Clinical trial NCT03525548
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-08-03; Completion date: 2018-12-28
Enrollment: 113 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation (F/F)

Detailed description:

Arms: arm 1: Following a run-in period of 4 weeks with Tezacaftor (TEZ)/Ivacaftor (IVA), participants received TEZ 100 milligram (mg)/IVA 150 mg as fixed-dose combination (FDC) tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the triple combination (TC) treatment period. arm 2: Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-445 200 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Interventions: intervention 1: VX-445/TEZ/IVA intervention 2: TEZ/IVA intervention 3: IVA intervention 4: Placebo intervention 5: Placebo
Intervention descriptions: intervention 1: Participants received VX-445/TEZ/IVA orally once daily in the morning. intervention 2: Participants received TEZ/IVA orally once daily in the morning. intervention 3: Participants received IVA orally once daily in the evening. intervention 4: Participants received placebo matched to VX-445/TEZ/IVA orally once daily in the morning. intervention 5: Participants received placebo matched TEZ/IVA orally once daily in the morning.

Protocol documents:
Prot_000.pdf: 
Page 1 of 67 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, Randomized, Double-blind, Controlled 
Study Evaluating the Efficacy and Safety of VX-445 
Combination Therapy in Subjects With Cystic 
Fibrosis Who Are Homozygous for the F508del 
Mutation (F/F) 
Vertex Study Number: VX17-445-103 
 
EudraCT Number: 2018-000184-89 
Date of Protocol: 19 July 2018 (Version 3.0)  
 
 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 




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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of 
VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the 
F508del Mutation (F/F) 
Brief Title 
A Phase 3 Study of VX-445 Combination Therapy in CF Subjects Homozygous for F508del 
(F/F) 
 
 
Clinical Phase 
and Clinical 
Study Type  
Phase 3, efficacy and safety  
 
 
Objectives 
Primary Objective 
To evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and 
ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del 
mutation (F/F)  
Secondary Objectives 
• To evaluate the safety of VX-445 in TC with TEZ and IVA  
• To evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA  
• To evaluate the pharmacokinetics (PK) of VX-445, TEZ, and IVA when administered in 
TC 
 
 
Endpoints 
Primary Endpoint 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline at Week 4 
Key Secondary Endpoints 
• Absolute change in sweat chloride (SwCl) from baseline at Week 4 
• Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain score from 
baseline at Week 4 
Other Secondary Endpoints 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values, ECGs, vital signs, and pulse oximetry 
• PK parameters of VX-445, TEZ, M1-TEZ, and IVA 
 
 
Number of 
Subjects 
Approximately 100 subjects will be randomized (1:1) to the TC VX-445/TEZ/IVA arm or the 
TEZ/IVA arm. 
 
 
Study 
Population 
Male and female subjects with CF who are 12 years of age or older who are homozygous for 
F508del (F/F) 
 
 


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Investigational 
Drug 
During the TEZ/IVA Run-in Period, study drug refers to TEZ/IVA and IVA.  
During the Treatment Period, study drug refers to VX-445/TEZ/IVA and matching placebo, 
TEZ/IVA and matching placebo, and IVA. 
Active study drugs will be orally administered as fixed-dose combination (FDC) film-coated 
tablets (2 VX-445/TEZ/IVA tablets or 1 TEZ/IVA tablet) in the morning and as 1 film-coated 
IVA tablet in the evening.  
 
Active substance: VX-445, TEZ (tezacaftor; VX-661), and IVA (ivacaftor, VX-770) 
 
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator (increased Cl− secretion) 
 
Strength: 100-mg VX-445/50-mg TEZ/75-mg IVA FDC tablet 
 
 
 
Active substance: TEZ (tezacaftor; VX-661) and IVA (ivacaftor; VX-770) 
 
Activity: CFTR corrector and CFTR potentiator (increased Cl− secretion) 
 
Strength: 100-mg TEZ/150-mg IVA FDC tablet 
 
 
 
Active substance: IVA (ivacaftor; VX-770) 
 
Activity: CFTR potentiator (increased Cl− secretion) 
 
Strength: 150-mg tablet 
 
 
Study Duration 
The total study duration is approximately 16 weeks (4 weeks for the Screening Period, 4 weeks 
for the TEZ/IVA Run-in Period, 4 weeks for the Treatment Period, and 4 weeks for the Safety 
Follow-up Period). 
 
 
Study Design 
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter 
study. 
 
 
In the TEZ/IVA Run-in Period, all subjects will receive TEZ 100 mg once daily (qd)/IVA 
150 mg every 12 hours (q12h). After completing the TEZ/IVA Run-in Period, subjects will be 
randomized (1:1) to the TC arm or TEZ/IVA arm for the Treatment Period. The Treatment 
Period dosages to be evaluated are shown in the table below. Randomization will be stratified 
by ppFEV1 determined during the TEZ/IVA Run-in Period (Day -14 assessment; <70 versus 
≥70) and age at the Screening Visit (<18 versus ≥18 years of age). If the Day -14 ppFEV1 


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value is not valid or not available, the most recent available ppFEV1 value will be used for 
stratification. 
Treatment Period Arms and Dosages  
Treatment Arm 
VX-445 Dosage 
TEZ Dosage 
IVA Dosage 
TC 
200 mg qd 
100 mg qd 
150 mg q12h 
TEZ/IVA 
0 mg 
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TC: triple combination; TEZ: tezacaftor  
 
 
Assessments 
Efficacy: Spirometry and CFQ-R 
PD: SwCl 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, and physical 
examinations 
PK: VX-445, TEZ, M1-TEZ, and IVA plasma concentrations 
 
 
Statistical 
Analyses 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline at Week 4. The 
primary null hypothesis to be tested is that the mean absolute change in ppFEV1 from baseline 
at Week 4 is the same for the TC and TEZ/IVA treatment groups. The null hypothesis will be 
tested at a 2-sided significance level of 0.05. 
Assuming a within-group SD of 7 percentage points and a 5% dropout rate at Week 4, a 
sample size of 50 subjects in each treatment group for a total of 100 subjects will have 
approximately 93% power to detect a difference of 5.0 percentage points for the mean absolute 
change in ppFEV1 from baseline at Week 4 between the 2 treatment groups, based on a 2-sided 
2-sample t-test at a significance level of 0.05. 
The primary analysis will be based on a mixed-effects model for repeated measures (MMRM). 
The model will include the absolute change from baseline in ppFEV1 at Day 15 and Week 4 as 
the dependent variable; treatment group, visit, and treatment-by-visit as fixed effects; with 
continuous baseline ppFEV1 and age at screening (<18 versus ≥18 years of age) as covariates; 
and an unstructured covariance structure for the within-subject errors. 
The primary result obtained from the model will be the estimated treatment difference at 
Week 4. The adjusted mean with a 2-sided 95% CI and a 2-sided P value will be provided. 
The safety endpoints include AEs, clinical laboratory values, ECGs, vital signs, and pulse 
oximetry through the Safety Follow-up Visit. The safety analysis will be descriptive only. 
 
 
IDMC Reviews 
An independent data monitoring committee (IDMC) will conduct safety review of study data 
as outlined in the IDMC charter. 




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Table 3-1 
Study VX17-445-103: Screening 
Event/Assessment 
Screening Period (Day -56 Through Day -29) 
ICF and assent (when applicable) 
X 
Inclusion and exclusion criteria review 
X 
Demographics 
X 
Medical history  
X 
CFQ-Ra 
X 
CFTR genotypeb 
X 
G6PD activity test 
X 
FSHc 
X 
Serum pregnancy test (all females of childbearing 
potential)d 
X 
Hematology 
X 
Coagulation 
X 
Serum chemistry 
X 
Urinalysis 
X 
Weight and heighte 
X 
Ophthalmologic examinationf 
X 
Complete physical examination 
X 
Vital signsg 
X 
Pulse oximetryg 
X 
Standard 12-lead ECGh 
X 
Spirometryi 
X 
Medications reviewj 
X 
Sweat chloride 
X 
AEs and SAEs 
Continuous from signing of the ICF through completion of 
study participation 
AE: adverse events; CFQ-R: CF-Questionnaire-Revised; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; SAE: serious adverse event  
 a 
The CFQ-R must be completed before the start of any other assessments scheduled for that visit. 
b 
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before Day -28, a 
previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who have been enrolled and whose 
screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.9).  
c 
FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be in the postmenopausal range, as determined by the laboratory performing the test, to 
be considered postmenopausal.  
d 
Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing 
potential and must have a serum pregnancy test. A definition of non-childbearing potential is provided in Section 11.7.7.1. 
e 
Weight and height will be measured with shoes off. 
f 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on the date of informed consent. 
For subjects with documentation of bilateral lens removal, ophthalmologic examinations are not required. The 
ophthalmologic examination does not need to be conducted if there is documentation of an examination meeting the 
protocol requirements that was conducted within 3 months before the date of informed consent (Section 11.7.6). The 
ophthalmologic examination will be conducted by a licensed ophthalmologist or optometrist.  
g 
Vital signs and pulse oximetry will be collected after the subject has been at rest for at least 5 minutes. 
h 
A standard 12-lead ECG will be performed after the subject has been at rest for at least 5 minutes. 
i 
Spirometry may be performed pre- or post-bronchodilator (Section 11.6.1). 
j 
Refer to Section 9.5 for details.  




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Table 3-2 
VX17-445-103: TEZ/IVA Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
TEZ/IVA Run-in Period 
(4 Weeks) 
Treatment Period (4 Weeks) 
ETT 
Visitb 
Safety Follow-up Visit 
28 (± 7) Days 
After the Last Dose of Study 
Drug (If Applicable)c 
Day -28 
± 1 Day 
Day -14  
(Day -15 to 
Day -3) 
Day 1d 
Day 15 
± 3 Days 
Week 4 
± 5 Days 
 
 
Vital signsj 
X 
 
X 
X 
X 
X 
X 
Pulse oximetryj  
X 
 
X 
X 
X 
X 
X 
Spirometryk 
 
X 
X 
X 
X 
X 
X 
Sweat chloridel 
 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X 
 
X 
X 
X 
Hematology 
Xm 
 
Xm 
X 
X 
X 
X 
Coagulation 
Xm 
 
Xm 
 
X 
X 
X 
Serum chemistry 
Xm 
 
Xm 
X 
X 
X 
X 
PK samplingn 
 
 
X 
 
X 
X 
 
j 
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest for at least 5 minutes. 
k 
Spirometry assessments must be performed before study drug dosing (see Section 9.6.1) and should be performed pre-bronchodilator (Section 11.6.1) at approximately the 
same time at each visit. 
l  
Sweat chloride collection will occur before study drug dosing (Section 11.4). At each time point, 2 samples will be collected, 1 from each arm (left and right). 
m  
Blood samples will be collected before the first dose of study drug in each study period. 
n 
The Day 1 predose PK sample must be collected before dosing. The Week 4 predose PK sample must be collected within 60 minutes before dosing for subjects who are 
receiving their first dose of study drug in an open-label study on the same day as the Week 4 Visit. For subjects who are not entering an open-label study on the same day as 
the Week 4 Visit, the Week 4 sample should be collected approximately 12 hours after the evening dose of IVA on the day prior to the Week 4 Visit (Section 11.3.1). 


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Table 3-2 
VX17-445-103: TEZ/IVA Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
TEZ/IVA Run-in Period 
(4 Weeks) 
Treatment Period (4 Weeks) 
ETT 
Visitb 
Safety Follow-up Visit 
28 (± 7) Days 
After the Last Dose of Study 
Drug (If Applicable)c 
Day -28 
± 1 Day 
Day -14  
(Day -15 to 
Day -3) 
Day 1d 
Day 15 
± 3 Days 
Week 4 
± 5 Days 
 
 
Run-in TEZ/IVA dosingq 
Day -28 to evening on Day -1 
 
 
 
Run-in TEZ/IVA drug count 
X 
X 
X 
 
 
 
 
Randomizationr 
 
 
X 
 
 
 
 
Randomized study drug dosings 
 
 
Day 1 through evening before the Week 4 Visit 
 
 
Randomized study drug count 
 
 
X 
X 
X 
X 
 
Medications reviewu 
Continuous from signing of ICF through completion of study participation 
Treatments and procedures reviewu 
Continuous from signing of ICF through completion of study participation 
AEs and SAEsu, v  
Continuous from signing of ICF through completion of study participation 
AE: adverse event; CF: cystic fibrosis; CFQ-R: CF Questionnaire-Revised; ETT: Early Termination of Treatment; GPS: Global Patient Safety; ICF: informed consent form; 
IV: intravenous; IVA: ivacaftor; PD: pharmacodynamic; 
; PK: pharmacokinetic; 
; SAE: serious adverse event; 
TEZ: tezacaftor; 
 
 q 
For the Run-in Period, TEZ/IVA should be administered as outlined in Section 9.6.1. On days of scheduled visits, refer to Section 9.6.1 for the timing of dosing relative to the 
assessments. The final dose during the Run-in Period will be administered on Day -1, the evening before the Day 1 Visit. 
r 
Randomization may occur on either Day -1 or Day 1, after conditions for entry into the Treatment Period (Section 9.1.3) have been satisfied. Randomization must occur 
before the first dose of study drug in the Treatment Period. 
s 
For the Treatment Period, the randomized study drug regimen should be administered as outlined in Section 9.6.1. On days of scheduled visits, refer to Section 9.6.1 for the 
timing of dosing relative to the assessments  The final dose of study drug in the Treatment Period will be administered the evening before the Week 4 Visit  
  
Completion of study participation is defined in Section 9.1.7. 
v  
SAEs that occur after completion of study participation and are considered related to study drug will be reported to Vertex GPS within 24 hours as described in 
Section 13.1.2.2. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 6 
4 
Table of Contents ................................................................................................................. 11 
List of Tables............................................................................................................................ 15 
List of Figures .......................................................................................................................... 15 
List of Abbreviations................................................................................................................ 16 
5 
Introduction.......................................................................................................................... 19 
5.1 
Background ..................................................................................................................... 19 
5.2 
Rationale for the Present Study ...................................................................................... 19 
6 
Study Objectives .................................................................................................................. 20 
6.1 
Primary Objective ........................................................................................................... 20 
6.2 
Secondary Objectives ..................................................................................................... 20 
7 
Study Endpoints ................................................................................................................... 20 
7.1 
Primary Endpoint ............................................................................................................ 20 
7.2 
Secondary Endpoints ...................................................................................................... 20 
7.2.1 
Key Secondary Endpoints ...................................................................................... 20 
7.2.2 
Other Secondary Endpoints .................................................................................... 20 
 
 
8 
Study Population .................................................................................................................. 20 
8.1 
Inclusion Criteria ............................................................................................................ 20 
8.2 
Exclusion Criteria ........................................................................................................... 21 
9 
Study Implementation ......................................................................................................... 22 
9.1 
Study Design .................................................................................................................. 22 
9.1.1 
Screening ................................................................................................................ 23 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 24 
9.1.1.2 
Rescreening ...................................................................................................... 24 
9.1.1.3 
Extension of Screening Period Window .......................................................... 24 
9.1.2 
Tezacaftor/Ivacaftor Run-in Period ........................................................................ 24 
9.1.3 
Treatment Period .................................................................................................... 24 
9.1.4 
Follow-up................................................................................................................ 25 
9.1.5 
Early Termination of Treatment ............................................................................. 25 
9.1.5.1 
Discontinuation During the Run-in Period ...................................................... 25 
9.1.5.2 
Discontinuation During the Treatment Period ................................................. 26 
9.1.6 
Lost to Follow-up ................................................................................................... 26 
9.1.7 
Completion of Study Participation ......................................................................... 26 
9.1.8 
Independent Data Monitoring Committee .............................................................. 26 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 27 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 27 
9.3.1 
Study Design........................................................................................................... 27 
9.3.2 
Study Drug Dose .................................................................................................... 27 
9.3.3 
Rationale for Study Population............................................................................... 28 
9.3.4 
Rationale for Study Assessments ........................................................................... 28 




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11.7.1 
Adverse Events ....................................................................................................... 42 
11.7.2 
Clinical Laboratory Assessments ........................................................................... 43 
11.7.3 
Physical Examinations and Vital Signs .................................................................. 45 
11.7.4 
Pulse Oximetry ....................................................................................................... 45 
11.7.5 
Electrocardiograms ................................................................................................. 45 
11.7.6 
Ophthalmologic Examination ................................................................................. 46 
11.7.7 
Contraception and Pregnancy ................................................................................. 46 
11.7.7.1 Contraception ................................................................................................... 46 
11.7.7.2 Pregnancy ......................................................................................................... 48 
12 Statistical and Analytical Plans .......................................................................................... 48 
12.1 Sample Size and Power .................................................................................................. 48 
12.2 Analysis Sets .................................................................................................................. 48 
12.3 Statistical Analysis ......................................................................................................... 49 
12.3.1 
General Considerations ........................................................................................... 49 
12.3.2 
Background Characteristics .................................................................................... 49 
12.3.2.1 Subject Disposition .......................................................................................... 49 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 50 
12.3.2.3 Prior and Concomitant Medications................................................................. 50 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 50 
12.3.2.5 Important Protocol Deviations ......................................................................... 51 
12.3.3 
Efficacy and Pharmacodynamic Analyses ............................................................. 51 
12.3.3.1 Analysis of Primary Variable ........................................................................... 51 
12.3.3.2 Analysis of Key Secondary Variables.............................................................. 52 
 
12.3.3.4 Multiplicity Adjustment ................................................................................... 52 
12.3.4 
Safety Analysis ....................................................................................................... 52 
12.3.4.1 Adverse Events................................................................................................. 53 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 54 
12.3.4.3 Electrocardiogram ............................................................................................ 54 
12.3.4.4 Vital Signs ........................................................................................................ 54 
12.3.4.5 Pulse Oximetry ................................................................................................. 55 
12.3.4.6 Physical Examination ....................................................................................... 55 
12.3.4.7 Other Safety Analysis ...................................................................................... 55 
 
 
12.3.6 
Interim and IDMC Analyses ................................................................................... 55 
12.3.6.1 Interim Analysis ............................................................................................... 55 
12.3.6.2 IDMC Analysis ................................................................................................ 55 
12.4 Clinical Pharmacology Analysis .................................................................................... 55 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 55 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 55 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 55 
13.1.1 
Adverse Events ....................................................................................................... 55 
13.1.1.1 Definition of an Adverse Event........................................................................ 55 
13.1.1.2 Clinically Significant Assessments .................................................................. 56 
13.1.1.3 Documentation of Adverse Events................................................................... 56 


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13.1.1.4 Adverse Event Severity .................................................................................... 57 
13.1.1.5 Adverse Event Causality .................................................................................. 57 
13.1.1.6 Study Drug Action Taken ................................................................................ 57 
13.1.1.7 Adverse Event Outcome .................................................................................. 58 
13.1.1.8 Treatment Given............................................................................................... 58 
13.1.2 
Serious Adverse Events .......................................................................................... 58 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 58 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 59 
13.1.2.3 Reporting Serious Adverse Events................................................................... 59 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 60 
13.2 Administrative Requirements ......................................................................................... 60 
13.2.1 
Ethical Considerations ............................................................................................ 60 
13.2.2 
Subject Information and Informed Consent ........................................................... 60 
13.2.3 
Investigator Compliance ......................................................................................... 60 
13.2.4 
Access to Records ................................................................................................... 61 
13.2.5 
Subject Privacy ....................................................................................................... 61 
13.2.6 
Record Retention .................................................................................................... 61 
13.2.7 
Study Termination .................................................................................................. 61 
13.2.8 
End of Study ........................................................................................................... 62 
13.3 Data Quality Assurance .................................................................................................. 62 
13.4 Monitoring ...................................................................................................................... 62 
13.5 Electronic Data Capture ................................................................................................. 62 
13.6 Publications and Clinical Study Report .......................................................................... 63 
13.6.1 
Publication of Study Results ................................................................................... 63 
13.6.2 
Clinical Study Report ............................................................................................. 63 
14 References ............................................................................................................................. 64 
15 Protocol Signature Pages .................................................................................................... 66 
15.1 Sponsor Signature Page .................................................................................................. 66 
15.2 Investigator Signature Page ............................................................................................ 67 
 


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List of Tables 
Table 3-1 
Study VX17-445-103: Screening ............................................................................ 7 
Table 3-2 
VX17-445-103: TEZ/IVA Run-in Period, Treatment Period, and Safety 
Follow-up Visit ....................................................................................................... 8 
Table 9-1 
Treatment Period Arms and Planned Dosages...................................................... 23 
Table 9-2 
Prohibited Medications ......................................................................................... 29 
Table 10-1 
Study Drug: Strength/Dosing Form/Route ........................................................... 35 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 44 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 47 
Table 13-1 
Grading of AE Severity ........................................................................................ 57 
Table 13-2 
Classifications for AE Causality ........................................................................... 57 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 58 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 58 
List of Figures 
Figure 9-1 
Schematic of the Study Design ............................................................................. 23 
 


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List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
CBC 
complete blood count 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
Cl− 
chloride ion 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
 
 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ETT 
Early Termination of Treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F/F 
homozygous for F508del 
F/MF 
heterozygous for F508del and a minimal CFTR function mutation  
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
 
  
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
 
 
G6PD 
Glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 


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Abbreviation 
Term 
 
 
 
 
IPD 
important protocol deviation 
IRB 
institutional review board 
IV 
intravenous 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LLN 
lower limit of normal 
LUM 
lumacaftor 
M1-TEZ 
metabolite of TEZ 
MAA 
Marketing Authorization Application 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal CFTR function mutation  
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
number of subjects 
OATP1B1 
organic anion transporting polypeptide 1B1 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PEx 
pulmonary exacerbation(s) 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 
qd 
once daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
 
 
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 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 


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Abbreviation 
Term 
 
 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious morbidities and 
frequent premature mortality. At present, there is no cure. CF affects approximately 
70,000 individuals worldwide1 (approximately 30,000 in the US1,2 and 39,000 in the EU3). Based 
on its prevalence, CF qualifies as an orphan disease.4, 5  
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene. The CFTR protein is an epithelial chloride channel that aids in regulating salt and 
water absorption and secretion and pH balance in sweat glands and multiple organs, including 
the lungs, pancreas, and other gastrointestinal organs. Despite progress in the treatment of CF 
with antibiotics and mucolytics, the predicted median age of survival for a person with CF is 
approximately 40 years.2,6 Progressive loss of lung function is the leading cause of mortality.7 
More effective treatments are needed for CF. 
The most common disease-causing CFTR mutation, F508del, accounts for 70% of the identified 
alleles in people with CF8, and approximately 40% of people with CF are homozygous for 
F508del (F/F).2, 3, 8 
Based on the understanding of the molecular defects caused by CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. Correctors facilitate 
the cellular processing and trafficking to increase the quantity of functional CFTR at the cell 
surface. Potentiators increase the channel open probability of the CFTR protein delivered to the 
cell surface to enhance ion transport. Depending on the amount of residual CFTR channel 
activity in the membrane, and the pathophysiology of that activity (reflecting the CFTR genotype 
of the patient and possibly other factors), both approaches may be required. 
The therapeutic activity of CFTR correctors and potentiators has been established with products 
that were developed by Vertex and approved for the treatment of CF: ivacaftor (IVA) 
monotherapy (Kalydeco®), and lumacaftor (LUM) in combination with IVA (Orkambi®). 
Kalydeco and Orkambi are approved to treat CF in patients with specific CFTR genotypes. A 
second corrector/potentiator combination, tezacaftor (TEZ)/IVA (Symdeko®) is approved in 
certain countries.  
VX-445 is a next-generation CFTR corrector being developed for administration in triple 
combination (TC) with TEZ/IVA for the treatment of CF. 
5.2 
Rationale for the Present Study 
This study will evaluate the efficacy and safety of VX-445 in TC with TEZ/IVA in subjects with 
CF who have an F/F genotype. These patients have continuing unmet need despite currently 
available CFTR modulators. The potential for benefit in these patients is supported by in vitro 
data and clinical data in F/F subjects; in addition, the TC of VX-445/TEZ/IVA is generally safe 
and well tolerated (refer to VX-445 Investigator’s Brochure). 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of VX-445 in TC with TEZ and IVA in subjects with CF who are 
homozygous for the F508del mutation (F/F) 
6.2 
Secondary Objectives 
• To evaluate the safety of VX-445 in TC with TEZ and IVA 
• To evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA 
• To evaluate the pharmacokinetics (PK) of VX-445, TEZ, and IVA when administered in TC 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change in ppFEV1 from baseline at Week 4 
7.2 
Secondary Endpoints 
7.2.1 
Key Secondary Endpoints 
• Absolute change in sweat chloride (SwCl) from baseline at Week 4 
• Absolute change in CFQ-R respiratory domain score from baseline at Week 4 
7.2.2 
Other Secondary Endpoints 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
ECGs, vital signs, and pulse oximetry 
• PK parameters of VX-445, TEZ, M1-TEZ, and IVA 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects receive study drug on Day -28. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 


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3. Age 12 years or older, on the date of informed consent. 
4. Confirmed diagnosis of CF as determined by the investigator. 
5. Subject has the F/F genotype. Note: If the screening CFTR genotype result is not received 
before Day -28, a previous CFTR genotype laboratory report may be used to establish 
eligibility. Subjects who have been enrolled and whose screening genotype is not confirmed 
to be F/F must be discontinued from the study (Section 9.9). 
6. Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for 
age, sex, and height (equations of the Global Lung Function Initiative [GLI])9 at the 
Screening Visit. Spirometry measurements must meet American Thoracic Society/European 
Respiratory Society criteria10 for acceptability and repeatability. 
7. Stable CF disease as judged by the investigator. 
8. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
• Clinically significant cirrhosis with or without portal hypertension. 
• Solid organ or hematological transplantation. 
• Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, 
and opiates, as deemed by the investigator. 
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (all 3 with no recurrence for the last 5 years). 
2. Any of the following abnormal laboratory values at screening: 
• Hemoglobin <10 g/dL 
• Total bilirubin ≥2 × ULN 
• Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 
(calculated by the Modification of Diet in Renal Disease Study Equation)11, 12 for subjects 
≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation)13 for subjects aged 12 to 17 years (inclusive) 
3. An acute upper or lower respiratory infection, pulmonary exacerbation(s) (PEx), or changes 
in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first 
dose of TEZ/IVA in the Run-in Period (Day -28).  
4. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus). For subjects who have had a history of a positive culture, the 


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investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms:  
• The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent. 
• The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent one within the 6 months before the 
date of informed consent. 
5. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
TEZ/IVA in the Run-in Period (Day -28). 
6. Ongoing or prior participation in a study of an investigational treatment other than a Vertex 
CFTR modulator within 28 days or 5 terminal half-lives (whichever is longer) before 
screening. The duration of the elapsed time may be longer if required by local regulations. 
7. Use of prohibited medications as defined in Table 9-2, within the specified window before 
the first dose of TEZ/IVA in the Run-in Period (Day -28). 
8. Pregnant or nursing females. Females of childbearing potential must have a negative 
pregnancy test at Screening/Day -56 (serum test) and TEZ/IVA Run-in Period/Day -28 (urine 
test). 
9. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be enrolled in the study provided that 
• the adult lives independently of and does not reside with the study staff member, and 
• the adult participates in the study at a site other than the site at which the family member 
is employed. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter study. 
A schematic of the study design is shown in Figure 9-1. 




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9.1.1.1 
Repetition of Screening Assessment(s) 
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may be rescreened once. If a subject is rescreened, all screening assessments will be 
repeated, except for:  
• CFTR genotyping 
• Follicle-stimulating hormone (FSH) level (if serum FSH level was in the postmenopausal 
range as determined by the laboratory performing the test during prior screening) 
• G6PD activity test  
• Ophthalmologic examination (if performed within 3 months of the date of informed consent, 
for subjects <18 years of age) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Scheduling of ophthalmologic examination (for subjects <18 years of age on the date of 
informed consent, Section 11.7.6) 
9.1.2 
Tezacaftor/Ivacaftor Run-in Period 
The TEZ/IVA Run-in Period has a 4-week duration and is designed to establish a reliable 
on-treatment (TEZ/IVA) baseline for the Treatment Period. The first dose of open-label 
TEZ/IVA will be administered at the Day -28 Visit. The last dose of open-label TEZ/IVA will be 
administered in the evening on Day -1 (1 day before the Day 1 Visit).  
On Day -14, spirometry and SwCl will be assessed. The Day -14 spirometry assessment will be 
used for stratification of randomization (Section 9.2). 
Subjects who prematurely discontinue study drug treatment during the Run-in Period will not be 
randomized or participate in the Treatment Period (Section 9.1.5.1). 
9.1.3 
Treatment Period 
The Treatment Period will be randomized, double-blind, and active-controlled. It will last 
approximately 4 weeks (Day 1 to Week 4). Study drug administration details are provided in 
Section 9.6. 


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Randomization will occur before the first dose of study drug during the Treatment Period and 
may occur on either Day -1 or Day 1. Randomization and stratification details are provided in 
Section 9.2. 
To enter the Treatment Period, subjects must have stable CF disease (as judged by the 
investigator) and have remained on a stable CF treatment regimen during the TEZ/IVA Run-in 
Period. Female subjects of childbearing potential also must have a negative pregnancy test at 
Day 1 before receiving randomized study drug. If these conditions are not met (for example, if 
the subject has an acute upper or lower respiratory infection, PEx, or changes in therapy 
[including antibiotics] for sinopulmonary disease within 28 days before the Day 1 Visit [first 
dose of study drug in the Treatment Period]), the subject is considered a run-in failure and cannot 
enter the Treatment Period or rescreen.  
Subjects who prematurely discontinue study drug treatment during the Treatment Period will 
remain in the study from the time of discontinuation of study drug treatment through the last 
scheduled study visit and complete the assessments for all study visits, as described in 
Section 9.1.5.2. 
9.1.4 
Follow-up 
The Safety Follow-up Visit will occur approximately 28 days after the last dose of study drug for 
subjects who complete study drug dosing and for subjects who prematurely discontinue study 
drug dosing, as described in Section 9.1.5. 
An open-label study will be available for subjects who complete the Week 4 Visit and are 
eligible. The Safety Follow-up Visit is not required for subjects who complete the Week 4 Visit 
and enroll in an open-label study within 28 days after the last dose of study drug. 
9.1.5 
Early Termination of Treatment 
If a subject prematurely discontinues study drug treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the decision to discontinue treatment. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety 
Follow-up Visit, approximately 28 days after their last dose of study drug. The assessments 
performed at the Safety Follow-up Visit are listed in Table 3-2. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent. 
9.1.5.1 
Discontinuation During the Run-in Period 
Subjects who prematurely discontinue study drug treatment during the Run-in Period will not be 
randomized or participate in the Treatment Period. These subjects will complete an ETT Visit 
and Safety Follow-up Visit (as applicable; see Section 9.1.5). The Safety Follow-up Visit will be 
their last visit in the study. 


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9.1.5.2 
Discontinuation During the Treatment Period 
Subjects who prematurely discontinue study drug treatment during the Treatment Period will 
continue to complete all scheduled study visits for assessments following completion of the ETT 
Visit, as detailed in Table 3-2. Data regarding concomitant antibiotic therapy for sinopulmonary 
signs/symptoms will also continue to be collected for these subjects. These subjects will 
complete an ETT Visit and Safety Follow-up Visit (as applicable; see Section 9.1.5). The Safety 
Follow-up Visit will be their last visit in the study. 
9.1.6 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.7 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as one of the following: 
• For subjects who complete the Treatment Period and enter an open-label study within 
28 days of the Week 4 Visit: the Week 4 Visit 
• For subjects who complete the Treatment Period and do not enter an open-label study within 
28 days of the Week 4 Visit: the Safety Follow-up Visit 
• For subjects who prematurely discontinue study drug treatment during the Treatment Period 
but do not withdraw consent (and assent, as applicable): The ETT or Safety Follow-up Visit 
(if required) 
• For subjects who prematurely discontinue study drug treatment during the TEZ/IVA Run-in 
Period but do not withdraw consent (and assent, as applicable): the ETT or Safety Follow-up 
Visit (if required) 
• For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9) 
If subjects are lost to follow-up (Section 9.1.6), the date of completion of study participation will 
be defined as the date of the last contact.  
The end of study is defined in Section 13.2.8. 
9.1.8 
Independent Data Monitoring Committee 
This study will be monitored by an independent data monitoring committee (IDMC), which will 
conduct periodic reviews of safety data from the study (Section 12.3.6.2). Procedural details of 
the IDMC structure and function, frequency of meetings, and data planned for review will be 
included in the IDMC charter. The IDMC charter will be finalized before the first subject is 
screened. 


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9.2 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized (1:1) to the TC VX-445/TEZ/IVA arm or to the TEZ/IVA arm. 
Randomization will be stratified by ppFEV1 determined during the TEZ/IVA Run-in Period 
(Day -14 assessment; <70 versus ≥70) and age at the Screening Visit (<18 versus ≥18 years of 
age). If the Day -14 ppFEV1 value is not valid or not available, the most recent available ppFEV1 
value will be used for stratification. 
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code list will be produced by Vertex Biometrics or a qualified randomization 
vendor. 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
This Phase 3 study will assess the efficacy, PD, safety, and PK of VX-445/TEZ/IVA TC therapy 
in subjects with CF who have an F/F genotype. 
A randomized, double-blind, controlled study design was selected to ascertain the effects of 
VX-445/TEZ/IVA while avoiding observer bias. TEZ/IVA is considered an appropriate active 
control since the efficacy and safety of TEZ/IVA in F/F subjects have been demonstrated in 
Study VX14-661-106 (Study 661-106).14 Study 661-106 met its primary endpoint of absolute 
change in ppFEV1 through Week 24, with a 4.0 percentage point treatment difference between 
TEZ/IVA and placebo. In Study 661-106, TEZ/IVA was well tolerated and no safety concerns 
attributable to TEZ/IVA were identified. 
A 4-week TEZ/IVA Run-in Period was incorporated into this study to establish a reliable 
on-treatment (TEZ/IVA) baseline for comparison during the Treatment Period. 
The study will have a 4-week treatment duration because previous studies of CFTR modulators 
(IVA, LUM/IVA, and TEZ/IVA) have demonstrated that efficacy related to lung function 
(ppFEV1) can be reliably established using an endpoint at Week 4. In these studies, rapid 
improvements in ppFEV1 are observed by Day 15, with a separation between the active 
treatment and placebo groups that is sustained through 24 weeks of treatment. These studies 
were conducted in patients with different genotypes, baseline ppFEV1, and age groups, using 
CFTR modulators that had different magnitudes of response. 
The extent of response to CFTR modulator treatment may depend on the subject’s ppFEV1 value 
(an index of disease severity) before the start of TC study drug dosing. Some subjects in this 
study may be receiving treatment with LUM/IVA or TEZ/IVA at Screening, while some subjects 
may not be receiving treatment with CFTR modulators. Therefore, randomization will be 
stratified by ppFEV1 value determined during the TEZ/IVA Run-in Period after at least 13 days 
of TEZ/IVA (Day -14 assessment). Randomization will also be stratified by age at screening. 
This will ensure a balanced evaluation of adult and pediatric subjects.  
9.3.2 
Study Drug Dose 
VX-445 Dosage 
A VX-445 dose of 200 mg qd was selected for the current study based on an assessment of the 
benefit-risk profile from the ongoing Phase 2 Study VX16-445-001 (Study 445-001) Parts D and 
E. In Study 445-001 Part D, a range of VX-445 doses (50 mg qd, 100 mg qd, and 200 mg qd) in 






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Table 9-2 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of Restriction 
End of 
Restriction 
longer) before 
screening  
participation  
Vertex CFTR 
modulators 
(investigational or 
approved), except 
for study drugs 
None allowed from 
the first dose of 
study drug on 
Day -28 
None allowed 
until after the last 
dose of study 
drug 
 
These agents may confound the results of this 
study. 
CYP: cytochrome P450; IVA: ivacaftor; OATP1B1: organic anion transporting polypeptide 1B1; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected from each subject’s source 
documentation for medications taken within 56 days before the Screening Visit through 
completion of study participation, as defined in Section 9.1.7. 
For subjects who are screened but are not subsequently randomized into the Treatment Period, 
details of prior medication will be documented only in the subjects’ source documents. 
• Subjects should remain on a stable treatment regimen for their CF from 28 days before the 
TEZ/IVA Run-in/Day -28 through completion of study participation. Stable treatment 
regimen is defined as the current treatment regimen for CF that subjects have been following 
for at least 28 days before the TEZ/IVA Run-in/Day -28. Subjects may remain on Vertex 
CFTR modulators (investigational or approved) during the Screening Period and may 
transition directly to the TEZ/IVA Run-in/Day -28 without a washout (Table 9-2). Subjects 
should not initiate long-term treatment with new medication from 28 days before the 
TEZ/IVA Run-in/Day -28 through completion of study participation. Guidelines for stable 
treatment regimens for CF are as follows:  
o Subjects who are taking inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who cycle onto and off of an inhaled antibiotic should continue on their prior 
schedule. The timing of the first dose of study drug on the Day 1 Visit should be 
synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in 
the cycle onto the inhaled antibiotic. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. The timing of the first dose of study drug on 
the Day 1 Visit should be synchronized as closely as possible (e.g., not more than 
± 3 days) to the first day in the cycle onto 1 of the inhaled antibiotics. 
• Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically, or 
up to 60 mg daily for up to 5 days. 


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• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.6.1. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally. All subjects will receive the same number of tablets each 
day to maintain the blind. Additional information is provided in the Pharmacy Manual. 
Study drug will be administered with a fat-containing meal or snack, such as a standard "CF" 
meal or snack or a standard meal. 
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
2. Study drug will be administered as fixed-dose combination (FDC) tablet(s) (e.g., 2 TC or 
matching placebo tablets; 1 TEZ/IVA or matching placebo tablet) in the morning and as 
1 IVA tablet in the evening. For each subject, doses of study drugs will be taken at 
approximately the same time (± 2 hours) each day. 
3. The date, amount taken, and time of study drug administration, including whether food was 
taken with each dose, will be recorded for the 2 doses before PK sample collection and the 
dose received on the morning of PK sample collection (if applicable). 
4. On days of scheduled visits, the morning dose of study drug (TC, TEZ/IVA, or placebo) 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 TC, TEZ/IVA, or placebo. 
5. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
• If the dose in the clinic will be within 6 hours of the subject’s scheduled morning dose, 
the subject should withhold their morning dose of TC, TEZ/IVA, or placebo and the 
morning dose will be administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
dose, the subject should take the morning dose of TC, TEZ/IVA, or placebo at home.  
• At the Day 15 Visit, the morning dose of TC, TEZ/IVA, or placebo must be administered 
in the clinic to enable post-dose ECG assessments relative to the dose. 
6. Subjects will be instructed to bring all used and unused materials associated with the study 
drug to the site; study drug will be dispensed at each visit, as appropriate.  
9.6.2 
Missed Doses 
9.6.2.1 
Morning Dose of Study Drug 
If a subject misses the morning dose of study drug (TC, TEZ/IVA, or placebo) and recalls within 
6 hours, the subject should take his/her dose with food. If more than 6 hours but fewer than 
12 hours have elapsed after his/her usual dosing time, the subject should take the morning dose 
of TC, TEZ/IVA, or placebo but skip the evening dose of study drug (IVA). If more than 
12 hours have elapsed after his/her usual dosing time, the subject should skip the morning dose 
of TC, TEZ/IVA, or placebo and take the evening dose of IVA.  


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9.6.2.2 
Evening Dose of Study Drug 
If a subject misses the evening dose of IVA and recalls 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.  
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. Treatment may be interrupted as outlined in 
Section 9.8. If any unacceptable toxicity arises, individual subjects will discontinue dosing 
(Section 9.1.5). 
9.8 
Study Drug Interruption and Stopping Rules 
The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or AST >3 × ULN and total 
bilirubin >2 × ULN that are derived from centrally submitted samples. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 
the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Study drug administration must be discontinued if the following criterion is met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, study drug administration may be resumed once 


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transaminases return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified prior to resumption of study 
drug. Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology.  
9.8.2 
Rash 
Individuals who develop generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher, or a rash that is 
considered a serious adverse event. The investigator will notify the medical monitor of any rash 
that results in interruption of study drug, is Grade 3 or higher (Section 13.1.1.4), or is a serious 
adverse event (SAE). Investigators should consider additional evaluation including laboratory 
testing (e.g., complete blood count [CBC] with differential, LFTs), photographs of the rash, and 
dermatology consultation. The investigator may consider resumption of study drug if considered 
clinically appropriate.  
9.9 
Removal of Subjects 
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided that the subject has not withdrawn consent (and assent, as applicable). 
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Has a screening CFTR genotype that does not confirm study eligibility if a previous CFTR 
genotype laboratory report was used to establish eligibility. These subjects must be 
discontinued from the study (Section 8.1) 
• Meets any of the stopping (discontinuation) criteria (Section 9.8) 
• Becomes pregnant (Section 11.7.7.2) 
Subjects who discontinue study drug treatment should return for study assessments, as noted in 
Section 9.1.5.2. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for an ETT Visit and Safety 
Follow-up Visit, if applicable (see Section 9.1.5), and follow up with the subject regarding any 
unresolved AEs. 
If the subject withdraws consent or assent for the study, no further assessments will be 
performed. Vertex may retain and continue using the study data and samples after the study is 
over, and may use the samples and information in the development of the study compound, and 
for other drugs and diagnostics, in publications and presentations, and for education purposes. If 


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the subject withdraws from the study, the study data and samples collected will remain part of 
the study. A subject will not be able to request the withdrawal of his/her information from the 
study data. A subject may request destruction of the samples collected from him/her during the 
study as long as those samples can be identified as his/her samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn before the first dose of study drug on Day 1 of the 
Treatment Period may be replaced. 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
During the TEZ/IVA Run-in Period, study drug refers to TEZ/IVA and IVA.  
During the Treatment Period, study drug refers to VX-445/TEZ/IVA and matching placebo, 
TEZ/IVA and matching placebo, and IVA.  
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
VX-445/TEZ/IVA will be supplied as FDC film-coated tablets containing 100 mg VX-445, 
50 mg TEZ, and 75 mg IVA. Matching VX-445/TEZ/IVA placebo tablets will be of similar size 
and appearance and contain 0 mg VX-445, 0 mg TEZ, and 0 mg IVA (Table 10-1). 
TEZ/IVA will be supplied as FDC film-coated tablets containing 100 mg TEZ and 150 mg IVA. 
A matching TEZ/IVA placebo tablet will be of similar size and appearance and contain 0 mg 
TEZ and 0 mg IVA (Table 10-1). 
IVA will be supplied as a tablet containing 150 mg IVA (Table 10-1). 
Blister cards must be stored under conditions noted in the Pharmacy Manual. 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 via the drug accountability forms as instructed by Vertex. 


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Table 10-1 
Study Drug: Strength/Dosing Form/Route 
Drug Name, Dosing Form, Route 
Strength 
VX-445/TEZ/IVA, FDC tablet, oral 
 
VX-445 
100 mg 
TEZ 
50 mg 
IVA 
75 mg 
VX-445/TEZ/IVA-matching placebo, tablet, oral 
0 mg 
TEZ/IVA, FDC tablet, oral 
 
TEZ 
100 mg 
IVA 
150 mg 
TEZ/IVA-matching placebo, tablet, oral 
0 mg 
IVA, tablet, oral 
150 mg 
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; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
10.6 
Compliance 
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study. 
10.7 
Blinding and Unblinding 
This will be a double-blind study. 


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10.7.1 
Blinding 
All subjects (and their parents/caregivers/companions), site personnel (including the investigator, 
the site monitor, and the study team), and members of the Vertex study team will be blinded to 
the treatment codes. 
Individuals who may be unblinded include only the following: 
• Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the subject 
and her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
• Vendor preparing the final (production) randomization list 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 
• IDMC 
• Vendor preparing the unblinded analysis of safety data for review by the IDMC  
• Bioanalytical contract research organization (CRO) analyzing PK samples and the Vertex 
Bioanalytical personnel who is not a member of the study team but reviews raw data from the 
Bioanalytical CRO. The Vertex Bioanalytical study team member will continue to be 
blinded. 
Access to Spirometry and SwCl Results: 
During the conduct of the study, the Vertex study team will not have access to the spirometry or 
SwCl results after the first dose of study drug in the Treatment Period.  
Shortly before any planned efficacy analysis is conducted, the spirometry and SwCl data will be 
reviewed for data cleaning purposes by a biostatistician who does not have access to the 
treatment codes. 
Individual SwCl test results will not be disclosed to the study sites with the exception of the 
screening values. Subjects and their parents/caregivers/companions should not be informed of 
study-related spirometry results until Vertex has determined that the study has completed 
(i.e., clinical study report [CSR] finalization), regardless of whether the subject has prematurely 
discontinued treatment.  
10.7.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 


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necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2. 
Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 and Table 3-2.  
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, medical and surgical histories, and any allergies. 
Height and weight will be measured with shoes off. Following screening, height will be collected 
only for subjects ≤21 years of age on the date of informed consent. 








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11.6 
Efficacy 
11.6.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines10 and according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
pre-bronchodilator. During the Treatment Period, spirometry assessments must be performed 
before study drug dosing (Section 9.6.1) at approximately the same time at each visit. In the 
event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
• If a subject’s Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent visit, 
the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
• If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments in Table 3-2) should be performed 
post-bronchodilator. 


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• Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. The investigator’s 
assessment of the spirometry results will be used for the screening assessment and determination 
of eligibility. 
See Section 10.7.1 for information about access to spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of GLI.9 
• FEV1 (L) 
11.6.2 
Cystic Fibrosis Questionnaire-Revised 
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF).  
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.19, 20 If there is no validated translation available in the subject’s native language, 
the subject will not complete the questionnaire. Copies of the CFQ-R used will be provided in 
the Study Reference Manual. Validated translations of the CFQ-R, if available, will be provided 
for participating centers in non-English-speaking countries.21, 22  
The CFQ-R will be completed before any other assessments are performed at that visit.  
Subjects who are 12 and 13 years of age at the date of informed consent will complete the 
CFQ-R Child version themselves, and their parents/caregivers will complete the CFQ-R Parent 
version, at all visits, regardless of whether the subject subsequently turns 14 years of age during 
the study. Subjects 14 years of age and older at the date of informed consent will complete the 
Adolescent/Adult version of the questionnaire themselves at all visits. 
11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, and clinical evaluation of 
vital signs, ECGs, PEs, and pulse oximetry. 
For subjects <18 years of age on the date of informed consent, ophthalmological examinations 
will also be performed at screening (if not done within preceding 3 months). 
11.7.1 
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 case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 


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11.7.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests. On Day -28 and Day 1, blood samples will be collected before the first dose of 
the study drug in the study period. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs. 
The safety laboratory test panels are shown in Table 11-1. 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total and direct bilirubin 
Alkaline phosphatase 
Aspartate transaminase  
Alanine transaminase  
Amylase 
Lipase 
Gamma-glutamyl transferase 
Protein 
Albumin 
Creatine kinase 
Total cholesterol 
Lactate dehydrogenase  
Hemoglobin 
Erythrocytes 
Mean corpuscular volume 
Platelets 
Reticulocytes 
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation Studies 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
 
Leukocyte esterase 
Nitrite 
Urobilinogen  
Urine protein  
pH 
Urine blood 
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
Note: Haptoglobin may be analyzed if judged to be clinically appropriate by the investigator. 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted.  
Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: Any 
female subject who does not meet the criteria for non-childbearing potential is considered to be 
of childbearing potential and must have a serum pregnancy test at screening. A definition of 
non-childbearing potential is provided in Section 11.7.7.1. Serum pregnancy tests will be 
performed at the study site and analyzed at the central laboratory. Urine pregnancy tests will be 
performed and analyzed at the site. The urine pregnancy test on Day -28 and Day 1 must be 
negative before the first dose of study drug in the study period. Additional pregnancy tests may 
be required according to local regulations and/or requirements. 
FSH (Screening Period Only): Blood samples for FSH will be measured for any suspected 
postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. Serum 
FSH levels must be in the postmenopausal range as determined by the laboratory performing the 
test.  
CFTR Genotype (Screening Period Only): CFTR genotyping will be performed for all subjects. 
If the screening CFTR genotype result is not received before Day -28, a previous CFTR genotype 
laboratory report may be used to establish eligibility. Subjects who have been enrolled and 
whose screening genotype is not confirmed to be F/F must be discontinued from the study 
(Section 9.9). 


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G6PD Activity Test (Screening Period Only): A blood sample will be collected for a quantitative 
G6PD activity assay, which will be performed in an established laboratory that runs the assay 
routinely. The use of a local laboratory that routinely runs the assay is permissible following 
approval by the medical monitor.  
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For the purposes of study conduct and unless noted otherwise (e.g., G6PD activity test), only 
laboratory tests done in the central laboratory may be used. Local laboratories may be used at the 
discretion of the local investigator for management of urgent medical issues. If a local laboratory 
test value is found to be abnormal and clinically significant, it will be verified by the central 
laboratory as soon as possible after the investigator becomes aware of the abnormal result. If it is 
not possible to send a timely specimen to the central laboratory (e.g., the subject was hospitalized 
elsewhere), the investigator may base the assessment of an AE on the local laboratory value. 
11.7.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits (see Table 3-1 and Table 3-2). At other visits, symptom-directed PEs and 
symptom-directed vital sign assessments will occur at any time if deemed necessary by the 
investigator or healthcare provider. 
A complete PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, 
nose, and throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After screening, any clinically significant abnormal findings in PEs 
will be reported as AEs. 
The abbreviated PE will include an assessment of the following body systems: EENT, 
cardiovascular system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. These will be assessed before dosing and following at least a 5-minute rest. 
11.7.4 
Pulse Oximetry 
Pulse oximetry 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 assessed following at least a 5-minute rest and before study drug dosing. At visits when 
study drug is taken at the site, pulse oximetry will be collected before study drug dosing 
(Section 9.6.1).  
11.7.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1 and Table 3-2). Additional standard 12-lead ECGs will be 
performed at any other time if clinically indicated. Subjects will be instructed to rest for at least 
5 minutes before having an ECG performed. 
The ECG traces will be manually read at the study site. A printout of the ECG traces will be 
made for safety review by the investigator and maintained with source documentation. Clinically 


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significant ECG abnormalities occurring during the study through completion of study 
participation will be recorded as AEs. 
To ensure the safety of the subjects, a qualified individual at the study site will make 
comparisons to baseline measurements. If the QTcF is increased by >60 msec from the baseline 
or an absolute QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be 
performed approximately 2 to 4 minutes apart to confirm the original measurement. If either of 
the QTcF values from these repeated ECGs remains above the threshold value (>60 msec from 
baseline or ≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement. Further 
details pertaining to ECGs will be provided to sites in the ECG Manual. 
11.7.6 
Ophthalmologic Examination 
Ophthalmologic examinations will be conducted at screening only for subjects who are 
<18 years of age on the date of informed consent. The examination does not need to be 
completed if there is documentation of bilateral lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include  
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
The screening examination does not need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of informed consent.  
Any clinically significant abnormal findings will be reported as AEs. 
For subjects who subsequently enroll in an open-label study, follow-up ophthalmologic 
examinations will be performed as per that study’s protocol. 
11.7.7 
Contraception and Pregnancy 
The effects of VX-445, TEZ, and IVA on conception, pregnancy, and lactation in humans are not 
known. VX-445, TEZ, and IVA did not show genotoxic potential in a standard battery of in vitro 
(Ames test, chromosomal aberration, or micronucleus in cultured mammalian cells) and in vivo 
(rodent micronucleus) studies. Reproductive toxicology studies of VX-445, TEZ, and IVA have 
not shown teratogenicity in rats and rabbits.  
11.7.7.1 
Contraception 
Contraception requirement for a couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the Screening Visit through 90 days after the last dose of study drug. 
• If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 


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• If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations) will be considered to be of 
childbearing potential. 
• Same-sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of consent (or 
assent, when applicable), approximately 28 days before the first dose of study drug on Day -28 
(unless otherwise noted), and until 90 days following the last dose of study drug. Additional 
contraception requirements may need to be followed according to local regulations and/or 
requirements. Acceptable methods of contraception are listed in Table 11-2.  
Table 11-2 
Acceptable Methods of Contraception 
 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed 
at least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
Yes 
Yes 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 
60 days before the first dose of study drug. 
Yes 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing.  
Additional notes: 
• Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
• Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug, with 
the exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 


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11.7.7.2 
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 female subject becomes pregnant during study participation, study drug will be permanently 
discontinued immediately. The investigator will notify the medical monitor and Vertex GPS 
within 24 hours of the site’s knowledge of the subject’s (or partner’s) pregnancy using the 
Pregnancy Information Collection Form. Male subjects with female partners who become 
pregnant during the study must use a male condom to avoid exposure of a potential embryo or 
fetus to study drug via the seminal fluid. 
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 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP), and clinical pharmacologic analysis 
details will be provided in the clinical pharmacology analysis plan (CPAP), both of which will be 
finalized before the clinical data lock for the study and treatment unblinding. 
12.1 
Sample Size and Power 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline at Week 4. The 
primary null hypothesis to be tested is that the mean absolute change in ppFEV1 from baseline at 
Week 4 is the same for the TC and TEZ/IVA treatment groups. The null hypothesis will be tested 
at a 2-sided significance level of 0.05. 
Assuming a within-group SD of 7 percentage points and a 5% dropout rate at Week 4, a sample 
size of 50 subjects in each treatment group for a total of 100 subjects will have approximately 
93% power to detect a difference of 5.0 percentage points for the mean absolute change in 
ppFEV1 from baseline at Week 4 between the 2 treatment groups, based on a 2-sided 2-sample 
t-test at a significance level of 0.05 
 
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. Additional analysis sets related to the Run-in Period will be defined in the SAP, as 
appropriate. 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified.  
The FAS will include all randomized subjects who carry the intended CFTR allele mutation and 
receive at least 1 dose of study drug in the Treatment Period. The FAS will be used to summarize 
subject demographics and baseline characteristics, and for all efficacy analyses in which subjects 
will be analyzed according to their randomized treatment group, unless otherwise specified. 


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The Safety Set will include all subjects who received at least 1 dose of study drug in the 
Treatment Period. The Safety Set will be used for all safety analyses in which subjects will be 
analyzed according to the treatment they received, unless otherwise specified. 
12.3 
Statistical Analysis 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). The precision of the measurement for each continuous variable will be specified in the 
SAP. Unless otherwise specified, min and max values will be reported with the same precision as 
the units of the raw data. The mean, median, and SD will be reported to 1 additional decimal 
place. Any values that require a transformation to standard units (metric or SI) will be converted 
with the appropriate precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
The baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period (i.e., the Day 1 Visit). For ECG, baseline will be defined as the most recent 
pretreatment measurement (or the average of triplicate measurements, if the most recent 
pretreatment measurement is obtained in triplicate) before the first dose of study drug in the 
Treatment Period (i.e., the Day 1 Visit). 
Absolute change from baseline will be calculated as post-baseline value – baseline value. 
The Treatment-emergent (TE) Period for the Run-in Period will be from the first dose date 
of study drug in the Run-in Period to (1) the first dose date of study drug in the Treatment Period 
for subjects who complete the Run-in Period and continue to the Treatment Period, or (2) 
28 days after the last dose date of study drug in the Run-in Period or to the completion of study 
participation date, whichever occurs first, for subjects who do not continue to the Treatment 
Period (e.g., subjects who do not meet the conditions to enter the Treatment Period). 
The TE Period for the Treatment Period will include the time from the first dose date of study 
drug in the Treatment Period (TC or placebo + TEZ/IVA) to 28 days after the last dose of the 
study drug or to the completion of study participation date (as defined in Section 9.1.7), 
whichever occurs first. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in the FAS, included in the Safety Set, completed Treatment Period, completed study, 
prematurely discontinued treatment or study with a breakdown of the reasons for 
discontinuation, and entered an open-label study) will be summarized overall and by treatment 
group. 
An additional subject disposition summary related to the TEZ/IVA Run-in Period will be defined 
in the SAP, as appropriate. 


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12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, medical history, and baseline characteristics will be summarized using descriptive 
summary statistics. 
The following demographics and baseline characteristics will be summarized overall and by 
treatment group for the FAS, and will include (but are not limited to): sex, race, baseline age, 
baseline weight, baseline height, baseline BMI, baseline ppFEV1, and baseline SwCl. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT) for the FAS.  
No statistical tests will be performed to evaluate baseline imbalance between treatment groups. 
12.3.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug-Dictionary and 
categorized as follows: 
• Prior medication: any medication that was administered during the 56 days before the first 
dose of study drug in the Treatment Period but not in the Run-in Period. For subjects who 
discontinue during the Run-in Period and whose first dose of study drug in the Treatment 
Period is not available, prior medication will be any medication that was administered during 
the 56 days before the last dose of study drug in the Run-in Period but before the first dose in 
the Run-in Period 
• Concomitant medication during the Run-in Period: medication continued or newly 
received during the TE Period for the Run-in Period  
• Concomitant medication during the Treatment Period: medication continued or newly 
received during the TE Period for the Treatment Period  
• Post-treatment medication: medication continued or newly received after: 
o the TE Period for the Run-in Period if the subject did not receive study drug in the 
Treatment Period  
o the TE Period for the Treatment Period for subjects who received study drug in the 
Treatment Period 
A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and if it cannot be determined whether it was taken before the first dose of 
study drug, concomitantly during the TE Period, or after the TE Period, it will be considered in 
all 3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name, overall, and by treatment group based on the FAS. Post-treatment medications will be 
provided separately in an individual subject data listing. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure and compliance will be summarized for the Treatment Period only. 


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Study drug exposure will be summarized overall and by treatment group, based on the Safety Set 
in terms of the duration of treatment a subject received (in days), defined as the last day – the 
first day of study drug plus 1, regardless of study drug interruption. 
Study drug compliance will be summarized overall and by treatment group based on the FAS, 
and will be calculated as: 100 × [1- (total number of days of study drug interruption) / (duration 
of study drug exposure in days)]. A study drug interruption on a given day is defined as an 
interruption of any study drug on that day. 
In addition, percentage of tablets taken will also be summarized overall and by treatment group 
based on the FAS, and will be calculated as 100 × [(total number of tablets dispensed for the 
Treatment Period) – (total number of tablets returned for the Treatment Period)] / (total number 
of tablets planned to be taken per day × duration of study drug exposure in days for the 
Treatment Period). 
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. The rules for identifying an IPD will be described in the SAP. 
All IPDs will be provided in an individual subject data listing and summarized, as appropriate. 
12.3.3 
Efficacy and Pharmacodynamic Analyses 
The primary objective of the study is the evaluation of the efficacy of VX-445 in TC with TEZ 
and IVA. The analysis in this section will be based on the FAS, unless otherwise specified. 
12.3.3.1 
Analysis of Primary Variable 
The primary efficacy variable is the absolute change in ppFEV1 from baseline at Week 4. The 
analysis of this variable will be performed using a mixed-effects model for repeated measures 
(MMRM) with absolute change from baseline in ppFEV1 at Day 15 and Week 4 as the dependent 
variable. The model will include treatment group, visit, and treatment-by-visit interaction as 
fixed effects, with continuous baseline ppFEV1 and age at screening (<18 versus ≥18 years of 
age) as covariates. The model will be estimated using restricted maximum likelihood. 
Denominator degrees of freedom for the F test for fixed effects will be estimated using the 
Kenward-Roger approximation. An unstructured covariance structure will be used to model the 
within-subject errors. If the model estimation does not converge, a compound symmetry 
covariance structure will be used instead. Conditional on the observed data and covariates, 
missing data will be assumed to be missing at random; consequently, no imputation of missing 
data will be performed. 
The primary result obtained from the model will be the estimated treatment difference at Week 4. 
The adjusted mean with a 2-sided 95% CI and a 2-sided P value will be provided. Furthermore, 
the treatment difference at each post-baseline visit will also be provided, obtained from the 
model. 
Sensitivity analyses for handling missing data will be described in the SAP. 
Supportive analyses and subgroup analyses by selected baseline characteristics will also be 
described in the SAP. 


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12.3.3.2 
Analysis of Key Secondary Variables 
The key secondary variables are: 
• Absolute change in SwCl from baseline at Week 4: Analysis of this pharmacodynamics 
(PD) variable will be based on an MMRM model similar to the analysis of the primary 
efficacy variable. Data obtained from the Day 15 and Week 4 Visits will be included in the 
model. 
• Absolute change in the CFQ-R respiratory domain score from baseline at Week 4: 
Analysis of this domain will be based on an MMRM model similar to the analysis of the 
primary efficacy variable. Data obtained from the Day 15 and Week 4 Visits will be included 
in the model. 
Details will be provided in the SAP.  
12.3.3.4 
Multiplicity Adjustment 
A hierarchical testing procedure will be used to control the overall type I error at an alpha of 0.05 
for the primary endpoint and the key secondary endpoints tested. The key secondary endpoints of 
absolute change in SwCl from baseline at Week 4 and absolute change in CFQ-R respiratory 
domain score from baseline at Week 4 will only be tested at an alpha of 0.05 if the primary 
endpoint of absolute change in ppFEV1 from baseline at Week 4 is statistically significant. The 
second key secondary endpoint will only be tested if the first key secondary endpoint is 
statistically significant. The testing order of the key secondary endpoints is as follows: 
1. First key secondary endpoint: Absolute change in SwCl from baseline at Week 4 
2. Second key secondary endpoint: Absolute change in CFQ-R respiratory domain score 
from baseline at Week 4 
12.3.4 
Safety Analysis 
All safety analyses will be based on data from the TE Period for all subjects in the Safety Set. 
The overall safety profile of study drug will be assessed based on the following safety and 
tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
• ECGs 
• Vital signs 


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• Pulse oximetry 
All safety data from the TE Period will be summarized by treatment group and overall. 
All safety data will be presented in individual subject data listings, including safety data from the 
Run-in Period. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs during the Run-in 
Period, TEAEs during the Treatment Period, or post-treatment AEs, defined as follows:  
• Pretreatment AE: any AE that occurred before the first dose date of study drug (TEZ/IVA) 
in the Run-in Period 
• TEAE during the Run-in Period: any AE that worsened (either in severity or seriousness) 
or that was newly developed at or after the first dose date of study drug (TEZ/IVA) through 
the end of the TE Period for the Run-in Period 
• TEAE during the Treatment Period: any AE that worsened (either in severity or 
seriousness) or that was newly developed at or after the first dose date of study drug (TC or 
placebo + TEZ/IVA) through the end of the TE Period for the Treatment Period 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after:  
o the TE Period for the Run-in Period if the subject did not receive treatment in the 
Treatment Period 
o the TE Period for the Treatment Period if the subject received treatment in the Treatment 
Period 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs corresponding to 
the Treatment Period. Unless otherwise specified, TEAE refers to TEAE during the Treatment 
Period. 
AE summary tables will be presented for TEAEs, by treatment group, and will include the 
following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Grade 3 and Grade 4 TEAEs 
• Serious TEAEs 
• TEAEs leading to death 
• Frequently reported TEAEs 


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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 in the relationship summaries. In 
addition, a listing containing individual subject level AE data for all deaths and other serious and 
significant AEs will be provided separately. All AEs, including pre- and post-treatment AEs, will 
be presented in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, serum chemistry, and coagulation results will be 
summarized in SI units by treatment group at each visit. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criterion 
shift from baseline will also be summarized for select laboratory parameters. The threshold 
analysis criteria and the parameter selection criteria will be provided in the SAP. 
Results of urinalysis and pregnancy tests will be listed in individual subject data listings only. In 
addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from scheduled and unscheduled visits. 
12.3.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided by treatment group, at each visit and time point, as applicable, 
for the following ECG interval measurements (in msec): RR, PR, QT, and QT corrected for HR 
(QTcF), QRS duration, and HR (beats per minute). 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criteria 
will be provided in the SAP. 
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized by treatment group at each visit. The following vital signs 
parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criteria 
will be provided in the SAP. 
Additional vital signs analyses may be described in the SAP. 


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12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided by treatment group, at each visit for the percent of 
oxygen saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
TE Period will be summarized overall and by treatment group. 
12.3.4.6 
Physical Examination 
PE findings will be presented in an individual subject data listing only. 
12.3.4.7 
Other Safety Analysis 
Not applicable. 
12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analysis 
Not applicable. 
12.3.6.2 
IDMC Analysis 
The IDMC (Section 9.1.8) will conduct safety review of study data. Details will be described in 
the IDMC charter. 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
PK analysis of VX-445, TEZ, M1-TEZ, and IVA may be performed using nonlinear 
mixed-effects modeling, as data allow. Descriptive statistics will be used to summarize predose 
plasma concentrations for all analytes. 
A detailed description of the planned PK analysis will be presented in the CPAP. 
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 


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occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed. 
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the subject completes study 
participation, as defined in Section 9.1.7. 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject’s source documents. The following data will be documented 
for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 


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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 
28 September 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” 
In considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in the 
CTCAE. The severity of an AE that does not appear in the CTCAE will be determined according 
to the definitions in Table 13-1.  
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 signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through completion of study participation, 
regardless of causality, will be reported by the investigator to Vertex GPS. In addition, all SAEs 
that occur after completion of study participation 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. When determining the age of the subject, other study eligibility criteria, and timing of 
collection applicable assessments, the informed consent will be used as the reference (e.g., age at 
time of informed consent, date of informed consent, timing of AE collection). 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 


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


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• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit or, for subjects who have been lost to 
follow-up, the last contact, whichever occurs later, for the latest completing 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 CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
Protocol deviations will be monitored and identified throughout study conduct as outlined in the 
Protocol Deviation Plan. 
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.  


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A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Publications and Clinical Study Report 
13.6.1 
Publication of Study Results 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between Vertex and the investigator and/or the 
investigator’s institution. 
13.6.2 
Clinical Study Report 
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations. 


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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 03 September 2015. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2014 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2015. 
3 
European Cystic Fibrosis Society. 2013 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2016. 
4 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 19 September 2016. 
5 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 19 September 2016. 
6 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: Annual Data Report 2014. Bromley, 
Kent, UK: Cystic Fibrosis Trust; 2015. 
7 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
8 
CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional 
TRanslation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins 
University, the Hospital for Sick Children. Available at: http://www.cftr2.org. Accessed 
19 July 2017. 
9 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
10 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
11 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-
70. 
12 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
13 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78. 
14 
Vertex Pharmaceuticals Incorporated. Tezacaftor (VX-661) Investigator's Brochure, 
Version 8.0. Report date: 07 November 2016. 


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19 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
20 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
21 
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. 
22 
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. 




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15.2 
Investigator Signature Page 
Protocol #:  
VX17-445-103 Version #: 
3.0 
Version Date: 
19 July 2018 
Study Title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy 
and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are 
Homozygous for the F508del Mutation (F/F) 
 
 
I have read Protocol VX17-445-103, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-445, tezacaftor, ivacaftor, and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 37 
Protocol Number: VX17-445-103 
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX17-445-103 Version 3.0 
(Final Analysis) 
 
 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating 
the Efficacy and Safety of VX-445 Combination Therapy in Subjects 
With Cystic Fibrosis Who Are Homozygous for the F508del Mutation 
(F/F) 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 25 Sep 2018 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
Vertex Pharmaceuticals Incorporated 
2 
TABLE OF CONTENTS 
 
1 
Title Page ................................................................................................................................ 1 
2 
Table of Contents ................................................................................................................... 2 
3 
Modifications .......................................................................................................................... 4 
3.1 
Modifications to the Approved Clinical Study Protocol .................................................. 4 
3.2 
Modifications to the Approved Statistical Analysis Plan ................................................. 4 
3.3 
Modifications to the Approved DMC Charter .................................................................. 4 
4 
Introduction............................................................................................................................ 5 
5 
Study Objectives .................................................................................................................... 5 
5.1 
Primary Objective ............................................................................................................. 5 
5.2 
Secondary Objectives ....................................................................................................... 5 
6 
Study Endpoints ..................................................................................................................... 5 
6.1 
Efficacy and Pharmacodynamic Endpoints ...................................................................... 5 
6.1.1 
Primary Efficacy Endpoint ....................................................................................... 5 
6.1.2 
Secondary Efficacy and Pharmacodynamic Endpoints ............................................ 5 
 
 
6.2 
Safety Endpoints ............................................................................................................... 6 
 
 
7 
Study Design ........................................................................................................................... 6 
7.1 
Overall Design .................................................................................................................. 6 
7.2 
Sample Size and Power .................................................................................................... 7 
7.3 
Randomization .................................................................................................................. 7 
7.4 
Blinding and Unblinding .................................................................................................. 7 
8 
Analysis Sets ........................................................................................................................... 7 
8.1 
All Subjects Set ................................................................................................................ 8 
8.2 
Full Analysis Set ............................................................................................................... 8 
8.3 
Safety Set .......................................................................................................................... 8 
9 
Statistical Analysis ................................................................................................................. 8 
9.1 
General Considerations .................................................................................................... 8 
9.2 
Background Characteristics .............................................................................................. 9 
9.2.1 
Subject Disposition ................................................................................................... 9 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 10 
9.2.3 
Medical History ...................................................................................................... 11 
9.2.4 
Prior and Concomitant Medications ....................................................................... 11 
9.2.5 
Study Drug Exposure.............................................................................................. 12 
9.2.6 
Study Drug Compliance ......................................................................................... 12 
9.2.7 
Important Protocol Deviations ................................................................................ 13 
9.3 
Efficacy Analysis ............................................................................................................ 13 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 13 
9.3.2 
Analysis of Key Secondary Variables .................................................................... 15 
 
 
9.4 
Safety Analysis ............................................................................................................... 17 


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9.4.1 
Adverse Events ....................................................................................................... 18 
9.4.2 
Clinical Laboratory ................................................................................................. 20 
9.4.3 
Electrocardiogram .................................................................................................. 20 
9.4.4 
Vital Signs .............................................................................................................. 20 
9.4.5 
Pulse Oximetry ....................................................................................................... 21 
9.4.6 
Physical Examination ............................................................................................. 21 
9.4.7 
Supportive Safety Analysis .................................................................................... 21 
 
 
10 Interim and DMC Analyses ................................................................................................ 22 
10.1 Interim Analysis ............................................................................................................. 22 
10.2 DMC analysis ................................................................................................................. 22 
11 References ............................................................................................................................. 23 
12 List of Appendices................................................................................................................ 24 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment ........................... 24 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 26 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ............................................. 27 
Appendix D: Steps for Multiple Imputation ............................................................................ 28 
Appendix E: Imputation Rules for Missing AE dates .............................................................. 30 
Appendix F: Criteria for Threshold Analysis .......................................................................... 32 
Appendix G: Adverse Events of Special Interest ..................................................................... 37 
 
 


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3 
MODIFICATIONS  
3.1 
Modifications to the Approved Clinical Study Protocol 
Not Applicable. 
3.2 
Modifications to the Approved Statistical Analysis Plan 
This is the 1st version of Statistical Analysis Plan.  
3.3 
Modifications to the Approved DMC Charter 
Not Applicable. 
 


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4 
INTRODUCTION 
This statistical analysis plan (SAP) is based on the most recent approved clinical study protocol 
(CSP), the most recent approved electronic case report form (eCRF), and the most recent 
approved eCRF completion guidelines.  
This SAP (Methods) documents the planned final statistical analyses of efficacy and safety 
endpoints defined in the VX17-445-103 study protocol. It also documents analyses for additional 
efficacy and safety variables not specified in the protocol, which will provide supportive 
information for the scientific understanding of the drug entity.  
The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of VX-445/TEZ/IVA in 
the F508del homozygous population also will be evaluated in the study. Selected analyses 
related to sweat chloride will be documented in this SAP, other PK and PD analyses will be 
documented separately in the clinical pharmacology analysis plan (CPAP) for the study. 
The Vertex Biometrics Department will perform the statistical analysis of the efficacy and safety 
data; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, figures, 
listings, and datasets). The SAP will be finalized and approved prior to the clinical database lock 
and treatment unblinding for the study. Any revisions to the approved SAP will be documented 
and approved in an amendment to the SAP prior to the clinical database lock for the final 
analysis. Any changes made to the SAP (Methods) after the clinical database lock has occurred 
will be documented in the clinical study report for this study. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and 
ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del 
mutation (F/F) 
5.2 
Secondary Objectives  
 To evaluate the safety of VX-445 in TC with TEZ and IVA  
 To evaluate the PD of VX-445 in TC with TEZ and IVA 
 To evaluate the PK of VX-445, TEZ, and IVA when administered in TC 
6 
STUDY ENDPOINTS 
6.1 
Efficacy and Pharmacodynamic Endpoints  
6.1.1 
Primary Efficacy Endpoint 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline at Week 4 
6.1.2 
Secondary Efficacy and Pharmacodynamic Endpoints 
The key secondary efficacy endpoints are as follows:  
 Absolute change in sweat chloride (SwCl) from baseline at Week 4 


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 Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain score from 
baseline at Week 4 
6.2 
Safety Endpoints 
Safety and tolerability will be evaluated via the following endpoints: 
 Adverse events (AEs) 
 Clinical laboratory values 
 Standard 12-lead ECGs 
 Vital signs 
 Pulse oximetry 
7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter study. 
A schematic of the study design is shown in Figure 7-1. 
In the TEZ/IVA Run-in Period, all subjects will receive TEZ 100 mg once daily (qd)/IVA 150 
mg every 12 hours (q12h). Following completion of the TEZ/IVA Run-in Period, approximately 
100 subjects will be randomized (1:1) to the TC arm or TEZ/IVA arm for the Treatment Period. 
The planned dosages for the Treatment Period are shown in Table 7-1.  
Table 7-1 
Treatment Period Arms and Dosages 
Treatment Arm 
VX-445 Dosage 
TEZ Dosage 
IVA Dosage 
VX-445/TEZ/IVA 
200 mg qd 
100 mg qd 
150 mg q12h 
TEZ/IVA 
0 mg  
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TC: triple combination; TEZ: tezacaftor  
 
All visits will occur within the windows specified. Please refer to the Table 3-1 and Table 3-2 of 
the CSP for more details about study visits and assessments. 
 




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8.1 
All Subjects Set 
The All Subjects Set will include all subjects who are randomized or receive at least 1 dose of 
study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified.  
8.2 
Full Analysis Set  
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended CFTR 
allele mutation and receive at least 1 dose of study drug in the Treatment Period. The FAS will 
be used to summarize subject demographics and baseline characteristics, and for all efficacy 
analyses in which subjects will be analyzed according to their randomized treatment group, 
unless otherwise specified. 
8.3 
Safety Set 
The Safety Set for the Run-in Period will include all subjects who receive at least 1 dose of 
TEZ/IVA in the Run-in Period. This safety set will be included in individual subject data listings, 
unless otherwise specified. 
The Safety Set for the Treatment Period will include all subjects who receive at least 1 dose of 
study drug in the Treatment Period. This safety set will be used for all safety analyses in which 
subjects will be analyzed according to the treatment they receive, unless otherwise specified. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of CSP. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max).  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value, unless otherwise specified, is defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period.  
Absolute change from baseline will be calculated as post-baseline value – baseline value. 
Relative change from baseline will be calculated as (post-baseline value – baseline 
value)/baseline value. 
The Treatment-emergent (TE) Period for the Run-in Period will be from the first dose of 
study drug in the Run-in Period to 
1) for subjects who complete the run-in period and continue to the Treatment Period, the 
first dose of study drug in the Treatment Period, or  


Statistical Analysis Plan (Methods) 
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2) for subjects who do not continue to the Treatment Period, either 28 days after the last 
dose date of study drug in the Run-in Period, or to the completion of study participation 
date, whichever occurs first. 
 
The TE Period for the Treatment Period will include the time from the first dose date of study 
drug in the Treatment Period (TC or placebo + TEZ/IVA) to 28 days after the last dose of the 
study drug or to the completion of study participation date, whichever occurs first. 
 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
A disposition table will be provided for the Run-in Period with the following categories:  
 All Subjects Set 
 Safety Set for the Run-in Period 
The number and percentage (based on Safety Set for the Run-in Period) of subjects in each of the 
following disposition categories will be summarized: 
 Prematurely discontinued treatment before randomization and the reason for treatment 
discontinuation 
 Prematurely discontinued study before randomization and the reason for study 
discontinuation 
A separate disposition table will be provided for the Treatment Period with the following 
categories:  
 Full Analysis Set 
 Safety Set for the Treatment Period 
 Randomized 
 Randomized but not dosed in the Treatment Period 
 Randomized or dosed in the Treatment Period 


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The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
 Completed study drug treatment 
 Prematurely discontinued treatment and the reason for discontinuation (i.e., discontinued all 
study drugs) 
 Completed study 
 Prematurely discontinued the study and the reason for discontinuation  
 Rollover to the open-label study 
A listing will be provided for subjects who discontinued treatment (including both the Run-in 
Period and Treatment Period) or who discontinued study with reasons for discontinuation.  
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS, and presented 
by treatment group and overall, as applicable. 
Demographic data will include the following: 
 Age at baseline (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 not collected per local regulations) 
 Geographic region (North America, Europe) 
Baseline characteristics will include the following: 
 Weight (kg) 
 Height (cm) 
 BMI (kg/m2) 
Stratification categories will include the following: 
 Age at Screening Visit (<18, ≥18 years) 
 ppFEV1 at Day -14 (<70, ≥70) 
Disease characteristics will include the following: 
 ppFEV1 at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
 ppFEV1 at baseline (continuous)  
 Sweat chloride at baseline (continuous) 
 CFQ-R respiratory domain score at baseline (continuous) 
 Prior use of dornase alfa before first dose of study drug in the Treatment Period (Yes, No) 


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 Prior use of azithromycin before first dose of study drug in the Treatment Period (Yes, No) 
 Prior use of inhaled antibiotic before first dose of study drug in the Treatment Period (Yes, 
No) 
 Prior use of bronchodilator before first dose of study drug in the Treatment Period (Yes, No)  
 Prior use of inhaled bronchodilator before first dose of study drug in the Treatment Period 
(Yes, No)  
 Prior use of inhaled hypertonic saline before first dose of study drug in the Treatment Period 
(Yes, No) 
 Prior use of inhaled corticosteroids before first dose of study drug in the Treatment Period 
(Yes, No) 
 Infection with Pseudomonas aeruginosa within 2 years prior to screening (Positive, 
Negative) 
In addition, data listings will also be provided for: 
 Informed consent; 
 Inclusion/Exclusion criteria violation for subjects with any such violations. 
9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). For the FAS, medical history will be summarized descriptively by system organ 
class and preferred term. The corresponding data listing will also be provided. 
In addition, the number of subjects reported to have had positive cultures for respiratory 
pathogens within the 2 years prior to screening (i.e., answered yes on the respiratory 
microbiology form) will be summarized for the FAS. The corresponding data listing will be 
provided. Hospitalization and clinic visit history in the year prior to the signing of informed 
consent will be listed. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
and categorized as follows: 
Prior medication: any medication that was administered during the 56 days before the first dose 
of study drug in the Treatment Period but not in the Run-in Period.  For subjects who discontinue 
during the Run-in Period and whose first dose of study drug in the Treatment Period is not 
available, prior medication will be any medication that was administered during the 56 days 
before the last dose of study drug in the Run-in Period but before the first dose in the Run-in 
Period.  
Concomitant medication during the Run-in Period: medication continued or newly received 
during the TE period for the Run-in Period. 
Concomitant medication during the Treatment Period: medication continued or newly 
received during the TE period for the Treatment Period. 
Post-treatment medication: medication continued or newly received after: 


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 the TE period for the Run-in Period if the subject did not receive study drug in the Treatment 
Period.  
 the TE period for the Treatment Period for subjects who received study drug in the Treatment 
Period. 
A given medication may be classified as any combination of the above categories, for example, 
prior and concomitant during the Run-in Period, concomitant during the Treatment Period and 
post-treatment, or concomitant for both periods and post-treatment.  
If a medication has completely missing or partially missing start/stop date and if it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly, or after 
the TE period, it will be classified as prior, concomitant for both periods, and post-treatment. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix B. 
Prior medications and concomitant medications will be summarized descriptively for FAS using 
frequency tables by: 1) treatment group and overall, preferred name (PN); and 2) treatment group 
and overall, anatomic class (ATC) level 1, ATC level 2, and PN.  
Prior and concomitant medication during the Run-in Period will be summarized together in one 
summary table. Post-treatment medications will be listed in the all medication listing. 
9.2.5 
Study Drug Exposure  
Study drug exposure will be summarized for the Treatment Period only based on the Safety Set 
for the Treatment Period, and will be presented by treatment group and overall. 
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug in 
the Treatment Period – first dose date of study drug in the Treatment Period + 1, regardless of 
study drug interruption, and will be summarized descriptively.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by interval: ≤2 weeks, >2- ≤4 
weeks, and > 4 weeks, using counts and percentages. Additionally, the total study drug exposure, 
defined as the sum total of the study drug exposure across all subjects (in patient-weeks), will be 
provided. 
9.2.6 
Study Drug Compliance 
Study drug compliance will be summarized for the Treatment Period only based on the FAS, and 
will be presented by treatment group and overall.   
Study drug compliance will be calculated as: 100 × [1 - (total number of days of study drug 
interruption during the Treatment Period) / (duration of study drug exposure in days during the 
Treatment Period)]. A study drug interruption on a given day is defined as an interruption of any 
study drugs on that day. A study drug interruption that continues through the end of the study 
participation (i.e., subject does not resume study drug before the end of the study participation) 
will not be included in the compliance calculation. 
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max.  It will also be summarized in categories: <80% and ≥80% using 
frequency tables. 


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In addition, percentage of tablets taken will be calculated using the following formula: 
100  [(total number of tablets dispensed for the Treatment Period) – (total number of tablets 
returned for the Treatment Period)] / (total number of tablets planned to be taken per 
day  duration of study drug exposure in days for the Treatment Period).  Summary similar to 
those for the study drug compliance will be produced based on the FAS. 
9.2.7 
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 database lock.  
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to:  
 Subject was enrolled in the study despite the violation of inclusion/exclusion criteria  
 Subject was less than 80% compliant with study drug for non-safety reasons 
 Subject received prohibited concomitant medications  
 Subject received the wrong treatment or incorrect doses  
 Subject remained in the study despite meeting withdrawal criteria  
Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being.  
IPDs (from the clinical database or from the site deviation log) will be summarized descriptively 
based on the FAS and presented by treatment group and overall. Additionally, IPDs will be 
provided in an individual subject data listing.  
9.3 
Efficacy Analysis  
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS.  
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Definition of Variable 
The primary efficacy variable is the absolute change in ppFEV1 from baseline at Week 4.  
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a 
percentage. The predicted FEV1 will be calculated using the Global Lung Function Initiative1 
(GLI); details are in Appendix C. 
9.3.1.2 
Primary Analysis  
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with the absolute change from baseline at Day 15 and Week 4 as the dependent 
variable. The model will include treatment group, visit, and treatment-by-visit interaction as 
fixed effects, with continuous baseline ppFEV1, and age at screening (<18 versus ≥18 years of 
age) as covariates. The model will be estimated using restricted maximum likelihood. 


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Denominator degrees of freedom for the F-test for fixed effects will be estimated using the 
Kenward-Roger approximation2. An unstructured covariance structure will be used to model the 
within-subject errors. If the model estimation does not converge, a compound symmetry 
covariance structure will be used instead. Conditional on the observed data and covariates, 
missing data will be assumed to be missing at random; consequently, no imputation of missing 
data will be performed.  
The primary result obtained from the model will be the estimated treatment difference at Week 4. 
The adjusted means with 2-sided 95% confidence intervals and 2-sided P values will be 
provided.  Furthermore, the treatment difference at each post-baseline visit obtained from the 
model will also be provided. 
The adjusted mean (with SE) obtained from the MMRM analysis at each post-baseline visit up to 
Week 4 will be plotted by treatment group. 
9.3.1.3 
Supportive Analysis  
There will be no supportive analysis for the primary efficacy endpoint. 
9.3.1.4 
Sensitivity Analysis  
MMRM based on Multiple Imputation (MI)  
An underlying assumption of the MMRM method is that data are missing at random. To 
minimize the amount of missing data, subjects who prematurely discontinue study drug 
treatment will continue to complete all scheduled study visits for spirometry and other efficacy 
assessments. 
To assess the impact of missing data and the assumption that data are missing at random, a 
multiple imputation algorithm will be used if at least 10% of the subjects have missing changes 
in ppFEV1 at Week 4 in any treatment group. Missing absolute change from baseline in ppFEV1 
assessments will be imputed starting from the first visit with missing values, for which all 
subsequent visits through Week 4 are also missing. For intermediate missing data, i.e., missing 
values that fall between two non-missing ones, it is reasonable to assume that they are missing at 
random and therefore will not be imputed. An MMRM analogous to that for the primary analysis 
of the primary endpoint will be applied to each imputed dataset and the relevant MI estimators 
will be reported. Details for the MI steps are presented in Appendix D. 
9.3.1.5 
Subgroup Analysis  
Subgroup analyses of the primary efficacy endpoint will be performed using a model similar to 
that of the primary analysis for each of the following subgroups. The primary result obtained 
from the model will be the treatment effect at Week 4: 
 Age at Screening (<18, ≥18 years) 
 ppFEV1 at baseline (< 70, ≥ 70)  
 Sex (male, female)  
 Geographic region (North America, Europe) 
 Prior use of inhaled antibiotic before the first of study drug in the Treatment Period (Yes, 
No) 


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 Prior use of dornase alfa before the first of study drug in the Treatment Period (Yes, No) 
 Prior use of inhaled bronchodilator before the first of study drug in the Treatment Period 
(Yes, No)  
 Prior use of inhaled hypertonic saline before the first of study drug in the Treatment Period 
(Yes, No)  
 Prior use of inhaled corticosteroids before the first of study drug in the Treatment Period 
(Yes, No)  
 Prior use of azithromycin before the first of study drug in the Treatment Period (Yes, No)  
 Infection with Pseudomonas aeruginosa within 2 years prior to screening (Positive, 
Negative) 
The MMRM used for the primary analysis will be used for the subgroup analysis, where the 
same model will be applied to each category of the subgroup. Note that for the subgroup analysis 
based on age, the covariate of age at screening (<18 versus ≥18 years) from the MMRM will be 
removed. The adjusted means with 2-sided 95% confidence intervals will be provided. 
Furthermore, the estimated treatment difference at Week 4 in different categories within a 
subgroup will also be presented in a forest plot. Note: The results from the subgroup analysis 
should be interpreted with caution in the cases where sample sizes are small. 
9.3.2 
Analysis of Key Secondary Variables  
9.3.2.1 
Definition of Variables 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit.  If one 
of the two arm measurements at a time point is missing, the other will be used as the mean.  A 
volume ≥15 μL is required for an accurate determination of sweat chloride.  Any results reported 
as having volume <15 μL will be considered missing.  Any sweat chloride values reported as 
<10 mmol/L or >160 mmol/L will be considered missing. 
Cystic Fibrosis Questionnaire-Revised (CFQ-R): The CFQ-R3,4,5 is a validated CF-specific 
instrument that measures quality-of-life domains.  This study utilizes three different versions of 
CFQ-R: 
 CFQ-R for Children ages 12 and 13 
 CFQ-R for Adolescents and Adults (subjects 14 years and older) 
 CFQ-R for Parents/Caregivers (subjects 13 years and younger) 
In all three versions, specific question belonging to a domain is scored 1, 2, 3, or 4.  The CFQ-R 
domain score, e.g., physical domain score or respiratory domain score, is defined as a scaled 
score as follows: 
                                                                           )   )  , 
where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – 
actual score, so that 1 always represents the worst condition and 4 the best condition.  The 
(scaled) domain score ranges from 0 (worst condition) to 100 (best condition).  The scaled score 


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for a specific domain will not be calculated if more than half of the questions in the domain have 
missing scores. 
The (scaled) domain score from the CFQ-R for Children ages 12 and 13 and for Adolescent and 
Adults will be pooled for the analysis purpose. 
9.3.2.2 
Analysis Method 
Absolute change in SwCl from baseline at Week 4:  
Analysis of absolute change from baseline in sweat chloride will be based on an MMRM similar 
to the primary analysis of the primary efficacy variable. The model will include treatment, visit, 
and treatment-by-visit interaction as fixed effects with continuous baseline ppFEV1, and age at 
screening (<18 versus ≥18 years of age) as covariates.  
Absolute change in CFQ-R respiratory domain score from baseline at Week 4:  
Analysis of absolute change from baseline in CFQ-R respiratory domain score will be based on 
an MMRM similar to the primary analysis of the primary efficacy variable. The model will 
include treatment, visit, and treatment-by-visit interaction as fixed effects with continuous 
baseline ppFEV1, and age at screening (<18 versus ≥18 years of age) as covariates.  
The LS mean (SE) of the within-treatment group change from baseline at each post-baseline visit 
up to Week 4 along with the 95% CI will be estimated from the corresponding MMRM.  The LS 
mean (SE) of the treatment difference between VX-445/TEZ/IVA and TEZ/IVA at each post-
baseline visit will be provided along with the corresponding 95% CI and P value.  The LS mean 
(SE) at each visit will also be plotted by treatment group.  In addition, the post-baseline raw 
values and the absolute change from baseline at each post-baseline visit up to Week 4 will be 
summarized descriptively (n, mean, SD, median, minimum, and maximum). 
9.3.2.3 
Multiplicity Adjustment 
The key secondary endpoints will be formally tested at an alpha of 0.05 only if the primary 
endpoint is statistically significant. A hierarchical testing procedure will be used to control the 
type I error rate for the multiple key secondary endpoints tested at an alpha of 0.05. For a test at 
any step to be considered statistically significant within the testing hierarchy, it must be 
statistically significant, and all previous tests (if any) within the hierarchy must be statistically 
significant at the 0.05 level.  The testing order of the key secondary endpoints is as follows: 
 Absolute change in SwCl from baseline at Week 4 
 Absolute change in CFQ-R respiratory domain score from baseline at Week 4 


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9.4 
Safety Analysis 
All safety analyses will be based on data from the TE period for the Treatment Period for all 
subjects in the corresponding Safety Set for the Treatment Period, unless otherwise specified. 
Subjects will be analyzed according to the treatment they actually received in the Treatment 
Period. For subjects receiving study drug from more than one treatment group, the treatment 
group allocation will be the higher treatment group (VX-445/TEZ/IVA > 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 
 ECGs 
 Vital signs 
 Pulse oximetry 


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Only descriptive analysis of safety will be performed and no statistical testing will be performed. 
The safety data during the Run-in Period will only be presented in listings, unless otherwise 
specified. 
9.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs during the Run-in 
Period, TEAEs during the Treatment Period, and post-treatment AEs, defined as follows:  
Pretreatment AE: any AE that occurred before the first dose date of study drug (TEZ/IVA) in 
the Run-in Period 
TEAE during the Run-in Period: any AE that worsened (either in severity or seriousness) or 
that was newly developed at or after the first dose date of study drug (TEZ/IVA) through the end 
of the TE period for the Run-in Period 
TEAE during the Treatment Period: any AE that worsened (either in severity or seriousness) 
or that was newly developed at or after the first dose date of study drug (TC or 
placebo+TEZ/IVA) through the end of the TE period for the Treatment Period 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after: 
 the TE period for Run-in Period if the subject did not receive treatment in the Treatment 
Period 
 the TE period for the Treatment Period if the subject received treatment in the Treatment 
Period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs are pre-treatment or TEAE during the Run-in Period or post-treatment, the AEs will 
be classified as TEAEs corresponding to the Treatment Period. Unless otherwise specified, 
TEAE refers to TEAE during the Treatment Period. 
Details for imputing missing or partial start dates of adverse events are described in Appendix E. 
An overview of all TEAEs by treatment group and overall will be summarized in the following 
categories: 
 Number of TEAEs (total number of TEAEs only) 
 Subjects with any TEAEs  
 Subjects with TEAEs by strongest relationship 
 Subjects with TEAEs by maximum severity 
 Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drugs) 
 Subjects with TEAEs leading to study drug interruption (interruption of any study drugs) 
 Subjects with Grade 3/4 TEAEs 
 Subjects with related TEAEs 
 Subjects with serious TEAEs 


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 Subjects with related serious TEAEs 
 Subjects with TEAE leading to death  
The following summary tables of TEAEs will be presented by treatment group: 
 All TEAEs 
 Grade 3/4 TEAEs 
 TEAEs by strongest relationship 
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 TEAEs leading to treatment interruption 
 Related TEAEs 
 Serious TEAEs 
 Related serious TEAEs 
 TEAEs leading to death 
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event or a continuing adverse event will be counted once, and only the 
maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries.  
Additional summary tables will be presented by treatment group for TEAEs showing number 
and percentage of subjects 
 All TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs for all applicable periods, and post-treatment AEs, 
will be presented in an individual subject data listing based on the All Subjects Set. In addition, 
separate listings containing individual subject adverse event data for TEAEs leading to treatment 
discontinuation, TEAEs leading to treatment interruption, Grade 3/4 TEAEs, SAEs and all 
deaths will be provided separately, with a flag indicating the TEAE status for SAEs and deaths. 
In addition, the following tables for the Run-in period will be presented by overall based on the 
Safety Set for the Run-in period.  
 An overview of TEAEs during the Run-in Period 
 All TEAEs during the Run-in Period by SOC and PT 
9.4.1.1 
Subgroup Analysis 
An overview of all TEAEs and a summary of TEAEs by SOC and PT for the following 
subgroups will be provided: 
 Age at screening (<18, ≥18 years) 


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 ppFEV1 at baseline (<70, ≥70) 
 Sex (male, female) 
 Geographic region (North America, Europe) 
9.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, coagulation and chemistry results will be 
summarized in SI units at each visit by treatment group.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event, 
during the TE period for Treatment Period, will be summarized by treatment group. The 
threshold analysis criterion shift from baseline will also be summarized for selected laboratory 
parameters. The threshold analysis criteria are provided in Appendix F.  
For selected LFT laboratory test (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-
emergent value versus the baseline value corresponding to ×ULN (upper limit of normal) will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, 
separately, versus the maximum treatment-emergent value of total bilirubin corresponding to 
×ULN will also be presented by treatment group.  
Results of urinalysis and positive urine/serum pregnancy test will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which are 
abnormally high will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from both scheduled and unscheduled visits.  
9.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit by treatment group for the following ECG interval 
measurements (in msec): RR interval, PR interval, QT interval, QTcF interval, QRS duration, 
and Heart Rate (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period for the Treatment Period will be summarized by treatment group. The threshold 
analysis criteria are provided in Appendix F. 
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits.  
9.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit by treatment group. The following vital signs 
parameters will be summarized: BMI (kg/m2), weight (kg), height (cm), systolic and diastolic 
blood pressure (mm Hg), body temperature (C), pulse rate (beats per minute), and respiratory 
rate (breaths per minute). 


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The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period for the Treatment Period will be summarized by treatment group. The threshold 
analysis criteria are provided in Appendix F. 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits.  
9.4.5 
Pulse Oximetry 
For the treatment-emergent oxygen saturation values by pulse oximetry, a summary of observed 
values and change from baseline values will be provided at each visit by treatment group. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
period for the Treatment Period will be summarized by treatment group. 
9.4.6 
Physical Examination  
Abnormal PE findings will be presented as an individual subject data listing only. 
9.4.7 
Supportive Safety Analysis 
9.4.7.1 
Adverse Events of Special Interest 
For this study, elevated transaminase events and rash events, as determined by MedDRA 
preferred terms in Appendix G, are considered as adverse events of special interest. 
For treatment-emergent elevated transaminase events and rash events, the following categories 
will be summarized by treatment group: 
 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 
In addition, for treatment-emergent rash events, these categories will be summarized for the 
following subgroups: 
 Sex (male, female) 
 Female subjects with concomitant hormonal therapy (Yes, No) 


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9.4.7.2 
Hormonal Therapy 
The number of subjects who used hormonal therapy concomitantly will be summarized by 
treatment group based on the Safety Set for the Treatment Period. 
10 
Interim and DMC Analyses 
10.1 
Interim Analysis 
No formal interim analysis is planned. 
10.2 
DMC analysis 
The DMC’s objectives and operational details are defined in a separate document (DMC 
Charter) which was finalized before the first subject was screened in the study. The DMC’s 
planned safety reviews of study data are outlined in the DMC Charter and DMC Statistical 
Analysis Plan.  


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11 
REFERENCES 
1 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2  Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
4 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life 
for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
5 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
6 Rubin, DB. and Schenker, N.. Interval estimation from multiply-imputed data: a case study 
using agriculture industry codes. Journal of the American Statistical Association. 1987; 81: 
366–374. 
 
 


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12 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4 
(in study days) 
Safety Assessment 
Serum Chemistry 
Hematology 
 
Day 1 (Baseline)  
Day 15 
Week 4 
Safety Follow-up 
1 
15 
29 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
Use nominal visit 
Standard 12-lead ECG 
Day 1 (Baseline)  
Day 15 Pre-dose 
and Postdose 
Week 4 
Safety Follow-up 
1 
Not applicable 
 
29 
Not applicable 
1 Pre-dose 
Use nominal visit 
 
(22, 43] 
Use nominal visit 
Coagulation 
Day 1 (Baseline)  
Week 4 
Safety Follow-up 
1 
29 
Not applicable 
1 Pre-dose 
[1, 43] 
Use nominal visit 
Vital Signs (excluding BMI, 
Weight, Height and their Z-scores) 
 
Day 1 (Baseline)  
Day 15 
Week 4 
Safety Follow-up 
1 
15 
29 
Not applicable 
1  
[1,22] 
(22, 43] 
Use nominal visit 
Efficacy Assessment and Pharmacodynamic Assessment  
Spirometry  
 
Day 1 (Baseline)  
Day 15 
Week 4 
Safety Follow-up 
1 
15 
29 
Not applicable 
1 Pre-dose 
(1,22] 
(22, 43] 
>43 
Sweat Chloride 
Day 1 (Baseline)  
Day 15 
Week 4 
1 
15 
29 
1 Pre-dose 
(1,22] 
(22, 43] 
CFQ-R  
Weight, Height and BMI 
Day 1 (Baseline)  
Day 15 
Week 4 
Safety Follow-up 
1 
15 
29 
Not applicable 
1 
(1,22] 
(22, 43] 
>43 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. 
 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4 
(in study days) 
3 For lab, ECG and vital sign measurement collected on the date of first dose of study drug in Treatment Period, if it 
cannot be determined whether the measurement is before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a subject 
doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >43, then the ETT visit will be 
mapped into Safety Follow-up analysis visit.  
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs 
(VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI and weight z-score): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital Signs 
(VS) page at the Screening Visit. 
Obtain the informed consent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + diff(first 
dose date or nominal visit date, informed consent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for a 
given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
5. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period.  If multiple ECG measurements are obtained on the same calendar day during the TE period,  
o 
For summary purpose, the calculated average ECG will be used as the ECG value on that day (except 
for Day 15 visit); 
o For threshold analysis purpose, all reported ECG values will be used. 
 
 
 


Statistical Analysis Plan (Methods) 
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Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date (in 
practical, use Jan. 01, 2000 to impute). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (in 
practical, use Dec. 31, 2050 to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Table 12-2 
Prior, Concomitant, and Post Categorization of a Medication 
Medication Start Date 
 
Medication Stop Date 
< First Dose 
Date of Run-in 
TE Period 
≥ First Dose Date and < 
End Date of Run-in TE 
Period  
≥ First Dose Date and ≤ End 
Date of Treatment TE Period  
> End Date of 
Treatment TE 
Period  
< First dose date of Run-in 
TE period  
P 
PC1 
PC1C2 
PC1C2A 
≥ First dose date and  
< End date of Run-in  TE 
Period 
- 
C1 
C1C2 
C1C2A 
≥ First dose date and  
≤ End date of Treatment TE 
Period 
- 
- 
C2 
C2A 
> End date of Treatment TE 
Period 
- 
- 
- 
A 
P: Prior; C1: Concomitant during the Run-in Period; C2: Concomitant during the Treatment Period; A: Post 
Imputation rules for missing and/or partial dates of non-pharmacological treatment/procedure 
will follow the same imputation rule. 
 
 


Statistical Analysis Plan (Methods) 
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Appendix C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, 
 
 
 using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed Mar 26, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed Mar 
26, 2018].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Mar 26, 2018]. 
Data handling rule for spirometry is as follows:  
 Input age with at least 2 decimal place 
 Use height at screening regardless if height is collected at other study visits for subjects 
whose age at informed consent is >21 years. For subjects with age <=21 years, height 
collected at the respective visit should be used; if the height at the respective visit is not 
available, the last non-missing record will be used. 
 For race, map the CRF reported Black or African American to Black, all other races in 
CRF (except White) are mapped to 'other'; multiple checks for race in CRF are also 
mapped to 'other'; white is a reference race in the equations and assumes 0 values for all 
race coefficients in the GLI  equations. 
 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
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Appendix D: Steps for Multiple Imputation 
For the multiple imputation (MI) to be applied to the MMRM model for the primary efficacy 
endpoint, the following steps will be followed: 
Imputation distribution  
The imputation distribution for the missing absolute change from baseline in ppFEV1 at visit t 
will be a normal distribution.  All randomized subjects will be classified into one of three 
categories based on the following rules:  
 Non-missing category: Subjects who have a ppFEV1 assessment at Week 4 (i.e., subjects 
who have a non-missing absolute change from baseline in ppFEV1 at Week 4).  
 Missing category 1: Subjects with missing absolute change from baseline in ppFEV1 at 
Week 4, who discontinued treatment because of adverse events, noncompliance with 
study drug, death, or physician decision, or because the subject refused further dosing or 
required prohibited medication.  
 Missing category 2: Subjects who discontinued treatment for any reason not listed in 
Category 1 and have missing absolute change from baseline in ppFEV1 at Week 4, or 
subjects who have completed 4 weeks treatment duration but are missing the absolute 
change from baseline in ppFEV1 at visit Week 4 
Imputation algorithm 
We will use the following algorithm that relates the mean of the missing absolute change from 
baseline in ppFEV1 at visit t to the missing categories defined above.  The algorithm will be 
implemented within each treatment group as follows: 
 Missing category 1: randomly draw a sample from the normal distribution       ), 
where      is the 25th percentile of the non-missing absolute changes from baseline in 
ppFEV1 at visit t and    is the sample variance estimated using the non-missing absolute 
changes at visit t. 
 Missing category 2: randomly draw a sample from the normal distribution     ), where 
  is the mean of the non-missing absolute changes from baseline in ppFEV1 at visit t and 
 2 is the sample variance estimated using the non-missing absolute changes at visit t. 
Analysis model 
The complete MI method is described below:  
 Form an “imputed dataset” by imputing missing values at each visit for those subjects 
who have a missing value at the visit and have all subsequent values missing. The 
appropriate normal distribution specified in the algorithm above will be used for each 
such subject, based on their category.  
 Repeat this process K (K=20) times to form K imputed datasets.  
 Fit the same MMRM model to each imputed dataset to estimate the absolute change at 
Week 4. 
 Combine the results from the K imputed datasets using the SAS procedure MIANALYZE 
to derive the MI estimator.  


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
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Let θ be the true treatment difference. Denote by  ̃  the estimate of θ from the     imputed 
dataset, and the corresponding estimate of the variance is denoted by   . The MI estimator of θ, 
 ̃  , is the average of the K individual estimates.  
The estimated variance of  ̃   is a combination of the between- and within-imputation variability 
as follows:       (   
 
 )  , where   
 
 ∑
  
 
   
 is the within-imputation variability 
and is   
 
   ∑
  ̃   ̃  ) 
 
   
 is the between-imputation variance. The statistic    ̃    
√    has an 
approximate    distribution, where       )   
 
 ) . 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
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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 the imputed AE start 
date is before the informed consent date, the AE start date will be imputed using the study 
informed consent date. 
 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 of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else if AE start year and month are equal to the month and year of first dose 
date of the Run-in Period, then impute the AE start day as the day of first dose 
date of the Run-in Period;  
 else impute the AE start day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Run-in Period, then impute the AE start day as the day of first dose date 
of the Run-in Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE during the Run-in Period, TEAE during the Treatment Period, 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 of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else if AE start year is equal to the year of first dose date of the Run-in Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Run-in Period;  
 else impute the AE start month as January and day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then  
 if AE start year is equal to the year of first dose date of the Run-in Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Run-in Period;  


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
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 else impute the AE start month as January and day as 1. 
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE during the Run-in Period, TEAE during the Treatment Period, 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 and 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the date of first 
dose date of the Treatment Period.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then impute the AE start date as the date of first dose date of the Run-in 
Period. 
o else impute AE date as the informed consent date. 
 
The imputation should ensure the imputed AE start date is not before the informed consent date. 
 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, end of study participation) if 
day is missing, or min (Dec, end of study participation) if month is missing. 
 
 


Statistical Analysis Plan (Methods) 
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Appendix F: Criteria for Threshold Analysis 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or 
(AST>ULN - ≤  3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x - ≤ 
5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - ≤  
8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x - 
≤ 20xULN) 
ALT>20xULN 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 Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
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. 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
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 
 
Platelet increased   
>ULN 
No CTCAE available 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
  
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
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 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
Vertex Pharmaceuticals Incorporated 
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
QTc 
 
>450 to <500ms (Male) or >470 to <500ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
 
Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
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 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
Vertex Pharmaceuticals Incorporated 
Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
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 
 
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 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3 
 
 
Table 12-6 
Threshold Analysis Criteria for Laboratory Tests (for labeling purpose) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
For labeling purpose 
 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX17-445-103 
 
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Appendix G: Adverse Events of Special Interest  
Table 12-7 MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
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 
Rash 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash maculovesicular, Rash vesicular, Rash pruritic, Rash 
follicular, Rash pustular, Rash generalized, Nodular rash, Drug 
eruption, Fixed eruption, Generalised erythema, Urticaria, 
Urticaria popular, Urticaria vesiculosa, Rash morbilliform, Rash 
popular, Rash papulosquamous, Rash rubelliform, Rash 
scarlatiniform , Drug hypersensitivity, Type IV hypersensitivity 
reaction, Dermatitis, Dermatitis atopic, Epidermolysis, Skin 
toxicity, Dermatitis allergic, Dermatitis exfoliative, Dermatitis 
exfoliative generalized, Erythema multiforme, Exfoliative rash, 
Mucocutaneous rash, Acute generalised exanthematous 
pustulosis, Cutaneous vasculitis, Urticarial vasculitis, Dermatitis 
bullous, Drug reaction with eosinophilia and systemic 
symptoms, Epidermal necrosis, Oculomucocutaneous syndrome, 
Skin exfoliation, Skin necrosis, Stevens-Johnson syndrome, 
Toxic epidermal necrolysis, Toxic skin eruption, Perioral 
dermatitis, Vasculitic rash 
Note: the preferred terms listed in the table is based on the MedDRA version applicable at the time of 
finalization of the SAP.  If the MedDRA version is upgraded at the time of the analysis, the 
corresponding preferred terms based on the upgraded version will be used in the analysis of adverse 
events of special interest.