Clinical trial NCT03559062
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-05-17; Completion date: 2018-12-21
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy of tezacaftor in combination with ivacaftor (TEZ/IVA) in participants with cystic fibrosis (CF) aged 6 through 11 years, who are homozygous for the F508del mutation (F/F) or heterozygous for F508del with an eligible residual function mutation (F/RF).

Detailed description:

Arms: arm 1: Participants with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks. arm 2: Participants with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Participants with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks. arm 3: Participants with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.
Interventions: intervention 1: TEZ/IVA intervention 2: IVA intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: Participants weighing \<40 kg received TEZ 50 mg/IVA 75 mg FDC tablet and those weighing ≥40 kg received TEZ 100 mg/IVA 150 mg FDC tablet. intervention 2: Participants weighing \<40 kg IVA 75 mg tablet and those weighing ≥40 kg received IVA 150 mg tablet. intervention 3: Placebo matched to TEZ/IVA FDC intervention 4: Placebo matched to IVA

Protocol documents:
Prot_000.pdf: 
Page 1of 69
1
TITLE PAGE
VERTEX PHARMACEUTICALS INCORPORATED
Clinical Study Protocol
A Phase 3, Double-blind, Parallel-group Study to 
Evaluate the Efficacy and Safety of Tezacaftor in 
Combination With Ivacaftor in Subjects Aged 6 
Through 11 Years With Cystic Fibrosis, Homozygous 
or Heterozygous for the F508del-CFTRMutation
Vertex Study Number: VX16-661-115
EudraCT Number: 2016-004479-35
Date of Protocol:17November2017(Version1.0) 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue
Boston, MA 02210-1862, USA
CONFIDENTIAL
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them.


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2 
PROTOCOL SYNOPSIS 
Title A Phase 3, Double-blind, Parallel-group Study to Evaluate the Efficacy and Safety of 
Tezacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With 
Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation 
Brief Title A Study to Evaluate Efficacy and Safety of TEZ/IVA in Subjects Aged 6 through 11 
Years With Cystic Fibrosis 
  
Clinical Phase and 
Clinical Study Type  
Phase 3, efficacy and safety 
  
Objectives Primary Objective 
To evaluate the efficacy of tezacaftor in combination with ivacaftor (TEZ/IVA) in 
subjects with cystic fibrosis (CF) aged 6 through 11 years, homozygous or heterozygous 
for F508del 
Secondary Objective 
To evaluate the safety of TEZ/IVA in subjects with CF aged 6 through 11 years, 
homozygous or heterozygous for F508del 
  
Endpoints Primary Endpoint 
Absolute change in lung clearance index2 5 (LCI
2 5) from baseline through Week 8 
Secondary Endpoints 
• Absolute change from baseline in sweat chloride at Week 8 
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory 
domain score from baseline through Week 8 
• Safety and tolerability as measured by adverse events (AEs), clinically 
significant changes in laboratory values (serum chemistry, hematology, 
coagulation studies, lipids, vitamin levels, and urinalysis), standard 12-lead 
ECGs, vital signs, pulse oximetry, serial lung function measurement, and 
ophthalmologic examinations.  


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Number of 
Subjects 
Approximately 65 subjects total, of which up to 15 subjects are heterozygous for F508del 
and a second CFTR allele that results in residual function (F/RF) 
  
Study Population Male and female subjects aged 6 through 11 years with CF who are F/F or F/RF 
  
Investigational 
Drug 
Active substance: TEZ and IVA 
 Activity: CFTR corrector and potentiator (increased Cl− secretion) 
 Strength and route of administration: TEZ 50 mg/IVA 75 mg fixed-dose combination 
(FDC) tablet or TEZ 100 mg/IVA 150 mg FDC tablet; oral administration 
  
 Active substance: IVA 
 Activity: CFTR potentiator (increased Cl− secretion) 
 Strength and route of administration: IVA 75- or 150-mg tablet; oral administration 
  
 Active substance: Not applicable 
 Activity: Placebo 
 Strength and route of administration: 0-mg matching placebo tablets for oral 
administration 
  
Study Duration Each subject will participate in the study for 16 weeks: 4-week Screening Period, 8-week 
Treatment Period, and 4-week Safety Follow-up Period.  
  


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Study Design This is a Phase 3, double-blind,parallel-group study in subjects with CF who are 
homozygous or heterozygous for the F508del-CFTRmutation. The study is designed to 
evaluate the efficacy and safetyofTEZ/IVA treatment in pediatric subjects aged 6 
through 11 years. 
Subjects will be stratified by genotype group(F/F or F/RF) and randomized 4:1 
(TEZ/IVA: blinding arm) and treated as shown in Figure 2-1. The blinding arm will be 
placebo for F/F subjects and IVA monotherapy (with TEZ-matchingplacebo) for F/RF 
subjects.
Figure 2-1 
VX16-661-115 Study Design 
Notes:Subjects who are taking commercially available CFTR modulators (Orkambi®
or Kalydeco®) are required to washout for 28days before the Day 1 Visit. Study 
drug dose is determined based on weight on Day 1(<40kg or ≥40 kg). Subjects 
will receive matched TEZ/IVA placebo or IVA placebo tablets as appropriate. See 
Table 9-2for additional information on study drug tablets and dosing.
Subjects will be offered the opportunity to enroll in a 96-week open-label TEZ/IVA 
extension study (Study VX17-661-116) after completing the Week 8 Visit. The Safety 
Follow-up Visit is not required for subjects who enroll in the extension study within 
4 weeks after the last dose of study drug. 
Subjects who prematurely discontinue study drug treatment will be asked to remain in the 
study and complete the efficacy assessments (LCI, CFQ-R, sweat chloride,  
 
 from the time of 
discontinuation through the end of the Treatment Period. Subjects who are discontinued 
due to having an ineligible genotype or due to lack of health authority approval will 
complete the ETT Visit and are not required to return for additional efficacy assessments
because they will be discontinued from the study.




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3 
SCHEDULE OF ASSESSMENTS 
The Schedule of Assessments is shown in Table 3-1. 
Table 3-1 
Study VX16-661-115: Screening, Treatment Period, Early Termination of Treatment, and Safety Follow-up 
Event/Assessmenta 
Screening Period 
Day -28 to Day -1 
Treatment Period 
Early 
Termination of 
Treatment 
(ETT) Visitb 
Safety Follow-up 
Visit 
(4 Weeks 
[± 7 Days] After 
Last Dose of 
Study Drug)c 
Day 1 
Week 2 
(± 3 Days) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days)d 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
Informed consent and assent (if 
applicable) 
X 
 
 
 
 
 
 
CFTR genotypee 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Medications review 
X 
 
 
 
 
 
 
CFQ-Rf 
 
X 
X 
X 
X 
X 
Xg 
Height and weighth  
X 
X 
X 
X 
X 
X 
X 
 
a  All assessments will be performed before study drug dosing unless noted otherwise (refer to Section 11.1). 
b  If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the subject decides to terminate treatment 
(refer to Section 9.1.4). Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 4 weeks 
(± 7 days) after their last dose of study drug. If the ETT Visit occurs 3 weeks or later after the last dose of study drug, then the Safety Follow up Visit will 
replace ETT Visit. 
c  The Safety Follow-up Visit is not required for subjects who enroll in the extension study within 28 days after the last dose of study drug. 
d  Subjects who complete the Week 8 Visit will be offered the opportunity to enroll in Study VX17-661-116, an open-label TEZ/IVA extension study, if they 
meet the eligibility criteria for the extension study. 
e All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype lab report. If the CFTR screening genotype 
result is not received before enrollment, a previous CFTR genotype lab report may be used to establish eligibility (Section 8.1). 
f  CFQ-R should be completed before the start of any other assessments. 
g  CFQ-R is only required at the Safety Follow-up Visit for subjects who prematurely discontinue study treatment and do not have the ETT visit. 
h  Height and weight will be measured with shoes off. On Day 1, height and weight will be measured before dosing with study drug. Body Mass Index (BMI) 
will be derived from assessment of height and weight. 


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Table 3-1 
Study VX16-661-115: Screening, Treatment Period, Early Termination of Treatment, and Safety Follow-up 
Event/Assessmenta 
Screening Period 
Day -28 to Day -1 
Treatment Period 
Early 
Termination of 
Treatment 
(ETT) Visitb 
Safety Follow-up 
Visit 
(4 Weeks 
[± 7 Days] After 
Last Dose of 
Study Drug)c 
Day 1 
Week 2 
(± 3 Days) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days)d 
Vital signs and pulse oximetryi 
X 
X 
X 
X 
X 
X 
X 
Ophthalmologic examinationj 
X 
 
 
 
 
X 
X 
Physical examinationk  
Full  
Abbreviated 
 
 
Abbreviated 
 
Abbreviated 
Standard 12-lead ECG
l 
X 
X 
X 
X 
X 
X 
X 
Sweat chloridem 
X 
X 
 
 
X 
 
X 
Pregnancy test (female subjects of 
childbearing potential)n 
Serum 
Urine 
 
Serum 
Serum 
Serum 
Serum 
 
i  Vital signs and pulse oximetry will be collected after the subject has been at rest for at least 5 minutes. 
j  Ophthalmologic examinations will be conducted by a licensed ophthalmologist or optometrist. Ophthalmologic examinations do not need to be completed if 
there is documentation of bilateral lens removal. The screening examination does not need to be repeated if there is documentation of an examination 
meeting the protocol requirements that was conducted within 3 months before the date of assent. For additional detail, see Section 11.5.7. For subjects who 
do not rollover into an extension study, a single end-of-study examination will be done at the ETT or SFUV. 
k  See Section 11.5.4. At other visits, symptom-directed physical examinations will occur if triggered by adverse events or if deemed necessary by the 
investigator. 
l  All standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes and before any other procedures that may affect heart 
rate, such as blood draws. During the Treatment Period, ECGs will be performed before dosing. ECGs collected on Day 1 before study drug dosing will be 
performed in triplicate. 
m  A sweat chloride test must be performed at Screening if an eligible sweat chloride value is not available in the subject’s medical records. For subjects using a 
sweat chloride value documented in their medical record to establish eligibility, the sweat chloride test at the Screening Visit is optional. Collection of sweat 
chloride will not overlap with any other study assessments. During the Treatment Period, sweat collection will be done approximately at the same time as 
predose blood collections.  
n  Any female subject who does not meet the criteria for non-childbearing potential (refer to Section 11.5.8.1) is considered to be of childbearing potential and 
must have pregnancy testing. 


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Table 3-1 
Study VX16-661-115: Screening, Treatment Period, Early Termination of Treatment, and Safety Follow-up 
Event/Assessmenta 
Screening Period 
Day -28 to Day -1 
Treatment Period 
Early 
Termination of 
Treatment 
(ETT) Visitb 
Safety Follow-up 
Visit 
(4 Weeks 
[± 7 Days] After 
Last Dose of 
Study Drug)c 
Day 1 
Week 2 
(± 3 Days) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days)d 
Urinalysiso 
X 
X 
 
 
X 
X 
X 
Lipid panelo 
 
Xp 
 
 
X 
X 
X 
Vitamin levelso 
 
Xp 
 
 
X 
X 
X 
Serum chemistryo 
X 
Xp 
X 
X 
X 
X 
X 
Hematologyo 
X 
Xp 
X 
 
X 
X 
X 
Coagulation studieso 
X 
 
 
 
X 
X 
X 
Multiple-breath washout (MBW)s 
X 
X 
X 
X 
X 
 
 
Spirometryt  
X 
X 
X 
X 
X 
X 
X 
Meal or snack at clinic 
 
X 
X 
X 
optional 
 
 
Study drug count 
 
 
X 
X 
X 
X 
 
 
o  See Section 11.5.2 for details. 
p    Blood samples to be collected predose on Day 1. At all other scheduled visits, these samples will be collected at any time during the visit. 
s  The MBW assessment will be performed in multiple replicates and before study drug dosing (see Section 11.4.1 and the Study Reference Manual). MBW 
should be performed pre-bronchodilator and will be performed before the spirometry assessment. 
t  At the Screening Visit, spirometry may be performed pre- or post-bronchodilator. At all visits during the Treatment Period, spirometry must be performed 
for all subjects before dosing and should be performed pre-bronchodilator. On Day 1 and Week 2, additional spirometry will be performed at 2 
(± 30 minutes) and 4 hours (± 30 minutes) postdose. If more than 1 spirometry assessment is required at a visit, bronchodilators should be withheld until the 
last scheduled spirometry assessment is completed. If study drug is not administered on the day of the visit (i.e., study drug interruption or permanent 
discontinuation of study drug)  the assessment will only be collected once   


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Table 3-1 
Study VX16-661-115: Screening, Treatment Period, Early Termination of Treatment, and Safety Follow-up 
Event/Assessmenta 
Screening Period 
Day -28 to Day -1 
Treatment Period 
Early 
Termination of 
Treatment 
(ETT) Visitb 
Safety Follow-up 
Visit 
(4 Weeks 
[± 7 Days] After 
Last Dose of 
Study Drug)c 
Day 1 
Week 2 
(± 3 Days) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days)d 
Study drug dosingv 
 
X 
X 
X 
 
 
 
Concomitant medications, 
treatments, and procedures 
Continuous from signing of informed consent form (and assent form, if applicable) through Safety Follow-up Visit 
Adverse events and serious adverse 
events 
Continuous from signing of informed consent form (and assent form, if applicable) through Safety Follow-up Visit 
 
v  The study drug should be administered within 30 minutes after starting a meal with fat-containing food. On days of scheduled visits, the dose of study drug 
 
will be administered at the site after predose assessments have been completed. At the Week 8 Visit, the morning dose of study drug will NOT be 
 
administered. The last dose of study drug will be the evening dose administered the day before the Week 8 Visit. Refer to Section 9.4 for details on study 
 
restrictions and Section 9 6 for details on study drug administration 








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13.2.5 Subject Privacy 
....................................................................................................... 61
 
13.2.6 Record Retention 
.................................................................................................... 62
 
13.2.7 Study Termination 
.................................................................................................. 62
 
13.2.8 End of Study 
........................................................................................................... 62 
13.3 Data Quality Assurance 
.................................................................................................. 63
 
13.4 Monitoring 
...................................................................................................................... 63 
13.5 Electronic Data Capture ................................................................................................. 63
 
13.6 Publications and Clinical Study Report 
.......................................................................... 64 
 
 
13.6.2 Clinical Study Report 
............................................................................................. 64
 
14 References 
............................................................................................................................. 65
 
15 Appendix 1: CFTR Mutations 
............................................................................................ 67
 
16 Protocol Signature Pages .................................................................................................... 68 
16.1 Sponsor Signature Page 
.................................................................................................. 68 
16.2 Investigator Signature Page 
............................................................................................ 69
 
 
 
 


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List of Tables 
Table 3-1 
Study VX16-661-115: Screening, Treatment Period, Early Termination of 
Treatment, and Safety Follow-up ........................................................................... 6 
Table 9-1
 
Lifestyle Guidelines and Study Restrictions 
......................................................... 30
 
Table 9-2
 
Study Drug Administration 
................................................................................... 32
 
Table 10-1
 Identity of Study Drugs, Dosage, and Storage 
...................................................... 35 
Table 11-1
 Safety Laboratory Test Panels 
.............................................................................. 43
 
Table 11-2 Acceptable Methods of Contraception.................................................................. 47 
Table 12-1 Target Enrollment by Genotype and Study Drug Treatment 
................................ 49 
Table 13-1
 Grading of AE Severity ........................................................................................ 58
 
Table 13-2
 Classifications for AE Causality 
........................................................................... 58
 
Table 13-3
 Classifications for Study Drug Action Taken With Regard to an AE 
.................. 58 
Table 13-4
 Classifications for Outcome of an AE 
.................................................................. 59
 
List of Figures 
Figure 2-1 
VX16-661-115 Study Design ................................................................................. 4 
Figure 9-1 
VX16-661-115 Study Design ............................................................................... 24 
 
 
 


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List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
ATS 
American Thoracic Society 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Clˉ 
chloride ion 
 
 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ERS 
European Respiratory Society 
ETT 
Early Termination of Treatment 
EU 
European Union 
F/F 
homozygous for F508del 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
F/RF 
heterozygous for F508del and a second allele with a residual function mutation 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act and associated regulations 
HR 
heart rate 
ICF 
informed consent form 




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Abbreviation 
Term 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
TEZ/IVA 
tezacaftor in combination with ivacaftor 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide.1 CF is a 
progressive, systemic, life-shortening, genetic disease that is caused by reduced quantity and/or 
function of the CFTR protein due to mutations in the CFTR gene. In people with CF, loss of 
chloride transport due to defects in CFTR result in the accumulation of thick, sticky mucus in the 
bronchi of the lungs, loss of exocrine pancreatic function, impaired intestinal absorption, 
reproductive dysfunction, and elevated sweat chloride concentration. Lung disease is the primary 
cause of morbidity and mortality in people with CF. The median predicted age of survival of 
individuals born today with CF is approximately 40 years of age.2,3  
Two complementary approaches to increase CFTR-mediated Cl− secretion in the airway epithelia 
have been studied.
9 One approach is to treat with a compound that will modify the cellular 
processing and trafficking of the CFTR protein to increase the amount of functional CFTR at the 
cell surface. This kind of compound has been termed a CFTR corrector. Another approach is to 
treat with a compound that increases the channel gating activity of CFTR at the cell surface to 
enhance ion transport. This kind of compound has been termed a potentiator.  
Tezacaftor (TEZ) and ivacaftor (IVA) are CFTR modulators with interdependent mechanisms of 
action in treating CF patients with CFTR mutations that require a combination therapy approach. 
TEZ and IVA both address the underlying cause of CF, and each has a different and essential 
role as a corrector (TEZ) or potentiator (IVA) of the CFTR protein in CF patients. 
TEZ (VX-661) and IVA (Kalydeco®; VX-770) were developed by Vertex Pharmaceuticals 
Incorporated (Vertex). IVA was the first CFTR modulator to show an improvement in CFTR 
function and clinical benefit in patients with CF and is marketed as Kalydeco. Kalydeco is 
indicated for the treatment of CF in patients as young as 2 years who have a G551D, certain 
gating, and certain residual function mutations CFTR. The indicated mutations and approved 
populations vary by country. Please refer to local prescribing information for your region for the 
current approved use of Kalydeco. 
Results from 2 pivotal Phase 3 Studies VX14-661-106 (Study 106) and VX14-661-108 
(Study 108) evaluating TEZ in combination with IVA (TEZ/IVA) have demonstrated clinically 
meaningful and statistically significant improvements in lung function and key secondary 
endpoints along with favorable safety and benefit/risk profiles with the TEZ daily (qd)/IVA 
every 12 hours (q12h) regimen in CF subjects homozygous or heterozygous for F508del aged 
≥12 years. 
Additional details about TEZ/IVA can be found in the TEZ Investigator
's Brochure. 


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5.2 
Study Rationale 
Efficacy, safety, and pharmacokinetics (PK) profiles have been established for TEZ/IVA in 
subjects with CF who are 12 years of age and older. Preliminary safety and PK profiles for 
TEZ/IVA have been established in subjects with CF who are 6 through 11 years of age and who 
are homozygous or heterozygous for the F508del in Part A of Study VX15-661-113 (Study 113). 
Ongoing Study 113 Part B is designed to obtain further PK, safety, tolerability, 
pharmacodynamics, and efficacy information to support an expanded indication for TEZ/IVA 
treatment in the pediatric population.  
Study 115 is designed to evaluate the efficacy (primary objective) and safety (secondary 
objective) of TEZ/IVA in subjects aged 6 through 11 years with CF, homozygous or 
heterozygous for F508del.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of TEZ/IVA in subjects with CF aged 6 through 11 years, homozygous 
or heterozygous for F508del 
6.2 
Secondary Objective 
To evaluate the safety of TEZ/IVA in subjects with CF aged 6 through 11 years, homozygous or 
heterozygous for F508del 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change in lung clearance index2.5 (LCI
2.5) from baseline through Week 8 
7.2 
Secondary Endpoints 
• Absolute change from baseline in sweat chloride at Week 8 
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline through Week 8 
• Safety and tolerability as measured by adverse events (AEs), clinically significant changes in 
laboratory values (serum chemistry, hematology, coagulation studies, lipids, vitamin levels, 
and urinalysis), standard 12-lead ECGs, vital signs, pulse oximetry, serial lung function 
measurement, and ophthalmologic examinations. 


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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
for the study. 
8.1 
Inclusion Criteria 
1. Subject’s legally appointed and authorized representative will sign and date an informed 
consent form (ICF) and the subject will sign and date an assent form (if applicable). 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Subjects (male and female) will be between the ages of 6 and 11 years, inclusive, on the 
date(s) of informed consent (and assent, if applicable). 
4. Subjects who weigh ≥15 kg without shoes at the Screening Visit.  
5. Genotypes as presented in Appendix 1. Genotype is to be confirmed during screening. If the 
CFTR screening genotype result is not received before enrollment, a previous CFTR 
genotype lab report may be used to establish eligibility. Subjects who have been enrolled and 
whose screening genotype does not confirm study eligibility must be discontinued from the 
study as described in Section 10.7. Note: Additional mutations may be evaluated and updates 
to approved mutations will be communicated to investigative sites through a memorandum. 
6. A confirmed diagnosis of CF4 as determined by the following criteria: 
a. For subjects who are F508del homozygous: confirmed diagnosis of CF defined as a 
sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis (as 
documented in the subject’s medical record OR from the sweat chloride test result 
obtained at the Screening Visit). 
b. For subjects who are F508del heterozygous:  
• Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis (as documented in the subject’s medical 
record [this value may be obtained from a record collected prior to use of 


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Kalydeco] OR from the sweat chloride test result obtained at the Screening Visit); 
OR 
• If the sweat chloride value is <60 mmol/L, there must be documented evidence of 
chronic sinopulmonary disease
4 and/or gastrointestinal disease consistent with a 
diagnosis of CF as judged by the principal investigator, manifest by at least 1 of 
the following: 
o Persistent colonization/infection, defined as ≥2 positive respiratory 
cultures within a 6 month period, with 1 or more typical CF pathogens 
(e.g., Staphylococcus aureus, Haemophilus influenzae, mucoid and 
nonmucoid Pseudomonas aeruginosa) 
o Chronic cough and sputum production 
o Persistent chest radiograph abnormalities consistent with CF pulmonary 
disease (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation) 
o Nasal polyps, chronic sinusitis as manifest by radiographic or computed 
tomographic abnormalities of the paranasal sinuses 
o Evidence of gastrointestinal disease consistent with the diagnosis of CF 
o Significant delays in growth and/or weight gain consistent with the 
diagnosis of CF 
9. Subjects with ppFEV
1 of ≥70 percentage points adjusted for age, sex, height, and ethnicity 
using the Global Lung Function Initiative (GLI) equation5 at the Screening Visit 
(Section 11.4.2).  
10. Subjects with a screening LCI2.5 result ≥7.5. 
11. Subjects with stable CF disease as deemed by the investigator at the Screening Visit. 
12. Subjects who are willing to remain on their stable CF medication regimen through Week 8 
or, if applicable, through the Safety Follow-up Visit. 
13. Subjects who are able to swallow tablets.  
14. Female subjects of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at the Day 1 Visit before receiving the 
first dose of study drug. 
15. Subjects of childbearing potential who are sexually active must meet the contraception 
requirements outlined in Section 11.5.8.1.  
16. As deemed by the investigator, the subject’s legally appointed and authorized representative 
(e.g., parent or legal guardian) must be able to understand protocol requirements, restrictions, 
and instructions. The subject’s legally appointed and authorized representative should be able 
to ensure that the subject will comply with and is likely to complete the study as planned. 
8.2 
Exclusion Criteria 
1. History of any comorbidity reviewed at the Screening Visit that, in the opinion of the 
investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject.  


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For example, history of cirrhosis with portal hypertension and/or history of risk factors for 
Torsades de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left 
ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history of 
arrhythmia [ventricular and atrial fibrillation], obesity, acute neurologic events [subarachnoid 
hemorrhage, intracranial hemorrhage, cerebrovascular accident, intracranial trauma], and 
autonomic neuropathy). 
2. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere 
with the study assessments or pose an undue risk for the subject (as deemed by the 
investigator). 
3. Any of the following abnormal laboratory values at the Screening Visit: 
• Hemoglobin <10 g/dL 
• Abnormal liver function defined as any 2 or more of the following:  
o ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST)  
o ≥3 × ULN alanine aminotransferase (ALT)  
o ≥3 × ULN gamma-glutamyl transpeptidase (GGT) 
o ≥3 × ULN alkaline phosphatase (ALP) 
o ≥2 × ULN total bilirubin 
• Abnormal liver function defined as any increase of ≥5 × ULN ALT or AST 
• Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 
(calculated by the Counahan-Barratt equation)6  
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study 
drug). 
5. Colonization with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at the 
Screening Visit. The investigator could be guided by the following suggested criteria for a 
subject to be considered free of colonization:  
• The subject should have had at least 2 respiratory tract cultures negative for these 
organisms within the past 12 months, with no subsequent positive cultures. 
• These 2 respiratory tract cultures should have been separated by at least 3 months. 
• One of these 2 respiratory tract cultures should have been obtained within the past 
6 months. 
6. A standard 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. If QTc 
exceeds 450 msec at the Screening Visit, the ECG should be repeated 2 more times during 
the Screening Period, and the average of the 3 QTc values should be used to determine the 
subject
's eligibility. 
7. History of solid organ or hematological transplantation at the Screening Visit. 


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8. Ongoing or prior participation in an investigational drug study or use of commercially 
available CFTR modulator that does not align with the following requirements: 
• A washout period of 30 days or 5 terminal half-lives of the previous investigational study 
drug, whichever is longer, must elapse before screening. 
o The duration of the elapsed time may be longer if required by local regulations.  
• A washout period of 28 days for investigational lumacaftor/IVA, or physician-prescribed 
Orkambi® or Kalydeco® must elapse before the Day 1 Visit.  
Note: Ongoing participation in a noninterventional study (including observational studies) is 
permitted. 
9. Use of restricted medication or food within a specified duration before the Screening Visit or 
first dose of study drug and/or unwillingness to maintain the restrictions as defined in 
Section 9.4.  
10. Pregnant and nursing females. 
11. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, double-blind, parallel-group study. A schematic of the study design is shown 
in Figure 9-1.  


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Figure 9-1 
VX16-661-115 Study Design 
Notes:Subjects who are taking commercially available CFTR modulators (Orkambi or Kalydeco) are required to 
washout for 28days before the Day 1 Visit. The study will enroll a total of approximately 65subjects, of which 
up to15subjects have anF/RF genotype.Subjects will be stratified by genotypegroup (F/F or F/RF) and 
randomized 4:1 (TEZ/IVA: blinding arm) before receiving the first dose of study drug on Day 1. The blinding
treatment arm will be placebo for F/F subjects and IVA monotherapy (with TEZ-matchingplacebo) for F/RF 
subjects.Studydrug dose is determined based on weight on Day 1(<40kg or ≥40kg). Subjects will receive 
matched TEZ/IVA placebo or IVA placebo tablets as appropriate. SeeTable 9-2for additional information on 
study drug tablets and dosing.
9.1.1
Screening
Screening Visit assessments are listed in Table 3-1.
The Screening Period will occur within 28 days before the first dose of study drug to confirm 
that subjects meet the selection criteria for the study. To participate in the study, the subject
's 
parent or legal guardian must sign and date a study-specific ICF and the subject must sign an 
assent form (if applicable) before any study-specific procedures can be performed. The ICF (and 
assent form, if applicable) will comply with all applicable regulations governing the protection of 
human subjects and will be approved by Vertex and the site
's IRB. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section9.4) and use of concomitant medications (Section 9.5). During the Screening Period, 
subjects who are being treated with Orkambi or Kalydeco will undergo a 28-day washout before 
the Day 1 Visit (Table 9-1).


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9.1.1.1 
Repetition of Screening Period Assessments 
Repetition of any individual Screening Visit assessment(s) that does not meet eligibility criteria 
is not permitted, with the following exceptions:  
• If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test may be 
permitted after discussion with the Vertex medical monitor or authorized designee. 
• If a convincing alternative etiology is identified for elevated transaminases, exclusionary 
liver function test (LFT) levels may be retested within 14 days of the original Screening Visit 
date. 
• If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by the American Thoracic Society (ATS)/European Respiratory Society (ERS) 
guidelines,
7 repeat spirometry evaluation may be performed once. 
• If the subject had difficulty completing the multiple-breath washout (MBW) assessment. 
• Patients taking physician-prescribed Orkambi or Kalydeco at the Screening Visit can repeat 
the screening MBW and sweat chloride assessments as needed after approximately 28 days 
of Orkambi washout. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed 
within the Screening Period window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may be rescreened after discussion with, and approval from, the Vertex medical 
monitor or authorized designee to account for exclusionary events that may not reflect the 
subject’s true baseline due to an acute event, which may resolve.  
If a subject is rescreened, all Screening Visit assessments will be repeated except for CFTR 
genotyping, sweat chloride, and the ophthalmologic examination (if the ophthalmologic 
examination was performed within 3 months before the Rescreening Visit). If a subject is 
rescreened, the screening window will begin after the first rescreening assessment has been 
initiated. 
9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks after approval by the 
medical monitor or authorized designee for the following reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Scheduling of the ophthalmologic examination (Section 11.5.7) 


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9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-1. All subjects will have study visits on 
Day 1, and Weeks 2, 4, and 8. 
The first dose of study drug will be administered on Day 1 and the last dose of study drug will be 
the evening dose administered the day before the Week 8 Visit. Dosing details are given in 
Section 9.3.2. 
Subjects will be offered the opportunity to enroll in a 96-week open-label TEZ/IVA extension 
study (Study VX17-661-116) after completing the Week 8 Visit. The Safety Follow-up Visit 
(Section 9.1.3) is not required for subjects who enroll in the extension study within 4 weeks after 
the last dose of study drug. 
9.1.3 
Safety Follow-up 
Table 3-1 lists the Safety Follow-up Visit assessments. Subjects will have a Safety Follow-up 
Visit 4 weeks (± 7 days) after the last dose of study drug. The Safety Follow-up Visit is not 
required for subjects who have enrolled in the extension study within 28 days after the last dose 
of study drug.  
9.1.4 
Early Termination of Treatment 
If the subject prematurely discontinues study treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the subject decides to terminate study 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the 
Safety Follow-up Visit, approximately 4 weeks ± 7 days after their last dose of study drug. If the 
ETT Visit occurs 3 weeks or later after the last dose of study drug, then the Safety Follow-up 
Visit will replace the ETT Visit and a separate ETT Visit is not required. Subjects who 
prematurely discontinue treatment will continue to complete all the other scheduled study visits 
for assessments of efficacy as detailed in the Schedules of Assessments (Table 3-1). 
During the course of study conduct, if local health authorities decline to approve, or if clinical 
benefit is not demonstrated for the use of TEZ/IVA for the treatment of CF in a corresponding 
adult population, pediatric subjects with the relevant CFTR genotypes may be discontinued after 
communication to investigators and IRBs/IECs of the risks/benefits related to the safety and 
efficacy observed for the subset of subjects. If subjects are discontinued from the study, an ETT 
Visit should occur as soon as possible after the last dose of study drug and a Safety Follow-up 
Visit should occur approximately 4 weeks ± 7 days after the last dose of study drug. Subjects 
who are discontinued due to having an ineligible genotype or due to lack of health authority 
approval (Section 9.8) will complete the ETT Visit and are not required to return for additional 
efficacy assessments, because they will be discontinued from the study. 
If the subject withdraws consent for the study no further evaluations should be performed, and no 
additional data should be collected. Vertex may retain and continue to use any data collected 
before such withdrawal of consent. 
9.1.5 
Independent Data Monitoring Committee 
Safety and tolerability data will be reviewed by an independent data monitoring committee 
(IDMC) to ensure the safety of the subjects in the study (Section 12.3.5). Procedural details of 
the IDMC
's structure and function, frequency of meetings, and data planned for review will be 


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included in the IDMC charter. The IDMC charter will be finalized before the first subject is 
screened.  
9.2 
Method of Assigning Subjects to Treatment Groups 
An interactive web or voice response system (IXRS) will be used to assign subjects to treatment. 
The randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the study execution team (SET).  
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
This is a Phase 3, double-blind, parallel-group study in subjects with CF aged 6 to 11 years, 
homozygous or heterozygous for F508del. Subjects will be: 
• homozygous for F508del (F/F), or  
• heterozygous for F508del and a second allele with a residual function mutation (F/RF). 
A list of the genotypes eligible for study enrollment is provided in Appendix 1.  
Approximately 65 subjects, of which up to15 subjects have an F/RF genotype, will be stratified 
by genotype and randomized 4:1 to study drug treatment.  
Because CF pulmonary disease progresses throughout life, it is not uncommon for patients in the 
6- to 11-year age group to have well-preserved or even normal spirometry (e.g., ppFEV1).
8,9 In 
spite of the potentially normal spirometry, patients in this age group with severe CF-causing 
mutations already have pulmonary structural aberrations observed through computed 
tomography scans
9,10 and MBW, which measures the degree of small airway disease by 
assessing ventilation inhomogeneity. These observations confirm that the disease process that 
results from lack of CFTR activity begins early in life before spirometry is affected. Because the 
underlying genetic and molecular etiology of the disease is consistent between this age group and 
older subjects who have been evaluated in previous TEZ/IVA studies, it is anticipated that 
TEZ/IVA therapy will be efficacious in this younger population as well. 
Efficacy, safety, and PK profiles for TEZ/IVA have been established in subjects ≥12 years of 
age. Results from 2 pivotal Phase 3 Studies Study 106 and Study 108 have demonstrated 
clinically meaningful and statistically significant improvements in lung function and key 
secondary endpoints with TEZ/IVA in CF subjects homozygous or heterozygous for F508del 
aged ≥12 years, along with favorable safety and benefit/risk profiles. Preliminary results from 
Study 113 Part A show that the exposure, safety, and tolerability of TEZ/IVA are favorable in 
subjects homozygous or heterozygous for F508del who are aged 6 through 11 years.  
This study is designed to evaluate the efficacy and safety of TEZ/IVA treatment in a younger 
pediatric population of CF subjects. 
9.3.2 
Study Drug Dose and Duration 
TEZ/IVA doses were selected based on the exposure, safety, and tolerability results from 
Study 113 Part A, and results from Study VX11-661-101 which were confirmed in pivotal 
Phase 3 Studies 106 and 108. All doses are based on subject weight at baseline. The same dose 


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will be given for the full duration of the study. The dose regimens of IVA (75 mg or 150 mg 
q12h) are the currently labeled dose regimens for certain populations of patients with CF. 
An 8-week Treatment Period duration was selected because significant improvements in lung 
function were observed after 2 to 4 weeks of treatment with TEZ/IVA and sustained through 24 
and 48 weeks of treatment in the pivotal Phase 3 Studies 106 and 108, and during open-label 
extension Study VX14-661-110 (Study 110), in CF subjects aged ≥12 years. 
9.3.2.1 
Study Drug Treatment Arms 
F/F Subjects Randomized to TEZ/IVA Treatment 
Subjects who are <40 kg at the Day 1 Visit will receive a morning dose of TEZ 50 mg/IVA 
75 mg (fixed-dose combination [FDC] tablet) and an evening dose of IVA 75 mg (tablet).  
Subjects who are ≥40 kg at the Day 1 Visit will receive a morning dose of TEZ 100 mg/IVA 
150 mg (FDC tablet) and an evening dose of IVA 150 mg (tablet).  
F/F Subjects Randomized to Placebo 
Subjects will receive a morning dose of TEZ/IVA-matching placebo (FDC tablet) and an 
evening dose of IVA-matching placebo (tablet).  
F/RF Subjects Randomized to TEZ/IVA Treatment 
Subjects who are <40 kg at the Day 1 Visit will receive a morning dose of TEZ 50 mg/IVA 
75 mg (FDC tablet), a morning dose of IVA-matching placebo (tablet), and an evening dose of 
IVA 75 mg (tablet).  
Subjects who are ≥40 kg at the Day 1 Visit will receive a morning dose of TEZ 100 mg/IVA 
150 mg (FDC tablet), a morning dose of IVA-matching placebo (tablet), and an evening dose of 
IVA 150 mg (tablet).  
F/RF Subjects Randomized to TEZ-matching placebo/IVA Treatment 
Subjects who are <40 kg at the Day 1 Visit will receive a morning dose of TEZ/IVA-matching 
placebo (FDC tablet), a morning dose of IVA 75 mg (tablet), and an evening dose of IVA 75 mg 
(tablet).  
Subjects who are ≥40 kg at the Day 1 Visit will receive a morning dose of TEZ/IVA-matching 
placebo (FDC tablet), a morning dose of IVA 150 mg (tablet), and an evening dose of IVA 
150 mg (tablet). 
9.3.3 
Rationale for Study Assessments 
The efficacy and safety assessments are standard parameters for clinical studies in drug 
development. The efficacy assessments are widely accepted and generally recognized as reliable, 
accurate, and relevant to the study of patients with CF. 
Multiple Breath Washout: LCI, as assessed by multiple breath washout, is a measure of 
ventilation inhomogeneity that is based on tidal breathing techniques which have been evaluated 
in patients as young as infants.
11,12 Studies have shown that LCI correlates with FEV
1 in its 
ability to measure airway disease in patients with impacted spirometry assessment but can also 
detect lung disease at an earlier stage than spirometry.13,14 Furthermore, data from 
Study VX10-770-106 in CF patients with an FEV
1 >90% showed LCI to be a more sensitive 
outcome measure than FEV1. 






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4 weeks before the Screening Period through the Safety Follow-up Visit will be recorded in each 
subject
's source documents and electronic case report form (eCRF).  
• It is recommended that subjects remain on their stable medication regimen for CF from 
4 weeks before Day 1 through Week 8 or, if applicable, through the Safety Follow-up Visit. 
Stable medication regimen is defined as the current medication regimen for CF (except for 
commercially available CFTR modulators) that subjects have been following for at least 
4 weeks before Day 1. Subjects must not initiate long-term treatment with new medication 
from 28 days before Day 1 through the Safety Follow-up Visit unless discussed and approved 
by the Vertex medical monitor. Guidelines for stable medication regimens for CF are as 
follows: 
o Subjects who are taking daily inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who are on inhaled cycling antibiotics should continue on their prior schedule. 
The timing of the first dose of study drug should be synchronized as closely as possible to 
the first day of inhaled cycling antibiotics in the cycle. 
o Subjects who alternate 2 different antibiotics monthly should remain on the same 
schedule during the study. The timing of the first dose of study drug should be 
synchronized as closely as possible to the first day of 1 of the inhaled alternating 
antibiotics. 
• Subjects may receive doses of prednisone (or prednisolone) of up to 10 mg/day (chronically), 
or prednisone (or prednisolone) 60 mg qd for up to 5 days with tapering down to 10 mg/day 
within 2 weeks, without prior approval of the medical monitor. 
• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.4.2. 
• Concomitant use of medications known to prolong the QT interval should be used with 
caution during the study, even though the effect of TEZ/IVA on the QT interval has been 
evaluated in a thorough QT study, which demonstrated no prolongation of the QT interval. 
Consideration should be given to obtaining an ECG when concomitant medication known to 
prolong the QT interval is administered. 


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9.6 
Administration 
On Day 1 through the evening dose administered the day before the Week 8 Visit (last dose of 
study drug), study drug tablets will be administered orally as shown in Table 9-2.  
Table 9-2 
Study Drug Administration 
Genotype 
Treatment 
Arm 
Subject 
Weight on 
Day 1 
Time 
Drug(s) and Dose(s) Administered;  
Route of Administration 
F/F 
TEZ qd/ 
IVA q12h 
<40 kg 
AM 
1 × TEZ 50-mg/IVA 75-mg FDC tablet; oral 
PM 
1 × IVA 75-mg tablet; oral 
≥40 kg 
AM 
1 × TEZ 100-mg/IVA 150-mg FDC tablet; oral 
PM 
1 × 150-mg tablet; oral 
Placebo 
<40 or 
≥40 kg 
AM 
1 × TEZ/IVA-matching placebo FDC tablet; oral 
PM 
1 × IVA-matching placebo tablet; oral 
F/RF  
TEZ qd/ 
IVA q12h 
<40 kg 
AM 
1 × TEZ 50-mg/IVA 75-mg FDC tablet; oral 
and 
1 × IVA-matching placebo tablet; oral 
PM 
1 × IVA 75-mg tablet; oral  
≥40 kg 
AM 
1 × TEZ 100-mg/IVA 150-mg FDC tablet; oral 
and 
1 × IVA-matching placebo tablet; oral 
PM 
1 × IVA 150-mg tablet; oral 
TEZ-matching 
placebo qd/ 
IVA q12h 
<40 kg 
AM 
1 × TEZ/IVA-matching placebo FDC tablet; oral 
and 
1 × IVA 75-mg tablet; oral 
PM 
1 × IVA 75-mg tablet; oral 
≥40 kg 
AM 
1 × TEZ/IVA-matching placebo FDC tablet; oral 
and 
1 × IVA 150-mg tablet; oral 
PM 
1 × IVA 150-mg tablet; oral 
 
Study drug should be administered within 30 minutes after starting a meal with fat-containing 
food such as a standard “CF” high-fat, high-calorie meal or snack according to the following 
guidelines: 
1. Study drug should be administered q12h (± 2 hours). For each subject, all doses (morning 
and evening) of study drugs should be administered at approximately the same time each 
day. For example, if the morning dose of study drug is administered at 08:00 on Day 1, all 
subsequent morning doses should be administered between 06:00 and 10:00. On days of 
scheduled visits, the morning dose of study drug will be administered at the site after predose 


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assessments have been completed. A meal or snack will be provided by the site for the 
morning dose of study drug.  
2. If a subject
's scheduled visit is to occur in the afternoon, the following guidelines must be 
used for administering either the morning or evening dose: 
• If the dose in the clinic will be within 6 hours of the subject
's scheduled morning dose, 
the subject should withhold their morning dose of study drug, and the morning dose will 
be administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject
's scheduled morning 
dose, the subject should take the morning dose at home, and the evening dose will be 
administered in the clinic. In this event, all assessments will be collected relative to the 
evening dose. 
3. For visits after Day 1, subjects will be instructed to bring all used and unused study drug and 
materials associated with the study drug to the site; study drug will be dispensed at each visit, 
as appropriate. 
4. At the Week 8 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 8 Visit. 
9.7 
Missed Doses 
If a subject misses a dose and recalls the missed dose within 6 hours, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 
subject should skip that dose and resume his/her normal schedule for the following dose. For 
example; 
• If the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
• If the morning dose of study drug should have been taken at approximately 08:00, and 
greater than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 
14:00), the subject would resume dosing with the evening dose at approximately 20:00. 
9.8 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided the subject has not withdrawn consent.  
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 a Safety Follow-up Visit, if 
applicable (see Section 9.1.3), and follow up with the subject regarding any unresolved AEs. 
If the subject withdraws consent for the study, no further evaluations should be performed, and 
no additional data should be collected. Vertex may retain and continue using the study data and 
samples after the study is over, and may use the samples and information in the development of 


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the study compound, 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/her information from the study data. A subject may request destruction of the samples 
collected from him/her during the study as long as those samples can be identified as his/her 
samples. 
9.9 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug Treatment Period will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
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 TEZ and IVA will be included in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Blister cards must be stored at room temperature according to Table 10-1 and to the instructions 
provided in the Pharmacy Manual. While at the clinical site, the investigator, or an authorized 
designee (e.g., a licensed pharmacist), will ensure that all investigational product is stored in a 
secured area, under recommended storage conditions, and in accordance with applicable 
regulatory requirements. To ensure adequate records, all study drugs will be accounted for in 
Section 10.4. 
Instructions regarding the storage and handling of study drug after dispensation to subjects will 
be provided to sites in the Pharmacy Manual. 


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Table 10-1  Identity of Study Drugs, Dosage, and Storage 
Drug Name 
Formulation/Route 
Dosage 
Storage Condition 
TEZ/IVA  
Fixed-dose combination 
tablet; oral 
 
TEZ 50 mg/IVA 75 mg 
or 
TEZ 100 mg/IVA 150 mg 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
IVA 
Tablet; oral 
75 mg or 150 mg 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
TEZ/IVA-matching 
placebo 
Fixed-dose combination 
tablet; oral 
 
TEZ 0 mg/IVA 0 mg 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
IVA-matching 
placebo 
Tablet; oral 
 
IVA 0 mg 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. 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 until inventoried by the study monitor. The study 
monitor will review study drug records and inventory throughout the study. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 
10.6 
Compliance  
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 will contact the medical monitor to discuss discontinuation of the subject 
from the study. 


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10.7 
Discontinuation of Study Participation  
If after review of a marketing application, local health authorities decline to approve, or if 
clinical benefit is not demonstrated for the use of TEZ/IVA for the treatment of CF in a 
corresponding population aged ≥12 years, pediatric subjects enrolled in Study 115, subjects with 
the relevant CFTR genotypes may be discontinued after communication to investigators and 
IRBs/IECs of the risks/benefits related to the safety and efficacy observed for the subset of 
subjects.  
If the CFTR screening genotype result is not received before enrollment and a previous CFTR 
genotype lab report is used to establish eligibility, enrolled subjects whose screening genotype 
does not confirm study eligibility must be discontinued from the study and complete an ETT 
and/or a Safety Follow-up Visit as described in Section 9.1.3 and Section 9.1.4). 
10.8 
Blinding and Unblinding 
This is a double-blind study.  
10.8.1 
Blinding  
All study personnel will be blinded to subject treatment assignments except for the following 
individuals:  
• Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the subject 
and the fetus in the event of a pregnancy 
• The unblinded site monitor and unblinded trip report reviewer 
• An unblinded pharmacist at the contract research organization (CRO) for dispensing study 
drug 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
• External vendor (unblinded) statistician preparing the final (production) randomization list 
who is not part of the study team 
• Vertex IXRS Management for IXRS oversight and system administration 
• Vertex Clinical Supply Chain 
• The bioanalytical CRO laboratory/vendor personnel managed by Vertex Bioanalysis 
• The Vertex bioanalytical personnel responsible for reviewing raw data from the bioanalytical 
CRO, who is not a member of the SET (the Vertex bioanalytical SET member will continue 
to be blinded). 
Vertex medical monitor may, for matters relating to safety concerns, unblind individual subjects 
at any time.  
10.8.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 


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Unblinding of the individual subject
's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject
's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the treating physician will have the final decision and unilateral 
right for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject
's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 
reason and the date of the unblinding will be documented clearly in the subject
's study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2.3. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The following assessments must be performed in the order specified below when more than 
1 assessment is required at a particular time point: 
1. The CFQ-R should be completed before the start of any other assessments scheduled at that 
visit.  
3. ECGs will be performed before dosing and before any other procedures that may affect heart 
rate (e.g., blood draws). 
4. The MBW assessment should be performed before spirometry. 




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• withheld their long-acting bronchodilator (e.g., salmeterol) more than 12 hours before the 
MBW testing; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the MBW testing. 
MBW testing should be performed “pre-bronchodilator.” MBW testing must be performed 
before dosing, unless noted otherwise. In the event that a subject forgets to withhold 
bronchodilator(s), MBW testing should be performed according to the following: 
• If a subject
's Day 1 MBW testing is pre-bronchodilator, but on a subsequent visit, the subject 
forgets to withhold bronchodilator use, post-bronchodilator MBW testing will be obtained for 
that visit only, and the visit will not be rescheduled. 
• If on Day 1, the subject forgets to withhold his/her dose of bronchodilator, MBW testing 
should be performed post-bronchodilator and all subsequent MBW testing (according to the 
Schedule of Assessments detailed for LCI in Table 3-1) should be performed 
post-bronchodilator.  
• Subjects and their parent/caregiver should not be informed of their study-related LCI results 
during the Treatment Period. 
11.4.2 
Spirometry 
Spirometry will be performed according to the ATS/ERS Guidelines
7 at the time points noted in 
Table 3-1 according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilator (e.g., albuterol) or anticholinergic (e.g., Atrovent) 
for more than 4 hours before the spirometry assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) 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. 
All spirometry assessments should be performed “pre-bronchodilator.” During the Treatment 
Period, spirometry assessments must be performed before dosing, unless noted otherwise. In the 
event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
• If a subject
's Day 1 spirometry is pre-bronchodilator, but on a subsequent visit, the subject 
forgets to withhold bronchodilator use, a post-bronchodilator spirometry will be obtained for 
that visit only, and the visit will not be rescheduled. 
• If on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry should 
be performed post-bronchodilator and all subsequent spirometric measurements (according to 
the Schedule of Assessments detailed in Table 3-1) should be performed post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre-bronchodilator 
or post-bronchodilator. 


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The parameters listed below will be normalized using the standards of GLI.
5  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow, midexpiratory phase (FEF
25%-75%) (L/s) 
All sites will be provided with spirometers and associated materials to be used for all study 
assessments by the central spirometry service. Spirometry data will be transmitted to a 
centralized spirometry service for quality review. 
Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results during the Treatment Period. 
11.4.3 
Sweat Chloride  
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Collection of sweat samples will be performed at visits specified in Table 3-1 using an 
approved collection device. Sweat samples will be sent to a central laboratory for testing and 
interpretation of results. Individual sweat chloride test results will not be disclosed to the study 
sites. Specific instructions for collection, handling, processing, and shipping of sweat chloride 
samples will be provided in a separate Laboratory Manual. 
The sweat chloride test must be conducted before dosing with study drug at visits during the 
Treatment Period. At each time point, 2 samples will be collected, 1 sample from each arm (left 
and right). During the Treatment Period, sweat collection will be done approximately at the same 
time as predose blood collections. 
Collection of sweat chloride will not overlap with any other study assessments. 
Subjects and their parent/caregiver should not be informed of their study-related sweat chloride 
results during the Treatment Period. 
11.4.5 
Cystic Fibrosis Questionnaire-Revised  
The CFQ-R will be completed at visits noted in Table 3-1. Subjects will be asked to complete the 
CFQ-R version in their native language if available. Parents/caregivers will complete the CFQ-R 
parent version each time the subject completes the CFQ-R. The version and format of CFQ-R 
will be based on age at baseline, regardless of whether the subject changes age during the study. 
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF). Copies of the CFQ-R used 
in this study will be provided in the Study Reference Manual. Validated translations of the 
CFQ-R, if available, will be provided for participating centers in non-English-speaking countries 
(if applicable).
23,24 The CFQ-R should be completed before the start of any assessments 
scheduled at that visit. 




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11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, pulse oximetry, PEs, spirometry, 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. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected as shown in Table 
3-1. On Day 1, blood samples will be collected before the first dose of study drug. At all other 
scheduled visits, these samples will be collected at any time during the visit. 
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (see Section 13.1). The safety laboratory test panels are shown in Table 11-1. 


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Table 11-1  Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogen  
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase  
Alanine transaminase 
Lactate dehydrogenase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Vitamin Levels 
Vitamins A, D, E, K, and B12 
Lipid Panel 
Total cholesterol, triglycerides 
Low-density lipoprotein (LDL) 
High-density lipoprotein (HDL) 
Hemoglobin  
Erythrocytes:  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin 
concentration 
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: Blood draws do not require fasting.  
 
Pregnancy Testing for Female Subjects of Childbearing Potential Who Are Not Abstinent 
(Section 11.5.8.1): 
Female subjects of childbearing potential must have a negative urine pregnancy test at the Day 1 
Visit. Serum pregnancy tests will be conducted at all other visits. 
If the urine pregnancy test is positive on Day 1, study drug will not be administered and the 
pregnancy will be confirmed with a serum beta-human chorionic gonadotropin (β-HCG) test. If 
confirmed the subject will not be eligible for the study.   
For pregnancy tests conducted after dosing, if a serum β-HCG test is positive, the pregnancy will 
be reported and the subject will be permanently withdrawn from study drug dosing as discussed 
in Section 11.5.8.2. If a pregnancy test is positive, the procedures outlined in Section 11.5.8.2 
will be followed. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged by the investigator to be clinically appropriate.  
 


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11.5.3 
Liver Function Test Parameters 
Liver function testing (ALT, AST, GGT, ALP, direct bilirubin, and total bilirubin) must be 
performed as noted in Table 11-1 for serum chemistry while subjects are receiving study drug 
treatment and at the Safety Follow-up Visit. These blood samples should be processed and 
shipped immediately per the Laboratory Manual. 
Subjects with new treatment-emergent ALT or AST elevations of ≥3 × ULN and clinical 
symptoms must be followed closely, including repeat confirmatory testing performed by the 
central laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of 
ALT and AST levels, as clinically indicated. In addition, if ALT or AST is >5 × ULN, repeat 
follow-up levels must be obtained within 7 ± 2 days. 
If a subject cannot return to the site for confirmatory liver function testing, a local laboratory 
may be used. Elevations in LFTs at the local laboratory must be reported immediately to the 
medical monitor, and the subject must have the tests repeated and sent to the central laboratory 
as soon as possible (ideally within 48 to 72 hours). 
Study Drug Interruption 
Study drug administration must be interrupted immediately (before confirmatory testing), and 
the medical monitor must be notified, if any of the following criteria is met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical jaundice 
A thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST levels 
have improved, study drug treatment must be permanently discontinued if repeat testing within 
48 to 72 hours confirms the initial elevation. Subjects in whom treatment is discontinued for 
elevated transaminases should have their transaminases monitored closely until levels normalize 
or return to baseline. 
Resumption of Study Drug 
If an alternative, reversible cause of transaminase elevation has been identified, study drug may 
be resumed once transaminases values decrease to ≤2 × ULN. Approval of the medical monitor 
is required before resumption of study drug. Upon resumption of study drug, transaminases 
should be assessed weekly for 4 weeks. If a protocol-defined transaminase elevation occurs 
within 4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by 
repeat testing within 48 to 72 hours), then the study drug must be permanently discontinued, 
regardless of the presumed etiology. 
11.5.4 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at select study visits (see 
Table 3-1). At other visits, symptom-directed PE and symptom-directed vital sign assessments 
can be performed at the discretion of the investigator or healthcare provider. 


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A full PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat 
(EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PE will be reported as 
AEs. 
The abbreviated PE will include an assessment of the following body systems: 
head/neck/thyroid, EENT, cardiovascular system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed.  
11.5.5 
Pulse Oximetry  
Arterial oxygen saturation by pulse oximetry will be measured at visits noted in Table 3-1. This 
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 the morning dose. This is a 
noninvasive measure of oxygen delivery to the tissues and has been correlated with clinical 
status and lung function. 
11.5.6 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1). Additional standard 12-lead ECGs will be performed at 
any other time if clinically indicated. The performance of all ECGs will adhere to the following 
guidelines: 
• The subject will be instructed to rest in the supine position for at least 5 minutes before 
having an ECG performed. 
• The ECG will be performed before any other procedures that may affect heart rate, such as 
blood draws. 
Clinically significant ECG abnormalities occurring during the study through the Safety 
Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >45 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 (>45 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. 
Further details pertaining to ECGs will be provided to sites in the ECG Manual. 
11.5.7 
Ophthalmologic Examination 
Ophthalmologic examinations will be conducted by a licensed ophthalmologist or optometrist 
according to the schedule in Table 3-1. Subjects with documentation of bilateral lens removal do 
not need ophthalmologic examinations. 


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The examination includes: 
• measurement of best corrected distance visual acuity of each eye, and 
• pharmacologically dilated examination of the lens with a slit lamp. 
The screening examination does not need to be repeated if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of assent.  
In addition, for subjects who receive at least 1 dose of study drug and do not roll over into an 
extension study with 28 days of the last dose of study drug in Study 115, a single end-of-study 
examination will be done at the ETT Visit or Safety Follow-up Visit.  
If a cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist or optometrist within Study 115, the subject and Vertex medical monitor will be 
notified. The subject may elect to continue or discontinue study drug treatment. If the subject 
discontinues study drug treatment, the subject should complete the ETT and Safety Follow-up 
Visits (see Sections 9.1.3 and 9.1.4). If the subject continues study drug treatment, more frequent 
ophthalmologic monitoring should be considered. 
11.5.8 
Contraception and Pregnancy 
Standard contraception- and pregnancy-related information and requirements are provided 
below. It should be noted that some of this information and requirements may have limited 
applicability in this pediatric population. 
11.5.8.1 
Contraception 
For subjects with an appropriate need for contraception, as determined by their physician, 
participation in this study requires a commitment from the subject and his/her partner to use at 
least 1 acceptable method of contraception, which must be used correctly with every act of 
sexual intercourse. Methods of contraception should be in successful use from at least 14 days 
before the first dose of study drug (unless otherwise noted) and until 90 days following the last 
dose of study drug. 
For female subjects using oral hormonal contraceptives: 
1. The oral hormonal contraceptives should be in successful use from at least 60 days before the 
first dose of study drug (unless otherwise noted) and until 90 days following the last dose of 
study drug. 
2. Female subjects who change their method of contraception to hormonal contraceptive during 
Study 115 must use a second form of approved contraception for at least 60 days after 
beginning oral contraceptives. 
Contraception for the couple is waived for the following: 
1. 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. 
2. If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen or by demonstration of the absence of the vas deferens by 
ultrasound before the first dose of study drug. 


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3. If the female is of non-childbearing potential, per the following: 
4. Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy. 
5. Has not achieved menarche (has not had her first menstrual period). If a female achieves 
menarche during the study, she will need to follow acceptable methods of contraception or 
abstinence. 
6. For subjects for whom contraception methods are not waived due to at least 1 of the reasons 
cited above, the following are acceptable contraceptive methods for male subjects and their 
female (non-study) partners, and for female subjects and their male (non-study) partners: 
Table 11-2 Acceptable Methods of Contraception 
• Male vasectomy at least 6 months previously, with a documented negative post-vasectomy semen analysis for 
sperm. 
• Male or female condom with or without spermicide (either as a single product if commercially available and/or as 
allowed according to local regulations; otherwise condom and spermicide as separate products). 
• Female bilateral tubal ligation performed at least 6 months previously. 
• Female diaphragm, cervical cap, or vaginal sponge, each with spermicide (where available). 
• Female continuous use of an intrauterine device (non-hormone releasing or hormone releasing) for at least 90 days 
before the first dose of study drug 
• Female combined (estrogen and progestogen-containing) or progestogen-only oral hormonal contraception 
associated with inhibition of ovulation if successfully used for at least 60 days before the first dose of study drug 
or with a second form of approved contraception for at least 60 days after beginning hormonal contraception. 
 
Important notes: 
• Local requirements may prohibit the use of some of these acceptable methods listed above. 
Please contact the medical monitor with any questions. 
• If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
• Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active. 
• Female condom used with male condom (as a double method of contraception) is not an 
acceptable method of contraception due to risk of tearing; a different acceptable method of 
birth control must be used as described in Table 11-2.  
• Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days following the last dose of study drug. 
• Female subjects should not nurse a child from the start of study drug dosing through 90 days 
following the last dose of study drug. 
Other situations that do not fall within the above specifications may be discussed with the Vertex 
medical monitor on an individual basis. 
11.5.8.2 
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 while participating in the 
study, study drug will be permanently discontinued immediately. The investigator will notify the 
medical monitor and Vertex GPS within 24 hours of the site
's knowledge of the subject
's (or 
partner
's) pregnancy using the Pregnancy Information Collection Form. 
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, provided informed consent is obtained. A separate ICF will be 
provided to explain these follow-up activities. Pregnancy itself does not constitute an AE.  
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
Sample Size and Power 
The sample size of this study is driven by demonstrating that the treatment effect of TEZ/IVA is 
based on a within-group comparison (change from baseline in LCI2.5 in subjects on TEZ/IVA) to 
exclude a maximum possible placebo effect. If the corresponding 2-sided 95% CI of the change 
from baseline in LCI2.5 in subjects on TEZ/IVA excludes the pre-defined maximum possible 
placebo effect, it will be considered that the study has achieved its primary objective.  
A placebo effect is not expected with LCI, because clinical study data with other Vertex CFTR 
modulator studies consistently demonstrated a worsening of lung function (i.e., an increase from 
baseline in LCI) in the absence of CFTR modulator treatment. Study VX14-809-109 (Study 809-
109) evaluated treatment with LUM/IVA in F/F subjects aged 6 through 11 years using change 
from baseline in LCI as the primary efficacy endpoint and provided the most relevant clinical 
LCI data available in the younger age group of CF subjects. In Study 809-109, the placebo group 
had a mean worsening in LCI2.5 of 0.08 units with an SD of 1.41 (higher numbers indicate a 
worsening of an LCI measurement); the one-sided 90% lower bound was -0.10 and is used as an 
estimate for the pre-defined maximum possible placebo effect for Study 115.  
Accounting for a 10% dropout rate, approximately 40 subjects on TEZ/IVA will provide at least 
90% power to exclude -0.10. The current estimate of the maximum possible placebo effect is 
based on Study 809-109 placebo data in pediatric F/F subjects with CF. The maximum possible 
placebo effect is subject to modification before the analysis of Study 115 data is conducted based 
on the availability of more relevant data; any changes will be documented in the statistical 
analysis plan (SAP).  
12.2 
Analysis Sets 
12.2.1 
All Subjects Set 
The All Subjects Set will be defined as all subjects who received at least 1 dose of study drug. 
This analysis set will be used for all individual subject data listings and the disposition summary 
table, unless specified otherwise.  
12.2.2 
Full Analysis Set 
The Full Analysis Set (FAS) will be defined as all subjects who were randomized and received at 
least 1 dose of study drug and had an eligible genotype. The FAS will be used for all efficacy 
analyses and subjects will be analyzed according to the treatment arm they are randomized to.  


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12.2.3 
Safety Set 
The Safety Set will be defined as all subjects who received at least 1 dose of study drug. The 
Safety Set will be used for all safety analyses, unless otherwise specified. The subjects will be 
analyzed according to the treatment they received. 
12.3 
Statistical Analysis 
The Vertex Biometrics Department or designee will analyze the safety and efficacy data. 
The primary objective of this study is efficacy. The secondary objective is safety. This section 
summarizes the statistical analysis of efficacy and safety data. Methodological and related details 
(e.g., missing data) will be provided in the SAP. 
The primary efficacy endpoint is the absolute change in LCI
2.5 from baseline through Week 8. 
The objective of primary efficacy endpoint analysis is to demonstrate that the mean absolute 
change from baseline in LCI
2.5 through Week 8 for subjects on TEZ/IVA excludes a pre-defined 
maximum placebo effect. The primary analysis of the primary efficacy endpoint will be based on a 
mixed-effects model for repeated measures (MMRM) with LCI2.5 at each time point as the outcome 
variable. The estimated mean change from baseline through Week 8 in LCI2.5 for subjects on 
TEZ/IVA along with the corresponding 95% CI will be provided. If the upper bound of the 95% 
CI is below the pre-defined maximum possible placebo effect, it will be interpreted as sufficient 
evidence to achieve the primary efficacy objective.  
The study plans to enroll approximately 50 F/F subjects and up to 15 F/RF subjects.  
A placebo group of F/F subjects and an IVA mono group of F/RF subjects will be included in 
this study. The main purpose is to preserve blinding, so that subjects and investigators do not 
assume a subject is receiving TEZ/IVA, which could introduce bias into the results. Descriptive 
statistics such as mean and SD will be provided for change from baseline in LCI2.5 at each post-
baseline visit for homozygous subjects in the placebo group.  
The target enrollment by genotype and treatment group is provided in the Table 12-1. 
Table 12-1 Target Enrollment by Genotype and Study Drug Treatment 
Genotype 
N 
Study Drug Treatment 
F/F  
40 
TEZ (50 or 100 mg qd) + IVA (75 or 150 mg q12h) 
10 
TEZ-matching placebo (qd) + IVA-matching placebo (q12h) 
F/RF 
12 
TEZ (50 or 100 mg qd) + IVA (75 or 150 mg q12h)  
3 
TEZ-matching placebo (qd) + IVA (75 or 150 mg q12h) 
 
12.3.1 
General Considerations 
The precision standards for reporting safety and efficacy variables are provided in an internal 
Biometrics document that specifies the programming rules including the precision for derived 
variables. 
All individual subject data for subjects who were randomized or received at least 1 dose of study 
drug will be presented in individual subject data listings. 


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Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, SE, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For 
ECGs, the baseline value will be defined as the average of the non-missing pretreatment 
measurements (triplicate) on Day 1. 
Change (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. 
Treatment-emergent (TE) Period will include the time from the first dose to the earliest of the 
following: the Safety Follow-up Visit, or 28 days after the last dose of the study drug for subjects 
who do not have a Safety Follow-up Visit. The TE period will be used for safety analyses unless 
specified otherwise. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules. 
• In the derivation of baseline/last on-treatment measurements. 
• In the derivation of maximum/minimum on-treatment values and maximum/minimum 
change from baseline values for safety analyses. 
• In individual subject data listings as appropriate. 
Visit windowing rules: The analysis visit windows for protocol-defined visits will be provided 
in the SAP. 
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
Multiplicity: No multiplicity adjustment will be performed for hypothesis testing. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized overall:  
• All Subjects Set 
• Safety Set 
• FAS  


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The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized overall and by treatment group: 
• Completed treatment 
• Prematurely discontinued the treatment and the reason for discontinuation  
• Completed study (i.e., completed Safety Follow-up Visit) 
• Prematurely discontinued the study and the reason for discontinuation  
• Enrolled in a rollover extension study 
A listing will be provided for subjects who discontinued study drug treatment or who 
discontinued the study with reasons for discontinuation.  
12.3.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history, and baseline characteristics will be summarized overall based on 
the FAS. 
Demographic data will include the following: 
• Age (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• Geographic region 
Disease characteristics will include the following: 
• Baseline LCI2.5  
• Baseline sweat chloride  
• Baseline score of CFQ-R respiratory domain 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). 
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and categorized as the following: 
Prior medication: any medication that started before the first dose date of study drug, regardless 
of when the medication ended. 


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Concomitant medication: medication continued or newly received on or after the first dose date 
of study drug through the end of TE period. 
A given medication may be classified as prior, concomitant, or both prior and concomitant.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date or concomitantly, it will be classified 
as prior and concomitant. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by Preferred Name.  
Summaries of medications will be based on the FAS.  
Details for imputing missing or partial start and/or stop dates of medication will be provided in 
the SAP. 
12.3.2.4 
Study Drug Exposure and Compliance 
Duration of study drug exposure (in days) will be calculated as: last dose date – first dose 
date + 1 day, regardless of study drug interruption.  
Exposure summaries will be based on the Safety Set. 
Study drug compliance based on the number of tablets taken will be calculated as: 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). The maximum 
percentage of tablets taken will be 100%. 
Study drug compliance based on study drug exposure will be calculated as: 100 × [1 − (total 
number of days of any study drug interruption) / (duration of study drug exposure in days)].  
Study drug compliance will be summarized descriptively by n, mean, SD, SE, median, min, and 
max. They will also be summarized in categories: <80% and ≥80% using frequency tables. 
Study drug compliance summaries will be based on the FAS. 
12.3.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless specified 
otherwise. The analysis will include all available measurements through the last scheduled on-
treatment visit, including measurements after treatment discontinuation. 
12.3.3.1 
Analysis of Primary Variables 
The objective of primary efficacy endpoint analysis is to demonstrate that the mean absolute 
change from baseline in LCI
2.5 through Week 8 excludes a pre-defined maximum placebo effect 
in subjects in the TEZ/IVA group. The primary analysis for the primary efficacy endpoint will be 
based on an MMRM using SAS PROC MIXED for the subjects in the TEZ/IVA treatment group 
in the FAS population. The MMRM will be used to estimate the within-group mean absolute 
change in LCI
2.5 through Week 8 in the TEZ/IVA treatment group. The estimated mean change 
from baseline through Week 8 in LCI
2.5 for subjects on TEZ/IVA along with the corresponding 
95% CI will be provided. If the upper bound of the 95% CI is below the pre-defined maximum 
possible placebo effect, it will be interpreted as sufficient evidence to reject the null hypothesis.  


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The model will include absolute change from baseline in LCI2.5 (including all measurements up 
to Week 8 [inclusive], both on treatment measurements and measurements after treatment 
discontinuation) as the dependent variable, and visit (as a class variable) as a fixed effect, with 
adjustment for mutation group based on the second CFTR allele (F/F and F/RF) and baseline 
LCI2.5 value as fixed effects, and subject as a random effect. An unconstructed covariance 
structure will be used to model the within-subject errors. 
Summary statistics (mean and SD) for change from baseline in LCI2.5 through Week 8, and at 
each visit will also be provided for subjects in the TEZ/IVA treatment group overall.  
For homozygous subjects in the placebo treatment group, summary statistics (mean and SD) will 
be provided for change from baseline in LCI2.5 through Week 8, and at each visit.  
12.3.3.2 
Analysis of Secondary Efficacy Variables 
A model similar to the MMRM for the primary analysis of the primary efficacy endpoint will be 
used with the addition of baseline sweat chloride as a covariate for subjects in the TEZ/IVA 
treatment group. Average absolute change from baseline in sweat chloride through Week 8 and 
absolute change from baseline in sweat chloride at each post baseline visit, including least 
squares (LS) means, SE, and the 2-sided 95% CI along with the P value will be provided based 
on the FAS. 
Analysis of absolute change in CFQ-R respiratory score from baseline though Week 8 will be 
performed using the same model as described for the primary analysis of the primary efficacy 
endpoint, with the addition of baseline CFQ-R respiratory score as a covariate. 
12.3.4 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• AEs 
• Clinical laboratory values (hematology and serum chemistry) 
• Standard 12-lead ECGs 
• Vital signs  
• Pulse oximetry  
• Physical examination  
• Ophthalmologic examination 
• Serial lung function 
Safety endpoints will be analyzed based on the Safety Set using data during the Safety analysis 
period (TE period). Only descriptive summaries will be presented and no statistical testing is 
planned.  


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12.3.4.1 
Adverse Events 
AEs will be classified as pretreatment AEs or treatment-emergent AEs (TEAEs), defined as 
follows:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed at 
or after the first dose date of study drug through the end of the TE period  
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of AEs are described in the SAP. 
AE summary tables will be presented for TEAEs only, overall and by treatment group, and will 
include the following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• TEAEs leading to death 
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 will be presented in the relationship 
summaries.  
In addition, a listing containing individual subject AE data for TEAEs leading to treatment 
discontinuation, SAEs, and deaths will be provided separately. All AEs, including pretreatment 
AEs, will be presented in an individual subject data listing. 
12.3.4.2 
Clinical Laboratory Assessments 
For treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous hematology and chemistry results, including coagulation studies will be 
summarized in SI units by treatment group and visit.  
The number and percentage of subjects with at least 1 laboratory event outside threshold criteria 
for the event during the TE period will be summarized overall and by treatment group, including 
a shift of the event from baseline to post-baseline. The threshold criteria will be provided in the 
SAP. 
For each LFT laboratory test (ALT, AST, ALP, GGT, and total bilirubin), a scatter plot of the 
maximum treatment-emergent value versus the baseline value corresponding to #× ULN will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, 


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separately, versus the maximum treatment-emergent value of total bilirubin corresponding to 
× ULN will also be presented. 
A listing of subjects with elevated LFT results during the TE period will be presented based on 
any of the following: AST >3 × ULN, ALT >3 × ULN, GGT >3 × ULN, ALP >3 × ULN or total 
bilirubin >2 × ULN. For each subject in the listing, LFT assessments at all time points will be 
included (scheduled and unscheduled). 
Results of urinalysis and the urine/serum pregnancy test will be listed in individual subject data 
listings only.  
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
outside the normal reference ranges will be provided. This listing will include data from both 
scheduled and unscheduled visits. 
12.3.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from baseline 
values will be provided by treatment group and visit for the following standard 12-lead ECG 
measurements: RR (msec), HR (beats per minute [bpm]), PR (msec), QRS duration (msec), QRS 
axis (degrees), QT (msec), and QT corrected for HR intervals (QTcF [msec]).  
The number and percentage of subjects with at least 1 ECG event outside of the threshold criteria 
during the TE period will be summarized overall and by treatment group. The threshold value 
criteria will be provided in the SAP. 
12.3.4.4 
Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized by treatment group and visit: systolic and diastolic blood pressure 
(mm Hg), body temperature (°C), HR (bpm), and respiration rate (breaths per minute). 
The number and percentage of subjects with at least 1 event outside the threshold criteria for a 
vital sign during the TE period will be summarized overall and by treatment group. The 
threshold value criteria will be provided in the SAP. 
12.3.4.5 
Physical Examination 
PE findings will be presented as an individual subject data listing only. 
12.3.4.6 
Other Safety Analysis 
12.3.4.6.1 Serial Lung Function  
For the 2-hour and 4-hour postdose spirometry measurements on Day 1 and Week 2, a summary 
of raw values for ppFEV1 will be provided at each time point. The absolute change from the 
predose value of ppFEV1 on the same day will be summarized at each time point. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
Not applicable. 


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12.3.5.2 
IDMC Analysis 
An IDMC will be formed. The IDMC’s objectives and operational details will be defined in a 
separate document (the IDMC charter). The IDMC will conduct regular planned safety reviews 
of study data as outlined in the IDMC charter. 
Details of the IDMC (Section 9.1.5) analysis will be provided in the IDMC Analysis Plan. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 


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A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 28 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug (see 
Section 9.1.4) 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject
's source documents. The following data will be documented 
for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
 The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
10 November 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” 
In considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in the 
CTCAE. The severity of an AE that does not appear in the CTCAE will be determined according 
to the definitions in Table 13-1. 


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Table 13-1  Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject
's medical record). 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3.  
Table 13-3  Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 


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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 shown in Table 13-4. 
Table 13-4  Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
• 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 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are considered related 
to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: 
 
Fax: 
  
For questions, contact telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, 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/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator
's 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(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 shall be limited to the site and the study physician and shall not be disclosed to 
Vertex. As required by applicable laws and regulations in the countries in which the study is 
being conducted, the investigator will allow Vertex and/or its representatives access to all 
pertinent medical records to allow for the verification of data gathered and the review of the data 
collection process. The FDA and regulatory authorities in other jurisdictions, including the 
IRB/IEC, may also request access to all study records, including source documentation, for 
inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”) an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• 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 contact) of the last subject in the study. 


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13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the data captured for the study/SAE Forms for 
completeness and clarity, and clarification of administrative matters will be performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the data 
captured for the study/SAE Forms and source documents. The study site monitor will ensure that 
the investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator
's responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject
's 
CRF. Source documentation supporting the CRF data will indicate the subject
's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user
's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator
's 
study file. 


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13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


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Confidential Information 
14 
REFERENCES
 
1  
Cystic Fibrosis Foundation Web Site [Internet]. Available from: 
http://www.cff.org/AboutCF/. Accessed 11 November 2014. 
2   
Cystic Fibrosis Foundation. Patient Registry: 2015 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2016. 
3  
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: Annual Data Report 2014. Bromley, 
Kent, UK: Cystic Fibrosis Trust; 2015. 
4   
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
5   
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. 
6  
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51:875-8. 
7  
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
8   
Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care. 
Chest. 2004;125: 1-39. 
9  
Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonal. 
2002; 34:228-31. 
10   Brody AS, Tiddens HA, Castile RG, Coxson HO, de Jong PA, Goldin J, et al. Computed 
tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med. 
2005;172(10): 1246-52. 
11 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med 
2009;103:793-9. 
12  
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in unsedated preterm neonate. Pediatr Pulmonol 2010;45:62-70. 
13   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. 
14  
Lum S, Gustafsson P, Ljungberg H, Hülskamp G, Bush A, Carr SB, et al. London Cystic 
Fibrosis Collaboration. Early detection of cystic fibrosis lung disease: multiple-breath 
washout versus raised volume tests. Thorax. 2007;62(4):341-7. 
15  
Wilschanski M, Zielenski J, Markiewicz D, Tsui LC, Corey M, Levison H, et al. 
Correlation of sweat chloride concentration with classes of the cystic fibrosis 
transmembrane conductance regulator gene mutations. J Pediatr. 1995;127:705-10. 
16  
Rowe SM, Accurso F, Clancy JP. Detection of cystic fibrosis transmembrane 
conductance regulator activity in early-phase clinical trials. Proc Am Thorac Soc. 
2007;4:387-98. 
17  
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. 
18  
Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:378-86. 
 


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19  
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. 
20 
Vertex Pharmaceuticals Incorporated. Report G241. A Phase 3, randomized, 
double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety 
of VX-770 in subjects with cystic fibrosis and the G551D mutation. Report date: 
17 August 2011. 
21 
Vertex Pharmaceuticals Incorporated. Report H028. A Phase 3, 2-part, randomized, 
double-blind, placebo-controlled, parallel-group study to evaluate the pharmacokinetics, 
efficacy and safety of VX-770 in subjects aged 6 to 11 years with cystic fibrosis and the 
G551D mutation. Report date: 29 March 2012. 
22 
Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery 
AB, et al. Efficacy and safety of inhaled aztreonam lysine for airway Pseudomonas in 
cystic fibrosis. Chest. 2009;135(5):1223-32. 
23  
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-relate quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
24  
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. 


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15 
APPENDIX 1: CFTR MUTATIONS 
Subjects can either be homozygous or heterozygous for the F508del mutation. Heterozygous 
subjects must have F508del on 1 allele and a second eligible CFTR allele. The list below 
represents acceptable mutations for the second CFTR allele for heterozygous subjects. Most 
mutations were evaluated in the TEZ/IVA pivotal Phase 3 studies. However, this is a non-
exhaustive list of CFTR mutations to be evaluated in this study. Additional mutations may be 
evaluated and updates to approved mutations will be communicated to investigative sites through 
a memorandum.  
CFTR Residual Function Mutations 
2789+5G→A 
D110E 
D579G 
D1152H 
3849+10kbC→T 
D110H 
S945L 
D1270N 
3272-26A→G 
R117C 
S977F 
E831X 
711+3A→G 
E193K 
F1052V 
A1067T 
E56K 
L206W 
K1060T 
 
P67L 
R352Q 
R1070W 
 
R74W 
A455E 
F1074L 
 
 
During the course of study conduct, if local health authorities decline to approve, or if clinical 
benefit is not demonstrated for the use of TEZ/IVA for the treatment of CF in a corresponding 
population aged ≥12 years, pediatric subjects enrolled in Study 115 with the relevant CFTR 
genotypes may not be enrolled into the study. Subjects who are enrolled in Study 115 may be 
discontinued after communication to investigators and IRBs/IECs of the risks/benefits related to 
the safety and efficacy observed for the subset of subjects. 




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16.2 
Investigator Signature Page 
Protocol #:  VX16-661-115 Version #: 1.0 
Version Date: 
17 November 2017 
Study Title: A Phase 3, Double-blind, Parallel-group Study to Evaluate the Efficacy and Safety 
of Tezacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With Cystic 
Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation 
 
 
I have read Protocol VX16-661-115, Version 1.0, and agree to conduct the study according to its 
terms. I understand that all information concerning 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) 
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9.4.1.2
TEAEs by SOC and PT...........................................................................18
9.4.1.3
TEAEs and SAEs by PT..........................................................................19
9.4.1.4
Respiratory Events and Symptoms...........................................................19
9.4.1.5
Elevated Transaminase............................................................................19
9.4.2
Clinical Laboratory........................................................................................20
9.4.3
Electrocardiogram..........................................................................................20
9.4.4
Vital Signs.....................................................................................................20
9.4.5
Pulse Oximetry..............................................................................................21
9.4.6
Physical Examination.....................................................................................21
9.4.7
Ophthalmologic Examination.........................................................................21
9.4.8
Other Safety Analysis....................................................................................21
9.4.8.1
Serial Lung Function (Post-dose Spirometry)...........................................21
10 Interim and DMC AnalysIs........................................................................................21
10.1Interim Analysis....................................................................................................21
10.2DMC Analysis.......................................................................................................21
11 References...................................................................................................................22
12 List of Appendices......................................................................................................23

Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments..........23

Appendix B: Stardards for Safety and Efficacy Variable Display in TFLs..............25

Appendix D: Imputation Rules for Missing Prior/Concomitant Medication Dates..27

Appendix E: Imputation Rules for Missing AE dates.............................................28

Appendix F: Details of GLI Equation for Calculating ppFEV
1...............................29

Appendix G: Criteria for Threshold Analysis.........................................................30


Statistical Analysis Plan (Methods) 
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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
CI
confidence interval
CRF
case report form
CRO
contract research organization
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
F508del
CFTRgene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position508 of the wild-type protein
FAS
full analysis set
FDC
VX-661 100-mg/IVA 150-mg fixed-dose tablet
FEF25-75%
forced expiratory flow, midexpiratory phase
FEV1
forced expiratory volume in 1second
F/F
homozygous for F508del
F/RF
heterozygous for F508deland a second allele with a residual function mutation 
FVC
forced vital capacity 
IVA
ivacaftor
LS means
Least squares means
LFT
liver function test
max
maximum value
MedDRA
Medical Dictionary for Regulatory Activities
min
minimum value
MMRM
mixed model repeated measure
N
number of subjects
PD
pharmacodynamic/pharmacodynamics 
PK
pharmacokinetic/pharmacokinetics
ppFEV1
percent predicted FEV1
PT
preferred term
q12h
every 12 hours
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 


Statistical Analysis Plan (Methods) 
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Abbreviation
Term
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error
SOC
system organ class
TEAE
treatment-emergent adverse event
TEZ
tezacaftor
ULN
upper limit of normal
WHODD
World Health Organization Drug Dictionary Enhanced






Statistical Analysis Plan (Methods) 
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6.2
Secondary Endpoints
Absolute change from baseline in sweat chloride at Week 8
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline through Week 8
Safety and tolerability as measured by adverse events (AEs), clinically significant 
changes in laboratory values (serum chemistry, hematology, coagulation studies, lipids, 
vitamin levels, and urinalysis), standard 12-lead ECGs, vital signs, pulse oximetry, serial 
lung function measurement(post-dose spirometry), and ophthalmologic examinations.
7
STUDY DESIGN 
7.1
Overall Design 
This is a Phase 3, double-blind, parallel-group study in subjects with CF aged 6 to 11 years, 
homozygous or heterozygous for F508del. Subjects will be:
homozygous for F508del(F/F), or
heterozygous for F508deland a second allele with a residual function mutation (F/RF).
A schematic of the study design is shown in Figure 6-1. 


Statistical Analysis Plan (Methods) 
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Figure7-1
VX16-661-115 Study Design
7.2
Sample Size and Power
The sample size of this study is driven by demonstrating that the treatment effect of 
TEZ/IVA excludes a maximum possible placebo effect, which is based on a within-group 
comparison (change from baseline in LCI2.5in subjects on TEZ/IVA). If the corresponding 2-
sided 95% CI of the change from baseline in LCI2.5in subjects on TEZ/IVA excludes the pre-
defined maximum possible placebo effect, it will be considered that the study has achieved 
its primary objective.
A placebo effect is not expected with LCI, because clinical data fromother Vertex CFTR 
modulator studies consistently demonstrated a worsening of lung function (i.e., an increase 
from baseline in LCI) in the absence of CFTR modulator treatment. Study VX14-809-109 
(Study 809-109) evaluated treatment with LUM/IVA in F/F subjects aged 6 through 11 years 
using change from baseline in LCI as the primary efficacy endpoint and provided the most 
relevant clinical LCI data available in the younger age group of CF subjects. In Study 809-


Statistical Analysis Plan (Methods) 
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109, the placebo group had a mean worsening in LCI2.5of 0.08 units with an SD of 1.41 
(higher numbers indicate a worsening of an LCI measurement); the one-sided 90% lower 
bound was -0.10 and is used as an estimate for the pre-defined maximum possible placebo 
effect for Study 115.
Accounting for a 10% dropout rate, approximately 40 subjects in the TEZ/IVA group will 
provide at least 90% power to exclude -0.10 if the true mean change is -0.9 with anSD of 
1.41 using a two-sided alpha of 0.05. The current estimate of the maximum possible placebo 
effect is based on Study 809-109 placebo data in pediatric F/F subjects with CF.
7.3
Randomization
Approximately 65 subjects, of which up to 15 subjects have F/RFgenotypes, will be 
stratified by genotype and randomized 4:1 to study drug treatment.
An interactive web or voice response system (IXRS) will be used to assign subjects to 
treatment. Detailed instructions for randomization will be provided separately.
7.4
Blinding and Unblinding
Refer to Section 10.8 of the CSP for details.
8
ANALYSIS SETS
The following analysis sets are defined: All Subjects Set, Full Analysis Set, and Safety Set.
8.1
All Subjects Set
The All Subjects Set will be defined as all subjects who were randomized or received at least 
1 dose of study drug. This analysis set will be used for all individual subject data listings and 
the disposition summary table, unless specified otherwise.
8.2
Full Analysis Set
The Full Analysis Set (FAS) will be defined as allsubjects who were randomized and 
received at least 1 dose of study drug and had an eligible genotype. The FAS will be used for 
all efficacy analyses and subjects will be analyzed according to the treatment arm they are 
randomized to.
8.3
Safety Set
The SafetySet will be defined as all subjects who received at least 1 dose of study drug. The 
Safety Set will be used for all safety analyses, unless otherwise specified. The subjects will 
be analyzed according to the treatment they received.


Statistical Analysis Plan (Methods) 
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9
STATISTICAL ANALYSIS
9.1
General Considerations
The Schedule of Assessments is provided in the clinical study protocol (CSP) Table 3-1. 
Individual subject data for subjects in the All Subjects Set will be presented in individual 
subject data listings. The precision standards are provided in Appendix B.
Continuous variableswill 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 variableswill be summarized using counts and percentages.
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For 
ECGs, the baseline value will be defined as the average of the non-missing pretreatment 
measurements (triplicate) on Day1.
Absolute change from baselinewill be calculated as Post-baselinevalue−Baseline value.
Relative change from baselinewill be calculated and expressed in percentage as 100% × 
(Post-baselinevalue−Baseline value) / Baseline value.
Treatment-emergent (TE) Periodwill include the time from the first dose to 28 days after 
the last dose of the study drug or to the completion of study
 participation date, whichever 
occurs first. Completion of study participation is defined as one of the following:
For subjects who complete the study and enroll in the extension study within 28 days 
of the Week 8 Visit: the last participation date 
For subjects who complete the study and do not enroll in the extension study within 
28 days of the Week 8 Visit: the Safety Follow-up Visit
For subjects who prematurely discontinue study drug treatment but do not withdraw 
consent: the latest of ETT Visit, or Safety Follow‑up Visit (if required)
For subjects who withdraw consent: date of withdrawal of consent
The TE period will be used for safety analyses unless specified otherwise.
Unscheduled visits:Unscheduled visit measurements will be included in analysis as follows:
In scheduled visit windows per specified visit windowing rules.
In the derivation of baseline/last on-treatment measurements.
In the derivation of maximum/minimum on-treatment values and maximum/minimum 
change from baseline values for safety analyses.
In individual subject data listings as appropriate.
Visit windowing rules:The analysis visit windows for protocol-defined visits are provided 
in Appendix A. 


Statistical Analysis Plan (Methods) 
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Incomplete/missing datawill not be imputed, unless specified otherwise. 
Outliers:No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless specified otherwise.
Multiplicity: No multiplicity adjustment will be performed for hypothesis testing.
9.2
Background Characteristics 
9.2.1
Subject Disposition
The number of subjects in the following categories will be summarized overall and by 
treatment group based on the All Subjects Set: 
All Subjects Set
Randomized
Randomized but not dosed
Full Analysis Set
Safety Set
The number and percentage of subjects in each of the following disposition categories will be 
summarized overall and by treatment group:
Completed study drug treatment
Prematurely discontinued the treatment and the reason for discontinuation 
Completed study
Prematurely discontinued the study and the reason for discontinuation 
Enrolled in a rollover extension study
A listing will be provided for subjects who discontinued treatment or who discontinued 
study, with reasons for discontinuation.
9.2.2
Demographics and Baseline Characteristics
Demographicsand baseline characteristicswill be summarized overall and by treatment 
group, based on the FAS.
Demographic data will include the following:
Age at screening (years)
Sex (female and male)
Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations)
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, not collected per local regulations, and 
Other)


Statistical Analysis Plan (Methods) 
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Geographic region (Europeand Australia)
Baseline characteristics will include the following:
Mutation (F/F, F/RF)
Weight group (<40 kg, >=40 kg)
BMI (kg/m2)
BMI z-score
Weight (kg)
Weight z-score
Height (cm)
Height z-score
Disease characteristics will include the following:
Baseline LCI2.5
Baseline ppFEV1
Baseline FEV1
Baseline score of CFQ-R respiratory domain
Baseline sweat chloride
In addition, the following data listings will also be provided:
Informedconsent
Subjects with any inclusion and exclusion criteria violation
9.2.3
Medical History
Medical history will becoded by using the Medical Dictionary for Regulatory Activities
(MedDRA).
Based on the FAS, medical history will be summarized descriptively by system organ class 
(SOC) and preferred term (PT). The corresponding data listing will also be provided. 
9.2.4
Prior and Concomitant Medications
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary (WHODD) and categorized as follows:
Prior medication:any medication that started before the first dose date of study 
drug, regardless of when the medication ended.
Concomitant medication:medication continued or newly received on or after the 
first dose date of study drug through the end of the TE period.
Post-treatment medication:medication continued or newly received after the TE 
period.


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A given medication may be classified as follows: prior, concomitant, post-treatment, both 
prior and concomitant, both concomitant and post-treatment, or prior, concomitant, and 
post-treatment. 
If a medication has a completely missing or partially missing start date or stop date and it 
cannot be determined whether it was taken before the first dose date, concomitantly, or after 
the TE period, it will be classified as prior, concomitant, and post-treatment.
Prior medications and concomitant medications will be summarized descriptively by: 1) 
preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, and PN, on the FAS 
and presented by treatment group and overall. Theywill also be listed for each subject.
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix D.
9.2.5
Study Drug Exposure
Study drug exposure will be summarized based on the Safety Set, and presented by treatment 
group and overall.
Duration of study drug exposure (in days) will be calculated as: last dose date–first dose 
date+1day, regardless of study drug interruption. 
Duration of study drug exposure will be summarized descriptively (n, mean, SD, median, 
minimum, and maximum). It will also be summarized in categories for exposure duration: >0 
to ≤2 weeks, >2 to ≤4 weeks, >4 to ≤8 weeks, and >8 weeks, using counts and percentages. 
Additionally, the total study drug exposure, defined as the sum total of the study
 drug 
exposure across all subjects (in patient-weeks), will be provided.
9.2.6
Study Drug Compliance
Study drug compliance will be summarized based on the FAS, and presented by treatment 
group and overall.
Study drug compliance will be calculated as: 100 × [1 − (total number of days of any study 
drug interruption) / (duration of study drug exposure in days)].
Study drug compliance will be summarizeddescriptively(n, mean, SD, median, minimum, 
and maximum), and also in categories: <80% and ≥80% using frequency and percentage.
9.2.7
Important Protocol Deviations
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, or reliability of the study data or that may significantly 
affect a subject’s rights, safety, or well-being. IPD rules will be developed and finalized 
before database lock.
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to:
Subject entered the study despite violation of any inclusion or exclusion criteria
Subject was less than 80% compliant with study drug for non-safety reason


Statistical Analysis Plan (Methods) 
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Subject received prohibited concomitant medications
Subject received the wrong treatment or incorrect doses
Subject remained in the study despite meeting withdrawal criteria
Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being. 
IPDs (from the clinical database or from the site deviation log) will be summarized 
descriptively based on the FAS and presented by treatment group and overall. Additionally, 
IPDs will be provided in an individual subject data listing.
9.3
Efficacy Analysis
There is no multiplicity adjustment in this study; P-values provided for the secondary and 
other endpoints are considered nominal.
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified. The analysis will include all available measurements through the last scheduled 
on-treatment visit, including measurements after treatment discontinuation.
9.3.1
Analysis of the Primary Efficacy Variable
The primary efficacy endpoint is the absolute change in LCI
2.5from baseline through Week 
8.The objective of the primary efficacy endpoint analysis is to demonstrate that the mean 
absolute change from baselinein LCI
2.5through Week 8 excludes a pre-defined maximum 
placebo effect in subjects in the TEZ/IVA group.
The primary analysis will be performed using a restricted maximum likelihood (REML)-
based mixed-effect model for repeated measures (MMRM) for the subjects in the TEZ/IVA 
treatment group in the FAS population. The model will include absolute change from 
baseline in LCI2.5(including all measurements up to Week 8 [inclusive], both on treatment 
measurements and measurements after treatment discontinuation)as the dependent variable, 
and visit (as a class variable) as a fixed effect, with adjustment for mutation group based on 
the second CFTRallele (F/F and F/RF) and baseline LCI
2.5(continuous) value as covariates, 
and subject as a random effect. An unconstructed covariance structure will be used to model 
the within-subject errors. If the model fails to converge, a compound symmetry covariance 
structure will be considered. The degrees of freedom of the denominator will be 
approximated by the Kenward-Roger’smethod 2.
The primary results obtained from the model will be the estimated average treatment effect 
through Week 8 in LCI
2.5for subjects on TEZ/IVA. The corresponding LSmean, standard 
error (SE), 95% CI, and p-valuewill be provided. If the upper boundof the 95% CI is below 
the pre-defined maximum possible placebo effect, which was specified in the protocol, it will 
be considered that the study has achieved its primary objective.Summary statistics for 
change from baseline in LCI
2.5through Week 8, andat each visit will also be provided for 
subjects in theTEZ/IVA treatment group by mutation groups and overall.


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For F/F subjects in the placebo treatment group, summary statistics will be provided for 
change from baseline in LCI
2.5through Week 8, and at each visit.
9.3.2
Analysis of Secondary Efficacy Variables
Absolute change in sweat chloride from baseline at Week 8
A similar MMRM model will be used for the above variable using the same approach as 
described for the analysis of the primary efficacy variable, with the addition of baseline 
sweat chloride as a covariate. The assessment of efficacy will be primarily based on the 
estimated mean change from baseline at Week 8.
Similar summary tables will also be provided using the same approach as described for the 
analysis of the primary efficacy variable.
Absolute change in the CFQ-R respiratory domain score from baseline through Week8
A similar MMRM model will be used for the CFQ-R respiratory domain score based on the 
children’s version,using the same approach as described for the analysis of the primary 
efficacy variable, with the addition of baseline CFQ-R respiratory score as a covariate.
Summary tables will also be provided for boththe children’s version and the 
parents/caregivers’version using the same approach as described for the analysis of the 
primary efficacy variable.


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9.4
Safety Analysis
All safety analyses will be based on the Safety Set. Subjects will be analyzed according to 
the treatment they actually received.Only descriptive analysis of safety will be performed 
(i.e., no statistical hypothesis testing will be performed). The safety endpoints will be 
summarized using descriptive summary statistics by treatment group and overall. Due to the
smallsample size, the summary on F/RF subjects treated with IVA and F/F subjects treated 
with placebo should be interpreted with caution.
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
Treatment-emergent adverse events(TEAEs)
Clinical laboratory values
Standard 12-lead ECGs
Vital signs 
Pulse oximetry
Ophthalmologic examination
Serial lung function(post-dose spirometry)
9.4.1
Adverse Events 
AEs will be coded according to MedDRA and classified as pretreatment AEs, TEAEs, or 
post-treatment AEs, defined as follows:
Pretreatment AE:any AE that started before the first dose date of study drug.
TEAE:any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose date of study drug through the end of the TE period.
Post-treatment AE:any AE that worsened (either in severity or seriousness) or that was 
newly developed beyond the TE period.
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial AE start/end dates are defined in Appendix E.
9.4.1.1
Overview of TEAEs
An overview table of TEAEs will be provided with the following categories:


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Number of TEAEs (total number of TEAEs)
Subjects with any TEAEs
Subjects with TEAEs by strongest relationship
Subjects with TEAEs by maximum severity
Subjects with related TEAEs
Subjects with Grade 3/4 TEAEs
Subjects with serious TEAEs
Subjects with related serious TEAEs
Subjects with TEAEs leading to treatment discontinuation
Subjects with TEAEs leading to treatment interruption
Subjects with TEAEs leading to death
In addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation, treatment interruptions, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths.
For all AEs, the action taken on the CRF for TEZ/IVA (AM dose) is collected separately 
from the AE action taken for IVA (PM dose). As a result, it is possible thatin the AE dataset, 
the AE actions taken for the two agents are different. The summaries of TEAEs Leading to 
Treatment Discontinuation or Interruptions account for discontinuation and interruptions for 
either agent.
9.4.1.2
TEAEs by SOC and PT
In addition, the following summary tables of TEAEs will be provided:
All TEAEs
Related TEAEs
Grade 3/4 TEAEs
Serious TEAEs
Related serious TEAES
TEAEs leading to treatment discontinuation
TEAEs leading to treatment interruption
TEAEs leading to death
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 


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presented in the severity summaries, and the strongest relationship level will be presented in 
the relationship summaries.
9.4.1.3
TEAEs and SAEs by PT
The number and percentage of subjects with TEAEs and SAEs will be summarized by PT, 
where multiple occurrences of the same adverse event or a continuing adverse event for the 
same subject will be counted once.
9.4.1.4
Respiratory Events and Symptoms
Respiratory symptoms are defined as any TEAEs for the following 3 PTs:
Chest discomfort
Dyspnoea
Respiration abnormal
Respiratory events are defined as any of the afore-mentioned respiratory symptoms, or any 
TEAEs for the following 4 additional PTs:
Asthma
Bronchial hyperreactivity
Bronchospasm
Wheezing
Summary tables of respiratory symptoms and events will be provided by PT.
9.4.1.5
Elevated Transaminase
The following AE preferred terms will be selected for elevated transaminase:
Alanine aminotransferase abnormal
Alanine aminotransferase increased
Aspartate aminotransferaseabnormal
Aspartate aminotransferase increased
Transaminases abnormal
Transaminases increased
Liver function test abnormal
Liver function test increased
Hypertransaminasaemia
Hepatic enzyme abnormal
Hepatic enzyme increased
A summary table will be providedfor elevated transaminases events by PT.


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9.4.2
Clinical Laboratory
For treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous hematology, chemistry, vitamin, lipids and coagulation results will 
be summarizedin SI units at each scheduled time point. 
The number and percentage of subjects with events meeting threshold criteria laboratory 
event during the TE period will be summarized by treatment group and overall. The 
threshold analysis criterion shift from baseline will also be summarized for selected 
laboratory parameters. The threshold criteria are provided in Appendix G.
Results of urinalysis and the urine/serum pregnancy test will be listed in individual subject 
data listings only.
In addition, a listing of each subject
's liver function test (LFT), non-LFT chemistry, 
hematology, vitamin, lipid, and coagulation results outside the reference ranges will be 
provided. This listing will include data from scheduled and unscheduled visits.
For liver function tests (LFTs) (i.e. alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], and total bilirubin), the following 
additional analyses will be presented:
A listing of subjects with elevated LFT resultsduring the TE period will be presented. 
For each subject in the listing, LFT assessments at all the time points will be included 
(scheduled and unscheduled).
Meanvalues (± SD) will be plotted by visit,and box plotsof the LFT values/ULN 
will be plotted by visit.
Summary tablesfor the shift from baseline to the value at Week 8 will be provided for 
vitamin levels and the lipid panel. Box plotsof vitamin levels and the lipid panel will also be 
plotted against visit.
9.4.3
Electrocardiogram
For treatment-emergent ECG measurements, a summary of raw values and change from 
baseline values will be provided at each scheduled time point for the following standard 12-
lead ECG measurements: RR (msec), HR (beats per minute [bpm]), PR (msec), QRS 
duration (msec), QT (msec), and QT corrected for HR intervals (QTcF [msec]). A 
corresponding listing will also be provided.
The number and percentage of subjects with at least 1 ECG event that meets the threshold 
criteria during the TE period will be summarized by time point. A corresponding listing will 
also be presented. This listing will include both scheduled and unscheduled visits. The 
threshold value criteria are provided in Appendix G.
9.4.4
Vital Signs
For treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized at each scheduled time point for the following measurements: 
systolic and diastolic blood pressure (mm Hg), body temperature (°C), HR (bpm), and 
respiration rate (breaths per minute). A corresponding listing will also be provided.


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The number and percentage of subjects with vital signparameters that meet the threshold 
criteria during the TE period will be summarized for each scheduled time point. The 
threshold value criteria are provided in Appendix G.
9.4.5
Pulse Oximetry
For treatment-emergent percent of oxygen saturation by pulse oximetry, a summary of raw 
values and change from baseline values will be provided at each scheduled time point.
9.4.6
Physical Examination 
Physical examination findings will be presented as a subject data listing only.
9.4.7
Ophthalmologic Examination
Ophthalmologic examination findings will be presented as a data listing.
9.4.8
Other Safety Analysis
9.4.8.1
Serial Lung Function(Post-dose Spirometry)
For the 2-hour and 4-hour post-dose spirometry measurements on Day 1 and Week 2, a 
summary of raw values and the absolute change from the predose value for ppFEV
1will be 
provided at each time point.
The number and percentage of subjects with ppFEV1decline ≥10, ≥15, and ≥20 
percentage points in the absolute change from baseline in predose value will be summarized 
for scheduled visits.
In addition, the number and percentage of subjects with ≥0.10 L or ≥0.20 L decrease in the 
absolute change from baseline through Week 8for FEV1 will also be summarized for 
scheduled visit.
Subjects with ≥10 percentage points decrease in absolute change from baseline through 
Week 8for ppFEV
1or ≥0.10 L decrease in the absolute change from baseline through Week 
8for FEV
1will be listed.
10
INTERIM AND DMC ANALYSIS
10.1
Interim Analysis
No formal interim analysis is planned.
10.2
DMC Analysis
An independent data monitoring committee (IDMC) was formed before study initiation to 
review the safety of the study. The IDMC’s objectives and operational details were defined 
in a separate document (IDMC Charter) which was finalized before the first subject was 
screened in the study. The IDMC conducted regular planned safety reviews of study data as 
outlined in the IDMC Charter and IDMC Analysis Plan.


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11
REFERENCES
1Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43.
2 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97.
3Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm.


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12
LIST OF APPENDICES
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments
Table 12-1
Visit Window Mapping Rules 
Assessments
Visit1
Target Study Day
Visit Window 
(in study days)
Safety Assessment
Standard 12-lead ECG
Vital signs
Pulse oximetry
Chemistry
Day 1
1
≤1 Pre-dose
Week 2
15
[1*, 22]
Week 4
29
(22, 43]
Week 8 
57
(43, 71]
Safety Follow-up Visit
N/A
Nominal
Hematology
Day 1
1
≤1 Pre-dose
Week 2
15
[1*, 36]
Week 8
57
[37, 71]
Safety Follow-up Visit
N/A
Nominal
Urinalysis
Lipid panel
Vitamin levels
Day 1
1
≤1 Pre-dose
Week 8
57
[1*, 71]
Safety Follow-up Visit
N/A
Nominal
Coagulation
Day 1
1
≤1 Pre-dose
Week 8
57
[1*, 71]
Safety Follow-up
N/A
Nominal
Efficacy Assessment
Spirometry (pre-dose)
CFQ-R
a
Weight and height
Day 1
1
≤1 Pre-dose
Week 2
15
[1*, 22]
Week 4
29
(22, 43]
Week 8 
57
(43, 71]
Safety Follow-up Visit
N/A
>71
LCI
Day 1
1
≤1 Pre-dose
Week 2
15
[1*, 22]
Week 4
29
(22, 43]
Week 8
57
(43, 71]
Sweat chloride
Day 1
1
≤1 Pre-dose
Week 8
57
[1*, 71]
Safety Follow-up Visit 
N/A
>71
* Only include day 1 post-dose measurements.
a CFQ-R is only required at the Safety Follow-up Visit for subjects who prematurely discontinue study 
treatment and do not have the ETT visit.
b Physical examination at Day 1, Week 8 and Safety Follow-up Visit are abbreviated ones.


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Note: 
1. Visit name for analysis purpose is used to reportdata in tables and figures.
2. The analysis visit windows will be applied for both scheduled and unscheduled visits.
3. If no measurement is available within a visit window, the assessment will be considered 
missing for the visit.
4. If there is more than one measurement available within the same visit window for 
efficacy parameters, the record at the scheduled visit will be used. Otherwise,
The record closest to the target day will be used.
If there are multiple records with the same distance to the target day, the latest record 
will be used.
Assessments at early treatment termination (ETT) visit will follow the windowing 
rules for regular visits up to Week 8.
Assessments at safety follow-up (SFU) visit will follow the windowing rules for 
regular visits if they fall within the upper boundary of the window for Week 8, or 
remain as SFU if they go beyond the upper boundary of the window for Week 8.
5. If there is more than one measurement available within the same visit window for safety 
parameters, then
The record closest to the target day will be used.
If there are multiple records within the same distance from the target day, the latest 
record will be used; or
SFU visit will not be windowed; instead, it will be used according to the nominal visit 
in relevant analyses.
6. Spirometry assessments, BMI, weight, and height will be used for 
 
safety purpose. Their measurements will follow the visit windowing rules for efficacy 
parameters.
7. For post-dose spirometry, Day 1 and Week 2 will be nominal.
Special handlingfor ECG:
On Day 1, the pre-dose measurements will be collected as triplets; the average of the 
triplicate will be used as pre-dose measurement on Day 1. Only pre-dose measurement 
with nominal visit names related to the triplets shall be used in this average.
For other post-dose visits, the visit window in the above table will apply.


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Appendix B: Stardards for Safety and Efficacy Variable Display in TFLs
Continuous Variables
The precision for continuous variables has been specified in the Vertex Standard 
Programming Rules document (Version 1.0, December 2015):
Categorical Variables: Percentages will be presented to 1 decimal place.




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Appendix D: 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 January 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 December 31, 2050 to impute).
In summary, the prior, concomitant or post categorization of a medication is described below.
Table 12-2
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 studydrug
P
PC
PCA
≥ First dose date and 
≤ End date of TE period
-
C
CA
> End date of TE period
-
-
A
A: Post; C: Concomitant; P: Prior


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


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Appendix F: Details of GLI Equation for Calculating ppFEV
1
Percent predicted values will be calculated for parameters of FEV
1, FVC, FEV
1/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 
predictedvalues are available in:
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja 
Stanojevic, Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at: 
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-
2012-regression-equations-and-lookup-tables.aspx
Accessed Sep 11, 2017. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:  
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. 
Cole, Janet Stocks. Version 19 July 2015. Available at: 
http://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/it-
engineers-and-manufacturers.aspx
Accessed Sep 11, 2017. 
GLI-2012 -SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at: 
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx
Accessed Sep 11, 2017.
Data handling rule for spirometry is as follows: 
Input age andheight with at least 2 decimal place
For race, map CRF black or AA 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 coeffiecients in the       
GLI  equations.


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Appendix G: Criteria for Threshold Analysis
Table 12-3Threshold Analysis Criteria for Clinical Chemistry, Hematology and Coagulation
Parameter
Threshold Criteria
Comments
LFT
ALT
>ULN -≤  3 xULN
>3 –≤  5 xULN
>5 –≤  8 xULN
>8 –≤  20.0 xULN
>20.0 x ULN
Per FDA DILI Guidance Jul2009 and 
CTCAE
AST
>ULN -≤  3 xULN
>3 –≤  5 xULN
>5 –≤  8 xULN
>8 –≤  20.0 xULN
>20.0 x ULN
FDA DILI Guidance and CTCAE
ALT or AST
(ALT>ULN and ALT ≤  3 xULN) or 
(AST>ULN and AST≤  3 xULN)
(ALT>3 xULN and ALT ≤  5 xULN) 
or (AST>3xULN and AST≤  5 xULN)
(ALT>5 xULN and ALT ≤  8 xULN) 
or (AST>5xULN and AST≤  8 xULN)
(ALT>8 xULN and ALT ≤  20 
xULN) or (AST>8xULN and AST≤  
20 xULN)
ALT>20 xULN or AST> 20 xULN
FDA DILI Guidance 
Alkaline Phosphatase
>ULN -≤ 1.5xULN
>1.5 –≤ 2.5 xULN
>2.5 –≤ 5.0 x ULN
>5.0 –≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance and CTCAE
Total Bilirubin
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2 x ULN
>2 –≤ 3 x ULN 
>3 –≤ 10 x ULN
>10 x ULN
FDA DILI Guidance and CTCAE
Direct Bilirubin
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2 x ULN
>2 –≤ 3 x ULN 
>3 –≤ 10 x ULN
>10 x ULN
Same Criteria as Total Bilirubin
No CTCAE 
Not in DILI Guidance
ALT and Total Bilirubin
ALT>3xULN and TBILI>2xULN
FDA DILI Guidance Jul2009 
AST and Total Bilirubin
AST>3xULN and TBILI>2xULN
FDA DILI Guidance Jul2009
(ALT or AST) and Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN
FDA DILI Guidance Jul2009 
GGT 
>ULN -≤ 2.5 x ULN
>2.5 –  ≤ 5.0 x ULN
>5.0 –≤ 20.0 x ULN 
>20.0 x ULN
CTCAE grade 1-4


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Non-LFT Chemistry
CPK
>ULN -≤ 2.5 x ULN
>2.5 -≤ 5 x ULN
>5 -≤ 10x ULN 
>10 x ULN
CTCAE grades 1-4
Creatinine
>ULN -≤ 1.5 x ULN
>1.5 -≤ 3.0 x ULN
>3.0 -≤ 6.0 x ULN
>6.0 x ULN
CTCAE grades 1-4
Blood Urea Nitrogen
>ULN -≤ 1.5 x ULN
>1.5 -≤ 3.0 x ULN
>3.0 -≤ 6.0 x ULN
>6.0 x ULN
Same criteria as creatinine 
No CTCAE 
Sodium
Hyponatremia
<LLN -≥130 mmol/L
<130 –≥120 mmol/L 
<120 mmol/L 
CTCAE grade 1, 3, 4
(No CTCAE grade 2)
Hypernatremia
>ULN -≤ 150 mmol/L
>150 mmol/L-≤155 mmol/L 
>155 mmol/L -≤ 160 mmol/L
>160 mmol/L
CTCAE grade 1-4
Potassium
Hypokalemia
<LLN –≥ 3.0 mmol/L
<3.0 –≥ 2.5 mmol/L
<2.5 mmol/L
CTCAE grade 1&2, 3, 4
(Grade 1 and 2 are the same)
Hyperkalemia
>ULN –≤ 5.5 mmol/L
>5.5 –  ≤ 6.0 mmol/L 
>6.0 –≤ 7.0 mmol/L 
>7.0 mmol/L
CTCAE grade 1-4
Glucose
Hypoglycemia 
<3.0 –≥ 2.2 mmol/L 
<2.2 -≥ 1.7 mmol/L
<1.7 mmol/L
CTCAE grade 1-4
Hyperglycemia 
>ULN -≤ 8.9 mmol/L
>8.9 –≤ 13.9 mmol/L
>13.9 –≤ 27.8 mmol/L 
>27.8 mmol/L
CTCAE grade 1-4
Albumin
<35 -≥ 30 g/L
<30 –≥ 20 g/L
<20 g/L 
CTCAE grade 1-3
Amylase
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2.0 x ULN 
>2.0 –≤ 5.0 x ULN
>5.0 x ULN
CTCAE grade 1-4
Lipase
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2.0 x ULN 
>2.0 –≤ 5.0 x ULN
>5.0 x ULN
CTCAE grade 1-4