Clinical trial NCT04183790
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2020-02-17; Completion date: 2024-02-24
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study evaluates the long-term safety, tolerability, efficacy, and pharmacodynamics of elexacaftor (ELX, VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in participants with cystic fibrosis (CF).

Detailed description:

Arms: arm 1: Participants greater than or equal to (≥) 6 years and less than (\<) 12 years of age and weighing \<30 kilograms (kg) received ELX (elexacaftor) 100 milligram (mg) once daily (qd) /TEZ (tezacaftor) 50 mg qd/IVA (ivacaftor) 75 mg every 12 hours (q12h) and those weighing (≥) 30 kg received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg in the treatment period for up to 192 weeks. Participants ≥12 years of age received ELX 200 mg qd/ TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for up to 192 weeks.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed-dose combination (FDC) tablet for oral administration intervention 2: Mono tablet for oral administration.

Protocol documents:
Prot_000.pdf: 
 
Page 1 of 59 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, Open-label Study Evaluating the 
Long-term Safety and Efficacy of VX-445/TEZ/IVA 
Combination Therapy in Subjects With Cystic 
Fibrosis Who Are 6 Years of Age and Older 
Vertex Study Number: VX19-445-107 
VX-445 IND Number: 132547 
EudraCT Number: 2019-001827-11  
Date of Protocol: 10 June 2021 (Version 2.0)  
Replaces Version 1.0, dated 07 June 2019 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


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Summary of Changes to the Protocol 
The previous version of this protocol (Version 1.0, 07 June 2019) was amended to create the 
current version (Version 2.0, 10 June 2021). The protocol history is provided below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 07 June 2019 
Original version 
Version 2.0, 10 June 2021 
Current version, updated to extend treatment period.  
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
Extended treatment from 96 weeks to 192 weeks (by adding Part B of 
96-weeks treatment duration) to evaluate the longer-term safety and 
efficacy of VX-445/TEZ/IVA 
Global; Section 2 (Synopsis: Study 
Duration, Study Design) and 
Sections 3, 8.2, 9.1, 9.1.1, 9.1.2, 
9.4.1, and 12 
Updated monitoring text to include flexibility for remote monitoring, as 
allowed by local regulations 
Section 13.4 
 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of 
VX-445/TEZ/IVA Combination Therapy in Subjects With Cystic Fibrosis Who 
Are 6 Years of Age and Older 
  
Brief Title 
Evaluation of Long-term Safety and Efficacy of VX-445 Combination Therapy in 
Subjects With Cystic Fibrosis Who Are 6 Years of Age and Older 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3, safety and efficacy  
 
 
Objectives 
Primary Objective 
To evaluate the long-term safety and tolerability of VX-445/tezacaftor 
(TEZ)/ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are 6 years of age 
and older  
Secondary Objective 
To evaluate the long-term efficacy and pharmacodynamics (PD) of 
VX-445/TEZ/IVA 
 
 
Endpoints 
 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, pulse oximetry, and ophthalmologic 
examinations  
Secondary Endpoints 
• 
Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) 
• 
Absolute change in sweat chloride (SwCl)  
• 
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain (RD) score  
• 
Absolute change in body mass index (BMI) and BMI-for-age z-score 
• 
Number of pulmonary exacerbations (PEx) and CF-related hospitalizations 
• 
Absolute change in lung clearance index2.5 (LCI2.5)  
• 
Absolute change in weight and weight-for-age z-score  
• 
Absolute change in height and height-for-age z-score  
Other Endpoints 
• 
Absolute change in fecal elastase-1 (FE-1) levels  
• 
Absolute change in serum levels of immunoreactive trypsinogen (IRT)  
 
 
Number of Subjects 
Subjects who participate in parent study VX18-445-106 Part B and meet 
eligibility criteria are eligible to enroll. Approximately 56 subjects are expected to 
enroll in this study. 
 
 


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Study Population 
Male and female subjects with CF who are 6 years of age and older who are 
homozygous for the F508del mutation or heterozygous for F508del and a minimal 
function mutation. 
 
 
Investigational Drug 
Study drug refers to VX-445/TEZ/IVA and IVA.  
Study drugs will be orally administered as 2 fixed-dose combination film-coated 
tablets (VX-445/TEZ/IVA) in the morning and as 1 film-coated tablet (IVA) in 
the evening.  
 
Active substance: VX-445/TEZ (VX-661)/IVA (VX-770) 
 
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator 
 
Strength:  
 
• 
100 mg VX-445/50 mg TEZ/75 mg IVA 
 
• 
50 mg VX-445/25 mg TEZ/37.5 mg IVA 
 
 
 
Active substance: IVA (VX-770) 
 
Activity: CFTR potentiator 
 
Strength:  
 
• 
150 mg IVA 
 
• 
75 mg IVA 
 
 
Study Duration 
For subjects who enroll in both Parts A and B, the total study duration is 
approximately 196 weeks from the Part A Day 1 Visit (96 weeks for the Part A 
Treatment Period, 96 weeks for the Part B Treatment Period, and 4 weeks for the 
Safety Follow-up Period).  
 
 
Study Design 
This is a Phase 3, 2-part, multicenter, open-label extension safety study for 
subjects who completed the Treatment Period in the parent study (VX18-445-106 
Part B) and meet eligibility criteria. The study design in shown in Figure 2-1. 
Subjects who complete Part A will have the opportunity to enroll in Part B for an 
additional 96 weeks. 
Figure 2-1 
Schematic of the Study Design 
 
IVA: ivacaftor; TEZ: tezacaftor 
Note: The parent study is VX18-445-106 Part B, a Phase 3 study investigating 
VX-445/TEZ/IVA in subjects 6 through 11 years of age. The figure is not drawn to 
scale. 
a 
Subjects whose Part B Day 1 Visit is on the same day or within 1 calendar day of the 
Part A Week 96 Visit do NOT have to repeat any Part B Day 1 assessments that were 
specified to be performed at the Part A Week 96 Visit. Subjects whose Part B Day 1 
Visit is more than 1 calendar day after the Part A Week 96 Visit must complete all 
assessments specified for the Part A Week 96 AND Part B Day 1 Visits.  


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All subjects will receive VX-445/TEZ/IVA at weight-appropriate dosage levels 
for 96 weeks in Part A. In Part B, subjects will receive VX-445/TEZ/IVA at 
age- and weight-appropriate dosage levels for 96 weeks (Table 2-1).  
Table 2-1 
Treatment Period Dosages 
Subject Weight 
VX-445 Dosage 
TEZ Dosage 
IVA Dosage 
Part A, subjects ≥6 years of age 
≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
<30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B, subjects ≥6 to <12 years of age 
≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
<30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B, subjects ≥12 years of age 
All weights 
200 mg qd 
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
 
 
 
Assessments 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, 
ophthalmologic examinations, and physical examinations 
Efficacy and PD: spirometry, SwCl, CFQ-R, weight, height, multiple breath 
washout, and documentation of other events related to outcome (e.g., PEx, 
CF-related hospitalizations) 
Other Assessments:  
FE-1 and IRT will be measured to assess exocrine pancreatic function.  
Blood samples for blood biomarker analysis will be collected at select study visits 
for potential exploratory evaluation of correlations between blood biomarkers 
with PD, treatment benefit, and AEs. 
 
 
Statistical Analyses 
The primary objective of the study is the evaluation of the long-term safety and 
tolerability of VX-445/TEZ/IVA. The safety endpoints of long-term treatment 
include AEs, clinical laboratory values, ECGs, vital signs, pulse oximetry, and 
ophthalmologic examinations from the first dose of study drug in this study, for 
subjects who receive at least 1 dose of study drug in this long-term safety study. 
The safety analysis will be descriptive. 
The secondary objective of the study is the evaluation of long-term efficacy and 
PD of VX-445/TEZ/IVA, as assessed by spirometry, SwCl, CFQ-R, PEx and 
CF-related hospitalizations, BMI, height, weight (and related z-scores), and 
LCI2.5. Methods of efficacy analyses will be similar to those used in the parent 
study unless otherwise specified. 
 
 
Interim Analyses 
Interim analyses may take place at any time at the discretion of the sponsor. 
 
 
IDMC Reviews 
An independent data monitoring committee (IDMC) will conduct regular safety 
reviews of study data as outlined in the IDMC charter. 


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3 
SCHEDULE OF ASSESSMENTS 
Table 3-1 and Table 3-2 provide the schedules of assessments. All visits are to be scheduled 
relative to the Day 1 Visit in each Part. 
The Cystic Fibrosis Questionnaire-Revised (CFQ-R) must be completed before any other 
assessment (except informed consent form [ICF] signing) at relevant clinic visits. Multiple 
breath washout (MBW) assessments should be performed before spirometry, and ECG should be 
performed before any assessments that may affect heart rate (such as blood draws). Remaining 
assessments may be performed in any order when more than 1 assessment is required at a 
particular time point. All assessments will be performed before study drug dosing 
(Section 9.6.1), unless noted otherwise. 
 


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Table 3-1 
Study VX19-445-107: Part A Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Part A Treatment Period (96 weeks) 
Part A 
ETT 
Visitb 
Part A Safety 
Follow-up Visitc 
(28 ± 7 Days 
After Last Dose 
of Study Drug) 
Comments 
Day 1d 
Weeks 8, 16, 
24, 36 
(± 5 Days) 
Weeks 4, 12, 20, 28, 32, 
40, 44, 52, 56, 64, 68, 76, 
80, 88, 92 (± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84 
(± 5 Days) 
Week 96e 
(± 5 Days) 
Clinic visit 
X 
X 
 
X 
X 
X 
X 
X 
 
Telephone contact 
 
 
X 
 
 
 
 
 
When telephone contact takes the 
place of a clinic visit, a urine 
pregnancy test will be performed 
with a home kit provided by the 
study site (Section 11.5.2). 
Informed consent 
and assent  
X 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
confirmation 
X 
 
 
 
 
 
 
 
See Section 8 for details. 
CFQ-R 
X 
Weeks 8, 24 
 
X 
Week 72 
X 
X 
X 
To be completed before any other 
assessments scheduled at relevant 
visits (Section 11.3.5). 
Ophthalmologic 
examination 
 
 
 
X 
 
X 
X 
 
Subjects will have an ophthalmologic 
examination at Week 48 and at 
Week 96 (Section 11.5.5). In 
addition, an ophthalmologic 
examination will be performed at the 
ETT Visit for subjects who 
discontinue study drug if the subject 
has received at least 12 weeks of 
study drug since their last study 
ophthalmologic examination. 
Full physical 
examination 
X 
 
 
 
 
X 
X 
 
Symptom-directed physical 
examinations will be performed at 
any time if deemed necessary by the 
investigator or healthcare provider 
(Section 11.5.3). 
Weight, height, and 
BMI 
X 
X 
 
X 
X 
X 
X 
X 
Weight and height measured with 
shoes off (Section 11.3.4). 
 
a 
All assessments will be performed before study drug dosing unless noted otherwise. 
b 
If a subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to discontinue treatment (Section 9.1.3).  
c 
The Safety Follow-up Visit is required for all subjects unless otherwise specified. If an ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit replaces the Safety 
Follow-up Visit (Section 9.1.2).  
d 
The Day 1 Visit should be on the same day as the last scheduled visit of the parent study (Section 9.1.1). Subjects whose Day 1 Visit is NOT within 1 day of the last scheduled visit of the parent study 
will repeat all Day 1 assessments. Subjects whose Day 1 Visit is within 1 day of the last scheduled visit of the parent study will NOT have to repeat any Day 1 assessments that were specified to be 
performed at the last scheduled visit in the parent study. 


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Table 3-1 
Study VX19-445-107: Part A Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Part A Treatment Period (96 weeks) 
Part A 
ETT 
Visitb 
Part A Safety 
Follow-up Visitc 
(28 ± 7 Days 
After Last Dose 
of Study Drug) 
Comments 
Day 1d 
Weeks 8, 16, 
24, 36 
(± 5 Days) 
Weeks 4, 12, 20, 28, 32, 
40, 44, 52, 56, 64, 68, 76, 
80, 88, 92 (± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84 
(± 5 Days) 
Week 96e 
(± 5 Days) 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
Performed after subject has been at 
rest (seated or supine) for at least 5 
minutes (Section 11.5.3). 
Pulse oximetry 
X 
X 
 
X 
X 
X 
X 
X 
Performed after subject has been at 
rest for at least 5 minutes 
(Section 11.5.3). 
Standard 12-lead 
ECG 
X 
Week 24 
 
X 
Week 72 
X 
X 
X 
Performed after subject has been at 
rest for at least 5 minutes 
(Section 11.5.4). 
Spirometry 
X 
X 
 
X 
X 
X 
X 
X 
Should be performed 
pre-bronchodilator at approximately 
the same time at each visit 
(Section 11.3.1). 
Sweat chloride  
X 
Week 24 
 
X 
Week 72 
X 
X 
 
At each time point, 2 samples will be 
collected (1 sample from each arm; 
Section 11.3.2). 
Pregnancy test (all 
female subjects) 
urine 
urine 
urine 
urine 
urine 
serum 
serum 
serum 
At telephone contact visits, a urine 
pregnancy test will be performed 
with a home kit provided by the 
study site (Section 11.5.2). 
Serum chemistry 
X 
X 
 
X 
X 
X 
X 
X 
Section 11.5.2 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
Section 11.5.2 
Coagulation 
X 
Week 24 
 
X 
Week 72 
X 
X 
X 
Section 11.5.2 
Urinalysis 
X 
 
 
X 
 
X 
X 
 
Section 11.5.2 
Multiple breath 
washout 
X 
Week 24  
 
X 
Week 72 
X 
X 
 
Performed in multiple replicates, 
pre-bronchodilator, and before the 
spirometry assessment 
(Section 11.3.3). 
Blood biomarker 
sample 
X 
 
 
X 
 
X 
X 
 
Section 11.4.2 
 
 
e 
Subjects whose Part B Day 1 Visit is on the same day or within 1 calendar day as the Part A Week 96 Visit do NOT have to repeat any Part B Day 1 assessments that were specified to be performed at 
the Part A Week 96 Visit. Subjects whose Part B Day 1 Visit is more than 1 calendar day after the Part A Week 96 Visit must complete all assessments specified for the Part A Week 96 AND Part B 
Day 1 Visits.  


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Table 3-1 
Study VX19-445-107: Part A Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Part A Treatment Period (96 weeks) 
Part A 
ETT 
Visitb 
Part A Safety 
Follow-up Visitc 
(28 ± 7 Days 
After Last Dose 
of Study Drug) 
Comments 
Day 1d 
Weeks 8, 16, 
24, 36 
(± 5 Days) 
Weeks 4, 12, 20, 28, 32, 
40, 44, 52, 56, 64, 68, 76, 
80, 88, 92 (± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84 
(± 5 Days) 
Week 96e 
(± 5 Days) 
FE-1 
X 
Week 24 
 
X 
 
X 
X 
 
Samples may be collected by the 
subject’s caregiver up to 24 hours 
before the study visit (e.g., at home). 
The sample may be collected pre- or 
postdose (Section 11.4.1). 
IRT 
X 
Week 24 
 
X 
Week 72 
X 
X 
 
Section 11.4.1 
Study drug dosing 
Day 1 through evening before Week 96 Visit 
 
 
 
Subjects on study drug interruption at 
the end of the parent study may not 
begin dosing until they meet the 
criteria in Section 9.8. Refer to 
Section 9.6.1 for study drug 
administration details.  
Study drug count 
 
X 
 
X 
X 
X 
X 
 
 
Other events related 
to outcome 
Continuous from signing of ICF through completion of study participation 
Includes PEx, administration of 
antibiotic therapy for sinopulmonary 
signs/symptoms, and hospitalizations 
for CF (Section 11.3.6). Completion 
of study participation is defined in 
Section 9.1.5.  
Medications review 
Continuous from signing of ICF through completion of study participation 
Completion of study participation is 
defined in Section 9.1.5.  
Treatment and 
procedures review 
Continuous from signing of ICF through completion of study participation 
Completion of study participation is 
defined in Section 9.1.5.  
AEs and SAEs 
Continuous from signing of ICF through completion of study participation 
Completion of study participation is 
defined in Section 9.1.5.  
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; ETT: Early Termination of Treatment; FE-1: fecal elastase-1; ICF: informed consent 
form; IRT: immunoreactive trypsinogen; PEx: pulmonary exacerbation; SAE: serious adverse event 
 
 


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Table 3-2 
Study VX19-445-107: Part B Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Part B Treatment Period (96 weeks) 
Part B 
ETT Visitb 
Part B Safety 
Follow-up Visitc 
(28 ± 7 Days 
After Last Dose 
of Study Drug) 
Comments 
Day 1d 
Weeks 4, 8, 16, 20, 28, 32, 
40, 44, 52, 56, 64, 68, 76, 80, 
88, 92 (± 5 Days) 
Weeks 12, 
36, 60, 84 
(± 5 Days) 
Weeks 24, 48, 
72 
(± 5 Days) 
Week 96 
(± 5 Days) 
 
Clinic visit 
X 
 
X 
X 
X 
X 
X 
 
Telephone contact 
 
X 
 
 
 
 
 
When telephone contact takes the 
place of a clinic visit, a urine 
pregnancy test will be performed with 
a home kit provided by the study site 
(Section 11.5.2). 
Part B Informed 
consent and assent  
X 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria confirmation 
X 
 
 
 
 
 
 
See Section 8 for details. 
CFQ-R 
X 
 
 
X 
X 
X 
X 
To be completed before any other 
assessments scheduled at relevant 
visits (Section 11.3.5). 
Ophthalmologic 
examination 
 
 
  
 
X 
X 
 
Subjects will have an ophthalmologic 
examination at Week 96 
(Section 11.5.5). In addition, an 
ophthalmologic examination will be 
performed at the ETT Visit for 
subjects who discontinue study drug if 
the subject has received at least 
12 weeks of study drug since their last 
study ophthalmologic examination. 
Full physical 
examination 
X 
 
 
 
X 
X 
 
Symptom-directed physical 
examinations will be performed at any 
time if deemed necessary by the 
investigator or healthcare provider 
(Section 11.5.3). 
Weight, height, and 
BMI 
X 
 
X 
X 
X 
X 
X 
Weight and height measured with 
shoes off (Section 11.3.4). 
Vital signs 
X 
 
X 
X 
X 
X 
X 
Performed after subject has been at 
rest (seated or supine) for at least 
5 minutes (Section 11.5.3). 
 
a 
All assessments will be performed before study drug dosing unless noted otherwise. 
b 
If a subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to discontinue treatment (Section 9.1.3).  
c 
The Safety Follow-up Visit is required for all subjects unless otherwise specified. If an ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit replaces the Safety 
Follow-up Visit (Section 9.1.2).  
d 
Subjects whose Part B Day 1 Visit is on the same day or within 1 calendar day as the Part A Week 96 Visit do NOT have to repeat any Part B Day 1 assessments that were specified to be performed at 
the Part A Week 96 Visit. Subjects whose Part B Day 1 Visit is more than 1 calendar day after the Part A Week 96 Visit must complete all assessments specified for the Part A Week 96 AND Part B 
Day 1 Visits. 


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Table 3-2 
Study VX19-445-107: Part B Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Part B Treatment Period (96 weeks) 
Part B 
ETT Visitb 
Part B Safety 
Follow-up Visitc 
(28 ± 7 Days 
After Last Dose 
of Study Drug) 
Comments 
Day 1d 
Weeks 4, 8, 16, 20, 28, 32, 
40, 44, 52, 56, 64, 68, 76, 80, 
88, 92 (± 5 Days) 
Weeks 12, 
36, 60, 84 
(± 5 Days) 
Weeks 24, 48, 
72 
(± 5 Days) 
Week 96 
(± 5 Days) 
 
Pulse oximetry 
X 
 
X 
X 
X 
X 
X 
Performed after subject has been at 
rest for at least 5 minutes 
(Section 11.5.3). 
Standard 12-lead ECG 
X 
 
 
X 
X 
X 
X 
Performed after subject has been at 
rest for at least 5 minutes 
(Section 11.5.4). 
Spirometry 
X 
 
X 
X 
X 
X 
X 
Should be performed 
pre-bronchodilator at approximately 
the same time at each visit 
(Section 11.3.1). 
Sweat chloride  
X 
 
 
X 
X 
X 
 
At each time point, 2 samples will be 
collected (1 sample from each arm; 
Section 11.3.2). 
Pregnancy test (all 
female subjects) 
urine 
urine 
urine 
urine 
serum 
serum 
serum 
At telephone contact visits, a urine 
pregnancy test will be performed with 
a home kit provided by the study site 
(Section 11.5.2). 
Serum chemistry 
X 
 
X 
X 
X 
X 
X 
Section 11.5.2 
Hematology 
X 
 
X 
X 
X 
X 
X 
Section 11.5.2 
Coagulation 
X 
 
 
X 
X 
X 
X 
Section 11.5.2 
Urinalysis 
X 
 
 
Week 48 
X 
X 
 
Section 11.5.2 
Multiple breath 
washout 
X 
 
 
X 
X 
X 
 
Performed in multiple replicates, 
pre-bronchodilator, and before the 
spirometry assessment 
(Section 11.3.3). 
Blood biomarker 
sample 
X 
 
 
Week 48 
X 
X 
 
Section 11.4.2 
 
FE-1 
X 
 
 
Week 48 
X 
X 
 
Samples may be collected by the 
subject’s caregiver up to 24 hours 
before the study visit (e.g., at home). 
The sample may be collected pre- or 
postdose (Section 11.4.1). 
IRT 
X 
 
 
X 
X 
X 
 
Section 11.4.1 


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Table 3-2 
Study VX19-445-107: Part B Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Part B Treatment Period (96 weeks) 
Part B 
ETT Visitb 
Part B Safety 
Follow-up Visitc 
(28 ± 7 Days 
After Last Dose 
of Study Drug) 
Comments 
Day 1d 
Weeks 4, 8, 16, 20, 28, 32, 
40, 44, 52, 56, 64, 68, 76, 80, 
88, 92 (± 5 Days) 
Weeks 12, 
36, 60, 84 
(± 5 Days) 
Weeks 24, 48, 
72 
(± 5 Days) 
Week 96 
(± 5 Days) 
 
Study drug dosing 
Day 1 through evening before Week 96 Visit 
 
 
 
Subjects on study drug interruption at 
the end of the parent study may not 
begin dosing until they meet the 
criteria in Section 9.8. Refer to Section 
9.6.1 for study drug administration 
details.  
Study drug count 
 
 
X 
X 
X 
X 
 
 
Other events related to 
outcome 
Continuous from signing of ICF through completion of study participation 
Includes PEx, administration of 
antibiotic therapy for sinopulmonary 
signs/symptoms, and hospitalizations 
for CF (Section 11.3.6). Completion of 
study participation is defined in 
Section 9.1.5.  
Medications review 
Continuous from signing of ICF through completion of study participation 
Completion of study participation is 
defined in Section 9.1.5.  
Treatment and 
procedures review 
Continuous from signing of ICF through completion of study participation 
Completion of study participation is 
defined in Section 9.1.5.  
AEs and SAEs 
Continuous from signing of ICF through completion of study participation 
Completion of study participation is 
defined in Section 9.1.5.  
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; ETT: Early Termination of Treatment; FE-1: fecal elastase-1; ICF: informed consent 
form; IRT: immunoreactive trypsinogen; PEx: pulmonary exacerbation; SAE: serious adverse event 


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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 ................................................................................................................. 13 
List of Tables............................................................................................................................ 16 
List of Figures .......................................................................................................................... 16 
List of Abbreviations................................................................................................................ 17 
5 
Introduction.......................................................................................................................... 19 
5.1 
Background ..................................................................................................................... 19 
5.2 
Study Rationale .............................................................................................................. 20 
6 
Study Objectives .................................................................................................................. 20 
6.1 
Primary Objective ........................................................................................................... 20 
6.2 
Secondary Objective ....................................................................................................... 20 
7 
Study Endpoints ................................................................................................................... 20 
7.1 
Primary Endpoint ............................................................................................................ 20 
7.2 
Secondary Endpoints ...................................................................................................... 20 
7.3 
Other Endpoints .............................................................................................................. 20 
8 
Study Population .................................................................................................................. 20 
8.1 
Part A .............................................................................................................................. 21 
8.1.1 
Inclusion Criteria .................................................................................................... 21 
8.1.2 
Exclusion Criteria ................................................................................................... 21 
8.2 
Part B .............................................................................................................................. 21 
8.2.1 
Inclusion Criteria .................................................................................................... 21 
8.2.2 
Exclusion Criteria ................................................................................................... 22 
9 
Study Implementation ......................................................................................................... 22 
9.1 
Study Design .................................................................................................................. 22 
9.1.1 
Treatment Period .................................................................................................... 24 
9.1.2 
Safety Follow-up .................................................................................................... 25 
9.1.3 
Early Termination of Treatment ............................................................................. 25 
9.1.4 
Lost to Follow-up ................................................................................................... 25 
9.1.5 
Completion of Study Participation ......................................................................... 25 
9.1.6 
Independent Data Monitoring Committee .............................................................. 26 
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 
Rationale for Study Assessments ........................................................................... 26 
9.4 
Study Restrictions ........................................................................................................... 27 
9.4.1 
Prohibited Medications ........................................................................................... 27 
9.5 
Prior and Concomitant Medications ............................................................................... 27 
9.6 
Administration ................................................................................................................ 28 
9.6.1 
Dosing ..................................................................................................................... 28 
9.6.2 
Missed Doses .......................................................................................................... 29 


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9.7 
Dose Modification for Toxicity ...................................................................................... 29 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 29 
9.8.1 
Liver Function Tests ............................................................................................... 29 
9.8.2 
Rash ........................................................................................................................ 30 
9.9 
Removal of Subjects ....................................................................................................... 31 
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 ....................................................................................................... 32 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 32 
10.6 Compliance ..................................................................................................................... 32 
10.7 Blinding and Unblinding ................................................................................................ 32 
11 Assessments .......................................................................................................................... 33 
11.1 Subject and Disease Characteristics ............................................................................... 33 
11.2 Pharmacokinetics ............................................................................................................ 33 
11.3 Efficacy and Pharmacodynamics ................................................................................... 33 
11.3.1 
Spirometry .............................................................................................................. 33 
11.3.2 
Sweat Chloride ....................................................................................................... 34 
11.3.3 
Multiple Breath Washout........................................................................................ 34 
11.3.4 
Height and Weight .................................................................................................. 34 
11.3.5 
Cystic Fibrosis Questionnaire-Revised .................................................................. 34 
11.3.6 
Other Events Related to Outcome .......................................................................... 35 
11.3.6.1 Antibiotic Therapy for Sinopulmonary Sign/Symptoms ................................. 35 
11.3.6.2 Hospitalization for CF ...................................................................................... 35 
11.4 Other Assessments .......................................................................................................... 35 
11.4.1 
FE-1 and IRT .......................................................................................................... 35 
11.4.2 
Blood Biomarkers ................................................................................................... 36 
11.5 Safety .............................................................................................................................. 36 
11.5.1 
Adverse Events ....................................................................................................... 36 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 36 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 38 
11.5.4 
Electrocardiograms ................................................................................................. 38 
11.5.5 
Ophthalmologic Examination ................................................................................. 38 
11.5.6 
Contraception and Pregnancy ................................................................................. 39 
11.5.6.1 Contraception ................................................................................................... 39 
11.5.6.2 Pregnancy ......................................................................................................... 40 
12 Statistical and Analytical Plans .......................................................................................... 41 
12.1 Sample Size .................................................................................................................... 41 
12.2 Analysis Sets .................................................................................................................. 41 
12.3 Statistical Analysis ......................................................................................................... 41 
12.3.1 
General Considerations ........................................................................................... 41 
12.3.2 
Background Characteristics .................................................................................... 42 
12.3.2.1 Subject Disposition .......................................................................................... 42 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 42 


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12.3.2.3 Prior and Concomitant Medications................................................................. 43 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 43 
12.3.2.5 Important Protocol Deviations ......................................................................... 43 
12.3.3 
Efficacy and Pharmacodynamic Analyses ............................................................. 43 
12.3.3.1 Analysis of Primary Endpoint .......................................................................... 44 
12.3.3.2 Analysis of Secondary Efficacy and Pharmacodynamic Endpoints ................ 44 
12.3.3.3 Multiplicity Adjustment ................................................................................... 44 
12.3.4 
Safety Analysis ....................................................................................................... 44 
12.3.4.1 Adverse Events................................................................................................. 45 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 46 
12.3.4.3 Electrocardiogram ............................................................................................ 46 
12.3.4.4 Vital Signs ........................................................................................................ 46 
12.3.4.5 Pulse Oximetry ................................................................................................. 46 
12.3.4.6 Physical Examination ....................................................................................... 47 
12.3.4.7 Other Safety Analyses ...................................................................................... 47 
12.3.5 
Other Analyses ....................................................................................................... 47 
12.3.6 
Interim and IDMC Analyses ................................................................................... 47 
12.3.6.1 Interim Analysis ............................................................................................... 47 
12.3.6.2 IDMC Analysis ................................................................................................ 47 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 47 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 47 
13.1.1 
Adverse Events ....................................................................................................... 47 
13.1.1.1 Definition of an Adverse Event........................................................................ 47 
13.1.1.2 Clinically Significant Assessments .................................................................. 47 
13.1.1.3 Documentation of Adverse Events................................................................... 48 
13.1.1.4 Adverse Event Severity .................................................................................... 48 
13.1.1.5 Adverse Event Causality .................................................................................. 49 
13.1.1.6 Study Drug Action Taken ................................................................................ 49 
13.1.1.7 Adverse Event Outcome .................................................................................. 50 
13.1.1.8 Treatment Given............................................................................................... 50 
13.1.2 
Serious Adverse Events .......................................................................................... 50 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 50 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 51 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 51 
13.2 Administrative Requirements ......................................................................................... 52 
13.2.1 
Ethical Considerations ............................................................................................ 52 
13.2.2 
Subject Information and Informed Consent ........................................................... 52 
13.2.3 
Investigator Compliance ......................................................................................... 52 
13.2.4 
Access to Records ................................................................................................... 52 
13.2.5 
Subject Privacy ....................................................................................................... 52 
13.2.6 
Record Retention .................................................................................................... 53 
13.2.7 
Study Termination .................................................................................................. 53 
13.2.8 
End of Study ........................................................................................................... 53 
13.3 Data Quality Assurance .................................................................................................. 54 
13.4 Monitoring ...................................................................................................................... 54 


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13.5 Electronic Data Capture ................................................................................................. 54 
13.6 Confidentiality and Disclosure ....................................................................................... 54 
13.7 Publications and Clinical Study Report .......................................................................... 55 
13.7.1 
Publication of Study Results ................................................................................... 55 
13.7.2 
Clinical Study Report ............................................................................................. 55 
14 References ............................................................................................................................. 56 
15 Protocol Signature Pages .................................................................................................... 58 
15.1 Sponsor Signature Page .................................................................................................. 58 
15.2 Investigator Signature Page ............................................................................................ 59 
 
List of Tables 
Table 2-1 
Treatment Period Dosages ...................................................................................... 5 
Table 3-1 
Study VX19-445-107: Part A Treatment Period and Safety Follow-up Visit ........ 7 
Table 3-2 
Study VX19-445-107: Part B Treatment Period and Safety Follow-up Visit ...... 10 
Table 9-1 
Treatment Period Dosages .................................................................................... 23 
Table 9-2 
Prohibited Medications ......................................................................................... 27 
Table 10-1 
Study Drug: Dosing Form/Route/Strength ........................................................... 32 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 37 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 40 
Table 13-1 
Grading of AE Severity ........................................................................................ 49 
Table 13-2 
Classifications for AE Causality ........................................................................... 49 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 49 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 50 
List of Figures 
Figure 2-1 
Schematic of the Study Design ............................................................................... 4 
Figure 9-1 
Schematic of the Study Design ............................................................................. 23 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ETT 
Early Termination of Treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FE-1 
fecal elastase-1 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial (cells) 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IND 
Investigational New Drug (application) (US) 
IPD 
important protocol deviation 
IRB 
institutional review board 
IRT 
immunoreactive trypsinogen 
IV 
intravenous 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LCI 
lung clearance index 
LCI2.5 
number of lung turnovers required to reduce the end tidal inert gas concentration to 
1/40th of its starting value 


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Abbreviation 
Definition 
LUM 
lumacaftor 
max 
maximum value 
MBW 
multiple-breath washout 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
number of subjects 
OL-FAS 
Open-label Full Analysis Set 
OL-SS 
Open-label Safety Set 
PD 
pharmacodynamics 
PE 
physical examination 
PEx 
pulmonary exacerbation 
P-gp 
P-glycoprotein 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 
qd 
once daily 
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 
RD 
respiratory domain 
RNA 
ribonucleic acid 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious morbidities and 
frequent premature mortality. CF affects more than 70,000 individuals worldwide1 
(approximately 30,000 in the US2 and 45,000 in the EU3). Based on its prevalence, CF qualifies 
as an orphan disease.4, 5 
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.6 CFTR is an ion channel that regulates the flow of chloride and other ions across 
epithelia in various tissues, including the lungs, pancreas and other gastrointestinal organs, and 
sweat glands.7 Decreased CFTR quantity or function results in the failure to regulate chloride 
transport in these tissues leading to the multisystem pathology associated with CF.8 In the lungs, 
obstruction of airways with thick mucus, establishment of a chronic bacterial infection in the 
airways, and damaging inflammatory responses are all thought to play a role in causing 
irreversible structural changes in the lungs, leading to respiratory failure. Progressive loss of lung 
function is the leading cause of mortality.9  
The most common disease-causing CFTR mutation is F508del, which accounts for 
approximately 70% of the identified alleles in people with CF.10 Approximately 40% to 45% of 
people with CF are homozygous for F508del (F/F), and approximately 85% have at least 
1 F508del allele.2, 3 
Based on the understanding of the molecular defects caused by CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. Correctors facilitate 
the cellular processing and trafficking to increase the quantity of CFTR at the cell surface. 
Potentiators increase the channel open probability (channel gating activity) of the CFTR protein 
delivered to the cell surface to enhance ion transport. With differing mechanisms of action, a 
combination of correctors and potentiators increases F508del CFTR-mediated chloride transport 
more than either type of modulator alone. 
The therapeutic activity of CFTR modulators has been established with products developed by 
Vertex Pharmaceuticals Incorporated and approved for the treatment of CF: ivacaftor (IVA) 
monotherapy (Kalydeco), lumacaftor (LUM)/IVA (Orkambi), and tezacaftor (TEZ)/IVA 
(Symdeko, Symkevi). 
VX-445 is a next-generation CFTR corrector. In vitro, the triple combination (TC) of VX-445, 
TEZ, and IVA (VX-445/TEZ/IVA) increased CFTR chloride transport more than any of the dual 
combinations (VX-445/TEZ, VX-445/IVA, and TEZ/IVA) or individual components (VX-445, 
TEZ, and IVA) when added to human bronchial epithelial (HBE) cells derived from 2 groups of 
CF patients: those heterozygous for F508del with a second CFTR allele carrying a minimal 
function (MF) mutation that is not responsive to TEZ, IVA, and TEZ/IVA (F/MF genotypes); 
and those homozygous for F508del (F/F genotypes). 
Additional information about VX-445/TEZ/IVA can be found in the Investigator’s Brochure.  


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5.2 
Study Rationale 
This study will provide data on the long-term safety, efficacy, and durability of 
VX-445/TEZ/IVA in subjects with CF who are 6 years of age and older and who are 
homozygous or heterozygous for the F508del mutation. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the long-term safety and tolerability of VX-445/TEZ/IVA in subjects with CF who 
are 6 years of age and older  
6.2 
Secondary Objective 
To evaluate the long-term efficacy and pharmacodynamics (PD) of VX-445/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
ECGs, vital signs, pulse oximetry, and ophthalmologic examinations 
7.2 
Secondary Endpoints 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
Absolute change in sweat chloride (SwCl)  
Absolute change in CFQ-R respiratory domain (RD) score  
Absolute change in body mass index (BMI) and BMI-for-age z-score 
Number of pulmonary exacerbations (PEx) and CF-related hospitalizations 
Absolute change in lung clearance index2.5 (LCI2.5)  
Absolute change in weight and weight-for-age z-score  
Absolute change in height and height-for-age z-score  
7.3 
Other Endpoints 
Absolute change in fecal elastase-1 (FE-1) levels  
Absolute change in serum levels of immunoreactive trypsinogen (IRT) 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled in Part A and Part B. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
In the criteria below, “parent study” is defined as VX18-445-106 Part B, a Phase 3 study 
investigating VX-445/TEZ/IVA in subjects 6 years of age and older. 


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8.1 
Part A 
8.1.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
ICF, and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Did not withdraw consent from the parent study.  
4. Meets at least 1 of the following criteria: 
• Completed study drug treatment in the parent study, or 
• Had study drug interruption(s) in the parent study, but did not permanently discontinue 
study drug, and completed study visits up to the last scheduled visit of the Treatment 
Period of the parent study. 
5. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.1.2 
Exclusion Criteria 
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject. 
2. Pregnant or breast-feeding females. Female subjects must have a negative pregnancy test at 
the Part A Day 1 Visit before receiving the first dose of study drug. 
3. History of drug intolerance in the parent study that would pose an additional risk to the 
subject in the opinion of the investigator (e.g., subjects with a history of allergy or 
hypersensitivity to the study drug). 
4. Current participation in an investigational drug study other than the parent study, or the 
current study. Participation in a noninterventional study and screening for another Vertex 
study is permitted.  
8.2 
Part B 
8.2.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
ICF, and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Did not withdraw consent in Part A.  
4. Meets at least 1 of the following criteria: 
• Completed study drug treatment in Part A, or 
• Had study drug interruption(s) in Part A, but did not permanently discontinue study drug, 
and completed study visits up to the last scheduled visit of the Treatment Period of 
Part A.  


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5. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2.2 
Exclusion Criteria 
5. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject. 
6. Pregnant or breast-feeding females. Female subjects must have a negative pregnancy test at 
the Part B Day 1 Visit before receiving the first dose of study drug. 
7. History of drug intolerance in the parent study or in Part A of this study that would pose an 
additional risk to the subject in the opinion of the investigator (e.g., subjects with a history 
of allergy or hypersensitivity to the study drug). 
8. Current participation in an investigational drug study other than the parent study, or the 
current study. Participation in a noninterventional study and screening for another Vertex 
study is permitted.  
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, 2-part, multicenter, open-label extension study for subjects who completed the 
Treatment Period in the parent study (VX18-445-106 Part B) and meet eligibility criteria. The 
study design is shown in Figure 9-1. 
Subjects who complete Part A will have the opportunity to enroll in Part B for an additional 
96 weeks.  
Study visits and assessments to be conducted are shown in Table 3-1 and Table 3-2. All visits 
will occur within the windows specified. 


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Figure 9-1 
Schematic of the Study Design 
 
IVA: ivacaftor; TEZ: tezacaftor  
Note: The parent study is VX18-445-106 Part B, a Phase 3 study investigating VX-445/TEZ/IVA in subjects 
6 through 11 years of age. The figure is not drawn to scale.  
a 
Subjects whose Part B Day 1 Visit is on the same day or within 1 calendar day of the Part A Week 96 Visit 
do NOT have to repeat any Part B Day 1 assessments that were specified to be performed at the Part A Week 
96 Visit. Subjects whose Part B Day 1 Visit is more than 1 calendar day after the Part A Week 96 Visit must 
complete all assessments specified for the Part A Week 96 AND Part B Day 1 Visits. 
All subjects will receive VX-445/TEZ/IVA at the weight-appropriate dosage levels for 96 weeks 
in Part A. In Part B, subjects will receive VX-445/TEZ/IVA at age- and weight-appropriate 
dosage levels for 96 weeks (Table 9-1).  
Table 9-1 
Treatment Period Dosages 
Subject Weight 
VX-445 Dosage 
TEZ Dosage 
IVA Dosage 
Part A, subjects ≥6 years of age 
≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
<30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B, subjects ≥6 to <12 years of age 
≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
<30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B, subjects ≥12 years of age 
All weights 
200 mg qd 
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor  
Note: Study drug administration is described in Section 9.6. 
Part A:  
Subjects weighing ≥30 kg at the Part A Day 1 Visit will receive 200 mg VX-445 once daily 
(qd)/100 mg TEZ qd/150 mg IVA every 12 hours (q12h) for the duration of the study. Subjects 
weighing <30 kg at the Part A Day 1 Visit will receive 100 mg VX-445 qd/50 mg TEZ qd/75 mg 
IVA q12h. If a subject enters the current study weighing <30 kg and subsequently weighs ≥30 kg 
at 2 consecutive clinic visits, the dose will be adjusted to the higher dose of 200 mg VX-445 
qd/100 mg TEZ qd/150 mg IVA q12h for the remainder of the study, starting with the second 
visit where subject’s weight is ≥30 kg.  
Part A Treatment Period 
VX-445/TEZ/IVA 
Part A Safety 
Follow-up 
Parent 
Study 
Part A Week 96
a 
Part A 
Day 1 
Part B Treatment Period 
VX-445/TEZ/IVA 
Part B Safety 
Follow-up 
Part B Week 96 
Part B Day 1
a 


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Part B:  
In Part B, subjects will receive 200 mg VX-445 qd/100 mg TEZ qd/150 mg IVA q12h if they 
meet any of the following criteria:  
• Subject is ≥12 years of age 
• Subject received 200 mg VX-445 qd/100 mg TEZ qd/150 mg IVA q12h in Part A 
• Subject is ≥30 kg on Part B Day 1 
All other subjects <12 years of age and <30 kg will receive 100 mg VX-445 qd/50 mg TEZ 
qd/75 mg IVA q12h until either:  
• The subject weighs ≥30 kg at 2 consecutive clinic visits in Part B, or 
• The subject turns 12 years of age 
Once either of the above criteria are met, the subject will receive 200 mg VX-445 qd/100 mg 
TEZ qd/150 mg IVA q12h for the remainder of the study.  
9.1.1 
Treatment Period 
Treatment Period assessments are listed in Table 3-1 and Table 3-2. 
Part A:  
Subjects will receive the first dose of study drug on Part A Day 1 after obtaining informed 
consent (and assent, when applicable) and confirming eligibility. Subjects who enroll in this 
study on a study drug interruption will NOT receive the first dose of study drug until they meet 
the resumption criteria in Section 9.8; before receiving study drug, subjects will repeat all Part A 
Day 1 assessments. 
Study drug administration details are provided in Section 9.6.  
Subjects whose Part A Day 1 Visit is NOT within 1 day of the last scheduled visit of the parent 
study will repeat all Part A Day 1 assessments. 
Subjects whose Part A Day 1 Visit is within 1 day of the last scheduled visit of the parent study 
will NOT have to repeat any Part A Day 1 assessments that were specified to be performed at the 
last scheduled visit in the parent study.  
Part B:  
For subjects who elect to enroll in Part B, the Part A Week 96 Visit will be the start of treatment 
in Part B (i.e., Part B Day 1).  
Subjects whose Part B Day 1 Visit is on the same day or within 1 calendar day of the Part A 
Week 96 Visit do NOT have to repeat any Part B Day 1 assessments that were specified to be 
performed at the Part A Week 96 Visit. Subjects whose Part B Day 1 Visit is more than 
1 calendar day after the Part A Week 96 Visit must complete all assessments specified for the 
Part A Week 96 AND Part B Day 1 Visits. 


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9.1.2 
Safety Follow-up 
In Parts A and B, the Safety Follow-up Visit is scheduled to occur 28 (± 7) days after the last 
dose of study drug. The Safety Follow-up Visit assessments are listed in Table 3-1 and 
Table 3-2.  
The Safety Follow-up Visit is required for all subjects. However, subjects will complete the 
respective Part A or Part B Week 96 Visit and will not have a Safety Follow-up Visit if the 
subject transitions within 28 days of the last dose of study drug to one of the following:  
• A commercially available Vertex CFTR modulator regimen, 
• Managed-access-program-supplied Vertex CFTR modulator regimen, 
• Or, to another Part of the current study or another qualified Vertex study. 
If the transition occurs before the Week 96 Visit, then subjects will complete the Early 
Termination of Treatment (ETT) Visit. In these cases, the Week 96 Visit or the ETT Visit, 
whichever is applicable, will replace the Safety Follow-up Visit.  
For subjects who complete an ETT Visit 3 weeks or later following the last dose of study drug, 
the ETT Visit will replace the Safety Follow-up Visit (Section 9.1.3). 
9.1.3 
Early Termination of Treatment 
If a subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as 
soon as possible after the decision to discontinue treatment. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent. 
9.1.4 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.5 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as: the Safety Follow-up 
Visit; or, in situations in which the ETT Visit or the Part A or B Week 96 Visit replaces the 
Safety Follow-up Visit (Section 9.1.2), the ETT Visit or Part A or B Week 96 Visit. 
If subjects withdraw consent or assent, completion of study participation is defined as date of 
withdrawal of consent or assent, whichever is earlier (Section 9.9). 


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If subjects are lost to follow-up (Section 9.1.4), the date of completion of study participation will 
be defined as the date of last contact.  
The end of study is defined in Section 13.2.8. 
9.1.6 
Independent Data Monitoring Committee 
This study will be monitored by an independent data monitoring committee (IDMC), which will 
conduct periodic reviews of safety data from the study (Section 12.3.6.2). Procedural details of 
the IDMC structure and function, frequency of meetings, and data planned for review will be 
included in the IDMC charter. The IDMC charter will be finalized before the first subject is 
enrolled. 
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. Randomization is not required because all subjects will be treated 
identically in a single cohort. An interactive web response system (IWRS) will be used to 
dispense dosage based on subject weight and age.  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
This Phase 3 study will enroll subjects who completed the last treatment period visit in the parent 
study of VX-445/TEZ/IVA and meet eligibility criteria. Results from this study will provide 
information on the long-term safety and efficacy of TC treatment with VX-445/TEZ/IVA in 
subjects with CF who are 6 years of age and older and homozygous or heterozygous for the 
F508del mutation.  
9.3.2 
Study Drug Dose and Duration 
To evaluate long-term safety, tolerability, and efficacy, the study drug doses evaluated are the 
same as the doses evaluated in the parent study. Subjects will receive a study drug dose 
appropriate for their weight, as described in Section 9.1. 
The overall treatment duration of 96 weeks in each Part was used in open-label extension studies 
for previously approved CFTR modulators, and is considered sufficient for the evaluation of 
long-term safety and efficacy. 
9.3.3 
Rationale for Study Assessments 
The safety, efficacy, and PD 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. Baseline and follow-up ophthalmologic examinations are recommended for 
monitoring of pediatric patients treated with regimens containing IVA, and have been included in 
the standard safety assessments. 
Obstruction of airways with thick mucus, chronic bacterial infection of the airways, and the 
inflammatory response all play a role in causing lung damage in CF. Therefore, assessment of 
inflammatory mediators such as IRT and other biomarkers is included. 
LCI is a measure of ventilation inhomogeneity that is based on tidal breathing techniques that 
have been evaluated in patients as young as infants.11, 12 Studies have shown that LCI correlates 
with FEV1 in its ability to measure airway disease and can detect lung disease at an earlier stage 


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than spirometry.13, 14 Furthermore, data from Studies VX10-770-106 and VX14-809-109 in CF 
patients with an FEV1 >90% showed LCI to be a more sensitive outcome measure than FEV1.  
9.4 
Study Restrictions 
9.4.1 
Prohibited Medications 
Table 9-2 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medication will be provided in the Study Reference Manual. Guidance for concomitant 
medications is provided in Section 9.5. 
Table 9-2 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
Moderate and strong 
CYP3A inducers 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Part A 
Day 1 
None allowed 
through 
completion of 
study 
participation 
VX-445, TEZ, and IVA are metabolized 
extensively via CYP3A4. Therefore, use of 
moderate and strong inducers of CYP3A and 
moderate and strong inhibitors of CYP3A, 
which have the potential to alter the exposure 
of VX-445, TEZ, or IVA, will be prohibited. 
Moderate and strong 
CYP3A inhibitors 
(except 
ciprofloxacin)a 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Part A 
Day 1 
None allowed 
through 
completion of 
study 
participation 
CFTR modulators 
(investigational or 
approved), except for 
study drugs in the 
parent study and this 
study 
None allowed 
within 28 days or 
5 terminal half-
lives (whichever is 
longer) before the 
first dose of the 
study drug on 
Part A Day 1 
None allowed 
until after the 
last dose of 
study drug 
These agents may confound the results of this 
study. 
IVA: ivacaftor; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected in each subject’s source 
documentation for medications taken within the 56 days before the first dose of study drug in this 
study through completion of study participation, as defined in Section 9.1.5. 
• Subjects should remain on a stable treatment regimen for their CF through completion of 
study participation. Stable treatment regimen is defined as the current treatment regimen for 
CF that subjects have been following for at least 28 days before Part A Day 1. Subjects 
should not initiate long-term treatment with new medication from 28 days before the Part A 
Day 1 Visit through completion of study participation. Guidelines for stable treatment 
regimens for CF are as follows: 


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o Subjects who are taking inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who cycle onto and off of an inhaled antibiotic should continue on their prior 
schedule. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. 
• Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically, or 
up to 60 mg daily for up to 5 days. 
• VX-445 may inhibit OATP1B1 and OATP1B3, which may increase the exposure of 
medicinal products that are substrates for these transporters. Substrates such as statins, 
glyburide, nateglinide, and repaglinide should be used with caution.  
• IVA is a weak inhibitor of P-glycoprotein (P-gp). Administration of IVA may increase 
systemic exposure of medicinal products that are sensitive substrates of P-gp, which may 
increase or prolong their therapeutic effect and adverse reactions. Digoxin or other substrates 
of P-gp with a narrow therapeutic index, such as cyclosporine, everolimus, sirolimus, and 
tacrolimus, should be used with caution and appropriate monitoring.  
• IVA may inhibit CYP2C9; therefore, during coadministration with warfarin, additional 
monitoring of the international normalized ratio is recommended. Other medicinal products 
that are CYP2C9 substrates for which exposure may be increased include glimepiride and 
glipizide; these should be used with caution. 
• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator should have their spirometry assessments performed 
according to the guidelines provided in Section 11.3.1. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally. Additional information is provided in the Pharmacy 
Manual. 
Study drug should be administered with a fat-containing meal or snack, such as a standard “CF” 
meal or snack or a standard meal. 
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
2. Study drug will be administered as 2 fixed-dose combination VX-445/TEZ/IVA tablets in the 
morning and as 1 IVA tablet in the evening. For each subject, doses of study drug should be 
taken at approximately the same time (± 2 hours) each day. 
3. On days of scheduled visits, the morning dose of VX-445/TEZ/IVA will be administered at 
the site after predose assessments have been completed. A meal or snack will be provided by 
the site for the morning dose of VX-445/TEZ/IVA. 


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4. If a subject’s scheduled clinic visit is to occur in the afternoon, the following guidelines 
should be used: 
• If the dose in the clinic will be within 6 hours of the subject’s scheduled morning dose, 
the subject should withhold their morning dose of VX-445/TEZ/IVA and the morning 
dose of VX-445/TEZ/IVA will be administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
dose of VX-445/TEZ/IVA, the subject should take the morning dose of 
VX-445/TEZ/IVA at home. 
5. Subjects will be instructed to bring all used and unused materials associated with the study 
drug to the site; study drug will be dispensed at each visit, as appropriate. 
9.6.2 
Missed Doses 
If 6 hours or less have passed since the missed morning or evening dose, the subject should take 
the missed dose as soon as possible and continue on the original schedule.  
Morning dose: If more than 6 hours have passed since the missed morning dose, the subject 
should take the missed dose as soon as possible and should not take the evening dose. 
Evening dose: If more than 6 hours have passed since the missed evening dose, the subject 
should not take the missed dose. The next scheduled morning dose should be taken at the usual 
time. 
Morning and evening doses should not be taken at the same time. 
9.7 
Dose Modification for Toxicity 
Modifications of the study drug dose are prohibited. Should any unacceptable toxicity arise, 
individual subjects will be withdrawn from the study and dosing will cease. 
9.8 
Study Drug Interruption and Stopping Rules 
In subjects who have interrupted study drug for >72 hours for any reason, the investigator should 
resume study drug only after a thorough investigation of the cause for interruption. The 
investigator will evaluate the subject’s clinical stability and should consider resumption of study 
drug only after the subject is clinically stable and there is no comorbidity or condition that, in the 
opinion of the investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. 
The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. In subjects for whom 
study drug was previously interrupted, the medical monitor should be notified of any plan to 
discontinue study drug, before the discontinuation has occurred, if possible. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of alanine transaminase (ALT) or 
aspartate transaminase (AST) >3 × upper limit of normal (ULN) and total bilirubin >2 × ULN 
that are derived from centrally submitted samples. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 


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the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are 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. 
Study drug administration must be discontinued if the following criteria are met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, study drug administration may be resumed once 
transaminase levels return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified before resumption of study drug. 
Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology. 
9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher (Section 13.1.1.4), or 
a rash that is considered a serious adverse event (SAE). The investigator will notify the medical 
monitor of any rash that results in interruption of study drug, is Grade 3 or higher, or is an SAE. 
Investigators should consider additional evaluation including laboratory testing (e.g., complete 
blood count with differential, liver function tests), photographs of the rash, and dermatology 
consultation. The investigator may consider resumption of study drug if considered clinically 
appropriate. 


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9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons.  
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Meets any of the stopping (discontinuation) criteria (Section 9.8) 
• Becomes pregnant (Section 11.5.6.2) 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. 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 return all 
unused investigational product(s), request that the subject return for an ETT Visit and Safety 
Follow-up Visit, if applicable (see Section 9.1.2), and follow up with the subject regarding any 
unresolved AEs. 
If the subject withdraws consent or assent for the study, no further assessments will be 
performed. 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 compounds, and 
for other drugs and diagnostics, in publications and presentations, and for education purposes. If 
the subject withdraws from the study, the study data and samples collected will remain part of 
the study. A subject will not be able to request the withdrawal of his or her information from the 
study data. A subject may request destruction of the samples collected from him or her during 
the study as long as those samples can be identified as his or her 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 
Study drug refers to VX-445/TEZ/IVA and IVA. 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Study drug will be supplied as film-coated tablets (Table 10-1). 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 


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applicable regulatory requirements. Detailed instructions regarding the storage, handling, and 
dispensation of the study drug will be provided in the Pharmacy Manual. 
Table 10-1 
Study Drug: Dosing Form/Route/Strength 
Drug Name, Dosing Form, Route 
Tablet Strength 
(Subjects ≥12 Years 
or ≥30 kg) 
Tablet Strength 
(Subjects <12 Years 
and <30 kg) 
VX-445/TEZ/IVA, FDC tablet, oral 
 
 
VX-445 
100 mg 
50 mg  
TEZ 
50 mg 
25 mg 
IVA 
75 mg 
37.5 mg 
IVA, tablet, oral 
150 mg 
75 mg  
FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
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 subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. 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 or 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 subjects 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 of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study.   
10.7 
Blinding and Unblinding 
This will be an open-label study; however, subjects and their legally appointed and authorized 
representative (e.g., parent or legal guardian) should not be informed of their study-related 
spirometry and LCI, SwCl, FE-1, and IRT results until the study has been completed, regardless 
if the subject permanently discontinues treatment. In addition, the Vertex study team will not 


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have access to the spirometry, LCI, or SwCl results of the present study until the database lock of 
the parent study.  
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 and Table 3-2. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Select demographic and medical history will be derived from the parent study. 
11.2 
Pharmacokinetics 
Not applicable. 
11.3 
Efficacy and Pharmacodynamics 
11.3.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines15 and 
according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
At all visits, all spirometry assessments should be performed pre-bronchodilator. During the 
Treatment Periods, spirometry assessments must be performed before study drug dosing 
(Section 9.6.1) at approximately the same time at each visit. In the event that a subject forgets to 
withhold bronchodilator(s), spirometry should be performed according to the following: 
• If a subject’s Part A Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent 
visit, the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
• If, on Part A Day 1, the subject forgets to withhold his or her dose of bronchodilator, 
spirometry should be performed post-bronchodilator, and all subsequent spirometric 
measurements (according to the schedule of assessments) should be performed 
post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review.  
See Section 10.7 for information about access to spirometry results. 


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The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of Global Lung Function Initiative (GLI).16  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.3.2 
Sweat Chloride 
The SwCl test is a standard diagnostic tool for CF, serving as a biomarker of CFTR activity. 
Sweat samples will be sent to a central laboratory for testing and interpretation of results. 
Individual SwCl test results will not be disclosed to the study sites. Specific instructions for 
collection, handling, processing, and shipping of SwCl samples to the central laboratory will be 
provided separately. The SwCl test must be conducted predose relative to the morning dose of 
study drug during the Treatment Periods. At each time point, 2 samples will be collected, 
1 sample from each arm (left and right). 
See Section 10.7 for information about access to SwCl results. 
11.3.3 
Multiple Breath Washout 
The N2-MBW testing will be performed in multiple replicates for each visit and the final LCI 
value will be calculated from the technically acceptable washout replicates by a central reader. 
The final LCI value at each visit will be the value provided by the LCI vendor based on the 
replicates.  
At all visits, MBW tests should be performed “pre-bronchodilator” as described in 
Section 11.3.1. The MBW test should be performed before the spirometry assessment. See 
Section 10.7 for information about access to LCI results. 
Detailed MBW procedures will be supplied separately in a Study Reference Manual. 
11.3.4 
Height and Weight 
Height and weight will be measured with shoes off and before the dose of the study drug at each 
clinic visit during the Treatment Periods. 
11.3.5 
Cystic Fibrosis Questionnaire-Revised 
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF). 
Subjects/caregivers will be asked to complete the CFQ-R in their native language, if validated 
translations are available.17, 18 If there is no validated translation available in the subject’s native 
language, the subject will not complete the questionnaire. Copies of the CFQ-R used will be 
provided in the Study Reference Manual. Validated translations of the CFQ-R, if available, will 
be provided for participating centers with non-English-speaking populations.19, 20 
The CFQ-R will be completed before any other assessments are performed at that visit. 


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11.3.6 
Other Events Related to Outcome  
11.3.6.1 
Antibiotic Therapy for Sinopulmonary Sign/Symptoms 
New or changed antibiotic therapy (intravenous [IV], inhaled, or oral) for the following 
sinopulmonary signs/symptoms will be determined and documented at visits as indicated in 
Table 3-1 and Table 3-2: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
For this study, PEx is defined as a new or change in antibiotic therapy (IV, inhaled, or oral) 
for any 4 or more of the above signs/symptoms. This definition is based on the definition of a 
PEx used in previous clinical studies, including IVA clinical studies.21, 22  
It is recommended that the study drug not be interrupted during a PEx unless, in the opinion of 
the investigator, it would be in the best interest of the subject. 
11.3.6.2 
Hospitalization for CF 
Subjects will be queried about planned and unplanned hospitalizations lasting ≥24 hours that 
occurred during the study. The dates of hospitalizations and the reasons for hospitalizations will 
be documented. 
For any hospitalization (planned and unplanned), the procedures for safety reporting should also 
be followed. 
11.4 
Other Assessments 
These data will be used for internal exploratory purposes and may or may not be included in the 
clinical study report (CSR). Detailed procedures for the collection of blood samples will be 
provided in a separate document. 
11.4.1 
FE-1 and IRT 
Assessments of FE-1 and IRT will be conducted to assess exocrine pancreatic function. 


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Fecal samples for assessment of FE-1 will be collected at the study center during the study visit; 
alternatively samples may be collected by the subject’s caregiver up to 24 hours before the study 
visit (e.g., at home) and brought to the study visit. The sample may be collected pre- or postdose. 
See Section 10.7 for information about access to FE-1 and IRT results. 
11.4.2 
Blood Biomarkers 
Blood samples for blood biomarker analysis will be collected and banked for potential 
exploratory evaluation of correlations between blood biomarkers (e.g., proteins, peptides, lipids, 
vitamins, endogenous metabolites, and RNA) with PD, treatment benefit, and AEs.  
Specific instructions for the collection, processing, storage, and shipment of blood biomarker 
samples will be provided in the Laboratory Manual. 
11.5 
Safety 
Safety evaluations will include reporting of AEs, clinical laboratory assessments, PEs, clinical 
evaluation of vital signs, pulse oximetry, standard 12-lead ECGs, and ophthalmologic 
examinations. 
11.5.1 
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. Electronic AE case report form (CRF) completion 
guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory with the exception of urine 
pregnancy tests, which will be analyzed locally. All blood samples will be collected while 
subjects are in a seated or supine position. Specific instructions for the collection, processing, 
and shipment of samples will be provided in a separate Laboratory Manual. Laboratory test 
results that are abnormal and considered clinically significant must be reported as AEs (see 
Section 13.1).  
The safety laboratory test panels are shown in Table 11-1. 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total and direct bilirubin 
Alkaline phosphatase 
Aspartate transaminase  
Alanine transaminase 
Amylase 
Lipase 
Gamma-glutamyl transferase 
Protein 
Albumin 
Creatine kinase 
Total cholesterol 
Lactate dehydrogenase  
Hemoglobin 
Erythrocytes 
Mean corpuscular volume 
Platelets 
Reticulocytes  
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
 
Leukocyte esterase 
Nitrite 
Urobilinogen  
Urine protein  
pH 
Urine blood 
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
Note: Haptoglobin may be analyzed if judged to be clinically appropriate by the investigator. 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and 
casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
Pregnancy (β-human chorionic gonadotropin) Tests for all Female Subjects: All female subjects 
must have a pregnancy test every 4 weeks. Serum pregnancy tests will be performed at the study 
site and analyzed at the central laboratory. Urine pregnancy tests will be performed and analyzed 
at the site or, at assessment time points when telephone contact takes the place of a clinic visit, at 
home by using a home kit provided by the study site. Results of a home urine pregnancy test will 
be reported to the site by telephone. Additional pregnancy tests may be required according to 
local regulations and/or requirements. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged by the investigator to be clinically appropriate.  
For the purposes of study conduct and unless noted otherwise, only laboratory tests done in the 
central laboratory may be used. Local laboratories may be used at the discretion of the local 
investigator for management of urgent medical issues. If a local laboratory test value is found to 
be abnormal and clinically significant, it will be verified by the central laboratory as soon as 
possible after the investigator becomes aware of the abnormal result. If it is not possible to send a 
timely specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value. 


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11.5.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at 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; respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. Any clinically significant abnormal findings in PEs will be reported as AEs. 
Weight, height, and BMI (derived) will also be assessed (Section 11.3.4). 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the seated or supine 
position. 
Arterial oxygen saturation by pulse oximetry will be assessed following at least a 5-minute rest 
and before study drug dosing. At visits when study drug is taken at the site, pulse oximetry will 
be collected before study drug dosing. 
11.5.4 
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. 
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 completion of study participation will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 
11.5.5 
Ophthalmologic Examination 
Ophthalmologic examinations do not need to be completed if there is documentation of bilateral 
lens removal for the subject. 


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All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
Ophthalmologic examinations are required at select study visits in the Treatment Periods (Table 
3-1 and Table 3-2). These examinations should be completed within 4 weeks of the relevant 
study visit. An ophthalmologic examination is also required at the ETT Visit for subjects whose 
cumulative VX-445/TEZ/IVA exposure (in the parent study and current study) is at least 
12 weeks since the last study ophthalmologic examination.  
Any clinically significant abnormal findings will be reported as AEs. 
11.5.6 
Contraception and Pregnancy 
The effects of VX-445 monotherapy or in TC with TEZ and IVA on conception, pregnancy, and 
lactation in humans are not known. VX-445, TEZ, and IVA did not show genotoxic potential in a 
standard battery of in vitro (Ames test, chromosomal aberration, or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies. Reproductive toxicology studies of 
VX-445, TEZ, and IVA have not shown teratogenicity in rats and rabbits. 
11.5.6.1 
Contraception 
Contraception requirement for a couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the date of informed consent through 90 days after the last dose of study 
drug. 
• If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 
• If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range for 
postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations) will be considered to be 
of childbearing potential. 
• Same-sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of consent (or 


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assent, when applicable), approximately 28 days before the first dose of study drug (unless 
otherwise noted), and until 90 days following the last dose of study drug. Additional 
contraception requirements may need to be followed according to local regulations and/or 
requirements. Acceptable methods of contraception are listed in Table 11-2. 
Table 11-2 
Acceptable Methods of Contraception 
 
Male Subjects and 
Their Female 
(Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, with 
a documented negative postvasectomy semen analysis 
for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
 
 
 Hormone-releasing 
Yes 
Yes 
 Non-hormone releasing 
Yes 
Yes 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 60 days 
before the first dose of study drug 
Yes 
 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing.  
Additional notes: 
• If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-2. 
• If over the course of the study the subject’s status changes and the subject does not meet the 
criteria for waiving the contraception requirements, the subject must begin following the 
contraceptive methods listed in Table 11-2.  
• Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
• Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug, with 
the exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 
11.5.6.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 


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If a subject, or the female partner of a male subject, becomes pregnant during study participation, 
study drug will be permanently discontinued immediately. The investigator will 1) notify the 
medical monitor and Vertex Global Patient Safety (GPS) within 24 hours of the site’s knowledge 
of the subject’s (or partner’s) pregnancy, and 2) send the Pregnancy Information Collection Form 
to Vertex GPS. Male subjects with female partners who become pregnant during the study must 
use a male condom to avoid exposure of a potential embryo or fetus to study drug via the seminal 
fluid.  
Provided informed consent is obtained, the subject or partner will be followed until the end of 
the pregnancy and the infant will be followed for 1 year after the birth. A separate ICF will be 
provided to explain these follow-up activities. Pregnancy itself does not constitute an AE.  
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP), which will be finalized before the 
clinical data lock for the study. 
12.1 
Sample Size 
The primary and secondary objectives of the study are the evaluation of the long-term safety, 
tolerability, and efficacy of VX-445/TEZ/IVA. This is an open-label study that will enroll 
subjects who complete study treatment in the parent study and meet eligibility criteria. 
Approximately 56 subjects are expected to enroll in this open-label study.  
12.2 
Analysis Sets 
The following analysis sets will be defined for Part A and Part B separately:  
The Open-label All Subjects Set for Part A or B is defined as all subjects who were enrolled 
(defined as subject having data in the corresponding clinical database) in the corresponding Part. 
This analysis set will be used for individual subject data listings and disposition summary tables 
unless otherwise specified. 
The Open-label Full Analysis Set (OL-FAS) for Part A or B is defined as all enrolled subjects 
who have received at least 1 dose of study drug in the corresponding Part. The OL-FAS will be 
used to summarize subject demographics and baseline characteristics and for all efficacy 
analyses unless otherwise specified. 
The Open-label Safety Set (OL-SS) for Part A or B is defined as all subjects who have received 
at least 1 dose of study drug in the corresponding Part. The OL-SS will be used for all safety 
analyses unless otherwise specified. 
12.3 
Statistical Analysis 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). The precision of the measurement for each continuous variable will be specified in the 
SAP. Unless otherwise specified, min and max values will be reported with the same precision as 
the units of the raw data. The mean, median, and SD will be reported to 1 additional decimal 


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place. Any values that require a transformation to standard units (metric or SI) will be converted 
with the appropriate precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
The baseline value, unless otherwise specified, will be the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
parent study. For assessments collected in replicates, the baseline will be defined as the average 
of non-missing values. 
Change (absolute change) from baseline will be calculated as post-baseline value – baseline 
value. 
The Efficacy Analysis Period for each Part will include the time from the first dose of study 
drug to the last scheduled efficacy visit in the corresponding Part, unless otherwise specified. 
The Treatment-emergent (TE) Period for each Part will include the time from the first dose of 
study drug to 28 days after the last dose of the study drug or to the date of completion of study 
participation in the corresponding Part (as defined in Section 9.1.5), whichever occurs first. 
Part A and Part B data will be analyzed separately, using the respective analysis set, efficacy 
analysis period, and TE period for each Part. For analysis of the number of PEx, events in the 
parent study and this study (Parts A and B, as applicable) may also be combined. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
Subject disposition will be summarized separately for each Part for the Open-label All Subjects 
Set. The number and percentage of subjects in the following categories will be summarized as 
appropriate: 
• Open-label All Subjects Set 
• Dosed (OL-SS) 
• Enrolled and dosed (OL-FAS) 
• Completed treatment 
• Prematurely discontinued treatment and the reasons for discontinuation 
• Completed study 
• Prematurely discontinued the study and the reasons for discontinuation 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized separately for each Part by 
descriptive summary statistics. Baseline characteristics will be the same as the parent study 
baseline characteristics. 
The following demographics and baseline characteristics will be summarized for the OL-FAS 
and will include (but are not limited to) sex, race, ethnicity, baseline age, baseline weight, 
baseline height, baseline BMI, baseline ppFEV1, baseline SwCl, and baseline CFQ-R RD score. 


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Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT) for the OL-FAS. 
12.3.2.3 
Prior and Concomitant Medications 
Medications will be coded using WHODrug and categorized as follows: 
• Prior medication: any medication that was administered within the 56 days before the first 
dose of study drug in each Part 
• Concomitant medication: medication continued or newly received during the TE Period in 
each Part 
• Post-treatment medication: medication continued or newly received after the TE Period in 
each Part 
A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and if it cannot be determined whether it was taken before initial dosing, 
concomitantly during the TE Period, or beyond the TE Period, it will be considered in all 
3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name based on the OL-FAS, separately for each Part. Post-treatment medications will be 
provided separately in an individual subject data listing. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure will be summarized separately for each Part based on the OL-SS, defined as 
the last day of study drug in each Part minus the first day of study drug in each Part plus 1, 
regardless of study drug interruption. 
Study drug compliance will be summarized based on the OL-FAS, and will be calculated as: 
100  [1 – (total number of days of study drug interruption in each Part) / (duration of study drug 
exposure in days in each Part)]. A study drug interruption on a given day is defined as an 
interruption of any study drug on that day. 
In addition, percentage of tablets taken will also be summarized based on the OL-FAS, and will 
be calculated as: 100  [(total number of tablets dispensed in each part) – (total number of tablets 
returned in each Part)] / (total number of tablets planned to be taken per day  duration of study 
drug exposure in days for each Part). 
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or wellbeing. The rules for identifying an IPD will be described in the SAP. 
All IPDs will be provided in an individual subject data listing, and summarized, as appropriate. 
12.3.3 
Efficacy and Pharmacodynamic Analyses 
The secondary objective of the study is the evaluation of the long-term efficacy and PD of 
VX-445/TEZ/IVA. 


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12.3.3.1 
Analysis of Primary Endpoint 
Not applicable. Efficacy and PD are not primary objectives. 
12.3.3.2 
Analysis of Secondary Efficacy and Pharmacodynamic Endpoints 
The secondary endpoints will be analyzed separately for each Part. 
• Absolute change in ppFEV1 
One of the secondary efficacy endpoints is the absolute change from baseline in ppFEV1 at visits 
in this open-label study, for subjects who receive at least 1 dose of study drug in each Part. The 
primary analysis for this secondary endpoint will be based on a mixed-effects model for repeated 
measures (MMRM), with the absolute change from baseline in ppFEV1 as the dependent variable 
for visits in each Part. The model will be similar to the one used in the parent study. 
The details including sensitivity analyses and supportive analysis will be described in the SAP. 
• Absolute change in SwCl 
Analysis of this PD endpoint will be based on an MMRM similar to the one used in the parent 
study. 
• Absolute change in CFQ-R RD score 
Analysis of this endpoint will be based on an MMRM similar to the one used in the parent study. 
• Absolute change in BMI and BMI-for-age z-score 
Analysis of this endpoint will be based on an MMRM similar to the one used in the parent study. 
• Number of PEx and CF-related hospitalizations 
Analysis of this endpoint will be based on summary statistics. Additional analysis may be 
provided and details will be discussed in the SAP. 
• Absolute change in LCI2.5 
Analysis of this endpoint will be based on an MMRM similar to the one used in the parent study. 
• Absolute change in weight and weight-for-age z-score  
Analysis of this endpoint will be based on an MMRM similar to the one used in the parent study. 
• Absolute change in height and height-for-age z-score  
Analysis of this endpoint will be based on an MMRM similar to the one used in the parent study. 
12.3.3.3 
Multiplicity Adjustment 
Not applicable. 
12.3.4 
Safety Analysis 
The primary objective of the study is the evaluation of the long-term safety and tolerability of 
VX-445/TEZ/IVA. Data from Part A and Part B will be analyzed separately. For each Part, all 
safety analyses will be based on the TE Period for subjects in the OL-SS, unless otherwise 
specified. 


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The overall long-term safety profile of study drug will be assessed in terms of the following 
safety and tolerability endpoints: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., serum chemistry, hematology, coagulation, and urinalysis) 
• ECGs 
• Vital signs 
• Pulse oximetry 
All safety data will be presented in individual subject data listings. Only descriptive analyses of 
safety data will be performed. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows: 
• Pretreatment AE: any AE that occurred before the first dose of study drug in the TE Period 
in each Part 
• TEAE: any AE that worsened (either in severity or seriousness) or newly developed at or 
after the first dose date of study drug in the TE Period in each Part 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or newly 
developed after the TE Period in each Part 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs 
• TEAEs leading to death 
• Grade 3 and Grade 4 TEAEs 
• 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 an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level in the relationship summaries. An AE 


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overview table will be provided. In addition, a listing containing individual subject level AE data 
for all deaths and other serious and significant AEs will be provided separately. All AEs, 
including pre- and post-treatment AEs, will be presented in individual subject data listings. 
Exposure-adjusted event rates may also be provided.  
12.3.4.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous laboratory parameters will be summarized in SI units at each 
time point during the TE Period in each Part. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period in each Part will be summarized. The shift of the threshold analysis criteria from 
baseline to post-baseline will also be summarized for selected laboratory parameters. The 
threshold analysis and parameter selection criteria will be provided in the SAP. 
Results of urinalysis and pregnancy tests will be listed in individual subject data listings only. In 
addition, a listing containing individual subject laboratory assessment values will be provided. 
This listing will include data from scheduled and unscheduled time points. 
Additional safety laboratory data analyses may be described in the SAP. 
12.3.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each time point during the TE Period in each Part, for the 
following standard 12-lead ECG interval measurements (in msec): RR, PR, QT, QTc for heart 
rate (HR) interval (QTcF), QRS duration, and HR (beats per minute). 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period in this open-label study will be summarized. The threshold analysis criteria will be 
provided in the SAP.  
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each time point during the TE Period in each Part. The 
following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), body temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per 
minute). 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period in each Part will be summarized. The threshold analysis criteria will be provided in 
the SAP. 
Additional vital signs analyses may be described in the SAP. 
12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each time point during the TE Period in each 
Part, for the percent of oxygen saturation by pulse oximetry. 


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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 will be summarized. 
12.3.4.6 
Physical Examination 
No tables/figures/listings will be provided for PE data. 
12.3.4.7 
Other Safety Analyses 
Details of other safety analyses may be included in the SAP. 
12.3.5 
Other Analyses 
Details of other analyses, including FE-1 and IRT, will be provided in a separate document. 
12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analysis 
Interim analyses may take place at any time at the discretion of the sponsor.  
12.3.6.2 
IDMC Analysis 
The IDMC (Section 9.1.6) will conduct regular safety reviews of study data as outlined in the 
IDMC charter. 
The IDMC’s objectives, responsibilities, and operational details will be defined in a separate 
document (IDMC charter), which will be finalized before the first subject is enrolled in the 
study. 
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). 


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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 completion of study 
participation (Section 9.1.5). 
All subjects’ 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. 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 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
February 2019). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” 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 
CTCAE. The severity of an AE described by a term that does not appear in the CTCAE 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  
AE: adverse event 
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). 
AE: adverse event 
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 
Classificationa 
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. 
AE: adverse event 
a 
Refer to Sections 9.7 and 9.8 for directions regarding what drug actions are permitted per protocol.  


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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 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
AE: adverse event 
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 
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 or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data provided to Vertex, study reports, and communications relating to 


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the study will identify subjects by assigned subject numbers, and access to subject names linked 
to such 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 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. Vertex 
will provide, or assess and approve, any electronic data capture (EDC) tools. 
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. Data 
collected during the study will be recorded in a data capture system for each enrolled subject. 
Each subject’s set of captured data records, once complete, will be signed and dated by the 
investigator. 
13.4 
Monitoring 
The study will be monitored by Vertex or its designee in accordance with written procedures. 
Monitoring and auditing procedures developed or approved by Vertex for these activities comply 
with GCP regulatory requirements and guidelines. The monitoring strategy may include onsite, 
remote, and central monitoring activities, in accordance with local regulations. The study site 
monitor will ensure that the investigation is conducted according to the protocol design and 
regulatory requirements. 
13.5 
Electronic Data Capture 
Sites will use an EDC tool to record data for each enrolled subject.  
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness 
of the data reported. 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, including the dates and details of study procedures, AEs, other observations, and subject 
status.  
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 data reported to Vertex, including 
any changes made, to endorse the final submitted data for the subjects for whom the investigator 
is responsible.  
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator's employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
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 


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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. 
13.7 
Publications and Clinical Study Report 
13.7.1 
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).23  
Publication Planning: Vertex staff along with the lead principal investigators, the steering 
committee, and/or the publication committee 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 criteria24: 
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 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 
presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration.  
13.7.2 
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 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 22 March 2018. 
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 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 19 September 2016. 
5 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: https://www.ema.europa.eu/en/committees/committee-orphan-
medicinal-products-comp. Accessed 07 December 2018. 
6 
Rommens J, Iannuzzi M, Kerem B, Drumm M, Melmer G, Dean M, et al. Identification 
of the cystic fibrosis gene: chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
7 
Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
8 
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-59. 
9 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
10 
CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional 
TRanslation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins 
University, the Hospital for Sick Children. Available at: http://www.cftr2.org. Accessed 
09 January 2018. 
11 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99. 
12 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70. 
13 
Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection 
of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. 
Thorax. 2007;62(4):341-47. 
14 
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout 
and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008;63(2):129-
34. 
15 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
16 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 


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17 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
18 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
19 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
20 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
21 
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365(18):1663-72. 
22 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331(10):637-42. 
23 
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. 
24 
(ICMJE). ICoMJE. Recommendations for conduct, reporting, editing, and publication of 
scholarly work in medical journals. [Internet]. Available from: Accessed April 9, 2018. 


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Page 58 of 59
15
PROTOCOL SIGNATURE PAGES
15.1
Sponsor Signature Page
Protocol #:
VX19-445-107
Version
2.0
Version Date:
10 June 2021
Study Title: A Phase 3, Open-label Study Evaluating the Long-term Safety and
of
VX-445/TEZ/IVA Combination Therapy in Subjects With Cystic Fibrosis Who Are 6
of
Age and Older
Vertex Pharmaceuticals Incorporated
Condential Information


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15.2 
Investigator Signature Page 
Protocol #:  
VX19-445-107 
Version #: 
2.0 
Version Date: 
10 June 2021 
Study Title: A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of 
VX-445/TEZ/IVA Combination Therapy in Subjects With Cystic Fibrosis Who Are 6 Years of 
Age and Older 
 
 
I have read Protocol VX19-445-107, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-445, TEZ, IVA and this protocol 
supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 55 
Protocol Number: VX19-445-107 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan  
(Methods) 
 
 
Protocol Number VX19-445-107, Version 2.0 
 
 
A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of 
ELX/TEZ/IVA Combination Therapy in Subjects With Cystic Fibrosis Who Are 6 
Years of Age and Older 
 
 
Author of SAP: 
 
 
 
Version: 3.0 
Version Date of SAP: 13 April 2023 
 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
Page 2 of 55 
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1 
TABLE OF CONTENTS 
1 
Table of Contents ........................................................................................................................... 2 
2 
List of Abbreviations ..................................................................................................................... 5 
3 
Modifications .................................................................................................................................. 7 
3.1 
Modifications to the Approved Clinical Study Protocol .......................................................... 7 
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 Objectives ................................................................................................................... 8 
5.2 
Secondary Objectives ............................................................................................................... 8 
6 
Study Endpoints ............................................................................................................................. 8 
6.1 
Primary Endpoint ...................................................................................................................... 8 
6.2 
Secondary Endpoints ................................................................................................................ 9 
6.3 
Exploratory Endpoints .............................................................................................................. 9 
7 
Study Design ................................................................................................................................... 9 
7.1 
Overall Design .......................................................................................................................... 9 
7.2 
Sample Size ............................................................................................................................ 11 
7.3 
Randomization ........................................................................................................................ 11 
7.4 
Blinding and Unblinding ........................................................................................................ 11 
8 
Analysis Sets ................................................................................................................................. 11 
8.1 
Analysis Sets for Part A Analysis .......................................................................................... 11 
8.1.1 
All Subjects Set .............................................................................................................. 11 
8.1.2 
Safety Set ........................................................................................................................ 12 
8.1.3 
Full Analysis Set ............................................................................................................. 12 
8.2 
Analysis Sets for Final Analysis ............................................................................................. 12 
8.2.1 
All Subjects Set .............................................................................................................. 12 
8.2.2 
Safety Set ........................................................................................................................ 12 
8.2.3 
Full Analysis Set ............................................................................................................. 12 
9 
ANALYSIS PERIOD................................................................................................................... 12 
9.1 
Parent Study Efficacy Period .................................................................................................. 13 
9.2 
Analysis Period for Part A Analysis ....................................................................................... 13 
9.3 
Analysis Period for Final Analysis ......................................................................................... 13 
10 Statistical Analysis ....................................................................................................................... 14 
10.1 General Considerations .......................................................................................................... 14 
10.2 Background Characteristics .................................................................................................... 15 
10.2.1 
Background Characteristics for Part A ........................................................................... 15 
10.2.1.1 Subject Disposition .................................................................................................. 15 
10.2.1.2 Demographics and Baseline Characteristics ............................................................ 15 
10.2.1.3 Medical History ........................................................................................................ 16 
10.2.1.4 Prior and Concomitant Medications......................................................................... 17 
10.2.1.5 Study Drug Exposure ............................................................................................... 17 
10.2.1.6 Study Drug Compliance ........................................................................................... 17 
10.2.1.7 Important Protocol Deviations ................................................................................. 18 


Statistical Analysis Plan (Methods)  
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10.2.2 
Background Characteristics for the OLE study .............................................................. 18 
10.2.2.1 Subject Disposition .................................................................................................. 18 
10.2.2.2 Demographics and Baseline Characteristics ............................................................ 19 
10.2.2.3 Medical History ........................................................................................................ 20 
10.2.2.4 Prior and Concomitant Medications......................................................................... 20 
10.2.2.5 Study Drug Exposure ............................................................................................... 21 
10.2.2.6 Study Drug Compliance ........................................................................................... 21 
10.2.2.7 Important Protocol Deviations ................................................................................. 21 
10.3 Efficacy Analysis .................................................................................................................... 22 
10.3.1 
Efficacy Analysis for Part A ........................................................................................... 22 
10.3.1.1 Analysis of Primary Efficacy Variables ................................................................... 22 
10.3.1.2 Analysis of Secondary Efficacy Variables ............................................................... 22 
10.3.2 
Efficacy Analysis for the OLE study .............................................................................. 27 
10.3.2.1 Analysis of Primary Efficacy Variables ................................................................... 27 
10.3.2.2 Analysis of Secondary Efficacy Variables ............................................................... 27 
10.4 Safety Analysis ....................................................................................................................... 31 
10.4.1 
Safety analysis for Part A ............................................................................................... 31 
10.4.1.1 Adverse Events......................................................................................................... 31 
10.4.1.2 Clinical Laboratory .................................................................................................. 33 
10.4.1.3 Electrocardiogram .................................................................................................... 33 
10.4.1.4 Vital Signs ................................................................................................................ 34 
10.4.1.5 Pulse Oximetry ......................................................................................................... 34 
10.4.1.6 Ophthalmologic Examinations ................................................................................. 34 
10.4.1.7 Physical Examination ............................................................................................... 34 
10.4.1.8 COVID-19 Impacted Visits...................................................................................... 34 
10.4.1.9 Supportive Safety Analysis ...................................................................................... 34 
10.4.2 
Safety analysis for the OLE study .................................................................................. 35 
10.4.2.1 Adverse Events......................................................................................................... 35 
10.4.2.2 Clinical Laboratory .................................................................................................. 37 
10.4.2.3 Electrocardiogram .................................................................................................... 37 
10.4.2.4 Vital Signs ................................................................................................................ 37 
10.4.2.5 Pulse Oximetry ......................................................................................................... 38 
10.4.2.6 Ophthalmologic Examinations ................................................................................. 38 
10.4.2.7 Physical Examination ............................................................................................... 38 
10.4.2.8 COVID-19 Impacted Visits...................................................................................... 38 
10.4.2.9 Supportive Safety Analysis ...................................................................................... 38 
11 Interim and DMC Analyses ........................................................................................................ 39 
11.1 Interim Analysis ..................................................................................................................... 39 
11.1.1 
Week 24 Interim Analysis .............................................................................................. 39 
11.1.2 
Week 144 Interim Analysis ............................................................................................ 39 
11.2 IDMC Analysis ....................................................................................................................... 40 
12 References ..................................................................................................................................... 41 
13 List of Appendices........................................................................................................................ 42 
 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ........................ 42 
 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ............... 48 


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 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ........................................... 49 
 
Appendix D: Imputation Rules for Missing AE Dates ........................................................... 50 
 
Appendix E: Criteria for Threshold Analysis ......................................................................... 51 
 
Appendix F: Analysis Visit Windows for Efficacy Assessments at Week 24 Interim Analysis
 ................................................................................................................................................ 55 
 


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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire – Revised 
CFTR 
cystic fibrosis transmembrane conductance regulator protein or the gene 
encoding the protein. 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELX 
elexacaftor, VX-445 
FAS 
full analysis set 
FDC 
fixed-dose combination 
FEF25-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FRC 
functional residual capacity 
FVC 
forced vital capacity  
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F/F 
homozygous for F508del 
F/MF 
heterozygous for F508del and a CFTR minimal function mutation 
IVA 
ivacaftor 
LS means 
Least squares means 
LFT 
liver function test 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed model repeated measure 
N 
number of subjects 
OLE 
open-label extension 
PD 
pharmacodynamic/pharmacodynamics  
PK 
pharmacokinetic/pharmacokinetics 
ppFEV1 
percent predicted FEV1 
PT 
preferred term 
q12h 
every 12 hours 


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Abbreviation 
Term 
QRS 
Q, R, and S-wave define the QRS-complex in an ECG 
QT 
QT interval: The duration of ventricular depolarization and subsequent 
repolarization; it is measured from the beginning of the QRS complex to the end 
of the T wave 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate with Fridericia’s correction  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TC 
triple combination 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
WHODD 
World Health Organization Drug Dictionary Enhanced 
 
 


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3 
MODIFICATIONS 
3.1 
Modifications to the Approved Clinical Study Protocol 
Section 12 of the Clinical Study Protocol (CSP, Version 2.0) states that data from Part A and Part B 
will be analyzed separately. In this SAP Version 3.0, safety data in Part A and Part B data will be 
pooled together to provide a comprehensive safety analysis for the entire Study 445-107. 
3.2 
Modifications to the Approved Statistical Analysis Plan 
The previous version of the Statistical Analysis Plan (SAP) Version 2.0, dated 28 April 2022, was 
amended to create the current SAP Version 3.0, dated 13 April 2023. The SAP history is provided 
below. 
SAP history 
Version and Date of SAP 
Comments 
Version 1.0, 18 December 2020. 
Original version. Finalized under Clinical Study 
Protocol (CSP) Version 1.0 
Version 2.0, 28 April 2022. 
Amendment according to CSP Version 2.0.  
Version 3.0, 13 April 2023 
Pre-planned amendment to provide analysis details for 
additional interim and final analysis.  
 
Major modifications since SAP Version 1.0 through SAP Version 3.0 are summarized below.  
Change and Rationale 
Affected Sections 
Updated study design according to 
CSP Version 2.0. 
SAP Version 2.0, Section 7. 
Editorial changes in Part A (e.g., 
visit names, end of participations). 
SAP Version 2.0, Sections 8, 9.2, 9.3, 10.2, 10.3, 10.4, 
Appendix A. 
Provided analysis details for final 
analysis 
SAP Version 3.0, Sections 8, 9, 10.2.2, 10.3.2, 10.4.2; 
Appendix A. 
Provided analysis details for Week 
144 interim analysis  
SAP Version 3.0, Section 11.1.2. Appendix A. 
 
3.3 
Modifications to the Approved IDMC Charter 
Not applicable. 


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4 
INTRODUCTION 
This statistical analysis plan (SAP) for Study 445-107 is based on the most recent approved clinical 
study protocol (CSP), the most recent approved electronic case report form (eCRF), and the most 
recent approved eCRF completion guidelines. 
This SAP (Methods) documents the planned statistical analyses of safety and efficacy endpoints for 
the study. It also documents analyses for additional safety and efficacy variables not specified in the 
protocol. PK and PD (if applicable) analyses will be documented separately in the clinical 
pharmacology analysis plan (CPAP) for the study. 
Due to the outbreak of COVID-19, to ensure continued safety of subjects who cannot travel to the 
study sites for their visits (for any reason due to COVID-19), specific alternative measures are being 
implemented to minimize the risk of exposure to COVID-19. This SAP summarizes the additional 
statistical analyses that are related to these alternative measures.  
The Vertex Biometrics Department or designee will perform the statistical analysis of the safety and 
efficacy data; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, 
figures, listings, and datasets).  
The SAP (Methods) Version 1.0 was finalized and approved prior to data cutoff for the Week 24 
Interim Analysis (IA). SAP Version 1.0 specified analysis details for both the Week 24 IA and the 
final analysis under CSP Version 1.0. After the Week 24 IA, the CSP Version 1.0 was amended to 
extend the study treatment period from 96 weeks (under CSP Version 1.0) to 192 weeks (under CSP 
Version 2.0). Accordingly, the SAP Version 1.0 was amended to Version 2.0 to incorporate study 
design changes in CSP Version 2.0. This SAP Version 3.0 was amended from SAP Version 2.0 to 
provide analysis details for a planned Week 144 IA (IA will be conducted based on the Part B Week 
48 data cutoff.  The safety analysis will be based on pooled Part A and Part B data. This IA will 
hereafter be called Week 144 IA) and the final analysis. This SAP Version 3.0 will be finalized before 
the data cutoff date of the Week 144 IA. Any revisions to this approved SAP Version 3.0 will be 
documented and approved in an amendment to this SAP before the data cutoff date of Week 144 IA. 
5 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
To evaluate the long-term safety and tolerability of ELX/TEZ/IVA in subjects with CF who are 
6 years of age and older  
5.2 
Secondary Objectives 
To evaluate the long-term efficacy and pharmacodynamics (PD) of ELX/TEZ/IVA 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 


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ECGs, vital signs, pulse oximetry, and ophthalmologic examinations 
6.2 
Secondary Endpoints 
• 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
• 
Absolute change in sweat chloride (SwCl) 
• 
Absolute change in CFQ-R respiratory domain (RD) score 
• 
Absolute change in body mass index (BMI) and BMI-for-age z-score 
• 
Number of pulmonary exacerbations (PEx) and CF-related hospitalizations 
• 
Absolute change in lung clearance index2.5 (LCI2.5) 
• 
Absolute change in weight and weight-for-age z-score 
• 
Absolute change in height and height-for-age z-score 
6.3 
Exploratory Endpoints 
• 
Absolute change in fecal elastase-1 (FE-1) levels  
• 
Absolute change in serum levels of immunoreactive trypsinogen (IRT)  
7 
STUDY DESIGN 
7.1 
Overall Design 
This is a Phase 3, multicenter, open-label extension study for subjects who completed the Treatment 
Period in the parent study (VX18-445-106 Part B) and meet eligibility criteria.  
A schematic of the study design is shown in Figure 7-1. 
Study visits and assessments to be conducted are shown in Table 3-1 and Table 3-2 of the CSP. All 
visits will occur within the windows specified.  


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Figure 7-1 
Schematic of the Study Design 
 
IVA: ivacaftor; TEZ: tezacaftor  
Note: The parent study is VX18-445-106 Part B, a Phase 3 study investigating ELX/TEZ/IVA in subjects 6 through 11 
years of age. The figure is not drawn to scale.  
a 
Subjects whose Part B Day 1 Visit is on the same day or within 1 calendar day of the Part A Week 96 Visit do NOT 
have to repeat any Part B Day 1 assessments that were specified to be performed at the Part A Week 96 Visit. 
Subjects whose Part B Day 1 Visit is more than 1 calendar day after the Part A Week 96 Visit must complete all 
assessments specified for the Part A Week 96 AND Part B Day 1 Visits. 
 
All subjects will receive ELX/TEZ/IVA at the weight-appropriate dosage levels for 96 weeks in Part 
A. In Part B, subjects will receive ELX/TEZ/IVA at age- and weight-appropriate dosage levels for 96 
weeks (Table 7-1).  
Table 7-1 
Treatment Period Dosages 
Subject Weight 
ELX Dosage 
TEZ Dosage 
IVA Dosage 
Part A, subjects ≥6 years of age 
≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
<30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B, subjects ≥6 to <12 years of age 
≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
<30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B, subjects ≥12 years of age 
All weights 
200 mg qd 
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor  
Note: Study drug administration is described in Section 9.6. 
Part A:  
Subjects weighing ≥30 kg at the Part A Day 1 Visit will receive 200 mg ELX once daily (qd)/100 mg 
TEZ qd/150 mg IVA every 12 hours (q12h) for the duration of the study. Subjects weighing <30 kg at 
the Part A Day 1 Visit will receive 100 mg ELX qd/50 mg TEZ qd/75 mg IVA q12h. If a subject 
enters the current study weighing <30 kg and subsequently weighs ≥30 kg at 2 consecutive clinic 
visits, the dose will be adjusted to the higher dose of 200 mg ELX qd/100 mg TEZ qd/150 mg IVA 
q12h for the remainder of the study, starting with the second visit where subject’s weight is ≥30 kg.  
Part A Treatment Period 
ELX/TEZ/IVA 
Part A Safety 
Follow-up 
Parent 
Study 
Part A Week 96
a 
Part A 
Day 1 
Part B Treatment Period 
ELX/TEZ/IVA 
Part B Safety 
Follow-up 
Part B Week 96 
Part B Day 1
a 


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Part B:  
In Part B, subjects will receive 200 mg ELX qd/100 mg TEZ qd/150 mg IVA q12h if they meet any 
of the following criteria: 
• 
Subject is ≥12 years of age 
• 
Subject received 200 mg ELX qd/100 mg TEZ qd/150 mg IVA q12h in Part A 
• 
Subject is ≥30 kg on Part B Day 1 
All other subjects <12 years of age and <30 kg will receive 100 mg ELX qd/50 mg TEZ qd/75 mg 
IVA q12h until either:  
• 
The subject weighs ≥30 kg at 2 consecutive clinic visits in Part B, or 
• 
The subject turns 12 years of age 
Once either of the above criteria are met, the subject will receive 200 mg ELX qd/100 mg TEZ 
qd/150 mg IVA q12h for the remainder of the study. 
  
7.2 
Sample Size 
The primary and secondary objectives of the study are the evaluation of the long-term safety, 
tolerability, and efficacy of ELX/TEZ/IVA. This is an open-label study that will enroll subjects who 
complete study treatment in the parent study and meet eligibility criteria. Sixty-four subjects enrolled 
in this open-label study.  
7.3 
Randomization 
Randomization is not required because all subjects will be treated identically in a single cohort. 
7.4 
Blinding and Unblinding 
This is an open-label study. Refer to the CSP section 10.7 for details. 
8 
ANALYSIS SETS 
8.1 
Analysis Sets for Part A Analysis 
8.1.1 
All Subjects Set 
The Open-label Extension All Subjects Set for Part A is defined as all subjects who were enrolled 
(defined as subject having data in the clinical database) in the corresponding Part. This analysis set 
will be used for individual subject data listings and disposition summary tables unless otherwise 
specified. 


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8.1.2 
Safety Set 
The Open-label Extension Safety Set (OLE-SS) for Part A is defined as all subjects who have 
received at least 1 dose of study drug in the corresponding Part. The OLE-SS will be used for all 
safety analyses unless otherwise specified.  
8.1.3 
Full Analysis Set 
The Study 106 Full Analysis Set (106-FAS) is defined the same as the FAS definition in the SAP of 
Study 106 Part B. 
The Open-label Extension Full Analysis Set (OLE-FAS) for Part A is defined as all enrolled 
subjects who have received at least 1 dose of study drug in the corresponding Part.  
The Cumulative TC Set includes subjects who were enrolled and received at least one dose of study 
drug during the parent study (445-106 Part B) and/or received at least one dose of study drug during 
the OLE Study. 
8.2 
Analysis Sets for Final Analysis 
8.2.1 
All Subjects Set 
The Open-label Extension All Subjects Set is defined as all subjects who were enrolled (defined as 
subject having data in the clinical database) in the open-label extension (OLE) study (Study 445-107). 
This analysis set will be used for individual subject data listings and disposition summary tables in the 
Week 144 IA and the final analysis unless otherwise specified. 
8.2.2 
Safety Set 
The Open-label Extension Safety Set (OLE-SS) is defined as all subjects who have received at least 
1 dose of study drug in the OLE study. This analysis set will be used for all safety analyses in the 
Week 144 IA and the final analysis unless otherwise specified. 
8.2.3 
Full Analysis Set 
The Study 106 Full Analysis Set (106-FAS) is defined the same as the FAS definition in the SAP of 
Study 106 Part B.  
The Open-label Extension Full Analysis Set (OLE-FAS) is defined as all enrolled subjects who 
have received at least 1 dose of study drug in the OLE study.  
The (OLE) Cumulative TC Set includes subjects who were enrolled and received at least one dose 
of study drug during the parent study (445-106 Part B) and/or received at least one dose of study drug 
during the OLE Study. 
 
9 
ANALYSIS PERIOD 
The analysis period used for safety and efficacy endpoints in the final analysis is described below.  


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9.1 
Parent Study Efficacy Period 
The definition of this analysis period is the same as the PEx analysis period defined in the SAP for 
Study 445-106 Part B. This analysis period will be used with the parent study efficacy analysis set 
(106-FAS) to analyze the efficacy data during the parent study.  
9.2 
Analysis Period for Part A Analysis 
OLE Efficacy Period for Part A: Time from the first dose of study drug in the corresponding Part until 
the last efficacy assessment, which may be collected up to the corresponding Week 96 Visit or the 
earlier of Day 673 and the end of study participation if subject does not have the corresponding Week 
96 Visit in the same Part. This analysis period will be used with the OLE-FAS for the corresponding 
Part to analyze efficacy data during the corresponding Part. 
OLE Safety Period for Part A: Time from the first dose of study drug in the corresponding Part to 
28 days after the last dose of the study drug in the corresponding Part or to the completion date of 
study participation (as defined in Section 9.1.5 of the CSP), whichever occurs first.  
The completion date of study participation will be obtained from the end of study page of the eCRF.  
The Treatment-emergent (TE) Period for Part A is same as the OLE Safety Period for the 
corresponding Part. 
Cumulative TC Efficacy Period for Part A: For subjects who enrolled in Part A, the time from the first 
dose of study drug in the parent study (445-106 Part B) until the last efficacy assessment in Part A, 
which may be collected up to the Part A Week 96 Visit or the earlier of Day 673 in Part A and the end 
of study participation if subject does not have the Part A Week 96 Visit. For subjects who did not 
enroll in the OLE study and were enrolled and received study drug in the parent study, definition of 
this analysis period is the same as the parent study efficacy period. 
9.3 
Analysis Period for Final Analysis 
OLE Efficacy Period: Time from the first dose of study drug in the OLE study to the last efficacy 
assessment, which may be collected up to OLE Part B Week 96 Visit or the earlier of Day 1345 and 
the end of study participation if subject does not have the OLE Part B Week 96. This analysis period 
will be used with the OLE-FAS to analyze efficacy data in the Week 144 IA and the final analysis.  
OLE Safety Period: Time from the first dose of study drug in the OLE study to 28 days after the last 
dose of the study drug in the OLE study or to the completion date of study participation (as defined in 
Section 9.1.5 of the CSP), whichever occurs first.  
The completion date of study participation will be obtained from the end of study page of the eCRF.  
The OLE Treatment-emergent (TE) Period is same as the OLE Safety Period. 
The OLE Cumulative TC Efficacy Period: For subjects who enrolled in the OLE study, the time from 
the first dose of study drug in the parent study (445-106 Part B) until the last efficacy assessment in 
the OLE study, which may be collected up to the Part B Week 96 Visit or the earlier of Day 1345 and 
the end of study participation if subject does not have the Part B Week 96 Visit. For subjects who did 
not enroll in the OLE study and were enrolled and received study drug in the parent study, definition 
of this analysis period is the same as the parent study efficacy period.  


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The Cumulative TC Efficacy periods will be used with the Cumulative TC sets for analysis of PEx 
data.  
10 
STATISTICAL ANALYSIS 
10.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of the CSP. 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. 
Continuous variables will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, standard deviation (SD), median, minimum value (min), and maximum 
value (max). 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline unless otherwise specified, is defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected prior to the first dose of study drug in the parent study. 
Note: for subjects who take Orkambi or Symdeko (branded as Symkevi in Europe) during the 28 days 
before the screening visit, the data collected at screening visit will not be used for baseline derivation 
for spirometry, sweat chloride and LCI. 
Absolute change from baseline will be calculated as Post-baseline value − Baseline value. 
Relative change from baseline will be calculated and expressed in percentage as 100% × (Post-
baseline value − Baseline value) / Baseline value. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline and last on-treatment measurements 
• In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
• In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A.  
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
Multiplicity: There will be no multiplicity adjustment as no hypothesis test is planned for safety 
analysis, unless specified otherwise. 


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10.2 
Background Characteristics 
10.2.1 
Background Characteristics for Part A  
10.2.1.1 
Subject Disposition 
The number of subjects in the following categories will be summarized based on the Open-label 
Extension All Subjects Set for Part A:  
• Open-label Extension All Subjects Set 
• Open-label Extension Safety Set 
• Open-label Extension Full Analysis Set 
• Never dosed 
The number and percentage (based on the OLE-FAS for Part A) of subjects in each of the following 
disposition categories will be summarized: 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation 
• Completed study  
• Prematurely discontinued the study and the reason for discontinuation 
• Rolled over to Part B (for Part A only).  
Additional disposition categories may be provided for interim analysis, e.g. completed Week 24 Visit 
and prematurely discontinued treatment before Week 24 Visit and the reason for discontinuation.  
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation. 
10.2.1.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the OLE-FAS for Part A. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
• Geographic region (North America, Europe [including Australia]) 
Baseline characteristics will include the following: 
• Weight group (<30 kg, and ≥30 kg) 
• Weight (kg) 


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• Weight z-score 
• Height (cm) 
• Height z-score 
• BMI (kg/m2) 
• BMI z-score 
Disease characteristics will include the following: 
• CFTR genotype group (F/F, F/MF) 
• ppFEV1 at baseline (<70, ≥70 to ≤90, and >90)  
• ppFEV1 at baseline (continuous) 
• Sweat chloride at baseline (continuous) 
• CFQ-R respiratory domain score at baseline (child’s version; continuous) 
• LCI2.5 at baseline (continuous) 
• Prior use of CFTR modulator (Yes, No) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No) 
• Prior use of any inhaled bronchodilator (Yes, No) 
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening of the parent study 
(Positive, Negative) 
Prior medication use definition is same as that for the baseline characteristics summary presented in 
the parent study. 
In addition, the following data listings will also be provided: 
• Informed consent/assent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 
10.2.1.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For 
the OLE-FAS for Part A, medical history will be summarized descriptively by system organ class 
(SOC) and preferred term (PT). The corresponding data listing will also be provided. 


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10.2.1.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug) and 
categorized as follows: 
• Prior medication: any medication that administered during the 56 days before the first dose 
of study drug in Part A. 
• Concomitant medication: medication continued or newly received during the OLE Safety 
Period for Part A. 
• Post-treatment medication: medication continued or newly received after the OLE Safety 
Period for Part A. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior and 
concomitant, both concomitant and post-treatment, or prior, concomitant, and post-treatment.  
If a medication has a completely missing or partially missing start date or stop date and it cannot be 
determined whether it was taken before the first dose date of Part A, concomitantly during the OLE 
Safety Period for Part A, or after the OLE Safety Period for Part A, it will be classified as prior, 
concomitant, and post-treatment. Details for imputing missing or partial start and/or stop dates of 
medication are described in Appendix B. 
Concomitant medications will be summarized descriptively for the OLE-FAS for Part A using 
frequency tables by 1) preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, and 
PN. Prior medications will also be summarized the same way as concomitant medications. All 
medications will be listed for each subject. 
10.2.1.5 
Study Drug Exposure 
Study drug exposure summaries will be based on the OLE-SS for Part A. 
Duration of study drug exposure (in days) will be calculated as [last dose date – first dose date 
+ 1 day] within the OLE Safety Period for Part A, regardless of study drug interruption. For subjects 
who are still on study drug at IA data cutoff date, the corresponding date will be used as the last dose 
date for the exposure calculation. 
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized into the following categories: <=24 
weeks, >24 to <=48 weeks, >48 to <=72 weeks, >72 to <=96 weeks, >96 weeks. Additionally, the 
total study drug exposure, defined as the sum total of the study drug exposure across all subjects (in 
patient-weeks and patient-years), will be provided. 
10.2.1.6 
Study Drug Compliance 
Study drug compliance will be summarized based on the OLE-FAS for Part A. 
Study drug compliance will be calculated as: 100 × [1 − (total number of days of study drug 
interruption started before last dose of study drug) / (duration of study drug exposure in days)]. A 
study drug interruption on a given day is defined as an interruption of any study drug dose or 
component on that day.  


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Study drug compliance will be summarized descriptively by the number of subjects (n), mean, SD, 
median, min, and max. It will also be summarized in categories: <80% and ≥80% using frequency 
tables. 
In addition, percentage of tablets taken will be calculated using the following formula: 100 × [(total 
number of tablets dispensed) − (total number of tablets returned)] / (total number of tablets planned to 
be taken per day × duration of study drug exposure in days). A summary similar to that for study drug 
compliance will be produced based on the OLE-FAS for Part A. 
10.2.1.7 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the completeness, 
accuracy, or reliability of the study data or that may significantly affect a subject’s rights, safety, or 
well-being. A protocol deviation review team will categorize IPDs according to the protocol deviation 
plan during the study. 
Protocol deviations that should be considered as potential IPDs include, but are not limited to: 
• Subject was enrolled in the study despite not satisfying one or more inclusion/exclusion 
criterion 
• Subject was less than 80% compliant with study drug for non-safety reasons 
• Subject received prohibited concomitant medications 
• Subject received the wrong treatment or incorrect doses 
IPDs will be summarized descriptively based on the OLE-FAS for Part A. Additionally, IPDs will be 
provided in an individual subject data listing. 
10.2.2 
Background Characteristics for the OLE study 
10.2.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized based on the Open-label 
Extension All Subjects Set:  
• Open-label Extension All Subjects Set 
• Open-label Extension Safety Set 
• Open-label Extension Full Analysis Set 
• Never dosed 
The number and percentage (based on the OLE-FAS) of subjects in each of the following disposition 
categories will be summarized: 
• Completed treatment in Part A 
• Prematurely discontinued treatment in Part A and the reason for discontinuation 
• Completed study in Part A  
• Prematurely discontinued the study in Part A and the reason for discontinuation 
• Rolled over to Part B 


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• Completed treatment in Part B 
• Prematurely discontinued treatment in Part B and the reason for discontinuation 
• Completed study in Part B 
• Prematurely discontinued the study in Part B and the reason for discontinuation 
Additional disposition categories may be provided for interim analysis (e.g., ongoing at Part B Week 
48 Visit, prematurely discontinued treatment before Part B Week 48 Visit and the reason for 
discontinuation).  
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation. 
10.2.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the OLE-FAS. Demographic 
data will include the following: 
• Age at parent study baseline (in years) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
• Geographic region (North America, Europe [including Australia]) 
Baseline characteristics based on parent study will include the following: 
• Weight group (<30 kg, and ≥30 kg) 
• Weight (kg) 
• Weight z-score 
• Height (cm) 
• Height z-score 
• BMI (kg/m2) 
• BMI z-score 
Disease characteristics based on parent study will include the following: 
• CFTR genotype group (F/F, F/MF) 
• ppFEV1 at baseline (<70, ≥70 to ≤90, and >90)  
• ppFEV1 at baseline (continuous) 
• Sweat chloride at baseline (continuous) 
• CFQ-R respiratory domain score at baseline (child’s version; continuous) 


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• LCI2.5 at baseline (continuous) 
• Prior use of CFTR modulator (Yes, No) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No) 
• Prior use of any inhaled bronchodilator (Yes, No) 
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening of the parent study 
(Positive, Negative) 
Prior medication use definition is same as that for the baseline characteristics summary presented in 
the parent study. 
In addition, the following data listings will also be provided: 
• Informed consent/assent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 
10.2.2.3 
Medical History 
Medical history will be coded using the MedDRA. For the OLE-FAS, medical history will be 
summarized descriptively by SOC and PT. The corresponding data listing will also be provided. 
10.2.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug) and 
categorized as follows: 
• Prior medication: any medication that administered during the 56 days before the first dose 
of study drug in the OLE study. 
• Concomitant medication: medication continued or newly received during the OLE Safety 
Period. 
• Post-treatment medication: medication continued or newly received after the OLE Safety 
Period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior and 
concomitant, both concomitant and post-treatment, or prior, concomitant, and post-treatment.  
If a medication has a completely missing or partially missing start date or stop date and it cannot be 
determined whether it was taken before the first dose date in the OLE study, concomitantly during the 
OLE Safety Period, or after the OLE Safety Period, it will be classified as prior, concomitant, and 
post-treatment. Details for imputing missing or partial start and/or stop dates of medication are 
described in Appendix B. 


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Concomitant medications will be summarized descriptively for the OLE-FAS using frequency tables 
by 1) preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, and PN. Prior 
medications will also be summarized the same way as concomitant medications. All medications will 
be listed for each subject. 
10.2.2.5 
Study Drug Exposure 
Study drug exposure summaries will be based on the OLE-SS. 
Duration of study drug exposure (in days) will be calculated as [last dose date – first dose date 
+ 1 day] within the OLE Safety Period, regardless of study drug interruption. For subjects who are 
still on study drug at IA data cutoff date, the corresponding cutoff date will be used as the last dose 
date for the exposure calculation. 
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized into the following categories: <=24 
weeks, >24 to <=48 weeks, >48 to <=72 weeks, >72 to <=96 weeks, >96 to <=120 weeks, >120 to 
<=144 weeks, >144 to <=168 weeks,  >168 to <=192 weeks, >192 weeks. Additionally, the total 
study drug exposure, defined as the sum total of the study drug exposure across all subjects (in 
patient-weeks and patient-years), will be provided. 
10.2.2.6 
Study Drug Compliance 
Study drug compliance will be summarized based on the OLE-FAS. 
Study drug compliance will be calculated as: 100 × [1 − (total number of days of study drug 
interruption started before last dose of study drug) / (duration of study drug exposure in days)]. A 
study drug interruption on a given day is defined as an interruption of any study drug dose or 
component on that day.  
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, SD, 
median, min, and max. It will also be summarized in categories: <80% and ≥80% using frequency 
tables. 
In addition, percentage of tablets taken will be calculated using the following formula: 100 × [(total 
number of tablets dispensed) − (total number of tablets returned)] / (total number of tablets planned to 
be taken per day × duration of study drug exposure in days). A summary similar to that for study drug 
compliance will be produced based on the OLE-FAS. 
10.2.2.7 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the completeness, 
accuracy, or reliability of the study data or that may significantly affect a subject’s rights, safety, or 
well-being. A protocol deviation review team will categorize IPDs according to the protocol deviation 
plan during the study. 
Protocol deviations that should be considered as potential IPDs include, but are not limited to: 
• Subject was enrolled in the study despite not satisfying one or more inclusion/exclusion 
criterion 
• Subject was less than 80% compliant with study drug for non-safety reasons 
• Subject received prohibited concomitant medications 


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• Subject received the wrong treatment or incorrect doses 
IPDs will be summarized descriptively based on the OLE-FAS. Additionally, IPDs will be provided 
in an individual subject data listing. 
10.3 
Efficacy Analysis 
10.3.1 
Efficacy Analysis for Part A 
All efficacy analyses described in this section will be based on the OLE-FAS for Part A, unless 
otherwise specified. The analysis will include all available measurements through the last scheduled 
visit in Part A, including measurements after treatment discontinuation. 
Continuous endpoints during the parent study will be analyzed using the same mixed-effects model 
for repeated measures (MMRM) approach as described in the SAP for the parent study. The resulting 
estimates will be identical to what is available in the final CSR of the parent study. Similarly, 
continuous endpoints during the OLE efficacy period for part A will be analyzed using a separate 
MMRM. The results obtained from the parent study and the OLE efficacy period for Part A will be 
displayed one followed by the other. 
There is no multiplicity adjustment. 
10.3.1.1 
Analysis of Primary Efficacy Variables 
Not applicable. 
10.3.1.2 
Analysis of Secondary Efficacy Variables 
10.3.1.2.1 
Definition of Variables 
Percent predicted FEV1 (ppFEV1): the ppFEV1 value is the ratio of FEV1 (L) and predicted FEV1 (L), 
expressed as a percentage. See Appendix C for more details. 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the non-
missing sweat chloride measurements obtained on the left and right arms at that visit. If one of the 
two arm measurements at a time point is missing, the other will be used as the mean. A volume ≥15 
µL is required for an accurate determination of sweat chloride. Any results reported as having volume 
<15 µL will be considered missing for analysis purposes. Any sweat chloride values reported as <10 
mmol/L or >160 mmol/L will be considered missing for analysis purposes. 
Cystic Fibrosis Questionnaire-Revised (CFQ-R): the CFQ-R1,4,6 is a validated CF-specific instrument 
that measures quality-of-life domains. This study utilizes two different versions of CFQ-R: 
• CFQ-R for Children ages 6 to 13 
• CFQ-R for Parents/Caregivers 
In both versions, specific questions belonging to a domain is scored 1, 2, 3, or 4. The CFQ-R domain 
score, e.g., physical domain score or respiratory domain score, is defined as a scaled score as follows: 
Scaled score for a domain = 100 × (mean (scores of all questions in the domain) − 1) / 3, 
where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – actual 
score, so that 1 always represents the worst condition and 4 the best condition. The (scaled) domain 


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score ranges from 0 (worst condition) to 100 (best condition). The scaled score for a specific domain 
will not be calculated if more than half of the questions in the domain have missing scores. 
Body mass index (BMI): the BMI at each visit is calculated using the weight and height at each visit 
as follows:  
BMI = Weight (kg) / [Height (m)]2 
BMI z-score: the BMI score, adjusted for age and sex, will be referred to as BMI-for-age z-score 
(BMI z-score). The BMI z-score will be calculated by using Centers for Disease Control and 
Prevention (CDC) growth charts7, with the age (in months) used for the calculation defined in 
Appendix A. 
Height z-score and Weight z-score: the height z-score and weight z-score, adjusted for age and sex, 
will be referred to as weight-for-age z-score (weight z-score) and height-for-age z-score (height z-
score). The weight z-score and height z-score will be calculated by using Centers for Disease Control 
and Prevention (CDC) growth charts7, with the age (in months) used for the calculation defined in 
Appendix A. 
Pulmonary exacerbation (PEx): A PEx is defined as a new or changed antibiotic therapy (intravenous 
[IV], inhaled, or oral) for any 4 or more of the following signs/symptoms: 
•  Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
The number of PEx is then defined as the total number of PEx during the Cumulative TC Efficacy 
period. 
Lung clearance index (LCI): the LCI assessments are derived from N2-multiple-breath washout 
(MBW) testing. Each MBW will be performed in multiple replicates for each visit and the final LCI 
value will be calculated from the technically acceptable washout replicates as graded and determined 
by a central reader. The following algorithm is used to derive the LCI values at each visit based on the 
multiple replicates: 


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• When there is only one acceptable replicate at the visit, the LCI values will not be calculated.  
The assessment for that subject at the corresponding visit will be missing. 
• Where there are 2 or more acceptable replicates at the visit, the mean of the values for the 
acceptable replicates will be calculated as the LCI value at the corresponding visit. 
10.3.1.2.2 
Analysis Method 
Absolute change in ppFEV1 from baseline: 
In the MMRM for the OLE efficacy period for Part A, the absolute change from baseline in ppFEV1 
will be analyzed using the MMRM approach based on the OLE-FAS for Part A. The model will 
include absolute change from baseline in ppFEV1 as the dependent variable, and visit as the fixed 
effect, with baseline ppFEV1 value and genotype group (F/F vs. F/MF) as covariates. The model will 
be estimated using restricted maximum likelihood. Denominator degrees of freedom for the F-test of 
fixed effects will be estimated using the Kenward-Roger approximation2. An unstructured covariance 
structure will be used to model the within-subject errors. If the model estimation does not converge, a 
compound symmetry covariance structure will be used instead. Conditional on the observed data and 
covariates, missing data will be assumed to be missing at random; consequently, no imputation of 
missing data will be performed. 
The estimated mean change from baseline in ppFEV1 at each post-baseline visit, along with the 
corresponding 2-sided 95% confidence interval (CI) will be provided.  
The analysis will be conducted with the clinic spirometry data only. An additional analysis may also 
be performed to include pooled spirometry data obtained in clinic and by Air Next Spirometer, if the 
Air Next Spirometry data are assessed to be reasonably consistent with clinic spirometry data.  
Absolute change in sweat chloride from baseline: 
Analysis of this PD variable will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1 from baseline with the baseline sweat chloride included as a covariate instead of 
baseline ppFEV1.  
Absolute change in the CFQ-R respiratory domain score from baseline: 
Analysis of this domain (child’s version) will be based on an MMRM similar to the analysis of the 
absolute change in ppFEV1 from baseline with the baseline CFQ-R respiratory domain score (child’s 
version) included as a covariate instead of baseline ppFEV1. The analysis will include clinic assessed 
CFQ-R RD score only. An additional analysis may be performed to include pooled CFQ-R RD score 
assessed at clinic and at home, if the home assessed data are reasonably consistent with the clinic 
assessed data.  
Absolute change in BMI and BMI-for-age z-score from baseline; 
Absolute change in weight and weight-for-age z-score from baseline; 
Absolute change in height and height-for-age z-score from baseline: 
Analysis of these variables will be based on an MMRM similar to the analysis of the absolute change 
in ppFEV1 from baseline with the corresponding baseline included as a covariate instead of baseline 
ppFEV1. The analysis will be conducted with clinic assessed data only. An additional analysis may be 


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performed to include data obtained in clinic and at home using the scales and stadiometers provided 
by Vertex, if the home assessed data are reasonably consistent with the clinic assessed data. 
Number of PEx and CF-related hospitalizations: 
The analysis of PEx will be based on Cumulative TC Set for Part A, and for the Cumulative TC 
Efficacy Period for Part A.  
PEx will be summarized as described below: 
• Number of events: 
o 
Number of PEx 
o 
Number of PEx requiring hospitalizations 
o 
Number of PEx requiring IV antibiotic therapy 
o 
Number of PEx requiring hospitalization or IV antibiotic therapy 
• Duration of events: 
o 
Number of days with PEx 
o 
Number of days with PEx requiring hospitalizations 
o 
Number of days with PEx requiring IV antibiotic therapy 
o 
Number of days with PEx requiring hospitalization or IV antibiotic therapy 
CF-related hospitalizations will be summarized as described below: 
• Number of events: 
o 
Number of planned hospitalizations for CF (i.e., antibiotic therapy) 
o 
Number of unplanned hospitalizations for reasons other than antibiotic therapy for 
sinopulmonary signs/symptoms 
• Duration of events: 
o 
Number of days of planned hospitalizations for CF (i.e., antibiotic therapy) 
o 
Number of days of unplanned hospitalizations for reasons other than antibiotic therapy for 
sinopulmonary signs/symptoms 
For number of events variables, subjects with multiple defined events during the PEx analysis period 
will be counted multiple times. The annualized duration of events for each subject will be the total 
number of days with the defined events times 48 weeks divided by the total number of weeks on 
study up to the end of the PEx analysis period. 
Absolute change in LCI2.5 from baseline: 
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute change in 
ppFEV1 from baseline with the baseline LCI2.5 included as a covariate instead of baseline ppFEV1.  
For all continuous endpoints, to better assess the longitudinal profile of the efficacy and 
pharmacodynamics assessments with repeated measures up to OLE Week 96, the LS means (±SE) for 
absolute change from baseline at each visit will also be plotted. In addition, the post-baseline raw 


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values and the absolute change from baseline at each post-baseline visit will be summarized 
descriptively (n, mean, SD, median, minimum, and maximum). 
10.3.1.2.3 
Sensitivity Analysis 
Not applicable because the primary endpoints are safety and tolerability assessments. 
10.3.1.2.4 
Analysis of Exploratory Efficacy Variables 
Absolute change in FE-1 levels from baseline; 
Summaries of observed values and change from baseline will be provided by visit. In addition, the 
number and percentage of subjects with shift changes from baseline (<15 mg/kg, ≥15 mg/kg to <200 
mg/kg, and ≥200 mg/kg) at each post-baseline visit (<15 mg/kg, ≥15 mg/kg to <200 mg/kg, and ≥200 
mg/kg) will also be provided. 
Absolute change in serum levels of IRT from baseline: 
Summaries of observed values and change from baseline will be provided by visit. In addition, the 
number and percentage of subjects with shift changes from baseline (<14ug/L, ≥14ug/L to <40ug/L, 
and ≥40ug/L) at each post-baseline visit (<14ug/L, ≥14ug/L to <40ug/L, and ≥40ug/L) will also be 
provided. 
10.3.1.2.5 
Analysis of Additional Efficacy Variables 
Analysis of Additional Spirometry Variables 
Summary statistics for raw values and for changes from baseline of the following spirometry 
measurements will be presented at each visit: 
• FEV1:  
o 
Absolute change from baseline in FEV1 (L) 
o 
Relative change from baseline in FEV1 (%) 
o 
Absolute change from baseline in percent predicted FEV1 (percentage points) 
o 
Relative change from baseline in percent predicted FEV1 (%) 
• FVC: 
o 
Absolute change from baseline in FVC (L) 
o 
Relative change from baseline in FVC (%) 
o 
Absolute change from baseline in percent predicted FVC (percentage points) 
o 
Relative change from baseline in percent predicted FVC (%) 
• FEF25-75%: 
o 
Absolute change from baseline in FEF25-75% (L/sec) 
o 
Relative change from baseline in FEF25-75% (%) 
o 
Absolute change from baseline in percent predicted FEF25-75% (percentage points) 
o 
Relative change from baseline in percent predicted FEF25-75% (%) 


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• FEV1/FVC: 
o 
Absolute change from baseline in FEV1/FVC 
o 
Relative change from baseline in FEV1/FVC (%) 
o 
Absolute change from baseline in percent predicted FEV1/FVC (percentage points) 
o 
Relative change from baseline in percent predicted FEV1/FVC (%) 
Analysis of Other CFQ-R Variables 
Summary statistics for raw values and for changes from baseline of the following CFQ-R domain 
scores will be presented at each visit. 
• CFQ-R respiratory domain score (parent’s version) 
• CFQ-R non-respiratory domain score (child’s version) 
• CFQ-R non-respiratory domain score (parent’s version) 
Analysis of Additional LCI Parameters 
Summary statistics for raw values and for changes from baseline of the following LCI parameters will 
be presented at each visit: LCI2.5, LCI5.0, and FRC. 
10.3.2 
Efficacy Analysis for the OLE study 
All efficacy analyses described in this section will be based on the OLE-FAS, unless otherwise 
specified. The analysis will include all available measurements through the last scheduled visit in the 
OLE study, including measurements after treatment discontinuation. 
Continuous endpoints during the parent study will be analyzed using the same mixed-effects model 
for repeated measures (MMRM) approach as described in the SAP for the parent study. The resulting 
estimates will be identical to what is available in the final CSR of the parent study. Similarly, 
continuous endpoints during the OLE efficacy period will also be analyzed using separate MMRM 
models for Parts A and B, so that Part A data will be analyzed consistently as what was done in the 
Part A analysis and the resulting estimates will be identical to the Part A analysis results. The results 
obtained from the parent study and the OLE efficacy period will be displayed one followed by the 
other. 
There is no multiplicity adjustment. 
10.3.2.1 
Analysis of Primary Efficacy Variables 
Not applicable. 
10.3.2.2 
Analysis of Secondary Efficacy Variables 
10.3.2.2.1 
Definition of Variables 
The list of variables and their definitions are identical to Section 10.3.1.2.1 
10.3.2.2.2 
Analysis Method 
Absolute change in ppFEV1 from baseline: 


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For Part A data during the OLE efficacy period, the same model in Section 10.3.1.2.2 will be 
repeated. For Part B data during the OLE efficacy period, similar MMRM model will be applied 
based on the OLE-FAS. The model will include absolute change from baseline in ppFEV1 as the 
dependent variable, and visit in Part B as the fixed effect, with baseline ppFEV1 value and genotype 
group (F/F vs. F/MF) as covariates. The model will be estimated using restricted maximum 
likelihood. Denominator degrees of freedom for the F-test of fixed effects will be estimated using the 
Kenward-Roger approximation2. An unstructured covariance structure will be used to model the 
within-subject errors. If the model estimation does not converge, a compound symmetry covariance 
structure will be used instead. Conditional on the observed data and covariates, missing data will be 
assumed to be missing at random; consequently, no imputation of missing data will be performed. 
The estimated mean change from baseline in ppFEV1 at each post-baseline visit, along with the 
corresponding 2-sided 95% confidence interval (CI) will be provided.  
The analysis will be conducted with the clinic spirometry data only. An additional analysis may also 
be performed to include pooled spirometry data obtained in clinic and by Air Next Spirometer, if the 
Air Next Spirometry data are assessed to be reasonably consistent with clinic spirometry data.  
Absolute change in sweat chloride from baseline: 
Analysis of this PD variable will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1 from baseline with the baseline sweat chloride included as a covariate instead of 
baseline ppFEV1.  
Absolute change in the CFQ-R respiratory domain score from baseline: 
Analysis of this domain (child’s version) will be based on an MMRM similar to the analysis of the 
absolute change in ppFEV1 from baseline with the baseline CFQ-R respiratory domain score (child’s 
version) included as a covariate instead of baseline ppFEV1. The analysis will include clinic assessed 
CFQ-R RD score only. An additional analysis may be performed to include pooled CFQ-R RD score 
assessed at clinic and at home, if the home assessed data are reasonably consistent with the clinic 
assessed data.  
Absolute change in BMI and BMI-for-age z-score from baseline; 
Absolute change in weight and weight-for-age z-score from baseline; 
Absolute change in height and height-for-age z-score from baseline: 
Analysis of these variables will be based on an MMRM similar to the analysis of the absolute change 
in ppFEV1 from baseline with the corresponding baseline included as a covariate instead of baseline 
ppFEV1. The analysis will be conducted with clinic assessed data only. An additional analysis may be 
performed to include data obtained in clinic and at home using the scales and stadiometers provided 
by Vertex, if the home assessed data are reasonably consistent with the clinic assessed data. 
Number of PEx and CF-related hospitalizations: 
The analysis of PEx will be based on OLE Cumulative TC Set and for the OLE Cumulative TC 
Efficacy Period.  
PEx will be summarized as described below: 
• Number of events: 


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o 
Number of PEx 
o 
Number of PEx requiring hospitalizations 
o 
Number of PEx requiring IV antibiotic therapy 
o 
Number of PEx requiring hospitalization or IV antibiotic therapy 
• Duration of events: 
o 
Number of days with PEx 
o 
Number of days with PEx requiring hospitalizations 
o 
Number of days with PEx requiring IV antibiotic therapy 
o 
Number of days with PEx requiring hospitalization or IV antibiotic therapy 
CF-related hospitalizations will be summarized as described below: 
• Number of events: 
o 
Number of planned hospitalizations for CF (i.e., antibiotic therapy) 
o 
Number of unplanned hospitalizations for reasons other than antibiotic therapy for 
sinopulmonary signs/symptoms 
• Duration of events: 
o 
Number of days of planned hospitalizations for CF (i.e., antibiotic therapy) 
o 
Number of days of unplanned hospitalizations for reasons other than antibiotic therapy for 
sinopulmonary signs/symptoms 
For number of events variables, subjects with multiple defined events during the PEx analysis period 
(i.e., OLE Cumulative TC Efficacy Period) will be counted multiple times. The annualized duration 
of events for each subject will be the total number of days with the defined events times 48 weeks 
divided by the total number of weeks on study up to the end of the PEx analysis period. 
Absolute change in LCI2.5 from baseline: 
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute change in 
ppFEV1 from baseline with the baseline LCI2.5 included as a covariate instead of baseline ppFEV1.  
For all continuous endpoints, to better assess the longitudinal profile of the efficacy and 
pharmacodynamics assessments with repeated measures up to OLE Part B Week 96, the LS means 
(±SE) for absolute change from baseline at each visit will also be plotted. In addition, the post-
baseline raw values and the absolute change from baseline at each post-baseline visit will be 
summarized descriptively (n, mean, SD, median, minimum, and maximum). 
10.3.2.2.3 
Sensitivity Analysis 
Not applicable because the primary endpoints are safety and tolerability assessments. 
10.3.2.2.4 
Analysis of Exploratory Efficacy Variables 
Absolute change in FE-1 levels from baseline; 


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Summaries of observed values and change from baseline will be provided by visit. In addition, the 
number and percentage of subjects with shift changes from baseline (<15 mg/kg, ≥15 mg/kg to <200 
mg/kg, and ≥200 mg/kg) at each post-baseline visit (<15 mg/kg, ≥15 mg/kg to <200 mg/kg, and ≥200 
mg/kg) will also be provided. 
Absolute change in serum levels of IRT from baseline: 
Summaries of observed values and change from baseline will be provided by visit. In addition, the 
number and percentage of subjects with shift changes from baseline (<14ug/L, ≥14ug/L to <40ug/L, 
and ≥40ug/L) at each post-baseline visit (<14ug/L, ≥14ug/L to <40ug/L, and ≥40ug/L) will also be 
provided. 
10.3.2.2.5 
Analysis of Additional Efficacy Variables 
Analysis of Additional Spirometry Variables 
Summary statistics for raw values and for changes from baseline of the following spirometry 
measurements will be presented at each visit: 
• FEV1:  
o 
Absolute change from baseline in FEV1 (L) 
o 
Relative change from baseline in FEV1 (%) 
o 
Absolute change from baseline in percent predicted FEV1 (percentage points) 
o 
Relative change from baseline in percent predicted FEV1 (%) 
• FVC: 
o 
Absolute change from baseline in FVC (L) 
o 
Relative change from baseline in FVC (%) 
o 
Absolute change from baseline in percent predicted FVC (percentage points) 
o 
Relative change from baseline in percent predicted FVC (%) 
• FEF25-75%: 
o 
Absolute change from baseline in FEF25-75% (L/sec) 
o 
Relative change from baseline in FEF25-75% (%) 
o 
Absolute change from baseline in percent predicted FEF25-75% (percentage points) 
o 
Relative change from baseline in percent predicted FEF25-75% (%) 
• FEV1/FVC: 
o 
Absolute change from baseline in FEV1/FVC 
o 
Relative change from baseline in FEV1/FVC (%) 
o 
Absolute change from baseline in percent predicted FEV1/FVC (percentage points) 
o 
Relative change from baseline in percent predicted FEV1/FVC (%) 


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Analysis of Other CFQ-R Variables 
Summary statistics for raw values and for changes from baseline of the following CFQ-R domain 
scores will be presented at each visit. 
• CFQ-R respiratory domain score (parent’s version) 
• CFQ-R non-respiratory domain score (child’s version) 
• CFQ-R non-respiratory domain score (parent’s version) 
Analysis of Additional LCI Parameters 
Summary statistics for raw values and for changes from baseline of the following LCI parameters will 
be presented at each visit: LCI2.5, LCI5.0, and FRC. 
10.4 
Safety Analysis 
10.4.1 
Safety analysis for Part A 
All safety analyses will be conducted based on data from the corresponding OLE Safety Period for 
Part A in the OLE-SS for Part A. 
The overall long-term safety profile of study drug will be assessed in terms of the following safety 
and tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• Standard 12-lead ECGs 
• Vital signs  
• Pulse oximetry 
In the AE summary tables, AE data from the OLE Safety Period for Part A may be displayed side-by-
side with the AE data from study 445-106 Part B. 
Only descriptive analysis of safety will be performed, and no statistical testing will be performed. 
10.4.1.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, 
defined as follows: 
• Pretreatment AE: any AE that occurred before the first dose date of study drug in the OLE 
Safety Period for Part A. 
• TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose date of study drug through the end of the OLE Safety Period for Part 
A. 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the OLE Safety Period for Part A. 


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For AEs with completely missing or partially missing start dates, if there is no clear evidence that the 
AEs were pretreatment or post-treatment, the AEs will be classified as TEAEs.  
Details for imputing missing or partial start dates of adverse events are defined in Appendix D.  
An overview of all TEAEs during OLE Safety Period for Part A will be provided with the following 
categories: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs 
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study drug) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drug) 
• Subjects with grade 3/4 TEAEs  
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAEs leading to death 
The frequency counts and percentages as well as the exposure adjusted event rate will be presented 
for the above overview table. The exposure adjusted rate will not be presented for strongest 
relationship and maximum severity categories. 
The following summary tables of TEAEs during OLE Safety Period will be presented: 
• All TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs 
• TEAEs leading to death 
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• Related TEAEs 
• Related serious TEAEs  
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event) and the exposure adjusted event rate (except 
for summary by strongest relationship and maximum severity). When summarizing the number and 


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percentage of subjects, subjects with multiple occurrences of the same AE or a continuing AE will be 
counted once and only the maximum severity level will be presented in the severity summaries, and 
the strongest relationship level will be presented in the relationship summaries.  
Additional summary table in which the frequency counts and percentages as well as the exposure 
adjusted event rate will be presented for TEAEs during the OLE Safety Period for Part A:  
• All TEAEs by PT 
All AEs in in Part A, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented 
in an individual subject data listing based on the OLE All Subjects Set for Part A. In addition, a listing 
containing individual subject adverse event data for TEAEs leading to treatment discontinuation, 
TEAEs leading to treatment interruption, Grade 3/4 TEAEs, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths. 
10.4.1.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from baseline 
values of the continuous hematology, coagulation and chemistry results will be summarized in SI 
units at each visit during the OLE Safety Period for Part A.  
The number and percentage of subjects with selected test values meeting at least 1 threshold analysis 
criterion event during the OLE Safety Period for Part A will be summarized. The threshold analysis 
criterion shift from baseline will also be summarized for selected laboratory parameters. The 
threshold analysis criteria are provided in Appendix E. 
For selected LFT laboratory tests (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-emergent 
value versus the baseline value corresponding to ×ULN (upper limit of normal) will be presented. 
Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, separately, versus 
the maximum treatment-emergent value of total bilirubin corresponding to ×ULN will also be 
presented. 
Results of urinalysis and the positive urine/serum pregnancy test will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which elevated 
above the upper limit of normal will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values will 
be provided. This listing will include data from both scheduled and unscheduled visits. 
10.4.1.3 
Electrocardiogram  
For the following ECG measurements during the OLE Safety Period for Part A, a summary of 
observed values and change from baseline values will be provided at each visit for the following ECG 
measurements (in msec): RR interval, PR interval, QT interval, QTcF interval, QRS duration, and 
Heart Rate (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the OLE 
Safety Period for Part A will be summarized. The threshold analysis criteria are provided in Appendix 
E.  
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 


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10.4.1.4 
Vital Signs 
For the vital signs measurements during the OLE Safety Period for Part A, the observed values and 
change from baseline values will be summarized at each visit. The following vital signs parameters 
will be summarized: systolic and diastolic blood pressure (mm Hg), body temperature (°C), pulse rate 
(beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the OLE 
Safety Period for Part A will be summarized. The threshold analysis criteria are provided in Appendix 
E. 
In addition, a listing containing individual subject vital sign values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
10.4.1.5 
Pulse Oximetry 
For the percent of oxygen saturation measurements using pulse oximetry during the OLE Safety 
Period for Part A, a summary of observed values and change from baseline values will be provided at 
each visit. 
The number and percentage of subjects with shift change from baseline (normal/missing and low 
according to the reference range) to the lowest percent of oxygen saturation during the OLE Safety 
Period for Part A will be summarized. The reference range for normal oxygen saturation is specified 
as >95%, and <=95% for low oxygen saturation. 
10.4.1.6 
Ophthalmologic Examinations 
The ophthalmologic examination results will be presented in individual subject data listings. 
10.4.1.7 
Physical Examination 
No tables/figures/listings will be provided for PE data.  
10.4.1.8 
COVID-19 Impacted Visits 
A listing containing subjects’ visits impacted due to COVID-19 will be provided.  
10.4.1.9 
Supportive Safety Analysis 
10.4.1.9.1 
Adverse Events of Special Interest 
For this study, elevated transaminases events and rash events, as determined by MedDRA Preferred 
Terms in the respective Customized MedDRA Queries (CMQ), are considered as adverse events of 
special interest.   
For treatment-emergent elevated transaminases events and rash events, the following categories will 
be summarized: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 


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• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event (with the first dose date of study drug in Part A as the reference 
while calculating time-to-onset) 
In addition, for treatment-emergent rash events, the above categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
10.4.2 
Safety analysis for the OLE study 
All safety analyses will be conducted based on the OLE Safety Period for subjects in the OLE-SS. 
The overall long-term safety profile of study drug will be assessed in terms of the following safety 
and tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• Standard 12-lead ECGs 
• Vital signs  
• Pulse oximetry 
In the AE summary tables, AE data from the OLE Safety Period may be displayed side-by-side with 
the AE data from the parent study 445-106 Part B. 
Only descriptive analysis of safety will be performed, and no statistical testing will be performed. 
10.4.2.1 
Adverse Events  
For analysis purpose, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, 
defined as follows: 
• Pretreatment AE: any AE that occurred before the first dose date of study drug in the OLE 
Safety Period. 
• TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose date of study drug through the end of the OLE Safety Period. 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the OLE Safety Period. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence that the 
AEs were pretreatment or post-treatment, the AEs will be classified as TEAEs.  
Details for imputing missing or partial start dates of adverse events are defined in Appendix D.  
An overview of all TEAEs during OLE Safety Period will be provided with the following categories: 
• Number of TEAEs (total number of TEAEs only) 


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• Subjects with any TEAEs 
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study drug) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drug) 
• Subjects with grade 3/4 TEAEs  
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAEs leading to death 
The frequency counts and percentages as well as the exposure adjusted event rate will be presented 
for the above overview table. The exposure adjusted rate will not be presented for strongest 
relationship and maximum severity categories. 
The following summary tables of TEAEs during OLE Safety Period will be presented: 
• All TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs 
• TEAEs leading to death 
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• Related TEAEs 
• Related serious TEAEs  
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event) and the exposure adjusted event rate (except 
for summary by strongest relationship and maximum severity). When summarizing the number and 
percentage of subjects, subjects with multiple occurrences of the same AE or a continuing AE will be 
counted once and only the maximum severity level will be presented in the severity summaries, and 
the strongest relationship level will be presented in the relationship summaries.  
Additional summary table in which the frequency counts and percentages as well as the exposure 
adjusted event rate will be presented for TEAEs during the OLE Safety Period:  
• All TEAEs by PT 


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All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the OLE All Subjects Set. In addition, a listing containing 
individual subject adverse event data for TEAEs leading to treatment discontinuation, TEAEs leading 
to treatment interruption, Grade 3/4 TEAEs, SAEs and all deaths will be provided separately, with a 
flag indicating the TEAE status for SAEs and deaths. 
10.4.2.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from baseline 
values of the continuous hematology, coagulation and chemistry results will be summarized in SI 
units at each visit during the OLE Safety Period.  
The number and percentage of subjects with selected test values meeting at least 1 threshold analysis 
criterion event during the OLE Safety Period will be summarized. The threshold analysis criterion 
shift from baseline will also be summarized for selected laboratory parameters. The threshold analysis 
criteria are provided in Appendix E. 
For selected LFT laboratory tests (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-emergent 
value versus the baseline value corresponding to ×ULN (upper limit of normal) will be presented. 
Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, separately, versus 
the maximum treatment-emergent value of total bilirubin corresponding to ×ULN will also be 
presented. 
Results of urinalysis and the positive urine/serum pregnancy test will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which elevated 
above the upper limit of normal will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values will 
be provided. This listing will include data from both scheduled and unscheduled visits. 
10.4.2.3 
Electrocardiogram  
For the following ECG measurements during the OLE Safety Period, a summary of observed values 
and change from baseline values will be provided at each visit for the following ECG measurements 
(in msec): RR interval, PR interval, QT interval, QTcF interval, QRS duration, and Heart Rate (beats 
per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the OLE 
Safety Period will be summarized. The threshold analysis criteria are provided in Appendix E.  
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
10.4.2.4 
Vital Signs 
For the vital signs measurements during the OLE Safety Period, the observed values and change from 
baseline values will be summarized at each visit. The following vital signs parameters will be 
summarized: systolic and diastolic blood pressure (mm Hg), body temperature (°C), pulse rate (beats 
per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the OLE 
Safety Period will be summarized. The threshold analysis criteria are provided in Appendix E. 


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In addition, a listing containing individual subject vital sign values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
10.4.2.5 
Pulse Oximetry 
For the percent of oxygen saturation measurements using pulse oximetry during the OLE Safety 
Period, a summary of observed values and change from baseline values will be provided at each visit. 
The number and percentage of subjects with shift change from baseline (normal/missing and low 
according to the reference range) to the lowest percent of oxygen saturation during the OLE Safety 
Period will be summarized. The reference range for normal oxygen saturation is specified as >95%, 
and <=95% for low oxygen saturation. 
10.4.2.6 
Ophthalmologic Examinations 
The ophthalmologic examination results will be presented in individual subject data listings. 
10.4.2.7 
Physical Examination 
No tables/figures/listings will be provided for PE data.  
10.4.2.8 
COVID-19 Impacted Visits 
A listing containing subjects’ visits impacted due to COVID-19 will be provided.  
10.4.2.9 
Supportive Safety Analysis 
10.4.2.9.1 
Adverse Events of Special Interest 
For this study, elevated transaminases events and rash events, as determined by MedDRA Preferred 
Terms in the respective Customized MedDRA Queries (CMQ), are considered as adverse events of 
special interest.   
For treatment-emergent elevated transaminases events and rash events, the following categories will 
be summarized: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event (with the first dose date of study drug in the OLE study as the 
reference while calculating time-to-onset) 
In addition, for treatment-emergent rash events, the above categories will be summarized for the 
following subgroups: 


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• Sex (male, female) 
11 
INTERIM AND DMC ANALYSES 
11.1 
Interim Analysis 
In the protocol it has been mentioned that IA may take place at any time during the study at the 
discretion of the sponsor to support regulatory and/or reimbursement dossiers. An interim analysis 
was conducted when the last subject reached Part A Week 24. The analysis details of the Week 24 
interim analysis were provided in Section 11.1.1 below. Another IA will be conducted when the last 
subject reaches Part B Week 48, i.e., Week 144 in the OLE study. The analysis details of the Week 
144 IA are provided in Section 11.1.2. Unless specified otherwise, the general rules, principles, and 
scopes specified in Section 10 apply to the IAs. 
11.1.1 
Week 24 Interim Analysis 
For the following efficacy endpoints, the model-based main analysis was performed using the models 
specified in Section 10.3.1.2.2 with the Extended OLE Week 24 Visit windowing rule defined in 
Appendix F. Additional analyses was performed using the exact same model but with the regular 
Week 24 visit windowing rule defined in Appendix A.  The descriptive summary for continuous 
efficacy endpoints also used the Extended OLE Week 24 Visit windowing rule. 
• 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
• 
Absolute change in sweat chloride (SwCl) 
• 
Absolute change in CFQ-R respiratory domain (RD) score 
• 
Absolute change in body mass index (BMI) and BMI-for-age z-score 
• 
Absolute change in lung clearance index2.5 (LCI2.5) 
• 
Absolute change in weight and weight-for-age z-score 
• 
Absolute change in height and height-for-age z-score 
The descriptive summary tables for continuous safety endpoints stayed with the regular OLE Week 
24 Visit windowing rule defined in Appendix A and were restricted to the last visit at which the 
number of subjects was at least 10. 
11.1.2 
Week 144 Interim Analysis 
The following efficacy endpoints will be analyzed using methods specified in Section 10.3.2.2.2. 
Both MMRM models and descriptive summaries will include data up to the OLE Part B Week 48 
(inclusive) analysis visit. The windowing rules are provided in Appendix B.  
• 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
• 
Absolute change in sweat chloride (SwCl) 
• 
Absolute change in CFQ-R respiratory domain (RD) score 
• 
Absolute change in body mass index (BMI) and BMI-for-age z-score 
• 
Absolute change in lung clearance index2.5 (LCI2.5) 


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• 
Absolute change in weight and weight-for-age z-score 
• 
Absolute change in height and height-for-age z-score 
• 
Pulmonary Exacerbation (PEx) and CF-related hospitalizations 
The study is conducted during the COVID-19 pandemic. If extra assessments (e.g., unscheduled 
visits) will be collected to mitigate the impact of COVID-19 pandemic on this Week 144 IA, 
Extended OLE Part B Week 48 analysis visit may replace the regular OLE Part B Week 48 analysis 
visit for efficacy analysis, using the exact same analysis methods. In such situations, MMRM models 
with the regular OLE Part B Week 48 analysis visit may be conducted as additional analysis. All 
efficacy analysis for the Week 144 IA will be based on clinical assessed data. 
The same definition on analysis period as described in Section 9 applies to this IA but the analysis 
period does not exceed the IA data cutoff date. The descriptive summary tables for continuous safety 
endpoints will stay with the regular visit windowing rule defined in Appendix A and will be restricted 
to the last visit at which the number of subjects is at least 10.  For AE, PEx, similar event base 
parameters, all available data will be included. 
11.2 
IDMC Analysis 
The IDMC’s objectives and operational details will be defined in a separate document (IDMC 
Charter) which was finalized before the first subject first visit. The IDMC’s planned safety reviews of 
study data are outlined in the IDMC Charter and IDMC Statistical Analysis Plan. 


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12 
REFERENCES 
1 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 2007;4:1-9. 
2 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 Meyer, R. Daniel, et al. Statistical Issues and Recommendations for Clinical Trials Conducted 
During the COVID-19 Pandemic. Statistics in Biopharmaceutical Research just accepted (2020): 1-
22. 
4 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life for 
children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
5 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference values 
for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 
2012;40(6):1324-43. 
6 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
7 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
 


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13 
LIST OF APPENDICES 
 Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 13-1 Analysis Visit Windows for Safety and Efficacy Assessments for Part A 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Safety Assessment  
Serum Chemistry 
Hematology 
Vital Signs (excluding 
Weight, Height, BMI, and 
corresponding z-scores)3  
 
Baseline  
OLE Part A Week 8 
OLE Part A Week 16 
OLE Part A Week 24 
OLE Part A Week 36 
OLE Part A Week 48 
OLE Part A Week 60 
OLE Part A Week 72 
OLE Part A Week 84 
OLE Part A Week 96 
Safety Follow-up4 
1 
57 
113 
169 
253 
337 
421 
505 
589 
673 
Not applicable 
defined in section 8.1 
[1, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 687] 
Use nominal visit 
Standard 12-lead ECG 
Coagulation 
Baseline  
OLE Part A Week 24 
OLE Part A Week 48 
OLE Part A Week 72 
OLE Part A Week 96 
Safety Follow-up4 
1 
169 
337 
505 
673 
Not applicable 
defined in section 8.1 
[1, 253] 
(253, 421] 
(421, 589] 
(589, 687] 
Use nominal visit 
Efficacy Assessment 
Spirometry 
Weight, Height and BMI (and 
the corresponding z-scores)  
Baseline  
OLE Part A Week 8 
OLE Part A Week 16 
OLE Part A Week 24 
OLE Part A Week 36 
OLE Part A Week 48 
OLE Part A Week 60 
OLE Part A Week 72 
OLE Part A Week 84 
OLE Part A Week 96 
Safety Follow-up5 
1 
57 
113 
169 
253 
337 
421 
505 
589 
673 
Not applicable 
defined in section 8.1 
(1, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 687] 
>687 


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Table 13-1 Analysis Visit Windows for Safety and Efficacy Assessments for Part A 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
CFQ-R 
Baseline  
OLE Part A Week 8 
OLE Part A Week 24 
OLE Part A Week 48 
OLE Part A Week 72 
OLE Part A Week 96 
Safety Follow-up5 
1 
57 
169 
337 
505 
673 
Not applicable 
defined in section 8.1 
(1, 113] 
(113, 253] 
(253, 421] 
(421, 589] 
(589, 687] 
>687 
Sweat chloride 
Lung Clearance Index 
IRT 
Baseline  
OLE Part A Week 24 
OLE Part A Week 48 
OLE Part A Week 72 
OLE Part A Week 96 
1 
169 
337 
505 
673 
defined in section 8.1 
(1, 253] 
(253, 421] 
(421, 589] 
(589, 687] 
FE-1 
Baseline  
OLE Part A Week 24 
OLE Part A Week 48 
OLE Part A Week 96 
1 
169 
337 
673 
defined in section 8.1 
(1, 211] 
(211, 505] 
(505, 687] 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. If no numerical measurement is available within a visit window, the measurement will be considered missing for 
the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement will 
be used. If the latest measurement cannot be determined, then unscheduled visit will be selected. 
 
3 For measurement collected on the date of first dose of study drug in Treatment Period, if it cannot be determined 
whether the measurement is before or after the first dose: 
1. Scheduled measurement will be treated as pre-dose observation. 
2. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety Assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >687, then the ETT visit 
will be mapped into Safety Follow-up analysis visit. 
5 For efficacy assessment, if a subject has nominal safety follow up visit with study day >687, then nominal Safety 
Follow-up visit will be mapped to Safety Follow-up visit; else if subject doesn’t have a nominal safety follow-up 
visit with study day > 687 but has an ETT visit with study day >687, then the ETT visit will be mapped into Safety 
Follow-up analysis visit; else if there are multiple assessments with >687 then select the earliest record. 
Derived Variables: 


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Table 13-1 Analysis Visit Windows for Safety and Efficacy Assessments for Part A 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
1. Age (in years) at first dose date and post-baseline visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent in “yy, mm” format (e.g., 24 years, 6 months) in parent study from the Vital 
Signs (VS) page at the Screening Visit in parent study and add 0.5 month to convert to days. 
Obtain the informed consent date in parent study. 
Then age (in years) at first dose or post-baseline visit = [(first dose date or post-baseline visit date – informed 
consent date in parent study) in days + age at informed consent (in days) in parent study]/365.25. 
2. Age (in months) at first dose date and post-baseline visit (for use in calculation of BMI): 
Obtain the age at informed consent in “yy, mm” format (e.g., 24 years, 6 months) in parent study from the VS 
page at the Screening Visit in the parent study. 
Obtain the informed consent date in parent study. 
Then age (in months) at first dose or post-baseline visit = integer part of {[(age at informed consent (in months) 
in parent study + 0.5 + diff(first dose date or post-baseline visit date, informed consent date) in months in parent 
study]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date of study drug is not available and there is no data to indicate that the subject discontinued 
treatment, the data cutoff date will be used instead.  
If the subject discontinued treatment and the last dose date is missing or partial date is reported, the last dose 
date will be imputed based on, in descending order priority, the Early Treatment Termination (ETT) visit date, 
last visit date before the Safety Follow-up, or the last study drug administration date from EX SDTM domain, 
as appropriate. The imputation algorithm will ensure the imputed last dose date does not exceed the data cutoff 
date. 
4. Electrocardiogram: 
        Baseline is defined in Section 8.1. If multiple ECG measurements are obtained on the same calendar day during   
        the TE period, 
o For summary purpose, the average value will be used as the ECG on that day; 
o For threshold analysis purpose, all ECG values will be used 
 


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Table 13-2  Analysis Visit Windows for Safety and Efficacy Assessments for the OLE study 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Safety Assessment  
Serum Chemistry 
Hematology 
Vital Signs (excluding 
Weight, Height, BMI, and 
corresponding z-scores)3  
 
Baseline  
OLE Part A Week 8 
OLE Part A Week 16 
OLE Part A Week 24 
OLE Part A Week 36 
OLE Part A Week 48 
OLE Part A Week 60 
OLE Part A Week 72 
OLE Part A Week 84 
OLE Part A Week 96 
OLE Part B Week 12 
OLE Part B Week 24 
OLE Part B Week 36 
OLE Part B Week 48 
OLE Part B Week 60 
OLE Part B Week 72 
OLE Part B Week 84 
OLE Part B Week 96 
Safety Follow-up4 
1 
57 
113 
169 
253 
337 
421 
505 
589 
673 
757 
841 
925 
1009 
1093 
1177 
1261 
1345 
Not applicable 
defined in section 8.1 
[1, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 715] 
(715, 799] 
(799, 883] 
(883, 967] 
(967, 1051] 
(1051, 1135] 
(1135, 1219] 
(1219, 1303] 
(1303, 1359] 
Use nominal visit 
Standard 12-lead ECG 
Coagulation 
Baseline  
OLE Part A Week 24 
OLE Part A Week 48 
OLE Part A Week 72 
OLE Part A Week 96 
OLE Part B Week 24 
OLE Part B Week 48 
OLE Part B Week 72 
OLE Part B Week 96 
Safety Follow-up4 
1 
169 
337 
505 
673 
841 
1009 
1177 
1345 
Not applicable 
defined in section 8.1 
[1, 253] 
(253, 421] 
(421, 589] 
(589, 757] 
(757, 925] 
(925, 1093] 
(1093, 1261] 
(1261, 1359] 
Use nominal visit 
Efficacy Assessment5  
Part A: same as in Table 13-1 
Part B: see below 


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Table 13-2  Analysis Visit Windows for Safety and Efficacy Assessments for the OLE study 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Spirometry 
Weight, Height and BMI (and 
the corresponding z-scores)  
Baseline  
OLE Part B Week 12 
OLE Part B Week 24 
OLE Part B Week 36 
OLE Part B Week 48 
OLE Part B Week 60 
OLE Part B Week 72 
OLE Part B Week 84 
OLE Part B Week 96 
Safety Follow-up6 
1 
757 
841 
925 
1009 
1093 
1177 
1261 
1345 
Not applicable 
defined in section 8.1 
(667, 799] 
(799, 883] 
(883, 967] 
(967, 1051] 
(1051, 1135] 
(1135, 1219] 
(1219, 1303] 
(1303, 1401] 
>1401 
CFQ-R 
Baseline  
OLE Part B Week 24 
OLE Part B Week 48 
OLE Part B Week 72 
OLE Part B Week 96 
Safety Follow-up6 
1 
841 
1009 
1177 
1345 
Not applicable 
defined in section 8.1 
(667, 925] 
(925, 1093] 
(1093, 1261] 
(1261, 1401] 
>1401 
Sweat chloride 
Lung Clearance Index 
IRT 
Baseline  
OLE Part B Week 24 
OLE Part B Week 48 
OLE Part B Week 72 
OLE Part B Week 96 
1 
841 
1009 
1177 
1345 
defined in section 8.1 
(667, 925] 
(925, 1093] 
(1093, 1261] 
(1261, 1401] 
FE-1 
Baseline  
OLE Part B Week 48 
OLE Part B Week 96 
1 
1009 
1345 
defined in section 8.1 
(667, 1177] 
(1177, 1401] 
Notes: 
 
1,2,3: See Table 13-1. 
4 For safety Assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject doesn’t have a nominal Safety Follow-up visit but has a Part A ETT visit with study day >687 or a Part B 
ETT visit with study day >1359, then the ETT visit will be mapped into Safety Follow-up analysis visit. 
5 For efficacy windowing rules, Part A data will only be used to derive Part A analysis visits using the window rules 
in Table 13-1. Part B data will only be used to derive Part B analysis visits using the window rules in this table. 
Note that Safety Follow-up visits from both Parts will be combined for efficacy summary tables. 
6 For efficacy assessment in Part B, if a subject has nominal Part B safety follow up visit with study day >1359, then 
nominal Safety Follow-up visit will be mapped to Safety Follow-up visit; else if subject doesn’t have a nominal 
safety follow-up visit with study day >1359 but has an ETT visit with study day >1359, then the ETT visit will be 
mapped into Safety Follow-up analysis visit; else if there are multiple assessments with >1401 then select the 
earliest record.  
Derived Variables: See Table 13-1. 


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Table 13-3  Efficacy Analysis Visit Windows for Week 144 Interim Analysis if Extended OLE Part B Week 48 
is used. 
Assessment 
Visit 
Target Study 
Day 
Analysis Visit Window 
(in study days) 
Efficacy Assessment 
Part A: same as in Table 13-1 
Part B: see below 
Spirometry 
Weight, Height and BMI 
(and the corresponding z-
scores)  
Baseline  
OLE Part B Week 12 
OLE Part B Week 24 
OLE Part B Week 36 
Extended OLE Part B Week 48 
1 
757 
841 
925 
1009 
defined in section 8.1 
(667, 799] 
(799, 883] 
(883, 967] 
>967 
CFQ-R 
Baseline  
OLE Part B Week 24 
Extended OLE Part B Week 48 
1 
841 
1009   
defined in section 8.1 
(667, 925] 
>925  
Sweat chloride 
Lung Clearance Index 
 
Baseline  
OLE Part B Week 24 
Extended OLE Part B Week 48 
1 
841 
1009 
defined in section 8.1 
(667, 925] 
>925 
 
Notes: The above analysis windows will be used only when mitigation plans regarding the impact of COVID-19 
pandemic will be implemented. See Section 11.1.2 for details. 
 
  See Table 13-1 table notes for detailed. 
 
 


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 Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date 
(in practical, use Jan. 01, 2000 to impute). 
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 practical, use Dec. 31, 2050 to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described 
below. 
Table 13-4 
Prior, Concomitant, and Post Categorization of a Medication  
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date 
and  
≤ End Date of TE 
Period 
> End Date of TE 
Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post 
 
Imputation rules for missing and/or partial dates of non-pharmacological treatment/procedure 
will follow the same imputation rule. 
 


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 Appendix C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 
Regression Equation and Lookup Tables (Version 7 April 2013). Global Lung Function 
Initiative. [online] Available at: https://www.ers-education.org/guidelines/global-lung-
function-initiative/spirometry-tools/it-engineers-and-manufacturers/ [Accessed  Sep 22, 
2020]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] 
Available at: https://www.ers-education.org/guidelines/global-lung-function-
initiative/spirometry-tools/it-engineers-and-manufacturers/ [Accessed  Sep 22, 2020].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: https://www.ers-education.org/guidelines/global-lung-
function-initiative/spirometry-tools/sas-macro/ [Accessed  Sep 22, 2020]. 
Data handling rule for spirometry is as follows:  
 Input age and height with at least 2 decimal place 
 Height collected at the respective visit should be used; if the height at the respective visit is 
not available, the last non-missing record will be used. 
 For race, map the CRF reported Black or African American to Black, all other races in 
CRF (except White) are mapped to 'other'; multiple checks for race in CRF are also 
mapped to 'other'; white is a reference race in the equations and assumes 0 values for all 
race coefficients in the GLI equations. 


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 Appendix D: Imputation Rules for Missing AE Dates 
Imputation rules for missing or partial AE start date are defined below. If the imputed AE 
start date is before the study informed consent/assent date, the AE start date will be imputed 
using the study informed consent/assent date. Ongoing events of the parent study will follow 
the imputation rule described in the SAP of parent study.  
 If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date or AE end 
date is missing, then  
 if AE start year and month are equal to the month and year of first dose 
date, then impute the AE start day as the day of first dose date;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date or AE end 
date is missing, then  
 if AE start year is equal to the year of first dose date, then impute the AE 
start month and day as the month and day of first dose date;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site.  
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then impute the AE start date as 
the first dose date.  
o else impute the AE start date as the informed consent date. 
 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, data cut-off, end of study) if 
day is missing, or min (Dec, data cut-off, end of study) if month is missing. 


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 Appendix E: Criteria for Threshold Analysis 
Table 13-5 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN to ≤3xULN 
>3x to ≤5xULN 
>5x to ≤8xULN 
>8x to ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN to ≤3xULN 
>3x to ≤5xULN 
>5x to ≤8xULN 
>8x to ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN to ≤ 3xULN) or (AST>ULN 
to ≤3xULN) 
(ALT>3x to ≤5xULN) or (AST>3x to 
≤5xULN) 
(ALT>5x to ≤8xULN) or (AST>5x to 
≤8xULN) 
(ALT>8x to ≤20xULN) or (AST>8x to 
≤20xULN) 
ALT>20xULN or AST>20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN to ≤1.5xULN 
>1.5x to ≤2.5xULN 
>2.5x to ≤5xULN 
>5x to ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN to ≤1.5xULN 
>1.5x to ≤2xULN 
>2x to ≤3xULN  
>3x to ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN to ≤1.5xULN 
>1.5x to ≤2xULN 
>2x to ≤3xULN  
>3x to ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Indirect Bilirubin 
>ULN to ≤1.5xULN 
>1.5x to ≤2xULN 
>2x to ≤3xULN  
>3x to ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 


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Table 13-5 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 
GGT 
>ULN to ≤2.5xULN 
>2.5x to ≤5xULN 
>5x to ≤20xULN  
>20xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN to ≥30 g/L 
<30 to ≥20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>ULN to ≤1.5xULN 
>1.5x to ≤2xULN 
>2x to ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN to ≤1.5xULN 
>1.5x to ≤3xULN 
>3x to ≤6xULN 
>6xULN 
CTCAE grades 1-4 
Lipase 
>ULN to ≤1.5xULN 
>1.5x to ≤2xULN 
>2x to ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN to ≤2.5xULN 
>2.5x to ≤5xULN 
>5x to ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN to ≥100 g/L 
<100 to ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN to ≤20 g/L above ULN 
>20 g/L above ULN to ≤40 g/L above 
ULN 
>40 g/L above ULN 
CTCAE grade 1-3 


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Table 13-5 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Platelets 
Platelet decreased 
<LLN to ≥75 x 10e9 /L 
<75 to ≥50 x 10e9 /L  
<50 to ≥25 x 10e9 /L  
<25 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)   
<LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time (PTT)  
 
>ULN to ≤1.5xULN 
>1.5 to ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN to ≤1.5xULN 
>1.5 to ≤2.5xULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
Table 13-6 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
≤50 bpm  
 
Tachycardia 
≥140 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
QTc 
Absolute values (ms) 
>450 ms (Male); >470 ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline 30-60 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
 
Table 13-7 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP 
 
>120 mmHg 
 
<70 mmHg 
 
DBP 
 
>80 mmHg 
 
<50 mmHg 
 


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Table 13-7 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Weight 
Weight gain 
≥5% increase from baseline 
 
Weight loss 
≥5% decrease from baseline 
 
 


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 Appendix F: Analysis Visit Windows for Efficacy Assessments at Week 24 Interim 
Analysis  
Table 13-8 Analysis Visit Windows for Efficacy Assessments  
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Efficacy Assessment 
Spirometry 
Weight, Height and BMI (and 
the corresponding z-scores)  
Baseline  
OLE Week 8 
OLE Week 16 
Extended OLE Week 24 
1 
57 
113 
169 
defined in section 8.1 
(1, 85] 
(85, 141] 
>141 
CFQ-R 
Baseline  
OLE Week 8 
Extended OLE Week 24 
1 
57 
169 
defined in section 8.1 
(1, 113] 
>113 
Sweat chloride 
Lung Clearance Index 
Baseline  
Extended OLE Week 24 
1 
169 
defined in section 8.1 
>1 
Notes: 
1Visit name for analysis purpose is used to report data in tables and figures. 
2The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. 
If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest 
measurement will be used. If the latest measurement cannot be determined, then unscheduled visit 
will be selected.