Conditions: Cystic Fibrosis
Keywords: Homozygous for the F508del CFTR Mutation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 510
Healthy volunteers: no

Brief summary:
This is a Phase 3, randomized, double blind, placebo controlled, parallel group, multicenter study in people with cystic fibrosis (CF) who are homozygous for the F508del CF transmembrane conductance regulator (CFTR) gene mutation.

Detailed description:
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in people with CF who are homozygous for the F508del-CFTR mutation. This study is designed to evaluate the efficacy and safety of VX-661 in combination with Ivacaftor (IVA, VX-770). The active treatment regimen comprised of a morning dose of a fixed-dose combination (FDC) tablet of 100 milligram (mg) VX-661/150 mg IVA once daily (qd) and an evening dose of IVA 150 mg to be taken approximately 12 hours after the morning dose. The placebo regimen was visually matched tablets to be taken with the same schedule as the active treatment.

Arms:
arm 1: Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24. arm 2: VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.

Interventions: intervention 1: VX-661 Plus Ivacaftor Combination intervention 2: Ivacaftor intervention 3: VX-661 Plus Ivacaftor Combination Placebo intervention 4: Ivacaftor placebo
Intervention descriptions: intervention 1: FDC tablet, oral use intervention 2: Tablet, oral use intervention 3: FDC tablet, oral use intervention 4: Tablet, oral use

Protocol document:
Prot_000.pdf: 




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2 
PROTOCOL SYNOPSIS 
Title A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in 
Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the 
F508del-CFTR Mutation 
  
Clinical Phase and 
Clinical Study Type 
Phase 3, efficacy and safety 
  
Objectives Primary 
To evaluate the efficacy of VX-661 in combination with ivacaftor 
(VX-661/ivacaftor) through 24 weeks of treatment in subjects with cystic fibrosis 
(CF) who are homozygous for the F508del mutation on the CF transmembrane 
conductance regulator (CFTR) gene 
Secondary 
• To evaluate the safety of VX-661 in combination with ivacaftor through 
Week 24 
• To investigate the pharmacokinetics (PK) of VX-661 and its metabolites, M1 
and M2 (M1-661 and M2-661, respectively) and ivacaftor and its metabolite 
M1 (M1-ivacaftor) 
  
Endpoints Primary 
Absolute change in percent predicted forced expiratory volume in 1 second 
(FEV
1) from baseline through Week 24 
Key Secondary  
• Relative change in percent predicted FEV1 from baseline through Week 24 
• Number of pulmonary exacerbations through Week 24 
• Absolute change in body mass index (BMI) from baseline at Week 24 
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score from baseline through Week 24 
Secondary 
• Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values (i.e., hematology, serum chemistry, coagulation studies, 
vitamin levels, lipid panel, and urinalysis), standard 12-lead 
electrocardiograms (ECGs), vital signs, pulse oximetry, and spirometry 
• Time-to-first pulmonary exacerbation through Week 24 
• Absolute change in sweat chloride from baseline through Week 24 
• Absolute change in BMI z-score from baseline at Week 24 (in subjects 
<20 years of age at time of screening) 
• Absolute change in body weight from baseline at Week 24 
• PK parameters of VX-661, M1-661, M2-661, ivacaftor, and M1-ivacaftor 
  
Number of Subjects Approximately 490 subjects will be randomized: 245 subjects in the 
VX-661/ivacaftor arm and 245 subjects in the placebo arm 
  


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Study Population Male and female subjects aged 12 years or older with CF who are homozygous for 
the F508del-CFTR mutation 
  
Investigational Drug Active substance: VX-661 and ivacaftor  
 Activity: cystic fibrosis transmembrane conductance regulator (CFTR) corrector 
and potentiator (increased chloride ion [Cl−] secretion) 
 Strength and Route of Administration: 100-mg VX-661/150-mg ivacaftor 
fixed-dose combination (light yellow) film-coated tablet for oral administration 
  
 Active substance: ivacaftor  
 Activity: cystic fibrosis transmembrane potentiator (increased chloride ion [Cl−] 
secretion) 
 Strength and Route of Administration: 150-mg ivacaftor (light blue) 
film-coated tablet for oral administration 
  
 Active substance: not applicable 
 Activity: placebo 
 Strength and Route of Administration: 0-mg film-coated matching placebo 
tablets for oral administration 
  
Study Duration Excluding the Screening Period (up to 28 days in duration), subjects who 
complete the Treatment Period (including those who prematurely discontinue 
study drug treatment) will participate in this study for up to 29 weeks.  
During the Treatment Period, study drug (VX-661/ivacaftor or placebo) will be 
administered up to 24 weeks. 
A Safety Follow-Up Visit will occur 28 days ± 7 days after the final dose of study 
drug. A Safety Follow-Up Visit is not required for subjects who have completed 
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. 
  
Study Design This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study in subjects with CF who are homozygous for the F508del-CFTR 
mutation. 
This study includes the following: 
• Screening Period (Day −28 through Day −1) 
• Treatment Period (Day 1 through Week 24 ± 5 days) 
• Safety Follow-up Visit (28 ± 7 days after the final dose of study drug) 
Subjects will be stratified by age at the Screening Visit (<18 versus ≥18 years of 
age), sex (male versus female), and FEV
1 severity determined during the 
Screening Period (<70% versus ≥70% predicted), and then randomized (1:1) to 
1 of the following 2 treatment arms: 
• VX-661/ivacaftor: 100 mg VX-661 once daily (qd) + 150 mg ivacaftor every 
12 hours (q12h) 
• Placebo: Placebo regimen with visually matched tablets 
  




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Statistical Analyses Statistical analysis details will be provided in the Statistical Analysis Plan (SAP), 
which will be finalized before the clinical data lock for the study and treatment 
unblinding. 
The null hypothesis to be tested is that the mean change from baseline in percent 
predicted FEV1 through Week 24 is the same for the 2 treatment arms. Assuming 
a common standard deviation (SD) of 8% and a 10% dropout rate, a sample size 
of 245 subjects in each treatment group will have at least 90% power to detect a 
treatment difference of 2.5% in percent predicted FEV
1 between treatment groups, 
using a 2-sided significance level of 0.05. If the above null hypothesis is rejected, 
the efficacy of VX-661/ivacaftor is considered established. 
The primary analysis for the primary efficacy endpoint will be based on a mixed 
model for repeated measures (MMRM). The model will include the absolute 
change from baseline in percent predicted FEV
1 (including all measurements up to 
Week 24 [inclusive] as the dependent variable; treatment, visit, and treatment-by-
visit interaction as fixed effects; and subject as a random effect with adjustment 
for sex, age group at screening, and percent predicted FEV
1 severity determined 
during the Screening Period. The primary result obtained from the model will be 
the estimated main treatment effect through Week 24. The estimated mean 
treatment effect, a 95% confidence interval, and a 2-sided P value will be 
provided. Furthermore, the treatment effect at each post-baseline visit, obtained 
from the model, will also be provided. 
  
IDMC Safety Reviews The Independent Data Monitoring Committee (IDMC) will conduct regular 
planned safety reviews of study data as outlined in the IDMC Charter 


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3 
SCHEDULE OF ASSESSMENTS 
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. 
All visits are to be scheduled relative to the Day 1 Visit (first dose of study drug). For 
example, the Week 8 (± 5 days) Visit would occur after 8 weeks of study drug administration 
has been completed (i.e., Day 57, first day of Week 9).


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Table 3-1 
Screening Period Assessments – Study VX14-661-106 
Event/Assessment 
Screening Period 
(Day -28 through Day -1) 
Informed consent and assent (when applicable) 
X 
Demographics 
X 
Medical history  
X 
Ophthalmological history  
X 
CFQ-Ra  
X 
 
 
 
 
 
 
CF genotypeb 
X 
FSHc 
X 
Serum pregnancy test (all females of childbearing potential)d 
X 
Hematology 
X 
Coagulation 
X 
Serum chemistry 
X 
Urinalysis 
X 
Weight and heighte 
X 
Ophthalmologic examinationf 
X 
Complete PE 
X 
Vital signsg 
X 
Pulse oximetryg 
X 
Standard 12-lead ECG
h 
X 
Spirometryi 
X 
 
 
Inclusion/exclusion criteria review 
X 
Prior and concomitant medications 
X 
Sweat chloride 
X 
AEs and SAEs 
Continuous from signing of the ICF and assent (where 
applicable) through the Safety Follow-up Visit 
AE: adverse event; CF: cystic fibrosis; CFQ-R: CF Questionnaire–Revised; 
; 
ECG: electrocardiogram; FSH: follicle-stimulating hormone; ICF: informed consent form; PE: physical examination; 
; SAE: serious adverse event; 
; US: United 
States. 
 
a The CFQ-R, 
 must be completed before the start of any other assessments scheduled for that 
visit. 
b All subjects will be tested for CF genotype. Specific instructions will be provided in the Laboratory Manual.  
c FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be ≥40 mIU/mL to be considered postmenopausal. 
d Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing 
potential and must have a serum pregnancy test. 
e Weight and height will be measured with shoes off. 
f 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 (Section 11.7.8). Subjects with clinically significant 
cataracts, lens opacity, Y-suture, or lamellar rings 
will be excluded. 
g Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes.  
h A standard 12-lead ECG will be performed after the subject has been supine for at least 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 
 
 
 


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Table 3-2 
Treatment Period and Safety Follow-up Visit Assessments – VX14-661-106 
Event/Assessmenta 
Day 1 
 
Day 15 
(± 3 days) 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 12 
(± 5 days) 
Week 16 
(± 5 days) 
Week 20 
(± 5 days) 
Week 24 
(± 5 days) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) days 
After the last dose of 
study drug (if 
applicable)c 
Clinic visit 
X 
X 
X 
X 
X 
X 
Xd 
X 
X 
X 
Telephone contact 
 
 
 
 
 
 
Xe 
 
 
 
Inclusion and exclusion criteria 
review 
X 
 
 
 
 
 
 
 
 
 
CFQ-Rf 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and heighth 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
a 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 discontinue treatment early will continue to complete all other scheduled study visits for assessments of 
efficacy (spirometry, CFQ-R, sweat chloride, height, and weight), 
, and other events related to outcome (hospitalizations, pulmonary 
exacerbations, etc.) as detailed in Section 8.1.4.  
b  If the subject prematurely discontinues study treatment, an Early Treatment Termination (ETT) Visit should be scheduled as soon as possible after the subject decides to terminate study 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 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 8.1.4. 
c A Safety Follow-Up Visit is not required for subjects who complete the Week 24 Visit and have enrolled in a separate extension study of VX-661 in combination with ivacaftor within 
28 days after the last dose of study drug. 
d  Females of childbearing potential will have a clinic visit for a urine pregnancy test. This clinic visit is not required for females who are not of childbearing potential or males. 
e Telephone contact will be made for female subjects not of childbearing potential and males to assess the subject
's status, any AEs, concomitant medications, treatments, and procedures. 
f 
All questionnaires must be completed before the start of any other assessments scheduled at that visit. The CFQ-R must be completed first, followed by the 
 
(Section 11.1). Subjects will need to complete a CFQ-R, 
 at the Early Treatment Termination Visit (Section 8.1.4).  
  
 
h 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 Period and Safety Follow-up Visit Assessments – VX14-661-106 
Event/Assessmenta 
Day 1 
 
Day 15 
(± 3 days) 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 12 
(± 5 days) 
Week 16 
(± 5 days) 
Week 20 
(± 5 days) 
Week 24 
(± 5 days) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) days 
After the last dose of 
study drug (if 
applicable)c 
Ophthalmologic exam 
 
 
 
 
 
 
 
X 
i 
X 
j 
X 
j 
Complete PEk 
X 
 
 
 
 
 
 
X 
X 
 
Pregnancy testl 
urine 
 
urine 
urine 
urine 
urine 
urine 
serum 
serum 
serum 
Standard 12-lead ECG
m 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital signsn 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Pulse oximetryn 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Spirometryo 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Sweat chloridep 
X 
 
X 
 
 
X 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
X 
X 
X 
 
i   A
ll subjects will have an ophthalmologic examination conducted by a licensed ophthalmologist at Week 24. This exam may be completed within 4 weeks before the Week 24 Visit, but 
must be completed by the end of the Week 24 Visit. Subjects <18 years of age at the Screening Visit who complete an ophthalmologic exam at the ETT Visit will not be required to 
complete another ophthalmologic exam at the Week 24 Visit.  
j  Subjects <18 years of age at the Screening Visit who discontinue treatment after receiving at least 1 dose of study drug treatment, and subjects <18 years of age at the screening who 
complete treatment but do not enroll in a separate extension study of VX-661/ivacaftor within 28 days of the last dose of study drug will have an ophthalmologic exam conducted by a 
licensed ophthalmologist at the Safety Follow-up Visit or ETT Visit (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 complete an ophthalmologic exam at the ETT Visit or Week 24 Visit will not be required to complete another ophthalmologic 
exam at a subsequent visit.  
k Subjects will have a complete physical examination (as defined in Section 11.7.3) as noted. Symptom-targeted physical examinations will occur at any time during the study if triggered 
by AEs or if deemed necessary by the investigator. 
l Pregnancy tests will be performed for all female subjects of childbearing potential. A urine β-hCG test will be performed on Day 1 (before first dose of study drug) and every 4 weeks 
thereafter.  
m All standard 12-lead ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes. At the Days 1 and 15 Visits, ECGs will be collected before dosing 
and at 1.5, 3, 4, and 6 hours after the morning dose; the 4-hour postdose ECG will be collected before the 4-hour postdose spirometry assessment. ECGs collected on Day 1 before dosing 
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. 
n 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. 
o At all visits, spirometry must be performed for all subjects before dosing and should be performed prebronchodilator (Section 11.6.1). At Day 1 and Day 15, subjects <18 years of age at 
the Screening Visit will have additional spirometry performed at 2 and 4 hours postdose. If more than 1 spirometry assessment is required at a visit, bronchodilators should be withheld 
until the last scheduled spirometry assessment is completed. 
p  Sweat chloride collection will 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). Collection of sweat chloride will not overlap with any other study assessments. 


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Table 3-2 
Treatment Period and Safety Follow-up Visit Assessments – VX14-661-106 
Event/Assessmenta 
Day 1 
 
Day 15 
(± 3 days) 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 12 
(± 5 days) 
Week 16 
(± 5 days) 
Week 20 
(± 5 days) 
Week 24 
(± 5 days) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) days 
After the last dose of 
study drug (if 
applicable)c 
Serum chemistry 
Xq 
X 
X 
X 
X 
X 
 
X 
X 
X 
Lipid panelr 
X 
 
 
 
X 
 
 
X 
X 
 
Vitamin levels 
X 
 
 
 
X 
 
 
X 
X 
 
PK samplings 
X 
 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other events related to outcomeu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomizationv 
X 
 
 
 
 
 
 
 
 
 
Meal(s) or snack(s) at sitew 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study drug dosingx 
Day 1 through Week 24 
 
 
Study drug count 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
q  Blood samples will be collected before the first dose of study drug. 
r  Blood samples will be collected for the lipid panel following at least a 4-hour fast.  
s PK samples will be collected on Day 1 at predose; at Week 12 (predose, 0.5, 3, and 6 hours after the morning dose); and at Week 16 (predose, 2, 4, and 8 hours after the morning dose). 
At the Safety Follow-up Visit and ETT Visit, a single blood sample for PK will be collected. If study drug is not administered on the visits of Weeks 12 and 16 (i.e., study drug 
interruption or permanent discontinuation of study drug), only 1 PK blood sample will be collected at each of these 2 visits. 
  
 
 
u Other events related to outcome include assessments relating to pulmonary exacerbations, administration of antibiotic therapy for sinopulmonary signs or symptoms, and hospitalizations 
(Section 11.6.12). 
v Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of study drug. Randomization will be done through IWRS. Randomization may occur 
on Day -1. 
w Fat-containing food such as a standard "CF" high-fat, high-calorie meal or snack will be provided at the site to subjects after all predose assessments have occurred. 
x The study drug should be administered every 12 hours (± 2 hours) within 30 minutes of starting a meal with fat-containing food such as a standard "CF" high-fat, high-calorie meal or 
snack. On days of scheduled visits, the morning dose of study drug will be administered at the site after predose assessments have been completed. The final dose of study drug will be 
administered the evening before the Week 24 Visit. 




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4 
TABLE OF CONTENTS 
1 Title Page 
.......................................................................................................................... 1
 
 
2 Protocol Synopsis 
............................................................................................................. 3 
3 Schedule of Assessments.................................................................................................. 7 
4 Table of Contents 
........................................................................................................... 13
 
List of Tables...................................................................................................................... 16 
List of Figures 
.................................................................................................................... 16
 
5 Introduction.................................................................................................................... 17 
6 Study Objectives 
............................................................................................................ 20
 
6.1 Primary Objective 
..................................................................................................... 20
 
6.2 Secondary Objectives 
............................................................................................... 20
 
7 Study Endpoints 
............................................................................................................. 20
 
7.1 Primary Endpoint 
...................................................................................................... 20 
7.2 Secondary Endpoints 
................................................................................................ 20 
7.2.1 Key Secondary Endpoints ................................................................................ 20 
7.2.2 Secondary Endpoints 
........................................................................................ 20 
 
 
8 Study Design 
................................................................................................................... 21
 
8.1 Overview of Study Design ....................................................................................... 21 
8.1.1 Screening 
.......................................................................................................... 22
 
8.1.2 Treatment Period (Day 1 Through Week 24) 
................................................... 23
 
8.1.3 Follow-up.......................................................................................................... 24 
8.1.4 Early Treatment Termination 
........................................................................... 24
 
8.1.5 Independent Data Monitoring Committee 
........................................................ 24 
8.2 Rationale for Study Design and Study Drug Regimens 
........................................... 25 
8.2.1 Study Design..................................................................................................... 25 
8.2.2 Study Drug Dose and Duration ........................................................................ 25 
8.2.3 Rationale for Study Population......................................................................... 25 
8.2.4 Rationale for Study Assessments ..................................................................... 26
 
9 Study Population 
............................................................................................................ 29
 
9.1 Inclusion Criteria 
...................................................................................................... 29
 
9.2 Exclusion Criteria 
..................................................................................................... 29
 
9.3 Study Restrictions 
..................................................................................................... 31
 
9.3.1 Additional Dietary Restrictions/Prohibited Medications ................................. 31
 
9.4 Prior and Concomitant Medications 
......................................................................... 32 
9.5 Removal of Subjects 
................................................................................................. 33 
9.6 Replacement of Subjects .......................................................................................... 34
 
10 Study Drug Administration and Management 
........................................................... 34
 
10.1 Preparation and Dispensing 
...................................................................................... 34 
10.2 Administration 
.......................................................................................................... 34
 
10.3 Method of Assigning Subjects to Treatment Groups 
............................................... 35 
10.4 Dose Modification for Toxicity 
................................................................................ 36 






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List of Tables 
Table 3-1
 
Screening Period Assessments – Study VX14-661-106 
................................... 8 
Table 3-2
 
Treatment Period and Safety Follow-up Visit Assessments – VX14-661-106  9 
Table 9-1
 
Study Restrictions 
........................................................................................... 32
 
Table 10-1 Study Drug Administration - Treatment Period.............................................. 34
 
Table 10-2
 Identity of Study Drugs, Dosage, and Storage 
................................................ 37 
Table 11-1
 Acceptable Pharmacokinetic Sampling Windows 
.......................................... 41 
Table 11-2 Safety Laboratory Test Panels 
........................................................................ 48
 
Table 13-1 Grading of AE Severity .................................................................................. 67
 
Table 13-2 Classifications for AE Causality 
..................................................................... 67
 
Table 13-3 Classifications for Study Drug Action Taken With Regard to an AE 
............ 69 
Table 13-4 Classifications for Outcome of an AE 
............................................................ 69
 
 
List of Figures 
Figure 8-1 
Schematic of the Study Design 
....................................................................... 22
 
 


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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 
Cystic fibrosis 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. 
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.
 16 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.
16 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).
 17 
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. 
Ivacaftor was also well tolerated, as evidenced by the rates and reasons for premature 
discontinuation and results of safety assessments.  
As of June 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, 
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 


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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.18,19 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of VX-661 in combination with ivacaftor through Week 24 in 
subjects with CF who are homozygous for the F508del mutation on the CF transmembrane 
conductance regulator (CFTR) gene 
6.2 
Secondary Objectives 
• To evaluate the safety of VX-661 in combination with ivacaftor through Week 24 
• To investigate the pharmacokinetics (PK) of VX-661 and its metabolites, M1 and M2 
(M1-661 and M2-661, respectively), 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 (FEV
1) from 
baseline through Week 24 
7.2 
Secondary Endpoints 
7.2.1 
Key Secondary Endpoints 
• Relative change in percent predicted FEV1 from baseline through Week 24 
• Number of pulmonary exacerbations through Week 24 
• Absolute change in body mass index (BMI) from baseline at Week 24 
• Absolute change in Cystic Fibrosis Questionnaire – Revised (CFQ-R) respiratory 
domain score from baseline through Week 24 
7.2.2 
Secondary Endpoints 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values (i.e., hematology, serum chemistry, coagulation studies, vitamin levels, lipid 
panel, and urinalysis), standard 12-lead electrocardiograms (ECGs), vital signs, pulse 
oximetry, and spirometry 
• Time-to-first pulmonary exacerbation through Week 24 
• Absolute change in sweat chloride from baseline through Week 24 
• Absolute change in BMI z-score from baseline at Week 24 (in subjects <20 years of 
age at time of screening) 
• Absolute change in body weight from baseline at Week 24 
• PK parameters of VX-661, M1-661, M2-661, ivacaftor, and M1-ivacaftor 






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8.1.1.1 
Repetition of Screening Assessment(s) 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted with the following exceptions:  
• If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test or 
assessment may be permitted with the approval of the medical monitor. 
• Exclusionary liver function test (LFT) levels, which may be retested within 14 days 
of the original screening date. 
If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society/European Respiratory Society guidelines,
20 repeat 
spirometry evaluation may be performed once. 
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 CF genotyping, follicle 
stimulating hormone (FSH) level (if serum FSH level was ≥40 mIU/mL during prior 
screening), sweat chloride level, and the 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 Screening Period Window 
A subject may have the Screening Period window extended by 1 week 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 (Day 1 Through Week 24) 
The Treatment Period will last approximately 24 weeks. Subjects will be randomized to 1 of 
2 treatment arms: 1 combination treatment arm and 1 placebo arm. The dosing regimen for 
each treatment arm is shown in Figure 8-1 and is as follows: 
• VX-661/ivacaftor: 100-mg VX-661/150-mg ivacaftor fixed-dose combination (light 
yellow) film-coated tablet for oral administration (morning dose); 150-mg ivacaftor 
(light blue) film-coated tablet for oral administration (evening dose) 
• Placebo: 0-mg film-coated matching placebo tablets for oral administration (1 light 
yellow for morning dose and 1 light blue for evening dose) 
The first dose of the study drug will be administered after randomization on Day 1. Dosing 
details are given in Section 10.2. 


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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 will remain in the study from the 
time of discontinuation of study drug treatment through the Week 24 Visit and complete 
assessments for all study visits, as described in Section 8.1.4. 
8.1.3 
Follow-up 
The Safety Follow-up Visit assessments are listed in Table 3-2. There will be an outpatient 
Safety Follow-up Visit approximately 28 (± 7) days after the last dose of study drug for 
subjects who complete study drug dosing and for subjects who prematurely discontinue study 
drug dosing. 
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. 
8.1.4 
Early Treatment Termination 
If the subject prematurely discontinues study treatment, an Early Treatment Termination 
Visit should be scheduled as soon as possible after the subject decides to terminate study 
treatment. Subjects who prematurely discontinue treatment will also be required to complete 
the Safety Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug. 
The assessments performed at the Safety Follow-up Visit are listed in Table 3-2. 
If the Early Treatment Termination Visit occurs 3 weeks or later following the last dose of 
study drug, then the Early Treatment Termination Visit will replace the Safety Follow-up 
Visit, and a separate Safety Follow-up Visit will not be required.  
Subjects will continue to complete all other scheduled study visits for assessments of efficacy 
(spirometry, CFQ-R, sweat chloride, height, and weight), 
 
, and other events related to outcome (hospitalizations, pulmonary exacerbations, 
etc.) as detailed in the Schedules of Assessments (Section 3). 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. Vertex may retain and continue to use any data collected before such withdrawal 
of consent. 
8.1.5 
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. 


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8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
Study 106 is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study in subjects aged 12 years and older with CF who are homozygous for the 
F508del-CFTR mutation. A randomized, double-blind study design will avoid observer bias 
and reduce symptoms or outcomes arising from the subjects
' knowledge of treatment. 
Study 106 is designed and powered to compare active treatment with VX-661 (100 mg qd) 
and ivacaftor (150 mg q12h) with a matched placebo treatment for 24 weeks. A significant 
response in FEV
1 is anticipated to be observed after 14 to 28 days of treatment with VX-661 
in combination with ivacaftor. The 24-week primary endpoint 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. Important secondary endpoints will be assessed at Week 24; the 24-week 
duration will facilitate the demonstration of significant changes in secondary efficacy 
endpoints including the number of pulmonary exacerbations, BMI, and time-to-first 
pulmonary exacerbation. 
Enrollment is planned for approximately 490 subjects. Subjects who meet the study entry 
criteria at screening will be eligible for study participation. This study includes a Screening 
Period, Treatment Period, and a Safety Follow-up Visit. 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 an extension study. 
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 sweat 
chloride collection and assay. 
There are no approved therapies for treatment of subjects homozygous for the F508del-CFTR 
function that target the underlying mechanism of disease that could be used as an active 
comparator for VX-661 in combination with ivacaftor. 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. All subjects enrolled in the study will continue their 
normal, stable treatment for CF throughout the study. 
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 
homozygous for the F508del-CFTR mutation. The F508del-CFTR mutation interferes with 
the processing and trafficking of the CFTR protein, resulting in decreased Cl− transport.
13,14 
Study 101 demonstrated statistically significant and clinically meaningful improvements in 
percent predicted FEV1 in subjects who were homozygous for the F508del-CFTR mutation 
and supported the study of this population in the Phase 3 study. The inclusion of subjects 


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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 FEV
1 (i.e., FEV
1 ≥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. 
8.2.4 
Rationale for Study Assessments 
The safety and PK assessments are standard parameters for clinical studies in drug 
development. The efficacy assessments are widely accepted and generally recognized as 
reliable, accurate, and relevant to the study of patients with CF. 
Spirometry: Since lung disease is the major cause of morbidity and mortality for patients 
with CF, CF lung disease is the desired primary target of VX-661/ivacaftor combination 
therapy. Spirometry (as measured by FEV
1) is the most widely implemented standardized 
assessment to evaluate lung function. Spirometry assessments will be performed predose in 
all subjects according to Section 11.6.1. To meet a request from a regulatory authority, 
subjects <18 years of age at the Screening Visit will have additional spirometry assessments 
performed after dosing at the time points noted in Table 3-2. 
Sweat Chloride Testing: In patients with CF, the underlying ion-transport defect in CFTR 
results in elevated sweat electrolyte levels.
21,22 The sweat chloride test (quantitative 
pilocarpine iontophoresis) is the most common diagnostic tool for CF. A sweat chloride 
concentration of ≥60 mmol/L is considered to indicate CF, whereas <40 mmol/L is 
considered normal. Based on the mechanisms of action of VX-661 and ivacaftor, the sweat 
chloride test was included in this study as a measure of the effect of VX-661in combination 
with ivacaftor on CFTR activity. 
Nutritional Status (measured by weight and BMI): Malnutrition is common in patients with 
CF because of increased energy expenditures due to lung disease and fat malabsorption. 
Given that VX-661 in combination with ivacaftor is a systemic therapy, it has the potential to 
improve extrapulmonary manifestations of CF, including those in the gastrointestinal system. 
Improved nutritional status, defined as an increase in weight and/or BMI, is considered an 
appropriate endpoint for therapies targeting CFTR and was used in previous clinical studies 
of CFTR-targeted therapies (Studies VX08-770-102 and VX08-770-103). To evaluate the 
effect of VX-661 in combination with ivacaftor on growth, change in weight and BMI will be 
determined. 
CFQ-R: The CFQ-R is a frequently used CF-specific instrument that measures the 
health-related quality of life of patients with CF.
23,24,25 As VX-661 in combination with 
ivacaftor is a systemic therapy, it has the potential to improve respiratory symptoms as well 
as other extrapulmonary manifestations of CF. These improvements can be captured by the 






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specifies 1 definition of pulmonary exacerbation which is based on the definition used for the 
other studies including the ivacaftor monotherapy initial registration studies 
(Section 11.6.12). Because signs and symptoms in the definition may occur without meeting 
the overall definition of a pulmonary exacerbation, the number and timing of outpatient sick 
visits to the clinic or hospital for CF that are unrelated to the study protocol will also be 
collected. 
9 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
9.1 
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible for this study: 
1. Subject (or their legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and where appropriate, 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, date of assent 
4. Homozygous for the F508del-CFTR mutation, genotype to be confirmed at the Screening 
Visit 
5. Confirmed diagnosis of CF35 defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis (as documented in the subject
's medical record OR 
from sweat chloride test result obtained during screening, if subject does not have a sweat 
chloride test result in the medical record)  
6. FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height (equations of Wang 
et al. or Hankinson et al.)
41,42 during screening (Section 11.6.1). Spirometry 
measurements must meet American Thoracic Society/European Respiratory Society 
criteria36 for acceptability and repeatability (Section 8.1.1.1).  
7. Stable CF disease as judged by the investigator 
8. Willing to remain on a stable CF medication regimen through Week 24 or, if applicable, 
the Safety Follow-up Visit 
9.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for this study: 
1. History of any comorbidity that, in the opinion of the investigator, might confound the 
results of the study or pose an additional risk in administering study drug to the subject. 
For example: 
• history of cirrhosis with portal hypertension, and/or history of risk factors for Torsade 
de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left 


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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: 
• Hemoglobin <10 g/dL 
• 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 
• Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT 
• 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)
37,38 for 
subjects ≥18 years of age and ≤45 mL/min/1.73 m
2 (calculated by the 
Counahan-Barratt equation)39 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 Screening. 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 (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 
8. Ongoing or prior participation in an investigational drug study (including studies 
investigating VX-661 and/or ivacaftor) within 30 days of screening. 
• Subjects are not eligible if they have participated in Studies VX12-809-103, 
VX12-809-104, or VX12-809-105 (including subjects who discontinued early or 
completed the study); have taken physician-prescribed lumacaftor/ivacaftor 
(Orkambi
®) for any duration; or have received lumacaftor/ivacaftor through an early- 
or extended-access program for any duration. 


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• A washout period of 5 terminal half-lives of the previous investigational study drug 
or 30 days, whichever is longer, must elapse before screening. The duration of the 
elapsed time may be longer if required by local regulations.  
• Ongoing participation in a noninterventional study (including observational studies 
and studies requiring assessment 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 Section 9.3. 
10. Pregnant or 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 11.7.5.1 
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 
• the adult lives independently of and does not reside with the study staff member 
• 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: 
• The subject should have had 2 respiratory tract cultures negative for these organisms 
within the past 12 months, with no subsequent positive cultures 
• These 2 respiratory tract cultures should have been separated by at least 3 months 
• One of these 2 respiratory tract cultures should have been obtained within the past 6 
months 
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) (Table 9-1). Both ivacaftor and VX-661 are metabolized at 
least in part via hepatic enzymatic pathway utilizing CYP3A4, hence the need to restrict 
usage of known CYP3A4 inducers and inhibitors. 
A nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. 


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Table 9-1 
Study Restrictions 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period through Safety 
Follow-up Visit 
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: 
o Subjects who are taking daily inhaled tobramycin or other chronically inhaled 
antibiotics should remain on that regimen throughout the study. 
o Subjects who are on inhaled cycling antibiotics should continue on their prior 
schedule. The timing of the first dose of study drug should be synchronized as 
closely as possible to the first day of inhaled cycling antibiotics in the cycle. 
o Subjects who alternate 2 different antibiotics monthly should remain on the same 
schedule during the study. The timing of the first dose of study drug should be 
synchronized as closely as possible to the first day of 1 of the inhaled alternating 
antibiotics. 
• Subjects may receive doses of prednisone of up to 10 mg/day (chronically) or 
prednisone 60 mg qd for up to 5 days without prior approval of the medical monitor. 


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• Information about bronchodilator use during the study will be collected and 
documented. Subjects who are using a bronchodilator must have their spirometry 
assessments performed according to the guidelines provided in Section 11.6.1. 
• Concomitant use of medications known to prolong the QT interval should be used 
with caution during the study, as the effect of VX-661 in combination with 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, 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 the subject’s 
outcome. The investigator will inquire about the reason for withdrawal, request that the 
subject return all unused investigational product(s), request that the subject return for a 
Safety Follow-up Visit, if applicable (see Section 8.1.4), 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. Subjects who discontinue study treatment early should continue to 
return for study assessments as noted in Section 8.1.4. 
The investigator should inquire about the reason for withdrawal of consent.  
Subjects must return all unused study drug and return for all scheduled visits. 
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. 
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 AE (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. 


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• 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. 
Subjects who discontinue study treatment early should continue to return for assessments as 
noted in Section 8.1.4. 
9.6 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug 
treatment period 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. 
Table 10-1 Study Drug Administration - Treatment Period 
Treatment Arm 
Time 
Drug(s) and Dose(s) Administered 
Route of Administration 
VX-661/ivacaftor 
 
AM 
VX-661 100-mg/IVA 150-mg fixed-dose tablet 
oral 
PM 
IVA 150-mg tablet 
oral 
Placebo 
 
AM 
VX-661/IVA matching placebo tablet 
oral 
PM 
IVA matching placebo tablet 
oral 
AM: morning; IVA: ivacaftor; PM: evening. 


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Study drug should be administered within 30 minutes of 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. Throughout the Treatment Period, study drugs will be administered after the start and 
before the end of a meal. 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.  
6. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
• If the dose in the clinic will be within 6 hours of the subject
's scheduled morning 
dose, the subject should withhold their morning dose of study drug and the morning 
dose will be administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject'
s scheduled 
morning dose, the subject should take the morning dose at home and the evening dose 
will be administered in the clinic. In this event, all assessments will be collected 
relative to the evening dose. 
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 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 490 subjects who meet the eligibility criteria will be randomized (1:1) to 
1 of 2 treatment arms. Randomization will be stratified by age at the Screening Visit (<18 
versus ≥18 years of age), sex (male versus female), and FEV1 severity collected during the 
Screening Period (<70% versus ≥70% predicted). 


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An interactive web response system (IWRS) will be used to assign subjects to treatment. 
Detailed instructions for randomization will be provided separately. 
10.4 
Dose Modification for Toxicity 
The dosage of VX-661 or ivacaftor cannot be altered, but the investigator can interrupt or 
stop treatment. 
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. 
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 100 mg VX-661/150 mg 
ivacaftor and 0 mg VX-661/0 mg ivacaftor, respectively.  
Ivacaftor (150 mg) and matching placebo will be supplied as light blue film-coated tablets of 
similar size and appearance containing 150 mg ivacaftor and 0 mg ivacaftor, respectively. 
Blister cards must be stored at room temperature according to Table 10-2 and to the 
instructions provided in the Pharmacy Manual. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended study conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs will be accounted for as detailed in 
Section 10.9.  


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Instructions regarding the storage and handling of study drug after dispensation to subjects 
will be provided to sites in the Pharmacy Manual. 
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, 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, 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 destruction or return of the study drug will be detailed in the Pharmacy 
Manual. 


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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. 
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 postdose spirometry 


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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 assessment 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 
locking the clinical database, after all study visits have been completed, access to treatment-
blinded sweat chloride data will be provided to a small group of individuals (a biostatistician, 
a statistical programmer, a validation statistical programmer, and a clinical reviewer) who are 
not part of the Vertex study team. This small group will review the sweat chloride data to 
ensure there are no significant data issues and will use the blinded data set to refine the 
statistical programs. 
10.12.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject
's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject
's study treatment 
is necessary for clinical management. In such cases, investigators should use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem that it is not necessary to 
unblind immediately, they will first attempt to contact the medical monitor to discuss and 
agree to the need for unblinding. If investigators have tried but are unable to reach the 
medical monitor, they should use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding without having successfully reached and 
discussed the situation with the medical monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center 
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject
's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor should be notified within 24 hours of the unblinding 
event. The reason and the date of the unblinding will be documented clearly in the subject
's 
study file. Information about the treatment assignment obtained from the unblinding will be 
maintained in a secure location with controlled access and will not be shared with sponsor 
(Vertex), contract research organization (CRO), or any site personnel (other than the 
physician treating the subject). In addition, the investigator will consider whether the clinical 


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event that prompted unblinding will be considered an SAE, according to the regulatory 
definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or designee, 
per Section 13.1.2. 
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. 
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: 
 
 
 
4. standard 12-lead ECG recordings  
5. vital signs and pulse oximetry 
6. spirometry 
7. sweat chloride  
8. safety laboratory assessments (i.e., blood draws) 
9. 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, if applicable, a subject number will be assigned. 
The subject will retain this number for the entire study. Detailed instructions on assigning 


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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. 
11.3 
Total Blood Volume 
Total blood volume will be outlined in the Laboratory Manual.  
11.4 
Pharmacokinetics 
11.4.1 
Blood Sampling 
Blood samples will be collected as shown in Table 3-1 and Table 3-2. 
At the visits and time points indicated in Table 3-2, blood samples will be collected for the 
determination of the concentrations of VX-661, M1-661, M2-661, ivacaftor, and 
M1-ivacaftor. Blood samples collected before dosing must be collected within 60 minutes 
before dosing. The acceptable windows for PK sampling time points are detailed in 
Table 11-1. 
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard 
operating procedures. 
For each visit with a PK blood draw, a record of study drug administration will be collected 
as described in Section 10.2. The collection date and time that each PK blood sample is 
drawn will also be recorded. 
Details on sample collection, processing, and shipping will be provided in a separate 
protocol-specific Laboratory Manual. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling time 
Time From Sampling Schedule Allowed 
Predose 
Within 60 minutes before study drug dose on the PK sampling date 
0.5 hours after 
study drug dosing 
± 10 minutes 
2, 3, 4, 6, and 8 
hours after study 
drug dosing 
± 30 minutes 
 




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11.6 
Efficacy 
11.6.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines40 at 
the time points noted in Table 3-1 and Table 3-2 according to the additional guidelines that 
follow. 
Prebronchodilator spirometry is defined as spirometry testing performed for subjects who 
have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent
®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours 
before the spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva
®]) for more than 24 hours before the spirometry assessment. 
During the Treatment Period, spirometry assessments must be performed before dosing.  In 
adolescent subjects (<18 years of age at the Screening Visit) additional postdose spirometry 
assessments on Day 1 and Day 15 will be collected.  
During the Screening Period, spirometry assessments may be performed pre- or 
postbronchodilator. At all other visits, all spirometry assessments should be performed 
"prebronchodilator." In the event that a subject forgets or is unable to withhold 
bronchodilator(s), spirometry should be performed according to the following: 
• If a subject
's Day 1 spirometry is prebronchodilator, but, on a subsequent visit, the 
subject does not withhold bronchodilator use, a postbronchodilator spirometry will be 
obtained for that visit only, and the visit will not be rescheduled. 
• If, on Day 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. 
• Spirometry assessments that occur after dosing (postdose) on Day 1 and Day 15 (for 
subjects <18 years of age) should be performed prebronchodilator. If Day 1 and/or 
Day 15 predose spirometry is performed postbronchodilator, the subject should 
withhold any further bronchodilator use until after completion of the 4-hour postdose 
spirometry. 
• 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 assessment. Spirometry 
data will be transmitted to a centralized spirometry service for quality review. 


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Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results during the Treatment Period (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 al41 (for 
female subjects aged 12 to 15 years [inclusive] and male subjects aged 12 to 17 years 
[inclusive]) or Hankinson et al
42 (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 (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 chloride collection on Day 1, Week 4, Week 16, and Week 24 will 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). 
Additionally, sweat collection will be performed at the Screening Visit and ETT Visit. 
Collection of sweat chloride will not overlap with any other study assessments. 
11.6.3 
Height and Weight 
Height and weight will be measured with shoes off at time points noted in Table 3-1 and 
Table 3-2. Height and weight will be measured before the morning dose of the study drug 
during the Treatment Period. During the Treatment Period and at the Safety Follow-up Visit, 
height will be collected only for subjects 21 years of age or younger. 
11.6.4 
Cystic Fibrosis Questionnaire-Revised 
Subjects will be asked to complete the CFQ-R in their native language. The CFQ-R will be 
completed before the start of any other assessments, as noted in Table 3-1 and Table 3-2. 
Subjects who are 12 and 13 years of age at Day 1 will complete the CFQ-R Child version 
themselves, and their parents/caregivers will complete the CFQ-R Parent version, on all 
visits, regardless of whether the subject subsequently turns 14 years of age during the study. 
Subjects 14 years of age and older at Day 1 will complete the Adolescent/Adult version of 
the questionnaire themselves at all visits. The questionnaires provide information about 
demographics; general quality of life, school, work, or daily activities; and symptom 
difficulties (pertaining to CF). Copies of the CFQ-R used in this study will be provided in the 
Study Reference Manual. Validated translations26,27 of the CFQ-R, if available, will be 
provided for participating centers in non-English-speaking countries.  






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• Time-to-first hospitalization for pulmonary exacerbation 
• Number of pulmonary exacerbations requiring IV antibiotic therapy 
• Number of days on IV antibiotic therapy for pulmonary exacerbations 
• Time-to-first IV antibiotic therapy for pulmonary exacerbations 
*For each treatment group, the number of days hospitalized for pulmonary exacerbations will 
be analyzed as 48 weeks times the total numbers of days in hospital for pulmonary 
exacerbation, divided by the total number of weeks on-treatment, for all subjects in the same 
treatment group.  
11.6.12.2 
Hospitalization for CF 
At the visits indicated in Table 3-2, subjects will be queried about planned and unplanned 
hospitalizations lasting ≥24 hours. The dates of hospitalizations and the reasons for 
hospitalizations will be documented. 
For any hospitalization (unplanned and planned), the procedures for safety reporting should 
be followed (see Section 13.1.2.3). 
The following information will be determined: 
• Number of planned hospitalizations for CF (i.e., prophylactic antibiotic therapy) 
• Number of all unplanned hospitalizations 
• Number of days of all unplanned hospitalizations 
• Time-to-first unplanned hospitalization 
11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of 
vital signs, ECGs, pulse oximetry, spirometry, and physical examinations. 
11.7.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report 
form completion guidelines for investigators as well as training will be provided. 


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11.7.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of urine 
pregnancy tests, which will be performed and analyzed at the site. Other blood samples 
requiring a 4-hour fast will be collected on Day 1, Week 12, and Week 24. Fasting is not 
required at other time points unless specified in assessment table. On Day 1, blood samples 
will be collected before the first dose of the study drug. At all other scheduled visits, these 
samples will be collected at any time during the visit, according to the order of assessments 
indicated in Section 11.1 and 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 11-2. 
Table 11-2  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 (LDL) 
High-density lipoprotein (HDL) 
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. 


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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 and analyzed 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.  
Follicle-stimulating Hormone (FSH; Screening Period only): Blood sample for FSH will be 
measured for any suspected postmenopausal female with at least 12 months of continuous 
spontaneous amenorrhea. Serum FSH levels must be ≥40 mIU/mL to be considered 
postmenopausal. 
CF Genotype (Screening Period only): CF genotyping will be performed on all subjects to 
confirm the genotype documented in the subject
's medical record. Specific instructions will 
be provided in the Laboratory Manual. 
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; 
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 physical examinations 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. 


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11.7.4 
Electrocardiograms 
11.7.4.1 
Standard 12-Lead Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1 and Table 3-2). Additional standard 12-lead ECGs will 
be performed at any other time if clinically indicated. The performance of all ECGs will 
adhere to the following guidelines: 
• The subject will be instructed to rest in the supine position for at least 5 minutes 
before having an ECG performed. 
• The ECG will be performed before any other procedures that may affect heart rate, 
such as blood draws. 
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 
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 in whom treatment is discontinued 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.
18,19 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 


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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 
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).  
o 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.  
• In countries where spermicide is not available, condom without spermicide will be 
considered acceptable. 
• Local regulations may require use of an additional acceptable method of 
contraception.  


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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.  
• In countries where spermicide is not available, barrier contraception without 
spermicide will be considered acceptable. 
• 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. 
• In countries where spermicide is not available, condom without spermicide will be 
considered acceptable.  
• 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 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. 


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• 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 
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. 


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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: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST 
levels have improved, study drug treatment must be permanently discontinued if repeat 
testing within 48 to 72 hours confirms the initial elevation. Subjects in whom treatment is 
discontinued for elevated transaminases should have their transaminases monitored closely 
until levels normalize or return to baseline. 
Resumption of Study Drug 
If an alternative, reversible cause of transaminase elevation has been identified, study drug 
may be resumed once transaminases 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 must be permanently discontinued, regardless of the presumed etiology. 


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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. 
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 Visits (see Section 8.1.4). If the subject 
continues study drug treatment, more frequent ophthalmologic monitoring should be 
considered. 
In addition to the screening examination, all subjects will have an ophthalmologic 
examination conducted by a licensed ophthalmologist at Week 24. This exam may be 
completed within 4 weeks before the Week 24 Visit, but must be completed by the end of the 
Week 24 Visit.  
In addition, 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 discontinue treatment after 
receiving at least 1 dose of study drug 
• subjects <18 years of age at the Screening Visit who complete treatment but do not 
enroll in a separate extension study of VX-661/ivacaftor within 28 days of 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 end of the Safety Follow-up Visit. Subjects <18 years of age at the 
Screening Visit are only required to complete 1 ophthalmologic exam at the end of treatment 
(Week 24 Visit, ETT Visit, or Safety Follow-Up Visit), as described in Table 3-2.  
Subjects ≥18 years of age at the Screening Visit are not required to complete the ETT or 
Safety Follow-Up Visit ophthalmologic exams. 


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Additional ophthalmologic examinations may be conducted at the discretion of the 
investigator. The medical monitor should be notified of any additional ophthalmologic 
examinations. 
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 


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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 
baseline through Week 24.  
The null hypothesis to be tested is that the mean change from baseline in percent predicted 
FEV1 through Week 24 is the same for the 2 treatment arms. Assuming a common standard 
deviation (SD) of 8% and a 10% dropout rate, a sample size of 245 subjects in each treatment 
group will have at least 90% power to detect a treatment difference of 2.5% in percent 
predicted FEV1 between treatment groups, using a 2-sided significance level of 0.05. If the 
above null hypothesis is rejected, the efficacy of VX-661/ivacaftor is considered established. 
Power for pulmonary exacerbation: 
Assuming the pulmonary exacerbation rate for placebo is 0.5 in 24 weeks, with 220 subjects 
in each treatment group, the power to detect a 40% reduction in the pulmonary exacerbation 
rate in the active arm versus the placebo arm is about 92%. The power to detect a 33% 
reduction in the pulmonary exacerbation rate is about 78%. 
This power calculation is based on an R simulation with 10,000 replications. 
To adjust for a 10% dropout, a total sample size of 490 subjects is needed. 
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 have been randomized or have received at 
least 1 dose of study medication. This analysis set will be used in subject listings and 
disposition summary table, unless otherwise specified. 
The Full Analysis Set (FAS) is defined as all randomized subjects 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 their randomized treatment group. 
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. 


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12.3 
Statistical Analysis 
The primary objective of this study is to evaluate the efficacy of VX-661 in combination with 
ivacaftor through 24 weeks of treatment in subjects with CF who are homozygous for the 
F508del-CFTR mutation. 
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. Statistical Analysis System 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. 
12.3.1 
General Considerations 
All individual subject data for all randomized subjects exposed to study drug will be 
presented in data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, SD, median, minimum value (min), and 
maximum value (max). The precision of the measurement for each continuous variable will 
be specified in the SAP.   
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the initial administration of study 
drug. For ECG, the baseline will be defined as the average of the 3 pretreatment 
measurements on Day 1. 
Change (absolute change) from baseline will be calculated as post-baseline value - baseline 
value. 
Relative change from baseline will be calculated as (post-baseline value - baseline 
value)/baseline value. 
The treatment-emergent (TE) period will include the time from the first dose to the Safety 
Follow-up Visit or 28 days after the last dose of the study medication for subjects who do not 
have a Safety Follow-up Visit. 


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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 
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 as 
appropriate: 
• All Subjects Set 
• Randomized 
• Dosed (Safety Set) 
• Randomized and dosed (FAS) 
• Completed study drug treatment 
• Prematurely discontinued the study during the Treatment Period and the reasons for 
discontinuation 
• Completed study/Safety Follow-up  
• Prematurely discontinued the study and the reasons for discontinuation 
• Rollover to extension study 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized. Protocol deviations/violations will be provided as a subject data listing only. 
Important protocol deviations/violations will be summarized. 
The following demographics and baseline characteristics will be summarized by dose group 
for the FAS: sex, race, ethnicity, age, weight, height, BMI, region, baseline percent predicted 
FEV1, baseline sweat chloride, and 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 the following:  
• Prior medication: any medication that started before initial dosing of study drug, 
regardless of when it ended. 
• Concomitant medication: medication continued or newly received at or after initial 
dosing of study drug through the end of the TE period. 
• Post-treatment medication: medication continued or newly received after the TE 
period.  


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A given medication 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 cannot be determined whether it was taken before initial dosing, 
concomitantly, or beyond the TE period, it will be considered as prior, concomitant, and 
post-treatment. 
Prior medications and concomitant medications will be summarized descriptively 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 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. 
Dosing compliance will be summarized for the FAS and is calculated as the actual number of 
dosing occasions at which study drug was administered, as a percentage of the planned 
number of dosing occasions. 
Duration of treatment and dosing compliance will be summarized by means of descriptive 
summary statistics. 
12.3.3 
Efficacy Analysis 
Assessment of efficacy of VX-661 in combination with ivacaftor is the primary objective of 
this study. 
12.3.3.1 
Analysis of Primary Variables 
The primary efficacy endpoint is the absolute change from baseline in percent predicted 
FEV1 through Week 24. The primary analysis will be based on a mixed model for repeated 
measures (MMRM) with percent predicted FEV1 at each time point as the outcome variable. 
The null hypothesis to be tested is that the mean change from baseline in percent predicted 
FEV1 through Week 24 is the same for the 2 treatment arms. A P value of 0.05 or less will be 
interpreted as sufficient evidence to reject the null hypothesis. 
The model will include the absolute change from baseline in percent predictedFEV1 at each 
visit as the dependent variables; treatment, visit, and treatment-by-visit interaction as fixed 
effects; and subject as a random effect, with adjustment for sex (male versus female), age 
group at the Screening Visit (<18 versus ≥18 years old), and percent predicted FEV1 severity 
determined during the Screening Period (<70% versus ≥70% predicted). 
In the model, visit will be treated as a class variable, assuming an unstructured covariance 
matrix to model the within-subject variability. This model imposes no assumptions on the 
correlational structure and is considered robust. Denominator degrees of freedom for the 
F-test for fixed effects will be estimated using the Kenward-Roger approximation.44 If there 
is a convergence problem due to the use of unstructured covariance matrix, a compound 
symmetry covariance structure will be used to model the within-subject errors. With a mixed-
effects model based on restricted maximum likelihood estimation used for the primary 




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• Absolute change in BMI z-score from baseline at Week 24: Analysis of this 
variable will be similar to the primary analysis with the addition of the BMI z-score at 
baseline as a covariate, for subjects <20 years of age at screening. 
• Absolute change in body weight from baseline at Week 24: Analysis of this 
variable will be similar to the primary analysis with the addition of the weight at 
baseline as a covariate. 
Adjustment for Multiple Comparisons 
A hierarchical testing procedure will be used to control the Type I error for the multiple 
endpoints tested at α = 0.05. For a test at any step to be considered statistically significant 
within the testing hierarchy, it must be statistically significant, and all previous tests (if any) 
within the hierarchy must be statistically significant at the 0.05 level. The testing hierarchy is 
as follows: 
1. Absolute change in percent predicted FEV1 from baseline through Week 24 
2. Relative change in percent predicted FEV1 from baseline through Week 24 
3. Number of pulmonary exacerbations through Week 24 
4. Absolute change in BMI from baseline at Week 24 
5. Absolute change in CFQ-R respiratory domain score from baseline through Week 24 
12.3.4 
Safety Analysis 
All safety analyses will be based on the set of data associated with the TE period for subjects 
in the Safety Set. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
• Incidence of treatment-emergent adverse event (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation studies, 
vitamin levels, lipid panel, and urinalysis) 
• ECGs 
• Vital signs 
• Pulse oximetry 
• Spirometry 
All safety data will also be presented in individual subject data listings. 


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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 initial dosing of study drug. 
• TEAE: any AE that increased in severity or that was newly developed at or after 
initial dosing of study drug through the end of TE period. 
• Post-treatment AE: any AE that increased in severity or that was newly developed 
beyond the TE period. 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study treatment, then the AEs will be classified as TEAEs. 
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 
• 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 as 
well as total number of events). 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. A separate table will summarize all TEAEs when each of them is 
considered unique, hereafter referred to as an AE count table. 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 
For the treatment-emergent laboratory measurements, the raw values and change from 
baseline values of the continuous laboratory parameters will be summarized in SI units by 
treatment group at each scheduled time point. In addition, 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) 


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shift from baseline will also be summarized for selected laboratory parameters. The PCS 
criteria and the parameter selection criteria will be provided in the SAP. 
 Results of urinalysis and the serum pregnancy test will be listed in individual subject data 
listings only. In addition, a listing containing individual subject laboratory assessment values 
outside the reference ranges will be provided. This listing will include data from scheduled 
and unscheduled time points. 
12.3.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of raw values and change from 
baseline values will be provided by treatment group at each scheduled time point for the 
following standard 12-lead ECG measurements: PR, QT, and QTc for HR intervals (QTcF), 
QRS duration, and HR. In addition, the mean value at each visit will be plotted by treatment 
groups for QTc. 
The number and percentage of subjects with at least 1 PCS event during the TE period will 
be summarized by treatment group. The PCS criteria will be provided in SAP. 
Additional ECG analyses will be described in the SAP. 
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the raw values and change from 
baseline values 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 summarized by treatment group. The PCS criteria will be provided in 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 
For the treatment-emergent pulse oximetry measurements, a summary of raw values and 
change from 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 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 and Day 15, a summary of raw 
values for percent predicted FEV1 will be provided by treatment group at each time point. 


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The absolute change from the predose value of percent predicted FEV1 on the same day will 
be provided by treatment group at each time point. In addition, a box plot by time point will 
be provided. Within each treatment group, 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 arm 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. 
12.3.5.2 
IDMC Analysis 
An independent data monitoring committee (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 in the study. 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.  


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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 
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 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 after the last dose of study drug 
(Section 8.1.4) 
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 CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the 
study will be recorded only in the subject
's source documents. The following data will be 
documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 


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• 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 
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.  


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Table 13-2 Classifications for AE Causality 
Classification 
Definition 
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 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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13.2.2 
Subject Information and Informed Consent and Assent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from 
the subject (if applicable), before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent 
will comply with ICH GCP and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator 
and Vertex. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (i.e., efficacy assessments) will require 
IRB/IEC notification before implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects. Vertex will submit all protocol 
modifications to the required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the 
protocol, the investigator will contact Vertex to discuss the planned course of action. If 
possible, contact will be made before the implementation of any changes. Any departures 
from 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 electronic case report forms (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. 


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13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs 
may terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not 
limited to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the 
qualifications of each investigator, inspect clinical study site facilities, and inform the 
investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. 
Vertex will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator 
for resolution. Any changes to study data will be made to the CRF and documented in an 
audit trail, which will be maintained within the clinical database. 






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14 
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Cystic Fibrosis Foundation Web Site [Internet]. Available from: 
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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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ult.htm. Accessed 11 November 2014. 
4   
The Committee for Orphan Medicinal Products (COMP). Available from: 
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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. 
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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 
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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. 
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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 
most cystic fibrosis. Cell. 1990;63:827-34. 
 


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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 
Vertex Pharmaceuticals Incorporated. Effects of VRT-893661 on CFTR-mediated 
chloride secretion in human bronchial epithelia isolated from cystic fibrosis subjects. 
Report G016. Report date: 17 Feb 2010. 
17  
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;268:21592-21598. 
18 
Vertex Pharmaceuticals Incorporated. VX-661 Investigator
's Brochure. Version 7.0, 
08 May 2015. 
19 
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator
's Brochure. 
Version 12.0, 08 May 2015. 
20  
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
21 
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. 
22  
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. 
23  
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. 
24  
Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4:1-9. 
25  
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. 
26  
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. 
27  
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 
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28   Lyczak JB, Cannon CL, Pier GB. Lung Infections Associated with Cystic Fibrosis. 
Clin Microbiol Rev. Apr 2002; 15(2): 194–222. 
29   Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. 
Clinical mechanism of the cystic fibrosis transmembrane conductance regulator 
potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 
2014;190(2):175-84. 
30 
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. 
31  
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331:637-42. 
32  
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. 
33  
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. 
34  
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. 
35  
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
36  
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
37  
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. 
38  
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. 
39   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. 
40  
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
41  
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. 
 


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42  
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. 
43  
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. 
44 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:983-97. 
 


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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: VX14-661-106 Version #: 4.0 
Version Date 06 May 2016 
 
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in 
Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR 
Mutation 
This Clinical Trial Protocol has been reviewed and approved by the sponsor. 
Printed Name 
 Title 
Signature 
 Date 


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15.2 
Investigator Signature Page 
Protocol #: VX14-661-106 Version #: 4.0 
Version Date 06 May 2016 
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in 
Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR 
Mutation 
I have read Protocol VX14-661-106, Version 4.0 and agree to conduct the study according to 
its terms. I understand that all information concerning VX-661 and ivacaftor and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential.  
Printed Name 
  
Signature 
 Date 
 
 
 

SAP_001.pdf: 






Statistical Analysis Plan (Methods)
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11.1 Schedule of Assessments.......................................................................................48
11.2 Analysis Visit Window Mapping Rules for Efficacy and Safety Measurements.....54
11.3 Coefficients for Hankinson and Wang Methods for Calculating Predicted 
Spirometry Parameters ..........................................................................................58
11.4 CFQ-R scoring manual..........................................................................................64
11.5 Threshold Analysis Criteria ...................................................................................65
11.6 Standards for Efficacy and Safety Variable Display in TFLs..................................74
11.7 Imputation Rules for Missing AE Start Date..........................................................77


Statistical Analysis Plan (Methods)
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List of Tables
Table 8-1
Logic for Determining the Category of a Medication .....................................20
Table 8-2
CFQ-R for Children Ages 12 and 13..............................................................27
Table 8-3
CFQ-R for Adolescents and Adults (Subjects 14 Years and Older) ................27
Table 8-4
CFQ-R for Parents/Caregivers (Subjects 13 Years and Younger) ...................28
Table 11-1
Screening Period Assessments – Study VX14-661-106..................................48
Table 11-2
Treatment Period and Safety Follow up Visit Assessments – VX14-661-106.50
Table 11-3
HNVs Equation Coefficients by Sex, Race, and Age......................................59
Table 11-4
WNVs Equation Coefficients by Sex and Age in White Boys and Girls .........60
Table 11-5
WNVs Equation Coefficients by Sex and Age in Black Boys and Girls..........62
Table 11-6
Threshold Criteria for Clinical Chemistry and Hematology............................65
Table 11-7
Threshold Criteria for Coagulation.................................................................70
Table 11-8
Threshold Criteria for ECGs ..........................................................................71
Table 11-9      Threshold Criteria for Vital Signs .................................................................72
Table 11-10    Precision Standards for Efficacy Variables....................................................74
Table 11-11   Standard Display Units in Percent Predicted FEV1 .......................................76
List of Figures
Figure 6-1
Schematic of the Study Design.......................................................................12








Statistical Analysis Plan (Methods)
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3
INTRODUCTION
This SAP, which describes the planned final analyses for Study VX14-661-106, is based on 
the following:

the approved clinical study protocol (Version 4.0, dated 06 May 2016),

the approved electronic case report forms (eCRF) (Version 3.0,  dated 14 October, 2015). 
Study VX14-661-106 is a Phase 3, randomized, double-blind, placebo-controlled, parallel-
group study designed to evaluate the efficacy and safety of tezacaftor in combination with 
ivacaftor (TEZ/IVA) in subjects aged 12 years and older with cystic fibrosis (CF), 
homozygous for the F508del mutation on the cystic fibrosis transmembrane conductance 
regulator (CFTR) gene (F508del-CFTR mutation).
This SAP (Methods) documents the planned final statistical analyses of efficacy and safety 
endpoints defined in the VX14-661-106 study protocol. It also documents analyses for 
additional efficacy and safety variables not specified in the protocol, which will provide 
supportive information for the scientific understanding of the drug entity.
The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of TEZ/IVA in the 
F508del homozygous population also will be evaluated in the study. The relevant PK and PD 
analyses, however, will not be documented in this SAP. Rather, PK and PD analyses will be 
documented separately in the clinical pharmacology analysis plan (CPAP) for the study.
In addition, some exploratory endpoints were described in the study protocol. Analyses of 
exploratory endpoints are outside of the scope of this SAP and will be documented separately.
The Vertex Biometrics Department will perform the statistical analysis of the efficacy and 
safety data; SAS (Version 9.2, or higher) will be used to generate all statistical outputs 
(tables, figures, listings, and datasets). The SAP will be finalized and approved prior to the 
final clinical data lock and treatment unblinding for the study.  If the methods in this SAP 
differ from the methods described in the protocol, the SAP will prevail.
4
STUDY OBJECTIVES
4.1
Primary Objective
The primary objective of the study is to evaluate the efficacy of TEZ/IVA through Week 24 
in subjects with CF who are homozygous for the F508del mutation on the CF 
transmembrane conductance regulator (CFTR) gene.
4.2
Secondary Objectives
The secondary objectives of the study are as follows:
o
To evaluate the safety of TEZ/IVA through Week 24


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o
To investigate the pharmacokinetics (PK) of tezacaftor and its metabolites, M1 and 
M2 (M1-661 and M2-661, respectively), and of ivacaftor and its metabolite, M1 
(M1-ivacaftor).
5
STUDY ENDPOINTS
5.1
Efficacy Endpoints
5.1.1 Primary Efficacy Endpoint
The primary endpoint is absolute change from baseline in percent predicted forced expiratory 
volume in 1 second (FEV1) through Week 24.
5.1.2 Secondary Efficacy Endpoints
The key secondary efficacy endpoints are as follows:
o
Relative change from baseline in percent predicted FEV1 through Week 24
o
Number of pulmonary exacerbations through Week 24
o
Absolute change in body mass index (BMI) from baseline at Week 24
o
Absolute change in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory 
domain score from baseline through Week 24
The following are other secondary efficacy endpoints:
o
Time-to-first pulmonary exacerbation through Week 24
o
Absolute change in sweat chloride from baseline through Week 24
o
Absolute change in BMI z-score from baseline at Week 24 (in subjects <20 years of 
age at time of screening)
o
Absolute change in body weight from baseline at Week 24
5.2
Safety Endpoints
Safety and tolerability are secondary endpoints which will be evaluated as follows:

Adverse events (AEs) 

Clinical laboratory values (hematology, serum chemistry, coagulation studies, vitamin 
levels, lipid panel, and urinalysis)

Standard 12-lead electrocardiograms (ECGs)

Vital signs

Pulse oximetry

Spirometry




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A schematic of the study design is shown in Figure 6-1.
Figure 6-1
Schematic of the Study Design
6.2
Sample Size and Power
The study is powered for both the primary endpoint  (change from baseline in ppFEV1)  and 
a secondary endpoint of clinical interest (relative risk of pulmonary exacerbations).
The primary efficacy endpoint is the absolute change from baseline in percent predicted 
FEV1 through Week 24. 
The null hypothesis to be tested is that the mean absolute change from baseline in percent 
predicted FEV1 through Week 24 is the same for TEZ/IVA and placebo. Assuming a 
common standard deviation (SD) of 8% in each arm, a sample size of 220 subjects in each 
treatment group will have at least 90% power to detect a treatment difference of 2.5% in 
percent predicted FEV1 between treatment groups, using a 2-sided significance level of 0.05. 
If the above null hypothesis is rejected, the efficacy of TEZ/IVA will be considered 
established.
Power for pulmonary exacerbation:
Assuming the pulmonary exacerbation rate for placebo is 0.5 events in 24 weeks, with 
220 subjects in each treatment group, the power to detect a 40% reduction in the pulmonary 
exacerbation rate in the active arm versus the placebo arm is about 92%. The power to detect 
a 33% reduction in the pulmonary exacerbation rate is about 78%.
Screening Period
Treatment Period
Safety Follow-up
Day
1b
Day
-1
Week
24
IVA: ivacaftor; q12h: every 12 hours; qd: once daily.
a
The Safety Follow-up Visit is scheduled to occur 28 (±7) days after the Week 24 Visit. The Safety Follow-up 
Visit is not required for subjects who complete the Week 24 Visit in this study, and are eligible and enroll in 
an extension study of TEZACAFTOR in combination with ivacaftor.
b
Approximately 490 subjects will be stratified by age at the Screening Visit (<18 versus ≥18 years of age), sex 
(male versus female), and FEV1 severity determined during the Screening Period (<70% versus 70% 
predicted) and randomized (1:1) before the first dose of study drug on Day 1.
Screening
Extension study
Safety 
Follow-up Visita
100 mg TEZACAFTOR qd placebo +
150 mg IVA q12h placebo
Placebo
(n = 245)
TEZACAFT
OR/
ivacaftor
(n
245)
100 mg TEZACAFTOR qd +
150 mg IVA q12h
Day
-28


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This power calculation is based on an R simulation with 10,000 replications.
To adjust for a 10% dropout, a total sample size of 490 subjects is needed.
6.3
Randomization
Approximately 490 subjects (245 per arm) who meet eligibility criteria will be stratified by 
age at Screening Visit (<18 versus ≥18 years of age), sex (male versus female), and percent 
predicted FEV1 severity determined during the Screening Period (<70 versus ≥70), and then 
randomized (1:1) to either TEZ/IVA or placebo. An interactive web response system (IWRS) 
will be used for randomization following a list of randomization codes generated by a 
designated vendor 
. 
6.4
Blinding and Unblinding
This is a double-blind study.
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. Such unblinding events will 
be fully documented (see below).

Any site personnel for whom this information is important to ensure the safety of the 
subject and her fetus in the event of a pregnancy. Such unblinding events will be fully 
documented (see below).

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. Such unblinding events will be fully documented (see below).


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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 and 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 assessment 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 post-dose sweat 
chloride data; dummy data will be used to develop statistical programs. During the process of 
locking the clinical database, after all study visits have been completed, access to treatment-
blinded sweat chloride data will be provided to a small group of individuals (a biostatistician, 
a statistical programmer, a validation statistical programmer, and a clinical reviewer) who are 
part of the Vertex study team. This small group will review the sweat chloride data to 
ensure there are no significant data issues and will use the blinded data set to refine the 
statistical programs.
6.4.2 Unblinding
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process.
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment 
is necessary for clinical management. In such cases, investigators should use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem that it is not necessary to 
unblind immediately, they will first attempt to contact the medical monitor to discuss and 
agree to the need for unblinding. If investigators have tried but are unable to reach the 
medical monitor, they should use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding.
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document.


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In addition, the Vertex Medical Information Call Center 
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup.
If a subject's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor should be notified within 24 hours of the unblinding 
event. The reason and the date of the unblinding will be documented clearly in the subject's 
study file. Information about the treatment assignment obtained from the unblinding will be 
maintained in a secure location with controlled access and will not be shared with sponsor 
(Vertex), contract research organization (CRO), or any site personnel (other than the 
physician treating the subject). In addition, the investigator will consider whether the clinical 
event that prompted unblinding will be considered an SAE, according to the regulatory 
definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or designee, 
per Protocol Section13.1.2.
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, Randomized Set, Full Analysis Set 
(FAS), and Safety Set.
The All Subjects Set is defined as all subjects who have been randomized or have received 
at least 1 dose of study medication. This analysis set will be used in subject listings and the 
disposition summary table, unless otherwise specified.
The Randomized Set is defined as all subjects who have been randomized.
The Full Analysis Set (FAS) is defined as all randomized subjects who carry the intended 
CFTR allele mutation and have received at least 1 dose of study drug. 
The Safety Set is defined as all subjects who received at least 1 dose of study drug.
8
STATISTICAL ANALYSIS
8.1
General Considerations
All individual subject data in the All Subject Set will be presented in data listings. The 
Schedule of Assessments is provided in Section 11.1. The precision standards are provided in 
Section 11.6.
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), median, minimum value 
(min), and maximum value (max).  
Categorical variables will be summarized using counts and percentages. 


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Baseline Value, unless otherwise specified, is defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected prior to or on the first dose of study drug. 
For ECGs, the baseline will be defined as the average of the 3 pre-treatment measurements 
(triplicate) on Day 1. For sweat chloride, the baseline value will be the mean of last 
assessment values on the left and the right arm prior to the first dose of the study drug.
Change (Absolute Change) from baseline will be calculated as Post-baseline value ̶
Baseline value.
Relative change from baseline will be calculated and expressed in percentage as 100×(Post-
baseline value ̶ Baseline value) / Baseline value.
Treatment Emergent (TE) Period will include the time from the first dose of study drug to 
the Safety Follow-up Visit, or to 28 days after the last dose of the study drug for subjects 
who do not have a Safety Follow-up Visit, or to the last participation date in the study (i.e.,
the day right before the first study dose in the extension study for subjects who enrolled into 
the extension study), whichever occurs first. The TE period will be used for safety analyses 
unless otherwise specified.
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 11.2 defines 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: 
o
For all efficacy parameters, if there are multiple measurements within a visit window, 
the record at the scheduled visit will be used. Otherwise,
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. 
o
Assessments at safety follow-up (SFU) visit will follow the windowing rules 
for regular visits if they fall within the upper boundary of the window for 


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Week 24, or remain as SFU if they go beyond the upper boundary of the 
window for Week 24.
o
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; or 
3) SFU visit will not be windowed; instead, it will be used according to the nominal 
visit in relevant analyses.
Note, spirometry assessments, BMI, weight, and height will be used for both efficacy and 
safety purposes. Their measurements will follow the visit windowing rules for efficacy 
parameters.
Incomplete/Missing data will not be imputed, unless otherwise specified. 
Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless otherwise specified.
8.2
Background Characteristics 
8.2.1 Subject Disposition
In the summary table of subject disposition, the number of subjects in the following 
categories will be presented by treatment and overall: 

All Subjects Set (randomized or dosed)

Randomized Set

Full Analysis Set (FAS)

Safety Set
The number and percentage of subjects in each of the following disposition categories will be 
presented by treatment and overall based on the Safety Set:

Completed treatment regimen

Prematurely discontinued the treatment  (any tablet) and the reason for discontinuations 

Completed study

Prematurely discontinued the study and the reasons for discontinuations 

Rollover to extension
A listing will be provided for subjects who discontinued treatment or who discontinued from 
the study, along with 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 randomized to each 
treatment group as the denominator. A randomization listing will be provided with subjects 
ordered by randomization date.


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8.2.2 Demographics and Baseline Characteristics
The following demographic data will be summarized by treatment and overall based on the 
FAS:

Age at Screening

Sex 

Ethnicity (Hispanic or Latino, not Hispanic or Latino, not collected per local regulations)

Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other)

Geographic region (North America, Europe)
The following baseline characteristics will be summarized:

Weight (kg)

Height (cm)

BMI (kg/m2)

Weight z-score (subjects <20 years old at screening)

Height z-score (subjects <20 years old at screening)

BMI z-score (subjects <20 years old at screening)
Stratification categories (in addition to sex) will also be summarized:

Age groups at screening (< 18, 18 years)

Percent predicted FEV1 at screening (<70, ≥70)
Disease characteristics at baseline will include the following:

Percent predicted FEV1 categories(<40, ≥40- <70, ≥70-≤90, >90)

Percent predicted FEV1

Sweat chloride 

CFQ-R Respiratory Symptoms domain 

FEV1 (L) 

FVC (L)

Percent predicted FVC 

FEF25-75% (L/sec) 

Percent predicted FEF25-75%

FEV1/FVC 


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
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 of Pseudomonas aeruginosa (Positive, Negative)
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 
system organ class and preferred term. The corresponding data listing will also be provided.
In addition, the number of subjects reported to have had positive cultures for respiratory 
pathogens in the 2 years prior to screening (i.e., answered yes on the respiratory 
microbiology form) will be summarized by test and subcategories within the test. The 
corresponding data listing will be provided. Hospitalization and clinic visit history in the past 
year will be listed.
8.2.4 Prior and Concomitant Medications
Medications taken during this study will be coded using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and categorized as the following:

Prior medication: any medication that started before the first dose of study drug, 
regardless of when the medication ended.

Concomitant medication: medication continued or newly received at or after the first 
dose of study drug through the end of TE period.

Post-treatment medication: medication continued or newly received after the TE period.
A given medication can be classified as a prior, a concomitant, or a post-treatment 
medication; both prior and concomitant; both concomitant and post-treatment; or prior, 
concomitant, and post-treatment. If a medication has a missing or partially missing start/end 
date and it cannot be determined whether it was taken before the first dose, concomitantly, or 
beyond the TE period, it will be considered as prior, concomitant, and post-treatment.


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For the FAS, prior medications and concomitant medications will be summarized 
descriptively by: 1) preferred name; and 2) anatomic class (ATC) level 1, ATC level 2, and 
preferred name. Frequent (≥5% in any treatment group) prior medications and concomitant 
medications will be summarized descriptively by preferred name. Post-treatment medications 
will be listed by subject. 
As an intermediate step for programming purposes, medications with missing or partially 
missing start dates will use 2000 to impute a missing year, January for a missing month, and 
1 for a missing day. Medications with missing or partially missing stop dates will use 2050 to 
impute for a missing year, December for a missing month, and the last day of the month for a 
missing day. The logic to decide the category of a medication is presented in Table 8-1:
Table 8-1
Logic for Determining the Category of a Medication
Medication start date
Medication end date
< first dose date of 
study drug
≥ first dose date and 
≤ End date of TE 
period
> End date of TE 
period
< first dose date of study drug
P
PC
PCA
≥ first dose date and 
≤ End date of TE period
-
C
CA
> End date of TE period
-
-
A
P: Prior; C: Concomitant; A: Post
8.2.5 Study Drug Exposure
Exposure summaries will be based on the FAS.
Duration of study drug exposure is defined as follows: last dose date – first dose date + 1 day, 
regardless of any interruption in dosing between the first and the last dose.                         
Duration of study drug exposure expressed in weeks will 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 - ≤16 weeks, and >16 - ≤24 
weeks, >24 weeks. Additionally, the total duration of study drug exposure, defined as the 
sum of the subject’s duration of treatment exposure and expressed in patient years, will be 
provided.
8.2.6 Study Drug Compliance
Study drug compliance will be measured by the compliance rate and be summarized based on 
the FAS.
Compliance rate will be calculated as follows: 
100 × [1 - (Total number of days study drug interrupted) / (Duration of study drug exposure)].


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The total number of days of study drug interrupted is defined as the sum of (number of 
unique 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. 
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% of compliance rate will 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. IPDs rules will be developed and 
finalized before database lock.
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to:

Subject entered the study despite violation of any  inclusion or exclusion criteria

Subject was less than 80% compliant with study medications

Subject received excluded concomitant medications

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 treatment. Additionally, IPDs will be 
provided as a subject data listing.
8.3
Efficacy Analysis
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS. The FAS will be used in the summary of demographics and baseline characteristics and 
analyses of the efficacy data; subjects will be analyzed according to their randomized 
treatment assignment.
8.3.1 Primary Efficacy Endpoint
8.3.1.1 Definition of Primary Efficacy Endpoint
The primary efficacy endpoint is the absolute change from baseline in percent predicted 
FEV1 (with a unit of percentage points) through Week 24. 










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
Increased cough

Increased dyspnea

Malaise, fatigue, or lethargy

Temperature above 38°C (equivalent to approximately 100.4°F)

Anorexia or weight loss

Sinus pain or tenderness

Change in sinus discharge

Change in physical examination (PE) of the chest

Decrease in pulmonary function by 10%

Radiographic changes indicative of pulmonary infection
The number of pulmonary exacerbations through Week 24 will be analyzed by comparing
the annualized number of pulmonary exacerbations for each treatment group. It will be 
calculated as 
48 × (total number of pulmonary exacerbations) / (total duration of post-baseline assessment
in weeks),
where total number of pulmonary exacerbations and total duration of post-baseline
assessment are obtained from all subjects in the same treatment group. 
Absolute change from baseline in BMI at Week 24
To calculate absolute change from baseline in BMI at Week 24, BMI will be calculated as:
BMI = Weight (kg)/(height [m2])
Absolute change from baseline in CFQ-R respiratory domain through Week 24
The absolute change from baseline in the respiratory domain of the CFQ-R (Pooled 'Children 
Ages 12 and 13' Version and 'Adolescents and Adults' Version) through Week 24 will be 
analyzed based on the CFQ-R scaled scores, as elaborated below.
The CFQ-R5,6,7is a valid CF-specific instrument that measures quality-of-life domains. This 
study uses three different versions of CFQ-R forms in this study: 

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.


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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 8-4 provide 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 11.4.
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
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


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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
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 Years and 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.
8.3.2.1.2 Other Secondary Efficacy Endpoints
Time to First Pulmonary Exacerbation through Week 24 
The time to first pulmonary exacerbation is defined as the number of days from the first dose 
of study drug to the date of the first pulmonary exacerbation.
Absolute change in sweat chloride from baseline through Week 24
Sweat chloride will be collected at baseline and 3 post-baseline time points (Weeks 4, 16, 
and 24). Values > 160 mmol/L or < 10 mmol/L will be set to missing.
Absolute change from baseline in sweat chloride will be calculated as, mean(SWLeft, SWRight)  ̶  
SWBase, where SWLeft and SWRight are the measurements obtained on the left and right arms, 
respectively, at a particular visit and SWbase is 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.


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Note:  A volume of ≥15 μL is required for an accurate determination of sweat chloride.  Any 
results reported as having volume <15 μL or “Quantity Not Sufficient” (QNS) will be 
considered missing.
Definition of Baseline: If sweat chloride collection was initiated for one arm prior to first 
dose and initiated for the other arm after the first dose, the baseline will consist of the single 
pre-dose measurement. If both sweat collections were initiated after the first dose, the 
baseline sweat chloride result will be considered missing for analysis purposes.
Absolute change from baseline in BMI z-score at Week 24 for subjects <20 years old at 
screening
BMI will be calculated from weight and height at baseline and at the 6 post-baseline time 
points (Day 15, Week 4, 8, 12, 16, and 24).
BMI, adjusted for age and sex, will be referred to as BMI-for-age z-score (BMI z-score). 
BMI z-score will be calculated by using Centers for Disease Control and Prevention (CDC) 
growth charts8. The BMI z-score will be calculated as follows:


























0
,
ln
0
,
1
L
S
M
X
L
LS
M
X
z
L
where X is the derived BMI value in kg/m2 based on the raw weight and raw height and L, M, 
and S are selected from the CDC BMI-for-age chart by subject sex and age. The BMIAGE 
file contains these parameters by sex (1=male, 2=female) and age; it is available at:
http://www.cdc.gov/growthcharts/percentile_data_files.htm. SAS code for calculating 
percentiles and z-scores is available at:   
http://www.cdc.gov/growthcharts/computer_programs.htm.
NOTE: The CDC BMI-for-age charts are designed for use in pediatric populations (2 to 20 
years of age); in this analysis plan, BMI z-score will be calculated only for subjects between 
2 and <20 years of age at screening.
Absolute change from baseline in body weight at Week 24
Weight will be collected at baseline and at 6 post-baseline time points (Day 15, Week 4, 8, 
12, 16, and 24) according to the Schedule of Assessments (see Section 11.1). The absolute 
change from baseline in body weight will be calculated at each post-baseline visit following 
the general definition of the change from baseline in Section 8.1.


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8.3.2.2 Analysis of Secondary Efficacy Endpoints
8.3.2.2.1 Analysis of Key Secondary Efficacy Endpoints
Relative change from baseline in ppFEV1 through Week 24
Analysis for the relative change from baseline in ppFEV1 through Week 24 will be similar to 
that for the primary analysis. The LS Mean (SE) of the overall treatment difference between 
TEZ/IVA and placebo in the relative change from baseline in percent predicted FEV1 from 
Day 15 through Week 24 will be presented along with the 95% confidence interval and a 
2-sided P value. 
The LS Mean (SE) of within-treatment group relative change from baseline at each post-
baseline visit along with the corresponding 95% CI and p-value will be estimated from the 
same MMRM model. The LS Mean (SE) of the treatment difference between TEZ/IVA and 
placebo at each post-baseline visit will be provided along with the corresponding 95% CI and 
p-value.  The LS means (with 95% CI) at each post-baseline visit will also be plotted by 
treatment group. Summary statistics of raw values and absolute change from baseline in 
ppFEV1 at each visit will be presented. The cumulative distribution of the average relative 
change from study baseline in ppFEV1 through week 24 will be plotted by treatment group.
Number of pulmonary exacerbations through Week 24
A negative binomial generalized linear model will be used to compare the rates of pulmonary 
exacerbations over the 24-week treatment period for the two treatment groups.  The estimat-
ed rate ratio and the associated 95% CI and p-value will be provided.  In this model, the de-
pendent variable will be the number of pulmonary exacerbations through Week 24, (includ-
ing both on treatment events and events after treatment discontinuation). Treatment, sex, age 
group at screening (<18 vs. ≥ 18 years old), and baseline percent predicted FEV1 will be in-
cluded as covariates. The log of time spent in the study will be treated as the offset in this 
model. A log link function will be used in this model. If the model does not converge, the 
negative binomial regression model will be replaced with a Poisson regression model with 
the same covariates, offset variable, and link function.
Absolute change in BMI from baseline at Week 24
Analysis of the absolute change from baseline in BMI at Week 24 will be based on an 
MMRM model similar to that used for the primary analysis, with baseline ppFEV1 replaced 
by baseline BMI, and baseline ppFEV1-by-visit interaction replaced by baseline BMI-by-visit
interaction. The treatment difference in terms of BMI at Week 24 will be estimated from this 
model, along with the 95% CI and the associated p-value.
The LS Mean (SE) of within-treatment group absolute change from baseline in BMI at each 
of the other post-baseline visits along with the corresponding 95% CI and p-value will be 
estimated from the same MMRM model. The LS Mean (SE) of the treatment difference 
between TEZ/IVA and placebo at the other post-baseline visit will be provided along with 
the corresponding 95% CI and p-value. The LS means (with 95% CI) at each post-baseline 
visit will also be plotted by treatment group. Summary statistics for the raw values and the 
absolute change from baseline in BMI at each visit will be presented. The cumulative 


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distribution of the absolute change from study baseline in BMI at week 24 will be plotted by 
treatment group.
Absolute change from baseline in CFQ-R respiratory domain through Week 24
Analysis for the absolute change from baseline in CFQ-R respiratory domain (Pooled 
'Children Ages 12 and 13' Version and 'Adolescents and Adults' Version) through Week 24 
will be similar to that used for the primary analysis, with baseline ppFEV1 replaced by 
baseline in CFQ-R respiratory domain, and baseline ppFEV1-by-visit interaction replaced by 
CFQ-R respiratory domain baseline-by-visit interaction. The LS Mean (SE) of the overall 
treatment difference between TEZ/IVA and placebo in CFQ-R respiratory domain from Day 
15 through Week 24 will be presented along with the 95% confidence interval and a 2-sided 
P value. 
The LS Mean (SE) of within-treatment group absolute change from baseline at each post-
baseline visit along with the corresponding 95% CI and p-value will be estimated from the 
same MMRM model. The LS Mean (SE) of the treatment difference between TEZ/IVA and 
placebo at each post-baseline visit also will be provided along with the corresponding 95% 
CI and p-value.  The LS means (with 95% CI) at each post-baseline visit also will be plotted 
by treatment group. Summary statistics for the raw values and the absolute change from 
baseline in CFQ-R respiratory domain at each visit will be presented. The cumulative 
distribution of the average relative change from study baseline in CFQ-R respiratory domain 
through week 24 will be plotted by treatment group.
8.3.2.2.2 Multiplicity adjustment
A hierarchical testing procedure will be used to control the overall Type I error for the 
multiple endpoints tested at α = 0.05. For a test at any step to be considered statistically 
significant within the testing hierarchy, the test must be statistically significant at the 0.05 
level, and all previous tests (if any) within the hierarchy must also be statistically significant. 
The testing hierarchy is as follows:
1. Absolute change from baseline in ppFEV1 through Week 24
2. Relative change from baseline in ppFEV1 through Week 24
3. Number of pulmonary exacerbations through Week 24
4. Absolute change in BMI from baseline at Week 24
5. Absolute change in CFQ-R respiratory domain score from baseline through Week 24
8.3.2.2.3 Analysis of Other Secondary Efficacy Endpoints
Time to first pulmonary exacerbation through Week 24
Analyses for the time to first pulmonary exacerbation through Week 24 will be based on a 
Cox regression model that will include treatment, sex, age group at screening (<18 vs. ≥18 
years old), and baseline ppFEV1 as covariates.   In addition, the Kaplan-Meier (KM) method 


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will be used to estimate the cumulative exacerbation-free rate; the associated plot will be 
provided. 
Subjects without any protocol-defined pulmonary exacerbation event by or prior to Week 24 
will be considered censored at the date of the last visit (up to Week 24).
Note: If in either treatment group fewer than 5 subjects have pulmonary exacerbations, the 
Cox regression will not be performed and analysis of time-to-first event will be restricted to 
the Kaplan-Meier estimates.
Absolute change in sweat chloride from baseline through Week 24
Analysis of this variable will be performed using a model analogous to that used for the 
primary endpoint, with baseline ppFEV1 replaced by baseline sweat chloride value, and 
baseline ppFEV1-by-visit interaction replaced by baseline sweat chloride value-by-visit
interaction. The LS Mean (SE) of the overall treatment difference between TEZ/IVA and 
placebo in absolute change from baseline in sweat chloride from Day 15 through Week 24 
will be presented along with the 95% confidence interval and a 2-sided P value.
The LS Mean (SE) of within-treatment group absolute change from baseline at each post-
baseline visit along with the corresponding 95% CI and p-value will be estimated from the 
same MMRM model. The LS Mean (SE) of the treatment difference between TEZ/IVA and 
placebo at each post-baseline visit also will be provided along with the corresponding 95% 
CI and p-value.  The LS means (with 95% CI) at each post-baseline visit also will be plotted 
by treatment group. Summary statistics for the raw values and the absolute change from 
baseline in sweat chloride at each visit will be presented.
Absolute change in BMI z-score from baseline at Week 24 for subjects <20 years old at 
screening
Analysis for BMI z-score will be based on an MMRM model similar to that used for the 
analysis of the absolute change from baseline in BMI at Week 24, with baseline BMI 
replaced by baseline BMI z-score, and baseline BMI-by-visit interaction replaced by baseline 
BMI z-score-by-visit interaction. The LS Mean (SE) of the treatment difference between 
TEZ/IVA and placebo in absolute change from baseline in BMI z-score at Week 24 will be 
presented along with the 95% confidence interval and a 2-sided P value.
The LS Mean (SE) of within-treatment group absolute change from baseline at each of the 
other post-baseline visits along with the corresponding 95% CI and p-value will be estimated 
from the same MMRM model. The LS Mean (SE) of the treatment difference between 
TEZ/IVA and placebo at each post-baseline visit also will be provided along with the 
corresponding 95% CI and p-value.  The LS means (with 95% CI) at each post-baseline visit 
also will be plotted by treatment group. Summary statistics for the raw values and the 
absolute change from baseline in BMI z-score at each visit will be presented.
Absolute change in body weight from baseline at Week 24
Analysis of body weight will be based on an MMRM model similar to that used for the 
analysis of the absolute change from baseline in BMI at Week 24 with baseline BMI replaced 
by baseline body weight, and baseline BMI-by-visit interaction replaced by baseline body 














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For the purpose of safety analyses, the entire study period will then be further divided into 3 
segments:

The pre-treatment period is the period after the informed consent/assent date and before 
the start date of the TE period.

The treatment-emergent period (TE period) is defined as above.

The post-treatment period is the period after the end of the TE period to the date of the 
last study record in the clinical database.
8.4.1 Adverse Events 
For analysis purposes, AEs will be categorized as pretreatment AEs, treatment-emergent 
adverse events (TEAEs), or post-treatment AEs:

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 at or after the first 
dose of study drug through the end of TE period.

Post-treatment AE: any AE that increased in severity or that was newly developed after 
the TE period.
For AEs with a missing or partial start date, if there is no clear evidence that the AEs started 
(or increased in severity) before or after the first dose date, the start date will be imputed to
be the first dose date and the AE will be considered to be a TEAE (see Section 11.7).
Similarly, if there is no clear evidence that the AEs started (or increased in severity) before or 
after the start of the post-treatment period, the start date will be imputed to be the earliest 
possible time in the TEAE period and the AE will be considered to be a TEAE. As an 
intermediate step for programming purposes, imputation rules for missing or partially 
missing AE start/end dates are defined in Section 10.7.
Based on the reported severity and relationship to study drugs, TEAEs can be categorized as 
follows:
By relationship to the study drugs, treatment emergent adverse events (TEAEs) will be 
classified into the 4 categories:

Not related

Unlikely related

Possibly related

Related.
By severity, TEAEs will be classified into the 4 categories:


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
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 and 5): Any adverse drug experience that places the 
subject, in the view of the investigator, at immediate risk of death.
8.4.1.1 Overview of Pre-treatment AEs and Treatment Emergent AEs
An overview of the pre-treatment AEs will be summarized in the following categories:

Any pre-treatment AEs

Grade 3/4 pre-treatment AEs

Pre-treatment SAEs by severity.
An overview of all TEAEs will be summarized in the following categories:

Any TEAEs 

Grade 3/4 TEAEs

TEAEs by relationship

TEAEs by severity

TEAEs leading to treatment discontinuation (this category will capture TEAEs leading to 
discontinuation of either the morning or the evening tablets)

TEAEs leading to treatment interruption (this category will capture TEAEs leading to 
interruption of either the morning or the evening tablets)

TE SAE by severity

TEAE leading to death 
8.4.1.2 TEAEs and TE SAEs by System Organ Class (SOC) and Preferred Term 
(PT)
The number and percentage of subjects with TEAEs will be summarized by treatment group, 
MedDRA system organ class (SOC), and preferred term (PT), 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 of frequencies in the TEZ/IVA treatment group. TE SAEs will 
be summarized similarly.
8.4.1.3 TEAEs and TE SAEs by Preferred Term (PT)
The number and percentage of subjects with TEAEs will be summarized by treatment group 
and PT, where multiple occurrences of the same AE for the same subject will be counted 


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only once. The summary table will be presented in descending order of frequencies in the 
TEZ/IVA treatment group. TE SAEs will be summarized similarly.
8.4.1.4 TEAEs and TE SAEs by SOC, PT, and Relationship
The number and percentage of subjects with TEAEs will be summarized by treatment group,
SOC, PT, and relationship, where multiple occurrences of the same AE for the same subject 
will be counted only once according to the worst relationship to study drug. The summary 
table will be presented in descending order of frequencies in the TEZ/IVA treatment group.
TE SAE will be summarized similarly.
8.4.1.5 TEAEs and TE SAEs by SOC, PT, and Severity
The number and percentage of subjects with TEAEs will be summarized by treatment group,
SOC, PT, and severity, where multiple occurrences of the same AE for the same subject will 
be counted only once according to the worst severity. The summary table will be presented in 
descending order of frequencies in the TEZ/IVA treatment group. TE SAE will be 
summarized similarly.
8.4.1.6 Respiratory Events and Symptoms
Respiratory symptoms are defined as any TEAEs for the following 3 PTs:

Chest discomfort

Dyspnoea

Respiration abnormal
Respiratory events are defined as any of the afore-mentioned respiratory symptoms, or 
any TEAEs for the following 4 additional PTs:

Asthma

Bronchial hyperreactivity

Bronchospasm

Wheezing
A summary of respiratory symptoms and events will be presented by preferred term.
8.4.1.7 Elevated Transaminase
The following AE preferred terms will be selected for elevated transaminase:

Alanine aminotransferase abnormal 

Alanine aminotransferase increased

Aspartate aminotransferase abnormal


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
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 transaminase will be presented by preferred term.
8.4.1.8 Summaries of Respiratory Events and Elevated Transaminase by 
Treatment Interval
Respiratory events and elevated transaminase also will be summarized by the following 
treatment intervals:
0-1 Weeks: [Day1, Day7]
>1 -2 Weeks: [Day8, Day14]
>2 -8 Weeks: [Day15, Day56]
>8-16 Weeks: [Day57, Day112]
>16 -24 Weeks: [Day113, Day168]
>24 Weeks: [Day169, end of TE period])
8.4.1.9 Subgroup Analysis 
TEAEs will be summarized by SOC and PT for the following subgroups:

Age at screening (<18, ≥18 years)

Percent predicted FEV1 at baseline (<40, ≥40-<70, ≥70)

Sex

Region (North America, Europe)
Separate listings will be presented for TEAEs leading to treatment discontinuation, TE SAEs, 
and all deaths.
For all AEs, the CRF captures the action taken for VX661/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 ivacaftor 
monotherapy) are different. The summaries and listings of “AE Leading to Treatment Dis-


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continuation” and “AE Leading to Treatment Interruption” account for discontinuation and 
interruptions for either agent. 
8.4.2 Clinical Laboratory Values
For treatment emergent laboratory measurements, the raw values and change from baseline 
values for the continuous hematology, chemistry and coagulation results will be summarized 
in SI units by treatment group at each scheduled time point. For hematology, chemistry and 
coagulation, the number and percentage of subjects with an abnormal low (<LLN) value and 
with an abnormal high (>ULN) value at each scheduled time point will be summarized.
The number and percentage of subjects with hematology, chemistry and coagulation values 
meeting the defined threshold criterion will be summarized by treatment, lab parameters, and 
visit. The threshold criteria are provided in Section 11.5, Table 11-6 and Table 11-7.
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 visits will be included.
o
For each of the LFTs, mean values (SD) will be plotted by visit, and a box plot of the 
LFT value/ULN will be plotted by visit. 
o
The incidence of LFTs meeting threshold criteria against the baseline threshold criteria 
also will be summarized by treatment group, LFT parameters, and visit (only shifts to 
values worse than baseline will be presented).
o
A scatter plot of the maximum ALT value across visits versus the maximum total 
bilirubin value also will 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 baseline to the value at Week 24 will be presented by 
treatment group for vitamin levels and lipid panel. A box plot of vitamin levels and lipid 
panel also will be plotted against visit.
In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from 
scheduled and unscheduled time points. Subjects with positive pregnancy test results will be 
listed. Abnormal urinalysis results also will be listed by treatment and subject.
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 


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duration, and HR. In addition, the mean value at each time point will be plotted by treatment 
group for QTcF and heart rate.
The number and percentage of subjects with ECG events meeting threshold criteria during 
the treatment-emergent period will be summarized by treatment, ECG parameters, and visit. 
The threshold criteria are provided in Section 11.5, Table 11-8.
8.4.4 Vital Signs
For treatment emergent vital signs measurements, the raw values and changes from baseline 
will be summarized by treatment group at each scheduled time point for systolic and diastolic 
blood pressure (mmHg), body temperature (oC), HR (beats per minute), and respiratory rate 
(breaths per minute). In addition, the mean value at each time point will be plotted by 
treatment group for systolic and diastolic blood pressure.
The number and percentage of subjects with vital signs meeting threshold criteria during the 
treatment-emergent period will be summarized by treatment, vital signs parameters, and visit. 
The threshold criteria are provided in Section 11.5, Table 11-9.
8.4.5 Pulse Oximetry
A summary of raw values and change from baseline values will be provided by treatment 
group 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 baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
treatment-emergent period will be tabulated by treatment groups.
8.4.6 Postdose Spirometry
For subjects < 18 years old at screening, a summary of the raw values and change from pre-
dose value for percent predicted FEV1 will be provided by treatment group at each time point 
(2-hour and 4-hour postdose) on Day 1 and Day 15 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 L]
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 arm and by assessment day and time. The number and percentage 
of subjects with ≥0.20 L decrease from baseline in FEV1 will be summarized by treatment 
arm and by assessment day and time.
8.4.7 Physical Examination
PE findings will be presented in a data listing only.






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10 REFERENCES
                                               
1 Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general U.S. population. Am J Respir Crit Care Med. 1999; 159:179-87.
2 Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 
and 18 years of age. Pediatr Pulmonol. 1993; 15:75-88.
3 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97.
4 Rubin, DB. and Schenker, N.. Interval estimation from multiply-imputed data: a case study 
using agriculture industry codes. Journal of the American Statistical Association. 1987; 81: 
366–374.
5 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure 
for children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32.
6 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9.
7 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.
8 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm.


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11 APPENDICES
11.1
Schedule of Assessments
Table 11-1
Screening Period Assessments – Study VX14-661-106
Event/Assessment
Screening Period
(Day -28 through Day -1)
Informed consent and assent (when applicable)
X
Demographics
X
Medical history 
X
Ophthalmological history 
X
CFQ-Ra
X
CF genotypeb
X
FSHc
X
Serum pregnancy test (all females of childbearing potential)d
X
Hematology
X
Coagulation
X
Serum chemistry
X
Urinalysis
X
Weight and heighte
X
Ophthalmologic examinationf
X
Complete PE
X
Vital signsg
X
Pulse oximetryg
X
Standard 12-lead ECGh
X
Spirometryi
X
Inclusion/exclusion criteria review
X
Prior and concomitant medications
X
Sweat chloride
X
                                               
a
The CFQ-R, 
 must be completed before the start of any other assessments scheduled for that 
visit.
b
All subjects will be tested for CF genotype. Specific instructions will be provided in the Laboratory Manual. 
c
FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be ≥40 mIU/mL to be considered postmenopausal.
d
Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing 
potential and must have a serum pregnancy test.
e
Weight and height will be measured with shoes off.
f
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 (Protocol Section 11.7.8). Subjects with clinically 
significant cataracts, lens opacity, Y-suture, or lamellar rings will be excluded.
g
Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes. 
h
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes.
i
Spirometry may be performed pre- or post-bronchodilator (Protocol Section 11.6.1).
j


Statistical Analysis Plan (Methods)
Page 49 of 77
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-1
Screening Period Assessments – Study VX14-661-106
Event/Assessment
Screening Period
(Day -28 through Day -1)
AEs and SAEs
Continuous from signing of the ICF and assent (where 
applicable) through the Safety Follow-up Visit
AE: adverse event; CF: cystic fibrosis; CFQ-R: CF Questionnaire–Revised; 
; 
ECG: electrocardiogram; FSH: follicle-stimulating hormone; ICF: informed consent form; PE: physical examination; 
 SAE: serious adverse event; 
; US: United 
States.


Statistical Analysis Plan (Methods)
Page 50 of 77
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-2
Treatment Period and Safety Follow up Visit Assessments – VX14-661-106
Event/Assessmentk
Day 1
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT
Visitl
Safety Follow-up 
Visit
28 (± 7) days
After the last dose of 
study drug (if 
applicable)m
Clinic visit
X
X
X
X
X
X
Xn
X
X
X
Telephone contact
Xo
Inclusion and exclusion criteria 
review
X
CFQ-Rp
X
X
X
X
X
X
X
X
Weight and heightr
X
X
X
X
X
X
X
X
X
                                               
k
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 discontinue treatment early will continue to complete all other scheduled study 
visits for assessments of efficacy (spirometry, CFQ-R, sweat chloride, height, and weight), 
, and other events related to outcome 
(hospitalizations, pulmonary exacerbations, etc.) as detailed in Protocol Section 8.1.4. 
l
If the subject prematurely discontinues study treatment, an Early Treatment Termination (ETT) Visit should be scheduled as soon as possible after the subject decides to terminate 
study treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 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 Protocol Section 8.1.4.
m
A Safety Follow-Up Visit is not required for subjects who complete the Week 24 Visit and have enrolled in a separate extension study of TEZACAFTOR in combination with 
ivacaftor within 28 days after the last dose of study drug.
n
Females of childbearing potential will have a clinic visit for a urine pregnancy test. This clinic visit is not required for females who are not of childbearing potential or males.
o
Telephone contact will be made for female subjects not of childbearing potential and males to assess the subject's status, any AEs, concomitant medications, treatments, and 
procedures.
p
All questionnaires must be completed before the start of any other assessments scheduled at that visit. The CFQ-R must be completed first, followed by the 
 
(Protocol Section 8.1.4 )Subjects will need to complete a CFQ-R, 
 at the Early Treatment Termination Visit (Protocol Section 8.1.4). 
r
Weight and height will be measured before dosing with shoes off. Height will be collected only for subjects 21 years of age or younger.


Statistical Analysis Plan (Methods)
Page 51 of 77
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-2
Treatment Period and Safety Follow up Visit Assessments – VX14-661-106
Event/Assessmentk
Day 1
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT
Visitl
Safety Follow-up 
Visit
28 (± 7) days
After the last dose of 
study drug (if 
applicable)m
Ophthalmologic exam
X s
X t
X j
Complete PEu
X
X
X
Pregnancy testv
urine
urine
urine
urine
urine
urine
serum
serum
serum
Standard 12-lead ECGw
X
X
X
X
X
X
X
X
X
Vital signsx
X
X
X
X
X
X
X
X
X
Pulse oximetryn
X
X
X
X
X
X
X
X
X
Spirometryy
X
X
X
X
X
X
X
X
X
Sweat chloridez
X
X
X
X
X
Urinalysis
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
                                               
s
All subjects will have an ophthalmologic examination conducted by a licensed ophthalmologist at Week 24. This exam may be completed within 4 weeks before the Week 24 Visit, 
but must be completed by the end of the Week 24 Visit. Subjects <18 years of age at the Screening Visit who complete an ophthalmologic exam at the ETT Visit will not be required 
to complete another ophthalmologic exam at the Week 24 Visit. 
t
Subjects <18 years of age at the Screening Visit who discontinue treatment after receiving at least 1 dose of study drug treatment, and subjects <18 years of age at the screening who 
complete treatment but do not enroll in a separate extension study of VX-661/ivacaftor within 28 days of the last dose of study drug will have an ophthalmologic exam conducted by 
a licensed ophthalmologist at the Safety Follow-up Visit or ETT Visit (see Protocol 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 complete an ophthalmologic exam at the ETT Visit or Week 24 Visit will not be required to complete 
another ophthalmologic exam at a subsequent visit. 
u
Subjects will have a complete physical examination (as defined in Protocol Section 11.7.3) as noted. Symptom-targeted physical examinations will occur at any time during the study 
if triggered by AEs or if deemed necessary by the investigator.
v
Pregnancy tests will be performed for all female subjects of childbearing potential. A urine β-hCG test will be performed on Day 1 (before first dose of study drug) and every 4 weeks 
thereafter. 
w
All standard 12-lead ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes. At the Days 1 and 15 Visits, ECGs will be collected before 
dosing and at 1.5, 3, 4, and 6 hours after the morning dose; the 4-hour postdose ECG will be collected before the 4-hour postdose spirometry assessment. ECGs collected on Day 1 
before dosing 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.
x
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.
y
At all visits, spirometry will be performed for all subjects prebronchodilator and before dosing (Protocol Section 11.6.1) At Day 1 and Day 15, subjects <18 years of age at the 
Screening Visit will have additional spirometry performed at 2 and 4 hours postdose. If more than 1 spirometry assessment is required at a visit, bronchodilators should be withheld 
until the last scheduled spirometry assessment is completed.
z
Sweat chloride collection will 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). Collection of sweat chloride will not overlap with any other study assessments.


Statistical Analysis Plan (Methods)
Page 52 of 77
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-2
Treatment Period and Safety Follow up Visit Assessments – VX14-661-106
Event/Assessmentk
Day 1
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT
Visitl
Safety Follow-up 
Visit
28 (± 7) days
After the last dose of 
study drug (if 
applicable)m
Coagulation
X
X
X
X
Serum chemistry
Xaa
X
X
X
X
X
X
X
X
Lipid panelbb
X
X
X
X
Vitamin levels
X
X
X
X
PK samplingcc
X
X
X
X
X
 
 
Other events related to outcomeee
X
X
X
X
X
X
X
X
X
Randomizationff
X
Meal(s) or snack(s) at sitegg
X
X
X
X
X
X
Study drug dosinghh
Day 1 through Week 24
Study drug count
X
X
X
X
X
X
X
                                               
aa
Blood samples will be collected before the first dose of study drug.
bb
Blood samples will be collected for the lipid panel following at least a 4-hour fast.
cc
PK samples will be collected on Day 1 at predose; at Week 12 (predose, 0.5, 3, and 6 hours after the morning dose); and at Week 16 (predose, 2, 4, and 8 hours after the morning 
dose). At the Safety Follow-up Visit and ETT Visit, a single blood sample for PK will be collected. If study drug is not administered on the visits of Weeks 12 and 16 (i.e., study drug 
interruption or permanent discontinuation of study drug), only 1 PK blood sample will be collected at each of these 2 visits.
 
ee
Other events related to outcome include assessments relating to pulmonary exacerbations, administration of antibiotic therapy for sinopulmonary signs or symptoms, and hospitalizations 
(Protocol Section 11.6.12).
ff
Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of study drug. Randomization will be done through IWRS. Randomization may occur 
on Day -1.
gg
Fat-containing food such as a standard "CF" high-fat, high-calorie meal or snack will be provided at the site to subjects after all predose assessments have occurred.
hh
The study drug should be administered every 12 hours (± 2 hours) within 30 minutes of starting a meal with fat-containing food such as a standard "CF" high-fat, high-calorie meal or 
snack. On days of scheduled visits, the morning dose of study drug will be administered at the site after predose assessments have been completed. The final dose of study drug will be 
administered the evening before the Week 24 Visit.




11.2
Analysis Visit Window Mapping Rules for Efficacy and Safety Measurements
Table 11-3
Visit Window Mapping Rules 
Assessments
Visit
Target Study Day
Visit Window 
(in study days)
Weight and height
Vital signs
Pulse oximetry
Labs
o Chemistry
o Hematology
Baseline 
1
[screening visit, pre-dose Day 1]
Day 15 
15
[1*, 22]
Week 4
29
[23,43]
Week 8 
57
[44, 71]
Week 12 
85
[72, 99]
Week 16 
113
[100, 141]
Week 24 
169
[142, 183]
ETT
N/A
Follow the individual visit 
window to be mapped to 
individual visits
Safety Follow-up Visit (SFU)
N/A
Efficacy assessments: follow the 
individual visit window to be 
mapped to individual visits if 
measured before / on Day 183 
or remain as SFU if otherwise.
Safety assessments: remain as 
SFU.
Spirometry
Standard 12-lead ECG
Baseline 
1
[screening visit, pre-dose Day 1]
Day 1 Predose and Postdose (Spirometry, or ECG)
1
Nominal
Day 15 Predose and Postdose (Spirometry, or ECG)
15
Nominal 
Day 15 Spirometry, or ECG
15
[2,15] if no nominal Day 15
Week 4 (Spirometry, or ECG)
29
[Nominal Day 15+1, 43] if there 
is nominal Day 15; 
[16, 43] otherwise.
Week 8 
57
[44, 71]
Week 12 
85
[72, 99]
Week 16 
113
[100, 141]


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Week 24 
169
[142, 183]
ETT
N/A
Follow the individual visit 
window to be mapped to 
individual visits
Safety Follow-up Visit  (SFU)
N/A
Efficacy assessments: follow the 
individual visit window to be 
mapped to individual visits if 
measured before / on Day 183 
or remain as SFU if otherwise. 
Safety assessments: remain as 
SFU.
CFQ-R
Baseline 
1
[screening visit, Day 1]
Week 4 
29
[2, 43]
Week 8
57
[44, 71]
Week 12
85
[72, 99]
Week 16
113
[100, 141]
Week 24 
169
[142, 183]
ETT
N/A
Follow the individual visit 
window to be mapped to 
individual visits
Sweat chloride
Baseline 
1
[screening visit, pre-dose Day 
1]
Week 4
29
[1*, 71]
Week 16 
113
[72, 141]
Week 24 
169
[142, 183]
ETT
N/A
Follow the individual visit 
window to be mapped to 
individual visits
Vitamin levels
Lipid panel
Baseline 
1
[screening visit, pre-dose Day 
1]
Week 12
85
[1*, 127]
Week 24
169
[128, 183]


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Complete PE

Labs
o Coagulation
o Urinalysis
Baseline 
1
[screening visit, pre-dose Day 
1]
Week 24
169
[1*, 183]
Safety Follow-up Visit (no Complete PE, 
 
)
N/A
Nominal
1* only include day 1 post-dose measurements.
Note: 
1.
To apply the above visit windows, please first determine the baseline measurements based on the first dose of study 
medication and then label Day 1 for the date of the first dose of study drug, and use the nominal visit names to label SFU (for 
safety).
2.
After baseline, and SFU (for safety) measurements are determined; the above visit windows will be applied to determine the 
analysis visit names for all remaining measures at scheduled or unscheduled visits. 
3.
For spirometry and ECG assessments on day 1 and Day 15, no visit windowing rule shall be applied. Instead, nominal visits
will be used.  
4.
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.  
5.
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; or 2) if there are multiple records within the same distance from the target day, the latest record will be used.
6.
Spirometry, BMI, Weight and Height are following the efficacy windowing rules.
Special handling for ECG:


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated

On Day 1 & Day 15, ECGs will be collected before dosing and at 1.5, 3, 4, and 6 hours after the morning dose. None of the 
measures on Day 1 or Day 15 will be mapped into other visits.
o
On Day 1, if there are assessments for triplicate prior to the first dose, the average of the triplicate will be used as the 
baseline. Only the pre-dose assessments of the triplicate will be used for the baseline. If all the measurements for triplets 
are missing or post-dose, the last non-missing pre-dose assessment will be used as the baseline.
o
Day 1 post-dose and Day 15 pre-/post-dose measurements will be analyzed based on nominal visit names. 

After the analysis visit names for Day 15 measurements are assigned, measures within the window [study day of Day 15 visit, 
43] will be mapped to Week 4 as appropriate for safety analysis (following rules in Section 8.1)

For other post-dose visits, the visit window in the above table will apply.


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
11.3
Coefficients for Hankinson and Wang Methods for Calculating Predicted Spirometry Parameters
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage. The predicted FEV1 (L) will 
be calculated using the Hankinson1 and Wang2 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 and the 
Hankinson standard at or after that birthday.
Hankinson Normal Values (HNVs) will be calculated for FEV1, forced vital capacity (FVC), forced expiratory flow mid 
expiratory phase (FEF25-75%), and FEV1/FVC% using the Hankinson equation: 
Predicted lung function parameter = b0+b1 × age+b2 × age2+ b3 × height2
In the equation, height is given in centimeters, age is given in years, and the coefficients b0, b1, b2, and b3 are determined based on 
subject’s sex, race, and age group as shown in Table 11-3.
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC using the Wang equation: 
ln(Predicted lung function parameter) = + βln (height)
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/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 11-4 and Table 11-5.
If either height or age is missing, and the spirometry measurement is non-missing, the last non-missing value of height and 
age will be used in the calculation of predicted values.


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-3
HNVs Equation Coefficients by Sex, Race, and Age
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


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
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
Source: Reference 1. (Tables 4, 5 and 6)
Table 11-4
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


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
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)


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-5
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


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Source: Reference 2. (Tables 4 and 5)




Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
11.5
Threshold Analysis Criteria
Table 11-6
Threshold Criteria for Clinical Chemistry and Hematology
Parameter
Threshold 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


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
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
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
CTCAE grade 1-4


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
>ULN - ≤ 2.9 mmol/L 
>2.9 – ≤ 3.1 mmol/L 
>3.1 – ≤ 3.4 mmol/L 
>3.4 mmol/L
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 Jul 2009 and 
CTCAE
AST
>ULN - ≤  3 xULN
>3 – ≤  5 xULN
>5 – ≤  8 xULN
>8 – ≤  20.0 xULN
>20.0 x ULN
FDA DILI Guidance and CTCAE
ALT or AST
(ALT>ULN and ALT ≤  3 xULN) or 
(AST>ULN and AST≤  3 xULN)
(ALT>3 xULN and ALT ≤  5 xULN) or 
FDA DILI Guidance 


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
(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
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 Jul 2009 
AST and Total 
Bilirubin
AST>3xULN and TBILI>2xULN
FDA DILI Guidance Jul 2009
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN
FDA DILI Guidance Jul 2009 
Hematology
WBC
WBC decreased
<LLN - ≥ 3.0 x 10e9 /L
<3.0 – ≥ 2.0 x 10e9 /L 
<2.0 – ≥ 1.0 x 10e9 /L 
<1.0 x 10e9 /L
CTCAE grade 1-4
Leukocytosis
>100 x 10e9 /L
CTCAE grade 3 (only Grade available) 
Lymphocytes
Lymphocyte decreased
<LLN - ≥ 0.8 x10e9 /L
<0.8 – ≥ 0.5 x10e9 /L 
<0.5 – ≥ 0.2 x10e9 /L 
<0.2 x10e9 /L
CTCAE grade 1-4
Lymphocyte increased
>4 – ≤ 20 x10e9/L 
>20 x10e9/L 
CTCAE grade 2, 3 (only Grades available)


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Neutrophils
Neutrophil decreased
<LLN - ≥ 1.5 x10e9 /L
<1.5 –  ≥ 1.0 x10e9 /L 
<1.0 –  ≥ 0.5 x10e9 /L 
<0.5 x10e9 /L
CTCAE grade 1-4
Hemoglobin
Hgb decreased (anemia)
<LLN - ≥ 100 g/L
<100 – ≥ 80 g/L 
< 80 g/L
CTCAE grade 1-3
Hgb increased
>ULN - ≤ 20 g/L above ULN
>20 g/L above ULN - ≤ 40 g/L above ULN
>40 g/L above ULN 
CTCAE grade 1-3
Platelets
Platelet decreased
<LLN - ≥ 75.0 x 10e9 /L
<75.0 – ≥ 50.0 x 10e9 /L 
<50.0 – ≥ 25.0 x 10e9 /L 
<25.0 x 10e9 /L
CTCAE grade 1-4


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-7
Threshold Criteria for Coagulation
Parameter
Threshold
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


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-8
Threshold Criteria for ECGs
Parameter
Threshold
Comments
HR
Bradycardia
<50 bpm 
<45 bpm
Decrease from baseline ≥10 bpm
Decrease from baseline ≥20 bpm
<50 bpm and decrease from baseline ≥10 bpm
<50 bpm and decrease from baseline ≥20 bpm
Per HV grade 2, 3, plus shift change
Tachycardia
>100 bpm
>115 bpm 
>130 bpm 
Increase from baseline ≥10 bpm
Increase from baseline ≥20 bpm 
>100 bpm and increase from baseline ≥10 bpm
>100 bpm and increase from baseline ≥20 bpm
Per HV grade 1, 2, 3, plus shift change
PR
≥240 ms
≥300 ms
≥200 ms and increase from baseline ≥40 ms
≥200 ms and increase from baseline ≥100 ms
QRS
>110 ms
>160 ms
Increase from baseline ≥20 ms
Increase from baseline ≥40 ms
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


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-9      Threshold Criteria for Vital 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


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
DBP
DBP increased
>90 mmHg
>100 mmHg
>5 mmHg increase from baseline
>10 mmHg increase from baseline
>90 mmHg and >5 mmHg increase from baseline
>90 mmHg and >10 mmHg increase from baseline
>100 mmHg and >5 mmHg increase from baseline
>100 mmHg and >10 mmHg increase from baseline
809/770 analyses
DBP decreased
<60 mmHg
<45 mmHg
>5 mmHg decrease from baseline
>10 mmHg decrease from baseline
<60 mmHg and >5 mmHg decrease from baseline
<60 mmHg and >10 mmHg decrease from baseline
<45 mmHg and >5 mmHg decrease from baseline
<45 mmHg and >10 mmHg decrease from baseline
Weight
Weight gain 
≥5 % increase from baseline  
≥10 % increase from baseline 
≥ 20% increase from baseline 
CTCAE grade 1-3
Weight loss 
≥5 % decrease from baseline  
≥10 % decrease from baseline 
≥ 20% decrease from baseline 
CTCAE grade 1-3


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
11.6
Standards for Efficacy and Safety Variable Display in TFLs
Table 11-10   Precision Standards for Efficacy Variables
Variable
Statistics
Number of Decimal Places
ppFEV1 (%, absolute or relative change)
Mean, LS mean, 95% CI
1
FEV1 (L, absolute or relative change)
FEF, FVC
Mean, LS mean, 95% CI
2
CFQ-R
Mean, LS mean, 95% CI
1
Sweat chloride (mmol/L)
Mean, LS mean, 95% CI
1
BMI (kg/m2)
Mean
LS mean, 95% CI
2
2
BMI-for-age z-score
Mean, LS mean, 95% CI
2
Weight (kg)
Mean
LS mean, 95% CI
1
1
Weight-for-age z-score
Mean, LS mean, 95% CI
2
Time-to-first clinical event of interest, e.g., pulmonary exacerbation
Proportion of event-free, 95% CI
Hazard ratio (HR), 95% CI for HR
3
2


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Normalized days with pulmonary exacerbations
Mean
1
Number of events 
0
Event rate
2
Number of decimal places for standard error and standard deviation will be the same as for the corresponding mean.


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
Table 11-11    Standard Display Units in Percent Predicted FEV1
Variable
Unit
Displayed Unit
ppFEV1
percent
N/A
Absolute change in ppFEV1
percent
Percentage points
Relative change in ppFEV1
percent
%


Statistical Analysis Plan (Methods)
Vertex Study: VX14-661-106
Vertex Pharmaceuticals Incorporated
11.7
Imputation Rules for Missing AE Start Date
For missing or partial AE start date, use the imputation rules 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 prior to 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 pre-treatment 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 prior to 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 pre-treatment 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 prior to the first dose date then the AE should be considered as 
a pre-treatment AE. Otherwise, the AE will be considered as TEAE.