Clinical trial NCT02392234
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2015-03-01; Completion date: 2017-02-01
Enrollment: 248 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of VX-661 in combination with ivacaftor (IVA, VX-770) and IVA monotherapy in participants with Cystic Fibrosis (CF) who are heterozygous for F508del-CFTR allele and a second allele with a CFTR mutation predicted to have residual function.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: VX-661/Ivacaftor intervention 2: Ivacaftor intervention 3: Placebo matched to VX-661/ ivacaftor intervention 4: Placebo matched to Ivacaftor
Intervention descriptions: intervention 1: Fixed dose combination tablet, oral use intervention 2: Tablet, oral use intervention 3: Fixed dose combination tablet, oral use intervention 4: Tablet, oral use

Protocol documents:
Prot_000.pdf: 














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3 
SCHEDULE OF ASSESSMENTS 
Table 3-1 and Table 3-2 provide the schedule of assessments during the study, from the 
Screening Period through the Safety Follow-up Visit. 
The Screening Period is scheduled relative to the Day 1 Visit (first dose of study drug in 
Table 3-2).  
Table 3-1 
Screening Period Assessments – Study VX14-661-108 
Event/Assessment 
Screening Period 
(Day -28 Through Day -1) 
ICF and assent (when applicable) 
X 
Demographics 
X 
Medical history  
X 
Ophthalmological history  
X 
CFTR genotypea 
X 
CFQ-Rb  
X 
 
 
Height and weightc 
X 
Ophthalmologic examinationd  
X 
Complete PE 
X 
FSHe 
X 
Serum pregnancy test (all females of childbearing potential)f 
X 
Standard digital ECGg 
X 
Vital signsh 
X 
Pulse oximetryh 
X 
Spirometryi 
X 
Sweat chloridej 
X 
Urinalysis 
X 
Hematology 
X 
 
a 
All subjects will be tested to assess CFTR genotype regardless of availability of a previous CFTR genotype laboratory 
report. Refer to the Laboratory Manual to determine the appropriate genotyping assay for each subject.  
b 
CFQ-R and 
 must be completed prior to the start of any other assessments scheduled at that visit. 
c 
Weight and height will be measured with shoes off. 
d 
An ophthalmologic examination will be conducted on subjects of all ages by an ophthalmologist. The ophthalmologic 
examination does not need to be repeated if there is documentation of an examination that met the protocol criteria and 
that was conducted within 3 months before the Screening Period. Subjects who have documentation of bilateral lens 
removal do not need an ophthalmologic exam (Section 11.7.8). Subjects with clinically significant cataracts, lens 
opacity, Y-suture, or lamellar rings will be excluded. 
e 
FSH will be measured for any potentially postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be ≥ 40 mIU/mL to be considered postmenopausal. 
f 
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. 
g 
A standard digital ECG will be performed after the subject has been supine for at least 5 minutes. 
h 
Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes.  
i 
Spirometry may be performed pre- or post-bronchodilator (Section 11.6.1). Screening spirometry evaluation may be 
repeated, as specified in Section 8.1.1.1. 
j  
A sweat chloride test must be performed if an eligible sweat chloride value is not available in the subject’s medical 
records. For subjects using a sweat chloride value documented in their medical record to establish eligibility, the sweat 
chloride test at the Screening Visit is optional. 




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In Table 3-2, all visits are scheduled relative to the Day 1 Visit (first dose of study drug). The 
Week 2 Visit occurs after 2 weeks of treatment have been completed (i.e., 
Day 15 [± 3] days). The Week 8 (± 5 days) Visit occurs after 8 weeks of study drug 
administration have been completed (i.e., Day 57 [± 5 days]).  
Similarly, during Treatment Period 2, the Day 113, Week 17 Visit is the first dose of study 
drug for Treatment Period 2. The Week 18 Visit of Treatment Period 2 occurs after 2 weeks 
of treatment have been completed in Treatment Period 2 (i.e., Day 127 [± 3 days] of the 
study). The Week 24 (± 5 days) Visit occurs after 8 weeks of study drug administration have 
been completed in Treatment Period 2 (i.e., Day 169 [± 5 days]). 


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Table 3-2 
Treatment Periods, Washout Period, ETT, and Safety Follow-up Visit Assessments – Study VX14-661-108 
 
Treatment Period 1 
Washouta 
Treatment Period 2 
 
 
Event/Assessmentb 
Week 1 
(Day 1) 
Week 2 
(Day 15) 
(± 3 Days) 
Week 4 
(Day 29) 
(± 5 Days) 
Week 8 
(Day 57) 
(± 5 Days) 
Safety 
Evaluation 
Visit 
Week 12  
(Day 85) 
(± 5 Days) 
Week 17a 
(Day 113) 
Week 18 
(Day 127) 
(± 3 Days ) 
Week 20 
(Day 141) 
(± 5 Days) 
Week 24 
(Day 169) 
 (± 5 Days) 
ETT 
Visitc 
Safety 
Follow-up 
Visit 
28 days 
(± 7 days) 
After Last 
Dosed 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion 
criteria review 
X 
 
 
 
 
Xe 
 
 
 
 
 
CFQ-Rf 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weightg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a 
The Washout Period starts the day after completion of the Week 8 Visit and continues for 8 weeks (+7 days). The Washout Period is considered to be complete when dosing 
has occurred at the Week 17 Visit. 
b 
All assessments will be performed before dosing unless noted otherwise. If study drug is not administered on the day of the visit (i.e., study drug interruption or premature 
discontinuation of study drug treatment), only 1 set of assessments will be collected. Subjects who prematurely discontinue study drug treatment will continue to complete all 
other scheduled study visits for assessments of efficacy (spirometry, sweat chloride, and CFQ-R) and 
 
 through the end of the Treatment Period in which discontinuation occurred, as described in Section 8.1.6. 
c 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study treatment. Subjects 
who prematurely discontinue study drug treatment will also be required to complete the Safety Follow-up Visit, approximately 28 (± 7) days after their last dose of study 
drug. If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety 
Follow-up Visit will not be required. See Section 8.1.5 and 8.1.6.  
d 
The Safety Follow-up Visit is not required for subjects who complete the Week 24 Visit and have enrolled in an extension study of VX-661 in combination with ivacaftor 
within 28 days after the last dose of study drug. 
e 
In order to continue in Treatment Period 2, subjects must not have an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including 
antibiotics) for pulmonary disease within 4 weeks before the Week 17 Visit (first dose of study drug in Treatment Period 2) and must not have any “non-CF-related” illness 
within 2 weeks before the Week 17 Visit. “Illness” is defined as an acute (serious or nonserious) condition (e.g., gastroenteritis). If the subjects do not meet these criteria, then 
the continuation of the subjects into Treatment Period 2 must be discussed with the Medical Monitor.  
f 
All questionnaires must be completed before the start of any other assessment scheduled for that visit. The CFQ-R must be completed first, followed by the 
. Subjects 
will need to complete a CFQ-R and 
 at the ETT Visit (Section 8.1.6).   
g 
Weight and height will be measured before dosing with shoes off. Height will be collected only for subjects 21 years of age or younger. 


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Table 3-2 
Treatment Periods, Washout Period, ETT, and Safety Follow-up Visit Assessments – Study VX14-661-108 
 
Treatment Period 1 
Washouta 
Treatment Period 2 
 
 
Event/Assessmentb 
Week 1 
(Day 1) 
Week 2 
(Day 15) 
(± 3 Days) 
Week 4 
(Day 29) 
(± 5 Days) 
Week 8 
(Day 57) 
(± 5 Days) 
Safety 
Evaluation 
Visit 
Week 12  
(Day 85) 
(± 5 Days) 
Week 17a 
(Day 113) 
Week 18 
(Day 127) 
(± 3 Days ) 
Week 20 
(Day 141) 
(± 5 Days) 
Week 24 
(Day 169) 
 (± 5 Days) 
ETT 
Visitc 
Safety 
Follow-up 
Visit 
28 days 
(± 7 days) 
After Last 
Dosed 
Ophthalmologic 
examinationh 
 
 
 
 
 
 
 
 
 
X 
X 
Complete PEi 
X 
 
 
 
 
X 
 
 
 
 
 
Pregnancy testj 
urine 
urine 
urine 
serum 
urine 
urine 
urine 
urine 
serum 
serum 
serum 
Standard digital ECGk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometrym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sweat chloriden 
X 
 
X 
X 
  
X 
 
X 
X 
 
  
Urinalysis 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
h  
Subjects < 18 years of age at screening who discontinue study drug treatment after receiving at least 1 dose of study drug, and subjects < 18 years of age at screening who 
complete treatment but do not enroll in a separate extension study of VX-661/ivacaftor within 28 days after the last dose of study drug will have an ophthalmologic exam 
conducted by a licensed ophthalmologist (see Section 11.7.8). The exam may be completed at either the ETT or Safety Follow-up Visit, but must be completed by the date of 
the Safety Follow-up Visit. Subjects who have documented bilateral lens removal do no need an ophthalmologic exam. 
i 
In addition to the complete PEs indicated, symptom-targeted PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. 
j 
Pregnancy tests will be performed for all female subjects of childbearing potential. 
k 
All standard digital ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes. At the Week 1, Week 2, Week 17, and Week 18 Visits, 
ECGs will be collected before dosing and at 1.5, 3, 4, and 6 hours after the morning dose. At the Week 1, Week 2, Week 17, and Week 18 visits the 4-hour postdose ECG will 
be collected before the 4-hour postdose spirometry assessment. The predose ECGs collected at the Week 1 (Day 1) visit will be performed in triplicate. If study drug is not 
administered on the day of the visit (i.e., because of study drug interruption or permanent discontinuation of study drug), only 1 ECG will be collected. 
l 
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest (seated or supine) for at least 5 minutes. 
m 
At all visits, spirometry must be performed for all subjects before dosing and should be performed prebronchodilator (Section 11.6.1). At Week 1, Week 2, Week 17, and 
Week 18, subjects < 18 years of age at the Screening Visit will have additional spirometry performed at 2 and 4 hours after the morning dose. If more than 1 spirometry 
assessment is required at a visit, bronchodilators will be withheld until completion of the last scheduled spirometry assessment is completed.  
n  
The Sweat collection on dosing visits should occur approximately 1 hour before the PK sample collection and before the morning dose of the study drugs. Sweat collection 
will not overlap with any other study assessments (Section 11.6.2). 






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4 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
 
2 
Protocol Synopsis ............................................................................................................. 4 
3 
Schedule of Assessments.................................................................................................. 8 
4 
Table of Contents ........................................................................................................... 15 
List of Tables...................................................................................................................... 19 
List of Figures .................................................................................................................... 19 
Glossary of Terms .............................................................................................................. 20 
5 
Introduction.................................................................................................................... 22 
6 
Study Objectives ............................................................................................................ 24 
6.1 
Primary Objectives ................................................................................................... 24 
6.2 
Secondary Objectives ............................................................................................... 24 
7 
Study Endpoints ............................................................................................................. 24 
7.1 
Primary Endpoint ...................................................................................................... 24 
7.2 
Key Secondary Endpoint .......................................................................................... 25 
7.3 
Secondary Endpoints ................................................................................................ 25 
 
 
8 
Study Design ................................................................................................................... 25 
8.1 
Overview of Study Design ....................................................................................... 25 
8.1.1 
Screening .......................................................................................................... 27 
8.1.1.1 
Repetition of Screening Assessment(s) ...................................................... 27 
8.1.1.2 
Rescreening ................................................................................................ 28 
8.1.1.3 
Extension of the Screening Period Window .............................................. 28 
8.1.2 
Treatment Period 1 (8 Weeks) .......................................................................... 28 
8.1.3 
Washout Period (8 Weeks) ............................................................................... 28 
8.1.4 
Treatment Period 2 (8 Weeks) .......................................................................... 28 
8.1.5 
Follow-up.......................................................................................................... 29 
8.1.6 
Early Treatment Termination ........................................................................... 29 
8.1.7 
Independent Data Monitoring Committee ........................................................ 30 
8.2 
Rationale for Study Design and Study Drug Regimens ........................................... 30 
8.2.1 
Study Design..................................................................................................... 30 
8.2.2 
Study Drug Dose and Duration ........................................................................ 31 
8.2.3 
Rationale for Study Population......................................................................... 31 
8.2.4 
Rationale for Study Assessments ..................................................................... 32 
9 
Study Population ............................................................................................................ 33 
9.1 
Inclusion Criteria ...................................................................................................... 34 
9.2 
Exclusion Criteria ..................................................................................................... 35 
9.3 
Study Restrictions ..................................................................................................... 37 
9.3.1 
Additional Dietary Restrictions/Prohibited Medications ................................. 37 
9.4 
Prior and Concomitant Medications ......................................................................... 37 
9.5 
Removal of Subjects ................................................................................................. 38 
9.6 
Replacement of Subjects .......................................................................................... 39 
10 Study Drug Administration and Management ........................................................... 39 




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11.7.6 
Pulse Oximetry ................................................................................................. 60 
11.7.7 
Liver Function Test Parameters ........................................................................ 60 
11.7.8 
Ophthalmologic Examination ........................................................................... 61 
12 Statistical and Analytical Plans .................................................................................... 62 
12.1 Sample Size and Power ............................................................................................ 62 
12.2 Analysis Sets ............................................................................................................ 63 
12.3 Statistical Analysis ................................................................................................... 63 
12.3.1 
General Considerations ..................................................................................... 64 
12.3.2 
Background Characteristics .............................................................................. 64 
12.3.2.1 Subject Disposition .................................................................................... 65 
12.3.2.2 Demographics and Baseline Characteristics .............................................. 65 
12.3.2.3 Prior and Concomitant Medications........................................................... 65 
12.3.2.4 Study Drug Exposure and Compliance ...................................................... 66 
12.3.3 
Efficacy Analysis .............................................................................................. 66 
12.3.3.1 Analysis of Primary Variables ................................................................... 67 
12.3.3.2 Analysis of Secondary Efficacy Variables ................................................. 67 
12.3.3.3 Adjustment for Multiple Comparisons ...................................................... 68 
12.3.4 
Safety Analysis ................................................................................................. 70 
12.3.4.1 Adverse Events........................................................................................... 70 
12.3.4.2 Clinical Laboratory Assessments ............................................................... 71 
12.3.4.3 Electrocardiogram ...................................................................................... 71 
12.3.4.4 Vital Signs .................................................................................................. 72 
12.3.4.5 Physical Examination ................................................................................. 72 
12.3.4.6 Other Safety Analysis ................................................................................ 72 
12.3.4.6.1 Pulse Oximetry .................................................................................... 72 
12.3.4.6.2 Postdose Spirometry ............................................................................ 72 
12.3.5 
Interim and IDMC Analyses ............................................................................. 72 
12.3.5.1 Interim Analysis ......................................................................................... 72 
12.3.5.2 IDMC Analysis .......................................................................................... 73 
12.4 Clinical Pharmacology Analysis .............................................................................. 73 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ..................... 73 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting .................................................................................................................. 73 
13.1.1 
Adverse Events ................................................................................................. 73 
13.1.1.1 Definition of an Adverse Event.................................................................. 73 
13.1.1.2 Clinically Significant Assessments ............................................................ 73 
13.1.1.3 Documentation of Adverse Events............................................................. 74 
13.1.1.4 Adverse Event Severity .............................................................................. 74 
13.1.1.5 Adverse Event Causality ............................................................................ 75 
13.1.1.6 Study Drug Action Taken .......................................................................... 76 
13.1.1.7 Adverse Event Outcome ............................................................................ 76 
13.1.1.8 Treatment Given......................................................................................... 76 
13.1.2 
Serious Adverse Events .................................................................................... 77 
13.1.2.1 Definition of a Serious Adverse Event....................................................... 77 
13.1.2.2 Documentation of Serious Adverse Events................................................ 77 


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13.1.2.3 Reporting Serious Adverse Events............................................................. 78 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ................................ 78 
13.2 Administrative Requirements ................................................................................... 78 
13.2.1 
Ethical Considerations ...................................................................................... 78 
13.2.2 
Subject Information and Informed Consent and Assent ................................... 78 
13.2.3 
Investigator Compliance ................................................................................... 79 
13.2.4 
Access to Records ............................................................................................. 79 
13.2.5 
Subject Privacy ................................................................................................. 79 
13.2.6 
Record Retention .............................................................................................. 79 
13.2.7 
Study Termination ............................................................................................ 80 
13.3 Data Quality Assurance ............................................................................................ 80 
13.4 Monitoring ................................................................................................................ 80 
13.5 Electronic Data Capture ........................................................................................... 81 
13.6 Publications and Clinical Study Report .................................................................... 81 
13.6.1 
Publication of Study Results ............................................................................. 81 
13.6.2 
Clinical Study Report ....................................................................................... 82 
14 References ....................................................................................................................... 83 
15 Protocol Signature Pages .............................................................................................. 87 
15.1 Sponsor Signature Page ............................................................................................ 87 
15.2 Investigator Signature Page ...................................................................................... 88 
16 Appendix A: Second CFTR Allele Mutations Included for Subjects who are 
Heterozygous for the F508del-CFTR Mutation .......................................................... 89 
 


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List of Tables 
Table 3-1 
Screening Period Assessments – Study VX14-661-108 ................................... 8 
Table 3-2 
Treatment Periods, Washout Period, ETT, and Safety Follow-up Visit 
Assessments – Study VX14-661-108 ............................................................. 11 
Table 9-1 
Study Restrictions ........................................................................................... 37 
Table 10-1 
Study Drug Administration – Treatment Period ............................................. 40 
Table 10-2 
Identity of Study Drugs, Dosage, and Storage ................................................ 43 
Table 11-1 
Safety Laboratory Test Panels ........................................................................ 55 
Table 13-1 
Grading of AE Severity .................................................................................. 75 
Table 13-2 
Classifications for AE Causality ..................................................................... 75 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ............ 76 
Table 13-4 
Classifications for Outcome of an AE ............................................................ 76 
List of Figures 
Figure 8-1 
Schematic of the Study Design ....................................................................... 27 
Figure 12-1 
 Testing Strategy for the Primary and Key Secondary Endpoint .................... 69 


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Glossary of Terms 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AM 
morning 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFFT TDN 
Cystic Fibrosis Foundation Therapeutics Development Network 
CFQ-R 
Cystic Fibrosis Questionnaire–Revised 
CFTR 
cystic fibrosis transmembrane conductance regulator protein 
CFTR 
cystic fibrosis transmembrane conductance regulator gene 
Cl− 
chloride ion 
CPAP 
Clinical Pharmacology Analysis Plan 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
EC 
ethics committee 
ECFS 
European Cystic Fibrosis Society 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EENT 
eyes/ears/nose/throat 
EU 
European Union 
ERS 
European Respiratory Society 
ETT 
Early Treatment Termination 
F508del 
cystic fibrosis transmembrane conductance regulator gene mutation with an in-frame 
deletion of a phenylalanine codon corresponding to position 508 of the wild-type 
protein 
F508del 
cystic fibrosis transmembrane conductance regulator protein lacking the 
phenylalanine normally found at position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEF25%-75% 
forced expiratory flow 25% to 75% 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
G551D 
cystic fibrosis transmembrane conductance regulator missense gene mutation that 
results in the replacement of a glycine residue at position 551 of cystic fibrosis 
transmembrane conductance regulator with an aspartic acid residue 
GCP 
Good Clinical Practice 


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Abbreviation 
Definition 
GGT 
gamma-glutamyl transpeptidase 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
 
 
IV 
intravenous 
IVA 
Ivacaftor (VX-770, Kalydeco) 
IWRS 
interactive web response system 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
mRNA 
messenger ribonucleic acid 
 
 
PBO 
placebo 
PCS 
potentially clinically significant 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic, pharmacokinetics 
PM 
evening 
q12h 
every 12 hours 
qd 
once daily 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia's formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
 
 
SI 
International System 
SOP 
standard operating procedure 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment emergent 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
v2 
version 2 
661/770 
VX-661 and ivacaftor (VX-770) combination treatment 
770 
ivacaftor (VX-770) 


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5 
INTRODUCTION 
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide1 and is the 
most common fatal genetic disease in persons of European descent.2 Based on the size of the 
population, CF qualifies as an orphan disease.3,4 Despite progress in the treatment of CF with 
antibiotics and mucolytics, the predicted median age of survival for a person with CF is in 
the mid-30s.2,5 Although the disease affects multiple organs, most morbidity and mortality 
are caused by progressive loss of lung function.6 
CF is an autosomal recessive genetic disease caused by a defect in the gene encoding the CF 
transmembrane conductance regulator (CFTR), an epithelial chloride ion (Cl−) channel 
activated by cyclic adenosine monophosphate-dependent protein kinase A that is responsible 
for aiding in the regulation of salt and water absorption and secretion in various tissues.2 This 
function is defective in patients with CF due to a loss of either cell surface expression and/or 
function. 
More than 1900 mutations in the CFTR gene have been identified.7 Mutations in the CFTR 
gene have been classified based on the molecular and functional consequence of the mutation 
on the CFTR protein8,9,10 and can be generally considered to reduce the quantity of 
functional CFTR protein that reaches the epithelial cell surface or reduce the function of 
CFTR protein located at the cell surface. CFTR gene mutations that affect the quantity of 
functional cell surface CFTR protein include defects that reduce CFTR protein synthesis and 
defects that impede the cellular processing and delivery of CFTR proteins to the cell surface. 
CFTR gene mutations associated with minimal CFTR function include 
• mutations associated with severe defects in ability of the CFTR channel to open and 
close, known as defective channel gating or "gating mutations"; 
• severe defects in the cellular processing of CFTR and its delivery to the cell surface; 
• no (or minimal) CFTR synthesis; and 
• severe defects in channel conductance. 
The most prevalent mutation is an in-frame deletion in the CFTR gene resulting in a loss of 
phenylalanine at position 508 in the CFTR protein (F508del-CFTR).10 In the US, almost 87% 
of patients with CF have at least 1 copy of the F508del-CFTR mutation, and about 47% have 
2 copies.11 In the European Union (EU), approximately 83% of patients with CF have 1 or 
2 copies of the F508del-CFTR mutation, and approximately 38.7% of patients with CF in the 
United Kingdom have 2 copies.12 The F508del-CFTR mutation interferes with the ability of 
the CFTR protein to reach and remain at the cell surface, as well as to open and close, 
resulting in decreased Cl− transport.13,14 The combined effect is a marked reduction in 
F508del-CFTR-mediated Cl− secretion that impairs fluid regulation and promotes 
accumulation of thick, sticky mucus in the airway. The mucus build-up obstructs the airways 
and predisposes the patient to chronic lung infections.15  


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Two complementary approaches to increase CFTR-mediated Cl− secretion in the airway 
epithelia have been studied.9 One approach is to treat with a compound that will modify the 
cellular processing and trafficking of the CFTR protein to increase the amount of functional 
CFTR at the cell surface. This kind of compound has been termed a CFTR corrector. Another 
approach is to treat with a compound that increases the channel gating activity of protein 
kinase A-activated CFTR at the cell surface to enhance ion transport. This kind of compound 
has been termed a potentiator. 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 to ameliorate lung 
disease in patients with CF. A modest restoration of Cl− secretion through the action of a 
potentiator and/or corrector could prevent the hyperabsorption of water across the apical 
surface of epithelial cells, allowing proper maintenance of airway hydration. Adequate 
airway hydration could alleviate the cycle of mucus plugging, infection, and inflammation, 
which leads to irreversible structural changes in the lungs and, eventually, respiratory failure 
for patients with CF. 
Residual function mutations are Class II through V mutations that have some residual 
chloride transport and result in a less severe clinical phenotype. Despite slower disease 
progression, patients with residual function mutations still develop chronic pulmonary 
disease, pulmonary exacerbations, and pancreatic insufficiency, and overall have a reduced 
lifespan. Ivacaftor (a potentiator) has been shown to increase the chloride transport in these 
mutations by increasing the open channel probability. Populations of patients with these 
mutations are both genotypically and phenotypically diverse, and it is anticipated that the 
second CFTR allele will have some responsiveness to a potentiator. Mutations were 
identified using 2 criteria: in vitro response to ivacaftor and population-level clinical 
phenotype from epidemiologic data 16 or published literature.17-24 
VX-661 is a compound developed by Vertex Pharmaceuticals Incorporated (Vertex) that has 
been shown to have CFTR corrector properties. Several lines of in vitro evidence suggest that 
VX-661 works by promoting the proper cellular processing and trafficking of a fraction of 
F508del-CFTR protein during its biogenesis and processing in the endoplasmic reticulum, 
allowing it to exit the endoplasmic reticulum and traffic the cell surface.25 When added for 
more than 24 hours to human bronchial epithelial (HBE) cells isolated and cultured from 
lung explants obtained from donors with CF (CF-HBE cells) who are homozygous for the 
F508del-CFTR mutation, a concentration-dependent increase in levels of mature (i.e., plasma 
membrane) F508del-CFTR was observed. The increased trafficking of F508del-CFTR to the 
cell surface resulted in a significant increase in Cl− secretion.25 VX-661 did not correct the 
processing and localization of other misfolded or normally folded proteins other than CFTR, 
suggesting that the mechanism of VX-661 action is selective for CFTR (CFTR corrector).26 
Ivacaftor (also known as VX-770) is the first CFTR modulator to show an improvement in 
CFTR function and clinical benefit in patients with CF. Results from several Phase 3 studies 
showed that ivacaftor is effective in the treatment of patients with CF who have mutations 
that result in gating defects, as evidenced by sustained improvements in CFTR channel 
function (measured by reduction in sweat chloride concentration) and corresponding 
substantial, durable improvements in lung function, respiratory symptoms, and weight gain. 


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Ivacaftor was also well tolerated, as evidenced by the rates and reasons for premature 
discontinuation and results of safety assessments.  
As of July 2015, in the US, Kalydeco is indicated for the treatment of CF in patients age 
2 years and older who have one of the following mutations in the CFTR gene: G551D, 
G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H. In the EU 
and in Israel, Kalydeco is indicated for the treatment of CF in patients age 6 years and older 
who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, 
G178R, G551S, S1251N, S1255P, S549N, or S549R. In Canada, Kalydeco is indicated for the 
treatment of CF in patients age 6 years and older who have one of the following mutations in 
the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, 
S549R, or G970R. It is also indicated for the treatment of CF in patients age 18 years and 
older who have the R117H mutation in the CFTR gene. In Australia, Kalydeco is indicated 
for the treatment of CF in patients age 6 years and older who have a G551D or other gating 
(class III) mutation in the CFTR gene. In New Zealand, Switzerland, and Liechtenstein, 
Kalydeco is currently indicated for the treatment of CF in patients 6 years of age and older 
who have the G551D mutation. 
Details about the VX-661 and ivacaftor development programs can be found in the 
Investigator's Brochures.27,28 
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
To evaluate the efficacy of VX-661 in combination with ivacaftor and ivacaftor monotherapy 
through 8 weeks of treatment in subjects with CF who are heterozygous for the F508del 
mutation on the CFTR gene and a second allele with a CFTR mutation predicted to have 
residual function. 
6.2 
Secondary Objectives 
• To evaluate the safety of VX-661 in combination with ivacaftor through 8 weeks of 
treatment 
• To evaluate the safety of ivacaftor monotherapy through 8 weeks of treatment 
• To investigate the pharmacokinetics (PK) of VX-661 and its metabolite M1 (M1-661), 
and ivacaftor and its metabolite M1 (M1-ivacaftor) 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change in percent predicted forced expiratory volume in 1 second (FEV1) from 
study baseline to the average of the Week 4 and Week 8 measurements in each Treatment 
Period. 




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• VX-661/ivacaftor combination treatment 
o Morning dose: 1 tablet fixed-dose combination of VX-661 100 mg/ivacaftor 150 mg 
and 1 tablet ivacaftor placebo 
o Evening dose: 1 tablet ivacaftor 150 mg 
• Ivacaftor monotherapy 
o Morning dose: 1 tablet placebo visually matched to the fixed-dose combination tablet 
and 1 tablet ivacaftor 150 mg 
o Evening dose: 1 tablet ivacaftor 150 mg 
• Placebo 
o Morning dose: 1 tablet placebo visually matched to the fixed-dose combination tablet 
and 1 tablet placebo visually matched to ivacaftor 150 mg 
o Evening dose: 1 tablet placebo visually matched to ivacaftor 150 mg 
This study includes a Screening Period (approximately 28 days), Treatment Period 1 
(8 weeks), Washout Period (8 weeks), Treatment Period 2 (8 weeks), and Safety Follow-up 
Visit (approximately 28 days). Approximately 204 subjects (34 per sequence) will be 
enrolled and stratified by age at the Screening Visit (<18 versus ≥18 years of age), FEV1 
severity (determined during the Screening Visit; <70% versus ≥70% predicted), and type of 
residual function mutation on the second CFTR allele (Class V non-canonical splice mutation 
versus Classes II to IV residual function mutation; see Section 16), and then randomized 
(1:1:1:1:1:1) to 1 of the 6 treatment sequences, as shown in Figure 8-1. A minimum of 25% 
of enrolled subjects will carry a Class II to IV mutation on the second CFTR allele (see 
Section 16). Stratification of enrollment will be managed through the interactive web 
response system (IWRS). Enrollment into the non-canonical splice strata will be limited to no 
more than 75% of total enrollment. 
• Sequence 1: VX-661/ivacaftor in Treatment Period 1→washout→ivacaftor monotherapy 
in Treatment Period 2  
• Sequence 2: ivacaftor monotherapy in Treatment Period 1→washout→VX-661/ivacaftor 
in Treatment Period 2 
• Sequence 3: VX-661/ivacaftor in Treatment Period 1→washout→placebo in Treatment 
Period 2 
• Sequence 4: placebo in Treatment Period 1→washout→VX-661/ivacaftor in Treatment 
Period 2 
• Sequence 5: ivacaftor monotherapy in Treatment Period 1→washout→ placebo in 
Treatment Period 2 
• Sequence 6: placebo in Treatment Period 1→washout→ivacaftor monotherapy in 
Treatment Period 2 
Subjects who complete the Week 24 Visit will be offered the opportunity to enroll in an 
extension study, if they meet the eligibility criteria for the extension study. 




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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. 
8.1.1.2 
Rescreening 
Subjects may only be rescreened with the approval of the Medical Monitor. 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 ≥40 mIU/mL during prior 
screening), sweat chloride, and ophthalmologic examination (if performed within the last 
3 months). If a subject is rescreened, the screening window will begin once the first 
rescreening assessment has been initiated. 
8.1.1.3 
Extension of the 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 8.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria  
• Additional time to conduct ophthalmologic examinations (Section 11.7.8) 
8.1.2 
Treatment Period 1 (8 Weeks) 
Treatment Period 1 will last approximately 8 weeks. Subjects will be randomized to 1 of 
6 sequences, as shown in Section 8.1. 
For subjects who are on a stable regimen of inhaled cycling antibiotics, the Treatment 
Period 1 Day 1 Visit should be timed to occur at the end of an off-cycle but no less than 
14 days after the last dose of inhaled antibiotics in the previous on-cycle. The first dose of 
study drug will be administered on Treatment Period 1 Day 1. Dosing details are given in 
Section 10.2. The first dose of a new cycle of inhaled cycling antibiotic should also occur on 
Treatment Period 1 Day 1.  
Study visits during the Treatment Period will occur as shown in Table 3-2. Subjects will be 
outpatients during the Treatment Period. All visits should occur within the windows 
specified. 
Subjects who prematurely discontinue study drug treatment during Treatment Period 1 will 
complete assessments through the Week 8 Visit as described in Section 8.1.6. 
8.1.3 
Washout Period (8 Weeks) 
The Washout Period starts the day after completion of the Week 8 Visit. It has a duration of 
8 weeks (+ 7 days) but may be extended with approval from the Medical Monitor. A safety 
evaluation visit will be conducted at Week 12 (± 5 days). 
8.1.4 
Treatment Period 2 (8 Weeks) 
Treatment Period 2 will last approximately 8 weeks. In order to continue in Treatment 
Period 2, subjects must not have an acute upper or lower respiratory infection, pulmonary 
exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 
4 weeks before the Week 17 Visit (first dose of study drug in Treatment Period 2) and must 




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collected. Vertex may retain and continue to use any data collected before such withdrawal 
of consent. 
8.1.7 
Independent Data Monitoring Committee 
The safety of administration of VX-661 in combination with ivacaftor will be monitored by 
an external independent data monitoring committee (IDMC), which will conduct periodic 
reviews of safety data. 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. 
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
The present study is 1 of 4 pivotal, Phase 3 clinical studies designed to demonstrate the 
clinical efficacy and safety of ivacaftor and VX-661 in combination with ivacaftor in subjects 
with CF. A randomized, double-blind study design will prevent observer bias and reduce 
symptoms or outcomes arising from the subjects’ knowledge of treatment. The study 
evaluates the efficacy and safety of 1 dose level of VX-661 (100 mg once daily [qd]) in 
combination with ivacaftor (150 mg every 12 hours [q12h]) as well as the efficacy and safety 
of 1 dose level of ivacaftor monotherapy (150 mg q12h). 
Subjects enrolled into this study will be heterozygous for the F508del-CFTR mutation, a 
processing mutation anticipated to respond to the combination of VX-661 and ivacaftor 
based on “proof-of-concept” Study VX-11-661-101 (Study 101). Results from Study 101, 
Group 7, in subjects heterozygous for F508del-CFTR and G551D-CFTR, suggest that 
clinically meaningful improvement in percent predicted FEV1 can be achieved with the 
combination of VX-661 and ivacaftor, even in the presence of a single F508del-CFTR allele 
when the second allele is also responsive to potentiator modulation.  
A crossover design with randomization to 6 treatment sequences will enable within-subject 
comparison of the effects of VX-661 in combination with ivacaftor and ivacaftor 
monotherapy. This design enhances the power to detect treatment differences by reducing the 
inherent between-subject variability present in a parallel-arm study. This is particularly 
important in studying the F508del-CFTR/residual function population, which has a low 
genotypic incidence (approximately 7% of the CF population worldwide). Furthermore, this 
population, as a whole, is heterogeneous with regard to baseline disease as well as potential 
degree of response to corrector and potentiator therapies.  
There are no approved therapies for treatment of subjects with F508del-CFTR/residual 
function that target the underlying mechanism of the disease that could be used as an active 
comparator for VX-661 in combination with ivacaftor or ivacaftor monotherapy. Therefore, 
the use of placebo in this study is deemed ethical and necessary to adequately assess the 
benefit of treatment with VX-661 in combination with ivacaftor and treatment with ivacaftor 
monotherapy. All subjects enrolled in the study will continue their normal, stable treatment 
for CF symptoms throughout the study. 


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8.2.2 
Study Drug Dose and Duration 
The dose regimen of VX-661 chosen for continued development in Phase 3 was studied in 
Study 101 in 2 CF populations: F508del-CFTR homozygous subjects (Group 4) and 
F508del-CFTR heterozygous subjects who had G551D-CFTR on the other allele (Group 7). 
The dose regimen of VX-661 100 mg qd in combination with ivacaftor 150 mg q12h 
provided clinically meaningful and statistically significant improvements in percent predicted 
FEV1 in both populations as well as a signal of CFTR modulation as assessed by the change 
in sweat chloride. 
The dose regimen of ivacaftor planned for this study (150 mg q12h) is the current labeled 
dose regimen for patients with CF with gating mutations who are aged 6 years and older. 
An 8-week period was selected as the duration for Treatment Periods 1 and 2. A significant 
response in FEV1 is anticipated to be observed after 2 to 4 weeks of treatment with VX-661 
in combination with ivacaftor. The primary endpoint, which is the absolute change in percent 
predicted FEV1 from study baseline to the average of measurements at Weeks 4 and 8 in each 
Treatment Period, was selected in order to obtain a more robust assessment of the durability 
of response that is less affected by short-term variability in FEV1. An 8-week period was 
selected as the duration for the Washout Period. Based on PK data collected in the healthy 
subjects (Study VX07-661-001 [Study 001]), the terminal half-life of VX-661 is 
approximately 116 hours.27 For ivacaftor, the estimated terminal half-life is approximately 
12 hours. Thus, following an 8-week washout, negligible concentration of VX-661 and 
ivacaftor is expected to remain in study subjects. Based on preliminary efficacy data from 
Study VX11-661-101 and efficacy data from previous ivacaftor studies, no residual effects of 
VX-661/ivacaftor combination therapy and ivacaftor monotherapy are expected by the end of 
the 8-week washout period. 
8.2.3 
Rationale for Study Population 
The study population will be subjects with CF who are 12 years of age and older and are 
heterozygous for the F508del-CFTR mutation and with a second CFTR mutation predicted to 
have residual function. Based on the results from Study 101 (Section 8.2.1), subjects with the 
F508del-CFTR mutation on only 1 allele may respond to VX-661/ivacaftor treatment when 
the second allele is also responsive to potentiator modulation. The inclusion of subjects with 
CF who are 12 to 17 years of age is justified based on severity of disease and allometric 
scaling. The overall disease status for the adolescent and adult populations to be enrolled in 
this study is anticipated to be similar based on the identical enrollment criteria, particularly 
the FEV1 (i.e., FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height at 
screening) and the requirement for clinical stability. Additionally, the expected maturity of 
the cytochrome P450 (CYP) enzymes in adolescents supports their inclusion. The dose 
regimen of ivacaftor planned for this study (150 mg q12h) is the current labeled dose 
regimen for patients with CF with gating mutations who are aged 6 years and older. Based on 
the historical data from the ivacaftor Phase 3 program and the US CF Foundation Registry on 
weight as a function of age in patients with CF, weights in the adolescent population are 
expected to be only slightly lower than those of the adult CF population. 






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9.1 
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible: 
1. Subject (or their legally appointed and authorized representative) will sign and date an 
informed consent form (ICF) and, where appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Subjects (males and females) will be aged 12 years or older on the date of informed 
consent or, where appropriate, assent. 
4. Heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to 
have residual function (see Section 16). The results of the confirmatory genotype sample 
obtained during screening must be reviewed before randomization. CFTR mutations that 
are predicted to have residual function were defined using the parameters in Section 16. 
5. FEV1 ≥ 40% and ≤ 90% of predicted normal for age, sex, and height (equations of Wang 
et al. or Hankinson et al.)43,44 during screening. Spirometry measurements must meet 
ATS/ERS criteria29 for acceptability and repeatability (Section 8.1.1.1). 
Subjects must meet Inclusion Criterion 6 or 7. 
6. Sweat chloride value ≥ 60 mmol/L from test results obtained during screening OR as 
documented in the subject’s medical record. 
7. If the sweat chloride value is < 60 mmol/L, there must be documented evidence of 
chronic sinopulmonary disease45 manifested by (but not limited to) at least 1 of the 
following: 
o Persistent colonization/infection with typical CF pathogens, including Staphylococcus 
aureus, Haemophilus influenzae, and mucoid and nonmucoid Pseudomonas 
aeruginosa 
o Chronic cough and sputum production 
o Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, 
hyperinflation) 
o Nasal polyps, chronic sinusitis; radiographic or computed tomographic abnormalities 
of the paranasal sinuses 
Specific criteria for such subjects must be discussed with and approved by the Medical 
Monitor prior to randomization. 
8. Stable CF disease as judged by the investigator. 
9. Willing to remain on a stable CF medication regimen through Week 24 or, if applicable, 
the Safety Follow-up Visit. 


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9.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible: 
1. History of any comorbidity that, in the opinion of the investigator, might confound the 
results of the study or pose an additional risk in administering study drug to the subject. 
For example: 
o history of cirrhosis with portal hypertension and/or history of risk factors for Torsades 
de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left 
ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history 
of arrhythmia [ventricular and atrial fibrillation], obesity, acute neurologic events 
[subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, and 
intracranial trauma], and autonomic neuropathy) 
2. Any of the following abnormal laboratory values at Screening Visit: 
o Hemoglobin <10 g/dL 
o Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit 
of normal (ULN) aspartate aminotransferase (AST), ≥3 × ULN alanine 
aminotransferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase (GGT), 
≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total bilirubin 
o Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT 
o 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)46,47 for 
subjects ≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the 
Counahan-Barratt equation)48 for subjects aged 12 to 17 years (inclusive) 
3. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in 
therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first 
dose of study drug) 
4. A 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. If QTc exceeds 
450 msec for the screening ECG, the ECG should be repeated 2 more times during the 
Screening Period, and the average of the 3 QTc values should be used to determine the 
subject’s eligibility. 
5. History of solid organ or hematological transplantation. 
6. History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be 
clinically significant by the ophthalmologist during the ophthalmologic examination 
during the Screening Period. The ophthalmologic examination does not need to be 
repeated if there is documentation of an examination meeting protocol criteria that was 
conducted within 3 months before the Screening Period. If the subject has documentation 
of bilateral lens removal, an ophthalmologic examination is not required and this criterion 
is not applicable (Section 11.7.8). 
7. History of alcohol or drug abuse, as deemed by the investigator, in the past year, 
including but not limited to cannabis, cocaine, and opiates. 


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8. Ongoing or prior participation in an investigational drug study (including studies 
investigating VX-661, lumacaftor [VX-809], and/or ivacaftor) or use of commercially 
available CFTR modulator (e.g., Kalydeco) within 30 days of screening. 
o A washout period of 30 days or 5 terminal half-lives of the previous investigational 
study drug or the commercially available CFTR modulator, whichever is longer, must 
elapse before screening. The duration of the elapsed time may be longer if required 
by local regulations.  
o Subjects who discontinue from Study VX12-809-105 after randomization will not be 
eligible to participate in this study. 
o Ongoing participation in a noninterventional study (including observational studies 
and studies requiring assessments without administration of study drug) is permitted. 
9. Use of restricted medications or foods within the specified window before the first dose 
of study drug as defined in Table 9-1. 
10. Pregnant and nursing females (females of childbearing potential must have a negative 
pregnancy test at Screening and Day 1). 
11. Sexually active subjects of reproductive potential who are not willing to follow the 
contraception requirements outlined in Section 11.7.5. 
12. 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. An adult (aged 18 years or older) who is a relative of a study staff 
member may be randomized in the study provided that 
o the adult lives independently of and does not reside with the study staff member 
o the adult participates in the study at a site other than the site at which the family 
member is employed 
13. Colonization with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). 
For subjects who have had a history of a positive culture in the past, the investigator 
could be guided by the following suggested criteria for a subject to be considered free of 
colonization:  
o The subject should have had 2 respiratory tract cultures negative for these organisms 
within the past 12 months, with no subsequent positive cultures 
o These 2 respiratory tract cultures should have been separated by at least 3 months 
o One of these 2 respiratory tract cultures should have been obtained within the past 
6 months 
14. Subjects will not be eligible to participate in optional NPD assessments if they have any 
additional medical conditions or physical or other complaints that in the opinion of the 
investigator may place the subject at significant risk, affect the performance of the 
procedure, or limit the interpretation of the test, including but not limited to: 
o Abnormalities of the nasal passages 


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o Required use of continuous (24 hours/day) supplemental oxygen by nasal cannula 
o Intranasal medication changes within 14 days prior to receiving the first dose of study 
drug (including corticosteroids, cromolyn, phenylephrine, etc.). 
9.3 
Study Restrictions 
9.3.1 
Additional Dietary Restrictions/Prohibited Medications 
Prohibited medications and certain foods are not allowed in this study (Screening Period 
through Safety Follow-up Visit) while subjects are receiving study drug (Table 9-1). Both 
ivacaftor and VX-661 are metabolized at least in part via hepatic enzymatic pathway utilizing 
CYP 3A4, hence the need to restrict usage of known CYP 3A4 inducers and inhibitors. 
A nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. 
Table 9-1 
Study Restrictions 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period 
Certain fruits and fruit juices 
(Grapefruit, grapefruit juice, 
Seville oranges, marmalade) 
None allowed within 14 days before 
the first dose of the study drug 
None allowed through the Safety 
Follow-up Visit 
Moderate and strong CYP3A 
inducers 
None allowed within 14 days before 
the first dose of the study drug 
None allowed through the Safety 
Follow-up Visit 
Moderate and strong CYP3A 
inhibitors (except for 
ciprofloxacin) 
None allowed within 14 days before 
the first dose of the study drug 
None allowed through the Safety 
Follow-up Visit 
Commercially available CFTR 
modulators (e.g., Kalydeco) 
None allowed within 30 days before 
and during screening 
None allowed through the Safety 
Follow-up Visit 
CYP: cytochrome P450. 
Note: The use of restricted medication by subjects with medical needs will be addressed on a case-by-case basis 
with the Medical Monitor. 
9.4 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered from 
28 days before the Screening Period through the Safety Follow-up Visit, if applicable, will be 
recorded in each subject's source documents. For subjects who are screened but are not 
subsequently randomized into the study, details of prior medication will only be documented 
in the subjects' source documents. 
• Subjects must remain on a stable medication (and supplement) regimen for their CF from 
28 days before Day 1 through the Safety Follow-up Visit. Stable medication regimen is 
defined as the current medication regimen for CF that subjects have been following for at 
least 28 days before Day 1. Subjects must not initiate long-term treatment with new 
medication from 28 days before Day 1 through the Safety Follow-up Visit unless 
discussed and approved by the Vertex Medical Monitor. Guidelines for stable medication 
regimens for CF are as follows: 


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o Subjects who are taking daily inhaled tobramycin or other chronically inhaled 
antibiotics should remain on that regimen throughout the study. 
o Subjects who are on a stable cycled regimen of a single inhaled antibiotic should 
continue on this antibiotic throughout the study. The timing of the first dose of study 
drug should be synchronized described in Section 8.1.2 and Section 8.1.4. 
o Subjects who alternate 2 different antibiotics monthly should remain on the same 
schedule during the study. To reduce variability, the inhaled antibiotic treatment 
should be the same and at the same stage through the cycle at the start of each study 
drug Treatment Period. 
o Subjects may receive doses of prednisone up to 10 mg/day (chronically) or 
prednisone 60 mg qd for up to 5 days without prior approval of the Medical Monitor. 
• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments 
performed according to the guidelines provided in Section 11.6.1. 
• Concomitant use of medications known to prolong the QT interval should be used with 
caution during the study, as the effect of VX-661/ivacaftor on the QT interval has not 
been evaluated in a thorough QT study. Consideration should be given to obtaining an 
ECG when concomitant medication known to prolong the QT interval is administered.  
9.5 
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 should continue to be 
followed as noted in Section 8.1.6, provided the subject has not withdrawn consent. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. 
The investigator will inquire about the reason for withdrawal, request that the subject return 
all unused investigational product(s), request that the subject return for an ETT and/or Safety 
Follow-up Visit, if applicable (Section 8.1.5, Section 8.1.6), and follow up with the subject 
regarding any unresolved AEs. 
If the subject withdraws consent, no further evaluations will be performed, and no additional 
data will be collected. Vertex may retain and continue to use any data collected before such 
withdrawal of consent.  
The investigator should inquire about the reason for withdrawal of consent.  
Subjects must return all unused study drug. 
A subject will be withdrawn from study drug treatment for any of the following reasons: 
• A female subject or a female partner of a male subject has a confirmed pregnancy. 
• A subject’s treatment is unblinded by the investigator. 


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A subject may be withdrawn from study drug treatment after a discussion between the 
investigator and the Medical Monitor for any of the following reasons: 
• A subject develops a medical condition that requires prolonged concomitant therapy with 
a prohibited medication or prolonged interruption of the study drug. 
• A subject develops a life-threatening AE or a serious adverse event (SAE) that places 
him/her at immediate risk, and discontinuation of study drug treatment and withdrawal 
from the study are deemed necessary. 
• A subject is noncompliant with study requirements. 
• A subject has an increase in transaminases (ALT or AST) according to evaluations and 
management described in Section 11.7.7. 
• A subject has an increase in QTc according to evaluations and management described in 
Section 11.7.4. 
• A subject develops a cataract or lens opacity (see Section 11.7.8). 
Subjects who prematurely discontinue study drug treatment should continue to return for 
assessments as noted in Section 8.1.6.  
9.6 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug 
Treatment Periods may be replaced at Vertex's discretion. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
Study drug refers to VX-661/ivacaftor, ivacaftor, and their matching placebos. 
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 
Administration 
Study drug tablets will be administered orally. Subjects will receive the same number of 
tablets each day to maintain the blind. Refer to Table 10-1. 


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Table 10-1 
Study Drug Administration – Treatment Period 
Treatment  
Time 
Drug(s) and Dose(s) Administered 
Route of Administration 
VX-661/ivacaftor 
AM 
VX-661 100-mg/IVA 150-mg fixed-dose tablet 
IVA matching placebo tablet 
oral 
PM 
IVA 150-mg tablet 
oral 
Ivacaftor 
AM 
VX-661/IVA matching placebo tablet 
IVA 150-mg tablet 
oral 
PM 
IVA 150-mg tablet 
oral 
Placebo 
AM 
VX-661/IVA matching placebo tablet 
IVA matching placebo tablet 
oral 
PM 
IVA matching placebo tablet 
oral 
AM: morning; IVA: ivacaftor; PM: evening. 
Study drug should be administered within 30 minutes after starting a meal with 
fat-containing food, such as a "standard CF" high-fat, high-calorie meal or snack, according 
to the following guidelines: 
1. Study drugs will be administered after the start and before the end of a meal throughout 
each of the 2 Treatment Periods. It is recommended that the duration of each meal 
associated with study drug intake (i.e., breakfast and dinner/snack, as applicable) should 
not exceed 30 minutes. 
2. Study drug should be administered q12h (± 2 hours). For each subject, all doses (morning 
and evening) of study drugs will be taken at approximately the same time each day. For 
example, the morning dose could be taken at 08:00 every morning and the evening dose 
could be taken at 20:00 every evening throughout the study. 
3. At the Day 1 Visit, all subjects will be observed for 6 hours after the morning dose of the 
study drug. 
4. The date, amount taken, and time of study drug administration, including whether food 
was taken with each dose, will be recorded for 2 days before PK sample collection and on 
the days of PK sample collection. 
5. On days of scheduled visits, the morning dose of study drug will be administered at the 
site after predose assessments have been completed. The meal or snack will be provided 
by the site for the morning dose of study drug.  


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6. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
o If the dose in the clinic will be within 6 hours of the subject's scheduled morning 
dose, the subject should withhold their morning dose of study drug, and the morning 
dose will be administered in the clinic. 
o If the dose in the clinic will be more than 6 hours after the subject's scheduled 
morning dose, the subject should take the morning dose at home, and the evening 
dose will be administered in the clinic. In this event, all assessments will be collected 
relative to the evening dose. 
7. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused 
study drug to the site; study drug will be dispensed at each visit, as appropriate. 
8. At the Week 8 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 8 
Visit.  
9. At the Week 24 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 24 
Visit.  
10.3 
Method of Assigning Subjects to Treatment Groups 
Approximately 204 subjects (34 per sequence) will be enrolled and stratified by age at the 
Screening Visit (<18 versus ≥18 years of age), FEV1 severity (determined at the Screening 
Visit; <70% versus ≥70% predicted), and type of residual function mutation on the second 
CFTR allele (Class V non-canonical splice mutation versus Classes II to IV residual function 
mutation; see Section 16), and then randomized (1:1:1:1:1:1) to 1 of the 6 treatment 
sequences, as shown in Section 8.1. A minimum of 25% of enrolled subjects will carry a 
Class II to IV mutation on the second CFTR allele (see Section 16). Enrollment into the non-
canonical splice strata will be limited to no more than 75% of total enrollment. 
An IWRS will be used to assign subjects to treatment and to ensure enrollment of at least 
25% of subject with Class II to IV residual function mutations. Detailed instructions for 
randomization will be provided separately.  
10.4 
Dose Modification for Toxicity 
The dosage of individual study drugs or the regimen cannot be altered, but the investigator 
can interrupt or stop treatment with all study drugs. 
10.5 
Study Drug Interruption 
If study drug dosing must be interrupted for more than 72 hours, the Medical Monitor must 
be notified. In these instances, study drug dosing may only resume after approval by the 
Medical Monitor. Specific instructions for interruption for elevated LFT levels and elevated 
QTc levels are provided in Section 11.7.7 and Section 11.7.4, respectively. 


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10.6 
Missed Doses 
If a subject misses a dose and recalls the missed dose within 6 hours, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 
subject should skip that dose and resume his/her normal schedule for the following dose. For 
example, 
• if the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
• if the morning dose of study drug should have been taken at approximately 08:00, and 
more than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 
14:00), the subject would resume dosing with the evening dose at approximately 20:00. 
10.7 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug cards will be 
provided and replaced via the IWRS. A detailed study drug dispensation plan will be 
provided in the Pharmacy Manual. 
Study drug labeling will be in compliance with applicable local and national regulations. 
10.8 
Study Drug Supply, Storage, and Handling 
VX-661/ivacaftor (100 mg/150 mg) and matching placebo will be supplied as light yellow 
film-coated tablets of similar size and appearance containing VX-661 100 mg/ivacaftor 
150 mg and VX-661 0 mg/ivacaftor 0 mg, respectively.  
Ivacaftor (150 mg) and matching placebo will be supplied as light blue film-coated tablets of 
similar size and appearance containing ivacaftor 150 mg and ivacaftor 0 mg, respectively. 
Blister cards must be stored at room temperature according to Table 10-2 and to the 
instructions provided in the Pharmacy Manual. While at the clinical site, the investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational 
products are stored in a secured area, under recommended study conditions, and in 
accordance with applicable regulatory requirement. To ensure adequate records, all study 
drugs will be accounted for as detailed in Section 10.9. 
Instructions regarding the storage and handling of study drug after dispensation to subjects 
will be provided to sites in the Pharmacy Manual. 


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Table 10-2 
Identity of Study Drugs, Dosage, and Storage 
Drug Name 
Strength/Formulation/Route 
Dosage 
Storage Condition 
VX-661/ivacaftor 
fixed-dose tablet 
100-mg/150-mg tablet; oral 
100 mg/ 
150 mg, morning dose 
≤ 25°C (77°F) with 
excursions to 30°C (86°F) 
Ivacaftor 
150-mg tablet, oral 
150 mg, morning and 
evening dose 
≤ 25°C (77°F) with 
excursions to 30°C (86°F) 
VX-661/ivacaftor 
matching placebo 
0-mg/0-mg tablet; oral 
0 mg/ 
0 mg, morning dose 
≤ 25°C (77°F) with 
excursions to 30°C (86°F) 
Ivacaftor, matching 
placebo 
0-mg tablet, oral 
0 mg, morning and 
evening dose 
≤ 25°C (77°F) with 
excursions to 30°C (86°F) 
 
10.9 
Drug Accountability 
The pharmacist or designated site staff will maintain records documenting the dates and 
amounts of  
• study drug received,  
• study drug dispensed to the subjects, and 
• study drug returned by the subjects.  
Subjects will be instructed to return all used, partially used, and full study drug blister cards 
to the site. These materials will be retained at the site according to instructions provided by 
Vertex or its designee until inventoried by the study monitor. The study monitor will verify 
study drug records and inventory throughout the study. 
10.10 
Disposal, Return, or Retention of Unused Drug 
The site staff or pharmacy personnel will retain all materials returned by the subjects until the 
site monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the 
study monitor authorizes destruction at the study site, the investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Vertex. Destruction will be 
adequately documented. 
Procedures for the destruction or return of the study drug will be detailed in the Pharmacy 
Manual. 
10.11 
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 contact the Medical Monitor to discuss discontinuation of the 
subject from the study treatment. 


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10.12 
Blinding and Unblinding 
This is a double-blind study.  
10.12.1 
Blinding 
The subjects and all site personnel, including the investigator, the site monitor, and the study 
team, will be blinded with the exception of 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 their fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
• Unblinded statistician preparing the final (production) randomization list who is not part 
of the study team 
• Vertex Clinical Operations IWRS management 
• Vertex Clinical Supply Chain 
• IDMC 
• Vendor preparing the unblinded analysis for the IDMC 
• Vendor analyzing PK samples 
• Vertex or vendor conducting the population PK analysis 
• Vertex Medical Monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
Vertex Drug Metabolism and Pharmacokinetics laboratory personnel will not be involved in 
the conduct of the study and will be unblinded to the bioanalysis results but will remain 
blinded to subject number and treatment assignment. 
Spirometry Data Blinding 
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has been administered active study drug or placebo. Therefore, during the 
conduct of the study, the Vertex study team will have no access to the post-dose spirometry 
data. The vendor for central reading of the spirometry data will only send the blinded 
spirometry files (blinded treatment group, with real values for screening and baseline, but 
with dummy values for all the spirometry assessments after baseline) to Vertex to be used for 
developing the statistical programs. Furthermore, subjects and their caregiver should not be 
informed of their study-related spirometry results during the Treatment Period regardless of 
whether the subject has prematurely discontinued study drug treatment. 






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11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 and Table 3-2.  
The CFQ-R questionnaire must be performed before any other assessment at the clinic visits 
when it is required. For the remaining assessments, the following assessments must be 
performed in the following order when more than 1 assessment is required at a particular 
time point: 
 
2. standard 12-lead ECG recordings  
3. vital signs and pulse oximetry 
4. spirometry 
5. sweat chloride 
6. safety laboratory assessments (including blood draws) 
7. PK sampling 
Note: if study drug is not administered on the day of the visit (for any reason, including study 
drug interruption or premature discontinuation of study drug), only 1 set of assessments will 
be collected (Table 3-2). 
11.1.1 
Informed Consent/Assent 
Each subject of age of consent (per local requirements) must sign and date a study-specific 
ICF before any study-specific procedures can be performed. Subjects not of age of consent 
must assent, if applicable per local requirements, to participate in the study, and the subject's 
parent or legal guardian must sign and date a study-specific ICF before any study-specific 
procedures can be performed. The consent forms will comply with all applicable regulations 
governing the protection of human subjects. An ICF and Assent Form, approved by Vertex 
and the site's institutional review board (IRB) or ethics committee (EC), must be used. 
11.1.2 
Assigning Subject Number 
Once a subject has signed an ICF or Assent Form, if applicable, a subject number will be 
assigned. The subject will retain this number for the entire study. Detailed instructions on 
assigning subject numbers will be provided in the Study Reference Manual. If a subject is 
rescreened, the subject retains the original subject number. 
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 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 shall include a complete review of 
systems, past medical and surgical histories, and any allergies. 






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• If, on Day 1 (Treatment Period 1), the subject does not withhold his/her dose of 
bronchodilator, spirometry should be performed postbronchodilator, and all subsequent 
spirometric measurements (according to the schedule of assessments detailed in 
Table 3-2) should be performed postbronchodilator. 
• For visits with postdose spirometry assessments (Weeks 1, 2, 17, and 18) , if the predose 
spirometry is performed postbronchodilator, the subject should withhold any further 
bronchodilator use until completion of the 4-hour postdose spirometry assessment on that 
day. 
• Each spirometry assessment will be recorded in the source documents as pre- or 
postbronchodilator. 
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. 
Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results from Day 1 through Week 24, regardless of whether the subject prematurely 
discontinues treatment. 
The parameters listed below will be normalized using the standards of Wang et al44 (for 
female subjects aged 12 to 15 years [inclusive] and male subjects aged 12 to 17 years 
[inclusive]) or Hankinson et al43 (for female subjects aged 16 years and older and male 
subjects aged 18 years and older):  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow 25% to 75% (FEF25%-75%) (L/s) 
11.6.2 
Sweat Chloride Testing 
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Collection of sweat samples will be performed at visits specified in Table 3-1 and 
Table 3-2, using an approved collection device. Sweat samples will be sent to a central 
laboratory for testing and interpretation of results. Individual sweat chloride test results will 
not be disclosed to the study sites. Specific instructions for collection, handling, processing, 
and shipping of sweat chloride samples to the central laboratory will be provided separately.  
The sweat collection on dosing visits should occur approximately 1 hour before the PK 
sample collection and before the morning dose of the study drugs. At each time point, 2 
samples will be collected, 1 from each arm (left and right).  
Sweat collection must be performed at the Screening Visit if the sweat chloride value is not 
available in the subject’s medical record. For subjects using a sweat chloride value 
documented in their medical record to establish eligibility, the sweat chloride test at the 
Screening Visit is optional. Collection of sweat chloride will not overlap with any other study 
assessments. 








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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 urine 
pregnancy tests, which will be performed and analyzed at the site. Blood samples requiring a 
4-hour fast will be collected on Day 1, Week 8, Week 17, Week 24, and the ETT Visit. 
Fasting is not required at other time points unless specified in the assessment table. On Day 1 
and Week 17 Visit, blood samples will be collected before the first dose of the study drug. At 
all the other scheduled visits, these samples will be collected at any time during the visit, 
relative to the order of assessments indicated in Section 11.1 and according to the schedule in 
Table 3-1 and Table 3-2.  
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1 and Table 3-2. Laboratory test results that are abnormal and considered clinically 
significant will be reported as AEs (see Section 13.1.1).  
The safety laboratory test panels are shown in Table 11-1. 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase  
Alanine aminotransferase 
Lactate dehydrogenase 
Gamma-glutamyl transpeptidase 
Total protein 
Albumin 
Creatine kinase 
Amylase 
Lipase 
Hemoglobin 
Erythrocytes 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Reticulocytes 
Platelets 
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  
Vitamin Levels 
Vitamins A, D, E, K, and B12 
Lipid Panel 
Total cholesterol 
Triglycerides 
Low-density lipoprotein  
High-density lipoprotein  
a 
If urine is positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of urine will 
be performed for leukocytes, erythrocytes, crystals, bacteria, and casts. 
Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: 
Serum samples will be obtained as specified in Table 3-1 and Table 3-2 and analyzed at the 
central laboratory. Urine pregnancy tests will be performed at the site as specified in 
Table 3-2. The urine pregnancy test on Day 1 must be negative before the first dose of study 
drug.  
FSH (Screening Period only): Blood sample for FSH will be measured for any potentially 
postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. 
Serum FSH levels must be ≥40 mIU/mL to be considered postmenopausal. 
CFTR Genotype (Screening Period only): CFTR genotyping will be performed on all 
subjects. Refer to the Laboratory Manual to determine the appropriate genotyping assay for 
each subject. 


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Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be 
used. At the discretion of the local investigator, local laboratories may be used for 
management of urgent medical issues. If a local laboratory test value is found to be abnormal 
and clinically significant, it should 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 can be performed at the discretion of the 
investigator or healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid, eyes/ears/nose/throat 
(EENT), respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal, and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be 
reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), oral temperature, pulse rate, and 
respiration rate. These will be assessed following a 5-minute rest in the seated or supine 
position.  
11.7.4 
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). A window of ± 15 minutes will be 
allowed around the nominal times for all postdose ECG assessments. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated.  
The performance of all ECGs will adhere to the following guidelines: 
• The subject will be instructed to rest in the supine position for at least 5 minutes before 
having an ECG performed. 
• The ECG will be performed before any other procedures that may affect heart rate (HR), 
such as blood draws. 
The ECG traces will be manually read at the study site at the Screening and Safety Follow-up 
Visits. A printout of the ECG traces will be made for safety review by the investigator and 
maintained with source documentation. Clinically significant ECG abnormalities occurring 
during the study through the Safety Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make 
comparisons to baseline measurements. If the QTcF is increased by >45 msec from the 
baseline or an absolute QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs 
will be performed approximately 2 to 4 minutes apart to confirm the original measurement. If 


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either of the QTcF values from these repeated ECGs remains above the threshold value 
(>45 msec from baseline or ≥500 msec), a single ECG will be repeated at least hourly until 
QTcF values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.  
If the QTcF value remains above the threshold value (>45 msec from the average of the 
3 predose values on Day 1 or ≥500 msec) on repeated measurement or is noted on 
>2 occasions with no identified alternative etiology for the increased QTcF study drug, then 
discontinuation from study drug treatment may be required after discussion with the Medical 
Monitor. 
Subjects who discontinue study drug treatment for increased QTc should have their QTc 
monitored closely until it normalizes or returns to baseline. 
11.7.5 
Contraception and Pregnancy 
11.7.5.1 
Contraception 
The effects of VX-661 monotherapy or in combination with ivacaftor on conception, 
pregnancy, and lactation in humans are not known. Neither VX-661 nor ivacaftor showed 
any genotoxic potential in a standard battery of in vitro (Ames test, Chinese hamster ovary 
cell chromosomal aberration) and in vivo (mouse micronucleus) studies. VX-661 and 
ivacaftor were each found to be nonteratogenic in reproductive toxicology studies in rats and 
rabbits.27,28 Subjects should follow the contraception requirements outlined in this study 
protocol. The effects of VX-661 monotherapy or in combination with ivacaftor on the PK of 
hormonal contraceptives are not known. Thus, hormonal contraception is not an acceptable 
method of contraception for female subjects though it is acceptable for the female partners of 
male subjects. 
At this stage in the development of VX-661 in combination with ivacaftor, participation in 
this study requires a commitment from the research subject and his/her partner to use at least 
1 effective method of birth control. Acceptable methods of contraception for participants of 
this study and their partners are listed below. Methods of contraception should be in 
successful use from signing of consent, approximately 28 days, before the first dose of study 
drug (unless otherwise noted) and until 90 days following the last dose of study drug. 
Contraception for the couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
• If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented 
through examination of a semen specimen or by demonstration of the absence of the vas 
deferens by ultrasound or medical record before the first dose of the study drug. 
• If the female is of non-childbearing potential, per the following: 
o Postmenopausal: spontaneous amenorrhea for at least 12 consecutive months and 
serum FSH level ≥40 mIU/mL at Screening 
o Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy 


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o Has not achieved menarche (has not had her first menstrual period). Females who fall 
into this category are considered not to be of childbearing potential only as long as 
they have not had their first menstrual period. If a female achieves menarche during 
the study, she will need to provide consent for compliance (proper method of 
contraception or abstinence).  
• NOTE: All other female subjects who have had their first menstrual period will be 
considered to be of childbearing potential. 
Acceptable contraceptive methods: 
Acceptable contraceptive methods for male subjects or male partners of female subjects 
include the following: 
• Vasectomy 6 months or more previously, with a documented negative postvasectomy 
semen analysis for sperm. 
• Condom and spermicide.  
o In countries where spermicide is not available, condom without spermicide will be 
considered acceptable. 
o Local regulations may require use of an additional acceptable method of 
contraception.  
Acceptable contraceptive methods for female subjects include the following: 
• Bilateral tubal ligation performed at least 6 months previously. 
• Continuous use of an intrauterine device (non-hormone-releasing) for at least 90 days 
before the first dose of study drug. 
• Barrier contraception (such as diaphragm, cervical cap, or female condom) and 
spermicide.  
o In countries where spermicide is not available, barrier contraception without 
spermicide will be considered acceptable. 
o Local regulations may require use of an additional acceptable method of 
contraception.  
• NOTE: Hormonal contraceptives will not be considered as an effective method; however, 
female subjects are not required to discontinue hormonal contraceptives. 
Acceptable contraceptive methods for female partners of male subjects:  
• Bilateral tubal ligation performed at least 6 months previously. 
• Continuous use of an intrauterine device for at least 90 days before first dose of study 
drug. 
• Barrier contraception (such as diaphragm, cervical cap, or female condom) and 
spermicide. 


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o In countries where spermicide is not available, condom without spermicide will be 
considered acceptable.  
o Local regulations may require use of an additional acceptable method of 
contraception. 
• Hormonal contraceptives, if successfully used for at least 60 days before first dose of 
study drug.  
Additional notes: 
• Acceptable methods of contraception listed above are examples. Local requirements may 
prohibit the use of some of these examples. Please contact the Medical Monitor with any 
questions. 
• A female condom cannot be used with a male condom (as a double method of 
contraception) due to risk of tearing. 
• Male and female subjects who are not sexually active at the time of screening must agree 
to follow the contraceptive requirements of this study if they become sexually active with 
a partner of the opposite sex. 
• If applicable, additional contraception requirements may need to be followed according 
to local regulations and/or requirements. 
• Male subjects must not donate sperm after the first dose of study drug, throughout the 
study, and for 90 days following the last dose of study drug. 
• Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days following the last dose of study drug. 
• Male subjects whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the subject received study 
drug) must be compliant with the contraception requirements. In this scenario, the male 
subject and his female partner must commit to using barrier methods of contraception (to 
ensure there is no exposure of the fetus to study drug) for the duration of the study and 
until 90 days after the last dose of study drug. 
• Female subjects should not nurse a child from the start of study drug dosing through 
90 days following the last dose of study drug. 
• Unique situations that may not fall within the above specifications should be discussed 
with the Medical Monitor. 
11.7.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during 
study treatment and within 90 days after the last dose of the study drug. 
If a female subject or the female partner of a male subject becomes pregnant while 
participating in the study, study drug must be permanently discontinued immediately. For 
male subjects, study drug does not need to be permanently discontinued if the female 
partner's pregnancy resulted from donated sperm or sperm banked before study drug 


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exposure (Section 11.7.5.1). The investigator must 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. 
If the subject is confirmed to be on study drug, 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. 
11.7.6 
Pulse Oximetry 
Arterial oxygen saturation by pulse oximetry will be measured at visits noted in Table 3-1 
and Table 3-2. This will be assessed following a 5-minute rest (seated or supine) and before 
study drug dosing. At visits when study drug is taken at the site, pulse oximetry will be 
collected before the morning dose. This is a noninvasive measure of oxygen delivery to the 
tissues and has been correlated with clinical status and lung function. 
11.7.7 
Liver Function Test Parameters 
Liver Function Testing 
Liver function testing (ALT, AST, GGT, ALP, direct bilirubin, and total bilirubin) must be 
performed as noted in Table 3-2 for serum chemistry, while subjects are receiving study drug 
treatment and at the Safety Follow-up Visit. 
These blood samples should be processed and shipped immediately per the Laboratory 
Manual. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN and clinical 
symptoms must be followed closely, including repeat confirmatory testing performed by the 
central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT and AST levels, as clinically indicated. In addition, if ALT or AST is 
>5 × ULN, repeat follow-up levels must be obtained within 7 ± 2 days. 
If a subject cannot return to the site for liver function testing, a local laboratory may be used. 
Elevations in LFTs at the local laboratory must be reported immediately to the Medical 
Monitor, and the subject must have the tests repeated and sent to the central laboratory as 
soon as possible (ideally within 48 to 72 hours). 
Study Drug Interruption 
Study drug administration must be interrupted immediately (prior to confirmatory testing), 
and the Medical Monitor must be notified, if any of the following criteria is met and 
confirmed with repeat testing: 
• 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 


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A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST 
levels have improved, study drug treatment must be permanently discontinued if repeat 
testing within 48 to 72 hours confirms the initial elevation. Subjects in whom treatment is 
discontinued for elevated transaminases should have their transaminases monitored closely 
until levels normalize or return to baseline.  
Resumption of Study Drug 
If an alternative, reversible cause of transaminase elevation has been identified, study drug 
may be resumed once transaminases return to baseline or are ≤2 × ULN, whichever is higher. 
Approval of the Medical Monitor is required before resumption of study drug. Upon 
resumption of study drug, transaminases should be assessed weekly for 4 weeks. If a 
protocol-defined transaminase elevation occurs within 4 weeks of rechallenge with the study 
drug (with confirmation of the initial elevation by repeat testing within 48 to 72 hours), then 
the study drug treatment must be permanently discontinued, regardless of the presumed 
etiology. 
11.7.8 
Ophthalmologic Examination 
Subjects will undergo an ophthalmologic examination performed by a licensed 
ophthalmologist at Screening, which includes 
• measurement of best corrected distance visual acuity of each eye 
• measurement of lens refracting power following cycloplegia (e.g., autorefractor or 
ophthalmoscopy streak) 
• pharmacologically dilated examination of the lens with a slit lamp 
The screening ophthalmologic examination must be completed and the results reviewed 
before randomization. This examination does not have to be repeated if there is 
documentation of an examination that met protocol criteria and that was within 3 months 
before the start of the Screening Period. Subjects who have documentation of bilateral lens 
removal do not need the ophthalmologic examination. 
If a cataract, lens opacity, Y-suture, or lamellar rings are identified and determined to be 
clinically significant by the ophthalmologist at the Screening examination, the subject is 
ineligible for study entry (see Section 9.2). If a cataract or lens opacity is identified and 
determined to be clinically significant by the ophthalmologist after dosing, the subject and 
Vertex Medical Monitor will be notified. After discussion with the Principal Investigator 
who collaborates with the Vertex Medical Monitor, the subject may elect to continue or 
discontinue study drug treatment. If the subject discontinues study drug treatment, the subject 
should complete the ETT and Safety Follow-up Visit (see Section 8.1.6). If the subject 
continues study drug treatment, more frequent ophthalmologic monitoring should be 
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In addition to the screening examination, an ophthalmologic examination will be performed 
by a licensed ophthalmologist at the Safety Follow-up Visit or ETT Visit for the following 
subjects: 
• subjects < 18 years of age at the Screening Visit who prematurely discontinue 
treatment after receiving at least 1 dose of study drug, 
• subjects < 18 years of age at the Screening Visit who complete study drug 
treatment but do not enroll in a separate extension study of VX-661/ivacaftor 
within 28 days after the last dose of study drug. 
This examination may be completed at either the ETT or Safety Follow-up Visit, but must be 
completed by the date of the Safety Follow-up Visit. Additional ophthalmologic 
examinations may be conducted at the discretion of the investigator. The Medical Monitor 
should be notified of any additional ophthalmologic examinations. 
Subjects who have documentation of bilateral lens removal are not required to complete the 
eye examination at the Safety Follow-up Visit or ETT Visit. 
In addition, at Screening, the following history will be obtained for all subjects: 
• history of steroid use 
• history or presence of diabetes 
• any prior ophthalmologic or optometric examinations 
• history of trauma to the eye 
• any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
• use of corrective lenses (contact lenses or eyeglasses) 
• history of prolonged exposure to sunlight or ultraviolet light and use of sunglasses 
• history of exposure to secondhand smoke 
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 percent predicted FEV1 from study 
baseline to the average of the Week 4 and Week 8 measurements in each Treatment Period.  
The null hypotheses to be tested are that the mean change from study baseline in percent 
predicted FEV1 to the average of the Week 4 and Week 8 measurements is the same for 
(i) VX-661/ivacaftor and placebo; and (ii) ivacaftor monotherapy and placebo.  


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Assuming a standard deviation (SD) of 7 percentage points, 30 subjects per sequence are 
needed to have at least 90% power to detect a 3 percentage point treatment difference 
between VX-661/ivacaftor and placebo when the mean values of the primary endpoint are 
being compared. A 2-sided significance level of 0.05 was used in the sample size 
calculations. Accounting for the hierarchical testing strategy, the proposed sample size will 
yield approximately an 85% chance of observing a statistically significant difference between 
ivacaftor monotherapy and placebo for the primary endpoint, under the assumption that 
ivacaftor monotherapy is also 3 percentage points better than placebo (refer to 
Section 12.3.3.2 for a detailed description of the testing strategy). The sample size estimate 
was based on 10,000 simulation runs with an incomplete block design assuming no dropouts. 
In the simulation, the correlation between responses to the 2 treatments within a subject was 
assumed to be zero. After adjusting for an assumed dropout rate of 10%, the sample size was 
increased to 34 subjects per sequence (204 total subjects). 
 
12.2 
Analysis Sets 
Assignment of subjects to analysis sets will be done before the clinical data lock for the 
study.  
The All Subjects Set is defined as all subjects who were randomized or dosed (i.e., all 
subjects in the study). All subject data listings will be referenced using the All Subjects Set, 
unless otherwise specified. 
The Full Analysis Set (FAS) is defined as all randomized subjects who carry the intended 
CFTR mutations (see Section 16) and who have received at least 1 dose of study drug. The 
FAS is to be used in efficacy analyses in which subjects will be analyzed according to the 
treatment to which they were assigned or according to the treatment sequence to which they 
were randomized. All analyses of background data and efficacy data will be based on the 
FAS. 
The Safety Set is defined as all subjects who received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses in which subjects will be analyzed according to 
the treatment they received. All analyses of safety data will be based on the Safety Set. 
12.3 
Statistical Analysis 
The primary objective of this study is to evaluate the efficacy of VX-661/ivacaftor and 
ivacaftor monotherapy through 8 weeks of treatment in subjects with CF who are 
heterozygous for the F508del mutation on the CFTR gene and a second allele with a CFTR 
mutation predicted to have residual function. 
This section presents a summary of the planned statistical analyses of efficacy and safety for 
this study. The Vertex Biometrics department or a designated CRO will analyze the data 
derived from this study. SAS® Version 9.2 or higher will be used to generate all statistical 
outputs (tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the SAP for the study. 


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12.3.1 
General Considerations 
All individual subject data for those randomized or exposed to study drug will be presented 
in data listings.  
Continuous variables will be summarized using the following descriptive summary 
statistics: number of subjects (n), mean, SD, standard error (SE), median, minimum value 
(min), and maximum value (max). The precision of the measurement for each continuous 
variable will be specified in the SAP.  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Treatment emergent (TE) period for Treatment Period 1 will correspond to data from the 
first dose of study drug in the first period to the safety evaluation visit  or 28 days after the 
last dose in the same period for subjects who do not have a safety evaluation visit. Similarly, 
TE period for Treatment Period 2 will correspond to data from first dose of study drug in the 
second period through the Safety Follow-up Visit or 28 days after the last dose in the same 
period for subjects who do not have an Safety Follow-up Visit.  
Baseline: For this crossover study, 2 types of baseline will be defined. The study baseline is 
defined as the most recent nonmissing measurement (scheduled or unscheduled) collected 
prior to the first dose of study drug in the study. The definition will be applied to all 
demographics, background, and baseline characteristics and also efficacy data analysis, 
including the primary endpoint analysis. In addition, period baseline is defined as the most 
recent nonmissing measurement (scheduled or unscheduled) collected before the first dose of 
study drug in each Treatment Period. For Treatment Period 2, the baseline should be from an 
assessment measured after the TE period for Treatment Period 1. This definition will be 
applied to all safety data analysis. For ECG, baseline for Period 1 will be defined as the 
average of the 3 pretreatment measurements on Day 1. For sweat chloride, the study baseline 
value will be the mean of assessment values on the left and the right arm at the most recent 
time point before the first dose of study drug in the study. 
Absolute change from study baseline will be calculated as post-baseline  
value – study baseline value.   
Relative change from study baseline will be calculated as 100 × (post-baseline value –
 study baseline value)/study baseline value.   
Absolute change from period baseline will be calculated as post-baseline  
value – period baseline value.  
Relative change from period baseline will be calculated as 100 × (post-baseline value –
 period baseline value)/period baseline value. 
12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure and compliance, and other background characteristics will 
be summarized. Additionally, all subject data will be presented in subject data listings. All 


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summaries will be based on the FAS unless otherwise specified in the SAP for the study. No 
statistical hypothesis testing will be performed on background characteristics. 
12.3.2.1 
Subject Disposition 
Number and percentage of subjects in the following categories will be summarized by 
treatment sequence: 
• All Subjects Set 
• All Randomized 
• Safety Set   
• FAS: Subjects who are randomized and dosed and carry the intended CFTR mutations 
(see Section 16) 
The number and percentage (based on the FAS) of subjects in each of the following 
disposition categories will be presented: 
• Completed study drug treatment 
• Prematurely discontinued study drug treatment and the reasons for discontinuation 
• Last scheduled on-treatment visit completed for subjects who discontinued study drug 
treatment 
• Completed study  
• Prematurely discontinued the study and the reasons for discontinuation 
• Prematurely discontinued the study during the Treatment Period and the reasons for 
discontinuation 
• Last scheduled visit completed 
• Rolled over to extension study 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized by treatment sequence. Protocol deviations/violations will be provided as a 
subject data listing only. Important protocol deviations/violations will be summarized. 
The following demographics and study baseline characteristics will be summarized by 
treatment sequence for the FAS: sex, race, ethnicity, age, weight, height, body mass index 
(BMI), region, study baseline percent predicted FEV1, study baseline sweat chloride, and 
study baseline score of CFQ-R respiratory domain.  
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced and categorized as follows:  


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• Prior medication: any medication that started before the first dose of study drug, 
regardless of when it ended. 
• Concomitant medication: medication continued or newly received during the TE period 
for Treatment Period 1 or Treatment Period 2. If a subject took a medication during a 
specific Treatment Period, this medication will be attributed to the treatment the subject 
received during this Treatment Period. As a result, 1 medication could be attributed to 
more than 1 treatment.  
• Post-treatment medication: medication continued or newly received beyond the TE 
period for Treatment Period 2, or between the TE periods for Treatment Period 1 and 
Treatment Period 2, or beyond the TE period for Treatment Period 1 for subjects who do 
not participate in Treatment Period 2.  
A given medication can 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 partial missing 
start/end date or time and it cannot be determined whether the medication was taken before 
initial dosing, concomitantly, or post-treatment, it will be considered as prior, concomitant, 
and post-treatment. 
Prior medications will be summarized by treatment sequence, and concomitant medications 
will be summarized by treatment based on the FAS. Post-treatment medications will be listed 
for each subject.  
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug (i.e., duration of treatment) will be summarized by treatment for the 
FAS in terms of duration of treatment a subject received (in days), defined as the last day 
minus the first day of study drug plus 1 within the Treatment Period. 
Study drug compliance will be calculated as follows:  
100 × [1 - (Total number of days study drug interrupted) / (Duration of study drug 
exposure)]. 
The total number of days of study drug interrupted is defined as the sum of (number of days 
of study drug interrupted in each interruption interval); where number of days of study 
drug interrupted in each interval is defined as the interruption end date - the 
corresponding interruption start date + 1. 
Duration of treatment and study drug compliance will be summarized by means of 
descriptive summary statistics. 
12.3.3 
Efficacy Analysis 
The primary objective of this study is to evaluate the efficacy of VX-661/ivacaftor and 
ivacaftor monotherapy. For efficacy analysis, the statistical inference will be based on change 
from study baseline. A hierarchical testing strategy will be used to preserve the overall type I 
error rate at the 0.05 level. 




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Secondary Endpoints 
• Relative change in percent predicted FEV1 from study baseline to the average of the 
Week 4 and Week 8 measurements of each of the Treatment Periods: Analysis of this 
variable will be similar to that of the primary analysis of the primary efficacy endpoint. 
• Absolute change in sweat chloride from study baseline to the average of the Week 4 
and Week 8 measurements in each Treatment Period: Analysis of this variable will be 
similar to that of the primary analysis of the primary efficacy endpoint. 
Sensitivity analysis, supportive analysis, and subgroup analysis of secondary variables may 
be described in the SAP. 
12.3.3.3 
Adjustment for Multiple Comparisons 
There are 3 potential treatment comparisons for the primary and key secondary endpoint: 
VX-661/ivacaftor versus placebo, ivacaftor monotherapy versus placebo, and 
VX-661/ivacaftor versus ivacaftor monotherapy. The testing strategy will be limited to the 
comparison of VX-661/ivacaftor versus placebo and ivacaftor monotherapy versus placebo. 
The testing procedure is summarized in Figure 12-1. 
 
 


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Figure 12-1 
 Testing Strategy for the Primary and Key Secondary Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVA: ivacaftor; PBO: placebo; ppFEV1: percent predicted forced expiratory volume in 1 second; 
CFQ-R: Cystic Fibrosis Questionnaire–Revised (respiratory domain) 
 
A hierarchical testing strategy with α = 0.05 will be used to strongly control the overall type I 
error rate at the 0.05 level. The testing hierarchy is as follows: 
1. Absolute change in percent predicted FEV1 from study baseline to the average of the 
Week 4 and Week 8 measurements for VX-661/ivacaftor versus placebo. 
2. Absolute change in percent predicted FEV1 from study baseline to the average of the 
Week 4 and Week 8 measurements for ivacaftor monotherapy versus placebo. 
3. Absolute change in CFQ-R respiratory domain score from study baseline to the 
average of the Week 4 and Week 8 measurements for VX-661/ivacaftor versus 
placebo. 
4. Absolute change in CFQ-R respiratory domain score from study baseline to the 
average of the Week 4 and Week 8 measurements for ivacaftor monotherapy versus 
placebo. 
 
Note that comparisons of VX-661/ivacaftor versus ivacaftor will be performed and the 
P-values will be reported, but the tests will be performed without strong Type I error control. 
VX-661/IVA versus PBO 
Absolute ppFEV1 
α = 0.05 
IVA versus PBO 
Absolute ppFEV1 
α = 0.05 
VX-661/IVA versus PBO 
Absolute CFQ-R 
α = 0.05 
IVA versus PBO 
Absolute CFQ-R 
α = 0.05 


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12.3.4 
Safety Analysis 
All safety analyses will be based on the set of data associated with the TE period for 
Treatment Period 1 and the TE period for Treatment Period 2. Safety analyses will use the 
Safety Set. The summaries will be by treatment received. 
For safety analysis, the period baseline will be used.  
All safety data will be presented in individual subject data listings. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, lipid panel, vitamin levels, 
urinalysis, and coagulation studies) 
• ECGs 
• Vital signs 
• Pulse oximetry 
• Spirometry 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
• Pretreatment AE: any AE that started before the first dose of study drug. 
• TEAE: any AE that increased in severity or that was newly developed during the TE 
period for Treatment Period 1 or Treatment Period 2. An AE that started (or increased in 
severity) during a specific Treatment Period will be attributed to the treatment the subject 
was receiving during the Treatment Period.  
• Post-treatment AE: any AE that increased in severity or that was newly developed 
beyond the TE period for Treatment Period 2, or between the TE periods for Treatment 
Period 1 and Treatment Period 2, or beyond the TE period for Treatment Period 1 for 
subjects who do not have Treatment Period 2.  
For AEs with missing or partial start date, if there is no clear evidence that the AEs started 
(or increased in severity) before the first dose, the start date will be imputed to the first 
dosing date and the AE assigned to the treatment in Treatment Period 1. 
AE summary tables will be presented for TEAE only and will include the following: 
• All TEAEs  
• TEAEs by relationship  
• TEAEs by maximal severity 
• TEAEs leading to treatment discontinuation 


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• Serious TEAEs 
• TEAEs leading to death 
• Frequently reported TEAEs 
Summaries will be presented by MedDRA system organ class and preferred term 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 worst/highest 
relationship level in the relationship summaries. An AE overview table will be provided. In 
addition, a listing containing individual subject 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 
The raw values and change from period baseline values of the continuous laboratory 
parameters will be summarized in SI units by treatment group at each scheduled time point 
during the TE period. In addition, the mean value at each visit will be plotted by treatment 
groups for each of the liver function parameters. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event during the TE period will be summarized by treatment group. The PCS (post-baseline) 
shift from period baseline will also be summarized by treatment group for selected laboratory 
parameters. The PCS criteria and the parameter selection criteria will be provided in the SAP.   
Results of urinalysis and serum pregnancy test will be listed in individual subject data listings 
only. In addition, a listing containing individual subject laboratory measurements outside the 
reference ranges will be provided. This listing will include data from scheduled and 
unscheduled time points. 
12.3.4.3 
Electrocardiogram 
A summary of raw values and change from period baseline values will be provided by 
treatment group at each scheduled time point during the TE period for the following standard 
digital ECG measurements: PR, QT, and QTc for HR interval (QTcF); QRS duration; and 
HR. In addition, the mean value at each visit will be plotted by treatment groups for QTcF. 
The number and percentage of subjects with at least 1 PCS event during the TE period will 
be tabulated by treatment group. The PCS criteria for ECG data will be provided in the SAP.  
Additional ECG analyses will be described in the SAP. 


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12.3.4.4 
Vital Signs 
The raw values and change from period baseline values during the TE period will be 
summarized by treatment group at each scheduled time point: systolic and diastolic blood 
pressure (mm Hg), body temperature (°C), HR (beats per minute [bpm]), and respiratory rate 
(breaths per minute).  
The number and percentage of subjects with at least 1 PCS event during the TE period will 
be tabulated by treatment group. The PCS criteria for vital signs data will be provided in the 
SAP.  
Additional vital sign analyses will be described in the SAP. 
12.3.4.5 
Physical Examination 
PE findings will be presented as a data listing only. Clinically relevant results identified after 
screening will be reported as AEs. 
12.3.4.6 
Other Safety Analysis 
12.3.4.6.1 
Pulse Oximetry 
A summary of raw values and change from period baseline values during the TE period will 
be provided by treatment groups at each scheduled time point for the percent of oxygen 
saturation by pulse oximetry. In addition, the mean value at each visit will be plotted by 
treatment group for the percent of oxygen saturation.  
The number and percentage of subjects with shift changes from period baseline 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the TE period will be tabulated by treatment group. 
12.3.4.6.2 
Postdose Spirometry 
For the 2-hour and 4-hour postdose measurements on Day 1 of each Treatment Period 
(Week 1 and Week 17), and at Day 15 of each Treatment Period (Week 2 and Week 18), a 
summary of raw values for percent predicted FEV1 will be provided by treatment at each 
time point. The absolute change from the predose value of percent predicted FEV1 on the 
same day will be summarized by treatment at each time point. In addition, a boxplot by time 
point will be provided. Within each treatment, Day 1 and Day 15 values will be presented on 
the same plot. 
The above analyses will be repeated for FEV1. 
In addition, the number and percentage of subjects with percent predicted FEV1 decline ≥10, 
≥15, and ≥20 percentage points in the absolute change from the predose value will be 
summarized by treatment and by assessment day and time. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
No interim analyses of efficacy are planned. 


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12.3.5.2 
IDMC Analysis 
An IDMC will be formed before study initiation. The IDMC’s objectives and operational 
details will be defined in a separate document (IDMC Charter), which will be finalized 
before the first subject is screened. The IDMC will conduct regular planned safety reviews of 
study data as outlined in the IDMC Charter. 
12.4 
Clinical Pharmacology Analysis 
A detailed description of the clinical pharmacology analyses will be provided in a CPAP. 
Listings of plasma concentration data of VX-661, ivacaftor, and their metabolites will be 
provided in the clinical study report. A population approach will be used to analyze the 
time-versus-plasma concentration data of VX-661, ivacaftor, and their metabolites. The 
PK/PD relationship between concentrations of VX-661 and ivacaftor and (their metabolites 
as appropriate) and efficacy and safety measurements may be investigated. The results of the 
PK and PK/PD analyses using a population approach will be presented in a separate report. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, 
Severity Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the 
event does not necessarily have a causal relationship with the treatment. This includes any 
newly occurring event or worsening of a preexisting 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 a clinically significant worsening from baseline 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 


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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 clinical status of the subject indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit  
• For enrolled subjects who do not have a Safety Follow-up Visit, through the earliest of  
o 28 days after the last dose of study drug 
o The ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(Section 8.1.6) 
o prior to the first dose of study drug in the extension study. 
All subjects will be queried, using non-leading 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 eCRF 
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 
• Indication of dose limiting toxicity 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and non-serious AEs. 
The guidance available at the following website will be consulted: Common Terminology 


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Criteria for Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (accessed 
August 2012). 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 experience 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 re-appeared 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). 
AE: adverse event. 


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13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action 
taken will be classified according to the categories shown in Table 13-3. 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE. 
Dose reduced 
Not applicable for this study 
Drug interrupted 
Study drug administration interrupted in response to an AE. 
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE. 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event. 
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) 
AE: adverse event. 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. "Yes" is used if any treatment was 
given in response to an AE, and may include treatments such as other medications, 
hospitalization, surgery, or physical therapy. "No" indicates the absence of any kind of 
treatment for an AE. 


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13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation in the study and is suspected of being a delayed toxicity due to 
administration of the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the outcomes 
listed above (e.g., an allergic bronchospasm requiring intensive treatment in an 
emergency room or at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure should 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) should not 
be considered to indicate an SAE. 
Clarification will be made between the terms “serious” and "severe,” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may 
be of relatively minor medical significance, such as a severe headache. This is not the same 
as “serious,” which is based on subject/event outcome or action described above, and is 
usually associated with events that pose a threat to a subject's life or functioning. 
Seriousness, not severity, serves as a guide for defining expedited regulatory reporting 
obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through 
the Safety Follow-up Visit, regardless of causality, will be reported by the investigator to 
Vertex GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form 
(hereafter referred to as the “SAE Form”) using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the investigator for relationship to the 




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the subject (if applicable), before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent 
will comply with ICH GCP and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator 
and Vertex. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (i.e., efficacy assessments) will require 
IRB/IEC notification before implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects. Vertex will submit all protocol 
modifications to the required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the 
protocol, the investigator will contact Vertex to discuss the planned course of action. If 
possible, contact will be made before the implementation of any changes. Any departures 
from 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, all eCRFs, study reports, and communications relating to 
the study will identify subjects by assigned subject numbers. As required by federal 
regulations, 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 eCRFs/SAE 
Forms and the review of the data collection process. The FDA (or other regulatory authority) 
may also request access to all study records, including source documentation, for inspection. 
As applicable, in accordance with the Health Insurance Portability and Accountability Act 
and associated privacy regulations, a subject authorization to use personally identifiable 
health information may be required from each subject before research activities begin. This 
authorization document will clearly specify which parties will have access to a subject's 
personal health information, for what purpose, 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 


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records, custody will be transferred to a person willing to accept the responsibility, and 
Vertex will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs 
may terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not 
limited to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
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 an eCRF 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 eCRF 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 eCRFs/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 






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14 
REFERENCES 
 
 
1 
Cystic Fibrosis Foundation Web Site [Internet]. Available from: 
http://www.cff.org/AboutCF/. Accessed 11 November 2014. 
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Kriendler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new 
therapies. Pharmacol Ther. 2010;125:219-29. 
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FDA Office of Orphan Products Development (OOPD). Available from: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/defa
ult.htm. Accessed 11 November 2014. 
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The Committee for Orphan Medicinal Products (COMP). Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_conte
nt_000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 11 November 2014. 
5 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2009 Annual 
Data Report. Bethesda, Maryland; 2011. 
6  
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
7 
Cystic Fibrosis Mutation Database (CFTR1). Cystic Fibrosis Centre at the Hospital 
for Sick Children in Toronto Web site. Available from: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed 11 November 
2014.  
8 
Castellani C, Bonizzato A, Cabrini G, Mastella G. Newborn screening strategy for 
cystic fibrosis: a field study in an area with high allelic heterogeneity. Acta Paediatr. 
1997;86(5):497-502. 
9 
Van Goor F, Hadida S, Grootenhuis P. Pharmacological rescue of mutant CFTR 
function for the treatment of cystic fibrosis. Top Med Chem. 2008;3:91-120. 
10 
McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype 
and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 
2003;361(9370):1671-6. 
11  
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2011 Annual 
Data Report. Bethesda, Maryland; 2012. 
12  
European Cystic Fibrosis Society. European Cystic Fibrosis Society Patient Registry 
2008-2009. Karup, Denmark; 2012. Available from: 
http://www.ecfs.eu/files/webfm/webfiles/File/ecfs_registry/ECFSPR_Report0809_v3
2012.pdf. Accessed 11 November 2014. 
13 
Cheng SH, Gregory RJ, Marshall J, Sucharita P, Souza DW, White GA, et al. 
Defective intracellular transport and processing of CFTR is the molecular basis of 
 


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most cystic fibrosis. Cell. 1990;63:827-34. 
14 
Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, et al. Altered 
chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. 
Nature. 1991;354:526-8. 
15 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 
2005;352:1992-2001. 
16  
CFTR2.org  [Internet]. Baltimore (MD): 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/index.php. Accessed 06 July 2015. 
17  
Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N et al. Defining the 
disease liability of variants in the cystic fibrosis transmembrane conductance 
regulator gene. Nature Gen 2013; published online 25 August 2013; 
doi:10.1038/ng.274. 
18 
Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, et al. VX-809 
corrects folding defects in cystic fibrosis transmembrane conductance regulator 
protein through action on membrane-spanning domain 1. Mol Biol Cell. 
2013;24(19):3016-24. 
19  
Cebotaru L, Rapino D, Cebotaru V, Guggino WB. Correcting the cystic fibrosis 
disease mutant, A455E CFTR. PLoS One. 2014;9[1]:e85183. 
20  
Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, et al. Mechanism-
based corrector combination restores ΔF508-CFTR folding and function. Nat Chem 
Biol. 2013;9[7]:444-54. 
21 
Padoan R, Bassotti A, Seia M, Ambrosioni A, Fiori S, Prandoni S, et al. Mutation and 
polymorphism report. Human Mutation, Mutation and Polymorphism Report #111. 
2000. Online. Available at: http://journals.wiley.com/1059-
7794/pdf/mutation/mpr111.pdf. 
22  
Padoan R, Genoni S, Moretti E, Seia M, Giunta A, Corbetta C. Genetic and clinical 
features of false-negative infants in a neonatal screening programme for cystic 
fibrosis. Acta Paediatr 2009; 91:82-7. 
23  
Mercier B, Verlingue C, Lissens W, Silber SJ, Novelli G, Bonduelle M. Is Congenital 
Bilateral Absence of Vas Deferens a Primary Form of Cystic Fibrosis? Analyses of 
the CFTR Gene in 67 Patients. Am J Hum Genet. 1995; 56:272-277. 
24  
Casals T, Bassas L, Ruiz-Romero J, Chillón M, Giménez J, Ramos MD, et al. 
Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: 
in 50% of cases only one CFTR allele could be detected. Hum Genet. 
1995;95(2):205-11. 
 


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25 
Vertex Pharmaceuticals Incorporated. Report G016. Effects of VRT-893661 on 
CFTR-mediated chloride secretion in human bronchial epithelia isolated from cystic 
fibrosis subjects. Report date: 17 February 2010. 
26 
Lukacs GL, Chang XB, Bear C, Kartner N, Mohamed A, Riordan JR, et al. The delta 
F508 mutation decreases the stability of cystic fibrosis transmembrane conductance 
regulator in the plasma membrane. Determination of functional half-lives on 
transfected cells. J Biol Chem. 1993;268:21592-8. 
27 
Vertex Pharmaceuticals Incorporated. VX-661 Investigator's Brochure, Version 7.0. 
Report date: 08 May 2015. 
28 
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator's Brochure, 
Version 13.0. Report date: 16 May 2016. 
29 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
30 
Wilcschanski M, Zielenski J, Markiewicz D, Tsui LC, Corey M, Levison H, et al. 
Correlation of sweat chloride concentration with classes of the cystic fibrosis 
transmembrane conductance regulator gene mutations. J Pediatr. 1995;127:705-10. 
31 
Rowe S, Accurso F, Clancy JP. Detection of cystic fibrosis transmembrane 
conductance regulator activity in early-phase clinical trials. Proc Am Thorac Soc. 
2007;4:387-98. 
32 
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. 
33 
Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4:1-9. 
34 
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. 
35 
Wenninger K, Aussage P, Wahn U, Staab D. German Cystic Fibrosis Questionnaire 
study group. The revised German Cystic Fibrosis Questionnaire: validation of a 
disease-specific health-relate quality of life instrument. Qual Life Res. 
2003;12(1):77-85. 
36 
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. 
37 
Mayer-Hamblett N, Ramsey BW, Kronmal RA. Advancing outcome measures for the 
new era of drug development in cystic fibrosis. Proc Am Thorac Soc. 
2007;4(4):370-7. 
38 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
 


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1994;331:637-42. 
39 
Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgomery AB, et 
al. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr. 
2001;139(3):359-65. 
40 
Rabin HR, Butler SM, Johnson CA, Colin AA, FitzSimmons SC, Geller DE, et al. 
Pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol. 2004;37(5):400-6. 
41 
Blumer, JL, Saiman L, Konstan MW, Melnick D. The efficacy and safety of 
meropenem and tobramycin vs. ceftazidime and tobramycin in the treatment of acute 
pulmonary exacerbations in patients with cystic fibrosis. Chest. 2005;128(4):2336-46. 
42 
Borowitz D, Baker SS, Duffy L, Baker RD, Fitzpatrick L, Gyamfi J, et al. Use of 
fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr. 
2004;145:322-6. 
43 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a 
sample of the general US population. Am J Respir Crit Care Med. 1999;159:179-87. 
44  
Wang X, Dockery DQ, Wypij D, Fay ME, Ferris BG. Pulmonary function between 
6 and 18 years of age. Pediatr Pulmonol. 1993;15:75-88. 
45 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
46 
Levey AS, Bosch JP, Breyer Lewis J, Greene T, Rogers N, Roth D. A more accurate 
method to estimate glomerular filtration rate from serum creatinine: a new prediction 
equation. Ann Intern Med. 1999;130:461-70. 
47 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang Y, 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;145:247-54. 
48  
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):875-8. 
49 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation 
of the cystic fibrosis questionnaire in the United States: a health-related quality of life 
measure for cystic fibrosis. Chest. 2005;128:2347-54. 
50 
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365:1663-72. 
51 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:983-97. 
 




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15.2 
Investigator Signature Page 
Protocol #: 
VX14-661-108 Version #: 
3.0 
Version Date 
10 June 2016  
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to 
Evaluate the Efficacy and Safety of Ivacaftor and VX-661 in Combination With Ivacaftor in 
Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508delCFTR 
Mutation, and a Second Allele With a CFTR Mutation Predicted to Have Residual Function 
 
 
I have read Protocol VX14-661-108, Version 3.0 and agree to conduct the study according to 
its terms. I understand that all information concerning VX-661and ivacaftor and this protocol 
supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential.  
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 


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16 
APPENDIX A: SECOND CFTR ALLELE MUTATIONS INCLUDED 
FOR SUBJECTS WHO ARE HETEROZYGOUS FOR THE 
F508del-CFTR MUTATION 
Per the study eligibility criteria, heterozygous F508del-CFTR subjects must have a second 
CFTR allele that encodes a mutation predicted to have residual function. Criteria for 
including a mutation are (1) having residual function based on population-level phenotypic 
data and (2) in vitro responsiveness to ivacaftor. The criteria for clinical phenotype are 
average sweat chloride <86 mmol/L (1 standard deviation from the average sweat chloride 
for the most common processing and trafficking mutation, F508del-CFTR), and incidence of 
pancreatic insufficiency ≤50% based on subjects with at least 1 copy of the mutation from 
epidemiologic data16 or published literature. 17 -24 In vitro response to ivacaftor was defined as 
an increase in percent normal chloride transport of  ≥10 percentage points in transfected 
Fischer Rat Thyroid (FRT) cells expressing the CFTR form produced by the mutation. The 
list below represents eligible mutations. 
CFTR Mutations Predicted to Have Residual Function and That May Be Responsive to 
Ivacaftor 
2789+5G→A 
R74W 
R352Q 
R1070W 
3849+10kbC→T 
D110E 
A455E 
F1074L 
3272-26A→G 
D110H 
D579G 
D1152H 
711+3A→G 
R117C 
S945L 
D1270N 
E56K 
E193K 
S977F 
 
P67L 
L206W 
F1052V 
 
E831X 
R347H 
K1060T 
 
 
 

SAP_001.pdf: 






SAP VX14-661-108, Version 1.1                                                                                                        Page 4of 72
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10.1Schedule of Assessments.......................................................................................47
10.2Analysis Visit Window Mapping Rules for Efficacy and Safety Measurements.....53
10.3Coefficients for Hankinson and Wang Methodsfor Calculating Predicted 
Spirometry Parameters..........................................................................................56
10.5Threshold Analysis Criteria...................................................................................61
10.6Standards for Efficacy and Safety Variable Display in TFLs..................................69
10.7Imputation Rules for Missing AE dates.................................................................70
10.8Second CFTR Allele Mutations Included for Subjects who are Heterozygous for the 
F508del-CFTR Mutation.......................................................................................71
11 REFERENCES...........................................................................................................72


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List of Tables
Table 8-1 
Logic for Determining the Category of a Medication.....................................21
Table 8-2
CFQ-R for Children Ages 12 and 13..............................................................29
Table 8-3
CFQ-R for Adolescents and Adults (subjects 14 years and older)...................30
Table 8-4
CFQ-R for Parents/Caregivers (subjects 13 years and younger)......................30
Table10-1 Screening Period Assessments.......................................................................47
Table10-2 Treatment Periods, Washout Period, ETT, and Safety Follow-up Visit 
Assessments................................................................................................................49
Table 10-3 Visit Window Mapping Rules (within Period)................................................53
Table 10-4 HNVs Equation Coefficients by Sex, Race, and Age......................................57
Table 10-5 WNVs Equation Coefficients by Sex and Age in White Boys and Girls.........58
Table 10-6 WNVs Equation Coefficients by Sex and Age in Black Boys and Girls..........59
Table10-7 Threshold Criteria for Laboratory Tests.........................................................61
Table10-8 Threshold Criteria for Coagulation.................................................................65
Table10-9 Threshold Criteria for ECGs..........................................................................66
Table 10-10 Threshold Criteria for Vital Signs....................................................................67


SAP VX14-661-108, Version 1.1                                                                                                        Page 6of 72
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List of Figures
Figure 6-1   Schematic of the Study Design.....................................................................11
Figure 8-1 Testing Strategy for the Primary and Key Secondary Endpoint......................32




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approved clinical study protocol (Version 3.0, dated 10 June 2016),
approved electronic case report form (eCRF) (Version 3.0, dated 14 January 2016). 
Study VX14-661-108 is a Phase 3, randomized, double-blind, placebo-controlled, 2-period, 
3-treatment, crossover, multicenter study in subjects aged 12 years and older with CF, 
heterozygous for the F508del-CFTR mutation, and a second allele with a CFTR mutation 
predicted to have residual function. The study is designed to evaluate (i) the efficacy and 
safety of tezacaftor (TEZ; VX-661) in combination with ivacaftor (IVA; VX-770)and (ii) the 
efficacy and safety of IVAmonotherapy in this patient population using an incomplete block 
design. 
This SAP (Methods) documents the planned final statistical analyses of efficacy and safety 
endpoints defined in the study protocol for VX14-661-108, and describes the corresponding 
data presentations. It also documents analyses for additional efficacy and safety variables not 
specified in the protocol, which will provide supportive information to enhance the scientific 
understanding of the drug entity.
The study will also evaluate the pharmacokinetic (PK) characteristics ofTEZ, IVA, and their 
metabolites in this patient population. PK analyses will be documented separately in the 
clinical pharmacology analysis plan (CPAP) for the study.
In addition, some exploratory endpoints were also described in the study protocol. Analysis 
of some of these endpoints is described in this SAP. Additional analyses of exploratory 
endpoints will be outside of the scope of this SAP and documented separately.
The Vertex Biometrics Department will perform the statistical analysis of the efficacyand 
safety data; SAS (Version 9.2or higher) will be used to generate all statistical outputs 
(tables, figures, listings, and datasets). The SAP will be finalized and approved prior to the 
final clinical databaselock and treatment unblinding for the study and if the methods in this 
SAP differ from the methods described in the protocol, the SAP prevails.
4 STUDY OBJECTIVES
4.1
Primary Objective
To evaluate the efficacy of TEZ/IVAand IVAmonotherapy through 8 weeks of treatment in 
subjects with CF who are heterozygous for the F508del mutation on the CFTR gene and a 
second allele with a CFTR mutation predicted to have residual function.
4.2
Secondary Objectives
To evaluate the safety of TEZ/IVAthrough 8 weeks of treatment
To evaluate the safety of IVAmonotherapy through 8 weeks of treatment
To investigate the pharmacokinetics (PK) of TEZand its metabolite M1 (M1-TEZ), and 
IVAand its metabolite M1 (M1-IVA)


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5 STUDY ENDPOINTS
5.1
Efficacy Endpoints
5.1.1 Primary Efficacy Endpoint
Absolute change in ppFEV1from study baseline to the average of the Week 4 and Week 8 
measurements in each Treatment Period.
5.1.2 Secondary Efficacy Endpoints
The key secondary efficacy endpointis:
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from study baseline to the average of the Week 4 and Week 8 measurements in 
each Treatment Period
The following are other secondary efficacy endpoints:
Relative change in ppFEV1from study baseline to the average of the Week 4 and Week 8 
measurements in each Treatment Period
Absolute change in sweat chloride from study baseline to the average of the Week 4 and 
Week 8 measurements in each Treatment Period
5.2
Safety Endpoints
Safety and tolerability are secondary endpoints which will be evaluated based on assessments 
of:
Adverse events (AEs) 
Clinical laboratory values (hematology, serum chemistry, coagulation studies, vitamin 
levels, lipid panel, and urinalysis)
Standard digital electrocardiograms (ECGs)
Vital signs
Pulse oximetry
spirometry
5.3
Pharmacokinetic Endpoints
PKparameters are secondary endpoints, which will be assessed based on the PK of TEZ,
M1-TEZ, IVA, and M1-IVA






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Subjects who prematurely discontinue study drug treatment will continue to complete all 
other scheduled study visits for assessment of efficacy through the end of the Treatment 
Period in which discontinuation occurred.
6.2
Sample Size and Power
The primary efficacy endpoint is the absolute change in ppFEV1from study baseline to the 
average of the Week 4 and Week 8 measurements in each Treatment Period. 
The null hypotheses to be tested are that the mean absolute change from study baseline in 
ppFEV1to the average of the Week 4 and Week 8 measurements is the same for (i)TEZ/IVA
and placebo; and (ii) IVAmonotherapy and placebo.
Assuming a standard deviation (SD) of 7percentage points, 30subjects per sequence are 
needed to have at least 90% power to detect a 3percentage point treatment difference 
between TEZ/IVAand placebo when the mean values of the primary endpoint are being 
compared. A 2-sided significance level of 0.05 was used in the sample size calculations. 
Accounting for the testing strategy, the proposed sample size will yield approximately an 
85% chance of observing a statistically significant difference between IVAmonotherapy and 
placebo for the primary endpoint, under the assumption that IVAmonotherapy is also 3 
percentage points better than placebo (refer to Section8.3.2.3for a detailed description of the 
testing strategy). The sample size estimate was based on 10,000 simulation runs with an 
incomplete block design assuming no dropouts. In the simulation, the correlation between 
responses to the 2 treatments within a subject was assumed to be zero. After adjusting for an 
assumed dropout rate of 10%, the sample size was increased to 34 subjects per sequence (204 
total subjects).
6.3
Randomization
Approximately 204subjects (34per sequence) who meet eligibility criteria will be stratified 
by age at the Screening Visit (<18versus ≥18 years of age), ppFEV1severity determined 
during the Screening Period (<70 versus ≥70), and type of residual function mutation on the 
second CFTR allele (Class V non-canonical splice mutation versus Classes II to IV residual 
function mutation; see section 16 of the clinical study protocol), and then randomized 
(1:1:1:1:1:1) to 1of the 6 treatment sequences, as shown in Section 6.1. A minimum of 25% 
of enrolled subjects will carry a Class II to IV mutation on the second CFTR allele (see 
Section 10.8).Enrollment into the non-canonical splice strata will be limited to no more than 
75% of total enrollment.
An IWRS will be used to assign subjects to treatment sequence and to ensure enrollment of at 
least 25% of subject with Class II to IV residual function mutations. The IWRS will use a list 
of randomization codes generated by a designated vendor 
. 
6.4
Blinding and Unblinding
This is a double-blind study.


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6.4.1 Blinding
The subjects and all site personnel, including the investigator, the site monitor, and the study 
team, will be blinded with the exception of 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 their fetus in the event of a pregnancy
Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE)processing and reporting regulations
Unblinded statistician preparing the final (production) randomization list who is not part 
of the study team
Vertex Clinical Operations IWRS management
Vertex Clinical Supply Chain
IDMC
Vendor preparing the unblinded analysis for the IDMC 
Vendor analyzing PK samples
Vertex or vendor conducting the population PK analysis
Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. Such unblindings will be fully documented (see below).
Vertex Drug Metabolism and Pharmacokinetics laboratory personnel will not be involved in 
the conduct of the study and will be unblinded to the bioanalysis results but will remain 
blinded to subject number and treatment assignment.
Spirometry Data Blinding
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has been administered active study drug or placebo. Therefore, during the 
conduct of the study, the Vertex study team will have no access to the post-dose spirometry 
data. The vendor for central reading of the spirometry data will only send the blinded 
spirometry files (blinded treatment group, with real values for screening and baseline, but 
with dummy values for all the spirometry assessments after baseline) to Vertex to be used for 
developing the statistical programs. Furthermore, subjects and their caregiver should not be 
informed of their study-related spirometry results during the Treatment Period regardless of 
whether the subject has prematurely discontinued treatment.
Sweat Chloride Data Blinding
Despite treatment blinding, knowledge of the sweat chloride data has the potential to suggest 
whether a subject has been administered active study drug or placebo. Therefore, during the 
conduct of the study, the Vertex study team will have no access to the postdose sweat 
chloride data; dummy data will be used to develop statistical programs. During the process of 




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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 Global Patient 
Safety (GPS) or designee, per Section 13.1.2 of the clinical study protocol.
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, the Vertex medical monitor may, for matters relating to 
safety concerns, unblind individual subjects at any time.
7 ANALYSIS SETS
The following analysis sets are defined: All Subjects Set, RandomizedSet, Full Analysis Set 
(FAS), and Safety Set. 
The All Subjects Setis defined as all subjects who have been randomized or have received 
at least 1 dose of study drug. 
The RandomizedSetis defined as all subjects who have been randomized. 
The Full Analysis Set(FAS) is defined as all randomized subjects who carry the intended 
CFTR mutations (see Section 10.8) and have received at least 1dose of study drug.
The Safety Setis defined as all subjects who received at least 1dose of study drug.
8 STATISTICAL ANALYSIS
8.1
General Considerations
All individual subject data for those randomized or exposed tostudy drug will be presented 
in data listings.The Schedule of Assessmentsis provided inSection 10.1. The precision 
standards are provided in Section 10.6.
Continuous variableswill be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), median, minimum value 
(min), and maximum value (max). 
Categorical variableswill be summarized using counts and percentages. 
Treatment Emergent (TE) Periodfor Treatment Period 1 will correspond to data from the 
first dose of study drug in the first period to the safety evaluation visit (Safety Follow-up 
Visit, if subject discontinues treatmentin Period 1) or 28 days after the last dose in the same 
period for subjects who do not have a safety evaluation visit. Similarly, the TE period for 
Treatment Period2 will correspond to data from the first dose of study drug in the second 
period through the Safety Follow-up Visit (SFUV) or 28 days after the last dose in the same 
period for subjects who do not have an SFUV. The TE period for Treatment Period 1 and 
Treatment Period 2 will not exceed the day before the first dose of study drug in the 
extension study for subjects who enrolled into the extension study.
Baseline Value:For this crossover study, 2 types of baseline will be defined. The study 
baselineis defined as the most recent non-missing measurement (scheduled or unscheduled) 
collected prior to the first dose of study drug in the study. The definition will be applied to all 


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demographics, background, and baseline characteristics and also to efficacy data analyses, 
including the primary endpoint analysis. In addition, period baselineis defined as the most 
recent non-missing measurement (scheduled or unscheduled) collected before the first dose 
of study drug in each Treatment Period. For Treatment Period 2, the baseline should be from 
an assessment measured after the TE period for Treatment Period 1. This definition will be 
applied to all safety data analysis. For ECG, baseline for Period 1 will be defined as the 
average of the 3pretreatment measurements on Day 1. For sweat chloride, the study baseline 
value will be the mean of assessment values on the left and the right arm at the most recent 
time point prior to the first dose of study drug in the study. If the result from only one of the 
arms is available then the result from that arm will be considered as baseline. 
Change (Absolute change)from study baselinewill be calculated as post-baseline value–
study baseline value. 
Relative change from study baselinewill be calculated as 100x(post-baseline value–study 
baseline value)/study baseline value. 
Change (Absolute change)from period baselinewill be calculated as post-baselinevalue–
period baseline value. 
Relative change from period baselinewill be calculated as 100x(post-baseline value–
period baseline value)/period baseline value.
Unscheduled Visits: Unscheduled visit measurements will be included in the following:
(1)derivations of measurements at scheduled visits per specified visit windowing rules 
below;
(2)derivations of baseline/last on-treatment measurements;
(3)derivations of the maximum/minimum on-treatment values and maximum/minimum 
changes from baseline values for safety analyses;
(4)data listings where appropriate.
Visit Windowing Rules:Section 10.2defines the windows for protocol-defined visits. The 
windows will be applied using the following rules for both scheduled and unscheduled visits:
(1)If no measurement is available within a visit window, the assessment will be considered 
missing for the visit;
(2)If there is more than one measurement available within the same visit window, use the 
following rules: 
For all efficacy parameters, if there are multiple measurements within a visit window, 
the record at the scheduled visit will be used. If there are no measurements at the 
scheduled visit:
o the record closest to the target day will be used.
o If there are multiple records with the same distance to the target day, the latest 
record will be used.  
o Assessments at early treatment termination (ETT) visit will follow the 
windowing rules for regular visits up to Week 24. 


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o A safety follow-upvisit(SFUV) assessment will follow the windowing rules 
for regular visits if it falls within the upper boundary of the visit window for
Week 8 (period 1) orWeek 24 (period 2), or remain as SFUVotherwise.
For all safety parameters, if there are multiple measurements within a visit window, 
then 1) the record closest to the target day will be used; 2) if there are multiple 
records within the same distance from the target day, the latest record will be used; 3) 
SFUVwill not be windowed, instead, used per nominal visit in relevant analyses.
Note:spirometryassessments, BMI, weight, and heightwill be used for both efficacy and
safety purposes. The corresponding measurements will follow visit windowing rules for 
efficacy.
Incomplete/Missing datawill not be imputed, unless otherwise specified. 
Outliers:No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless otherwise specified.
8.2
Background Characteristics 
Unless otherwise defined, the FAS will be used for all analyses ofbackground data.The 
background analyses will be performed according to the treatment to which the subject was 
assigned in each period.
8.2.1 Subject Disposition
The number of subjects in the following categories will be presented by treatment group: 
All Subjects Set (randomized or dosed)
Randomized
Full Analysis Set (FAS)
Safety Set
The number of subjects in the following categories will be presented bytreatment groupfor 
each period (Period 1 and Period 2): 
Full Analysis Set (FAS)
Safety Set
The number and percentage (based on Safety Set) of subjects in eachof the following 
disposition categories will be presentedby treatmentgroupfor each period (Period 1 and 
Period 2):
Completed treatmentregimen
Prematurely discontinued the treatment(any tablet)and the reasonsfor discontinuations 
Prematurely discontinued the study and the reasons for discontinuations 


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The number and percentage (based on the overall Safety Set) of subjects in eachof the 
following disposition categories will be presented by treatment group:
Completed treatment regimen in both periods
Completed study
Rollover to extension
A listing will be provided for subjects who discontinued treatment or who discontinued 
study, alongwith reasons for discontinuations. 
The number and percentage of randomized subjects will be summarized by stratification 
factor, and by country and by site, using the number of subjects being randomizedin each 
treatment sequenceas the denominator. A randomization listing also will be provided.
8.2.2 Demographics and Baseline Characteristics
Demographic and study baseline characteristics data will be summarized by treatment group
based on the FASfor each period (Period 1 and Period 2).
Demographic data will include the following:
Ageat screening
Age groupat screening (< 18, and 18 years)
Sex 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations)
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other)
Geographic region (North AmericaandEurope)
Note: Australia and Israel will be presented under Europe.
Baseline characteristics will include the following:
Weight (kg) at study baseline
Height (cm) at study baseline
BMI (kg/m2) at study baseline
Stratification categories will include the following:
ppFEV1at screening (<70, and ≥70)
Residual function mutation (Class V non-canonical splice, and Classes II to IV residual 
function)
Disease characteristics will include the following:
ppFEV1at study baseline (<40, ≥40 to <70,≥70 to ≤90and>90)


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ppFEV1at study baseline
Sweat chloride at study baseline
CFQ-R at study baseline
FEV1(L) at study baseline
FVC (L) at study baseline
Percent predicted FVC at study baseline
FEF25-75%(L/sec) atstudy baseline
Percent predicted FEF
25-75%at study baseline
FEV1/FVC at study baseline
Use of dornase alfa 
Use of inhaled antibiotic  
Use of azithromycin
Use of bronchodilator 
Use of inhaled bronchodilator (short-acting only, [short-acting and long-acting] or long-
acting only) 
Use of inhaled hypertonic saline 
Use of inhaled corticosteroids 
Colonization ofPseudomonas aeruginosa(Positive, Negative)
Pancreatic Insufficient (defined as fecal elastase-1 value of <200 µg/g)
In addition, data listings will also be provided for:
informed consent
Inclusion/Exclusion criteria violation (for subjects with any such violations)
8.2.3 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 treatmentgroup, system 
organ class (SOC) and preferred term (PT)for each period (Period 1 and Period 2). The 
corresponding data listingalsowill be provided.
In addition, the number of subjects reported to have had positive cultures for respiratory 
pathogens in 2 years prior to screening (i.e., answered yes on the respiratory microbiology 
form) will be summarized by test and subcategories within the testfor each period. The 
corresponding data listing will be provided.Hospitalization and clinic visit history in the past 
year will be listed.


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8.2.4 Prior and Concomitant Medications
Medications taken duringthis study will be coded using the World Health Organization Drug 
Dictionary Enhanced(WHO-DDE)and categorized as follows: 
Prior medication: any medication that started before the first dose of study drugin the 
study, regardless of when it ended.
Concomitant medication: medication continued or newly received during the TE period 
for Treatment Period 1 or Treatment Period 2. If a subject took a medication during a 
specific Treatment Period, this medication will be attributed to the treatmentthe subject 
received during this Treatment Period. As a result, 1 medication could be attributed to 
more than 1 study drug for an individual subject.
Post-treatment medication: medication continued or newly received after the TE period 
for Treatment Period 2, or between the TE periods for Treatment Period 1 and Treatment 
Period 2, or after the TE period for Treatment Period 1 for subjects who do not have 
Treatment Period 2.
A given medication can 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 partial missing 
start/end date or time and it cannot be determined whether the medication was taken before 
initial dosing, concomitantly, or post-treatment, it will be considered as prior, concomitant, 
and post-treatment.
For the FAS, prior medications and concomitant medications will be summarized 
descriptively by: 1) treatment group, preferred name (PN); and 2)treatment group,anatomic 
class (ATC) level 1, ATC level 2, and PN. Prior medication summaries will be by period 
(Period 1 and Period 2). Post-treatment medications will be listed for each subject.
As an intermediate step for programming purposes, medications with missing or partially 
missing start dates will use 2000 to impute for the missing year, January for the missing 
month, and 1 for the missing day. Medications with missing or partially missing stop dates 
will use 2050 to impute for the missing year, December for the missing month, and the last 
day of the month for the missing day. The logic to decide the category of a medication is 
presented in Table 8-1:


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Table 8-1
Logic for Determining the Category of a Medication
Medication start date
Medication end date
< Start date of 
TE Period 1
≥ Start date of TE Period 1 
and ≤ End date of TE Period 1
> End date of TE Period 1 and 
< Start date of TE Period 2
≥ Start date of TE Period 2 and 
≤ End date of TE Period 2
> End date of 
TE Period 2
< Start date of TE Period 1
P
PC1
PC1A
PC1C2A
PC1C2A
≥ Start date of TE Period 1 and ≤ 
End date of TE Period 1
-
C1
C1A
C1C2A
C1C2A
> End date of TE Period 1 and < 
Start date of TE Period 2
-
-
A
C2A
C2A
≥ Start date of TE Period 2 and ≤ 
End date of TE Period 2
-
-
-
C2
C2A
> End date of TE Period 2
-
-
-
-
A
P –Prior; C1 –Concomitant for the Treatmentin Period1; C2 –Concomitant for the Treatment in Period 2; A –Post-Treatment.


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8.2.5 Study Drug Exposure
Exposure summaries will be based on the FAS and presented by treatment group.
Duration of study drug exposure is defined as follows: last dose date –first dose date + 1 day 
within the treatment period, regardless of any interruption in dosing between the first and the 
last dose.
Duration of study drug exposureexpressed in weekswill be summarized descriptively 
(number, mean, SD, median, minimum, and maximum)and also into the following 
categories: ≤2 weeks, >2 -≤4 weeks, >4 -≤8 weeks, >8 weeks. Additionally, the total
duration of study drug exposure, defined as the total of duration of study drug exposure of all 
subjects and expressed in patient years, will be provided. 
8.2.6 Study Drug Compliance
Study drug compliance will be measured by the compliance rate;summarized based on the 
FAS and presented by treatment group.
Compliance ratewill be calculated as follows: 
100×[1 -(Total number ofdays study druginterrupted)/(Duration of study drug 
exposure)].
The total number of days study druginterrupted is defined as the totalofnumber of days the
study drugwas interrupted in each interruption interval; where number of days study 
druginterrupted in each interval is defined as the interruptionend date -the 
correspondinginterruptionstart date + 1.
The Compliance rate will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max and into the categories of <80% or ≥80%.
A list of subjects with <80% compliance ratewill be provided.
8.2.7 Important Protocol Deviations
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject
's rights, safety, or well-being. 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:
Violation of subjects rights, safety or well-being
Subject entered the study despite violation of any inclusion or exclusion criteria
Subject was less than 80% compliant with study medications
Subject received excluded concomitant medications


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Subject received the wrong treatment or incorrect doses
Subject remained in study despite meeting withdrawal criteria
Occurrence of any of these events should be considered as potential IPDs, but the blinded 
team should categorize them as IPDs only if they have the potential to affect interpretation of 
study results. 
IPDs (from the clinical database or from the site deviation log) will be summarized 
descriptively based on the FAS and presented by treatmentsequence. Additionally, IPDs will 
be provided as a subject data listing.
8.3
Efficacy Analysis
The primary objective of this study is to evaluate the efficacy of TEZ/IVAand IVA
monotherapy. For efficacy analysis, the statistical inference will be based on change from 
study baseline. Unless otherwise defined, all efficacy analyses described in this section will 
usethe FAS.The efficacy analyses will be performed according to the treatment to which the 
subject was assigned in each period.Data for a period will be used provided that the subject 
received at least one dose of study drug in that treatment period.
8.3.1 Analysis ofPrimary Efficacy Endpoint
The analysis will include all available measurements up to Week 8 [inclusive] during each 
treatment period, both on-treatment measurements and measurements after treatment 
discontinuation, per the visit windowing rules (Section 8.1).
8.3.1.1Definition of Primary Efficacy Endpoint
The primary efficacy endpoint is the absolute change in ppFEV1from study baseline to the 
average of the Week 4 and Week 8 measurements in each of the two Treatment Periods. 
ppFEV1is the ratio of FEV
1(L) to the predicted FEV
1(L), expressed as a percentage. The 
predicted FEV
1will be calculated using the Hankinson
1and Wang
2standards;detailsarein
Section 10.3.
8.3.1.2Primary Analysis of Primary Efficacy Endpoint
The primary efficacy analysis will be based on a mixed effects model using SAS procedure 
MIXED. The null hypotheses to be tested are that the mean absolute change from study 
baseline in ppFEV1to the average of the Week 4 and Week 8 measurements is the same for 
(i) TEZ/IVAand placebo and (ii) IVAmonotherapy and placebo. 
The primary analysis model will include the absolute change from study baseline in ppFEV1
to the average of the Week 4 and Week 8 measurements as the dependent variableand the 
following fixed effects:treatment, period, ppFEV1at study baseline, and subject as a random 
effect. The within-subject covariance will be assumed to have the same compound symmetry 
(CS) structure for sequences containing placebo treatment but will be different from the CS 
structure for sequences containing active treatment in both periods. Denominator degrees of


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freedom for the F-test for fixed effectswill be estimated using the Kenward-Roger 
approximation3. The estimated mean of the dependent variable, a 95% confidence interval, 
and a 2-sided Pvalue will be provided for each treatment. Similarly, the estimated between 
group treatment differences along with the corresponding 95% CI and 2-sided Pvalues will 
be presented.  
No imputation of missing data will be performed. Subjects who have data only for one of the 
periods will have a data structure similar to a parallel-group trial. Assuming that these
subjects have dropped out at random, an estimate of treatment effect based on such subjects 
will be combined with the estimate from subjects who have data in both treatment periods 
with weights based on the precision of these estimates4. 
The drop-out rate is expected to be low based on the experience with other CF studies (for 
example, drop-out rate in Study VX12-809-103 was 4.6%, Study VX12-809-104 was 5.2% 
and Study VX12-770-111, a crossover study, was 7.7%). Notethatcarryover effects are not 
included in the model; such effects are not expected because of the long washout period.
The SAS code to implement the primary analysis will be similar to the code presented below:
proc mixed data=xxx;
    class subject period treatment group;
    model primary efficacy endpoint = period treatment
               ppFEV1 at study baseline/ddfm=KR;
    repeated period/sub=subject type=cs group=group;
    lsmeans treatment / pdiff cl;
run;
where“primary efficacy endpoint” is the average absolute change from study baseline in 
ppFEV1at weeks 4 and 8 in each treatment period. The Group= statement will specify the 
variable so that the covariance structure will be different for each value of the variable. 
Descriptive statistics associated with the raw value and the absolute change from study 
baseline in ppFEV1 at post-baseline visits (Day 15, Weeks 4, and 8) along with the average 
ppFEV1 at Weeks 4 and 8 and the average absolute change from study baseline in ppFEV1 at 
Weeks 4 and 8 will be summarized by treatment group. Subjects with missing ppFEV1at 
both Week 4 and Week 8 visits will have missing average ppFEV1at Weeks 4 and 8. 
Therefore, they will not be included in the related summaries.The cumulative distribution of 
the average absolute change from study baseline in ppFEV1at Weeks 4 and 8 in each 
treatment periodwill be plotted by treatment group.
In addition, analysis based on an ANCOVA model using absolute change from study 
baseline in ppFEV1to the average of the Week 4 and Week 8 measurements from Treatment 
Period1 will be performed to assess the treatment effect difference in case there is a 
carryover effect. The resulting model will include treatment, age groupat screening(<18 vs.
≥18 years old), ppFEV1at study baseline and category of residual function mutation (Class V 
non-canonical splice mutation versus Classes II to IV residual function mutation).The 
estimated mean of the dependent variable for each treatment and between treatment 
differences will be presented along with the 95% CI.










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The CFQ-R
6,7,8is a validatedCF-specific instrument that measures quality-of-life domains. 
This study uses three different versions of CFQ-R forms:
CFQ-R for Children Ages 12 and 13 has a total of 35 questions to form 8 domains. All 
questions are scored 1, 2, 3, or 4.
CFQ-R for Adolescents and Adult (subjects 14 years and older) has a total of 50 
questions to form 12 domains. Question 43, which is scored 1, 2, 3, 4, or 5, is not used in 
calculating any domain; all the other 49 questions are scored 1, 2, 3, or 4.
CFQ-R for Parents/Caregivers (subjects 13 years and younger) has a total of 44 questions 
to form 11 domains. Question 37, which is scored 1, 2, 3, 4, or 5, is not used in 
calculating any domains; all the other 43 questions are scored 1, 2, 3, or 4.
For all three CFQ-R versions, to calculate the score for each domain, the response scores on 
the negatively phrased questions are reversed (reversed scores = 5 –response scores) so that 
1 always represents the worst condition and 4 always represents the best condition. 
The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition). It 
is calculated as follows:
Scaled score for a domain = 100 × (mean(scores of all questions in that domain) -1)/3
The scaled score for a specific domain will not be calculated if more than half of the 
questions in the domain have missing scores.
Table 8-2, Table 8-3, and Table 8-4provide the questions included in each domain, the 
questions with the reversed scores, as well as the maximum number of missing questions for 
the CFQ-R for Children Ages 12 and 13, the CFQ-R for Adolescents and Adults, and the 
CFQ-R for Parents/Caregivers respectively. The CFQ-R scoring manual is also provided in 
Section 10.4.
Table 8-2
CFQ-R for Children Ages 12 and 13 
Domain
Questions
Reversed questions
Maximum number of 
missing questions
Total
Individual
Physical
6
1, 2, 3, 4, 5, 6
1, 2, 3, 4, 5
3
Emotion
8
7, 8, 9, 10, 11, 12, 13, 14
14
4
Social
7
20, 21, 22, 23, 24, 25, 26
20, 22, 24, 26
3
Body
3 
27, 28, 29
-
1
Eat
3 
15, 17, 19
19
1
Treatment burden
3 
16, 18, 30
18
1
Respiration
4
31, 32, 33, 34
-
2
Digestion
1 
35
-
0


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Table 8-3
CFQ-R for Adolescents and Adults (subjects 14 years and older) 
Domain
Questions
Reversed questions
Maximum number of 
missing questions
Total
Individual
Physical
8
1, 2, 3, 4, 5, 13, 19, 20
13
4
Role
4
35, 36, 37, 38
35
2
Vitality
4
6, 9, 10, 11
6, 10
2
Emotion
5
7, 8, 12, 31, 33
-
2
Social
6
22, 23, 27, 28, 29, 30
23, 28, 30
3
Body
3 
24, 25, 26
-
1
Eat
3 
14, 21, 50
-
1
Treatment burden
3 
15, 16, 17
15, 17
1
Health perceptions
3 
18, 32, 34
18, 32, 34
1
Weight
1 
39
-
0
Respiration*
6
40, 41, 42, 44, 45, 46
43
3
Digestion
3 
47, 48, 49
-
1
*: Question 43 not used to calculate a domain. 
Table 8-4
CFQ-R for Parents/Caregivers (subjects 13 yearsand younger) 
Domain
Questions
Reversed questions
Maximum number of 
missing questions
Total
Individual
Physical
9
1, 2, 3, 4, 5, 13, 14, 15, 16
15
4
Vitality
5
8, 9, 10, 11, 12
10, 12
2
Emotion
5
6, 7, 23, 25, 26
6
2
School
3 
27, 28, 29
28
1
Body
3 
19, 20, 21
-
1
Eat
2 
17, 44
-
0
Treatment burden
3 
18, 30, 31
31
1
Health perceptions
3 
22, 24, 32
22, 24, 32
1
Weight
1 
33
-
0
Respiration*
6
34, 35, 36, 38, 39, 40
37
3
Digestion
3 
41, 42, 43
-
1
*: Question 37 not used to calculate a domain. 


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8.3.2.1.2Other Secondary Efficacy Endpoints
Relative change in ppFEV1from study baseline to the average of the Week 4 and Week 
8 measurements in each Treatment Period
The calculations of ppFEV1 and the relative change from study baseline will follow the 
definitions in Section 8.3.1.1and Section 8.1.
Absolute change in sweat chloride from study baseline to the average of the Week 4 and 
Week 8 measurements in each Treatment Period
Sweat chloride will be collected at baseline and 2 post-baseline time points (Weeks4 and 8) 
in each treatment period. Values > 160 mmol/L or < 10 mmol/L will be set to missing and 
excluded from the analysis.
Absolute change from study baseline in sweat chloride will be calculated asmean(SWLeft, 
SWRight)  
̶  SW
Base, where SWLeftand SWRightare the measurements obtained on the left and 
right arms, respectively, at a particular visit and SWbaseis the mean of right and left baseline 
measurements.  If one of the two measurements at a time point is missing, the other will be 
used as the mean.
Note:  A volume of ≥15μL is required for an accurate determination of sweat chloride.  Any 
results reported as having volume <15μL or “Quantity Not Sufficient” (QNS) will be 
considered missing.
8.3.2.2Analysis of Key Secondary Efficacy Endpoint
Absolute change in CFQ-R respiratory domain score from study baseline to the average 
of the Week 4 and Week 8 measurements in each Treatment Period
Analysis for the absolute change from study baseline in CFQ-R respiratory domain (Pooled 
'Children Ages 12 and 13
' Version and 
'Adolescents and Adults
' Version) score to the 
average of Week 4 and Week 8 scores in each treatment period will be similar to the primary 
analysis of the primary efficacy endpoint. However, ppFEV1at study baseline will be 
replaced by CFQ-R respiratory domain scoreat study baselinein the model.
The estimated mean of absolute change from study baseline in CFQ-R respiratory domain 
score to the average of Week 4 and Week 8 scores will be presented along with the 95% CI 
and the 2-sided P value. Similarly, the estimated differences between treatment groupsand 
the associated 95% CI and Pvaluewill be presented. 
The raw value and absolute change from study baseline in CFQ-R respiratory domain score 
at post-baseline visits (Weeks 4 and 8) will be summarized by treatment group using 
descriptive statistics. Similar descriptive statistics will also be presented for average CFQ-R 
respiratory domain score at Weeks 4 and 8 and the average absolute change from study 
baseline in CFQ-R respiratory domain scoreat Weeks 4 and 8. The cumulative distribution 
plot will be created for this endpoint.


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8.3.2.3Multiplicity Adjustment
There are 3 potential treatment comparisons for the primary and key secondary endpoint: 
TEZ/IVAversus placebo, IVAmonotherapy versus placebo, and TEZ/IVAversus IVA
monotherapy. The testing strategy
 will be limited to the comparison of TEZ/IVAversus 
placebo and IVAmonotherapy versus placebo.To control for multiplicity of endpoints and 
treatments (the probability of Type 1 error), each endpoint will be assessed sequentially using 
a gatekeeping approach where statistical significance can be claimed for the key secondary 
endpoint only if the primary endpoint meets the requirements for significance. Additionally, 
as there are two treatments foreach endpoint, the gatekeeping approach will also be applied,
i.e., IVA monotherapy for a given endpoint can achieve significance only if the comparison 
for TEZ/IVA for the same endpoint is significant (Figure 8-1). For each endpoint, and for 
each treatment group, the comparison with placebo will be conducted using a significance 
level (alpha) set at 0.05 (2-sided).
Figure 8-1
Testing Strategy for the Primary and Key Secondary Endpoint
IVA: ivacaftor; TEZ: VX-661; PBO: placebo; ppFEV1: percent predicted forced expiratory volume in 1 second; 
CFQ-R:Cystic Fibrosis Questionnaire–Revised (respiratory domain); Avg: Average












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of TE period for Treatment Period 1 to the date of the last study record in the clinical 
database will be considered as post-treatment period. 
8.4.1 Adverse Events 
For analysis purpose, AEs will be categorized as pretreatment AEs, treatment-emergent 
adverse events (TEAEs), or post-treatment AEs:
Pretreatment AE:any AE that started before initial dosing of study drugin the study.
TEAE: any AE that increased in severity or that was newly developed during the TE 
period for Treatment Period 1 or Treatment Period 2. If an AE started (or increased in 
severity) during a specific Treatment Period, this AE will be attributed to the treatment
thesubject was receiving during the Treatment Period. 
Post-treatment AE:any AE that increased in severity or that was newly developed 
beyond the TE period for Treatment Period 2, or between the TE periods for Treatment 
Period 1 and Treatment Period 2, or beyond the TE period for Treatment Period 1 for 
subjects who do not have Treatment Period 2.
For AEs with missing or partial start date, if there is no clear evidence that the AEs started 
(or increased in severity) before the first dose, the start date willbe imputed to the first 
dosing date and the AE assigned to the treatment in Treatment Period 1.As an intermediate 
step for programming purposes, imputation rules for missing or partially missing AE 
start/end dates are defined in Section 10.7.
By relationship to the study drugregimen, TEAEs will be classified into the 4 categories:
Not related
Unlikely related
Possibly related
Related
By severity, TEAEs will be classified intothe 4 categories:
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 (Grade3): Significant level of discomfort and prevents regular activities
Life-threatening (Grade4): Any adverse drug experience that places the subject, in 
the view of the investigator, at immediate risk of death
8.4.1.1Overview of Treatment Emergent AEs
An overview of all TEAEs willbe summarized in the following categories:


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Any TEAEs 
TEAEs by relationship
Related TEAEs
TEAEs by severity
Grade 3/4 TEAEs
Serious TEAEs
Related Serious TEAEs
TEAEs leading to treatment discontinuation (this will includeTEAEs leading to 
discontinuation ofeither TEZ/IVA tablet or the IVAtablet)
TEAEs leading to treatment interruption (this will includeTEAEs leading to interruption 
ofeither TEZ/IVA tablet or the IVA tablet)
TEAEsleading to death 
8.4.1.2TEAEs and TESAEs by System Organ Class and Preferred Term
The number and percentage of subjects with TEAEswill be summarized by treatment group, 
MedDRA system organ class (SOC) and preferred term (PT), where multiple occurrences of 
the same AEfor the same subject will be counted only once. The summary tablewill be 
presented in descending order of frequencies in the TEZ/IVA treatment group.TESAEswill 
be summarizedsimilarly.
8.4.1.3TEAEs and TESAEs by PT
The number and percentage of subjects with TEAEs will be summarizedbytreatment group 
andPT, where multiple occurrences of the same AEfor the same subject will be counted 
only once. TESAEswill be summarizedsimilarly.
8.4.1.4Related TEAEs and TESAEs by SOC, PT
The number and percentage of subjects with related TEAEs will be summarizedby treatment 
group,SOC,andPT, where multiple occurrences of the same AEfor the same subject will be 
counted only once. The summary table will be presented in descending order of frequencies 
in the TEZ/IVA treatment group.TEAEs in the following relationship to study drug regimen 
categories will be considered as related: Related, Possibly Related and Missing. TE SAEs 
will be summarized similarly.
8.4.1.5Grade 3/4 TEAEs by SOC, PT
The number and percentage of subjects with Grade 3/4TEAEs will be summarizedby 
treatment group,SOC,andPT, where multiple occurrences of the same AE for the same 
subject will be counted only once. The summary table will be presented in descending order 


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of frequencies in the TEZ/IVA treatment group.Grade 3/4 TEAEs include severe and life-
threatening adverse events. 
8.4.1.6Respiratory Events and Symptoms
Respiratory symptoms aredefined asany TEAEs forthe following 3PTs:
Chest discomfort
Dyspnoea
Respiration abnormal
Respiratory events aredefined asanyof the afore-mentioned respiratory symptoms, or any 
TEAEs forthe following 4 additionalPTs:
Asthma
Bronchial hyperreactivity
Bronchospasm
Wheezing
A summary of respiratory symptoms and events will be presented by PT.
8.4.1.7Elevated Transaminase
The following AE PTswill be selected for elevated transaminase:
Alanine aminotransferase abnormal 
Alanine aminotransferase increased
Aspartate aminotransferase abnormal
Aspartate aminotransferase increased
Transaminases abnormal
Transaminases increased
Liver function test abnormal
Liver function test increased
Hypertransaminasaemia
Hepatic enzyme abnormal
Hepatic enzyme increased.
A summary of elevated transaminasewill be presented by PT.


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8.4.1.8Summaries of Respiratory Events, Respiratory Symptomsand 
Elevated Transaminaseby Treatment Interval
Respiratory events, Respiratory symptoms and elevated transaminasewill also be 
summarized by the following treatment interval:
0-1 Weeks: [Day1, Day7]
>1 -2 Weeks: [Day8, Day14]
>0-8 Weeks: [Day1, Day56]
>8 Weeks: [Day57, end of TE period])
8.4.1.9Subgroup Analysis 
TEAEsby SOC and PT also will be summarized forthe following subgroups.
Age at screening (<18,18 years)
ppFEV1at study baseline (<40, ≥40 to <70, ≥70)
Sex 
Residual function mutation (Class V non-canonical splice, Classes II to IV residual 
function)
Region (North America,Europe)
Furthermore, TEAEs leading to treatment discontinuation,TEAEs leading to treatment 
interruption, and TEAEs leading to deathwill be summarized by SOC and PT. In addition, a 
listing containing individual subject adverse event data for TEAEs leading to treatment 
discontinuation,TEAEs leading to treatment interruption, SAEs and all deaths will be 
provided separately, with a flag indicating the TE status for SAEs and deaths.
For all AEs, the CRF captures the action taken for TEZ/IVA pills separately from the AE 
action taken for IVA monotherapy pills. As a result, it is possible that, in the final database 
(after DBL), the AE actions taken for the two agents (fixed dose TEZ/IVA and IVA 
monotherapy) are different. The summaries and listings of “TEAEsLeading to Treatment 
Discontinuation” and “TEAEsLeading to Treatment Interruption” account for 
discontinuation and interruptions for either agent.
8.4.2 Clinical LaboratoryValues
For treatment-emergent laboratory measurements, the raw values and change from period 
baseline values forthe continuous hematology,chemistry and coagulationresultswill be 
summarized in SI units by treatment group at each scheduled time point. For hematology, 
coagulation and chemistry measurements, the number and percentage of subjects with an 
abnormal low (<LLN)valueand an abnormal high (>ULN) value at each analysis visit will 
be summarized.


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The number and percentage of subjects with hematology, chemistry and coagulationvalues 
meeting the defined threshold criteriaduring the visit window for analysis visitswill be 
summarized by analysis visit. Similarly, the hematology, chemistry and coagulationvalues 
meeting the defined threshold criteriaduring the overall TE period will be presented.The 
threshold analysiscriteria are provided inSection 10.5(Table10-7and Table10-8).
For all LFT results (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], direct bilirubin, total bilirubin, and gamma-glutamyl transferase 
[GGT]), the following additional analyses will be conducted:
o
A listing of subjects with elevated LFT results during the TE period will be presented. 
For each subject in the listing, LFT assessments at all visitsduring the TE period with 
elevated LFTwill be included.
o
For each of the LFTs, mean values (SD) will be plotted byvisit. 
o
The incidence of LFTs meeting threshold analysis criteriaduring the TE period against 
the period baseline threshold criteria will be summarized by treatment group(only 
worsening of the shift from period baseline will be presented).  
o
A scatter plot of the maximum ALT valueacross visitsversus the maximum total 
bilirubinvalue alsowill be presented. The ALT and Total bilirubin values will be 
presented on a logarithmic scale. The graph will be divided into 4 quadrants with a 
vertical line corresponding to 3xULN for ALT and a horizontal line corresponding to 
2xULN for total bilirubin. A similar graph of maximum AST value versus maximum 
total bilirubin value will be presented as well.
A summary table for the shift from period baseline to the value at Week 8 will be presented 
by treatmentgroupfor vitamin levels and lipid panel. A box plot of vitamin levels and lipid 
panel will also be plotted against visit.
For amylase and lipase, mean values (SD) will be plotted by visit.
In addition, a listing containing individual subject hematology, chemistry, and coagulation 
resultsoutside the reference ranges will be provided. This listing will include data from 
scheduled and unscheduled visits.Subjects with positive pregnancy test results will be listed. 
Abnormal urinalysis results also will be listed. 
8.4.3 Standard 12-Lead Electrocardiogram
For treatment-emergent ECG measurements, a summary of raw values and change from 
period baseline values will be provided by treatment group at each scheduled time point for 
the following standard 12-lead ECG measurements: PR, QTc for HR intervals (QTcF), QRS 
duration, and HR. In addition, the mean value at each time point will be plotted by treatment 
group for QTcFand heart rate.
The number and percentage of subjects with ECGmeasurementsmeeting the threshold 
analysis criteriaduring the visit window foranalysis visits will be summarized by analysis 
visit. Similarly, the ECG measurements meeting the threshold analysis criteria during the 


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overall TE period will be presented.Thethreshold analysiscriteria are provided in Section 
10.5(Table10-9).
8.4.4 Vital Signs
The raw values and change from period baseline values will be summarized by treatment 
group at each scheduled time pointfor the following treatment-emergent vital signs 
measurements: systolic and diastolic blood pressure (mm Hg), body temperature (oC), HR 
(beats per minute), and respiratory rate (breaths per minute).In addition, the mean value at 
each time point will be plottedby treatment groupfor systolic and diastolic blood pressure.
The number and percentage of subjects with vital signsmeeting the threshold analysis 
criteria during the visit window foranalysis visits will be summarized by analysis visit. 
Similarly, the vital signs meeting the threshold analysis criteria during the overall TE period 
will be presented.The threshold analysiscriteria are provided in Section 10.5(Table 10-10).
8.4.5 Pulse Oximetry
For treatment-emergent pulse oximetry measurements, a summary of raw values and change 
from period baseline values will be provided by treatment groups at each scheduled time 
point for the percent of oxygen saturation by pulse oximetry. In addition, the mean value at 
each visit will be plotted by treatment group for the percent of oxygen saturation. 
The number and percentage of subjects with shift changes from period baseline 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the TEperiod will be tabulated by treatment groups.Note: Normal oxygen 
saturation is defined as >95% and low oxygen saturation is defined as <=95%.
8.4.6 Postdose Spirometry
For the 2-hour and 4-hour postdose measurements on Day 1 and Day 15 of each treatment 
period, a summary of raw values for ppFEV1will be provided by treatmentgroupat each 
time point. The absolute change from the predose value of ppFEV1on the same day will be 
provided by treatment at each time point. In addition, a box plot by study day and treatment 
group will be provided for each time point.The above analyses will be repeated for FEV1.
In addition, the number and percentage of subjects with (i)ppFEV1decline ≥10, ≥15, 
and≥20percentage points in the absolute change from the predose value(ii) FEV1decline of 
≥0.2 L will be summarized by treatmentgroupand by assessment day and time.
8.4.7 Physical Examination
Abnormal physical examination findings will be presented ina data listing.
8.4.8 Ophthalmologic Examination
Ophthalmologic examination findings will be presented ina data listing.








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10 APPENDICES
10.1
Schedule of Assessments
Table10-1
Screening Period Assessments
Event/Assessment
Screening Period
(Day -28 Through Day-1)
ICF and assent (when applicable)
X
Demographics
X
Medical history 
X
Ophthalmological history 
X
CFTRgenotypea
X
CFQ-R
b
X
Height and weightc
X
Ophthalmologic examinationd
X
Complete PE
X
FSHe
X
Serum pregnancy test (all females of childbearing potential)f
X
Standard digital ECGg
X
Vital signsh
X
Pulseoximetry
h
X
Spirometryi
X
Sweat chloridej
X
Urinalysis
X
Hematology
X
Coagulation
X
Serum chemistry
X
                                               
a
All subjects will be tested for CFTR genotype and results must be confirmed before randomization. Specific instructions 
will be provided in the Laboratory Manual. 
b
CFQ-R and 
must be completed prior to the start of any other assessments scheduled at that visit.
c
Weight and height will be measured with shoes off.
d
An ophthalmologic examination will be conducted on subjects of all ages by an ophthalmologist. The ophthalmologic 
examination does not need to be repeatedif there is documentation of an examination that met the protocol criteria and that 
was conducted within 3 months before the Screening Period or if there is a documentation of bilateral lens removal 
(Section11.7.8 of the CSP). Subjects with clinically significant cataracts, lens opacity, Y-suture, or lamellar ringswill be 
excluded.
e
FSH will be measured for any potentially postmenopausal female with at least 12months of continuous spontaneous 
amenorrhea. Serum FSH levels must be ≥40mIU/mL to be considered postmenopausal.
f
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.
g
A standard digital ECG will be performed after the subject has been supine for at least 5minutes.
h
Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5minutes. 
i
Spirometry may be performed pre-or post-bronchodilator (Section11.6.1 of the CSP). Screening spirometry evaluation 
may be repeated, as specified in Section8.1.1.1 of the CSP.
j
A sweat chloride test must be performed if an eligible sweat chloride value is not available in the subject’s medical 
records. For subjects using a sweat chloride value documented in their medical record to establish eligibility, the sweat 
chloride test at the Screening Visit is optional.




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Table10-2 Treatment Periods, Washout Period, ETT, and Safety Follow-up Visit Assessments
Treatment Period 1
Washouta
Treatment Period 2
Event/Assessmentb
Week 1
(Day 1)
Week 2
(Day 15)
(± 3Days)
Week 4
(Day 29)
(±5Days)
Week 8
(Day 57)
(±5Days)
Safety 
Evaluation 
Visit 
Week 12 
(Day 85) 
(±5Days)
Week 17a
(Day 113)
Week 18
(Day 127)
(± 3Days )
Week 20
(Day 141)
(±5Days)
Week 24 
(Day 169)
(±5Days)
ETT
Visitc
Safety 
Follow-up 
Visit
28 days 
(±7days)
After Last 
Dosed
Clinic visit
X 
X 
X 
X
X
X 
X 
X 
X 
X 
X
Inclusion and exclusion 
criteria review
X
Xe
CFQ-R
f
X
X 
X
X
X
X 
X 
X 
X
Height and weightg
X 
X 
X 
X
X
X 
X 
X 
X 
X 
X
                                               
a
The Washout Period starts the day after completion of the Week8 Visit and continues for 8 weeks (+7days). The Washout Period is considered to be complete when dosing has occurred 
at the Week 17 Visit.
b
All assessments will be performed before dosing unless noted otherwise. If study drug is not administered on the day of the visit (i.e., study drug interruption or premature discontinuation 
of study drug treatment), only 1 set of assessments will be collected. Subjects who prematurely discontinue study drug treatment will continue to complete all other scheduled study visits for 
assessments of efficacy (spirometry, sweat chloride, and CFQ-R) and 
 through the 
end of the Treatment Period in which discontinuation occurred, as described in Section8.1.6 of Clinical Study Protocol.
c
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study treatment. Subjects who 
prematurely discontinue study drug treatment will also be required to complete the Safety Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug. If the ETTVisit 
occurs 3weeks 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. See 
Section 8.1.5 and 8.1.6 of Clinical Study Protocol. 
d
The Safety Follow-up Visit is not required for subjects who complete the Week24 Visit and have enrolled in an extension study of TEZin combination with IVAwithin 28days after the 
last dose of study drug.
e
In order to continue in Treatment Period 2, subjects must not have an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for 
pulmonary disease within 4 weeks before the Week 17 Visit (first dose of study drug in Treatment Period 2) and must not have any “non-CF-related” illness within 2 weeks before the Week 
17 Visit. “Illness” is defined as an acute (serious or nonserious) condition (e.g., gastroenteritis). If the subjects do not meet these criteria, then the continuation of the subjects into Treatment 
Period 2 must be discussed with theMedical Monitor. 
f
All questionnaires must be completed before the start of any other assessment scheduled for that visit. The CFQ-R must be completed first, followed by the 
 Subjects will need to 
complete a CFQ-R and 
 at the ETT Visit (Section 8.1.6 of Clinical Study Protocol).  
g
Weight and height will be measured before dosing with shoes off. Height will be collected only for subjects 21 years of age or younger.


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Table10-2 Treatment Periods, Washout Period, ETT, and Safety Follow-up Visit Assessments
Treatment Period 1
Washouta
Treatment Period 2
Event/Assessmentb
Week 1
(Day 1)
Week 2
(Day 15)
(± 3Days)
Week 4
(Day 29)
(±5Days)
Week 8
(Day 57)
(±5Days)
Safety 
Evaluation 
Visit 
Week 12 
(Day 85) 
(±5Days)
Week 17a
(Day 113)
Week 18
(Day 127)
(± 3Days )
Week 20
(Day 141)
(±5Days)
Week 24 
(Day 169)
(±5Days)
ETT
Visitc
Safety 
Follow-up 
Visit
28 days 
(±7days)
After Last 
Dosed
Ophthalmologic 
examination
h
X 
X
Complete PEi
X
X
Pregnancy testj
urine 
urine 
urine
serum
urine 
urine 
urine 
urine
serum 
serum 
serum
Standard digital ECGk
X 
X 
X 
X
X
X 
X 
X 
X 
X 
X
Vital signsl
X 
X 
X 
X
X
X 
X 
X 
X 
X 
X
Pulse oximetryl
X 
X 
X 
X
X
X 
X 
X 
X 
X 
X
Spirometrym
X 
X 
X 
X
X
X 
X 
X 
X 
X 
X
Sweat chloriden
X
X 
X
X
X 
X
Urinalysis
X
X
X
X
X 
X 
X
                                               
h
Subjects <18years of age at screening who discontinue study drug treatment after receiving at least 1dose of study drug, and subjects <18years of age at screening who complete 
treatment but do not enroll in a separate extension study of TEZ/IVAwithin 28days after the last dose of study drug will have an ophthalmologic exam conducted by a licensed 
ophthalmologist (see Section11.7.8of Clinical Study Protocol). The exam may be completed at either the ETT or Safety Follow-up Visit, but must be completed by the date of the Safety 
Follow-up Visit. Subjects who have documented bilateral lens removal do no need an ophthalmologic exam.
i
In addition to the complete PEs indicated, symptom-targeted PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator.
j
Pregnancy tests will be performed for all female subjects of childbearing potential.
k
All standard digital ECGs will be performed before dosing and after the subject has been supine for at least 5minutes. At the Week 1, Week 2, Week17, and Week18 Visits, ECGs will 
be collected before dosing and at 1.5, 3, 4, and 6hours after the morning dose. At the Week 1, Week 2, Week17, and Week18 visits the 4-hour postdose ECG will be collected before the 
4-hour postdose spirometry assessment. The predose ECGs collected at the Week 1 (Day1) visit will be performed in triplicate. If study drug is not administered on the day of the visit (i.e., 
because of study drug interruption or permanent discontinuation of study drug), only 1 ECG will be collected.
l
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest (seated or supine) for at least 5minutes.
m
At all visits, spirometry must be performed for all subjects before dosing and should be performed prebronchodilator (Section11.6.1 of Clinical Study Protocol). At Week1, Week 2, 
Week 17,and Week18,subjects <18years of age at the Screening Visit will have additional spirometry performed at 2and 4hours after the morning dose. If more than 1 spirometry 
assessment is required at a visit, bronchodilators will be withheld until completion of the last scheduled spirometryassessment is completed. 
n
The Sweat collection on dosing visits should occur approximately 1hour before the PK samplecollection and before the morning dose of the study drugs. Sweat collection will not 
overlap with any other study assessments (Section11.6.2 of Clinical Study Protocol).






SAP VX14-661-108, Version 1.1                                                                                                     Page 53of 72
10.2
Analysis Visit Window Mapping Rules for Efficacy and Safety 
Measurements
Table 10-3
Visit Window Mapping Rules (within Period)
Assessments
Period –Visit
Analysis 
Visit
Target 
Study Day
Visit Window 
(in study days)
Weight and height
Vital signs
Pulse oximetry
Labs
oChemistry
oHematology
1-Baseline
Baseline
1
[screening visit, pre-dose Day 1]
1 –Day 15
Day 15
15
[1*, 22]
1 –Week 4
Week 4
29
[23, 43]
1 –Week 8
Week 8
57
[44, 71]
1 -Week 12 (Safety Evaluation 
Visit)
Safety 
Follow-
up Visit 
NA
Use the nominal visit name†
2 -Baseline
Baseline
1
[end of TE period for first period +1 , 
pre-dose Week 17]
2 –Week 18
Day 15
15
[1*, 22]
2 –Week 20
Week 4
29
[23, 43]
2 –Week 24
Week 8
57
[44, 71]
ETT
NA
Follow the individual visit window to 
be mapped to individual visits
2 –Safety Follow-up Visit
Safety 
Follow-
up Visit
NA
Use the nominal visit name†
CFQ-R
1-Baseline
Baseline
1
[screening visit, Day 1]
1 -Week 4 
Week 4
29
[1*, 43]
1 -Week 8 
Week 8
57
[44, 71]
1 -Week 12 (Safety Evaluation 
Visit)
Safety 
Follow-
up Visit 
NA
Use the nominal visit name†
2-Baseline
Baseline
1
[end of TE period for first period +1 , 
Week 17]
2 -Week 20
Week 4
29
[1*, 43]
2-Week 24
Week 8
57
[44, 71]
ETT
NA
Follow the individual visit window to 
be mapped to individual visits
2 -Safety Follow-up Visit 
Safety 
Follow-
up Visit 
NA
Use thenominal visit name
†
Sweat Chloride
1-Baseline
Baseline
1
[screening visit, pre-dose Day 1]
1 -Week 4 
Week 4
29
[1*, 43]
1 -Week 8 
Week 8
57
[44, 71]
2-Baseline
Baseline
1
[end of TE period for first period +1 , 
pre-dose Week 17]
2 -Week 20
Week 4
29
[1*, 43]
2 -Week 24
Week 8
57
[44, 71]
ETT
NA
Follow the individual visit window to 
be mapped to individual visits
 
 
 


SAP VX14-661-108,Version 1.1                                                                                                   Page 54of 72
Vertex Pharmaceuticals Incorporated
 
Labs
o
Coagulation
o
Urinalysis
1-Baseline
Baseline
1
[screening visit, pre-dose Day 1]
1 -Week 8
Week 8
57
[1*, 71]
1 -Week 12 (Safety Evaluation 
Visit)
Safety 
Follow-
up Visit
NA
Use the nominalvisit name
2-Baseline
Baseline
1
[end of TE period for first period +1 , 
pre-dose Week 17]
2 -Week 24
Week 8
57
[1*, 71]
ETT
NA
Follow the individual visit window to 
be mapped to individual visits
2 -Safety Follow-up Visit 
Safety 
Follow-
up Visit
NA
Use the nominal visit name
Labs
o
Vitamin levels
o
Lipid panel
1-Baseline
Baseline
1
[screening visit, pre-dose Day 1]
1 -Week 8
Week 8
57
[1*, 71]
2-Baseline
Baseline
1
[end of TE period for first period +1 , 
pre-dose Week 17]
2 -Week 24
Week 8
57
[1*, 71]
ETT
NA
Follow the individual visit window to 
be mapped to individual visits
Spirometry
Standard 12-lead ECG
1-Baseline
Baseline
1
[screening visit, pre-dose Day 1]
1 –Day 1 Predose and Postdose
Day 1
1
Nominal
1 –Day 15 Predose and Postdose
Day 15
15
Nominal
Day 15
15
[1*, 15] if no nominal Day 15
1 –Week 4 
Week 4
29
[Nominal Day 15+1, 43] if there is 
nominal Day 15; 
[16, 43] otherwise.
1 –Week 8
Week 8
57
[44, 71]
1 -Week 12 (Safety Evaluation 
Visit)
Safety 
Follow-
up Visit 
NA
Use the nominal visit name†
2 -Baseline
Baseline
1
[end of TE period for first period +1 , 
pre-dose Week 17]
2–Week 17 Predose and Postdose
Day 1
1
Nominal
2–Week 18 Predose and Postdose
Day 15
15
Nominal
Day 15
15
[1*, 15] if no nominal Week 18
2–Week 20 
Week 4
29
[Nominal Week 18+1, 43] if there is 
nominal Week 18; 
[16, 43] otherwise.
2–Week 24
Week 8
57
[44, 71]
ETT
NA
Follow the individual visit window to 
be mapped to individual visits
2 -Safety Follow-up Visit 
Safety 
Follow-
up Visit
NA
Use the nominal visit name†
* only include day
 1 post-dose measurementsin each period
† for safety assessments use nominal visit and for efficacy assessments use nominal visit if visit day is greater
than the upper boundary of the visit window for Week 8 (period 1) or Week 24 (period 2)


SAP VX14-661-108,Version 1.1                                                                                                   Page 55of 72
Vertex Pharmaceuticals Incorporated
Note: 
1. For spirometry and ECG data on Day 1 and Day 15 of each treatment period, no visit 
windowing rule shall be applied. Instead, nominal visit will be used.  
2. On Day 1of period 1, the pre-dose ECG measurements are collected as triplicates. The 
average of pre-dose triplicates will be used as baseline. Only the pre-dose assessments of 
the triplicate will be used for the baseline. If all the measurements for triplicatesare 
missing or post-dose, the last non-missing pre-dose assessment will be used as the 
baseline.
3. For all efficacy parameters, if there are multiple measurements within a visit window, 
the record at the scheduled visit will be used. 
If there are no measurements at the scheduled visit, then the record closest to the 
target day will be used 
If there are multiple records with the same distance to the target day, the latest 
record will be used.  
Assessments at early treatment termination (ETT) visit will follow the windowing 
rules for regular visits up to Week 24. 
A safety follow-upvisit(SFUV) assessment will follow the windowing rules for 
regular visits if it falls within the upper boundary of the visit window forWeek 8 
(period 1) or Week 24 (period 2), or remain as SFUVotherwise.
4. For all safety parameters:
If there are multiple measurements within a visit window, then the record closest 
to the target day will be used 
If there are multiple records with the same distance to the target day, the latest 
record will be used.  
5. Spirometry, BMI, Weight and Height will follow the efficacy windowing rules.


SAP VX14-661-108,Version 1.1                                                                                                   Page 56of 72
Vertex Pharmaceuticals Incorporated
10.3
Coefficients for Hankinson and Wang Methods for Calculating 
Predicted Spirometry Parameters
Percent predicted FEV1is the ratio of FEV
1(L) to the predicted FEV
1(L), expressed as a 
percentage. The predicted FEV1(L) will be calculated using the Hankinson1and Wang
2
standards. 
The Hankinson standard will be applied to male subjects 18 years and older and female 
subjects 16 years and older; the Wang standard will be applied to male subjects 6 to 17 years 
and female subjects 6 to 15 years of age.During the study, the subjects who have a birthday
 
that would move them from Wang to Hankinson will use the Wang standard before that 
birthday andthe Hankinson standard at or after that birthday.
Hankinson Normal Values (HNVs) will be calculated for FEV
1, forced vital capacity (FVC), 
forced expiratory flow mid expiratory phase (FEF
25-75%), and FEV
1/FVC% using the 
Hankinson equation: 
Predicted lungfunction parameter = b0+b1 × age+b2 × age2+ b3 × height2
In the equation, height is given in centimeters, age is given in years, and the coefficients b
0, 
b1, b
2, and b
3are determined based on subject’s sex, race, and age group as shown in Table 
10-4.
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF
25-75%, and FEV
1/FVC 
using the Wang equation: 
ln(Predicted lung function parameter) = + βln (height)
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF
25-75%, and FEV
1/FVC 
using the Wang equation. In the equation, height is given in meters, and the coefficients α 
and β are determined based on subject’s sex, race, and age as shown in Table 10-5and Table 
10-6. 
If either height or age is missing, and the spirometry measurement is non-missing, the last 
non-missing value of height and agewill be used in the calculation of predicted values.


SAP VX14-661-108,Version 1.1                                                                                                   Page 57of 72
Vertex Pharmaceuticals Incorporated
Table 10-4 HNVs Equation Coefficients by Sex, Race, and Age
Source: Reference 1 (Tables 4, 5 and 6)
Parameter
Sex
Race
Age 
(years)
bo
b1
b2
b3
HNVFEV1
Male
Caucasian
<20
-0.7453
-0.04106
0.004477
0.00014098
≥20
0.5536
-0.01303
-0.000172
0.00014098
African 
American
<20
-0.7048
-0.05711
0.004316
0.00013194
≥20
0.3411
-0.02309
0.00013194
Mexican 
American
<20
-0.8218
-0.04248
0.004291
0.00015104
≥20
0.6306
-0.02928
0.00015104
Female
Caucasian
<18
-0.8710
0.06537
0.00011496
≥18
0.4333
-0.00361
-0.000194
0.00011496
African 
American
<18
-0.9630
0.05799
0.00010846
≥18
0.3433
-0.01283
-0.000097
0.00010846
Mexican 
American
<18
-0.9641
0.06490
0.00012154
≥18
0.4529
-0.01178
-0.000113
0.00012154
HNVFVC
Male
Caucasian
<20
-0.2584
-0.20415
0.010133
0.00018642
≥20
-0.1933
0.00064
-0.000269
0.00018642
African 
American
<20
-0.4971
-0.15497
0.007701
0.00016643
≥20
-0.1517
-0.01821
0.00016643
Mexican 
American
<20
-0.7571
-0.09520
0.006619
0.00017823
≥20
0.2376
-0.00891
-0.000182
0.00017823
Female
Caucasian
<18
-1.2082
0.05916
0.00014815
≥18
-0.3560
0.01870
-0.000382
0.00014815
African 
American
<18
-0.6166
-0.04687
0.003602
0.00013606
≥18
-0.3039
0.00536
-0.000265
0.00013606
Mexican 
American
<18
-1.2507
0.07501
0.00014246
≥18
0.1210
0.00307
-0.000237
0.00014246
HNVFEF25-75%
Male
Caucasian
<20
-1.0863
0.13939
0.00010345
≥20
2.7006
-0.04995
0.00010345
African 
American
<20
-1.1627
0.12314
0.00010461
≥20
2.1477
-0.04238
0.00010461
Mexican 
American
<20
-1.3592
0.10529
0.00014473
≥20
1.7503
-0.05018
0.00014473
Female
Caucasian
<18
-2.5284
0.52490
-0.015309
0.00006982
≥18
2.3670
-0.01904
-0.000200
0.00006982
African 
American
<18
-2.5379
0.43755
-0.012154
0.00008572
≥18
2.0828
-0.03793
0.00008572
Mexican 
American
<18
-2.1825
0.42451
-0.012415
0.00009610
≥18
1.7456
-0.01195
-0.000291
0.00009610
HNVFEV1/FVC%
Male
Caucasian
88.066
-0.2066
African 
American
89.239
-0.1828
Mexican 
American
90.024
-0.2186
Female
Caucasian
90.809
-0.2125
African 
American
91.655
-0.2039
Mexican 
American
92.360
-0.2248


SAP VX14-661-108,Version 1.1                                                                                                   Page 58of 72
Vertex Pharmaceuticals Incorporated
Table 10-5
WNVs Equation Coefficients by Sex and Age in White Boys and Girls
FEV1
FVC
FEF25-75%
FEV1/FVC
Sex
Age
α 
β 
α 
β 
α 
β 
α 
β
Male
6 
-0.109
2.252
-0.024
2.470
-0.078
-0.248
7 
-0.104
2.270
-0.018
2.489
-0.086
-0.220
8 
-0.089
2.257 
0.005 
2.443 
0.264 
1.505
-0.091
-0.199
9 
-0.063
2.197 
0.017 
2.426 
0.308 
1.443
-0.086
-0.206
10 
-0.057
2.212 
0.030 
2.407 
0.290 
1.557
-0.081
-0.209
11 
-0.093
2.324 
0.009 
2.468 
0.242 
1.738
-0.101
-0.147
12 
-0.161
2.512
-0.061
2.649 
0.165 
1.982
-0.101
-0.133
13 
-0.292
2.843
-0.175
2.924 
0.007 
2.396
-0.116
-0.085
14 
-0.329
2.983
-0.219
3.060 
0.014 
2.483
-0.106
-0.087
15 
-0.141
2.709
-0.079
2.859 
0.241 
2.163
-0.060
-0.155
16
0.062 
2.409 
0.104 
2.591 
0.503 
1.764
-0.045
-0.178
17
0.262 
2.099 
0.253 
2.374 
0.762 
1.368 
0.008
-0.272
Female
6 
-0.109
1.949
-0.013
2.007
-0.097
-0.055
7 
-0.144
2.243
-0.062
2.385
-0.084
-0.132
8 
-0.137
2.239
-0.055
2.381 
0.247 
1.668
-0.079
-0.152
9 
-0.123
2.222
-0.039
2.351 
0.254 
1.710
-0.084
-0.128
10 
-0.161
2.364
-0.068
2.458 
0.195 
1.933
-0.092
-0.097
11 
-0.223
2.558
-0.120
2.617 
0.161 
2.091
-0.102
-0.061
12 
-0.264
2.709
-0.174
2.776 
0.185 
2.120
-0.090
-0.067
13 
-0.153
2.535
-0.061
2.576 
0.294 
1.976
-0.093
-0.040
14
0.046 
2.178 
0.139 
2.208 
0.450 
1.711
-0.096
-0.026
15
0.148 
2.008 
0.210 
2.099 
0.581 
1.486
-0.062
-0.093
Source: Reference 2 (Tables 2 and 3)


SAP VX14-661-108,Version 1.1                                                                                                   Page 59of 72
Vertex Pharmaceuticals Incorporated
Table 10-6
WNVs Equation Coefficients by Sex and Age in Black Boys and Girls
FEV1
FVC
FEF25-75%
FEV1/FVC
Sex
Age
α 
β 
α 
β 
α 
β 
α 
β
Male
6 
-0.166
1.723
-0.088
1.961
-0.091
-0.152
7 
-0.122
1.846
-0.040
2.040
-0.091
-0.153
8 
-0.225
2.271
-0.094
2.323 
0.097 
1.544
-0.118
-0.104
9 
-0.142
2.059
-0.074
2.308 
0.255 
1.248
-0.079
-0.218
10 
-0.157
2.117
-0.110
2.417 
0.230 
1.428
-0.047
-0.303
11 
-0.176
2.166
-0.138
2.453 
0.256 
1.438
-0.048
-0.263
12 
-0.307
2.548
-0.224
2.710 
0.085 
1.936
-0.084
-0.162
13 
-0.486
2.962
-0.342
2.975
-0.121
2.476
-0.141
-0.018
14 
-0.472
3.010
-0.337
3.035
-0.115
2.536
-0.123
-0.050
15 
-0.318
2.789
-0.226
2.889 
0.170 
2.120
-0.070
-0.140
16
0.074 
2.140 
0.058 
2.425 
0.663 
1.299 
0.018
-0.289
17
0.053 
2.223 
0.148 
2.310 
0.505 
1.618
-0.095
-0.087
Female
6 
-0.288
2.182
-0.172
2.117
-0.109
0.059
7 
-0.250
2.158
-0.135
2.132
-0.104
-0.030
8 
-0.276
2.295
-0.176
2.362
-0.283
2.990
-0.103
-0.066
9 
-0.294
2.330
-0.200
2.452 
0.025 
2.062
-0.097
-0.104
10 
-0.344
2.507
-0.230
2.571 
0.051 
2.028
-0.120
-0.043
11 
-0.308
2.460
-0.204
2.526 
0.078 
2.006
-0.089
-0.105
12 
-0.219
2.312
-0.107
2.342 
0.225 
1.804
-0.115
-0.021
13 
-0.117
2.196
-0.042
2.294 
0.418 
1.504
-0.051
-0.148
14
0.041 
1.920 
0.105 
2.021 
0.574 
1.257
-0.063
-0.103
15
0.203 
1.662 
0.253 
1.787 
0.599 
1.281
-0.043
-0.139
Source: Reference 2 (Tables 4 and 5)




SAP VX14-661-108,Version 1.1                                                                                                   Page 61of 72
Vertex Pharmaceuticals Incorporated
10.5
Threshold Analysis Criteria
Table10-7
Threshold Criteria for Laboratory Tests
Parameter
Criteria
Comments
Clinical Chemistry
CPK
>ULN -≤ 2.5 x ULN
>2.5 -≤ 5 x ULN
>5 -≤ 10x ULN 
>10 x ULN
CTCAE grades 1-4
Creatinine
>ULN -≤ 1.5 x ULN
>1.5 -≤ 3.0 x ULN
>3.0 -≤ 6.0 x ULN
>6.0 x ULN
CTCAE grades 1-4
Blood Urea 
Nitrogen
>ULN -≤ 1.5 x ULN
>1.5 -≤ 3.0 x ULN
>3.0 -≤ 6.0 x ULN
>6.0 x ULN
Same criteria as creatinine 
No CTCAE 
Sodium
Hyponatremia
<LLN -≥130 mmol/L
<130 –≥120 mmol/L 
<120 mmol/L 
CTCAE grade 1, 3, 4
(No CTCAE grade 2)
Hypernatremia
>ULN -≤ 150 mmol/L
>150 mmol/L-≤155 mmol/L 
>155 mmol/L -≤ 160 mmol/L
>160 mmol/L
CTCAE grade 1-4
Potassium
Hypokalemia
<LLN –≥ 3.0 mmol/L
<3.0 –≥ 2.5 mmol/L
<2.5 mmol/L
CTCAE grade 1&2, 3, 4
(Grade 1 and 2 are the same)
Hyperkalemia
>ULN –≤ 5.5 mmol/L
>5.5 –  ≤ 6.0 mmol/L 
>6.0 –≤ 7.0 mmol/L 
>7.0 mmol/L
CTCAE grade 1-4
Total Cholesterol
>ULN –≤ 7.75 mmol/L
>7.75 –≤ 10.34 mmol/L 
>10.34 –≤ 12.92 mmol/L
>12.92 mmol/L
CTCAE grade 1-4
Triglycerides
>1.71 –≤ 3.42 mmol/L 
>3.42 –≤ 5.7 mmol/L 
>5.7 –≤ 11.4 mmol/L 
>11.4 mmol/L
CTCAE grade 1-4
Glucose
Hypoglycemia
<3.0 –≥ 2.2 mmol/L 
<2.2 -≥ 1.7 mmol/L
<1.7 mmol/L
CTCAE grade 1-4
Hyperglycemia 
>ULN -≤ 8.9 mmol/L
>8.9 –≤ 13.9 mmol/L
>13.9 –≤ 27.8 mmol/L 
>27.8 mmol/L
CTCAE grade 1-4


SAP VX14-661-108,Version 1.1                                                                                                   Page 62of 72
Vertex Pharmaceuticals Incorporated
Albumin
<35-≥ 30 g/L
<30 –≥ 20 g/L
<20 g/L 
CTCAE grade 1-3
Amylase
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2.0 x ULN 
>2.0 –≤ 5.0 x ULN
>5.0 x ULN
CTCAE grade 1-4
Lipase
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2.0 x ULN 
>2.0 –≤ 5.0 x ULN
>5.0 x ULN
CTCAE grade 1-4
Direct bilirubin
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2 x ULN
>2 –≤ 3 x ULN 
>3 –≤ 10 x ULN
>10 x ULN
Same Criteria as Total Bilirubin
No CTCAE 
Not in DILI Guidance
GGT 
>ULN -≤ 2.5 x ULN
>2.5–  ≤ 5.0 x ULN
>5.0 –  ≤ 20.0 x ULN 
>20.0 x ULN
CTCAE grade 1-4
Calcium
Hypercalcemia
>ULN -≤ 2.9 mmol/L 
>2.9 –≤ 3.1 mmol/L 
>3.1 –≤ 3.4 mmol/L 
>3.4 mmol/L
CTCAE grade 1-4
Hypocalcemia
<LLN -≥ 2.0 mmol/L
<2.0 –≥1.75 mmol/L 
<1.75 –≥ 1.5 mmol/L 
<1.5 mmol/L 
CTCAE grade 1-4
Magnesium
Hypermagnesemia
>ULN -≤ 1.23 mmol/L
>1.23 –≤ 3.30 mmol/L
>3.30 mmol/L
CTCAE grade 1, 3, 4
No CTCAE grade 2
Hypomagnesemia
<LLN -≥ 0.5 mmol/L
<0.5 –≥ 0.4 mmol/L
<0.4 –≥ 0.3 mmol/L 
<0.3 mmol/L 
CTCAE grade 1-4
Inorganic 
phosphate
Hypophosphatemia
<0.74–≥ 0.6mmol/L
<0.6 –≥ 0.3 mmol/L
<0.3 mmol/L
CTCAE grade 1-4
ALT
>ULN -≤  3 xULN
>3 –≤  5 xULN
>5 –≤  8 xULN
>8 –≤  20.0 xULN
>20.0 x ULN
Per FDA DILI Guidance Jul2009 and 
CTCAE
AST
>ULN -≤  3 xULN
>3 –≤  5 xULN
>5 –≤  8 xULN
>8 –≤  20.0 xULN
>20.0 x ULN
FDA DILI Guidance and CTCAE


SAP VX14-661-108,Version 1.1                                                                                                   Page 63of 72
Vertex Pharmaceuticals Incorporated
ALT or AST
(ALT>ULN and ALT ≤  3 xULN) or 
(AST>ULN and AST≤  3 xULN)
(ALT>3 xULN and ALT ≤  5 xULN) or 
(AST>3xULN and AST≤  5 xULN)
(ALT>5 xULN and ALT ≤  8 xULN) or 
(AST>5xULN and AST≤  8 xULN)
(ALT>8 xULN and ALT ≤  20 xULN) or 
(AST>8xULN and AST≤  20 xULN)
ALT>20 xULN or AST> 20 xULN
FDA DILI Guidance
Alkaline 
Phosphatase
>ULN -≤ 1.5xULN
>1.5 –≤ 2.5 xULN
>2.5 –≤ 5.0 x ULN
>5.0 –≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance and CTCAE
Total Bilirubin
>ULN -≤ 1.5 x ULN
>1.5 –≤ 2 x ULN
>2 –≤ 3 x ULN 
>3 –≤ 10 x ULN
>10 x ULN
FDA DILI Guidance and CTCAE
ALT and Total 
Bilirubin
ALT>3xULN and TBILI>2xULN
FDA DILI Guidance Jul2009 
AST and Total 
Bilirubin
AST>3xULN and TBILI>2xULN
FDA DILI Guidance Jul2009
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN
FDA DILI Guidance Jul2009 
Hematology
WBC
WBC decreased
<LLN -≥ 3.0x 10e9 /L
<3.0 –≥ 2.0 x 10e9 /L 
<2.0 –≥ 1.0 x 10e9 /L 
<1.0 x 10e9 /L
CTCAE grade 1-4
Leukocytosis
>100 x 10e9 /L
CTCAE grade 3 (only Grade available) 
Lymphocytes
Lymphocyte decreased
<LLN -≥ 0.8 x10e9 /L
<0.8 –≥ 0.5 x10e9 /L 
<0.5 –≥ 0.2 x10e9 /L 
<0.2 x10e9 /L
CTCAE grade 1-4
Lymphocyte increased
>4 –≤ 20 x10e9/L 
>20 x10e9/L 
CTCAE grade 2, 3 (only Grades available)
Neutrophils
Neutrophil decreased
<LLN -≥ 1.5 x10e9 /L
<1.5 –  ≥ 1.0 x10e9 /L 
<1.0 –  ≥ 0.5 x10e9 /L 
<0.5x10e9 /L
CTCAE grade 1-4
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
CTCAE grade 1-4


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<75.0 –≥ 50.0 x 10e9 /L 
<50.0 –≥ 25.0 x 10e9 /L 
<25.0 x 10e9 /L


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Table10-8
Threshold Criteria forCoagulation
Parameter
Criteria
Comments
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


SAP VX14-661-108,Version 1.1                                                                                                   Page 66of 72
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Table10-9
Threshold Criteria forECGs
Parameter
Criteria
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
QTc
>450 ms (Male) 
>470 ms (Female)
≥500 ms
Increase from baseline >10 ms
Increase from baseline >20 ms
Increase from baseline >40 ms
Increase from baseline >60 ms


SAP VX14-661-108,Version 1.1                                                                                                   Page 67of 72
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Table 10-10Threshold Criteria forVital Signs
Parameter
Threshold Criteria
Comments
HR
Same PCS as above in ECG category
SBP
SBP increased
>140 mmHg
>160 mmHg
>10 mmHg increase from baseline
>20 mmHg increase from baseline
>140 mmHg & >10 mmHg increase from baseline
>140 mmHg & >20 mmHg increase from baseline
>160 mmHg & >10 mmHg increase from baseline
>160 mmHg & >20 mmHg increase from baseline
809/770 analyses
SBP decrease
<90 mmHg
<80 mmHg
>10 mmHg decrease from baseline
>20 mmHg decrease from baseline
<90 mmHg and >10 mmHg decrease from baseline
<90 mmHg and >20 mmHg decrease from baseline
<80 mmHg and >10 mmHg decrease from baseline
<80 mmHg and >20 mmHg decrease from baseline
Per HV grade 1, 3, plus shift change
DBP
DBP increased
>90 mmHg
>100 mmHg
>5 mmHg increase from baseline
>10 mmHg increase from baseline
>90 mmHg and >5 mmHg increase from baseline
>90 mmHg and >10 mmHg increase from baseline
>100 mmHg and >5 mmHg increase from baseline
>100 mmHg and >10 mmHg increase from baseline
809/770analyses
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


SAP VX14-661-108,Version 1.1                                                                                                   Page 68of 72
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Weight loss 
≥5 % decrease from baseline  
≥10 % decrease from baseline 
≥ 20% decrease from baseline 
CTCAE grade 1-3


SAP VX14-661-108,Version 1.1                                                                                                   Page 69of 72
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10.6
Standards for Efficacyand SafetyVariable Display in TFLs
Continuous Variables
The precision for continuous variables has been specified in the Vertex Standard 
Programming Rules document (Version 1.0, December 2015):
http://collab.vrtx.com/sites/biometrics/biostatistics/Documents/Standard%20Programm
ing%20Rules_V1.0%20Final%20Dec%2017%202015.doc
The precision of the measurement in raw values for other continuous variables will be used 
to determine the number of decimal places to present in tables, figures, and derived listings.
Minimum and maximum values will be reported with the same precision as the units of 
measure. The mean, median, and SD will be reported to 1greater decimal place. 
Categorical Variables: Percentages will be presented to 1 decimal place.


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10.7
Imputation Rules for Missing AE dates
Imputation rules for missing or partial AE start date are defined below:
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose date, then:
If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute 
the AE start day as 1.
Otherwise, impute the AE start day as 1.
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE.
If Day and Month of AE start date are missing:
If AE start year=first dose year, then:
If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1.
Otherwise, impute the AE start MONTH as January and the DAY as 1.
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE.
If Year of AE start date is missing:
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial)AE end date to the first dose date. If the AE 
end date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE.
The imputation rule will be applied with respect to treatment start date for both periods and 
preference will be given to treatment in period 1 in case the AE is assigned to treatmentsin 
both periods.Missing or partially missing AE end date will not be imputed.


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10.8
Second CFTRAllele Mutations Included for Subjects who are 
Heterozygous for the F508del-CFTRMutation 
Per the study eligibility criteria, heterozygous F508del-CFTRsubjects must have a second 
CFTRallele that encodes a mutation predicted to have residual function. Criteria for 
including a mutation are (1) having residual function based on population-level phenotypic 
data and (2) in vitro responsiveness to IVA. The criteria for clinical phenoty
pe are average 
sweat chloride <86mmol/L (1 standard deviation from theaverage sweat chloride for the 
most common processing and trafficking mutation, F508del-CFTR), and incidence of 
pancreatic insufficiency ≤50% based on subjects with at least 1 copy of the mutation from 
epidemiologic data or published literature.In vitro response to IVAwas defined as an 
increase in percent normal chloride transport of ≥10 percentage points in transfected FRT 
cells expressing the CFTR form produced by the mutation. The list below represents eligible 
mutations.
CFTRMutations Predicted to Have Residual Function and That May Be Responsive to 
IVA
2789+5G→A
R74W
R352Q
R1070W
3849+10kbC→T
D110E
A455E
F1074L
3272-26A→G
D110H
D579G
D1152H
711+3A→G
R117C
S945L
D1270N
E56K
E193K
S977F
P67L
L206W
F1052V
E831X
R347H
K1060T


SAP VX14-661-108, Version 1.1                                                                                                     Page 72of 72
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life for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45.
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Chapman & Hall/CRC; 2014.
10Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm.