Clinical trial NCT03537651
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-04-25; Completion date: 2023-09-29
Enrollment: 130 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the long-term safety and tolerability of tezacaftor in combination with ivacaftor (TEZ/IVA) in participants with cystic fibrosis (CF) aged 6 years and older, homozygous or heterozygous for the F508del mutation.

Detailed description:

Arms: arm 1: Part A: Participants weighing less than (\<)40 kilograms (kg) at Day 1 received tezacaftor (TEZ) 50 milligrams (mg) once daily (qd)/ivacaftor (IVA) 75 mg every 12 hours (q12h) and the participants weighing greater than or equals to (\>=) 40 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks. Doses were adjusted upward for changes in body weight and/or age.

Part B: Participants weighing \<30 kg at Day 1 received TEZ 50 mg qd/IVA 75 mg q12h and the participants weighing \>=30 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period up to 192 weeks. Doses were adjusted upward for changes in body weight and/or age.
Interventions: intervention 1: TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed-dose combination tablet for oral administration. intervention 2: Tablet for oral administration.

Protocol documents:
Prot_000.pdf: 
 
Page 1 of 63 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, Open-label, Rollover Study to Evaluate the 
Safety and Efficacy of Long-term Treatment With 
Tezacaftor in Combination With Ivacaftor in Subjects With 
Cystic Fibrosis Aged 6 Years and Older, Homozygous or 
Heterozygous for the F508del-CFTR Mutation 
Vertex Study Number: VX17-661-116 
 
 
EudraCT Number: 2017-002968-40 
Date of Protocol: 08 Nov 2019 (Version 2.3 US) 
Replaces Version 1.0 (dated 08 December 2017) 
 
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, Open-label, Rollover Study to Evaluate the Safety and Efficacy of 
Long-term Treatment With Tezacaftor in Combination With Ivacaftor in Subjects 
With Cystic Fibrosis Aged 6 Years and Older, Homozygous or Heterozygous for 
the F508del-CFTR Mutation 
Brief Title 
A Study to Evaluate the Safety and Efficacy of Long-term Treatment With 
TEZ/IVA in CF Subjects With an F508del-CFTR Mutation 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3, safety and efficacy 
 
 
Objectives 
Primary Objective 
To evaluate the long-term safety and tolerability of tezacaftor in combination with 
ivacaftor (TEZ/IVA) in subjects with cystic fibrosis (CF) aged 6 years and older, 
homozygous or heterozygous for the F508del mutation  
Secondary Objective 
To evaluate the long-term efficacy of TEZ/IVA in subjects with CF aged 6 years 
and older, homozygous or heterozygous for the F508del mutation  
 
 
Endpoints 
Primary Endpoint 
Safety and tolerability of long-term TEZ/IVA treatment based on adverse events 
(AEs), clinical laboratory values (serum chemistry, hematology, lipids, and 
vitamins), standard 12-lead ECGs, physical examinations (PEs), vital signs, 
ophthalmologic examinations, and pulse oximetry 
Secondary Endpoints 
 Absolute change from baseline in lung clearance index2.5 (LCI2.5; for subjects 
from Study VX16-661-115 [Study 115] and the Study VX15-661-113 Part B 
[Study 113B] LCI Substudy only) 
 Absolute change from baseline in sweat chloride 
 Absolute change from baseline in Cystic Fibrosis Questionnaire–Revised 
(CFQ-R) respiratory domain score 
 Absolute change from baseline in body mass index (BMI) 


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Number of Subjects 
Study VX17-661-116 is a rollover study.  
Approximately 56 subjects from Study 113B and 65 subjects from Study 115 are 
potentially eligible for enrollment. Up to approximately 121 subjects are potentially 
eligible for enrollment. 
 
 
Study Population 
Male and female subjects with CF aged 6 years and older, who completed 
Study 113 B or Study 115 and are 
 
homozygous for F508del (F/F),  
 
heterozygous for F508del and a second allele with a residual CFTR-
function mutation (F/RF), or 
 
heterozygous for F508del and a second allele that has been shown to be 
responsive to TEZ/IVA  
 
 
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 
 
 
Study Design 
This is a Phase 3, multicenter, open-label, rollover study in subjects with CF who 
are homozygous or heterozygous for F508del and who completed the Week 24 
Visit in Study 113B or the Week 8 Visit in Study 115. The study is designed to 
evaluate the safety and efficacy of long-term TEZ/IVA treatment in pediatric 
subjects aged 6 years and older. 
During the course of study conduct, if TEZ/IVA receives marketing authorization 
and is available for the treatment of CF in populations enrolled in this study, 
subjects with the approved CFTR genotypes may be discontinued from this rollover 
study at the discretion of the sponsor. If a subject continues onto a commercially 
available Vertex CFTR modulator, the Early Treatment Termination (ETT) Visit 
will be completed before dosing with commercial drug begins, and the Safety 
Follow-up Visit will not be required. 
If a subject is continuing onto TEZ/IVA supplied via a Vertex-sponsored managed 
access program (MAP), the ETT Visit will be completed before dosing with 
TEZ/IVA via the MAP, and the Safety Follow-up Visit will not be required. 
Alternatively, if local health authorities decline to grant marketing authorization, or 
if clinical benefit is not demonstrated for the use of TEZ/IVA for the treatment of 
CF in populations enrolled in this study, subjects with the relevant CFTR genotypes 


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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 within 
7 days of the last dose of study drug and a Safety Follow-up Visit should occur 
within 28 (± 7) days after the last dose of study drug.  
 
 
Assessments 
Safety Assessments 
AEs, clinical laboratory values (serum chemistry, hematology, lipids, and vitamins), 
standard 12-lead ECGs, vital signs, pulse oximetry, PEs, and ophthalmologic 
examinations 
Efficacy Assessments 
LCI, 
 sweat chloride, CFQ-R, weight, height, BMI,
 
 
 
 
Statistical Analyses 
Statistical analysis details will be provided in the statistical analysis plan (SAP), 
which will be finalized before the clinical database lock for the study. 
The safety analysis will be performed on all subjects in the Safety Set. The efficacy 
analysis will be performed on all subjects in the Full Analysis Set for each parent 
study respectively. The methods used for the efficacy analyses will be similar for 
those used in the parent studies.  
The least square (LS) mean and the associated 95% CI at each defined analysis visit 
will be provided for the corresponding efficacy endpoints. Descriptive summary 
statistics will be provided for relevant safety and efficacy parameters.  
Interim analyses (IAs) may occur at any time during the study. The timing and IA 
analysis plans will be documented in the SAP. 
 
 
IDMC Reviews 
An independent data monitoring committee (IDMC) will conduct regular planned 
safety reviews of study data as outlined in the IDMC charter. 


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3 
SCHEDULE OF ASSESSMENTS 
The Schedule of Assessments is shown in Error! Reference source not found.. 
Table 3-1 
Study VX17-661-116: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT 
Visitb,c 
Safety Follow-up 
Visit 
28 (±7) Days 
After Last Study 
Drug Doseb,c 
Day 1d 
Study 115 Subjects Only 
Weeks 12, 24, 36, 
48, 60, 72, 84,  
and 96 
(±7 days) 
Day 15 
(± 3 days)  
Week 4 
(±7 days)  
Clinic visit 
X 
X 
X 
X 
X 
X 
Informed consent/assent 
X 
 
 
 
 
 
Inclusion and exclusion criteria review 
X 
 
 
 
 
 
CFTR genotypee 
X 
 
 
 
 
 
CFQ-Rf 
X 
X 
X 
X 
X 
 
Height and weightg 
X 
X 
X 
X 
X 
X 
Ophthalmologic examinationh 
Xi 
 
 
Weeks 48 and 96j 
Xk 
Xj,k 
 
a 
All assessments will be performed before dosing unless noted otherwise. 
b  
If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the subject decides to terminate study treatment. Subjects 
who prematurely discontinue treatment will also complete the Safety Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug. If the ETT Visit occurs 
3 weeks or later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required.  
c  
If a subject is continuing onto a commercially available Vertex CFTR modulator, or if the subject will receive TEZ/IVA via a Vertex-sponsored managed access program 
(MAP), the ETT Visit will be completed before dosing with commercial drug or MAP drug begins, and the Safety Follow-up Visit will not be required.  
d 
The Day 1 Visit of Study 116 may be on the same day as the last scheduled visit of the parent study; this will occur at the Week 24 Visit for subjects from Study 113B and at 
the Week 8 Visit for subjects from Study 115. Subjects will NOT have to repeat any Study 116 Day 1 assessments that were specified to be performed at the last scheduled 
visit in the parent study. For subjects who were enrolled in Study 116, but had Day 1 study drug administration procedures delayed, Section 9.1.1 describes the assessments to 
be performed on Day 1. 
e  
The CFTR genotype result can be taken from Study 113 or Study 115. If the genotype result is not available, subjects will be tested for CFTR genotype; if the genotype result 
from the confirmatory test is exclusionary, then the subject will be removed from the study.  
f 
The CFQ-R must be completed before the start of any other assessments scheduled at that visit.  
g 
Height and weight will be measured with shoes off and before dosing with study drug. BMI will be derived from height and weight. 
h   Ophthalmologic examinations will be performed by a licensed ophthalmologist or optometrist. 
i  
Subjects who did not have an ophthalmologic examination at the end of Study 113B or Study 115 will have an ophthalmologic examination at the Day 1 Visit, or no more 
than 28 days after. Subjects who had an ophthalmological examination in the parent study less than 28 days before Day 1 of Study 116 do not need to repeat the examination. 
j  
An ophthalmologic examination will occur either at the Week 96 Visit (± 28 days) or the Safety Follow-up Visit, but must be completed by the date of the Safety Follow-up 
Visit.  
k 
Subjects who discontinue treatment after receiving at least 1 dose of study drug will have an ophthalmologic examination. The examination may be completed at either the 
ETT or Safety Follow-up Visit, but must be completed by the date of the Safety Follow-up Visit. 


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Table 3-1 
Study VX17-661-116: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT 
Visitb,c 
Safety Follow-up 
Visit 
28 (±7) Days 
After Last Study 
Drug Doseb,c 
Day 1d 
Study 115 Subjects Only 
Weeks 12, 24, 36, 
48, 60, 72, 84,  
and 96 
(±7 days) 
Day 15 
(± 3 days)  
Week 4 
(±7 days)  
Complete physical examinationl 
X 
 
 
Week 96 
X 
X 
Standard 12-lead ECGm  
X 
 
 
Weeks 24, 48, 72, 
and 96 
X 
X 
Pregnancy testn 
X 
 
 
Weeks 24, 48, 72, 
and 96 
X 
X 
Vital signso 
X 
X 
X 
X 
X 
X 
Pulse oximetryo 
X 
X 
X 
X 
X 
X 
MBWp (Study 113B LCI Substudy and 
Study 115 subjects only) 
X 
X 
X 
Weeks 24, 48, 72, 
and 96 
X 
 
Hematology 
Xr 
X 
 
X 
X 
X 
Serum chemistry 
Xr 
X 
 
X 
X 
X 
Lipid panel 
Xr 
 
 
Weeks 24, 48, 72, 
and 96 
X 
X 
Vitamin levels 
Xr 
 
 
Weeks 24, 48, 72, 
and 96 
X 
X 
 
Symptom-directed physical examinations will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. 
m 
All standard 12-lead ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes. ECGs collected on Day 1 before dosing will be 
performed in triplicate. 
n 
Serum pregnancy tests will be performed at the site for all female subjects of childbearing potential. All pregnancy tests will be serum tests, except for the Day 1 Visit, when a 
urine pregnancy test will be performed at the site and results reviewed before dosing with study drug.  
o 
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest for at least 5 minutes. 
p  
The MBW assessment will be performed on multiple replicates and before study drug dosing (see Section 11.3.1 and the Study Reference Manual). MBW should be 
performed pre-bronchodilator
 
 
r  
Blood samples should be collected before the first dose of study drug on Day 1. Blood sampling for all other clinical visits except the Day 1 Visit may be conducted at any 
time after the ECG assessment and before the snack or meal. 


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Table 3-1 
Study VX17-661-116: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT 
Visitb,c 
Safety Follow-up 
Visit 
28 (±7) Days 
After Last Study 
Drug Doseb,c 
Day 1d 
Study 115 Subjects Only 
Weeks 12, 24, 36, 
48, 60, 72, 84,  
and 96 
(±7 days) 
Day 15 
(± 3 days)  
Week 4 
(±7 days)  
Sweat chloridet 
X 
 
 
Weeks 24, 48, and 
96 
X 
 
Meal(s) or snack(s) at sitev 
X 
X 
X 
Xw 
 
 
Study drug count 
 
X 
X 
X 
X 
 
Study drug dosingx 
Day 1 to Week 96 
 
Medications review 
Continuous from signing of the ICF and assent (where applicable) through the Safety Follow-up Visit 
Treatment and procedures review 
Continuous from signing of the ICF and assent (where applicable) through the Safety Follow-up Visit 
AEs and SAEsy 
Continuous from signing of the ICF and assent (where applicable) through the Safety Follow-up Visit 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFQ-R: CF Questionnaire–Revised; ETT: Early Treatment Termination; ICF: informed consent form; IVA: 
ivacaftor; LCI: lung clearance index; MBW: multiple-breath washout; SAE: serious adverse event; TEZ: tezacaftor 
 
t   No other assessments should overlap with sweat chloride collection. 
v 
A fat-containing meal or snack will be provided at the site to subjects after all predose assessments have occurred.  
w  
Providing a meal or snack is optional at the Week 96 Visit. 
x 
The study drug should be administered every 12 hours (± 2 hours) within 30 minutes after starting a meal with fat-containing food. On days of scheduled visits, the morning 
dose of study drug will be administered at the site after the predose assessments have been completed. The final dose of study drug will be administered the evening before the 
Week 96 Visit. 
y  
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will be reported to Vertex Global Patient Safety within 24 hours as described in 
Section 13.1.2.3 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 10 
List of Tables............................................................................................................................ 13 
List of Figures .......................................................................................................................... 13 
List of Abbreviations................................................................................................................ 14 
5 
Introduction.......................................................................................................................... 17 
5.1 
Background ..................................................................................................................... 17 
5.2 
Study Rationale .............................................................................................................. 17 
6 
Study Objectives .................................................................................................................. 18 
6.1 
Primary Objective ........................................................................................................... 18 
6.2 
Secondary Objective ....................................................................................................... 18 
7 
Study Endpoints ................................................................................................................... 18 
7.1 
Primary Endpoint ............................................................................................................ 18 
7.2 
Secondary Endpoints ...................................................................................................... 18 
8 
Study Population .................................................................................................................. 19 
8.1 
Inclusion Criteria ............................................................................................................ 19 
8.2 
Exclusion Criteria ........................................................................................................... 20 
9 
Study Implementation ......................................................................................................... 20 
9.1 
Study Design .................................................................................................................. 20 
9.1.1 
Treatment Period .................................................................................................... 21 
9.1.2 
Safety Follow-up .................................................................................................... 21 
9.1.3 
Early Termination of Treatment ............................................................................. 22 
9.1.4 
Independent Data Monitoring Committee .............................................................. 22 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 22 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 22 
9.3.1 
Study Design........................................................................................................... 22 
9.3.2 
Study Drug Dose and Duration .............................................................................. 23 
9.3.3 
Rationale for Study Assessments ........................................................................... 23 
9.4 
Study Restrictions ........................................................................................................... 25 
9.5 
Prior and Concomitant Medications ............................................................................... 26 
9.6 
Administration ................................................................................................................ 26 
9.7 
Missed Doses .................................................................................................................. 28 
9.8 
Dose Modification for Use With Concomitant CYP3A Inhibitors ................................ 28 
9.9 
Discontinuation of Study Participation .......................................................................... 29 
9.10 Removal of Subjects ....................................................................................................... 29 
9.11 Replacement of Subjects ................................................................................................ 29 
10 Study Drug Information and Management ....................................................................... 29 
10.1 Preparation and Dispensing ............................................................................................ 29 
10.2 Packaging and Labeling ................................................................................................. 30 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 30 


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10.4 Drug Accountability ....................................................................................................... 30 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 30 
10.6 Compliance ..................................................................................................................... 31 
10.7 Blinding and Unblinding ................................................................................................ 31 
11 Assessments .......................................................................................................................... 31 
11.1 Timing of Assessments ................................................................................................... 31 
11.2 Subject and Disease Characteristics ............................................................................... 31 
11.3 Efficacy ........................................................................................................................... 32 
11.3.1 
Lung Clearance Index (Study 115 and Study 113B LCI Substudy Subjects Only) 32 
11.3.3 
Sweat Chloride ....................................................................................................... 33 
11.3.4 
Weight, Height, and BMI ....................................................................................... 34 
11.3.5 
Cystic Fibrosis Questionnaire-Revised .................................................................. 34 
11.4 Safety .............................................................................................................................. 36 
11.4.1 
Adverse Events ....................................................................................................... 36 
11.4.2 
Clinical Laboratory Assessments ........................................................................... 36 
11.4.3 
Liver Function Test Parameters .............................................................................. 37 
11.4.4 
Physical Examinations and Vital Signs .................................................................. 38 
11.4.5 
Pulse Oximetry ....................................................................................................... 39 
11.4.6 
Electrocardiograms ................................................................................................. 39 
11.4.7 
Ophthalmologic Examination ................................................................................. 39 
11.4.8 
Contraception and Pregnancy ................................................................................. 40 
11.4.8.1 Contraception ................................................................................................... 40 
11.4.8.2 Pregnancy ......................................................................................................... 42 
12 Statistical and Analytical Plans .......................................................................................... 42 
12.1 Sample Size and Power .................................................................................................. 42 
12.2 Analysis Sets .................................................................................................................. 42 
12.2.1 
All Subjects Set ...................................................................................................... 42 
12.2.2 
Full Analysis Set ..................................................................................................... 42 
12.2.3 
Safety Set ................................................................................................................ 42 
12.3 Statistical Analysis ......................................................................................................... 42 
12.3.1 
General Considerations ........................................................................................... 43 
12.3.2 
Background Characteristics .................................................................................... 44 
12.3.2.1 Subject Disposition .......................................................................................... 44 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 45 
12.3.2.3 Prior and Concomitant Medications................................................................. 45 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 46 
12.3.3 
Efficacy Analysis .................................................................................................... 46 
12.3.3.1 Analysis of Primary Efficacy Variables ........................................................... 46 
12.3.3.2 Analysis of Secondary Efficacy Variables ....................................................... 46 


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12.3.4 
Safety Analysis ....................................................................................................... 47 
12.3.4.1 Adverse Events................................................................................................. 47 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 48 
12.3.4.3 Electrocardiogram ............................................................................................ 48 
12.3.4.4 Vital Signs ........................................................................................................ 48 
12.3.4.5 Physical Examination ....................................................................................... 49 
12.3.4.6 Other Safety Analysis ...................................................................................... 49 
12.3.5 
Interim and IDMC Analyses ................................................................................... 49 
12.3.5.1 Interim Analysis ............................................................................................... 49 
12.3.5.2 IDMC Analysis ................................................................................................ 49 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 49 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 49 
13.1.1 
Adverse Events ....................................................................................................... 49 
13.1.1.1 Definition of an Adverse Event........................................................................ 49 
13.1.1.2 Clinically Significant Assessments .................................................................. 49 
13.1.1.3 Documentation of Adverse Events................................................................... 50 
13.1.1.4 Adverse Event Severity .................................................................................... 50 
13.1.1.5 Adverse Event Causality .................................................................................. 51 
13.1.1.6 Study Drug Action Taken ................................................................................ 51 
13.1.1.7 Adverse Event Outcome .................................................................................. 52 
13.1.1.8 Treatment Given............................................................................................... 52 
13.1.2 
Serious Adverse Events .......................................................................................... 52 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 52 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 53 
13.1.2.3 Reporting Serious Adverse Events................................................................... 53 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 54 
13.2 Administrative Requirements ......................................................................................... 54 
13.2.1 
Ethical Considerations ............................................................................................ 54 
13.2.2 
Subject Information and Informed Consent ........................................................... 54 
13.2.3 
Investigator Compliance ......................................................................................... 54 
13.2.4 
Access to Records ................................................................................................... 55 
13.2.5 
Subject Privacy ....................................................................................................... 55 
13.2.6 
Record Retention .................................................................................................... 55 
13.2.7 
Study Termination .................................................................................................. 55 
13.2.8 
End of Study ........................................................................................................... 56 
13.3 Data Quality Assurance .................................................................................................. 56 
13.4 Monitoring ...................................................................................................................... 56 
13.5 Electronic Data Capture ................................................................................................. 56 
13.6 Publications and Clinical Study Report .......................................................................... 57 
13.6.2 
Clinical Study Report ............................................................................................. 57 
14 References ............................................................................................................................. 58 
15 Appendix 1: CFTR Mutations ............................................................................................ 61 
16 Protocol Signature Pages .................................................................................................... 62 
16.1 Sponsor Signature Page .................................................................................................. 62 


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16.2 Investigator Signature Page ............................................................................................ 63 
List of Tables 
Table 3-1 
Study VX17-661-116: Treatment Period and Safety Follow-up Visit ................... 7 
Table 9-1 
Study Restrictions ................................................................................................. 25 
Table 9-2 
Study Drug Administration ................................................................................... 27 
Table 9-3 
Dosing Recommendations for Subjects Taking Concomitant CYP3A Inhibitors 28 
Table 10-1 
Identity of Study Drugs, Dosage, and Storage ...................................................... 30 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 36 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 41 
Table 13-1 
Grading of AE Severity ........................................................................................ 51 
Table 13-2 
Classifications for AE Causality ........................................................................... 51 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 52 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 52 
List of Figures 
Figure 9-1 
VX17-661-116 Study Design ............................................................................... 21 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BPM 
beats per minute 
CD 
compact disc 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator protein 
CFTR 
CF transmembrane conductance regulator gene 
CI 
confidence interval 
Cl− 
chloride ion 
CRF 
case report form 
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 
ETT 
Early Termination of Treatment 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FEV1 
forced expiratory volume in 1 second 
F/F 
homozygous for F508del 
F/RF 
heterozygous for F508del and a second mutation that results in residual CFTR 
function 
 
 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HDL 
high-density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act  
HR 
heart rate 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonization 


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Abbreviation 
Definition 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
 
 
IV 
intravenous 
IVA 
ivacaftor 
LCI 
lung clearance index 
LCI2.5 
number of lung turnovers required to reduce the end tidal inert gas concentration to 
1/40th of its starting value 
 
 
 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LS 
least square 
MAP 
managed access program 
max 
maximum value 
MBW 
multiple-breath washout 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
number of subjects 
PE 
physical examination 
 
 
P-gp 
P-glycoprotein 
PI 
principal investigator 
 
 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 
qd 
daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
R117H 
CFTR missense gene mutation that results in the replacement of an arginine residue at 
position 117 of CFTR with a histidine residue 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SET 
study execution team 
SI 
SI units (International System of Units) 


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Abbreviation 
Definition 
SOC 
System Organ Class 
SUSARs 
suspected, unexpected, serious adverse reaction 
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.1, 2 
Two complementary approaches to increase CFTR-mediated Cl− secretion in the airway epithelia 
have been studied.3 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 (VX-770) were developed by Vertex Pharmaceuticals Incorporated 
(Vertex). TEZ/IVA combination therapy (trade names Symdeko™ and Symkevi™) is indicated 
for the treatment of CF in patients as young as 6 years of age homozygous for F508del or who 
have another indicated CFTR genotype. IVA monotherapy (Kalydeco™) is indicated for the 
treatment of CF in patients as young as 2 years old with specific CFTR mutations including 
certain gating mutations as well the R117H mutation. The indicated mutations and approved 
populations for Symdeko/Symkevi and Kalydeco vary by country. Please refer to local 
prescribing information or summary of product characteristics for your region for the current 
approved use of Symdeko/Symkevi and Kalydeco. 
Results from 2 pivotal Phase 3 Studies, VX14-661-106 (Study 106) and VX14-661-108 
(Study 108), that evaluated TEZ in combination with IVA (TEZ/IVA) 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 for F508del (F/F), or heterozygous 
for F508del and a second mutation that results in residual CFTR function (F/RF), aged 
≥12 years. 
Additional details about TEZ/IVA can be found in the TEZ/IVA Investigator's Brochure. 
5.2 
Study Rationale 
To date, the long-term safety of TEZ/IVA has not yet been evaluated in subjects with CF aged 
6 to 11 years. Therefore, the primary objective of this study is to evaluate the long-term safety 
and tolerability of TEZ/IVA in subjects with CF in this age group, who are homozygous or 


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heterozygous for F508del. The secondary objective is to evaluate the long-term efficacy of 
treatment with TEZ/IVA.  
This study will enroll subjects who completed Studies VX15-661-113 Part B (Study 113B) or 
VX16-661-115 (Study 115). In both parent studies, subjects were 6 to 11 years of age at 
Screening and are homozygous or heterozygous for F508del.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the long-term safety and tolerability of TEZ/IVA in subjects with CF aged 6 years 
and older, who are homozygous or heterozygous for F508del 
6.2 
Secondary Objective 
To evaluate the long-term efficacy of TEZ/IVA in subjects with CF aged 6 years and older, who 
are homozygous or heterozygous for F508del 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability of long-term TEZ/IVA treatment based on adverse events (AEs), clinical 
laboratory values (serum chemistry, hematology, lipids, and vitamins), standard 12-lead ECGs, 
physical examinations (PEs), vital signs, ophthalmologic examinations, and pulse oximetry 
7.2 
Secondary Endpoints 
 Absolute change from baseline in lung clearance index2.5 (LCI2.5; for subjects from 
Study 115 and the Study 113B LCI Substudy only) 
 Absolute change from baseline in sweat chloride 
 Absolute change from baseline in Cystic Fibrosis Questionnaire–Revised (CFQ-R) 
respiratory domain score  
 Absolute change from baseline in body mass index (BMI) 


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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 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. Completed the Week 24 Visit in Study 113B or the Week 8 Visit in Study 115.   
Added guidance: 
 Subjects who had a study drug interruption at the last scheduled visit of Study 113B or 
Study 115, subjects who required study drug interruption that was to be continued or 
initiated at Day 1 in Study 116, or subjects who resumed study drug in the parent study 
after a study drug interruption due to elevated transaminases, but who did not complete at 
least 4 weeks of rechallenge with study drug (due to the timing of the rechallenge versus 
the time remaining in the parent study), must receive approval from the Vertex medical 
monitor. 
Note: Subjects who permanently discontinue study drug treatment during the parent study, 
including at the last visit of the Treatment Period, are not eligible. 
4. Did not withdraw consent from the parent study. 
5. Subjects must have a genotype listed in Appendix 1: CFTR Mutations. Note: Additional 
mutations may be evaluated and updates to the list of eligible mutations will be 
communicated to investigative sites through a memorandum. If TEZ/IVA receives marketing 
authorization for additional mutations in any country/region for patients ≥12 years old, a 
memorandum will be sent to investigative sites in that country/region and the newly 
approved mutations will also be eligible. 
6. Willing to remain on a stable CF medication regimen through the Safety Follow-up Visit. 


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8.2 
Exclusion Criteria 
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject.  
For example, history of cirrhosis with portal hypertension, and/or history of risk factors for 
Torsade 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, and intracranial trauma], and 
autonomic neuropathy). 
2. Pregnant and nursing females. Females of childbearing potential must have a negative 
pregnancy test at the Day 1 Visit before receiving the first dose of study drug 
(Section 11.4.2). 
3. Sexually active subjects of reproductive potential who are not willing to follow the 
contraception requirements outlined in Section 11.4.8. 
4. History of drug intolerance in the parent study that would pose an additional risk to the 
subject in the opinion of the investigator, and which should be discussed with the Vertex 
medical monitor. Examples of subjects who may not be eligible for the study include (but are 
not limited to) the following:  
 Subjects with a history of allergy or hypersensitivity to the study drug 
 Liver function test (LFT) abnormality during study drug treatment in the parent study or 
other qualified Vertex study that required permanent study drug discontinuation  
 Other severe or life-threatening reactions to the study drug in the previous study 
5. History of poor compliance with study drug and/or procedures in a previous study as deemed 
by the investigator. 
6. Ongoing participation in another study with investigational drug. Ongoing participation in a 
non-interventional study (including observational studies) is permitted. During the Treatment 
Period, subjects may screen for another Vertex-sponsored study of CFTR modulators, 
excluding studies of IVA monotherapy and lumacaftor in combination with IVA. If a subject 
chooses to enroll in the other Vertex-sponsored study, they will be terminated from 
Study 116 and will not be allowed to re-enroll in Study 116. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, open-label, rollover study. A schematic of the study design is shown in 
Figure 9-1. 


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Figure 9-1 
VX17-661-116 Study Design 
 
IVA: ivacaftor, q12h: every 12 hours, qd: daily, TEZ: tezacaftor 
9.1.1 
Treatment Period 
Treatment Period assessments are listed in Table 3-1. 
The Day 1 Visit of Study 116 will be on the same day as the last scheduled visit of the parent 
study; this will occur at the Week 24 Visit for subjects from Study 113B and at the Week 8 Visit 
for subjects from Study 115. Subjects will NOT have to repeat any Study 116 Day 1 Visit 
assessments that were specified to be performed at the last scheduled visit in the parent study.  
Subjects who were enrolled in Study 116, but had Day 1 study drug administration procedures 
delayed (e.g., due to an AE), will repeat the safety, LCI (if applicable), 
 
assessments that were specified to be performed at the Day 1 Visit before receiving their first 
dose of study drug.  
For subjects at Study 116 sites that have NOT been activated by the time the subject has 
completed the last scheduled visit in the parent study, the Day 1 Visit of Study 116 will NOT 
coincide with the last scheduled visit of the parent study. Subjects at these sites with delayed 
activation will have to repeat any Study 116 Day 1 assessments that were specified to be 
performed at the last scheduled visit in the parent study. 
All subjects will have study visits on Day 1 and at Weeks 12, 24, 36, 48, 60, 72, 84, and 96. 
Study Visits on Day 15 and Week 4 are only required for subjects from Study 115. 
9.1.2 
Safety Follow-up 
Subjects will have a Safety Follow-up Visit 28 (±7) days after the last dose of study drug. Safety 
Follow-up Visit assessments are listed in Table 3-1. 
If a subject chooses to continue onto a commercially available Vertex CFTR modulator 
(i.e., TEZ/IVA [if approved for marketing], Kalydeco, Orkambi™ [lumacaftor/IVA], or another 
approved TEZ/IVA-containing regimen), the Early Termination of Treatment (ETT) Visit will be 
completed before dosing with the commercial drug begins, and the Safety Follow-up Visit will 
not be required. 
If a subject is continuing onto TEZ/IVA supplied via a Vertex-sponsored managed access 
program (MAP), the ETT Visit will be completed before dosing with TEZ/IVA via the MAP, 
and the Safety Follow-up Visit will not be required (see Section 9.1.3).   


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9.1.3 
Early Termination of Treatment  
If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as 
soon as possible after the subject/caregiver decides to terminate study treatment. Subjects who 
prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, 
approximately 28 (± 7) days after their last dose of study drug.  
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required.  
If a subject chooses to continue onto a commercially available Vertex CFTR modulator (i.e., 
TEZ/IVA [Symdeko], Kalydeco, Orkambi™, or another approved TEZ/IVA-containing drug), 
the ETT Visit will be completed before dosing with the commercial drug begins, and the Safety 
Follow-up Visit (Section 9.1.2) will not be required.  
If a subject is continuing onto TEZ/IVA supplied via a Vertex-sponsored managed access 
program (MAP), the ETT Visit will be completed before dosing with TEZ/IVA via the MAP, 
and the Safety Follow-up Visit will not be required. 
Alternatively, 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 populations enrolled in 
Study 116, 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 concerned. If subjects are discontinued from the study, an ETT Visit 
should occur within 7 days of the last dose of study drug and a Safety Follow-up Visit should 
occur within 28 (± 7) days after the last dose of study drug. 
If the subject/caregiver 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 and samples collected before such withdrawal of consent. 
9.1.4 
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 12.3.5.2). Procedural details of 
the IDMC's structure and function, frequency of meetings, and data planned for review will be 
included in the IDMC charter. The IDMC charter will be finalized before the first subject is 
enrolled.  
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. Randomization is not required. 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
This is a Phase 3, multicenter, open-label, rollover study in subjects with CF aged 6 years and 
older, who are homozygous or heterozygous for F508del, and who completed the Week 24 Visit 
in Study 113B or the Week 8 Visit in Study 115.  


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Approximately 56 subjects from Study 113B and 65 subjects from Study 115 will be enrolled in 
the study. This study is designed to evaluate the safety and efficacy of long-term TEZ/IVA 
treatment in subjects who were aged 6 through 11 years at the start of the parent study. 
Study 113B and Study 115 were designed to evaluate pharmacokinetics, safety, tolerability, 
pharmacodynamics, and efficacy to support an expanded indication for TEZ/IVA in subjects 
6 through 11 years of age, inclusive, who are homozygous or heterozygous for F508del. The 
long-term safety and efficacy of TEZ/IVA treatment has not yet been evaluated in this age group. 
Therefore, results from Study 116 will provide information on the safety and efficacy of 
long-term TEZ/IVA treatment in subjects with CF aged 6 years and older, homozygous or 
heterozygous for F508del.   
Interim analyses (IAs), as described in the statistical analysis plan (SAP), may occur at any time 
during the study (Section 12.3.5.1).  
9.3.2 
Study Drug Dose and Duration 
The approved Symdeko dosing regimen for this age group will be used.  
9.3.2.1 
Subjects ≥12 Years of Age 
Subjects who are ≥12 years of age at enrollment, or who turn 12 years of age during the study, 
will receive a morning dose of TEZ 100 mg/IVA 150 mg (FDC tablet) and an evening dose of 
IVA 150 mg (tablet).  
9.3.2.2 
Subjects <12 Years of Age 
Subjects who are <12 years of age and weigh <30 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 <12 years of age and ≥30 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).If a subject who weighs <30 kg at enrollment subsequently weighs ≥30 kg at 
2 consecutive study visits, the study drug dose will be adjusted upward at the second visit such 
that the subject receives a morning dose of TEZ 100 mg/IVA 150 mg (FDC tablet) and an 
evening dose of IVA 150 mg (tablet).  
9.3.3 
Rationale for Study Assessments 
The safety and efficacy 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. 
Ophthalmologic Examinations: A juvenile rat toxicity study performed to support dosing of IVA 
in subjects <2 years of age demonstrated lens opacities in some animals. Prior studies in rats and 
dogs of older age did not demonstrate similar findings. Given substantial differences between 
human and rat lens development, the finding is of unlikely relevance to humans. To confirm this 
interpretation, periodic ophthalmologic examinations will be performed in this study. The overall 
data acquired to date do not suggest an association between IVA treatment and cataract 
development; however, a potential association has not been fully excluded. 
LCI Assessment (Subjects From Study 113B LCI Substudy and Study 115 Only): LCI is a 
measure of ventilation inhomogeneity that is based on tidal breathing techniques which have 
been evaluated in patients as young as infants.4, 5 Studies have shown that LCI correlates with 


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forced expiratory volume in 1 second (FEV1) 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.6, 7 Furthermore, data from Study VX10-770-106 in CF subjects with an FEV1 >90% 
showed LCI to be a more sensitive outcome measure than FEV1. 
Sweat Chloride: In patients with CF, the underlying CFTR ion transport defect results in elevated 
sweat electrolyte levels.8, 9 The sweat chloride test (quantitative pilocarpine iontophoresis) is the 
most common diagnostic tool for CF. A sweat chloride concentration of 60 mmol/L is 
considered to be diagnostic of CF, whereas <40 mmol/L is considered normal. Based on the 
mechanisms of action of TEZ and IVA, the sweat chloride test is included in this study as a 
measure of the effect of TEZ/IVA on CFTR activity. 
Nutritional Status (Measured by Weight and BMI): Malnutrition is common in patients with CF 
because of increased energy expenditures due to lung disease and fat malabsorption. Given that 
TEZ/IVA is a systemic therapy, it has the potential to improve extrapulmonary manifestations of 
CF, including those in the gastrointestinal system. Improved nutritional status, defined as an 
increase in weight and/or BMI, is considered an appropriate endpoint for therapies targeting 
CFTR and was used in previous clinical studies of CFTR-targeted therapies. To evaluate the 
effect of TEZ/IVA on growth, change in weight and BMI will be determined. 
As children gain weight and height as part of normal growth, adjustment for age and sex is 
necessary to assess changes in nutritional status.
 
Height and weight will be collected 
at the study visits indicated in the schedule of assessments. 
CFQ-R: The CFQ-R is a validated CF-specific instrument that measures the health-related 
quality of life of patients with CF.3, 10, 11 The CFQ-R measures quality-of-life domains including 
respiratory symptoms, digestive symptoms, emotion, and health perception. Furthermore, the 
CFQ-R has been evaluated in clinical studies involving therapies for CF lung disease.12-14 
Linguistically validated versions of the CFQ-R15, 16 are available, thereby allowing consistent 
interpretation of the results in global studies. 


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9.4 
Study Restrictions 
Study restrictions are summarized in Table 9-1. 
Both TEZ and IVA are metabolized predominantly via the hepatic enzymatic pathway utilizing 
CYP3A4. Co-administration of TEZ and IVA with moderate and strong CYP3A inducers such as 
rifampin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum) 
has the potential to significantly reduce TEZ and IVA exposure and is restricted in this study. 
Case-by-case exceptions for concomitant use of a moderate CYP3A inducer with TEZ/IVA may 
be granted by the Vertex medical monitor if it is the principal investigator’s opinion that the 
benefits outweigh the risks for the subject in question. 
A more detailed, but non-exhaustive, list of study prohibitions and cautions for food and 
medication will be provided in the Study Reference Manual. 
Table 9-1 
Study Restrictions  
Restricted Medication/Food 
Study Period 
Certain fruits and fruit juices (grapefruit, 
grapefruit juice, Seville oranges, 
marmalade) 
None allowed within 14 days before the first dose of study drug 
through the Safety Follow-up Visit 
Moderate and strong CYP3A inducers 
None allowed within 14 days before the first dose of study drug 
through the Safety Follow-up Visit 
Physician-prescribed or investigational 
(from another study) IVA [Kalydeco] or 
lumacaftor/IVA [Orkambi] 
None allowed within 30 days before the first dose of study drug 
through the last dose of study drug 
Commercially available TEZ/IVA 
None allowed within 30 days before the first dose of study drug 
through the last dose of study drug 
CYP: cytochrome P450, IVA: ivacaftor, TEZ: tezacaftor  


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9.5 
Prior and Concomitant Medications 
Medicinal products affected by TEZ/IVA (CYP3A, P-glycoprotein, or CYP2C9 substrates) 
Co-administration of TEZ/IVA with (oral) midazolam, a sensitive CYP3A substrate, did not 
affect midazolam exposure. No dose adjustment is required when co-administered with CYP3A 
substrates. 
Based on in vitro data, IVA and its M1 metabolite have the potential to inhibit P-glycoprotein 
(P-gp). Co-administration of TEZ/IVA with digoxin, a sensitive P-glycoprotein (P-gp) substrate, 
increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by IVA. 
Administration of TEZ/IVA may increase systemic exposure of medicinal products that are 
sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse 
reactions. When using concomitant digoxin or other substrates of P-gp with a narrow therapeutic 
index, TEZ/IVA should be used with caution and appropriate monitoring. IVA may inhibit 
CYP2C9; therefore, monitoring of the international normalized ratio during co-administration of 
TEZ/IVA with warfarin is recommended. 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered at or after 
completion of treatment in the parent study through the Safety Follow-up Visit, if applicable, 
will be recorded in each subject's source documents.  
 Subjects should remain on a stable CF medication (and supplement) regimen through the 
Safety Follow-up Visit. Stable medication regimen is defined as the current medication 
regimen for CF that subjects have been following for at least 28 days before Day 1. 
Medication changes required for clinical management are allowed during the course of the 
study and will be recorded in the electronic case report form (eCRF). Restricted/prohibited 
medication guidelines should still be followed (see Section 9.4 and Table 9-1). 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. 
 There are no restrictions on the concomitant use of corticosteroids. 
 
 
9.6 
Administration 
On Day 1 through the last dose of study drug (the evening dose administered the day before the 
Week 96 Visit), study drug tablets will be administered orally as shown in Table 9-2.  


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At each study visit the TEZ/IVA dose for each subject will be reassessed based on body weight 
and age and adjusted upward if necessary.  
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: 
Table 9-2 
Study Drug Administration 
Subjects 
Treatment 
Time 
Drug(s) and Dose(s) 
Administered 
 6 to 11 years of age and 
<30 kg at enrollmenta,b 
TEZ 50 mg qd + IVA 
75 mg q12h 
AM 
1 × TEZ 50-mg/  
IVA 75-mg  
FDC tablet  
PM 
1 × IVA 75-mg tablet 
 6 to 11 years of age and ≥30 kg 
at enrollmenta,b 
 6 to 11 years of age and <30 kg 
at enrollment who subsequently 
weighs ≥30 kg during the 
studya,b 
 ≥12 years of age at enrollment, 
or subjects who turn 12 years of 
age during the study 
TEZ 100 mg qd + IVA 
150 mg q12h 
AM 
1 × TEZ 100-mg/  
IVA 150-mg  
FDC tablet  
PM 
1 × IVA 150-mg tablet 
FDC: fixed-dose combination, IVA: ivacaftor, q12h: every 12 hours, qd: daily, TEZ: tezacaftor 
Note: Additional details regarding study drug administration for TEZ and IVA will be included in the Pharmacy 
Manual. 
a 
No downward dose adjustments will be made if a subject’s weight decreases.  
b 
Doses may be adjusted upward as follows: if a subject who is 6 to 11 years of age and weighs <30 kg at 
enrollment subsequently weighs ≥30 kg at 2 consecutive visits, the study drug dose will be adjusted upward at 
the second visit such that the subject receives TEZ 100 mg qd/IVA 150 mg q12h.  
 
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 
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. 


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 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 96 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 96 Visit. 
Providing a meal or snack during this visit is optional. 
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 
Dose Modification for Use With Concomitant CYP3A Inhibitors  
Dosing recommendations for subjects taking concomitant CYP3A inhibitors are described in 
Table 9-3. The dosage of TEZ/IVA can be altered only when co-administered with moderate or 
strong inhibitors of CYP3A. The dosage of TEZ/IVA cannot be otherwise altered, but the 
investigator can interrupt or stop treatment. 
Table 9-3 
Dosing Recommendations for Subjects Taking Concomitant CYP3A 
Inhibitors 
Type of Inhibitor 
Example of Inhibitor 
TEZ/IVA FDC  
IVA  
Strong CYP3A 
inhibitor 
ketoconazole, itraconazole, 
posaconazole, voriconazole, 
telithromycin, and 
clarithromycin  
1 tablet twice a week in the 
morning (3 to 4 days between 
doses) 
No evening dose  
Moderate CYP3A 
inhibitor 
fluconazole, erythromycin 
1 tablet of TEZ/IVA FDC or 1 tablet of IVA in the 
morning, taken on alternate days. No evening dose. 
CYP: cytochrome P450, FDC: fixed-dose combination, IVA: ivacaftor, TEZ: tezacaftor 
Note: A more detailed, but nonexhaustive, list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. 
 


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9.9 
Discontinuation of Study Participation  
If after review of a marketing application, local health authorities decline to approve TEZ/IVA 
for the treatment of CF in a corresponding population aged ≥12 years, pediatric subjects enrolled 
in Study 116 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. In addition, if evaluation of efficacy data from Phase 3 Study 
VX14-661-110 suggests that the TEZ/IVA treatment does not provide clinically meaningful 
benefit for a population enrolled in Study 116, Vertex may recommend that subjects with 
relevant CFTR genotypes discontinue the study. 
Subjects who become eligible to receive commercially available TEZ/IVA by prescription of a 
physician may be discontinued from this rollover study at the discretion of the sponsor. The 
timing of assessments after study discontinuation is described in Section 9.1.2 and Section 9.1.3. 
9.10 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request or at the caregiver’s 
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/caregiver. 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/caregiver 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/caregiver 
regarding any unresolved AEs. 
If the subject/caregiver withdraws consent for the study, no further evaluations should be 
performed, and no additional data should be collected. Vertex may retain and continue using the 
study data and samples after the study is over, and may use the samples and information in the 
development of the study compound, and for other drugs and diagnostics, in publications 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/caregiver will not be able to 
request the withdrawal of his/her information from the study data. A subject/caregiver 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. 
9.11 
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. 


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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 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 as 
described 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. 
Table 10-1 
Identity of Study Drugs, Dosage, and Storage 
Drug Name 
Formulation/Route 
Dosage 
Storage Condition 
TEZ/IVA  
FDC; oral 
 
TEZ 50 mg/IVA 75 mg 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
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) 
FDC, fixed-dose combination, IVA: ivacaftor, TEZ; tezacaftor 
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/caregivers; and (3) 
study drug returned by the subjects. Subjects/caregivers 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/caregivers 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. 


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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/caregiver of study drug dosing requirements. 
Compliance will also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should contact the medical monitor to discuss discontinuation of the 
subject from the study. 
10.7 
Blinding and Unblinding 
This will be an open-label study. However, subjects and their parent/caregiver should not be 
informed of their study-related LCI,
 or sweat chloride results during the study 
regardless of whether the subject has prematurely discontinued treatment or not. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
All information regarding the timing assessments is shown in the schedule of assessments 
(Table 3-1). 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 must be completed before the start of any other assessments scheduled at that 
visit. 
2. Height and weight measurements should be performed before dosing.  
3. ECGs will be performed before dosing and before any other procedures that may affect heart 
rate (e.g., blood draws). 
4. The multiple-breath washout (MBW) assessment (performed for subjects from Study 115 
and the Study 113B LCI Substudy only) will be performed 
 
5. Both MBW 
will be performed before dosing and should be 
performed before use of bronchodilators. 
6. Blood sampling for clinical laboratory assessments at all visits, except the Day 1 Visit, may 
be conducted at any time during the visit after the ECG is performed and before the meal or 
snack. 
7. No other assessments should overlap with sweat chloride collection. 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Select demographic and baseline characteristic data and medical history will be 
derived from the parent study. Age, sex, race, and ethnicity will be derived from the parent 
study,
 
 


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11.3 
Efficacy 
11.3.1 
Lung Clearance Index (Study 115 and Study 113B LCI Substudy 
Subjects Only) 
LCI derived from N2-MBW testing will be conducted at visits specified in Table 3-1 to evaluate 
the effect of TEZ/IVA on lung ventilation inhomogeneity. LCI2.5 represents the number of lung 
turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value, 
Pre-bronchodilator MBW testing is defined as MBW 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 MBW testing; 
 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. 
 Each MBW test will be recorded in the source documents as pre-bronchodilator or 
post-bronchodilator. 
MBW 
assessments will be performed in multiple replicates. Detailed LCI procedures will be supplied in 
a separate study manual. 
Subjects and their parent/caregiver should not be informed of their study-related LCI results 
during the Treatment Period.  


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11.3.3 
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 each time point, 
2 samples will be collected, 1 sample from each arm (left and right). No other assessments 
should overlap with collection of sweat chloride.  
Subjects and their parent/caregiver should not be informed of their study-related sweat chloride 
results during the Treatment Period. 


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11.3.4 
Weight, Height, and BMI 
Weight, height, and BMI (derived) will be assessed. Weight and height will be measured with 
shoes off and before dosing with study drug at time points noted in Table 3-1. 
11.3.5 
Cystic Fibrosis Questionnaire-Revised  
The questionnaire provides information about demographics; general quality of life, school, 
work, 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).15, 16 
Subjects will be asked to complete the CFQ-R in their native language. The CFQ-R will be 
completed before dosing at visits noted in Table 3-1. The CFQ-R should be completed before the 
start of any assessments scheduled at that visit. 
The version and format of CFQ-R will be based on age at baseline, regardless of whether the 
subject changes age during the study. Parents/caregivers will complete the CFQ-R Parent version 
on all visits. At the Day 1 Visit of Study 116, all subjects will complete the same version of the 
CFQ-R that was completed in Study 113B or Study 115. Subjects who are ≥12 years of age after 
the Day 1 Visit will complete the CFQ-R Child Version themselves, and their parents/caregivers 
will complete the CFQ-R Parent Version. 




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11.4 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, pulse oximetry, PEs, and ophthalmologic examinations. 
11.4.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.4.2 
Clinical Laboratory Assessments 
Blood 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, but not before 
the ECG is performed (Section 11.1). Subjects are not required to fast before collection of blood 
samples; however the meal or snack should be provided after blood collection. 
Blood and urine samples will be analyzed at a local or central laboratory. For purposes of study 
data collection, only laboratory tests done in the central laboratory may be used. Local 
laboratories may be used at the discretion of the local investigator only 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. 
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Glucose  
Blood urea nitrogen   
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase  
Alanine transaminase  
Lactate dehydrogenase 
Hemoglobin  
Erythrocytes:  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils  
Basophils  
Neutrophils  
Lymphocytes  
Monocytes  
 


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Table 11-1 
Safety Laboratory Test Panels 
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) 
Note: Blood draws do not require fasting, but should occur before the meal or snack.  
CFTR Genotype: 
The CFTR genotype result can be taken from Study 113 or Study 115. If the genotype result is 
not available, subjects will be tested for CFTR genotype; if the genotype result from the 
confirmatory test is exclusionary, then the subject will be removed from the study. 
Instructions for collecting a sample for CFTR genotyping will be included in the Laboratory 
Manual. 
Pregnancy Testing for Female Subjects of Childbearing Potential Who Are Not Abstinent 
(Section 11.4.8.1): 
Female subjects of childbearing potential must have a negative urine pregnancy test at the Day 1 
Visit. Serum pregnancy tests will be conducted at other visits specified in Table 3-1. 
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 
pregnancy is 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 11.4.8.2. If a pregnancy test is positive, the procedures outlined in Section 11.4.8.2 
will be followed. 
Additional Evaluations:  
Additional clinical laboratory evaluations will be performed at other times if judged by the 
investigator to be clinically appropriate.  
11.4.3 
Liver Function Test Parameters 
Liver function testing (alanine transaminase [ALT], aspartate transaminase [AST], gamma-
glutamyl transferase [GGT], alkaline phosphatase [ALP], direct bilirubin, and total bilirubin) 
must be performed as noted in Table 3-1 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. 


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Subjects with new treatment-emergent ALT or AST elevations of >3 × upper limit of normal 
(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 or to baseline levels (as defined in 
Section 12.3.1). 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. 
11.4.4 
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 PEs and symptom-directed vital sign assessments 
can be performed at the discretion of the investigator or healthcare provider. PEs will also occur 
at any time during the study if triggered by AEs. 
A PE includes a review of the following systems: head/neck/thyroid; eyes, ears, nose, and throat 
(EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After consenting, any clinically significant abnormal findings in PEs will be reported 
as AEs. 


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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.  
11.4.5 
Pulse Oximetry  
This is a noninvasive measure of oxygen delivery to the tissues and has been correlated with 
clinical status and lung function. 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 study drug administration.  
11.4.6 
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. 
 ECGs will be performed in triplicate on Day 1. 
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 
Study 116 Day 1 measurements. If the QTcF is increased by >45 msec from Day 1 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 Day 1 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. 
11.4.7 
Ophthalmologic Examination 
Ophthalmologic examinations will be performed by a licensed ophthalmologist or optometrist. 
Subjects with documentation of bilateral lens removal do not need the ophthalmologic 
examination. 
Subjects who did not have an ophthalmologic examination at the end of the parent study will 
have an ophthalmologic examination at the Day 1 Visit of Study 116 or no more than 28 days 
after. If a subject had an ophthalmological examination in the parent study less than 28 days 
before the Day 1 Visit of Study 116, the examination does not need to be repeated on Day 1. 
The examination includes: 
 measurement of best corrected distance visual acuity of each eye 


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 pharmacologically dilated examination of the lens with a slit lamp 
Subjects will have ophthalmologic examinations as noted in Table 3-1. An ophthalmologic 
examination will be performed at the Week 48 Visit. Subjects will also have an examination at 
either the Week 96 Visit (± 28 days) OR the Safety Follow-up Visit, but the examination must be 
completed by the date of the Safety Follow-up Visit. For subjects who discontinue treatment 
after receiving at least 1 dose of study drug, this examination may be completed at the ETT Visit 
or the Safety Follow-up Visit (if applicable [Section 9.1.2]), but must be completed by the date 
of the 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 116, the subject/caregiver and Vertex medical 
monitor will be notified. The subject/caregiver may elect to continue or discontinue study drug 
treatment. If the subject discontinues study drug treatment, the subject should complete the ETT 
and the Safety Follow-up Visits (see Sections 9.1.2 and 9.1.3). If the subject continues study 
drug treatment, more frequent ophthalmologic monitoring should be considered. 
11.4.8 
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. 
11.4.8.1 
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 116 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: 
 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. 
 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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 If the female is of non-childbearing potential, per the following: 
o Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy. 
o 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. 
 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 informed consent 
signature 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. 


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11.4.8.2 
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. 
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 Global Patient Safety (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 
This open-label rollover study will enroll subjects from Study 113B and Study 115. No formal 
sample size calculations have been performed. Approximately 56 subjects from Study 113B and 
approximately 65 subjects from Study 115 are potentially eligible for enrollment.  
12.2 
Analysis Sets 
12.2.1 
All Subjects Set 
The All Subjects Set will be defined as all subjects who are enrolled in Study 116 or received at 
least 1 dose of TEZ/IVA in Study 116. 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 are enrolled in Study 116, who 
received at least 1 dose of TEZ/IVA in Study 116, and have an eligible genotype. The FAS will 
be used for efficacy analyses, unless otherwise specified. 
The 115 FAS will be defined as the subset of FAS who were enrolled in parent Study 115. The 
113B FAS will be defined as the subset of FAS who were enrolled in parent Study 113. The 
113B LCI FAS will be defined as the subset of Study 113B subjects who had LCI data collected 
in parent Study 113B. 
12.2.3 
Safety Set 
The Safety Set will be defined as all subjects who are enrolled in Study 116 and who received at 
least 1 dose of TEZ/IVA in Study 116. The Safety Set will be used for all safety analyses, unless 
otherwise specified. 
12.3 
Statistical Analysis 
The Vertex Biometrics Department or designee will analyze the safety and efficacy data. 
The primary objective of this study is long-term safety and tolerability. The secondary objective 
is long-term efficacy. This section summarizes the statistical analysis of safety and efficacy data. 
Methodological and related details (e.g., missing data) will be provided in the SAP, which will 
be finalized before clinical database lock. 


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The data from Study 116 will be integrated with data from the parent studies for the purpose of 
safety and efficacy analyses. 
The safety analysis period is defined as the treatment-emergent (TE) Period. The safety 
analysis period begins at the first dose of study drug in Study 116 and ends 28 days after the last 
dose of study drug in Study 116, or at the date of Study 116 participation completion, whichever 
occurs first. Completion of Study 116 participation will be defined in the SAP.  
The safety analyses will be performed on the Safety Set over the Safety Analysis Period, unless 
otherwise specified. 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, PEs, ophthalmologic examinations, clinical laboratory values, vital signs, ECG 
measurements, and pulse oximetry. Only descriptive summaries will be presented and no 
statistical testing is planned. 
The efficacy analysis period begins at the first dose of study drug in Study 116 and ends at the 
last study visit at which efficacy data are collected in Study 116. The efficacy analysis will be 
performed on all subjects in the FAS by parent study for the efficacy analysis period, unless 
specified otherwise.  
Methods of efficacy analyses will be similar for those used in the parent studies. Each of the 
secondary endpoints (LCI2.5, sweat chloride, CFQ-R, and BMI) will be analyzed using a 
mixed-effects model for repeated measures (MMRM) with absolute change from baseline during 
the efficacy analysis period as the dependent variable. The least square (LS) mean and the 
associated 95% CI at each defined analysis visit will be provided for the corresponding efficacy 
endpoints. 
In addition, descriptive summary statistics will be provided for relevant safety and efficacy 
parameters.  
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 enrolled in a parent study and who received at 
least 1 dose of TEZ/IVA in either parent study or in Study 116 will be presented in individual 
subject data listings. 
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. 
Day 1, unless specified otherwise, will be defined as the day of the first dose of TEZ/IVA, 
whether the first dose was taken in the parent study or in Study 116. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of TEZ/IVA, whether 
the first dose was taken in the parent study or in Study 116. For ECGs, the baseline value will be 
defined as the average of the last non-missing pretreatment measurements (scheduled or 


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unscheduled) before the first dose of TEZ/IVA or the average of measurements (triplicate) 
before the first dose of TEZ/IVA, whether the first dose was taken in the parent study or in 
Study 116. 
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. 
The data from Study 116 will be integrated with data from the parent studies for the purpose of 
providing robust safety and efficacy analyses. 
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. 
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  
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  
A listing will be provided for subjects who discontinued study drug treatment or who 
discontinued the study with reasons for discontinuation.  


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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. 
Concomitant medication: medication continued or newly received on or after the first dose date 
of study drug through the end of the 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.  


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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 the 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 performed by parent study based on the 
FAS (115 FAS and 113B FAS), unless specified otherwise. LCI analysis will be based on the 
115 FAS and the 113B LCI FAS. The analysis will include all available measurements during 
the efficacy analysis period. 
12.3.3.1 
Analysis of Primary Efficacy Variables 
Not applicable. 
12.3.3.2 
Analysis of Secondary Efficacy Variables 
Methods of efficacy analyses will be similar for those used in the parent studies. Each of the 
secondary endpoints (LCI2.5, sweat chloride, BMI, and CFQ-R) will be analyzed using a 
MMRM, with absolute change from baseline during the efficacy analysis period as the dependent 
variable. For subjects from Study 115, only those who were randomized to TEZ/IVA treatment 
group will be included in the MMRM model. 
The model will include the absolute change from baseline as the dependent variable; visit as a 
fixed effect; and subject as a random effect, with or without adjustment for age, genotype 
mutation group, and baseline value. 
In the model, visit will be treated as a class variable, assuming an unstructured covariance matrix 
to model the within-subject variability. This model imposes no assumptions on the correlational 
structure and is considered robust. Denominator degrees of freedom for the F test for fixed 
effects will be estimated using the Kenward-Roger approximation. If there is a convergence 
problem due to the use of an unstructured covariance matrix, a compound symmetry covariance 
structure will be used to model the within-subject errors. With a mixed-effects model based on a 
restricted maximum likelihood estimation used for the primary analysis and assuming that, 
conditional on fixed and random effects, data are missing at random, no imputation of missing 
data will be performed. 


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The LS mean and the associated 95% CI at each defined analysis visit will be provided for the 
corresponding efficacy endpoints. 
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  
 PE 
 Ophthalmologic examination 
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.  
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 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 


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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, serious adverse events (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 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. 
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 the urine/serum pregnancy test will be listed in individual subject data listings only.  
In addition, a listing containing individual subject hematology and chemistry values outside the 
normal reference ranges will be provided. This listing will include data from both scheduled and 
unscheduled visits. 
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 
(mmHg), 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. 


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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 
Not applicable. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
IAs may occur at any time during the study. The timing and IA analysis plans will be 
documented in the SAP. If a parent study is not completely unblinded during an IA, the analysis 
will be performed according to the relevant unblinding plan. The details of the unblinding 
process will be provided in the Unblinding Plan. 
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 9.1.4) 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 


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 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
 For subjects who do not enroll: until time of 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 9.1.3) 
 For enrolled subjects who do not have a Safety Follow-up Visit because they will transition 
to commercially available CFTR modulator, or if the subject will receive TEZ/IVA through a 
Vertex-sponsored MAP: through the ETT Visit (Section 9.1.3) 
All subjects/caregivers 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. For subjects who consent, but do not subsequently enroll in the study, AEs 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 
September 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life threatening.” In 


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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. 
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.  


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, 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  


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 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/caregiver signed the ICF, and the hospitalization or procedure was 
planned before the subject/caregiver signed the ICF, the hospitalization or procedure will not be 
considered to indicate an SAE, unless an AE caused the hospitalization or procedure to be 
rescheduled sooner or to be prolonged relative to what was planned. In addition, hospitalizations 
clearly not associated with an AE (e.g., social hospitalization for purposes of respite care) will 
not be considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject's life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent 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.  


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Please send completed SAE Forms to Vertex GPS via: 
Email: 
 (preferred choice) 
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.  
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 


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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 
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 


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Vertex Pharmaceuticals Incorporated 
 
 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. 
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. 


Protocol VX17-661-116, Version 2.3 US 
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Vertex Pharmaceuticals Incorporated 
 
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. 
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. 


Protocol VX17-661-116, Version 2.3 US 
Page 58 of 63 
Vertex Pharmaceuticals Incorporated 
 
14 
REFERENCES 
1 
Cystic Fibrosis Foundation. Patient Registry: 2015 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2016. 
2 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: Annual Data Report 2014. Bromley, 
Kent, UK: Cystic Fibrosis Trust; 2015. 
3 
Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measures 
for children with respiratory conditions. Paediatr Respir Rev. 2008;9(3):220-32. 
4 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70. 
5 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99. 
6 
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. 
7 
Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection 
of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. 
Thorax. 2007;62(4):341-47. 
8 
Wilschanski M, Zielenski J, Markiewicz D, Tsui L-C, Corey M, Levison H, et al. 
Correlation of sweat chloride concentration with classes of the cystic fibrosis 
transmembrane conductance regulator gene mutations. J Pediatr. 1995;127(5):705-10. 
9 
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(4):387-98. 
10 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
11 
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. 
12 
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. 
13 
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. 


Protocol VX17-661-116, Version 2.3 US 
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Vertex Pharmaceuticals Incorporated 
 
14 
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. 
15 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
16 
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. 




Protocol VX17-661-116, Version 2.3 US 
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Vertex Pharmaceuticals Incorporated 
 
15 
APPENDIX 1: CFTR MUTATIONS 
Subjects can either be homozygous or heterozygous for the F508del-CFTR mutation. 
Heterozygous subjects must have 1 F508del allele and a second eligible residual-function CFTR 
allele or another allele that has been shown to be TEZ/IVA responsive.  
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 the list of eligible mutations will be communicated to 
investigative sites through a memorandum. If TEZ/IVA receives marketing approval for 
additional mutations in any country/region for patients ≥12 years old, a memorandum will be 
sent to investigative sites in that country/region and the newly approved mutations will also be 
eligible.  
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 
 
 
 


Protocol VX17—661-116,
2.3 US
Page 62 of63
16
PROTOCOL SIGNATURE PAGES
16.1
Sponsor Signature Page
Protocol #:
VXl7—66l-l 16
Version #:
2.3 (US)
Version Date:
08 Nov 2019
Study Title: A Phase
Open-label, Rollover Study to
the Safety and Efcacy of
Long-term Treatment With Tezacaftor in Combination With Ivacaftor in Subjects With Cystic
Fibrosis Aged 6 Years and Older, Homozygous or Heterozygous for the F5
TR
Mutation
This Clinical Study Protocol has been reviewed and approved by the sponsor.
Pharmaceuticals Incorporated


Protocol VX17-661-116, Version 2.3 US 
Page 63 of 63 
Vertex Pharmaceuticals Incorporated 
 
16.2 
Investigator Signature Page 
Protocol #:  
VX17-661-116 Version #: 
2.3 (US) 
Version Date: 
08 Nov 2019 
Study Title: A Phase 3, Open-label, Rollover Study to Evaluate the Safety and Efficacy of 
Long-term Treatment With Tezacaftor in Combination With Ivacaftor in Subjects With Cystic 
Fibrosis Aged 6 Years and Older, Homozygous or Heterozygous for the F508del-CFTR 
Mutation 
 
 
I have read Protocol VX17-661-116, Version 2.3 (US), and agree to conduct the study according 
to its terms. I understand that all information concerning TEZ and IVA and this protocol supplied 
to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 


Page 1 of 8 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol Addendum  
for Cystic Fibrosis  
Cystic Fibrosis Studies for the Following Programs 
 
 
Tezacaftor/Ivacaftor (VX-661/VX-770) 
 
 
 
Version and Date of Protocol Addendum: Version 3.0, 29 July 2020 
Replaces Version 2.0, dated 15 May 2020  
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 2 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes to Cystic Fibrosis Clinical Study Protocols 
Vertex is currently evaluating several CFTR modulators in clinical studies for the treatment of 
cystic fibrosis (CF), a serious and life-threatening disease. In completed studies, treatment with 
these CFTR modulators has generally resulted in rapid, robust, clinically meaningful, and 
statistically significant improvements in clinical measures, and are generally safe and well 
tolerated. Adverse events (AEs) seen with these treatments are mostly consistent with common 
manifestations of CF disease or with common illnesses in CF subjects.  
During this COVID-19 pandemic, the safety of the subjects, investigators, and site personnel 
participating in these clinical studies is Vertex’s first priority, thus it is important to minimize 
any unnecessary risk to COVID-19 exposure through travel to study sites. This addendum 
summarizes the measures taken for ongoing CF clinical studies. These operational adjustments 
were implemented to align with Health Authority guidance ensuring the protection of subjects, 
investigators, and site personnel while maintaining compliance with GCP and minimizing impact 
to the integrity of the studies. Overall, the benefit-risk of these studies remains favorable. 
Vertex recommends that subjects and sites refer to local guidance regarding travel restrictions. 
There are no operational changes to the study protocols for subjects who can travel to the study 
sites for their visits. However, to ensure continued safety of subjects who cannot travel to the 
study sites for their visits (for any reason due to COVID-19), specific alternative measures are 
being implemented to minimize the risk of exposure to COVID-19 (see table below). As the 
COVID-19 pandemic evolves, Vertex will continue to assess the need for additional actions to 
ensure the safety of all involved in these clinical studies. 
Addendum Version 3.0 summarizes additional measures taken for these ongoing CF clinical 
studies (see table below) to ensure continued safety. 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 3 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Version 3.0, dated 29 July 2020 
Assessments 
 
Unscheduled visit(s) will be permissible at the discretion of the investigator(s) 
or Vertex. The unscheduled visit(s) may be conducted at any time during the 
study (including after the protocol defined last study visit) in the event 
assessments specified to be collected at a scheduled visit were not collected 
due to COVID-19.  
 
To ensure subject safety and/or to facilitate evaluation of 
safety and/or efficacy if assessments are not performed 
per the schedule in the protocol due to COVID-19. 
 
 
 
 
 
 
 
VX17-661-116 
 
 
 
 
 
 
 
 
 
 
 
 
Implementaion of measures described in addenda versions 1.0 and 2.0, as 
applicable. 
To ensure subject safety and/or to facilitate evaluation of 
safety and/or efficacy while maintaining study integrity 
and the safety of subjects and site personnel. 
 
 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 4 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Version 2.0, dated 15 May 2020 
Assessments 
 
Weight and height/length/stature may be assessed by subjects or their 
caregivers using medical grade scales and stadiometers, as indicated per 
protocol and per local regulation. Sites and subjects will receive training and 
guidance as needed on these devices.  
 
Subjects or caregivers will provide these measurements to site personnel by 
telephone or video call. Investigators will review results and contact subjects 
for follow-up as needed. All data will continue to be retained in the subject’s 
source files. 
To allow for collection of key data to assess safety and/or 
efficacy while maintaining study integrity and the safety 
of subjects and site personnel. 
 
Addendum 1 allowed for these assessments to be 
performed by qualified personnel conducting the in-home 
visits. Addendum 2 allows for these assessments to be 
performed by subjects or caregivers. 
 
 
 
 
 
 
 
VX17-661-116 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 5 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Consenting of Subjects 
ICFs may be provided electronically or by post mail to subjects (and/or caregivers, as 
indicated per protocol). The subjects and/or caregivers will review the ICF with an 
appropriately qualified member of the investigator’s team via telephone contact or video call. 
After this review, subjects and/or caregivers will consent (or assent, if applicable), and/or 
reconsent verbally and by signing and dating the ICF and returning it to the site via post mail. 
The signed and dated ICF will then be signed and dated by the investigator.  
 
Subjects participating in select studies may have the opportunity to enroll in longterm 
extension studies. Informed consent (or assent, if applicable), and/or reconsent for subjects 
(and/or caregivers, as indicated per protocol) may be obtained per the same process described 
above, as applicable. 
To provide alternative methods of 
obtaining reconsent or consent, as 
applicable, while ensuring subject 
safety. 
 
 
 
 
 
 
 
VX17-661-116 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Shipping 
Study drug may be shipped directly from the site to the subject, as applicable, and if permitted 
by local regulations; subject protected health information will not be released to Vertex.  
 
Reconciliation, return, and destruction of study drug will continue to occur at the clinical site 
as indicated per protocol and in adherence to local regulations. 
To ensure subjects can continue 
treatment with study drug without 
interruption while ensuring their safety. 
 
To clarify that despite these alternative 
measures, reconciliation, return, and 
destruction of study drug will remain as 
indicated per protocol. 
In-home Visits and/or Telephone Contact 
Study visits may be conducted as in-home visits by qualified personnel as requested by 
participating sites on a per-subject basis. In addition, all subjects may be contacted by site 
personnel by telephone or video call, irrespective of in-home visits. 
To provide subjects the opportunity to 
continue participation in the clinical 
studies while ensuring their safety by 
minimizing the risk to COVID-19 
exposure through travel. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 6 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Safety Assessments and Reporting 
Safety assessments, as indicated per protocol, may be performed by qualified personnel 
conducting the in-home visits (e.g., personnel from site or qualified health care agency). These 
assessments may include the following, as indicated per protocol, and per local regulation:  
• vital signs 
• pulse oximetry 
• height/length/stature 
• weight 
• physical examination 
(complete or abbreviated) 
• pregnancy test  
(serum or urine) 
• urinalysis 
• blood draws for safety test panels 
(chemistry, LFT panel, lipid panel, 
hematology, coagulation).  
Blood and/or urine samples for safety assessments are analyzed as indicated per protocol for 
subjects who have in-home visits. 
Blood and/or urine samples for safety assessments may be collected and analyzed at local 
laboratories for subjects who do not have in-home visits, but do not complete the assessment 
at the site. 
In addition, safety assessents will be evaluated by telephone. These assessments may include 
the review of the following:  
• AEs 
• signs and symptoms/systems for CF 
• medications 
• planned or unplanned hospitalizations for CF 
• study drug administration 
• outcomes related to PEx  
• outcomes related to antibiotic treatment 
Investigators will review results (in-home and telephone) and contact subjects for follow-up as 
needed. 
All data will continue to be retained in the subject’s source files. 
Any clinically significant finding (e.g., AE, SAE, laboratory abnormalities) will continue to be 
reported as indicated per protocol. 
To assess the safety and tolerability of 
the CFTR modulator evaluated in the 
specific clinical study while ensuring 
subject safety. These safety 
assessments will continue to provide 
safety data while minimizing burden to 
subjects and site personnel.  
 
To clarify that despite these alternative 
measures, all adverse events and 
serious adverse events should be 
reported as indicated per protocol. 
 
 
 
 
 
 
 
VX17-661-116 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 7 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Efficacy and Other Assessments 
Efficacy and other assessments, as indicated per protocol, may be performed by qualified 
personnel conducting the in-home visits. These assessments may include the following, as 
indicated per protocol, and per local regulation. 
 
 
Patient Reported Outcome 
CFQ-R questionnaires may be provided to subjects (electronically or post mail) to be 
completed at home as indicated per protocol. Subjects will return these questionnaires to the 
site via post mail. 
Other Assessments  
• ECGs  
• sweat chloride 
• blood samples for CFTR genotype testing,
 PK, FSH, 
 
 and vitamin levels  
 
 
To be able to assess safety, treatment 
effectiveness, and quality of life 
measures of the CFTR modulator 
evaluated in the specific clinical study 
while ensuring subject safety. 
 
All Efficacy and 
Other 
Assessments 
 
VX17-661-116 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Other Outcomes 
Only 
 
 
 
 
 
 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 8 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Remote Monitoring 
Vertex has implemented remote monitoring visits where applicable, including remote source 
data verification, as allowed per local regulations. Remote monitoring will focus on collection 
of safety data, and data supporting primary and key secondary endpoints. 
To allow for review of key data to 
inform on the safety of subjects 
receiving treatment. 
 
To allow for review of other key data 
to inform on the objectives of the study 
while maintaining study integrity and 
the safety of subjects and site 
personnel. 
 
 
 
 
 
 
 
 
 
VX17-661-116 
 
 
 
 
 
 
 
 
 
 
 
 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; ECG: electrocardiogram; 
 
FSH: follicle-stimulating hormone; GCP: Good Clinical Practice; ICF: informed consent form; 
 LFT: liver function test; 
 PK: pharmacokinetic; SAE: serious adverse event; 
 
 
 

SAP_001.pdf: 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan  
(Methods) 
for Final Analysis 
Part A  
 
Protocol Number VX17-661-116, Version 2.0 
 
A Phase 3, Open-label, Rollover Study to Evaluate the Safety and Efficacy 
of Long-term Treatment With Tezacaftor in Combination With Ivacaftor 
in Subjects With Cystic Fibrosis Aged 6 Years and Older, Homozygous or 
Heterozygous for the F508del-CFTR Mutation 
 
Author of SAP (Methods): 
 
Version of SAP: 1.0 
Date of SAP: 19 August 2020 
 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenues 
Boston, MA 02210, 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. 
 
 


1 TABLE OF CONTENTS 
1 
Table of Contents ................................................................................................................... 2 
2 
List of Abbreviations ............................................................................................................. 4 
4 
Introduction............................................................................................................................ 6 
5 
Study Objectives .................................................................................................................... 6 
5.1 
Primary Objective ............................................................................................................. 6 
5.2 
Secondary Objective ......................................................................................................... 6 
6 
Study Endpoints ..................................................................................................................... 7 
6.1 
Primary Endpoint .............................................................................................................. 7 
6.2 
Secondary Endpoints ........................................................................................................ 7 
7 
Study Design ........................................................................................................................... 8 
7.1 
Overall Design .................................................................................................................. 8 
7.2 
Sample Size and Power .................................................................................................... 8 
7.3 
Randomization .................................................................................................................. 8 
7.4 
Blinding and Unblinding .................................................................................................. 8 
8 
Analysis Sets ........................................................................................................................... 9 
9 
Analysis Period....................................................................................................................... 9 
9.1 
Study 116 Analysis Periods .............................................................................................. 9 
10 Statistical Analysis ............................................................................................................... 10 
10.1 General Considerations .................................................................................................. 10 
10.2 Background Characteristics ............................................................................................ 11 
10.2.1 
Subject Disposition ................................................................................................. 11 
10.2.2 
Demographics and Baseline Characteristics ........................................................... 12 
10.2.3 
Medical History ...................................................................................................... 13 
10.2.4 
Prior and Concomitant Medications ....................................................................... 13 
10.2.5 
Study Drug Exposure.............................................................................................. 14 
10.2.6 
Study Drug Compliance ......................................................................................... 14 
10.2.7 
Important Protocol Deviations ................................................................................ 14 
10.3 Safety Analysis ............................................................................................................... 15 
10.3.1 
Adverse Events ....................................................................................................... 15 
10.3.2 
Clinical Laboratory Values ..................................................................................... 18 
10.3.3 
Electrocardiogram .................................................................................................. 18 
10.3.4 
Vital Signs .............................................................................................................. 19 
10.3.5 
Pulse Oximetry ....................................................................................................... 19 
10.3.6 
Ophthalmologic Examination ................................................................................. 19 
10.4 Efficacy Analysis ............................................................................................................ 19 
10.4.1 
Analysis of Primary Efficacy Variables ................................................................. 19 
10.4.2 
Analysis of Secondary Efficacy Variables ............................................................. 19 
12 Appendices............................................................................................................................ 27 


 
Appendix A: Analysis Visit Window Mapping Rules ................................................... 27 
 
Appendix B: Standards for Safety Variable Display in TFLs ........................................ 30 
 
Appendix D: Imputation Rules for Missing Prior/Concomitant Medication Dates ....... 32 
 
Appendix E: Imputation Rules for Missing AE dates .................................................... 33 
 
Appendix G: Criteria for Threshold Analysis ................................................................ 35 
 
Appendix H: TEAEs of Special Interest ........................................................................ 41 


 
 
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 
CFTR 
cystic fibrosis transmembrane conductance regulator  
CRF 
case report form 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
 
 
 
  
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
IDMC 
independent data monitoring committee 
IVA 
ivacaftor 
LCI 
lung clearance index 
LFT 
liver function test 
LLN 
lower limit of normal 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
N 
number of subjects 
PBO 
placebo 
 
 
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 
QTcF 
QT interval corrected for heart rate with Fridericia’s correction  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
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) - Final 
Page 6 of 41 
Vertex Study: VX17-661-116 Part A 
 
 
Vertex Pharmaceuticals Incorporated 
 
4 
INTRODUCTION 
Study VX17-661-116 (Study 116) is a Phase 3, Open-label, rollover study to evaluate the 
safety and efficacy of long-term treatment with tezacaftor in combination with ivacaftor 
(TEZ/IVA) in subjects with cystic fibrosis (CF) aged 6 years and older, homozygous or 
heterozygous for the F508del-CFTR mutation.  
Study 116 Part A evaluates safety and efficacy of treatment with TEZ/IVA over 96 weeks in 
subjects aged 6 years and older who were enrolled in parent Study VX15-661-113 Part B 
(Study 113B) or Study VX16-661-115 (Study 115).   
This statistical analysis plan (SAP) is for the final analysis of Study 116 Part A which is 
based on an approved clinical study protocol (CSP) (Version 2.0, dated 08 November 2019), 
as well as the most recent approved electronic case report form (eCRF), and the most recent 
approved eCRF completion guidelines. 
This SAP (Methods) documents the statistical analyses and data presentation of the safety 
and efficacy endpoints during Study 116 Part A for subjects who previously participated in 
Study 113 Part B or Study 115 and subsequently enrolled in Study 116 Part A.  
Due to the outbreak of COVID-19 during Study 116 Part A, to ensure continued safety of 
subjects who cannot travel to the study sites for their visits (for any reason due to COVID 
19); specific alternative measures are being implemented to minimize the risk of exposure to 
COVID 19 (COVID-19 Clinical Study Protocol Addendum for Cystic Fibrosis [Version 2.0, 
dated 15 May 2020]). This SAP summarizes the additional statistical analyses that are related 
to these alternative measures.  
The Vertex Biometrics Department or designee will perform the statistical analysis described 
in this document; SAS (Version 9.4 or higher) will be used to generate all statistical outputs 
(tables, figures, listings, and datasets). This SAP will be finalized and approved prior to the 
database lock of Study 116 Part A.  
Any revisions to the approved SAP will be documented and approved in an amendment to 
the SAP. 
5 
STUDY OBJECTIVES 
5.1 
Primary Objective 
To evaluate the long-term safety and tolerability of TEZ/IVA in subjects with CF aged 6 
years and older, who are homozygous or heterozygous for F508del in Part A. 
5.2 
Secondary Objective 
To evaluate the long-term efficacy of TEZ/IVA in subjects with CF aged 6 years and older, 
who are homozygous or heterozygous for F508del in Part A. 


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6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Safety and tolerability of long-term TEZ/IVA treatment in Study 116 Part A will be 
evaluated based on adverse events (AEs), clinical laboratory values (serum chemistry, 
hematology, lipids, and vitamins), standard 12-lead ECGs, physical examinations (PEs), vital 
signs, ophthalmologic examinations, and pulse oximetry. 
6.2 
Secondary Endpoints 
As secondary endpoints, the following efficacy endpoints will be analyzed: 
• Absolute change from baseline in lung clearance index2.5 (LCI2.5; for subjects from Study 
115 and the Study 113 Part B LCI Sub study only) 
• Absolute change from baseline in sweat chloride 
• Absolute change from baseline in Cystic Fibrosis Questionnaire–Revised (CFQ-R) 
respiratory domain score 
• Absolute change from baseline in body mass index (BMI) 


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7 
STUDY DESIGN  
7.1 
Overall Design  
Study 116 is a Phase 3, multicenter, open-label, 2-part, rollover study in subjects with CF 
aged 6 years and older, who are homozygous or heterozygous for F508del and who 
completed the Week 24 Visit in Study 113 Part B or the Week 8 Visit in Study 115. A 
schematic of the study design is shown in Figure 7-1. 
 
Figure 7-1 
VX17-661-116 Study Design 
 
Note: Subjects ≥12 years old will receive TEZ 100 mg qd/IVA 150 mg q12h regardless of weight (in Part A and 
Part B). 
IVA: ivacaftor, q12h: every 12 hours, qd: daily, TEZ: tezacaftor 
 
7.2 
 Sample Size and Power 
Study 116 Part A enrolled subjects from Study 113 Part B and Study 115. No formal sample 
size calculations were performed. Approximately 56 subjects from Study 113 Part B and 
approximately 65 subjects from Study 115 were potentially eligible for enrollment. 
7.3 
Randomization 
Study 116 Part A is an open-label study with a single treatment arm, and dose is determined 
by body weight and age. Subjects are not randomized. 
7.4 
Blinding and Unblinding 
Study 116 Part A is an open-label study. Subjects  and their parent/caregiver were not informed 
of their study related LCI, 
or sweat chloride results during the study regardless of 
whether the subject has prematurely discontinued treatment or not. 


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8 
ANALYSIS SETS 
The following analysis sets are defined for Study 116 Part A:  All Subjects Set, Safety Set, 
Full Analysis Set, 113B/116 Full Analysis Set, 115/116 Full Analysis Set, and 113B/116 LCI 
Full Analysis Set.  
Enrolled subjects are those who signed a consent/assent form and had an enrollment date in 
the CRF for Part A.  
 All Subjects Set 
The All Subjects Set will be defined as all subjects who were enrolled in Study 116 Part A 
or received at least 1 dose of TEZ/IVA in Study 116 Part A. This analysis set will be used for 
all individual subject data listings and the disposition summary table, unless specified 
otherwise. 
 Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will be defined as all subjects who were enrolled in Study 116 
Part A, who received at least 1 dose of TEZ/IVA in Study 116 Part A and have an eligible 
genotype. The FAS will be used for efficacy analyses, unless otherwise specified. 
115/116 Full Analysis Set (FAS), 113B/116 FAS and 113B LCI /116 FAS 
The 115/116 FAS will be defined as the subset of FAS who were enrolled in parent Study 
115. The 113B/116 FAS will be defined as the subset of FAS who were enrolled in parent 
Study 113B. The 113B/116 LCI FAS will be defined as the subset of Study 113B subjects 
who participated in the LCI sub-study in Study 113B. 
 Safety Set 
The Safety Set will be defined as all subjects who are in enrolled in study 116 Part A and 
who received at least 1 dose of TEZ/IVA in Study 116 Part A. The Safety Set will be used 
for all safety analyses, unless otherwise specified. 
9 
ANALYSIS PERIOD 
The analysis period used for safety and efficacy endpoints is described below.  
9.1 
Study 116 Analysis Periods 
The Safety analysis period is defined as the treatment emergent (TE) Period. The safety 
analysis period begins at the first dose of study drug in Study 116 Part A and ends 28 days 
after the last dose of study drug in Study 116 Part A, or at the date of Study 116 Part A 
participation completion, whichever occurs first.  
The safety analyses will be performed on the Safety Set over the Safety Analysis Period, 
unless otherwise specified. 


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Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, Physical Exams, ophthalmologic examinations, clinical laboratory values, vital signs, 
ECG measurements, and pulse oximetry.  
Only descriptive summaries will be presented, and no statistical testing is planned. 
Completion of study participation in Study 116 Part A is defined as one of the following: 
• For subjects who complete Study 116 Part A and do not roll over to Part B: The 
Safety Follow-up Visit 
• For subjects who complete Study 116 Part A and roll over to Part B or transition to 
Commercial Drug: The Week 96 Visit 
• For subjects who prematurely discontinue study drug treatment but do not withdraw 
consent in Study 116 Part A: the latest of early treatment termination (ETT) Visit, or 
Safety Follow-up Visit (if applicable) 
• For subjects who withdraw consent in Study 116 Part A: date of withdrawal of 
consent  
• For subjects who are lost to follow-up in Study 116 Part  A: the date of last contact 
The efficacy analysis period begins at the first dose of study drug in Study 116 Part A and 
ends at the last study visit at which efficacy data are collected in Study 116 Part A as 
described in the visit window in the Appendix A. The efficacy analysis will be performed on 
all subjects in the FAS by parent study for the efficacy analysis period, unless specified 
otherwise.  
10 
STATISTICAL ANALYSIS 
10.1 
General Considerations 
The Schedule of Assessments is provided in the clinical study protocol (CSP) Table 3-1. 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 enrolled in a parent study and who received 
at least 1 dose of TEZ/IVA in either parent study or in Study 116 will be presented in 
individual subject data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), median, minimum value 
(min), and maximum value (max).   
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place.  


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Day 1, unless specified otherwise, will be defined as the day of the first dose of TEZ/IVA,  in 
the Study 116 Part A. 
Baseline value for safety analysis will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of TEZ/IVA, 
whether the first dose was taken in the parent study or in Study 116 Part A. For ECGs, the 
baseline value will be defined as the last non-missing measurement (scheduled or 
unscheduled) before the first dose of TEZ/IVA or the average of measurements (triplicate) 
before the first dose of TEZ/IVA, whether the first dose was taken in the parent study or in 
Study 116 Part A. 
Baseline value for efficacy analysis will be defined as the same as baseline of the parent 
study. 
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. 
The data from Study 116 will be integrated with data from the parent studies for the purpose 
of providing robust safety and efficacy analyses. 
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 measurements. 
• In the derivation of maximum/minimum 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. 
Incomplete/Missing data will not be imputed, unless otherwise specified.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless otherwise specified. 
Multiplicity: No multiplicity adjustment will be performed. 
10.2 
Background Characteristics 
10.2.1 
Subject Disposition 
A summary table of subjects’ disposition will be presented for the All Subjects Set for the 
following categories: 
• All Subjects Set 
• Safety Set 
• Full Analysis Set 


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The number and percentage of subjects in each of the following disposition categories will be 
presented based on the Safety Set: 
• Completed study drug treatment in Part A 
• Prematurely discontinued the treatment in Part A and the reason for discontinuation  
• Completed Safety Follow-up in Part A 
• Did not complete Safety Follow-up in Part A and the reason for not completing  
A listing will be provided for subjects who discontinued treatment during Study 116 Part A 
or who discontinued Study 116 Part A, with reasons for discontinuation. 
10.2.2 
Demographics and Baseline Characteristics 
Demographics and treatment baseline characteristics will be summarized based on the FAS, 
and will be presented by 115/116 FAS, and 113B/116 FAS, and overall. Note: all efficacy 
analysis will be presented by parent study, hence this may be informative. 
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) 
• Geographic region (North America, Europe, and Australia) 
• CFTR genotype group (F508del/F508del; F508del/Residual Function) 
Baseline characteristics will include the following: 
• Weight (kg)  
• Weight group (<30 kg, 30-40kg, and ≥40 kg) 
 
  
• Height (cm)  
 
 
• BMI (kg/m2)  
 
 
Disease characteristics will include the following: 
 
 
 
 
• Sweat chloride at treatment baseline 


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• CFQ-R respiratory domain score at treatment baseline 
• LCI2.5 at treatment baseline (Study 115 subjects and 113B LCI sub study subjects 
only) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No) 
• Prior use of any inhaled bronchodilator (Yes, No) 
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Prior use of any inhaled corticosteroids (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to parent study screening 
(Positive, Negative) 
Prior medication use refers to medication taken before the first dose date of TEZ/IVA 
regimen in either the parent study (if the subject received the first dose of TEZ/IVA regimen 
in the parent study) or Study 116 Part A (if the subject received the first dose of TEZ/IVA 
regimen in Study 116 Part A).  
10.2.3 
Medical History 
Medical history (referenced to the start of parent study) will be coded by using the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred 
term (PT), and will be summarized based on the FAS and displayed by 115/116 FAS, and 
113B/116 FAS, and overall.  
10.2.4 
Prior and Concomitant Medications 
Medications will be coded 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  
• Concomitant medication: medication continued or newly received during the 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. 
• Post-treatment medication: medication continued or newly received after the TE 
period.  
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, based on 
the 116A FAS and will be presented by 115/116 FAS, and 113B/116 FAS, and overall. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix D. 


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10.2.5 
Study Drug Exposure 
Duration of study drug exposure (in days) will be calculated as: last dose date – first dose 
date + 1 day, regardless of study drug interruption.  The first and last dose dates of Study 116 
Part A will be used for the calculation. 
Study drug exposure will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max based on the 116A Safety Set. It will also be summarized into the 
following categories: >0 to ≤12 weeks, >12 to ≤24 weeks, >24 to ≤36 weeks, >36 to ≤48 
weeks, >48 to ≤60 weeks, >60 to ≤72 weeks, >72 to ≤84 weeks, >84 to ≤96 weeks, >96 
weeks, using counts and percentages.  
Additionally, the total study drug exposure, defined as the sum of the study drug exposure 
across all subjects (in patient-years), will be provided. 
Exposure summaries will be based on the Safety Set. 
10.2.6 
Study Drug Compliance 
The study drug compliance will be calculated based on the study exposure (in days) as well 
as based on the number of tablets taken; summary of both calculations will be provided. 
 
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 based on the number of tablets taken will be calculated as: 
100 x [(total number of tablets dispensed) – (total number of tablets returned)]/(total number 
of tablets planned to be taken per day x duration of study drug exposure in days). The 
maximum percentage of tablets taken will be 100%. 
Both Study drug compliance variables will be summarized descriptively by the n, mean, SD,  
median, minimum, and maximum. They will also be summarized in categories: <80% and 
≥80% using frequency tables. 
Study drug compliance summaries will be based on the FAS, and will be presented by 115-
116 FAS, and 113B-116 FAS, and overall. 
10.2.7 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being. IPD rules will be developed and finalized before the 
data lock for Part A. 
Protocol deviations that should be considered as potential IPDs include, but are not limited 
to: 
• Subject was enrolled in the study despite not satisfying one or more 
inclusion/exclusion criterion 
• Subject was less than 80% compliant with study drug for non-safety reasons 
• Subject received prohibited concomitant medications 


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• Subject received the wrong treatment or incorrect doses 
• Subject remained in the study despite meeting withdrawal criteria 
The occurrence of any of these events should be considered as a potential IPD, but the team 
should categorize such an event as an IPD only if it has the potential to affect the 
completeness, accuracy, or reliability of the study data or the subject’s rights, safety, or well-
being. 
An individual subject data listing and a summary table of IPDs based on the FAS will also be 
provided. 
10.3 
Safety Analysis 
The primary objective of Study 116 Part A is to evaluate the long-term safety and tolerability 
of TEZ/IVA. 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 
Analysis of AEs will be based on events that occur during the TE period of the Part A, for all 
subjects in the Safety Set. Pooled AE data from Study 113 Part B and Study 115 (only those 
who received TEZ/IVA) will be displayed side-by-side with AE data from Study 116 Part A. 
When displayed side-by-side with parent study results, exposure-adjusted rates will be 
provided. 
Other safety analyses will be based on data from the TE period for all subjects in the Safety 
Set; and will be presented overall. The Safety Set will be used for all listings unless 
otherwise specified. 
Baseline value will be used to calculate change from baseline for continuous safety 
endpoints.  
Only descriptive summaries will be presented, and no statistical testing is planned. 
10.3.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment adverse events (AEs), TEAEs, 
or post-treatment AEs, defined as follows: 
• Pretreatment AE any AE that started before the first dose of study drug. 
• TEAE: any AE that worsened (either in severity or seriousness) or that was newly 
developed during the TE period. 


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• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after 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 the first dose of study drug during the respective TE 
period, the AEs will be classified as TEAEs. 
Details for imputing missing or partial AE start/end dates are defined in Appendix E. 
10.3.1.1 
Overview of TEAEs 
An overview table of TEAEs will be provided with the following categories: 
• 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 (possibly related, related or missing)  
• Subjects with TEAEs leading to treatment discontinuation 
• Subjects with TEAEs leading to treatment interruption 
• Subjects with TEAEs leading to death 
The frequency counts and percentages will be presented for the above overview table. 
Exposure adjusted event rates may also be provided. 
In addition, listings 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. 
10.3.1.2 
TEAEs by SOC and PT 
The following summary tables of TEAEs will be provided: 
• All TEAEs 
• Related TEAEs 
• Grade 3/4 TEAEs 
• Serious TEAEs 
• Related Serious TEAEs (possibly related, related or missing) 
• TEAEs by strongest relationship  
• TEAEs by maximum severity  


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• 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). For selected summary 
tables, the exposure adjusted event rate may also be provided.  
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. While summarizing the 
number of events for the exposure adjusted even rate, all occurrences will be counted.  
10.3.1.3 
TEAEs and SAEs by PT 
The number and percentage of subjects with TEAEs and SAEs will be summarized by PT. 
Exposure adjusted event rates may also be provided.  When summarizing the number and 
percentage of subjects with an event, multiple occurrences of the same adverse event or a 
continuing adverse event for the same subject will be counted once. While summarizing the 
number of events for the exposure adjusted event rate, all occurrences will be counted.  
10.3.1.4 
TEAEs of Special Interest 
For treatment-emergent elevated transaminase events, respiratory symptoms, and respiratory 
events (PT lists are provided in  
 
 


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Appendix H), the following categories will be summarized in terms of frequency counts: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
10.3.2 
Clinical Laboratory Values  
For laboratory measurements, the raw values and change from treatment baseline values of 
the continuous hematology, chemistry, vitamin, and lipids results will be summarized in SI 
units at each scheduled time point in the TE period based on the Safety Set. 
The number and percentage of subjects with laboratory measurements meeting threshold 
criteria during the TE period will be summarized based on the Safety Set for selected 
laboratory measurements.  
The threshold criterion shift from treatment baseline during the TE period will also be 
summarized for selected LFT laboratory parameters. The threshold criteria are provided in 
Appendix G. 
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 the time 
points will be included (scheduled and unscheduled). 
In addition, a listing containing individual subject hematology and chemistry values outside the 
normal reference ranges will be provided. This listing will include data from both scheduled and 
unscheduled visits. 
Only central lab results will be used for the tables. Local lab results will be included in the 
listings. 
10.3.3 
Electrocardiogram 
A summary of raw values and change from treatment baseline values will be provided based 
on the Safety Set at each scheduled time point in the TE period 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 listing of ECG assessments of subjects with at least 1 abnormal finding will be provided.  


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The number and percentage of subjects with at least 1 ECG event meeting the threshold 
criteria during the TE period will be summarized based on the Safety Set in the TE period. 
The threshold value criteria are provided in Appendix G. 
10.3.4 
Vital Signs  
For vital signs measurements, the raw values and change from treatment baseline values will 
be summarized based on the Safety Set at each scheduled time point during the TE period for 
the following measurements: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), HR (bpm), and respiration rate (breaths per minute).  
The number and percentage of subjects meeting threshold criteria during the TE period will 
be summarized by vital signs parameters based on the Safety Set. The threshold value criteria 
are provided in Appendix G. 
10.3.5 
Pulse Oximetry  
For percent of oxygen saturation by pulse oximetry, a summary of raw values and change 
from treatment baseline values will be provided at each scheduled time point during the TE 
period based on the Safety Set.  
The number and percentage of subjects with shift changes from treatment baseline values 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the TE period will be summarized.  
The reference range for normal oxygen saturation is specified as >95%, and <=95% for low 
oxygen saturation. 
10.3.6 
Ophthalmologic Examination  
Ophthalmologic examination abnormal findings will be presented as a subject data listing. 
10.4 
Efficacy Analysis  
All efficacy analyses described in this section will be performed by parent study based on the 
FAS (115/116 FAS and 113B/116 FAS) unless specified otherwise. LCI analysis will be 
based on the 115/116 FAS and the 113B/116 LCI FAS.  
The analysis will include all available measurements during the efficacy analysis period.  
10.4.1 
Analysis of Primary Efficacy Variables 
Not applicable 
10.4.2 
Analysis of Secondary Efficacy Variables 
Methods of efficacy analyses will be similar for those used in the parent studies. Each of the 
secondary endpoints (LCI2.5, sweat chloride, BMI, and CFQ-R) will be analyzed using a 
Mixed Model Repeated Measures (MMRM) model, with absolute change from baseline 
during the efficacy analysis period as the dependent variable.  
Note: For study 113B the change from baseline in LCI2.5, will be provided as descriptive 
summary statistics only. 
The model will include the absolute change from baseline as the dependent variable; visit as 
a fixed effect; and subject as a random effect, and baseline value as a covariate.  For 


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consistency with the models in the parent studies, models for subjects from Study 115 will 
also include mutation group (F/F vs. F/RF)  and baseline LCI2.5 as a fixed effect. 
 In the model, visit will be treated as a class variable, assuming an unstructured covariance 
matrix to model the within-subject variability. This model imposes no assumptions on the 
correlational structure and is considered robust. Denominator degrees of freedom for the F 
test for fixed effects will be estimated using the Kenward-Roger approximation. If there is a 
convergence problem due to the use of an unstructured covariance matrix, a compound 
symmetry covariance structure will be used to model the within-subject errors.  
With a mixed-effects model based on a restricted maximum likelihood estimation used for 
the analysis and assuming that, conditional on fixed and random effects, data are missing at 
random, no imputation of missing data will be performed. 
Note: Missing data due to COVID-19 outbreak will be considered as missing at random.  
Since the underlying assumption of the MMRM method is that data are missing at random, 
for the secondary endpoints no further analysis will be performed to investigate the impact of 
the COVID-19 outbreak.  
10.4.2.1 
Change from Baseline in Lung Clearance Index LCI2.5 
The absolute change from baseline in LCI2.5 at Day 15, Weeks 4, 24, 48, 72 and 96 will be 
analyzed using a MMRM as specified above.   
The analysis will be performed using a restricted maximum likelihood (REML)-based 
mixed-effect model for repeated measures (MMRM) for the subjects in the 115/116 FAS 
only. 
For 115/116 FAS , the model will include absolute change from baseline in LCI2.5 
measurements at Day 15, Weeks 4, 24, 48, 72 and 96  as the dependent variable, and visit (as 
a class variable), mutation group (F/F and F/RF) as a fixed effects,  and baseline LCI2.5 
(continuous) value as covariate, and subject as a random effect.  
For subjects from Study 115, only those who were randomized to TEZ/IVA treatment group 
will be included in the MMRM model. 
For each visit, the LS mean, standard error (SE), and associated 95% CI, will be provided. 
The LS mean and associated 95% CI at each visit will also be plotted. 
The raw values and change from the baseline values of LCI2.5 will be summarized for 
subjects in the 113B/116 LCI FAS at Week 24, 48, 72, 96, for subjects in the 115/116 FAS 
who were randomized to TEZ/IVA (in Study 115),  and for the 115/116 FAS overall at Day 
15, Weeks 4, 24, 48, 72 and 96. 
10.4.2.2 
Absolute Change from Baseline in Sweat Chloride 
The absolute change from baseline in sweat chloride at Weeks 24, 48 and 96 will be analyzed 
using a MMRM as specified above.   
The analysis will be performed using a restricted maximum likelihood (REML)-based 
mixed-effect model for repeated measures (MMRM) for the subjects in the 115/116 FAS and 
the 113B/116 FAS separately.  


Statistical Analysis Plan (Methods) - Final 
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Vertex Study: VX17-661-116 Part A 
 
 
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For 115/116 FAS , the model will include absolute change from baseline in sweat chloride 
measurements at Weeks  24, 48 and 96  as the dependent variable, and visit (as a class 
variable), mutation group (F/F and F/RF) as a fixed effects,  and baseline sweat chloride 
(continuous) value and baseline LCI2.5 as covariates, and subject as a random effect.  
For 113B/116 FAS, the model will include absolute change from baseline in sweat chloride 
measurements at Weeks 24, 48 and 96 as the dependent variable, and visit (as a class 
variable) as a fixed effect, baseline sweat chloride (continuous) value as covariate, and 
subject as a random effect.  
For subjects from Study 115, only those who were randomized to TEZ/IVA treatment group 
will be included in the MMRM model. 
For each visit, the LS mean, standard error (SE), and associated 95% CI, will be provided. 
The LS mean and associated 95% CI at each visit will also be plotted. 
Additionally, the raw values and change from baseline values of sweat chloride 
measurements will be summarized for subjects in the 113B/116 FAS , for subjects in the 
115/116 FAS who were randomized to TEZ/IVA (in Study 115),  and for the 115/116 FAS 
overall at weeks 24, 48 and 96. 
10.4.2.3 
 Absolute change in the CFQ-R respiratory domain score from baseline  
The absolute change from baseline in CFQ-R at Day 15, Weeks 4, 12, 24, 36, 48, 60, 72, 84 
and 96 will be analyzed using a MMRM as specified above.   
The analysis will be performed using a restricted maximum likelihood (REML)-based 
mixed-effect model for repeated measures (MMRM) for the subjects in the 115/116 FAS and 
the 113B/116 FAS separately.  
For 115/116 FAS, the model will include absolute change from baseline in CFQ-R 
respiratory score at Day 15, Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 as the dependent 
variable, and visit (as a class variable), mutation group (F/F and F/RF) as a fixed effects, and 
baseline CFQ-R respiratory score (continuous) value and baseline LCI2.5 as covariates, and 
subject as a random effect.  
For 113B/116 FAS, the model will include absolute change from baseline in CFQ-R 
respiratory score at weeks 12, 24, 36, 48, 60, 72, 84 and 96 as the dependent variable, and 
visit (as a class variable) as a fixed effect, baseline CFQ-R respiratory score (continuous) 
value as covariate, and subject as a random effect. 
 For subjects from Study 115, only those who were randomized to TEZ/IVA treatment group 
will be included in the MMRM model. 
For each visit, the LS mean, standard error (SE), and associated 95% CI, will be provided. 
The LS mean and associated 95% CI at each visit will also be plotted. 
Additionally, the raw values and change from baseline values of CFQ-R measurements will 
be summarized for subjects in the 113B/116 FAS , for subjects in the 115/116 FAS who were 
randomized to TEZ/IVA (in Study 115),  and for the 115/116 FAS overall at each scheduled 
time point in Study 116 Part A. 


Statistical Analysis Plan (Methods) - Final 
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Note: due to COVID-19 outbreak some of the CFQ-R assessments were completed at home, 
therefore the analysis for the CFQ-R will be performed with and without home assessments  
included. If the analysis with at-home assessment included is showing inconsistency with the 
analysis of the in-clinic data only, the in-clinic CFQ-R assessments will be considered as the 
main analysis. 
10.4.2.4 
Absolute change from baseline in body mass index (BMI) 
The absolute change from baseline in BMI at Day 15, Weeks  4, 12, 24, 36, 48, 60, 72, 84 
and 96  will be analyzed using a MMRM as specified above.   
The analysis will be performed using a restricted maximum likelihood (REML)-based 
mixed-effect model for repeated measures (MMRM) for the subjects in the 115/116 FAS and 
the 113B/116 FAS separately.  
For 115/116 FAS, the model will include absolute change from baseline in BMI at Day 15, 
Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 as the dependent variable, and visit (as a class 
variable), mutation group (F/F and F/RF) as a fixed effects, and baseline BMI (continuous) 
value and baseline LCI2.5 as covariates, and subject as a random effect.  
For 113B/116 FAS, the model will include absolute change from baseline in BMI at Weeks 
12, 24,36, 48, 60, 72,84 and 96 as the dependent variable, and visit (as a class variable) as a 
fixed effect,  baseline BMI (continuous) value as covariate, and subject as a random effect.  
For subjects from Study 115, only those who were randomized to TEZ/IVA treatment group 
will be included in the MMRM model. 
For each visit, the LS mean, standard error (SE), and associated 95% CI, will be provided. 
The LS mean and associated 95% CI at each visit will also be plotted. 
Additionally, the raw values and change from baseline values of BMI measurements will be 
summarized for subjects in the 113B/116 FAS , for subjects in the 115/116 FAS who were 
randomized to TEZ/IVA (in Study 115),  and for the 115/116 FAS overall at each scheduled 
time point in Study 116 Part A. 










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12 
APPENDICES 
 Appendix A: Analysis Visit Window Mapping Rules  
 Table 12-1 Visit Window Mapping Rules for Safety and Efficacy Measurements 
Assessments 
Parent Study 
Study 116 Visit 
Target 
Study Day 
Visit Window  
(in study days) 
Safety Assessment 
• Vital Signs 
• Pulse Oximetry 
 
Study 113 Part B 
Baseline 
-- 
Defined in Section 10.1  
116A  Week 12 
85 
[1*, 127] 
116A Week 24  
169 
(127, 211] 
116A Week 36 
253 
(211, 295] 
116A Week 48  
337 
(295, 379] 
116A Week 60  
421 
(379, 463] 
116A Week 72 
505 
(463, 547] 
116A Week 84  
589 
(547, 631] 
116A on Week 96  
673 
(631, 687] 
116A Safety Follow-up  
N/A 
Nominal 
Study 115 
 Baseline 
-- 
Defined in Section 10.1 
116A Day 15 
15 
[1*, 22] 
116A Week 4 
29 
(22, 57] 
116A Week 12 
85 
(57, 127] 
116A Week 24 
169 
(127, 211] 
116A Week 36 
253 
(211, 295] 
116A Week 48 
337 
(295, 379] 
116A Week 60 
421 
(379, 463] 
116A Week 72 
505 
(463, 547] 
116A Week 84 
589 
(547, 631] 
116A Week 96 
673 
(631, 687] 
116A Safety Follow-up 
N/A 
Nominal 
• Hematology 
• Serum Chemistry 
Study 113 Part B 
Baseline 
-- 
Defined in Section 10.1 
116A Week 12 
85 
[1*, 127] 
116A Week 24  
169 
(127, 211] 
116A Week 36 
253 
(211, 295] 
116A Week 48  
337 
(295, 379] 
116A Week 60  
421 
(379, 463] 
116A Week 72 
505 
(463, 547] 
116A Week 84  
589 
(547, 631] 
116A Week 96  
673 
(631, 687] 
116A Safety Follow-up  
N/A 
Nominal 
Study 115 
Baseline 
-- 
Defined in Section 10.1 
116A Day 15 
15 
[1*, 50] 
116A Week 12 
85 
(50, 127] 
116A Week 24 
169 
(127, 211] 
116A Week 36 
253 
(211, 295] 


Statistical Analysis Plan (Methods) - Final 
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116A Week 48 
337 
(295, 379] 
116A Week 60 
421 
(379, 463] 
116A Week 72 
505 
(463, 547] 
116A Week 84 
589 
(547, 631] 
116A Week 96 
673 
(631, 687] 
116A Safety Follow-up 
N/A 
Nominal 
• ECG 
• Lipid Panel 
• Vitamin Levels 
Study 113 Part B 
and  
Study 115 
Baseline 
-- 
Defined in Section 10.1 
116 Week 24  
169 
[1*, 253] 
116 Week 48  
337 
(253, 421] 
116 Week 72 
505 
(421, 589] 
116 Week 96  
673 
(589, 687] 
116A Safety Follow-up  
N/A 
Nominal 
Efficacy Assessment 
 
 
• LCI 
Study 113 Part B 
Baseline 
-- 
Defined in Section 10.1 
116A Week 24  
169 
[1*, 253] 
116A Week 48  
337 
(253, 421] 
116A Week 72 
505 
(421, 589] 
116A Week 96  
673 
(589, 687] 
Study 115 
Baseline 
-- 
Defined in Section 10.1 
116A Day 15 
15 
[1*, 22] 
116A Week 4 
29 
(22, 99] 
116A Week 24  
169 
(99, 253] 
116A Week 48  
337 
(253, 421] 
116A Week 72 
505 
(421, 589] 
116A Week 96  
673 
(589, 687] 
• Sweat chloride 
 
Study 113 Part B 
and Study 115 
Baseline 
-- 
Defined in Section 10.1 
116A Week 24 
169 
[1*, 253] 
116A Week 48 
337 
(253, 505] 
116A Week 96 
673 
(505, 687] 
• CFQ-R 
• Weight, height, 
BMI 
 
  
Study 113 Part B 
Baseline 
-- 
Defined in Section 10.1  
116A Week 12 
85 
[1*, 127] 
116A Week 24 
169 
(127, 211] 
116A Week 36 
253 
(211, 295] 
116A Week 48 
337 
(295, 379] 
116A Week 60 
421 
(379, 463] 
116A Week 72 
505 
(463, 547] 
116A Week 84 
589 
(547, 631] 
116A Week 96 
673 
(631, 687] 
Study 115 
Baseline 
-- 
Defined in Section 10.1  
116A Day 15 
15 
[1*, 22] 
116A Week 4 
29 
(22, 57] 
116A Week 12 
85 
(57, 127] 
116A Week 24 
169 
(127, 211] 
116A Week 36 
253 
(211, 295] 
116A Week 48 
337 
(295, 379] 
116A Week 60 
421 
(379, 463] 


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116A Week 72 
505 
(463, 547] 
116A Week 84 
589 
(547, 631] 
116A Week 96 
673 
(631, 687] 
* Only include Day 1 post-dose measurements. 
+ Weight will also be used in the threshold analysis in which the treatment baseline will be used 
to calculate the change;
 
.  
Note: 
1. Visit name for analysis purpose is used to report data 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. Assessments at early treatment termination (ETT) visit will follow the windowing rules for 
regular visits up to 116A Week 96 if the ETT visit has a study day ≤ 687; otherwise, the ETT 
visit will be mapped into 116A Safety Follow-up (SFU) visit, if the subject doesn’t have a 
nominal SFU visit.  
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. 
• SFU visit will not be windowed; instead, it will be used according to the nominal visit in 
relevant analyses. 
6. 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 within the same distance from the target day, the latest 
record will be used. 
• SFU visit will not be windowed; instead, it will remain as SFU.  
7. 
weight, height, and BMI assessments will be used for both efficacy and safety 
purposes. Their measurements will follow the visit windowing rules for efficacy parameters. 


Statistical Analysis Plan (Methods) - Final 
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 Appendix B: Standards for Safety 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 study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
A: Post; C: Concomitant; P: Prior 
 
 
 


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 Appendix 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 G: Criteria for Threshold Analysis 
Table 12-3 Threshold Analysis Criteria for Clinical Chemistry and Hematology  
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 Jul 2009 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 Jul 2009  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009 
 
(ALT or AST) and Total Bilirubin  
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009  
 
GGT  
>ULN - ≤ 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 


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Calcium 
Hypercalcemia 
>ULN - ≤ 2.9 mmol/L  
>2.9 – ≤ 3.1 mmol/L  
>3.1 – ≤ 3.4 mmol/L  
>3.4 mmol/L 
CTCAE grade 1-4 
Hypocalcemia 
<LLN - ≥ 2.0 mmol/L 
<2.0 – ≥1.75 mmol/L  
<1.75 – ≥ 1.5 mmol/L  
<1.5 mmol/L  
CTCAE grade 1-4 
Magnesium 
 
Hypermagnesemia 
>ULN - ≤ 1.23 mmol/L 
>1.23 – ≤ 3.30 mmol/L 
>3.30 mmol/L 
CTCAE grade 1, 3, 4 
 
No CTCAE grade 2 
Hypomagnesemia 
<LLN - ≥ 0.5 mmol/L 
<0.5 – ≥ 0.4 mmol/L 
<0.4 – ≥ 0.3 mmol/L  
<0.3 mmol/L  
CTCAE grade 1-4 
Inorganic phosphate 
Hypophosphatemia 
<0.74 – ≥ 0.6 mmol/L 
<0.6 – ≥ 0.3 mmol/L 
<0.3 mmol/L 
CTCAE grade 1-4 
Lipid Panel 
Total Cholesterol 
>ULN – ≤ 7.75 mmol/L 
>7.75 – ≤ 10.34 mmol/L  
>10.34 – ≤ 12.92 mmol/L 
>12.92 mmol/L 
CTCAE grade 1-4 
Triglycerides 
>1.71 – ≤ 3.42 mmol/L  
>3.42 – ≤ 5.7 mmol/L  
>5.7 – ≤ 11.4 mmol/L  
>11.4 mmol/L 
CTCAE grade 1-4 
Hematology 
WBC 
WBC decreased 
<LLN - ≥ 3.0 x 10e9 /L 
<3.0 – ≥ 2.0 x 10e9 /L  
<2.0 – ≥ 1.0 x 10e9 /L  
<1.0 x 10e9 /L 
CTCAE grade 1-4 
Leukocytosis 
>100 x 10e9 /L 
CTCAE grade 3 (only Grade 
available)  
Lymphocytes 
Lymphocyte decreased 
<LLN - ≥ 0.8 x10e9 /L 
<0.8 – ≥ 0.5 x10e9 /L  
<0.5 – ≥ 0.2 x10e9 /L  
<0.2 x10e9 /L 
CTCAE grade 1-4 
Lymphocyte increased 
>4 – ≤ 20 x10e9/L  
>20 x10e9/L  
CTCAE grade 2, 3 (only Grades 
available) 
Neutrophils 
Neutrophil decreased 
<LLN - ≥ 1.5 x10e9 /L 
<1.5 –  ≥ 1.0 x10e9 /L  
<1.0 –  ≥ 0.5 x10e9 /L  
<0.5 x10e9 /L 
CTCAE grade 1-4 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
CTCAE grade 1-3 


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<100 – ≥ 80 g/L  
< 80 g/L 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above 
ULN 
>40 g/L above ULN  
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Table 12-4 Threshold Criteria for ECGs 
Ref.: CPMP 1997 guideline. 
Parameter 
Threshold 
Comments 
HR 
 
 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Per HV grade 2, 3, plus shift change 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
 
QT/QTcF 
 
>450 ms (Male) or >470 ms (Female) 
≥500 ms 
 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline between 30-60 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 


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Table 12-5 Threshold Criteria for Vital Signs 
Parameter 
Threshold Criteria 
Comments 
HR 
 
Same criteria as above in ECG category 
 
SBP 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from baseline 
>140 mmHg & >20 mmHg increase from baseline 
>160 mmHg & >10 mmHg increase from baseline 
>160 mmHg & >20 mmHg increase from baseline 
809/770 analyses 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from baseline 
<90 mmHg and >20 mmHg decrease from baseline 
<80 mmHg and >10 mmHg decrease from baseline 
<80 mmHg and >20 mmHg decrease from baseline 
Per HV grade 1, 3, plus shift change 
 
DBP 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from baseline 
>90 mmHg and >10 mmHg increase from baseline 
>100 mmHg and >5 mmHg increase from baseline 
>100 mmHg and >10 mmHg increase from baseline 
809/770 analyses 
DBP decreased 
  
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from baseline 
<60 mmHg and >10 mmHg decrease from baseline 
<45 mmHg and >5 mmHg decrease from baseline 
<45 mmHg and >10 mmHg decrease from baseline 
 
Weight 
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
CTCAE grade 1-3 
 


Statistical Analysis Plan (Methods) - Final 
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Vertex Study: VX17-661-116 Part A 
 
 
Vertex Pharmaceuticals Incorporated 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3 
 
 
 
 


Statistical Analysis Plan (Methods) - Final 
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Vertex Study: VX17-661-116 Part A 
 
 
Vertex Pharmaceuticals Incorporated 
 
 Appendix H: TEAEs of Special Interest 
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 
The following AE preferred terms will be selected for elevated transaminase: 
• Alanine aminotransferase abnormal 
• Alanine aminotransferase increased 
• Aspartate aminotransferase abnormal 
• Aspartate aminotransferase increased 
• Transaminases abnormal 
• Transaminases increased 
• Liver function test abnormal 
• Liver function test increased 
• Hypertransaminasaemia 
• Hepatic enzyme abnormal 
• Hepatic enzyme increased