 24 hours of identification. 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 of identification. 
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, the SAE Form will be completed for new/initial events as well as to 
report follow-up information on previously reported events. Investigators are asked to report 
follow-up information as soon as it becomes available to ensure timely reporting to health 
authorities. 
Please send completed SAE Forms to Vertex GPS via: 
Email: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159 
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(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 the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, 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. 


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It is the responsibility of the investigator or designee to promptly notify the local IRB/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 be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject’s parent or legal guardian before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent will 
comply with ICH GCP and all applicable laws and regulations and will be subject to approval by 
Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log. 
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol. 
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 


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numbers will be limited to the site and the study physician and will 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 US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will 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: 
• 
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. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 


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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 subject. 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. 
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. 
13.4 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible. 
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected. 
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, 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 compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 
13.5 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 


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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. 
13.6 
Publications and Clinical Study Report 
13.6.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).19 
Publication Planning: Vertex staff along with the lead principal investigators (PIs), the steering 
committee (SC), and/or the publication committee (PC) will work together to develop a 
publication plan. 
Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria:20 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data; 
2. Drafting of the article or revising it critically for important intellectual content; 
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship. 
Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors (ICMJE) criteria for authorship will not be listed as authors, but their 
contribution will be acknowledged and specified either as a group (e.g., “study investigators”) or 
individually (e.g., “served as scientific advisor”). 
Publication Review: As required by a separate clinical study agreement, Vertex must have the 
opportunity to review all publications, including any manuscripts, abstracts, oral/slide 


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presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration. 
13.6.2 
Clinical Study Report 
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations. 


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14 
REFERENCES 
1 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2017 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2018. 
3 
European Cystic Fibrosis Society. 2016 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2018. 
4 
Cystic Fibrosis Foundation. Patient Registry: 2016 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2017. 
5 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: 2015 Annual Data Report. London, 
UK: Cystic Fibrosis Trust; 2016. 
6 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10:88. 
7 
Cystic Fibrosis Australia. Cystic Fibrosis in Australia 2014: 17th Annual Report from the 
Australian Cystic Fibrosis Data Registry. North Ryde, NSW, Australia: Cystic Fibrosis 
Australia; 2016. 
8 
Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry: 2016 Annual Report. 
Toronto, Ontario: Cystic Fibrosis Canada; 2017. 
9 
Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, Spear SL, et al. 
Cystic Fibrosis Foundation evidence-based guidelines for management of infants with 
cystic fibrosis. J Pediatr. 2009;155(6 Suppl):S73-93. 
10 
O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-904. 
11 
Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, et 
al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after 
newborn screening. J Pediatr. 2009;155(5):623-28. 
12 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: A consensus statement. J 
Pediatr. 1998;132(4):589-95. 
13 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-37. 
14 
ICH E11. Clinical Investigation of Medicinal Products in the Pediatric Population. 20 
July 2000. 
15 
Vertex Pharmaceuticals Incorporated. Report L172. Effect of VXc-152 on chloride 
transport in bronchial epithelial cells isolated from CF donors homozygous or 
heterozygous for the F508del-CFTR mutation. Report date: 24 July 2015. 
16 
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. 
17 
Sontag MK, Corey M, Hokanson JE, Marshall JA, Sommer SS, Zerbe GO, et al. Genetic 
and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants 
with cystic fibrosis identified through newborn screening. J Pediatr. 2006;149(5):650- 
57.e2. 
18 
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. 


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19 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
20 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 


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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
 
Protocol #: 
VX19-809- 
124 
Version #: 
2.0 
Version Date: 
12 February 
2021 
Study Title: A Phase 3, Open-label, and Rollover Study to Evaluate the Long-term Safety and 
Tolerability of Lumacaftor/Ivacaftor Treatment in Subjects With Cystic Fibrosis Who Are 
Homozygous for F508del and 12 to <24 Months of Age at Treatment Initiation 
 
This clinical study protocol has been reviewed and approved by the sponsor. 
 
 
 
Printed Name 
Title 
 
 
 
Signature 
Date 


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15.2 
Investigator Signature Page 
 
Protocol #: 
VX19-809- 
124 
Version #: 
2.0 
Version Date: 
12 February 
2021 
Study Title: A Phase 3, Open-label, and Rollover Study to Evaluate the Long-term Safety and 
Tolerability of Lumacaftor/Ivacaftor Treatment in Subjects With Cystic Fibrosis Who Are 
Homozygous for F508del and 12 to <24 Months of Age at Treatment Initiation 
 
 
I have read Protocol VX19-809-124, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning LUM/IVA and this protocol supplied to me 
by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
 
Printed Name 
 
 
 
Signature 
Date 

SAP_001.pdf: 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan (Methods) 
For Final Analysis 
 
Protocol Number:  VX19-809-124  
 
 
A Phase 3, Open-label, and Rollover Study to Evaluate the Long-term 
Safety and Tolerability of Lumacaftor/Ivacaftor Treatment in Subjects 
With Cystic Fibrosis Who Are Homozygous for F508del and 12 to <24 
Months of Age at Treatment Initiation 
 
  
 
Version: 1.0    
Version Date of SAP: 3 August 2023 
 
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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1 
TABLE OF CONTENTS 
1 
Table of Contents ....................................................................................................................... 2 
2 
List of Abbreviations ................................................................................................................. 4 
3 
Modifications .............................................................................................................................. 6 
3.1 
Modifications to the Approved Clinical Study Protocol ...................................................... 6 
3.2 
Modifications to the Approved Statistical Analysis Plan ..................................................... 7 
3.3 
Modifications to the Approved IDMC Charter .................................................................... 7 
4 
Introduction ............................................................................................................................... 8 
5 
Study Objectives ........................................................................................................................ 8 
5.1 
Primary Objective ................................................................................................................. 8 
5.2 
Secondary Objective ............................................................................................................. 8 
5.3 
Other Objectives ................................................................................................................... 8 
6 
Study Endpoints ......................................................................................................................... 8 
6.1 
Primary Endpoint ................................................................................................................. 8 
6.2 
Secondary Endpoint ............................................................................................................. 8 
6.3 
Exploratory Endpoints .......................................................................................................... 8 
7 
Study Design ............................................................................................................................... 9 
7.1 
Overall Design ...................................................................................................................... 9 
7.2 
Sample Size and Power ...................................................................................................... 11 
7.3 
Randomization .................................................................................................................... 11 
7.4 
Blinding and Unblinding .................................................................................................... 11 
8 
Analysis Sets ............................................................................................................................. 11 
9 
Analysis Period ........................................................................................................................ 11 
10 Statistical Analysis ................................................................................................................... 11 
10.1 General Considerations ...................................................................................................... 11 
10.2 Background Characteristics ................................................................................................ 13 
10.2.1 
Subject Disposition ..................................................................................................... 13 
10.2.2 
Demographics and Baseline Characteristics .............................................................. 13 
10.2.3 
Prior and Concomitant Medications ........................................................................... 14 
10.2.4 
Study Drug Exposure ................................................................................................. 14 
10.2.5 
Study Drug Compliance ............................................................................................. 15 
10.2.6 
Important Protocol Deviations ................................................................................... 15 
10.3 Efficacy Analysis ............................................................................................................... 16 
Not applicable. ............................................................................................................................. 16 
10.4 Secondary Endpoint Analysis............................................................................................. 16 
10.4.1 
Absolute Change from Baseline in Sweat Chloride ................................................... 16 
10.5 Exploratory Endpoint Analysis .......................................................................................... 16 
10.5.1 
Absolute Change from Baseline in Growth Parameters ............................................. 16 
10.5.2 
Absolute Change from Baseline in Markers of Pancreatic Function ......................... 17 
10.5.3 
Absolute Change from Baseline in Fecal Calprotectin .............................................. 18 
10.6 Safety Analysis ................................................................................................................... 18 
10.6.1 
Adverse Events ........................................................................................................... 19 
10.6.2 
Clinical Laboratory ..................................................................................................... 21 
10.6.3 
Electrocardiogram ...................................................................................................... 22 
10.6.4 
Vital Signs .................................................................................................................. 22 
10.6.5 
Physical Examination ................................................................................................. 23 
10.6.6 
Pulse Oximetry ........................................................................................................... 23 


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10.6.7 
Ophthalmological Examinations ................................................................................ 23 
10.6.8 
COVID-19 Impacted Visits ........................................................................................ 23 
11 List of Appendices ................................................................................................................... 24 
Appendix A   Analysis Visit Windows for Safety and  Pharmacodynamic Assessments ........ 25 
Appendix B   Imputation Rules for Missing Prior/Concomitant Medication Dates .................... 28 
Appendix C   Imputation Rules for Missing AE dates ................................................................ 29 
Appendix D   Criteria for Threshold Analysis ............................................................................. 30 
Appendix E   Blood Pressure Normal Levels for Boys and Girls by Age and Height Percentile 33 
Appendix F   Programmable Important Protocol Deviation Programming Rules (Based on the 
Clinical Database) .............................................................................................................. 34 
Appendix G   Computing Z-Scores Using WHO Standards ........................................................ 35 
 


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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest  
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator protein  
CI 
confidence interval 
CMQ 
Custom MedDRA Queries 
CRF 
case report form 
DBP 
diastolic blood pressure 
DMC 
data monitoring committee 
ECG 
electrocardiogram  
eCRF 
electronic CRF 
ETT 
early termination of treatment 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine 
codon corresponding to position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FE-1 
fecal elastase-1 
HR 
heart rate 
ICF 
informed consent form 
IPD 
important protocol deviation 
IRT 
immunoreactive trypsin and trypsinogen 
IVA 
Ivacaftor 
LFT 
liver function test  
LLN 
lower limit of normal  
LUM 
Lumacaftor 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHLBI 
National Heart, Lung, and Blood Institute 
OE 
ophthalmological examination 
PD 
pharmacodynamics(s)  
PE 
physical examination  
PR 
PR interval 
PT 
preferred term  
PY 
patient-year: a patient with 48 weeks of treatment-emergent duration 
q12h 
every 12 hours 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together 
representing ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SBP 
systolic blood pressure 


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SD 
standard deviation 
SE 
standard error 
SFU 
safety follow-up  
SI 
SI units (International System of Units)  
SOC 
system organ class 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WHODrug 
World Health Organization Drug Dictionary  
 
 
 


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3 
MODIFICATIONS  
3.1 
Modifications to the Approved Clinical Study Protocol 
Typographical and administrative changes were made to improve the clarity of the document. 
 
 


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3.2 
Modifications to the Approved Statistical Analysis Plan 
This is the first version of the SAP (Methods) for the final analysis. 
3.3 
Modifications to the Approved IDMC Charter 
None. 
 
 


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4 
INTRODUCTION 
Study VX19-809-124 is a Phase 3, open-label, and rollover study to evaluate the long-term safety 
and tolerability of Lumacaftor/Ivacaftor (LUM/IVA) treatment in subjects with cystic fibrosis (CF) 
who are homozygous for F508del and 12 to <24 months of age at treatment initiation. 
This statistical analysis plan (SAP) is for the final analysis of Study VX19-809-124 (Study 124) data 
and is based on the: 
• approved clinical study protocol, dated 12 February 2021, Version 2.0 
• approved electronic case report form (eCRF), dated 10 April 2021, Version 6.0 
This SAP (Methods) documents the planned statistical methods and data presentations of the final 
analysis for Study 124. It also documents additional analyses not prespecified in the protocol, but 
necessary for the scientific understanding of the drug entity. 
The Vertex Biometrics Department or designee will perform the statistical analysis described in 
this document; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, 
figures, listings, and datasets).  
This SAP will be finalized and approved prior to the data cut for the final analysis of Study 124. 
Any revisions to the approved SAP will be documented and approved in an amendment to the SAP. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the safety and tolerability of long-term LUM/IVA treatment in subjects with CF, who 
are homozygous for F508del and 12 to <24 months of age at treatment initiation. 
5.2 
Secondary Objective 
To evaluate the pharmacodynamics (PD) of long-term LUM/IVA treatment in subjects with CF, 
who are homozygous for F508del and 12 to <24 months of age at treatment initiation. 
5.3 
Other Objectives 
Not Applicable. 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory (serum 
chemistry and hematology), standard 12-lead electrocardiograms (ECGs), vital signs, pulse 
oximetry, and ophthalmological examinations (OEs). 
6.2 
Secondary Endpoint 
Absolute change from baseline in sweat chloride. 
6.3 
Exploratory Endpoints 
Absolute change from baseline in the following growth parameters: 
• Body mass index (BMI)-for-age z-score and BMI 
• Weight-for-age z-score and weight 


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• Length/height-for-age z-score and length/height 
• Weight-for-length z-score  
Absolute change from baseline in the following markers of pancreatic function: 
• Fecal elastase-1 (FE-1) levels 
• Serum immunoreactive trypsin and trypsinogen (IRT) levels 
Absolute change from baseline in fecal calprotectin, a marker of intestinal inflammation. 
7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3, multicenter, open-label study in subjects who are 12 to <24 months of age at 
initiation of LUM/IVA treatment ( 
Figure 7-1). The study will enroll approximately 50 subjects. 
Rollover Subjects 
Subjects who participated in parent study VX16-809-122 Part B (Study 122B) and meet all 
eligibility requirements can rollover into Study 124. 
For rollover subjects at sites activated by the Study 122B Safety Follow-up (SFU) Visit, their Study 
124 Day 1 Visit will be on the same day as their Study 122B SFU Visit; any Study 124 Day 1 
assessments that are specified to be performed at the Study 122B SFU Visit will not need to be 
repeated. 
If the Study 124 Day 1 Visit does not coincide with the Study 122B SFU Visit, and if Study 124 
Day 1 is ≤9 days after the Study 122B SFU Visit, the Study 124 Day 1 assessments will not need to 
be repeated. Otherwise, if Study 124 Day 1 is >9 days after the Study 122B SFU Visit, the subject 
will need to complete all Study 124 Day 1 assessments (except the OE if it was performed ≤12 
weeks before the Study 124 Day 1 Visit).    
Rollover subjects may receive treatment for up to 120 weeks (24 weeks in Study 122B and 96 weeks 
in Study 124). 
LUM/IVA-naïve Subjects 
Subjects who did not participate in Study 122B and are 12 to <24 months of age at Study 124 Day 1 
can enroll by age group if they meet Study 124 eligibility requirements: 
• Subjects who are 18 to <24 months of age can enroll in Study 124 after a minimum of 10 
subjects (aged 18 to <24 months) have enrolled in Study 122B and after an assessment of safety 
data from Study 122B through Week 12 for ≥5 subjects aged 18 to <24 months. 
• Subjects who are 12 to <18 months of age can enroll in Study 124 after a minimum of 10 
subjects (aged 12 to <18 months) have enrolled in Study 122B and after an assessment of safety 
data from Study 122B through Week 12 for ≥5 subjects aged 12 to <18 months. 
Note: Subjects aged 18 to <24 months will start enrolling in Study 124 before any subjects 12 to <18 
months of age can enroll as a result of the staggered timing from the Study 122 study design, which 
includes sequential age cohorts. 
LUM/IVA-naïve subjects may receive treatment for up to 96 weeks in Study 124. 


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Figure 7-1 
Schematic of Study 124 Design 
 
 
IVA: ivacaftor; LUM: lumacaftor; OE: ophthalmological examination; q12h: every 12 hours; wks: weeks 
a 
LUM/IVA-naïve subjects (by age group: 18 to <24 months and 12 to <18 months) will be able to enroll in Study 124 once 
minimum enrollment has been met in Study 122B (n = 10 subjects in each age group), and after an assessment of safety data 
from Study 122B through Week 12 for ≥5 subjects in each age group. 
b 
For rollover subjects, the Day 1 Visit should be the same day as the Safety Follow-up Visit in Study 122B. 
c 
The Safety Follow-up Visit will not be required for subjects transitioning to commercial LUM/IVA. 
d          For LUM/IVA-naïve subjects, doses will be determined by weight at screening. 


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7.2 
Sample Size and Power 
No formal sample size calculations have been performed for this study. The study will enroll 
approximately 50 subjects to provide data for the assessment of long-term safety in the target 
patient population, as requested by a regulatory agency. 
7.3 
Randomization 
This is an open-label study with weight-based treatment dosing. Randomization is not 
required. 
7.4 
Blinding and Unblinding 
This is an open-label study.  
8 
ANALYSIS SETS 
The following analysis sets are defined. Enrolled subjects are those who signed 
consent/assent form and had an enrollment date in the database.  
All Subjects Set: All subjects who are enrolled or dosed in Study 124. This analysis set will 
be used for individual subject data listings and disposition summary tables unless otherwise 
specified. 
Safety Set: All subjects who are exposed to any amount of study drug in Study 124. This 
analysis set will be used for all safety analysis unless otherwise specified. 
Full Analysis Set: All subjects who are enrolled and dosed in Study 124. This analysis set will 
be used for all analysis of PD and exploratory endpoints unless otherwise specified. 
9 
ANALYSIS PERIOD 
The analysis periods are described below. 
The Treatment-emergent (TE) Period will start on or after the first dose date of study drug 
in Study 124 to 18 days (inclusive) after the last dose date of study drug in Study 124 or up to 
the last day in Study 124, whichever occurs first.  
10 
STATISTICAL ANALYSIS 
10.1 
General Considerations 
The Schedule of Assessments is provided in the CSP for Study 124. 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 will be presented in data listings based on the All Subjects Set. 
Continuous variables will be summarized using the following descriptive summary 
statistics: number of subjects, mean, standard deviation (SD), standard error (SE), median, 
minimum value (min), and maximum value (max).  
Categorical variables will be summarized using counts and percentages.  


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Baseline value will be defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected on or before the first dose of LUM/IVA in Study 124. 
For sweat chloride, values at each visit will be based on averaged measurements from left 
and right arms. For Rollover Subjects, baseline will be defined as the most recent non-
missing measurement (scheduled or unscheduled) collected on or before the first dose of 
LUM/IVA in Study 124. For LUM/IVA-naïve Subjects, baseline will be defined as the 
average of the values at screening and the pretreatment measurement on Day 1 of Study 124. 
If only 1 pre-first dose measurement of sweat chloride is available, that measurement will be 
considered the baseline. 
Change (Absolute Change) from baseline will be calculated as postbaseline value − 
baseline value. 
Unscheduled visits will be included in the analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline measurements or last on-treatment visit 
• In individual subject data listings, as appropriate 
• In the derivation of max/min values and max/min change from baseline values 
Visit windowing rules: Appendix  defines the visit window mapping rules to derive the 
analysis visits for Study 124. 
Repeated observations within the same visits window: 
• For all PD parameters, if there are multiple measurements within a visit window, the record 
at the scheduled visit will be used. If there are no measurements at the scheduled visit, then 
1) the record closest to the target day will be used; or 2) if there are multiple records with 
the same distance to the target day, the latest record will be used.   
• For all safety parameters, if there are multiple measurements within a visit window, then 
1) the record closest to the target day will be used; or 2) if there are multiple records with 
the same distance to the target day, the latest record will be used. 
• If there are local lab results and central lab results at same visit point, then the central lab 
results will be used. 
BMI, weight, and length will follow PD parameter visit window rules when evaluated as PD 
endpoints; they will follow safety parameter visit window rules when evaluated as safety 
endpoints. Their corresponding z-scores will be assigned analysis visit window rules the 
same as BMI, weight, and length, respectively.  
For clinical laboratory, ECG and vital sign measurements collected on the date of the first 
dose of study drug, if it cannot be determined whether the measurement was taken before or 
after the first dose, scheduled measurements will be treated as pre-dose observations, and 
unscheduled measurements will be treated as post-dose observations. 
If ETT visit happens on or after 10 days of last LUM/IVA dose and there are no SFU 
assessments collected, then ETT Visit will be mapped to SFU Visit. 
Incomplete/missing data will not be imputed, unless specified otherwise.  


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Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless specified otherwise. 
Multiplicity: No multiplicity adjustment will be performed, and there is no hypothesis 
testing. 
10.2 
Background Characteristics  
10.2.1 
Subject Disposition 
The number of subjects in the following categories for the population will be provided: 
• All Subjects Set 
• Safety Set 
• FAS 
• Enrolled but never dosed 
Number and percentage (based on the Safety Set) of subjects in each of the following 
categories will be provided: 
• Completed study drug treatment 
• Prematurely discontinued study drug treatment and the reason for discontinuation 
• Completed study  
• Prematurely discontinued the study and the reason for discontinuation 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation.  
10.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on Safety Set.  
Demographic data will include the following: 
• Sex (male and female) 
• Age at treatment initiation (months) 
• Age group at treatment initiation 
• Ethnicity (Hispanic or Latino; Not Hispanic or Latino; 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; Other) 
Baseline characteristics will include the following: 
• Weight (kg)  
• Length/height (cm) 


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• BMI (kg/m2) 
• Weight-for-age z-score   
• Length/height-for-age z-score   
• BMI-for-age z-score 
• Weight-for-length/height z-score 
• Sweat chloride (mmol/L) 
• FE-1 Levels (mg/kg) 
• Serum IRT Levels (ug/L) 
• Fecal Calprotectin Levels (mg/kg) 
Medical history will be summarized based on Safety Set using the Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT). All 
demographic and baseline characteristic data will be listed. 
10.2.3 
Prior and Concomitant Medications 
Medications used will be coded using the World Health Organization Drug Dictionary 
(WHODrug) and categorized as the following: 
Prior medication: Any medication that started before the date of the first dose of study drug 
in Study 124. 
Concomitant medication: Any medication continued or newly received during the TE 
Period. 
Post-treatment medication: Any medication continued or newly received after the end of 
the TE Period. 
A given medication can be classified as prior; concomitant; post-treatment; both prior and 
concomitant; both concomitant and post-treatment; prior, concomitant, and post-treatment. 
 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by preferred name and by ATC level 1 and 2 based on Safety Set. 
All medications will be listed for each subject. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix . 
10.2.4 
Study Drug Exposure  
Duration of study drug exposure is defined as follows: last dose date in the TE Period − first 
dose date in the TE Period + 1 day, regardless of any dose interruptions. If the last dose date 
of study drug is missing and the ETT visit is available, use the ETT visit as the last dose date. 
Otherwise, if there is no ETT visit, the last known study participation date will be used for 
analysis purposes.  


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Duration of study drug exposure as well as number of sticks administered, defined as (total 
number of sticks dispensed) − (total number of sticks returned), will be summarized 
descriptively based on the Safety Set for the the TE Period. Additionally, the total duration of 
treatment exposure, defined as the sum of the subject’s duration of treatment exposure and 
expressed in patient-years (1 patient-year is defined as one patient with 48 weeks of 
treatment), will be provided. 
Study drug administration data will be presented in individual subject data listings. 
Duration of exposure will also be summarized as a categorical variable (>0 to ≤8 weeks; >8 
to ≤24 weeks; >24 to ≤48 weeks; >48 to ≤72 weeks; >72 to ≤96 weeks; >96 weeks). 
10.2.5 
Study Drug Compliance  
Study drug compliance will be calculated as follows: 100 × (1 − [total number of days of 
study drug interruption in the TE Period] / [duration of study drug exposure]).  
The total number of days of study drug interruption is defined as the sum of the number of 
days of each study drug interruption in the TE Period, where the number of days of each 
study drug interruption is defined as the interruption end date − the corresponding 
interruption start date + 1.  
Percent of stick packs taken will be calculated as follows: 100 × (total number of stick packs 
administered) / (2 × [duration of study drug exposure in the TE Period]). 
Treatment compliance percentages and percent of stick packs taken will be summarized 
descriptively based on the Safety Set. The number and percentage of subjects whose 
compliance is <80% or ≥80% and the number and percentage of subjects whose percent of 
stick packs taken is <80% or ≥80% will be summarized. 
Study drug compliance and study drug interruption data will be presented in individual subject 
data listings in addition. 
10.2.6 
Important Protocol Deviations  
A protocol deviation is any change, divergence, or departure from the study design or 
procedure defined in the protocol. An important protocol deviation (IPD) is a protocol 
deviation 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.  
IPDs will be identified by the Protocol Deviation Review Team according to the Protocol 
Deviation Plan. 
The rules for identifying programmable IPDs based on the clinical database are defined in 
Appendix . 
All IPDs will be summarized and presented in an individual subject data listing. 


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10.3 
Efficacy Analysis 
Not applicable. 
10.4 
Secondary Endpoint Analysis 
10.4.1 
Absolute Change from Baseline in Sweat Chloride 
For each subject and at each time point, two sweat chloride measurements will be collected: 
one from the right arm and one from the left arm. Of the two measurements, only sweat 
chloride values obtained from sample volume ≥15 µL will be included in any analysis as a 
sample volume of at least 15 µL is required for testing. If a subject has replicated 
measurements at a postbaseline time point, then the median of the values will be used in data 
analyses. If the sweat chloride values for the left and right arms are both from sample volume 
≥15 µL, these values will be averaged together for the analysis; if only one arm is from 
sample volume ≥15 µL, only that value will be used. Any sweat chloride values outside of 
the reportable range (i.e., <10 mmol/L or >160 mmol/L) will not be included in the analysis.  
Raw values and absolute change from baseline in sweat chloride at each visit will be 
summarized descriptively (n, mean, SD, SE, median, minimum, and maximum) based on the 
FAS. In addition, the 95% confidence interval (CI) based on Normal approximation of the 
absolute change from baseline values will be provided. The mean (95% CI) of the absolute 
change from baseline at each scheduled time point will be plotted.  
10.5 
 Exploratory Endpoint Analysis 
10.5.1 
 Absolute Change from Baseline in Growth Parameters 
 
Absolute Change from Baseline in BMI-for-Age Z-score and BMI 
 
BMI z-score will be calculated by using WHO BMI-for-age charts. The BMI-for-age z-score 
will be calculated as follows: 










=







−






=
0
,
ln
0
,
1
L
S
M
X
L
LS
M
X
z
L
 
Where X is the derived BMI value in kg/m2 based on the raw weight and raw height and L, 
M, and S are selected from the WHO BMI-for-age charts by subject sex and age. The BMI-
for-AGE z-score tables contain these parameters by sex and age; they are available at 
(accessed Jun 09, 2023):  
• https://www.who.int/toolkits/child-growth-standards/standards/body-mass-index-for-
age-bmi-for-age  


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Raw values and absolute change from baseline in BMI and BMI-for-age z-score at each visit 
will be summarized descriptively (n, mean, SD, SE, median, minimum, and maximum) based 
on the FAS. In addition, the 95% CI of the absolute change from baseline values will be 
provided. The mean (95% CI) of the absolute change from baseline values will be plotted at 
each scheduled visit. 
Absolute Change from Baseline in Weight-for-Age Z-score and Weight 
 
Weight-for-age z-score will be calculated by using WHO weight-for-age tables. The same 
equation used to calculate BMI-for-age z-score will be used to calculate weight-for-age z-
score, where X in the equation will be the collected weight. L, M, and S parameters will be 
selected from the WHO weight-for-age tables. The weight-for-age z-score tables contain 
these parameters by sex and age; they are available at (accessed Jun 09, 2023): 
• https://www.who.int/tools/child-growth-standards/standards/weight-for-age  
Weight-for-age z-score and weight will be analyzed in a similar way to BMI-for-age z-score 
and BMI.  
Absolute Change from Baseline in Length/Height-for-Age Z-score and Length/Height 
 
Length-for-age z-score will be calculated by using WHO length-for-age tables. The same 
equation used to calculate BMI-for-age z-score will be used to calculate length-for-age z-
score, however X in the equation will be the collected length. L, M, and S parameters will be 
selected from the WHO length -for-age tables. The length-for-age z-score tables contain 
these parameters by sex and age; they are available at (accessed Jun 09, 2023):  
• https://www.who.int/tools/child-growth-standards/standards/length-height-for-age 
See Appendix G   Computing Z-Scores Using WHO Standards for further details on 
determining length/height and necessary adjustment. 
Length/height-for-age z-score and length/height will be analyzed in a similar way to BMI-for-
age z-score and BMI.  
Absolute Change from Baseline in Weight-for-Length Z-Score 
 
Weight-for-length z-score will be calculated by using WHO weight-for-length tables. The 
same equation used to calculate BMI-for-age z-score will be used to calculate weight-for-
length z-score, where X in the equation will be the collected weight. L, M, and S parameters 
will be selected from the WHO weight-for-length/height tables. The weight-for-length z-
score tables contain these parameters by sex and length/height; they are available at 
(accessed Jun 09, 2023): 
• https://www.who.int/tools/child-growth-standards/standards/weight-for-length-height  
See Appendix G   Computing Z-Scores Using WHO StandardsG for further details on 
determining length/height and necessary adjustment. 
Weight-for-length z-score will be analyzed in a similar way to BMI-for-age z-score.  
10.5.2 
Absolute Change from Baseline in Markers of Pancreatic Function 
Absolute Change from Baseline in FE-1 Levels 
 


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Raw values and absolute change from baseline in FE-1 levels at each visit will be 
summarized descriptively (n, mean, SD, SE, median, minimum, and maximum) based on the 
FAS. In addition, the 95% CI of the absolute change from baseline values will be provided. 
In addition, the number and percentage of subjects with FE-1 levels consistent with 
pancreatic insufficiency (defined as FE-1 level <200 mg/kg) will be provided at baseline and 
at each visit.  
The number and percentage of subjects with shift changes from baseline at each visit will be 
summarized using the following two categories: <200 mg/kg; ≥200 mg/kg.  
The mean (95% CI) of the absolute change from baseline in FE-1 values will be plotted at 
each scheduled visit. 
Absolute Change from Baseline in Serum IRT Levels 
 
Raw values and absolute change from baseline in serum IRT levels at each visit will be 
summarized descriptively (n, mean, SD, SE, median, minimum, and maximum) based on the 
FAS. In addition, the 95% CI of the absolute change from baseline values will be provided. 
The mean (95% CI) of the absolute change from baseline in serum IRT values will be plotted 
at each scheduled visit. 
10.5.3 
 Absolute Change from Baseline in Fecal Calprotectin 
Raw values and absolute change from baseline in fecal calprotectin levels at each visit will be 
summarized descriptively (n, mean, SD, SE, median, minimum, and maximum) based on the 
FAS. In addition, the 95% CI of the absolute change from baseline values will be provided. 
The mean (95% CI) of the absolute change from baseline in fecal calprotectin values will be 
plotted at each scheduled visit. 
10.6 
Safety Analysis 
Evaluating the safety and tolerability of long-term LUM/IVA treatment is the primary 
objective of this study. The safety profile of the study drug will be assessed in terms of the 
following safety and tolerability endpoints: 
• AEs 
• Clinical laboratory measurements (serum chemistry and hematology) 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
• Physical Examinations 
• OEs 
Safety endpoints will be summarized descriptively based on the Safety Set.  
All listings will be provided based on the All Subjects Set.  


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10.6.1 
Adverse Events  
AEs will be classified as pretreatment AEs, treatment-emergent adverse events (TEAEs), or 
post-treatment AEs, defined as follows:  
Pretreatment AE: Any AE that started before the first dose date of study drug in Study 124.  
TEAE: Any AE that worsened (either in severity or seriousness) or that was newly 
developed on or after the first dose date of study drug through the end of the TE Period. 
Post-treatment AE: Any AE that increased in severity or was newly developed after the 
TE Period. 
For AEs with missing or partial 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 . 
TEAE summaries will be presented using number and percentages of subjects for the TE 
Period based on the Safety Set. 
An overview of the TEAE profile will be provided, including total number of TEAEs, with 
number and percentage of subjects and for the following categories: (1) Any TEAEs; (2) 
Grade 3/4 TEAEs; (3) TEAEs by Strongest Relationship to the Drug; (4) TEAEs by 
Maximum Severity; (5) TEAEs Leading to Treatment Interruption; (6) TEAEs Leading to 
Treatment Discontinuation; (7) Serious TEAEs; (8) Related Serious TEAEs; (9) TEAEs 
Leading to Death. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs  
• Grades 3/4 TEAEs 
• TEAEs by Strongest Relationship 
• TEAEs by Maximum Severity 
• Related TEAEs 
• TEAEs Leading to Treatment Interruption 
• TEAEs Leading to Treatment Discontinuation 
• Serious TEAEs 
• Related Serious TEAEs 
• TEAEs Leading to Death 
• Frequently Reported TEAEs (≥5% at the PT level) 
These summaries will be presented by MedDRA SOC and PT using frequency counts and 
percentages (i.e., number and percentage of subjects with any event) and exposure-adjusted 
number of events in 100PY. When summarizing the number of events, a subject with 
multiple events within a category is counted multiple times in that category. When 


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summarizing the number and percentage of subjects with any 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 only the strongest relationship 
level will be presented in the relationship summaries. 
Additional summary table in which the frequency counts and percentages will be presented 
for TEAEs during the TE period for the following: 
• All TEAEs by PT 
• Non-Serious TEAEs by SOC and PT 
• Related Non-Serious TEAEs by SOC and PT 
In addition, listings containing individual subject data for all TEAEs leading to treatment 
interruption, TEAEs leading to treatment discontinuation, deaths, and serious adverse events 
(SAEs) will be provided separately for the TE Period. All AEs, including pre- and post-
treatment AEs, will be presented in individual subject data listings for the TE Period. 
Note that if an event increases in its severity, it will be reported as a separate event in the 
clinical database and thus may be counted more than once. 
Analysis of AEs of Special Interest (AESI):  
Three types of AESIs are proposed for Study 124; the Customized MedDRA Queries (CMQ) 
used may change before database lock. 
1.  Elevated Transaminases AESI 
The AESI of elevated transaminases is defined as AEs whose PTs fall into any of the 
following categories:  
• 
Alanine aminotransferase abnormal  
• 
Alanine aminotransferase increased  
• 
Aspartate aminotransferase abnormal 
• 
Aspartate aminotransferase increased 
• 
Transaminases abnormal 
• 
Transaminases increased 
• 
Liver function test abnormal 
• 
Liver function test increased 
• 
Hypertransaminasaemia 
• 
Hepatic enzyme increased 
• 
Hepatic enzyme abnormal 
2. Respiratory Symptom AESI 
The AESI of respiratory symptoms is defined as AEs whose PTs fall into any of the 
following categories: 


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• 
Chest discomfort 
• 
Dyspnoea 
• 
Respiration abnormal 
3. Respiratory Event AESI (including respiratory symptoms or reactive airways) 
The AESI of respiratory symptoms or reactive airways is defined as AEs whose PTs fall 
into any of the following categories: 
• 
Asthma 
• 
Bronchial hyperreactivity 
• 
Bronchospasm  
• 
Chest Discomfort 
• 
Dyspnoea 
• 
Respiration abnormal 
• 
Wheezing 
TE AESIs will be summarized using the Safety Set by: 
1. Number and percentage of subjects by PT 
2. Number and percentage of subjects by Maximum Severity 
3. Descriptive summary of duration of events (days) 
4. Descriptive summary of time-to-onset of the first event (days, relative to first dose 
date) 
5. Number and percentage of subjects with exposure-adjusted number of events in 
100PY for: (1) TEAEs Leading to Treatment Interruption; (2) TEAEs Leading to 
Treatment Discontinuation; (3) Serious TEAEs; (4) Related Serious TEAEs; and (5) 
TEAEs Leading to Death 
10.6.2 
Clinical Laboratory 
For laboratory measurements, raw values and change from baseline values for the continuous 
hematology and chemistry results will be summarized in SI units at each visit of the TE 
Period. 
Laboratory tests done in the local laboratory may be used in data analyses if data from the 
central laboratory are not available. 
For hematology and chemistry, the number and percentage of subjects with abnormally low 
(< lower limit of normal [LLN]) values and with abnormally high (> upper limit of normal 
[ULN]) values at each visit will be summarized.  
The number and percentage of subjects meeting the threshold analysis criterion during the 
TE Period of the TE Period will be summarized for selected laboratory parameters based on 
the Safety Set. The threshold analysis criteria are provided in Appendix . 


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In addition, listings containing individual subject hematology and chemistry values outside of 
the normal reference ranges will be provided. These listings will include data from both 
scheduled and unscheduled visits. 
LFT elevations meeting ALT or AST > 5xULN, or ALT > 3xULN and total bilirubin > 
2xULN, or AST > 3xULN and total bilirubin > 2xULN at one visit during the TE period will 
also be listed. 
10.6.3 
Electrocardiogram 
For ECG measurements, raw values and change from baseline values will be summarized at 
each visit of the TE Period for the following standard digital ECG measurements: RR (ms), 
PR (ms), QT (ms), QT corrected for HR (QTc) intervals (Fridericia's correction QTc (ms) = 
QT/RR1/3), QRS duration (ms), and HR (bpm). In addition, the mean value (95% CI) at each 
visit will be plotted for QTc. 
The number and percentage of subjects meeting the threshold analysis criterion during the 
TE Period of the TE Period will be summarized for selected ECG parameters based on the 
Safety Set. The threshold analysis criteria are provided in Appendix . 
Listings will be provided for the ECG measurements. 
10.6.4 
Vital Signs 
For vital signs measurements, raw values and change from baseline values will be 
summarized at each visit of the TE Period for the following parameters: systolic and diastolic 
blood pressure (SBP/DBP) (mmHg), temperature (C), pulse rate (beats per minute), 
respiratory rate (breaths per minute), weight (kg), length/height (cm), and BMI (kg/m2). 
The number and percentage of subjects with at least one potentially abnormal SBP and/or 
DBP during the TE Period of the TE Period will be summarized separately based on the 
Safety Set using threshold criteria provided in Appendix . Potentially abnormal SBP and 
DBP by percentile (adjusted for sex, age, and length/height) will be provided, including: 
• Number and percentage of subjects in categories: ≥90% to <95%; ≥95% to <99% + 5 
mmHg; ≥99% + 5 mmHg, during the TE Period 
• Number and percentage of subjects with SBP and DBP percentiles ≥95% at least once 
and at least twice during the TE Period 
• Number and percentage of subjects with SBP and DBP percentiles ≥95% at each visit in 
the TE Period 
The length/height adjustment will be based on length/height-for-age z-scores and their 
corresponding percentiles using the standard normal distribution (Appendix ). The 
length/height percentiles will be further mapped per the following rules displayed in Table 
9-1: 
 
Table 9-1   Grouped Percentiles for Length/Height-for-Age Z-scores 
Calculated Percentiles (%) 
Grouped Percentiles (%) 


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0 – <7.5 
5 
7.5 – <17.5 
10 
17.5 – <37.5 
25 
37.5 – <62.5 
50 
62.5 – <82.5 
75 
82.5 – <92.5 
90 
92.5 – 100 
95 
The sex- and age-adjusted normal range for SBP and DBP for each grouped length/height 
percentile is based on the SBP/DBP table on the National Heart, Lung, and Blood Institute 
(NHLBI) website (http://www.nhlbi.nih.gov/health-pro/guidelines/current/hypertension-
pediatric-jnc-4/blood-pressure-tables, accessed Oct 26, 2021).  
Listings of subjects with potentially abnormal SBP and/or DBP will be provided.  
The mean (+/- SD) value at each visit will be plotted separately for SBP and DBP. 
Listings will be provided for vital signs parameters.  
10.6.5 
Physical Examination  
Listings will be provided for physical examination findings. 
10.6.6 
Pulse Oximetry 
For pulse oximetry measurements, raw values and change from baseline values will be 
summarized at each visit of the TE Period for the percent of oxygen saturation by pulse 
oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
TE Period of the TE Period will be summarized based on the Safety Set. 
Listings for pulse oximetry measurements will be included in vital signs listings. 
10.6.7 
Ophthalmological Examinations 
OE findings will be presented as data listings. 
10.6.8 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
 


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11 
LIST OF APPENDICES 
 


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Appendix A   Analysis Visit Windows for Safety and Pharmacodynamic 
Assessments 
Table 11-1   Visit Window Mapping Rules for Rollover Subjects (809-124) 
Assessments 
Visit 
Target Study Day 
Visit Window  
(in study days) 
•  Weight and 
length/height 
•  Vital signs 
•  Pulse oximetry 
•  Labs 
o  LFTs Only 
 
 
Day 15 
15 
(1, 50] 
Week 12 
85 
[51, 127] 
Week 24 
169 
[128, 211] 
Week 36 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Follow-up Visit 
253 
337 
421 
505 
589 
673 
687 
[212, 295] 
[296, 379] 
[380, 463] 
[464, 547] 
[548, 631] 
[632, 680] 
Nominal Visit 
•  IRT  
•  Labs 
o  Chemistry 
o  Hematology  
Week 12 
Week 24 
Week 36 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Follow-up Visit 
85 
169 
253 
337 
421 
505 
589 
673 
687 
(1, 127] 
[128, 211] 
[212, 295] 
[296, 379] 
[380, 463] 
[464, 547] 
[548, 631] 
[632, 680] 
Nominal Visit 
•  Standard 12-Lead ECG  
•  Sweat chloride 
•  Fecal Sample 
o Fecal Calprotectin 
o Fecal Elastase-1 
Week 24 
Week 48 
Week 96 
Follow-up Visit 
169 
337 
673 
687 
(1, 253] 
[254, 505] 
[506, 680] 
Nominal Visit 
•  Ophthalmological 
Examination                      
Week 24 
Week 48 
Week 72 
Week 96 
Follow-up Visit 
169 
337 
505 
673 
687 
(1, 253] 
[254, 421] 
[422, 589] 
[590, 680] 
Nominal Visit 
If ETT visit happens on or after 10 days of last LUM/IVA dose and there are no SFU 
assessments collected, then ETT Visit will be mapped to SFU analysis Visit. 
 
 
 
 
 
 
 
 
 


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Table 11-2   Visits Window Mapping Rules for LUM/IVA-naïve Subjects (809-124) 
Assessments 
Visit 
Target Study Day 
Visit Window  
(in study days) 
•  Weight and 
length/height 
•  Vital signs 
•  Pulse oximetry 
•  Labs 
o  LFTs Only 
 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
15 
29 
57 
85 
113 
(1, 22] 
[23, 43] 
[44, 71] 
[72, 99] 
[100, 141] 
Week 24 
169 
[142, 211] 
Week 36 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Follow-up Visit 
253 
337 
421 
505 
589 
673 
687 
[212, 295] 
[296, 379] 
[380, 463] 
[464, 547] 
[548, 631] 
[632, 680] 
Nominal Visit 
•  Standard 12-Lead ECG 
Week 4 
Week 12 
Week 24 
Week 48 
Week 96 
Follow-up Visit 
29 
85 
169 
337 
673 
687 
(1, 57] 
[58, 127] 
[128, 253] 
[254, 505] 
[506, 680] 
Nominal Visit 
•  Labs 
o  Chemistry  
o  Hematology 
 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Week 36 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Follow-up Visit 
29 
57 
85 
113 
169 
253 
337 
421 
505 
589 
673 
687 
[23, 43] 
[44, 71] 
[72, 99] 
[100, 141] 
[142, 211]  
[212, 295] 
[296, 379] 
[380, 463] 
[464, 547] 
[548, 631] 
[632, 680] 
Nominal Visit 
•  IRT 
 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Follow-up Visit 
29 
85 
169 
253 
337 
421 
505 
589 
673 
687 
(1, 57] 
[58, 127] 
[128, 211] 
[212, 295] 
[296, 379] 
[380, 463] 
[464, 547] 
[548, 631] 
[632, 680] 
Nominal Visit 


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•  Sweat chloride 
•  Fecal Sample 
                                   
Week 4 
Week 12 
Week 24 
Week 48 
Week 96 
Follow-up Visit 
29 
85 
169 
337 
673 
687 
(1, 57] 
[58, 127] 
[128, 253] 
[254, 505] 
[506, 680] 
Nominal Visit 
•  Ophthalmological 
Examination 
Week 24 
Week 48  
Week 72 
Week 96 
Follow-up Visit 
169 
337 
505 
673 
687 
(1, 253] 
[254, 421] 
[422, 589] 
[590, 680] 
Nominal Visit 
The study days are based on the first dose in Study 124. 
For Vital signs the Nominal Day 15 predose assessments will be mapped to Day 15. 


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Appendix B   Imputation Rules for Missing Prior/Concomitant Medication 
Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use the informed consent date.  
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop 
date (in practice, use the end of study date to impute). 
In summary, the prior, concomitant or post categorization of a medication is described below. 
Table 11-3   Prior, Concomitant, and Post Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date 
and ≤ End Date of 
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 ofTE period 
- 
- 
A 
A: Post; C: Concomitant; P: Prior; TE: treatment-emergent 
 


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


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Appendix D   Criteria for Threshold Analysis 
Table 11-4   Threshold Analysis Criteria for Laboratory Tests 
Parameter 
Categorical change 
Comments 
Clinical Chemistry 
ALT 
≤3xULN*(Not a categorical change) 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009.  
AST 
≤3xULN*(Not a categorical change) 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
ALT>3xULN or AST>3xULN 
Vertex LFT working group 2014 
ALT or AST 
ALT>5xULN or AST>5xULN 
 
ALT or AST 
ALT>8xULN or AST>8xULN 
 
Alkaline 
Phosphatase 
>1.5xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>1.5x - ≤2xULN 
>2xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment phase, 
whatever the interval between measurements. 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment phase, 
whatever the interval between measurements. 
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
Vertex LFT working group 2014 
CPK 
>3x - ≤ 10xULN 
>10xULN 
FDA criteria Feb 2005. 
Am J Cardiol April 2006. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 


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


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Table 10-5   Threshold Analysis Criteria for ECGs 
Parameter 
Categorical change 
Comments 
HR 
≤70 bpm 
≥150 bpm 
 
PR 
 
≥150 ms 
 
QRS 
≥80 ms 
 
QTc 
 
Absolute values (ms) 
 
Prolonged: >450 ms (Male and Female) 
To be applied to any kind of QT correction 
formula.  
 
  


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Appendix E   Blood Pressure Normal Levels for Boys and Girls by Age and 
Height Percentile 
https://www.nhlbi.nih.gov/sites/default/files/media/docs/hbp_ped.pdf (pages: 10-13; 
accessed Oct 26, 2021) 


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Appendix F   Programmable Important Protocol Deviation Programming Rules 
(Based on the Clinical Database) 
Important Protocol Deviations during the Treatment Period: 
• Compliance < 80% in Study 124 
• Rollover Subject Study 122B completion 
• LUM/IVA-naïve Subject age and inclusion/exclusion criteria 


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Appendix G   Computing Z-Scores Using WHO Standards  
Adjusting Length/Height for Recumbent vs. Standing Position 
In calculation of z-scores relating to length/height, an adjustment may be necessary 
depending on how the length/height data were collected and the child’s age (World Health 
Organization, 2006; Schumacher, 2020). 
If the Measures are KNOWN to Be Either Recumbent Length or Standing Height:  
• If the subject's age is ≤ 24 Months (730 days), measure of recumbent length should be 
used. If standing height measure is collected instead, 0.7 cm must be ADDED to the 
standing height measure to adjust. 
• If the subject's age is > 24 Months (730 days), measure of standing height should be 
used. If recumbent length measure is collected instead, 0.7 cm must be 
SUBTRACTED from the recumbent length measure to adjust. 
If the Measures are UNSPECIFIED to Be Either Recumbent Length or Standing Height: 
• If AGE at the Visit is Not Missing  
o If child age is ≤ 24 Months (730 days), the measure is to be considered as 
recumbent length 
o If child age is > 24 Months (730 days), the measure is to be considered as 
standing height  
• If Age at the Visit is Missing  
o If the measure is < 87cm, it is to be considered as recumbent length 
o If the measure is ≥ 87cm, it is to be considered as standing height 
If necessary, all ages collected in months can be converted to days using 1 month = 30.4375 
days.  
 
Linear Interpolation of Length/Height Measurements 
The WHO standard tables for Weight-for-Length/ Height comes with tabulated 
Length/Height (𝑋) values with 1 decimal place and at 0.1 intervals. In practice, if the 
collected Length/Height (𝑋) values fall between the intervals, the following interpolation 
approach is suggested to obtain the appropriate values for 𝐿, 𝑀, and 𝑆 (World Health 
Organization, 2006): 
1. Round the Length/Height (𝑋) to the nearest 1 decimal place value lower than the 
collected value (e.g., round 73.265 to 73.2), and obtain the 𝐿, 𝑀, and 𝑆 values using 
the standard table. Let us denote the rounded value as (𝑋௟) and the tabulated values as 
𝐿௟, 𝑀௟, and 𝑆௟.  
2. Round the Length/Height to the nearest 1 decimal place value higher than the 
collected value (e.g., round 73.265 to 73.3), and obtain the 𝐿, 𝑀, and 𝑆 values using 


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the standard table. Let us denote the rounded value as (𝑋௨) and the tabulated values as 
𝐿௨, 𝑀௨, and 𝑆௨. 
3. Obtain the interpolated values of 𝐿, 𝑀, and 𝑆 as: 
𝐿∗= 𝐿௟+ ൬𝑋−𝑋௟
0.1 ൰(𝐿௨−𝐿௟) 
𝑀∗= 𝑀௟+ ൬𝑋−𝑋௟
0.1 ൰(𝑀௨−𝑀௟) 
𝑆∗= 𝑆௟+ ൬𝑋−𝑋௟
0.1 ൰(𝑆௨−𝑆௟) 
Finally, use the values 𝐿∗, 𝑀∗, and 𝑆∗ in z-score calculations. 
 
Adjustment for Weight-based z-scores in the Extreme Tails of the Distribution 
The weight-based z-scores (e.g., Weight-for-Age, Weight-for-Length, Weight-for-Height, 
and BMI-for-Age) beyond ±3 SD need to be adjusted (World Health Organization, 2006) as 
described in following: 
1. Calculate the initial z-score using the following formula, as described above: 
𝑧=
⎩
⎪
⎨
⎪
⎧ቀ𝑋
𝑀ቁ
௅
−1
𝐿𝑆
,
𝐿≠0
ln ቀ𝑋
𝑀ቁ
𝑆
,
𝐿= 0
 
2. Compute the final z-score (𝑧∗) of the child as: 
𝑧∗=
⎩⎪⎨
⎪⎧
𝑧
,
if |𝑧| ≤3
3 + ቀ
௑ିୗୈయౌో౏
ୗୈమయౌో౏ቁ
,
if 𝑧> 3
−3 + ቀ
௑ିୗୈయొుృ
ୗୈమయొుృቁ
,
if 𝑧< −3
                  where, 
SDଷ୔୓ୗ and SDଷ୒୉ୋ are the cut-off 3 SD and -3 SD, respectively, calculated by the LMS 
methods: 
SDଷ୔୓ୗ= 𝑀[1 + 3𝐿𝑆]
ଵ
௅ 
SDଷ୒୉ୋ= 𝑀[1 −3𝐿𝑆]
ଵ
௅ 
SDଶଷ୔୓ୗ and SDଶଷ୒୉ୋ are the difference between the cut-offs (3 SD and 2 SD) and (-2 SD 
and -3 SD), respectively, calculated by the LMS methods: 
SDଶଷ୔୓ୗ= 𝑀[1 + 3𝐿𝑆]
ଵ
௅−𝑀[1 + 2𝐿𝑆]
ଵ
௅ 
SDଶଷ୒୉ୋ= 𝑀[1 −2𝐿𝑆]
ଵ
௅−𝑀[1 −3𝐿𝑆]
ଵ
௅ 
 
 
 


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References 
Schumacher, D. (2020). anthro: Computation of the WHO Child Growth Standards. R 
package version 0.9.4. Retrieved from https://CRAN.R-project.org/package=anthro 
World Health Organization. (2006). WHO Child Growth Standards: length/height-for-age, 
weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods 
and development. Retrieved from 
https://www.who.int/childgrowth/standards/Technical_report.pdf