Clinical trial NCT02730208
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-09-01; Completion date: 2018-07-01
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of study is to evaluate the treatment effect of tezacaftor in combination with ivacaftor (TEZ/IVA) on chest imaging endpoints using low-dose computed tomography (LDCT) at Week 72, and to evaluate the safety of TEZ/IVA through Week 72.

Detailed description:

Arms: arm 1: Participants received TEZ 100 milligram (mg)/IVA 150 mg fixed dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 72 weeks. arm 2: Participants received placebo matched to TEZ/IVA fixed dose combination tablet orally once daily in the morning and placebo matched to IVA tablet orally once daily in the evening for 72 weeks.
Interventions: intervention 1: Tezacaftor/Ivacaftor intervention 2: Ivacaftor intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: TEZ 100 mg/IVA 150 mg fixed-dose combination tablet. intervention 2: IVA 150 mg tablet. intervention 3: Placebo matched to TEZ/IVA fixed-dose combination tablet. intervention 4: Placebo matched to IVA tablet.

Protocol documents:
Prot_000.pdf: 




Protocol VX15-661-112, Version 5.0 
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2 
SYNOPSIS 
Title A Phase 2, Randomized, Placebo-Controlled, Double-blind Study to Evaluate the 
Effect of VX-661 in Combination With Ivacaftor on Chest Imaging Endpoints in 
Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the 
F508del CFTR Mutation 
Brief Title A Study to Evaluate the Effect of VX-661 in Combination With Ivacaftor on 
Chest Imaging Endpoints in Subjects With Cystic Fibrosis, Homozygous for the 
F508del CFTR Mutation 
  
Clinical Phase and 
Clinical Study Type  
Phase 2 efficacy and safety 
  
Objectives Primary:  
To evaluate the treatment effect of VX-661 in combination with ivacaftor 
(VX-661/ivacaftor) on chest imaging endpoints as evaluated using low-dose 
computed tomography (LDCT) at Week 72 in subjects with CF who are 
homozygous for the F508del mutation on the CF transmembrane conductance 
regulator (CFTR) gene 
Secondary: 
• To evaluate the safety of VX-661/ivacaftor through Week 72 
 
Endpoints Primary:  
• Absolute change in Total Brody/CF-CT score from baseline at Week 72 using 
LDCT 
Secondary:  
• Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values (hematology, serum chemistry, lipid and vitamin levels, 
coagulation studies, and urinalysis), standard digital electrocardiograms (ECGs), 
vital signs, and pulse oximetry 
 
  
Number of Subjects Approximately 40 
  






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3 
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1 and Table 3-2. 
Table 3-1 
Study VX15-661-112: Screening  
Event/Assessment 
Screening Period (Day -28 through Day -1) 
Informed consent (and assent, when applicable) 
X 
Demographics 
X 
Medical history  
X 
Ophthalmological history  
X 
CF genotypea 
X 
FSHb 
X 
Serum pregnancy test (all females of childbearing potential)c 
X 
Hematology 
X 
Coagulation 
X 
Serum chemistry 
X 
Urinalysis 
X 
Weight and heightd 
X 
Ophthalmologic examinatione 
X 
Complete physical examination 
X 
Vital signsf 
X 
Pulse oximetryf 
X 
Standard 12-lead ECGg 
X 
Spirometryh 
X 
Inclusion/exclusion criteria review 
X 
Prior and concomitant medications 
X 
Sweat chloridei 
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; ECG: electrocardiogram; FSH: follicle-stimulating hormone; ICF: informed consent 
form; SAE: serious adverse event. 
 
a 
All subjects will be tested for CF genotype. Specific instructions will be provided in the Laboratory Manual. CF 
genotyping may be waived if the subject has a documented result from a previous Vertex study. 
b 
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. 
c 
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. 
d 
Weight and height will be measured with shoes off. 
e 
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 
was conducted within 3 months before the start of the Screening Period or if there is documentation of bilateral lens 
removal (Section 11.6.8).  
f 
Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes.  
g 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
h 
Spirometry may be performed pre- or postbronchodilator 
  
i 
A sweat chloride test must be performed at the Screening Visit if an eligible sweat chloride value is not available in the 
subject’s medical records and the Screening Visit value is needed to establish eligibility. For subjects using sweat 
chloride values documented in their medical records to establish eligibility, the sweat chloride test at the Screening 
Visit is optional.  
 


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Table 3-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early Termination of Treatment Visit, and 
Safety Follow-up Visit Assessments 
Event/Assessmenta 
Day 1 
Day 15 
(± 3 days) 
Week 4, Week 12,  
(± 1 week) 
Week 24 
(± 1 week) 
Week 36, 
Week 48, 
Week 60 
(± 1 week) 
Week 72 
(± 1 week) 
Early Termination 
of Treatment Visit 
(Within 7 days 
After Last Dose of 
Study Drug) 
Safety 
Follow-up Visit 
4 weeks 
(± 7 days) 
After Last 
Dose of Study 
Drugb 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion criteria 
reviewc 
X 
 
 
 
 
 
 
 
Randomizationd 
X 
 
 
 
 
 
 
 
Complete physical examinationf 
X 
 
 
 
 
X 
X 
X 
Pregnancy testg  
urine 
 
urine 
urine 
urine 
urine 
serum 
serum 
 
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.  
b  
The Safety Follow-up Visit is not required for subjects who complete the Week 72 Visit and have enrolled in the TEZ/IVA open-label extension study, VX14-661-110, within 
28 days after the last dose of study drug. 
c 
The screening inclusion and exclusion criteria should be re-reviewed before administration of study drug on Day 1. 
d 
Randomization must occur after the informed consent/assent has been obtained and all inclusion and exclusion criteria are met and before the first dose of study drug. 
Randomization will be done through an interactive web response system. Randomization may occur on Day −1 if the above conditions for randomization have been met. 
f 
In addition to the indicated visits, a symptom-targeted physical examinations will occur at any time during the study if triggered by adverse events (AEs) or if deemed 
necessary by the investigator. 
g 
Pregnancy tests will be performed for all female subjects of childbearing potential. Day 1 results will be reviewed before dosing and the Low-dose CT scan. Week 72 results 
will be reviewed before the Low-dose CT scan.  


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Table 3-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early Termination of Treatment Visit, and 
Safety Follow-up Visit Assessments 
Event/Assessmenta 
Day 1 
Day 15 
(± 3 days) 
Week 4, Week 12,  
(± 1 week) 
Week 24 
(± 1 week) 
Week 36, 
Week 48, 
Week 60 
(± 1 week) 
Week 72 
(± 1 week) 
Early Termination 
of Treatment Visit 
(Within 7 days 
After Last Dose of 
Study Drug) 
Safety 
Follow-up Visit 
4 weeks 
(± 7 days) 
After Last 
Dose of Study 
Drugb 
Low-dose CT scanh 
X 
 
 
 
 
X 
 
 
Standard digital ECGm 
X 
X 
X 
X 
X 
X 
X 
 X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryn 
X 
X 
X 
X 
X 
X 
X 
X 
 
h 
Low-dose CT scans 
 should be performed on the same day. If not possible for logistical reasons, Low-dose CT scans 
 should be performed 
within ± 4 days of the scheduled visit. Day 1 assessments must be completed before dosing. The Week 72 CT scan may be delayed for up to 60 days if the subject is 
recovering from a pulmonary exacerbation. The medical monitor should be notified about the extension. The scan should be done after the pulmonary exacerbation is resolved 
and at least 28 days after the antibiotic regimen for the treatment of pulmonary infection has been completed. If this antibiotic regimen is not completed by the end of the 60-
day extension, the subject may complete the CT scan within the first 30 days of enrolling in Study VX14-661-110; or within 1 week of the end of the 60-day extension if they 
do not enroll in Study VX14-661-110. No extension is permitted for any other assessment.  
 
All standard 12-lead ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes. The predose ECGs collected at the Day 1 Visit will be 
performed in triplicate.  
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. In addition to the indicated visits, 
symptom-targeted vital signs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. 




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Table 3-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early Termination of Treatment Visit, and 
Safety Follow-up Visit Assessments 
Event/Assessmenta 
Day 1 
Day 15 
(± 3 days) 
Week 4, Week 12,  
(± 1 week) 
Week 24 
(± 1 week) 
Week 36, 
Week 48, 
Week 60 
(± 1 week) 
Week 72 
(± 1 week) 
Early Termination 
of Treatment Visit 
(Within 7 days 
After Last Dose of 
Study Drug) 
Safety 
Follow-up Visit 
4 weeks 
(± 7 days) 
After Last 
Dose of Study 
Drugb 
Study drug dosingr 
Day 1 through Week 72 
 
 
Ophthalmologic examination 
 
 
 
 
 
Xs 
Xt 
Xt 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatments and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events and 
serious adverse events 
Continuous from signing of the informed consent form and assent (where applicable) through the Safety Follow-up Visit 
 
 
r 
Subjects will take study drug as specified in Section 10.2. On days of scheduled visits, the subject’s dose of study drug will be administered at the site after predose 
assessments have been completed. Study drug administration should be completed within 5 minutes. At the Week 72 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 72 Visit. If the Week 72 CT scan is delayed to allow a subject to 
recover from a pulmonary exacerbation, study drug will continue for up to 60 days until the Week 72 CT scan has been completed or the subject has enrolled in 
Study VX14-661-110; for these subjects, the last dose of study drug will be the evening dose administered the day before the CT scan or before the Day 1 Visit of 
Study VX14-661-110.  
s 
All subjects <18 years of age at the Screening Visit will have an ophthalmologic examination conducted by a licensed ophthalmologist at Week 72. This exam may be 
completed within 4 weeks before the Week 72 Visit, but must be completed by the end of the Week 72 Visit.   
t 
Subjects <18 years of age at the Screening Visit who discontinue treatment after receiving at least 1 dose of study drug will have an ophthalmologic examination performed 
by a licensed ophthalmologist at the Safety Follow-up or the Early Termination of Treatment Visit. This examination may be completed at either the Early Termination of 
Treatment or Safety Follow-up Visit, but must be completed by the end of the Safety Follow-up Visit.  


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4 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
 
2 
Synopsis ............................................................................................................................ 3 
3 
Schedule of Assessments.................................................................................................. 6 
4 
Table of Contents ........................................................................................................... 11 
List of Tables...................................................................................................................... 15 
List of Figures .................................................................................................................... 15 
5 
Introduction.................................................................................................................... 16 
6 
Study Objectives ............................................................................................................ 17 
6.1 
Primary Objective ..................................................................................................... 17 
6.2 
Secondary Objective ................................................................................................. 18 
7 
Study Endpoints ............................................................................................................. 18 
7.1 
Primary Endpoint ...................................................................................................... 18 
7.2 
Secondary Endpoints ................................................................................................ 18 
8 
Study Design ................................................................................................................... 18 
8.1 
Overview of Study Design ....................................................................................... 18 
8.1.1 
Screening .......................................................................................................... 19 
8.1.1.1 
Repetition of Screening Assessment(s) ...................................................... 20 
8.1.1.2 
Rescreening ................................................................................................ 20 
8.1.1.3 
Extension of Screening Period Window .................................................... 20 
8.1.2 
Treatment Period .............................................................................................. 20 
8.1.3 
Follow-up.......................................................................................................... 21 
8.1.4 
Early Termination of Treatment ....................................................................... 21 
8.1.5 
Independent Data Monitoring Committee ........................................................ 22 
8.2 
Rationale for Study Design and Study Drug Regimens ........................................... 22 
8.2.1 
Study Design..................................................................................................... 22 
8.2.2 
Study Drug Dose and Duration ........................................................................ 22 
8.2.3 
Rationale for Study Assessments ..................................................................... 23 
9 
Study Population ............................................................................................................ 24 
9.1 
Inclusion Criteria ...................................................................................................... 24 
9.2 
Exclusion Criteria ..................................................................................................... 24 
9.3 
Study Restrictions ..................................................................................................... 26 
9.3.1 
Additional Dietary Restrictions ........................................................................ 26 
9.4 
Prior and Concomitant Medications ......................................................................... 27 
9.5 
Removal of Subjects ................................................................................................. 28 
9.6 
Replacement of Subjects .......................................................................................... 29 
10 Study Drug Administration and Management ........................................................... 29 
10.1 Preparation and Dispensing ...................................................................................... 29 
10.2 Administration .......................................................................................................... 29 
10.3 Method of Assigning Subjects to Treatment Groups ............................................... 30 
10.4 Dose Modification for Toxicity ................................................................................ 31 


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10.5 Study Drug Interruption and Missed Doses ............................................................. 31 
10.5.1 
Study Drug Interruption.................................................................................... 31 
10.5.2 
Missed Doses .................................................................................................... 31 
10.6 Discontinuation of Study Participation .................................................................... 31 
10.7 Packaging and Labeling ........................................................................................... 32 
10.8 Study Drug Supply, Storage, and Handling ............................................................. 32 
10.9 Drug Accountability ................................................................................................. 33 
10.10 Disposal, Return, or Retention of Unused Drug ....................................................... 33 
10.11 Compliance ............................................................................................................... 33 
10.12 Blinding and Unblinding .......................................................................................... 33 
10.12.1 Blinding ............................................................................................................ 33 
10.12.2 Unblinding ........................................................................................................ 35 
11 Assessments .................................................................................................................... 35 
11.1 Timing of Assessments ............................................................................................. 35 
11.1.1 
Informed Consent/Assent ................................................................................. 36 
11.1.2 
Assigning Subject Number ............................................................................... 36 
11.2 Subject and Disease Characteristics ......................................................................... 36 
11.3 Pharmacokinetics ...................................................................................................... 37 
11.4 Pharmacodynamics ................................................................................................... 37 
11.5 Efficacy ..................................................................................................................... 37 
11.5.1 
Chest Imaging ................................................................................................... 37 
11.5.1.1 Low-Dose Computed Tomography ........................................................... 37 
 
11.5.1.3 Imaging Scoring ......................................................................................... 39 
11.6 Safety ........................................................................................................................ 43 
11.6.1 
Adverse Events ................................................................................................. 43 
11.6.2 
Clinical Laboratory Assessments ..................................................................... 43 
11.6.3 
Liver Function Test Parameters ........................................................................ 45 
11.6.4 
Physical Examinations and Vital Signs ............................................................ 46 
11.6.5 
Electrocardiograms ........................................................................................... 46 
11.6.6 
Contraception and Pregnancy ........................................................................... 47 
11.6.6.1 Contraception ............................................................................................. 47 
11.6.6.2 Pregnancy ................................................................................................... 50 
11.6.7 
Pulse Oximetry ................................................................................................. 50 
11.6.8 
Ophthalmologic Examination ........................................................................... 50 
12 Statistical and Analytical Plans .................................................................................... 52 
12.1 Sample Size and Power ............................................................................................ 52 
12.2 Analysis Sets ............................................................................................................ 52 




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13.2.6 
Record Retention .............................................................................................. 64 
13.2.7 
Study Termination ............................................................................................ 64 
13.3 Data Quality Assurance ............................................................................................ 65 
13.4 Monitoring ................................................................................................................ 65 
13.5 Electronic Data Capture ........................................................................................... 65 
13.6 Publications and Clinical Study Report .................................................................... 66 
 
 
13.6.2 
Clinical Study Report ....................................................................................... 66 
14 References ....................................................................................................................... 67 
15 Protocol Signature Pages .............................................................................................. 71 
15.1 Sponsor Signature Page ............................................................................................ 71 
15.2 Investigator Signature Page ...................................................................................... 72 
 


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List of Tables 
Table 3-1 
Study VX15-661-112: Screening ...................................................................... 6 
Table 3-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early 
Termination of Treatment Visit, and Safety Follow-up Visit Assessments ..... 7 
Table 9-1 
Study Restrictions ........................................................................................... 27 
Table 10-1 
Study Drug Administration: Treatment Period ............................................... 29 
Table 10-2 
Identity of Study Drugs, Dosage, and Storage ................................................ 32 
Table 11-1 
Safety Laboratory Test Panels ........................................................................ 44 
Table 13-1 
Grading of AE Severity .................................................................................. 60 
Table 13-2 
Classifications for AE Causality ..................................................................... 60 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ............ 60 
Table 13-4 
Classifications for Outcome of an AE ............................................................ 61 
List of Figures 
Figure 8-1 
VX15-661-112: Study Design ........................................................................ 19 


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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 
approximately 40 years.2,5 Although the disease affects multiple organs, most morbidity and 
mortality are caused by progressive loss of lung function.6 
CF is an autosomal recessive genetic disease caused by a defect in the gene encoding the CF 
transmembrane conductance regulator (CFTR), an epithelial chloride ion (Cl−) channel 
activated by cyclic adenosine monophosphate-dependent protein kinase A that is responsible 
for aiding in the regulation of salt and water absorption and secretion in various tissues.2 This 
function is defective in patients with CF due to a loss of cell surface expression and/or 
function. 
CF affects approximately 30,000 individuals in the United States (US)5, 32,000 individuals in 
the European Union (EU)7, 4,000 individuals in Canada8, and 3,100 individuals in Australia.9 
Of the more than 1900 mutations in the CFTR gene that have been identified,10 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 (d l-CFTR).11 In the US, almost 87% of 
patients with CF have at least 1 copy of the F508del-CFTR mutation.5 The proportion of 
patients with CF who have 2 copies of the F508del-CFTR mutation is similar in the US 
(approximately 47%), the EU (approximately 44%), Canada (49%), and Australia 
(52%).5,7,8,9 Orkambi™ (lumacaftor/ivacaftor) was recently approved in the US to treat 
patients 12 years and older with CF who have 2 copies of the F508del-CFTR, but no 
therapies to treat the underlying defect in this population are currently approved in other 
regions, including Australia. 
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.12,13 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.14  
Two complementary approaches to increase CFTR-mediated Cl− secretion in the airway 
epithelia have been studied.15 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 
CFTR modulator, such as a potentiator and/or corrector, could prevent the hyperabsorption of 




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6.2 
Secondary Objective 
• To evaluate the safety of VX-661/ivacaftor through Week 72 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
• Absolute change in Total Brody/CF-CT score from baseline at Week 72 using LDCT 
7.2 
Secondary Endpoints 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values (hematology, serum chemistry, lipid and vitamin levels, coagulation studies, 
and urinalysis), standard digital electrocardiograms (ECGs), vital signs, and pulse 
oximetry 
8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a Phase 2, randomized, placebo-controlled, double-blind parallel-group, multicenter 
study in subjects with CF who are homozygous for the F508del-CFTR mutation. This study 
is designed to evaluate the treatment effect of VX-661/ivacaftor on chest imaging endpoints 
during 72 weeks of treatment. LDCT 
will be used for chest imaging. The 
images will be evaluated using the Brody/CF-CT scoring system. Safety over 72 weeks of 
treatment will also be evaluated. 
Figure 8-1 shows a schematic of the study design. This study includes a Screening Period, a 
72-week Treatment Period, and a Safety Follow-up Visit. Following a 28-day screening 




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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,17 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. 
The Screening Period window may be extended by 2 weeks for the following reason: 
• Additional time to conduct ophthalmologic examinations (Section 11.6.8). 
8.1.2 
Treatment Period 
The Treatment Period will last approximately 72 weeks. The Treatment Period can be 
extended up to 60 days in the event of a pulmonary exacerbation. Antibiotics taken for a 
pulmonary infection or exacerbation must be completed at least 28 days before the Week 72 
CT scan. Subjects will be randomized to 1 of 2 treatment arms: 1 active combination 
treatment arm and 1 placebo arm. The dosing regimen for each treatment arm is as follows: 
• VX-661/ivacaftor: VX-661 100-mg /ivacaftor 150-mg FDC (light yellow) film-coated 
tablet for oral administration (morning dose); ivacaftor 150-mg (light blue) 
film-coated tablet for oral administration (evening dose) 


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• 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. Study 
drug administration details are given in Section 10. 
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. 
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 72 Visit and 
have enrolled in the TEZ/IVA open-label extension study, VX14-661-110 (Study 110), 
within 28 days after the last dose of study drug. 
8.1.4 
Early Termination of Treatment 
If the subject prematurely discontinues study drug treatment, an Early Termination of 
Treatment (ETT) Visit should be scheduled as soon as possible after termination of study 
drug 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 ETT Visit and Safety Follow-up Visit are 
listed in Table 3-2. 
The ETT Visit should occur within 7 days after the 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.  
During the course of study conduct, if VX-661 in combination with ivacaftor is approved by 
local health authorities and is available for the treatment of the population enrolled in this 
study, subjects may be discontinued from this study at the discretion of the sponsor 
(Section 10.6). If a subject is continuing onto commercially available VX-661/ivacaftor, the 
ETT Visit will be completed before dosing with commercially available drug begins, and the 
Safety Follow-up Visit will not be required.  
Alternatively, if after review of a marketing application, local health authorities decline to 
approve, or if clinically meaningful benefit is not demonstrated for the use of 
VX-661/ivacaftor for the treatment of CF in populations enrolled in this study, subjects 
within those populations may be discontinued after communication to investigators and 
institutional review boards (IRBs)/independent ethics committees (IECs) of the risks/benefits 
related to the safety and efficacy. If subjects are discontinued from the study, an ETT Visit 
should occur within 7 days after the last dose of study drug and a Safety Follow-up Visit 
should occur within 28 (± 7) days after the last dose of study drug. 


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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 
Safety and tolerability data will be reviewed by an IDMC to ensure the safety of the subjects 
in the study (Section 12.3.5.2). Procedural details of the IDMC’s structure and function, 
frequency of meetings, and data planned for review will be included in the IDMC charter. 
The IDMC charter will be finalized before the first subject is screened.  
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
This is a Phase 2, randomized, placebo-controlled, double-blind, parallel-group, multicenter 
study in subjects aged 12 years and older with CF who are homozygous for the 
F508del-CFTR mutation with a percent predicted forced expiratory volume in 1 second 
(ppFEV1) ≥70. A randomized, double-blind study design will avoid observer bias and reduce 
symptoms or outcomes arising from the subjects’ knowledge of treatment.  
8.2.2 
Study Drug Dose and Duration 
VX-661 was studied at different doses alone and in combination with ivacaftor in the Phase 2 
proof-of-concept Study VX11-661-101 (Study 101). The regimen of VX-661 100 mg once 
daily (qd) in combination with ivacaftor 150 mg every 12 hours (q12h) 
(VX-661 100 mg qd/ivacaftor 150 mg q12h) provided clinically meaningful and statistically 
significant improvement in ppFEV1 compared to placebo, while VX-661 100 mg 
monotherapy did not (see VX-661 Investigator’s Brochure). Based on the data in Study 101, 
VX-661 100 mg qd/ivacaftor 150 mg q12h was selected for continued development in the 
ongoing Phase 3 program and this study. 
Placebo control is necessary to assess the effect of VX-661/ivacaftor combination treatment 
over time. Use of placebo is justified because there is no approved treatment available to 
address the underlying cause of CF for this population in Australia. All subjects will maintain 
their current standard of care and concomitant medication regimen throughout the study, 
including the use of antibiotics and hypertonic saline. Additionally, only subjects with mild 
to moderate pulmonary disease (baseline ppFEV1 ≥70) will be enrolled. Furthermore, 
subjects who have had 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) will be excluded. A study showed that patients 
who had pulmonary exacerbations that were treated with intravenous (IV) antibiotics showed 
good resolution of structural and functional abnormalities comparable to CF patients in 
clinically stable condition 
 within 1 month of completion of antibiotic therapy. 18 
CF is a chronic, slowly progressive disease. It is hypothesized that a notable change will be 
observed during the 72-week duration of this study, based on review of the natural history 
progression of radiographic changes demonstrated on longitudinal studies seen on CT scans. 
In a 2-year natural history study in 48 children with CF, with a mean age of 11 years at the 




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group. This will avoid observer bias arising from the readers’ knowledge of treatment. 
  
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 his or her 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 12 years of age 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 with testing 
performed at the Screening Visit. If the CFTR screening genotype result is not received 
before randomization, a previous CFTR genotype laboratory report may be used to 
establish eligibility. Note: Subjects who have been randomized and whose screening 
genotype results do not confirm study eligibility must be discontinued from the study as 
described in Section 9.5. CFTR genotyping may be waived if the subject has a 
documented result from a previous Vertex study. 
5. Confirmed diagnosis of CF31 defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis. A sweat chloride test must be performed at the 
Screening Visit if an eligible sweat chloride value is not available in the subject’s medical 
records and the Screening Visit value is needed to establish eligibility. For subjects using 
sweat chloride values documented in their medical records to establish eligibility, the 
sweat chloride test at the Screening Visit is optional. 
6. ppFEV1 ≥70% of predicted normal for age, sex, and height (equations of Wang et al. or 
Hankinson et al.)36,37 during screening. Spirometry measurements must meet American 
Thoracic Society/European Respiratory Society criteria17 for acceptability and 
repeatability.  
7. Stable CF disease as judged by the investigator 
8. Willing to remain on a stable CF medication regimen through the end of the treatment 
period (up to 72 weeks) and, if applicable, the ETT visit and 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: 


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• History of cirrhosis with portal hypertension, and/or history of risk factors for 
Torsade de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left 
ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history 
of arrhythmia [ventricular and atrial fibrillation], obesity, acute neurologic events 
[subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, and 
intracranial trauma], and autonomic neuropathy) 
2. 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 in 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)32,33 for 
subjects ≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the 
Counahan-Barratt equation)34 for subjects aged 12 to 17 years (inclusive) 
3. For an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in 
therapy (including antibiotics) for pulmonary disease before Day 1 (first dose of study 
drug), antibiotic regimen for the treatment of a pulmonary infection must have been 
completed at least 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. If the subject has documentation 
of bilateral lens removal, an ophthalmologic examination is not required and this criterion 
is not applicable (Section 11.6.8).  
7. History of alcohol or drug abuse, as deemed by the investigator, in the past year, 
including but not limited to cannabis, cocaine, and opiates. 


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8. Ongoing participation in an investigational drug study (including studies investigating 
VX-661, lumacaftor [VX-809], and/or ivacaftor) within 30 days of screening 
• 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 [results reviewed before dosing]).  
11. Sexually active subjects of reproductive potential who are not willing to follow the 
contraception requirements outlined in Section 11.6.6.1 
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 or 
• 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. 
14. Any contraindication to undergoing LDCT 
 as per the site’s institutional 
guidelines 
9.3 
Study Restrictions 
9.3.1 
Additional Dietary Restrictions 
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 using cytochrome P450 (CYP) 3A4, hence the 
need to restrict usage of known CYP3A4 inducers and inhibitors. 


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A nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. This list may be updated throughout the study and 
updates will be communicated by the study team. 
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 
the Screening Visit 
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: 
• Subjects who are taking daily inhaled tobramycin or other chronically inhaled 
antibiotics should remain on that regimen throughout the study. 
• 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. 
• 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 


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synchronized as closely as possible to the first day of 1 of the inhaled alternating 
antibiotics. 
• Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day 
(chronically), or prednisone or prednisolone 60 mg qd for up to 5 days without prior 
approval of the medical monitor. 
• Information about bronchodilator use during the study will be collected and 
documented. Subjects who are using a bronchodilator must have their spirometry 
assessments performed according to the guidelines provided 
. 
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 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 8.1.3), 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. 
• A subject has an increase in transaminases (ALT or AST) according to evaluations and 
management described in Section 11.6.3. 


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• A subject has an increase in QTc according to evaluations and management described in 
Section 11.6.5. 
• A subject develops a cataract or lens opacity. 
Subjects who are randomized and whose screening CFTR genotype results do not confirm 
study eligibility must be discontinued from study drug treatment, undergo ETT and/or Safety 
Follow-up Visits per Section 8.1.3 and Section 8.1.4, and be discontinued from the study. 
After discontinuation of study drug treatment, these subjects will not undergo any further 
assessments other than those performed at the ETT and/or Safety Follow-up Visits. 
9.6 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug 
treatment period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
Study drug refers to VX-661/ivacaftor and matching placebo. 
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 after starting a meal with 
fat-containing food, such as a standard “CF” high-fat, high-calorie meal or snack, according 
to the following guidelines: 
1. 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. 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.  
4. 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 his or her 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. 
5. For visits after the Day 1 Visit, subjects will be instructed to bring all unused study 
drug to the site; study drug will be dispensed at each visit, as appropriate. 
6. At the Week 72 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 72 
Visit.  
7. If the Treatment Period has been extended and the Week 72 CT scan is delayed because 
of a pulmonary exacerbation (Section 11.1), subjects should continue to take study drug 
until the Week 72 CT scan has been completed or the subject enrolls in Study 110. The 
last dose of study drug for these subjects will be the evening dose administered the day 
before the CT scan or the evening dose administered before the Day 1 Study 110 Visit, 
whichever occurs first. 
10.3 
Method of Assigning Subjects to Treatment Groups 
Approximately 40 subjects who meet the eligibility criteria will be randomized (1:1) to 
1 of 2 treatment arms. 
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 


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randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the Study Execution Team.  
10.4 
Dose Modification for Toxicity 
The dosage of individual study drugs or the regimen cannot be altered, but the investigator 
can interrupt or stop treatment with all study drugs. 
10.5 
Study Drug Interruption and Missed Doses 
10.5.1 
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 resume only after approval by the medical 
monitor. Specific instructions for interruption for elevated LFT levels are provided in 
Section 11.6.3 and instructions for elevated QTc levels are provided in Section 11.6.5. 
10.5.2 
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, the 
subject 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. 
10.6 
Discontinuation of Study Participation 
If after review of a marketing application, local health authorities decline to approve, or if 
clinically meaningful benefit is not demonstrated for the use of VX-661/ivacaftor for the 
treatment of CF in populations enrolled in this study, subjects within those populations may 
be discontinued after communication to investigators and IRBs/IECs of the risks/benefits 
related to the safety and efficacy. In addition, if evaluation of efficacy data from the Phase 3 
studies (Studies VX14-661-106, VX14-661-107, VX14-661-108, and VX14-661-109) 
suggest that the VX-661/ivacaftor treatment does not provide clinically meaningful benefit, 
Vertex may recommend that subjects are discontinued or the study is terminated (see 
Section 13.2.7). 
Subjects who are able to receive commercially-available VX-661/ivacaftor by prescription of 
a physician may be discontinued from the study at the discretion of the sponsor. If a subject 
is continuing onto commercially available VX-661/ivacaftor, the ETT Visit (Section 8.1.4) 
will be completed before dosing with commercial drug begins, and the Safety Follow-up 
Visit (Section 8.1.3) will not be required. 


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A subject may be discontinued at any time due to safety reasons. If a subject discontinues 
study drug, he/she should complete the ETT Visit (Section 8.1.4) and Safety Follow-up Visit 
(Section 8.1.3).  
If during the time when a subject is participating in the study a cataract or lens opacity is 
identified and determined to be clinically significant by the ophthalmologist after dosing, 
discussion as to that subject’s continuance in the study is provided in Section 11.6.8. 
10.7 
Packaging and Labeling 
Vertex will supply the study drug tablets in blister cards. Study drug cards will be provided 
and replaced via the IWRS. A detailed study drug dispensation plan will be provided in the 
Pharmacy Manual. 
Study drug labeling will be in compliance with applicable local and national regulations.  
10.8 
Study Drug Supply, Storage, and Handling 
VX-661/ivacaftor (100 mg/150 mg) and matching placebo will be supplied as light yellow 
film-coated tablets of similar size and appearance containing VX-661 100-mg/ivacaftor 
150-mg and VX-661 0-mg/ivacaftor 0-mg, respectively.  
Ivacaftor (150 mg) and matching placebo will be supplied as light blue film-coated tablets of 
similar size and appearance containing ivacaftor 150-mg and ivacaftor 0-mg, respectively. 
Blister cards must be stored at room temperature according to Table 10-2 and to the 
instructions provided in the Pharmacy Manual. 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 10.10.  
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) 
 


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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 study site staff or pharmacy personnel will retain all materials returned by the subjects 
until the study monitor has performed drug accountability. At the end of the study, the study 
monitor will provide instructions as to the disposition of any unused investigational product. 
If the study monitor authorizes destruction at the study site, the investigator will ensure that 
the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Vertex. Destruction will be 
adequately documented. 
10.11 
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 
10.12.1 
Blinding 
This is a double-blind study. 
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 her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy 
SAE processing and reporting regulations 


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• 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 IA and IDMC (Section 12.3.5)  
• Vertex medical monitor may unblind individual subjects at any time for matters 
relating to safety concerns. 
For the purpose of the IA described in Section 12.3.5.1, a small team at Vertex, who are not 
involved with study conduct, will be unblinded. The members of this IA team will be 
documented in an unblinding plan. 
Imaging Data Blinding 
Despite treatment blinding, knowledge of the LDCT 
 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 
imaging data. The vendor for central reading of the imaging data will send only the blinded 
files (blinded treatment group, with real scores for baseline, but with dummy scores for all 
the imaging assessments after baseline) to Vertex to be used for developing the statistical 
programs. Furthermore, subjects and their caregiver should not be informed of their 
study-related imaging results during the Treatment Period regardless of whether the subject 
has prematurely discontinued treatment. 
CT scans 
 will have a clinical over-read by a site radiologist blinded to 
study drug assignment. Any urgent safety-related findings should be communicated to the 
Vertex medical monitor, who may recommend follow-up by the site principal investigator. 
The Vertex medical monitor will facilitate any discussion with the central readers as needed.  






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Sputum microbiology, as documented in the subject’s medical record over the past 2 years, 
will be collected during screening.  
A sweat chloride test must be performed at the Screening Visit if an eligible sweat chloride 
value is not available in the subject’s medical records and the Screening Visit value is needed 
to establish eligibility. For subjects using sweat chloride values documented in their medical 
records to establish eligibility, the sweat chloride test at the Screening Visit is optional. 
Collection of sweat samples will be performed using an approved collection device. Sweat 
samples will be sent to a central laboratory for testing and interpretation of results. Specific 
instructions for collection, handling, processing, and shipping of sweat chloride samples to 
the central laboratory will be provided separately. 
11.3 
Pharmacokinetics 
Not applicable 
11.4 
Pharmacodynamics 
Not applicable 
11.5 
Efficacy 
11.5.1 
Chest Imaging 
Chest imaging, as performed by LDCT 
 has the potential to reveal structural CF 
pulmonary disease even when a patient has normal spirometric function. As such, this study 
will explore the effect of VX-661/ivacaftor treatment on endpoints obtained through chest 
imaging. 
11.5.1.1 
Low-Dose Computed Tomography 
Inspiratory and expiratory LDCT scans will be obtained at the time points noted in Table 3-2, 
using a standard low-dose ionizing radiation protocol. CT scans will be obtained using a 
spirometry-controlled volumetric technique. Additional technique information specific to 
each manufacturer and model of CT scanner will be provided. Estimated dose for both 
inspiratory and expiratory scans will total <2.5 mSv combined. Dose calculations will be 
performed for each CT scanner.  
Images will be reconstructed at 5 mm thickness and at <1 mm thickness (exact thickness will 
be specified for each manufacturer) using a high frequency reconstruction algorithm for 
5 mm sections and standard reconstruction for <1 mm sections.  
CT scans involve exposure to ionizing radiation. The CT scans used in this research are 
optimized for low radiation dose and high image quality. While the range of radiation 
exposure is highly variable, Australians on average are exposed to 1.5 mSv each year from 
natural sources. No direct evidence of human health effects has been seen in ionizing 
radiation doses of up to 10 mSv.35 The 2 CT scans used in this study will each use about 
2 to 2.5 mSv. 




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11.5.1.3 
Imaging Scoring 
All CT 
 scans will be evaluated by centralized expert readers using the 
Brody/CF-CT scoring system. 
• The Brody/CF-CT scoring system semiquantitatively scores the degree of structural 
lung disease as shown on CT in patients with CF. It has been extensively tested and 


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validated (see Section 8.2.3). This score provides both localization and quantification 
of 5 abnormalities characteristic of CF lung disease: bronchiectasis, air trapping, 
mucous plugging, bronchial wall thickening, and parenchymal changes (includes 
parenchymal opacities, ground glass opacities, and cysts/bullae).  
• Scores from other scoring algorithms for measuring the features of the Brody CF-CT 
scoring systems, as well as other features associated with structural lung disease, may 
be assessed.   






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11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, and clinical evaluation 
of vital signs, pulse oximetry, ECGs, and PEs. 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. Section 13.1 
outlines the definitions, collection periods, criteria, and procedures for documenting, grading, 
and reporting AEs. A separate document that details AE case report form (CRF) completion 
guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, except for urine pregnancy 
tests, which will be analyzed at the site. Fasting is not required at any time point. 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 in the order specified in Section 11.1.  
Laboratory test results that are abnormal and considered clinically significant will be reported 
as AEs (see Section 13.1).  
The safety laboratory test panels are shown in Table 11-1.  


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
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. 
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 test kits will be provided by the central laboratory and 
performed and analyzed at the site as specified in Table 3-2. The urine pregnancy test may be 
performed on Day 1 and must be negative before the randomization. Tests must also be 
reviewed and confirmed as negative before each LDCT scan. 
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. CF genotyping may be 
waived if the subject has a documented result from a previous Vertex study. Specific 
instructions will be provided in the Laboratory Manual.  


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Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be 
used. At the discretion of the local investigator, local laboratories may be used for 
management of urgent medical issues. If a local laboratory test value is found to be abnormal 
and clinically significant, it should be verified by the central laboratory as soon as possible 
after the investigator becomes aware of the abnormal result. If it is not possible to send a 
timely specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value. 
11.6.3 
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). 


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Study Drug Interruption 
Study drug administration must be interrupted immediately (before confirmatory testing), 
and the medical monitor must be notified, if any of the following criteria is met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or 
clinical jaundice 
A thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST 
levels have improved, study drug treatment must be permanently discontinued if repeat 
testing within 48 to 72 hours confirms the initial elevation. Subjects in whom treatment is 
discontinued for elevated transaminases should have their transaminases monitored closely 
until levels normalize or return to baseline. 
Resumption of Study Drug 
If an alternative, reversible cause of transaminase elevation has been identified, study drug 
may be resumed once transaminases 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. 
11.6.4 
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). Symptom-targeted PEs and symptom-
targeted vital sign assessments will occur at any other time during the study if triggered by 
AEs or if deemed necessary by the investigator.  
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat 
(EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be 
reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), oral temperature, pulse rate, and 
respiration rate. These will be assessed following a 5-minute rest in the supine position. 
11.6.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1 and Table 3-2). Additional standard 12-lead ECGs will 


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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 Visit and Safety 
Follow-up Visit. 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. 
11.6.6 
Contraception and Pregnancy 
11.6.6.1 
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 (see VX-661 and VX-770 Investigator’s Brochures). Subjects should follow the 
contraception requirements outlined in this study protocol. The effects of VX-661 
monotherapy or in combination with ivacaftor on the pharmacokinetics (PK) of hormonal 
contraceptives are not known. Thus, hormonal contraception is not an acceptable method of 
contraception for female subjects though it is acceptable for the female partners of male 
subjects. 
At this stage in the development of VX-661 in combination with ivacaftor, participation in 
this study requires a commitment from the research subject and his/her partner to use at least 


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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  
o 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.  
Acceptable contraceptive methods for female subjects include the following: 
• Bilateral tubal ligation performed at least 6 months previously 


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• Continuous use of an intrauterine device (nonhormone-releasing) for at least 90 days 
before the first dose of study drug 
• Barrier contraception (such as diaphragm, cervical cap, or female condom) and 
spermicide 
o In countries where spermicide is not available, barrier contraception without 
spermicide will be considered acceptable. 
• 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 
o 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. 
• 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. 


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• 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. 
11.6.6.2 
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 11.6.6.1). 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. 
11.6.7 
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 
administration of study drug. At visits when study drug is taken at the site, pulse oximetry 
will be collected before the morning dose. This is a noninvasive measure of oxygen delivery 
to the tissues and has been correlated with clinical status and lung function. 
11.6.8 
Ophthalmologic Examination 
At Screening, subjects who have documentation of bilateral lens removal are not required to 
complete any ophthalmologic examinations. 
All other 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; 


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• measurement of lens refracting power following cycloplegia (e.g., autorefractor or 
ophthalmoscopy streak); and 
• 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 or if there is documentation of a medical history of 
bilateral lens removal. 
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 (see Section 8.1.4) 
and Safety Follow-up Visits (see Section 8.1.3). If the subject continues study drug 
treatment, more frequent ophthalmologic monitoring should be considered. 
In addition to the screening examination, subjects <18 years of age at the Screening Visit will 
have an ophthalmologic examination conducted by a licensed ophthalmologist at Week 72. 
This exam may be completed within 4 weeks before the Week 72 Visit, but must be 
completed by the end of the Week 72 Visit. 
For subjects <18 years of age at the Screening Visit who discontinue treatment after 
receiving at least 1 dose of study drug, an ophthalmologic examination will be performed by 
a licensed ophthalmologist at the Safety Follow-up Visit or ETT Visit. 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 required to 
complete only 1 ophthalmologic exam at the end of treatment (Week 72 Visit, ETT Visit, or 
Safety Follow-Up Visit), as described in Table 3-2.  
For all subjects, additional ophthalmologic examinations may be conducted at the discretion 
of the investigator. The medical monitor should be notified of any additional ophthalmologic 
examinations.  
Lastly, 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 


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• Use of corrective lenses (contact lenses or eyeglasses) 
• History of prolonged exposure to sunlight or ultraviolet light and use of 
sunglasses 
• History of exposure to secondhand smoke 
12 
STATISTICAL AND ANALYTICAL PLANS 
Analysis of all data will be performed by Vertex or its designee. The results of all parts of the 
study will be reported in the clinical study report. A detailed analysis plan for the analysis of 
safety and efficacy data will be presented in a statistical analysis plan (SAP) before the 
database is locked for analysis. 
12.1 
Sample Size and Power 
The primary endpoint is the absolute change from baseline of Total Brody/CF-CT score 
measured by the Brody/CF-CT score system at Week 72 using LDCT. The difference 
between the VX-661/ivacaftor group and the placebo group in the mean change from 
baseline in Total Brody/CF-CT score at Week 72 will be estimated. 
This is an exploratory, Phase 2 study; the sample size is not based on statistical power. With 
40 subjects (20 per arm), the study is aimed to explore changes in the Total Brody score over 
a 72 week period and for VX-661/ivacaftor versus placebo, based on the published 
literature.19,20 
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects 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 drug. 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. 
12.3 
Statistical Analysis 
This section presents a summary of the planned statistical analyses of efficacy and safety for 
this study. Statistical analysis details will be provided in the SAP for this study, which will be 
finalized before clinical database lock. 


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12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum value (min), and maximum value (max).   
Categorical variables will be summarized using counts and percentages.  
Baseline value, unless otherwise specified, is defined as the most recent nonmissing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For 
ECGs, the baseline will be defined as the average of the 3 pretreatment measurements 
(triplicate) on Day 1.   
Change (Absolute Change) from baseline will be calculated as Postbaseline value - 
Baseline value.  
Relative change from baseline will be calculated and expressed in percentage as 
100% × (Postbaseline value - Baseline value)/Baseline value 
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 drug for subjects who do not have 
a Safety Follow-up Visit. The TE period will be used for safety analyses unless otherwise 
specified. 
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 treatment and the reasons for discontinuation 
• Completed study/Safety Follow-up  
• Prematurely discontinued the study/Safety Follow-up and the reasons for 
discontinuation 




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(ANCOVA) model with the change from baseline of Total Brody/CF-CT score at Week 72 
as dependent variable, treatment, sex (male versus female), and age as covariates. LDCT 
images will be scored by 2 central reader(s) blinded to treatment group and visit time point, 
as described in Section 11.5.1.3. The difference between the VX-661/ivacaftor group and the 
placebo group in mean change from baseline in Total Brody/CF-CT score at Week 72 will be 
estimated. 
The primary result obtained from the model will be the estimated treatment effect in each 
treatment group (with a 95% confidence interval), the estimated between-group difference in 
treatment effects, and a 95% confidence interval (CI) for the difference. For missing data, no 
imputation will be performed. 
Methodological details will be provided in the study SAP. 
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, lipid and vitamin 
levels, coagulation studies, and urinalysis) 
• ECGs 


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• Vital signs 
• Pulse oximetry 
All safety data will also be presented in individual subject data listings. 
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 TEAEs 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 
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 will be presented in the relationship summaries. An 
AE overview table will be provided. A separate table will summarize all TEAEs when each 
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. 


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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 (postbaseline) 
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. 
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).  
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. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
No interim analysis will be done. 


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12.3.5.2 
IDMC Analysis 
An IDMC will be formed before study initiation. The IDMC’s objectives and operational 
details will be defined in a separate document (IDMC Charter), which will be finalized 
before the first subject is screened in the study. The IDMC will conduct regular planned 
safety reviews of study data as outlined in the IDMC Charter.   
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, 
Severity Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the 
event does not necessarily have a causal relationship with the treatment. This includes any 
newly occurring event or worsening of a pre-existing condition (e.g., increase in its severity 
or frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed, 
and those deemed a clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather 
than the abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a 
diagnosis, the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine 
or decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more 
of the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of 
whether the study assessment results are clinically significant will be made by the 
investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory 
value will be an SAE if the 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: 


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• For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 28 days after the last dose of study drug,  
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 8.1.4), or 
o before the first dose of study drug in another study (if applicable).  
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the 
study will be recorded only in the subject’s source documents. The following data will be 
documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. 
The guidance available at the following website will be consulted: Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
June 2015). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In 
considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in 
the CTCAE. The severity of an AE that does not appear in the CTCAE will be determined 
according to the definitions in Table 13-1.  


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


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13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved 
With Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was 
given in response to an AE, and may include treatments such as other medications, 
hospitalization, surgery, or physical therapy. “No” indicates the absence of any kind of 
treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation in the study and is suspected of being a delayed toxicity due to 
administration of the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the outcomes 
listed above (e.g., an allergic bronchospasm requiring intensive treatment in an 
emergency room or at home)  




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13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. In addition, Vertex, or authorized designee, will be responsible for the submission 
of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/local 
IEC of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in 
accordance with local applicable laws and regulations. The IRB/IEC will review all 
appropriate study documentation to safeguard the rights, safety, and well-being of the 
subjects. The study will only be conducted at sites where IRB/IEC approval has been 
obtained. The protocol, Investigator’s Brochure, sample ICF, advertisements (if applicable), 
written information given to the subjects (including diary cards), safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by 
the investigator or Vertex, as allowable by local applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from 
the subject (if applicable), before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent 
form 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 subjects. Vertex will submit all protocol 
modifications to the required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the 
protocol, the investigator will contact Vertex to discuss the planned course of action. If 
possible, contact will be made before the implementation of any changes. Any departures 
from the protocol will be fully documented in the source documentation and in a protocol 
deviation log.  


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


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• 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. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness 
and clarity, cross-checking with source documents, and clarification of administrative matters 
will be performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s 
responsibility to ensure the accuracy, completeness, clarity, and timeliness of the data 
reported in the subject’s CRF. Source documentation supporting the CRF data will indicate 
the subject’s participation in the study and will document the dates and details of study 
procedures, AEs, other observations, and subject status. 


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The investigator, or designated representative, will complete the CRF as soon as possible 
after information is collected. 
The audit trail entry will show the user’s identification information and the date and time of 
any correction. The investigator will provide formal approval of all the information in the 
CRFs, including any changes made to the CRFs, to endorse the final submitted data for the 
subjects for whom the investigator is responsible. 
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival 
CRF in the form of a CD or other electronic media will be placed in the investigators 
study file. 
13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted 
in accordance with local regulations.  
 


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14 
REFERENCES 
 
1 
Cystic Fibrosis Foundation Web Site [Internet]. Bethesda, MD. Available at: 
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2 
Kriendler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new 
therapies. Pharmacol Ther. 2010;125:219-29. 
3  
United States Department of Health and Human Services. Food and Drug 
Administration. Office of Orphan Products Development (OOPD). Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/defa
ult.htm. Accessed 6 June 2015. 
4  
European Medicines Agency. The Committee for Orphan Medicinal Products 
(COMP). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_conte
nt_000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 6 June 2015. 
5 
Cystic Fibrosis Foundation. Patient Registry: 2012 Annual Data Report. Bethesda, 
MD: Cystic Fibrosis Foundation; 2013. 
6  
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012:10(1):88. 
7  
European Cystic Fibrosis Society. ECFS Patient Registry: 2010 Annual Report. 
Version 01.2014. Karup, Denmark: 2014. 
8  
Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry: 2012 Annual Report. 
Toronto, Canada: 2014. 
9  
Cystic Fibrosis Australia. Cystic fibrosis in Australia 2012: 15th annual report from 
the Australian cystic fibrosis data registry. Baulkham Hills, Australia: 2013. 
10  
Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto [Internet]. Cystic 
Fibrosis Mutation Database (CFTR1). Available at: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed 15 June 2015. 
11  
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. 
12 
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. 
13 
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. 
14 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 
 


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2005;352:1992-2001. 
15  
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. 
16 
Vertex Pharmaceuticals Incorporated. Report G016. Effects of VRT-893661 on 
CFTR-mediated chloride secretion in human bronchial epithelia isolated from cystic 
fibrosis subjects. Report date: 17 February 2010. 
17 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry  Eur Respir J  2005;26:319-38  
19  
de Jong PA, Nakano Y, Lequin MH, Mayo JR, Woods R, Paré PD, et al. Progressive 
damage on high resolution computed tomography despite stable lung function in 
cystic fibrosis. Eur Resp J. 2004;23:93-7. 
20  
Sheik J, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes D Jr. Computed 
tomography correlates with improvement with ivacaftor in cystic fibrosis patients 
with G551D mutation. J Cyst Fibros. 2015;14(1):84-9. 
24  
de Jong PA, Ottink MD, Robben SG, Lequin MH, Hop WC, Hendriks JJ, et al. 
Pulmonary disease assessment in cystic fibrosis: comparison of CT scoring systems 
and value of bronchial and arterial dimension measurements. Radiology. 
2004;231(2):434-9. 
25  
Baltieri S, Pinali L, Bortoluzzi C, Volpi S, Tridello G, Tiddens HA, et al. Evaluation 
of lung disease progression with CT Brody score in patients with cystic fibrosis. 
Presented at: European Congress of Radiology, 6-10 March 2014, Vienna. 
26  
Brody AS, Klein JS, Molina PL, Quan J, Bean JA, Wilmott RW. High-resolution 
computed tomography in young patients with cystic fibrosis: distribution of 
abnormalities and correlation with pulmonary function tests. J Pediatr. 
2004;145(1):32-8. 
 


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27  
Loeve M, Gerbrands K, Hop WC, Rosenfeld M, Hartmann IC, Tiddens HA. 
Bronchiectasis and pulmonary exacerbations in children and young adults with cystic 
fibrosis. Chest. 2011;140(1):178-85. 
28  
Robinson TE, Leung AN, Chen X, Moss RB, Emond MJ. Cystic fibrosis HRCT 
scores correlate strongly with Pseudomonas infection. Pediatr Pulmonol. 
2009;44(11):1107-17. 
29  
Moss RB, Rodman D, Spencer LT, Aitken ML, Zeitlin PL, et al., Repeated adeno-
associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator 
gene transfer to the lungs of patients with cystic fibrosis. Chest. 2004; 125:509–521. 
30  
Brody AS, Kosorok MR, Li Z, Broderick LS, Foster JL, Laxova A, et al. 
Reproducibility of a scoring system for computed tomography scanning in cystic 
fibrosis. J Thorac Imaging. 2006 Mar;21(1):14-21. 
31 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
32 
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. 
33 
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. 
34  
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. 
35  
Australian Radiation Protection and Nuclear Safety Agency. [Internet] Available at: 
http://www.arpansa.gov.au/pubs/factsheets/IonisingRadiationandHealth.pdf Accessed 
30 July 2015. 
36 
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. 
37 
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. 






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15.2 
Investigator Signature Page 
Protocol #: 
VX15-661-112 
Version #: 
5.0 
Version Date 
26 February 2018 
Study Title: A Phase 2, Randomized, Placebo-Controlled, Double-blind Study to Evaluate 
the Effect of VX-661 in Combination With Ivacaftor on Chest Imaging Endpoints in Subjects 
Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del CFTR 
Mutation 
 
 
I have read Protocol VX15-661-112, Version 5.0 and agree to conduct the study according to 
its terms. I understand that all information concerning VX-661, ivacaftor, and this protocol 
supplied to me by Vertex Pharmaceuticals Incorporated is confidential.   
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 

SAP_001.pdf: 
Statistical Analysis Plan Module 1: Methods 
Page 1 
Protocol Number: VX15-661-112, Version 1.0, 07 May 2018 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
Module 1: Methods 
Protocol Number VX15-661-112 
A Phase 2, Randomized, Placebo-Controlled, Double-blind Study to Evaluate the 
Effect of VX-661 in Combination With Ivacaftor on Chest Imaging Endpoints in 
Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the 
F508del-CFTR Mutation 
Author of SAP: 
  
Version: Version 1.0, Final 
Version Date of SAP: 7 May, 2018 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the  
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan Module 1: Methods 
Page 2 
Protocol Number: VX15-661-112, Version 1.0, 07 May 2018 
 
Vertex Pharmaceuticals Incorporated 
 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 2 
3 
Introduction...................................................................................................................... 4 
4 
Study Objectives .............................................................................................................. 4 
4.1 
Primary Objective(s) .................................................................................................. 4 
4.2 
Secondary Objectives ................................................................................................. 4 
5 
Study Endpoints ............................................................................................................... 5 
5.1 
Efficacy Endpoints ..................................................................................................... 5 
5.2 
Safety Endpoints ......................................................................................................... 5 
6 
Study Design ..................................................................................................................... 5 
6.1 
Overall Design ............................................................................................................ 5 
6.2 
Sample Size and Power .............................................................................................. 6 
6.3 
Randomization ............................................................................................................ 6 
6.4 
Blinding ...................................................................................................................... 7 
7 
Analysis Sets ..................................................................................................................... 7 
8 
Statistical Analysis ........................................................................................................... 7 
8.1 
General Considerations .............................................................................................. 7 
8.2 
Background Characteristics ........................................................................................ 9 
8.2.1 
Subject Disposition ............................................................................................. 9 
8.2.2 
Subject Demographics and Baseline Characteristics .......................................... 9 
8.2.3 
Prior and Concomitant Medications ................................................................. 10 
8.2.4 
Study Drug Exposure........................................................................................ 11 
8.2.5 
Study Drug Compliance ................................................................................... 11 
8.2.6 
Important Protocol Deviations .......................................................................... 12 
8.3 
Efficacy Analysis ...................................................................................................... 12 
8.3.1 
Analysis of Primary Efficacy Endpoint ............................................................ 12 
8.4 
Safety Analysis ......................................................................................................... 19 
8.4.1 
Adverse Events ................................................................................................. 19 
8.4.2 
Clinical Laboratory ........................................................................................... 21 
8.4.3 
Standard 12-Lead Electrocardiogram ............................................................... 22 
8.4.4 
Vital Signs ........................................................................................................ 22 


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8.4.5 
Pulse Oximetry ................................................................................................. 22 
8.4.6 
Physical Examination ....................................................................................... 22 
9 
Interim and DMC Analyses .......................................................................................... 22 
9.1 
Interim Analysis ....................................................................................................... 22 
9.2 
DMC Analysis .......................................................................................................... 22 
10 List of Appendices.......................................................................................................... 23 
10.1 Appendix A: Schedule of Assessments .................................................................... 23 
10.2 Appendix B: Analysis Visit Window Mapping Rules for Efficacy and Safety 
Measurements ........................................................................................................... 28 
10.3 Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates . 29 
10.4 Appendix D: Coefficients for Hankinson and Wang Methods for Calculating 
Predicted Spirometry Parameters 
 30 
10.7 Appendix G: Imputation Rules for Missing AE Start Dates .................................... 36 
10.8 Appendix H: Threshold Analysis Criteria ................................................................ 37 
11 References ....................................................................................................................... 44 
 


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3 
INTRODUCTION 
Study VX15-661-112 is a phase 2, randomized, placebo-controlled, double-blind study to 
evaluate the effect of vx-661 in combination with ivacaftor on chest imaging endpoints in 
subjects aged 12 years and older with cystic fibrosis, homozygous for the F508del CFTR 
mutation. 
This statistical analysis plan (SAP) Methods is based on the approved clinical study protocol 
(CSP), dated 26 February 2018, version 5.0. This SAP addresses the efficacy and safety 
objective of the study and describes the planned statistical analyses and data presentations for 
the CSR.  
Vertex Biometrics department or a designated Contract Research Organization (CRO) will 
perform the statistical analysis of the safety and efficacy data.  SAS® Version 9.4 Software 
(SAS Institute, Cary, North Carolina, USA) or higher will be used to generate all statistical 
outputs (tables, figures, listings, and datasets).  The SAP will be finalized and approved prior 
to final database lock. 
4 
STUDY OBJECTIVES  
4.1 Primary Objective(s) 
• To evaluate the treatment effect of VX-661 in combination with ivacaftor 
(VX-661/ivacaftor) on chest imaging endpoints as evaluated using low-dose 
computed tomography (LDCT) at Week 72 in subjects with CF who are homozygous 
for the F508del mutation on the CF transmembrane conductance regulator (CFTR) 
gene 
4.2 Secondary Objectives  
• To evaluate the safety of VX-661/ivacaftor through Week 72 


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5 
STUDY ENDPOINTS 
5.1 Efficacy Endpoints 
• Absolute change in Total Brody/CF-CT score from baseline at Week 72 using LDCT.  
5.2 Safety Endpoints 
The safety and tolerability is evaluated via the following endpoints: 
• Adverse events (AEs)  
• Clinical laboratory values (hematology, serum chemistry, coagulation studies,   
vitamin levels, lipid panel, and urinalysis) 
• Standard digital electrocardiograms (ECGs) 
• Vital signs 
• Pulse Oximetry 
6 
STUDY DESIGN  
6.1 Overall Design  
This is a Phase 2, randomized, placebo-controlled, double-blind parallel-group, multicenter 
study in subjects with CF who are homozygous for the F508del-CFTR mutation. This study 
is designed to evaluate the treatment effect of VX-661/ivacaftor on chest imaging endpoints 
during 72 weeks of treatment. LDCT 
 will be used for chest imaging. The 
images will be evaluated using the Brody/CF-CT scoring system. Safety over 72 weeks of 
treatment will also be evaluated. 
Figure 6-1 shows a schematic of the study design. This study includes a Screening Period, a 
72-week Treatment Period, and a Safety Follow-up Visit. Following a 28-day screening 
period, approximately 40 subjects will be randomized (1:1) to 1 of the 2 treatment arms, 
active or placebo, on Day 1.  
The active treatment regimen will be comprised of a morning dose of a fixed-dose 
combination (FDC) tablet of VX-661 100-mg/ivacaftor 150-mg and an evening dose of 




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6.4 Blinding  
This is a double-blind study. 
Imaging Data Blinding 
Despite treatment blinding, knowledge of the LDCT 
 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 
imaging data. The vendor for central reading of the imaging data will send only the blinded 
files (blinded treatment group, with real scores for baseline, but with dummy scores for all 
the imaging assessments after baseline) to Vertex to be used for developing the statistical 
programs. Furthermore, subjects and their caregiver should not be informed of their 
study-related imaging results during the Treatment Period regardless of whether the subject 
has prematurely discontinued treatment. 
CT scans 
 will have a clinical over-read by a site radiologist blinded to 
study drug assignment. Any urgent safety-related findings should be communicated to the 
Vertex medical monitor, who may recommend follow-up by the site principal investigator. 
The Vertex medical monitor will facilitate any discussion with the central readers as needed.  
7 
ANALYSIS SETS 
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. 
8 
STATISTICAL ANALYSIS 
8.1 General Considerations 
The Schedule of Assessments is provided in Appendix A (Section 10.1). 


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All individual subject data for those randomized or exposed to study drug will be presented 
in data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum value (min), and maximum value (max).   
Categorical variables will be summarized using counts and percentages.  
Baseline Value, unless otherwise specified, is defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected prior to the first dose of study drug. For 
ECGs, the baseline will be defined as the average of the 3 pretreatment measurements 
(triplicate) on Day 1.  
Absolute Change from baseline will be calculated as Postbaseline value - Baseline value.  
Relative change from baseline will be calculated and expressed in percentage as 
100%×(Postbaseline value - Baseline value)/Baseline value.  
Treatment Emergent (TE) Period will include the time from the first dose to Safety 
Follow-up Visit.  For subjects who do not have a Safety Follow-up Visit because they rolled 
over into the open-label extension study within 28 days after the last dose of study drug, the 
end of the TE period will be the date of rollover into the extension study.  For subjects who 
do not have a Safety Follow-up Visit and did not roll over into the extension study, the end of 
the the TE period will be 28 days after the date of last dose. The TE period will be used for 
safety analyses unless otherwise specified.  
 
Unscheduled Visits: Unscheduled visit measurements will be included in the analysis as 
follows: 
• In scheduled visit windows per specified visit windowing rules; 
• In the derivation of baseline and last on-treatment measurements; 
• In the derivation of maximum/minimum on-treatment values and maximum/minimum 
changes from baseline values for safety analyses; 
• In individual subject data listings where appropriate. 
 
Visit Windowing Rules: The analysis visit windows for protocol-defined visits are provided 
in Appendix B (Section 10.2). The windows will be applied using the following rules for 
both scheduled and unscheduled visits: 
1. If no measurement is available within a visit window, the assessment will be 
considered missing for the visit; 
2. If there is more than one measurement available within the same visit window, use 
the following rules:  
For all efficacy parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used. Otherwise, 
o If there are no measurements at the scheduled visit, then the record closest to 
the target day will be used;  




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• Sex (female and male) 
• Age 
• Age group at screening (<18, and ≥18 years) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
Disease characteristics will include the following: 
• Percent predicted FEV1 at baseline 
• Sweat Chloride at screening 
• Use of dornase alfa 
• Use of inhaled antibiotic 
• Use of bronchodilator  
• Use of inhaled bronchodilator  
• Use of inhaled hypertonic saline 
• Use of inhaled corticosteroids 
• Colonization of Pseudomonas aeruginosa (Positive, Negative) 
• Brody/CF-CT total score at baseline 
8.2.3 
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. 


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• 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. 
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.  
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C (Section 10.3). 
8.2.4 
Study Drug Exposure  
Exposure summaries will be based on the Safety Set. 
Duration of study drug exposure is defined as: last dose date – first dose date + 1 day, 
regardless of any interruption in dosing between the first and the last dose. For the purposes 
of DMC, if the date from End of Dosing CRF page is not available, the end of treatment date 
will be assumed to be the date of datacut.  
Duration of study drug exposure, as well as number of tablets administered defined as (Total 
number of tablets dispensed) - (Total number of tablets returned), will be summarized 
descriptively (number, mean, SD, SE, median, minimum, and maximum). 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.  
If the last dose date of study drug is missing, the latest of the date of subject’s treatment 
discontinuation or the date of treatment completion will be used for analysis purposes. 
8.2.5 Study Drug Compliance 
Study drug compliance will be measured by the compliance rate; summarized based on the 
Safety Set and presented by treatment group. 
Compliance rate will be calculated as follows:  
100 × [1 - (Total number of days study drug interrupted) / (Duration of study drug 
exposure)]. 
The total number of days study drug interrupted is defined as the total of number of days the 
study drug was interrupted in each interruption interval; where number of days study 
drug interrupted in each interval is defined as the interruption end date - the 
corresponding interruption start date + 1.  


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The Compliance rate will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max and into the categories of <80% or ≥80%. 
A list of subjects with <80% compliance rate will be provided. 
8.2.6 
Important Protocol Deviations 
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject's rights, safety, or well-being. IPD rules will be developed and 
finalized before database lock. 
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
• Violation of subjects rights, safety or well-being 
• Subject entered the study despite violation of any inclusion or exclusion criteria 
• Subject was less than 80% compliant with study medications 
• Subject received excluded concomitant medications 
• 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 group. Additionally, IPDs will be 
provided as a subject data listing. 
8.3 Efficacy Analysis  
Assessment of efficacy of VX-661/ivacaftor is the primary objective of this study. 
8.3.1 Analysis of Primary Efficacy Endpoint 
The primary endpoint is the absolute change from baseline of Total Brody/CF-CT score at 
Week 72 using LDCT. The primary analysis will be based on an analysis of covariance 
(ANCOVA) model with the change from baseline of Total Brody/CF-CT score at Week 72 
as dependent variable, treatment, sex (male versus female), and age (12-17 years vs. 18 years 
and older) as covariates. LDCT images will be scored by 2 central reader(s) blinded to 
treatment group and visit time point. The difference between the VX-661/ivacaftor group and 
the placebo group in mean change from baseline in Total Brody/CF-CT score at Week 72 
will be estimated using the FAS. 
The primary result obtained from the model will be the estimated treatment effect in each 
treatment group (with a 95% confidence interval), the estimated between-group difference in 
treatment effects, and a 95% confidence interval (CI) for the difference. For missing data, no 
imputation will be performed. 


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Summary statistics (n, mean, SD, SE, median, minimum, and maximum) will be presented 
by treatment group at each scheduled visit and for absolute change from baseline at each 
scheduled visit. 
 












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8.4 Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:   
• Adverse events 
• Clinical laboratory values (hematology, serum chemistry, coagulation studies, vitamin 
levels, lipid panel, and urinalysis) 
• Standard 12-lead ECGs 
• Vital signs  
• Pulse oximetry 
Safety endpoints will be analyzed based on the Safety Set (for each applicable treatment 
period). Only descriptive analysis of safety will be performed and no statistical testing will 
be performed.  
 
8.4.1 
Adverse Events  
For analysis purpose, AEs will be categorized as pretreatment AEs, treatment-emergent 
adverse events (TEAEs), or post-treatment AEs: 
Pretreatment AE: any AE that started before 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 missing or partial start dates, AE start dates will be imputed according to the 
rules in Appendix G (Section 10.7).  


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An adverse event overview table will be provided with the following for TE period:  
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs  
• Subjects with TEAEs by relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to treatment discontinuation 
• Subjects with TEAEs leading to treatment interruption 
• Subjects with grade 3/4 TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAE leading to death  
The following summary tables of TEAEs will be presented by treatment group:   
• All TEAEs  
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity  
• TEAEs leading to treatment discontinuation  
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
When summarizing the number and percentages of subjects, subjects with multiple 
occurrences of the same adverse event or a continuing adverse event will be counted once, 
and only the maximum severity level will be presented in the severity summaries, and the 
worst/highest relationship level in the relationship summaries.   
The following summary tables will be presented by treatment showing number and 
percentage of subjects 
• TEAEs and SAEs by SOC and PT 
• TEAEs and SAEs by PT 
• TEAEs and SAEs by SOC and PT and Severity 


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• TEAEs and SAEs by SOC and PT and Relationship 
In addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation, SAEs and all deaths will be provided separately, with a flag 
indicating the TEAE status for SAEs and deaths. 
8.4.2 
Clinical Laboratory 
For the treatment emergent laboratory measurements, the raw values and change from 
baseline values of the continuous hematology and chemistry results will be summarized in SI 
units by treatment group at each scheduled time point. For hematology and chemistry, the 
number and percentage of subjects with abnormal low (<LLN) value and with abnormal high 
(>ULN) value at each scheduled time point will be summarized. 
For LFT and CPK results (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], serum alkaline phosphatase [ALP], total bilirubin and CPK), the following additional 
analyses will be conducted: 
• The number and percentage of subjects who meet the thresholds for LFT and CPK 
according to the criteria defined in Appendix H (Section 10.8) will be summarized by 
visit and during the TE period. The shift of the threshold criteria from baseline to post 
baseline will be summarized.  
• For each LFT, the box plot of LFT value/ULN will be provided against visit.  
• A scatter plot of maximum values of ALT versus maximum values of total bilirubin will 
also be presented. Note that the ALT and Total bilirubin values are 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 values of AST versus maximum values of total 
bilirubin will be presented as well. 
• 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. 
Results of GI/Nutrition laboratory parameters (specified in SAP M2) will be summarized and 
subject data listings will be provided. The number and percentage of subjects with abnormal 
low (<LLN) value and with abnormal high (>ULN) value at each scheduled time point will 
be summarized for GI/nutritional parameter and listed separately.  In addition, boxplots by 
visit will be provided for GI/Nutrition laboratory parameters. 
Results of serum pregnancy test, urinalysis, and the urine/serum pregnancy test will be listed 
in individual subject data listings only.  
In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. These listings will include data from 
scheduled and unscheduled time points. 
 


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8.4.3 
Standard 12-Lead 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.  
The number and percentage of subjects with ECG event meeting threshold criteria during the 
treatment-emergent period will be summarized by treatment, ECG parameters, and visit. The 
threshold criteria are provided in Appendix H (Section 10.8).  
 
8.4.4 
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 (oC), HR (beats per minute), and 
respiratory rate (breaths per minute). 
The number and percentage of subjects with vital signs meeting threshold during the 
treatment-emergent period will be summarized by treatment, vital signs parameters, and visit. 
The threshold criteria are provided in Appendix H (Section 10.8).  
 
8.4.5 
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.  
 
8.4.6 Physical Examination 
PE findings will be presented as a data listing only. 
 
9 
INTERIM AND DMC ANALYSES 
9.1 Interim Analysis 
No formal interim analysis is planned. 
9.2 DMC 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. 
Analyses for IDMC purposes are described in a separate IDMC SAP. 


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10 LIST OF APPENDICES 
10.1 Appendix A: Schedule of Assessments 
Table 10-1    Study VX15-661-112: Screening  
Event/Assessment 
Screening Period (Day -28 through Day -1) 
Informed consent (and assent, when applicable) 
X 
Demographics 
X 
Medical history  
X 
Ophthalmological history  
X 
CF genotypea 
X 
FSHb 
X 
Serum pregnancy test (all females of childbearing 
potential)c 
X 
Hematology 
X 
Coagulation 
X 
Serum chemistry 
X 
Urinalysis 
X 
Weight and heightd 
X 
Ophthalmologic examinatione 
X 
Complete physical examination 
X 
Vital signsf 
X 
Pulse oximetryf 
X 
Standard 12-lead ECGg 
X 
Spirometryh 
X 
Inclusion/exclusion criteria review 
X 
Prior and concomitant medications 
X 
Sweat chloridei 
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; ECG: electrocardiogram; FSH: follicle-stimulating hormone; ICF: 
informed consent form; SAE: serious adverse event. 
                                                 
a 
All subjects will be tested for CF genotype. Specific instructions will be provided in the Laboratory Manual. CF 
genotyping may be waived if the subject has a documented result from a previous Vertex study. 
b 
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. 
c 
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. 
d 
Weight and height will be measured with shoes off. 
e 
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 
was conducted within 3 months before the start of the Screening Period or if there is documentation of bilateral lens 
removal (Section 11.6.8 of Clinical Study Protocol).  
f 
Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes.  
g 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
h 
Spirometry may be performed pre- or postbronchodilator (Section 11.5.2).  
i 
A sweat chloride test must be performed at the Screening Visit if an eligible sweat chloride value is not available in the 
subject’s medical records and the Screening Visit value is needed to establish eligibility. For subjects using sweat 
chloride values documented in their medical records to establish eligibility, the sweat chloride test at the Screening 
Visit is optional.  
 


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Table 10-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early Termination of Treatment Visit, and 
Safety Follow-up Visit Assessments 
Event/Assessmenta 
Day 1 
Day 15 
(± 3 days) 
Week 4, Week 12,  
(± 1 week) 
Week 24 
(± 1 week) 
Week 36, 
Week 48, 
Week 60 
(± 1 week) 
Week 72 
(± 1 week) 
Early 
Termination of 
Treatment Visit 
(Within 7 days 
After Last Dose of 
Study Drug) 
Safety 
Follow-up 
Visit 
4 weeks 
(± 7 days) 
After Last 
Dose of Study 
Drugb 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion criteria 
reviewc 
X 
 
 
 
 
 
 
 
Randomizationd 
X 
 
 
 
 
 
 
 
Complete physical examinationf 
X 
 
 
 
 
X 
X 
X 
Pregnancy testg  
urine 
 
urine 
urine 
urine 
urine 
serum 
serum 
                                                 
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.  
b  
The Safety Follow-up Visit is not required for subjects who complete the Week 72 Visit and have enrolled in the TEZ/IVA open-label extension study, VX14-661-110, 
within 28 days after the last dose of study drug. 
c 
The screening inclusion and exclusion criteria should be re-reviewed before administration of study drug on Day 1. 
d 
Randomization must occur after the informed consent/assent has been obtained and all inclusion and exclusion criteria are met and before the first dose of study drug. 
Randomization will be done through an interactive web response system. Randomization may occur on Day −1 if the above conditions for randomization have been met. 
 
In addition to the indicated visits, a symptom-targeted physical examinations will occur at any time during the study if triggered by adverse events (AEs) or if deemed 
necessary by the investigator. 
g 
Pregnancy tests will be performed for all female subjects of childbearing potential. Day 1 results will be reviewed before dosing and the Low-dose CT scan. Week 72 
results will be reviewed before the Low-dose CT scan.  


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Table 10-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early Termination of Treatment Visit, and 
Safety Follow-up Visit Assessments 
Event/Assessmenta 
Day 1 
Day 15 
(± 3 days) 
Week 4, Week 12,  
(± 1 week) 
Week 24 
(± 1 week) 
Week 36, 
Week 48, 
Week 60 
(± 1 week) 
Week 72 
(± 1 week) 
Early 
Termination of 
Treatment Visit 
(Within 7 days 
After Last Dose of 
Study Drug) 
Safety 
Follow-up 
Visit 
4 weeks 
(± 7 days) 
After Last 
Dose of Study 
Drugb 
Low-dose CT scanh 
X 
 
 
 
 
X 
 
 
Standard digital ECGm 
X 
X 
X 
X 
X 
X 
X 
 X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryn 
X 
X 
X 
X 
X 
X 
X 
X 
                                                 
h 
Low-dose CT scans 
 should be performed on the same day. If not possible for logistical reasons, Low-dose CT scans 
 should be 
performed within ± 4 days of the scheduled visit. Day 1 assessments must be completed before dosing. The Week 72 CT scan may be delayed for up to 60 days if the 
subject is recovering from a pulmonary exacerbation. The medical monitor should be notified about the extension. The scan should be done after the pulmonary 
exacerbation is resolved and at least 28 days after the antibiotic regimen for the treatment of pulmonary infection has been completed. If this antibiotic regimen is not 
completed by the end of the 60-day extension, the subject may complete the CT scan within the first 30 days of enrolling in Study VX14-661-110; or within 1 week of 
m 
All standard 12-lead ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes. The predose ECGs collected at the Day 1 Visit 
will be performed in triplicate.  
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. In addition to the indicated 
visits  symptom-targeted vital signs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. 


Statistical Analysis Plan Module 1: Methods 
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Table 10-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early Termination of Treatment Visit, and 
Safety Follow-up Visit Assessments 
Event/Assessmenta 
Day 1 
Day 15 
(± 3 days) 
Week 4, Week 12,  
(± 1 week) 
Week 24 
(± 1 week) 
Week 36, 
Week 48, 
Week 60 
(± 1 week) 
Week 72 
(± 1 week) 
Early 
Termination of 
Treatment Visit 
(Within 7 days 
After Last Dose of 
Study Drug) 
Safety 
Follow-up 
Visit 
4 weeks 
(± 7 days) 
After Last 
Dose of Study 
Drugb 
Hematology 
X 
 
 
X 
Wk 48 only 
X 
X 
X 
Lipid and vitamin levels 
X 
 
 
X 
Wk 48 only 
X 
X 
X 
Coagulation 
X 
 
 
 
 
X 
 
X 
Serum chemistryp 
X 
X 
X 
LFT only 
LFT only 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
X 
 
X 
Study drug count 
 
X 
X 
X 
X 
X 
 
 
Meal(s) or snack(s) at siteq 
X 
X 
X 
X 
X 
 
 
 
 CT: computed tomography; ECG:  electrocardiogram; LFT: liver function test; 
  
                                                 
p 
Blood samples will be collected before the dose of study drug. At Weeks 24, 36, 48, and 60, only samples for LFT analysis will be collected. 
q 
Food will be provided after all predose assessments have occurred. 


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Table 10-2 
Study VX15-661-112: Treatment Period (Day 1 to Week 72), Early Termination of Treatment Visit, and 
Safety Follow-up Visit Assessments 
Event/Assessmenta 
Day 1 
Day 15 
(± 3 days) 
Week 4, Week 12,  
(± 1 week) 
Week 24 
(± 1 week) 
Week 36, 
Week 48, 
Week 60 
(± 1 week) 
Week 72 
(± 1 week) 
Early 
Termination of 
Treatment Visit 
(Within 7 days 
After Last Dose of 
Study Drug) 
Safety 
Follow-up 
Visit 
4 weeks 
(± 7 days) 
After Last 
Dose of Study 
Drugb 
Study drug dosingr 
Day 1 through Week 72 
 
 
Ophthalmologic examination 
 
 
 
 
 
Xs 
Xt 
Xt 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatments and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events and 
serious adverse events 
Continuous from signing of the informed consent form and assent (where applicable) through the Safety Follow-up Visit 
 
 
 
 
 
 
                                                 
r 
Subjects will take study drug as specified in Section 10.2. On days of scheduled visits, the subject’s dose of study drug will be administered at the site after predose 
assessments have been completed. Study drug administration should be completed within 5 minutes. At the Week 72 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 72 Visit. If the Week 72 CT scan is delayed to allow a subject to 
recover from 
, study drug will continue for up to 60 days until the Week 72 CT scan has been completed or the subject has enrolled in 
Study VX14-661-110; for these subjects, the last dose of study drug will be the evening dose administered the day before the CT scan or before the Day 1 Visit of 
Study VX14-661-110.  
s 
All subjects <18 years of age at the Screening Visit will have an ophthalmologic examination conducted by a licensed ophthalmologist at Week 72. This exam may be 
completed within 4 weeks before the Week 72 Visit, but must be completed by the end of the Week 72 Visit.   
t 
Subjects <18 years of age at the Screening Visit who discontinue treatment after receiving at least 1 dose of study drug will have an ophthalmologic examination 
performed by a licensed ophthalmologist at the Safety Follow-up or the Early Termination of Treatment Visit. This examination may be completed at either the Early 
Termination of Treatment or Safety Follow-up Visit, but must be completed by the end of the Safety Follow-up Visit.  


Statistical Analysis Plan Module 1: Methods 
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Vertex Pharmaceuticals Incorporated 
 
 
10.2 Appendix B: Analysis Visit Window Mapping Rules for Efficacy and 
Safety Measurements 
Table  10-3 
Visit Window Mapping Rules  
Assessments 
Visit 
Target Study Day 
Visit Window  
(in study days) 
Standard 12-lead ECG 
Vital signs 
Pulse oximetry 
Serum Chemistry 
 
 
Baseline 
1 
≤1 
Day 15 
15 
[2, 22] 
Week 4 
29 
[23, 57] 
Week 12 
85 
[58, 127] 
Week 24 
169 
[128, 211] 
Week 36 
253 
[212, 295] 
Week 48 
337 
[296, 379] 
Week 60 
421 
[380, 463] 
Week 72 
505 
[464, 519] 
ETT 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
Safety Follow-up Visit 
N/A 
Nominal 
Hematology 
Lipid and Vitamin Levels 
Baseline 
1 
≤1 
Week 24 
169 
[2, 253] 
Week 48 
337 
[254, 421] 
Week 72 
505 
[422, 519] 
ETT 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
Safety Follow-up Visit 
N/A 
Nominal 
Coagulation 
Baseline 
1 
≤1 
Week 72 
505 
[464, 519] 
Safety Follow-up Visit 
N/A 
Nominal 


Statistical Analysis Plan Module 1: Methods 
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10.3 Appendix C: Imputation Rules for Missing Prior/Concomitant Medication 
Dates 
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 10-4: 
Table 10-4 
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  
 
 




Statistical Analysis Plan Module 1: Methods 
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Confidential Information 
 
Table  10-5 
HNVs Equation Coefficients by Sex, Race, and Age 
Source: Reference (Hankinson JL, 1999) (Tables 4, 5 and 6) 
Parameter 
Sex 
Race 
Age 
(years) 
bo 
b1 
b2 
b3 
HNVFEV1 
Male 
Caucasian 
<20 
-0.7453 
-0.04106 
0.004477 
0.00014098 
≥20 
0.5536 
-0.01303 
-0.000172 
0.00014098 
African 
American 
<20 
-0.7048 
-0.05711 
0.004316 
0.00013194 
≥20 
0.3411 
-0.02309 
 
0.00013194 
Mexican 
American 
<20 
-0.8218 
-0.04248 
0.004291 
0.00015104 
≥20 
0.6306 
-0.02928 
 
0.00015104 
Female 
Caucasian 
<18 
-0.8710 
0.06537 
 
0.00011496 
≥18 
0.4333 
-0.00361 
-0.000194 
0.00011496 
African 
American 
<18 
-0.9630 
0.05799 
 
0.00010846 
≥18 
0.3433 
-0.01283 
-0.000097 
0.00010846 
Mexican 
American 
<18 
-0.9641 
0.06490 
 
0.00012154 
≥18 
0.4529 
-0.01178 
-0.000113 
0.00012154 
HNVFVC 
Male 
Caucasian 
<20 
-0.2584 
-0.20415 
0.010133 
0.00018642 
≥20 
-0.1933 
0.00064 
-0.000269 
0.00018642 
African 
American 
<20 
-0.4971 
-0.15497 
0.007701 
0.00016643 
≥20 
-0.1517 
-0.01821 
 
0.00016643 
Mexican 
American 
<20 
-0.7571 
-0.09520 
0.006619 
0.00017823 
≥20 
0.2376 
-0.00891 
-0.000182 
0.00017823 
Female 
Caucasian 
<18 
-1.2082 
0.05916 
 
0.00014815 
≥18 
-0.3560 
0.01870 
-0.000382 
0.00014815 
African 
American 
<18 
-0.6166 
-0.04687 
0.003602 
0.00013606 
≥18 
-0.3039 
0.00536 
-0.000265 
0.00013606 
Mexican 
American 
<18 
-1.2507 
0.07501 
 
0.00014246 
≥18 
0.1210 
0.00307 
-0.000237 
0.00014246 
HNVFEF25-75% 
Male 
Caucasian 
<20 
-1.0863 
0.13939 
 
0.00010345 
≥20 
2.7006 
-0.04995 
 
0.00010345 
African 
American 
<20 
-1.1627 
0.12314 
 
0.00010461 
≥20 
2.1477 
-0.04238 
 
0.00010461 
Mexican 
American 
<20 
-1.3592 
0.10529 
 
0.00014473 
≥20 
1.7503 
-0.05018 
 
0.00014473 
Female 
Caucasian 
<18 
-2.5284 
0.52490 
-0.015309 
0.00006982 
≥18 
2.3670 
-0.01904 
-0.000200 
0.00006982 
African 
American 
<18 
-2.5379 
0.43755 
-0.012154 
0.00008572 
≥18 
2.0828 
-0.03793 
 
0.00008572 
Mexican 
American 
<18 
-2.1825 
0.42451 
-0.012415 
0.00009610 
≥18 
1.7456 
-0.01195 
-0.000291 
0.00009610 
HNVFEV1/FVC% 
Male 
Caucasian 
 
88.066 
-0.2066 
 
 
African 
American 
 
89.239 
-0.1828 
 
 
Mexican 
American 
 
90.024 
-0.2186 
 
 
Female 
Caucasian 
 
90.809 
-0.2125 
 
 
African 
American 
 
91.655 
-0.2039 
 
 
 
 
Mexican 
American 
 
92.360 
-0.2248 
 
 


Statistical Analysis Plan Module 1: Methods 
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Confidential Information 
 
Table  10-6 WNVs Equation Coefficients by Sex and Age in White Boys and Girls 
 
 
FEV1 
FVC 
FEF25-75% 
FEV1/FVC 
Sex 
Age 
α 
β 
α 
β 
α 
β 
α 
β 
Male 
6 
-0.109 
2.252 
-0.024 
2.470 
 
 
-0.078 
-0.248 
7 
-0.104 
2.270 
-0.018 
2.489 
 
 
-0.086 
-0.220 
8 
-0.089 
2.257 
0.005 
2.443 
0.264 
1.505 
-0.091 
-0.199 
9 
-0.063 
2.197 
0.017 
2.426 
0.308 
1.443 
-0.086 
-0.206 
10 
-0.057 
2.212 
0.030 
2.407 
0.290 
1.557 
-0.081 
-0.209 
11 
-0.093 
2.324 
0.009 
2.468 
0.242 
1.738 
-0.101 
-0.147 
12 
-0.161 
2.512 
-0.061 
2.649 
0.165 
1.982 
-0.101 
-0.133 
13 
-0.292 
2.843 
-0.175 
2.924 
0.007 
2.396 
-0.116 
-0.085 
14 
-0.329 
2.983 
-0.219 
3.060 
0.014 
2.483 
-0.106 
-0.087 
15 
-0.141 
2.709 
-0.079 
2.859 
0.241 
2.163 
-0.060 
-0.155 
16 
0.062 
2.409 
0.104 
2.591 
0.503 
1.764 
-0.045 
-0.178 
17 
0.262 
2.099 
0.253 
2.374 
0.762 
1.368 
0.008 
-0.272 
Female 
6 
-0.109 
1.949 
-0.013 
2.007 
 
 
-0.097 
-0.055 
7 
-0.144 
2.243 
-0.062 
2.385 
 
 
-0.084 
-0.132 
8 
-0.137 
2.239 
-0.055 
2.381 
0.247 
1.668 
-0.079 
-0.152 
9 
-0.123 
2.222 
-0.039 
2.351 
0.254 
1.710 
-0.084 
-0.128 
10 
-0.161 
2.364 
-0.068 
2.458 
0.195 
1.933 
-0.092 
-0.097 
11 
-0.223 
2.558 
-0.120 
2.617 
0.161 
2.091 
-0.102 
-0.061 
12 
-0.264 
2.709 
-0.174 
2.776 
0.185 
2.120 
-0.090 
-0.067 
13 
-0.153 
2.535 
-0.061 
2.576 
0.294 
1.976 
-0.093 
-0.040 
14 
0.046 
2.178 
0.139 
2.208 
0.450 
1.711 
-0.096 
-0.026 
15 
0.148 
2.008 
0.210 
2.099 
0.581 
1.486 
-0.062 
-0.093 
Source: Reference (Wang X, 1993) (Tables 2 and 3) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan Module 1: Methods 
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Protocol Number: VX15-661-112, Version 1.0, 07 May 2018 
 
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Confidential Information 
 
Table  10-7 
WNVs Equation Coefficients by Sex and Age in Black Boys and Girls 
 
 
FEV1 
FVC 
FEF25-75% 
FEV1/FVC 
Sex 
Age 
α 
β 
α 
β 
α 
β 
α 
β 
Male 
6 
-0.166 
1.723 
-0.088 
1.961 
 
 
-0.091 
-0.152 
7 
-0.122 
1.846 
-0.040 
2.040 
 
 
-0.091 
-0.153 
8 
-0.225 
2.271 
-0.094 
2.323 
0.097 
1.544 
-0.118 
-0.104 
9 
-0.142 
2.059 
-0.074 
2.308 
0.255 
1.248 
-0.079 
-0.218 
10 
-0.157 
2.117 
-0.110 
2.417 
0.230 
1.428 
-0.047 
-0.303 
11 
-0.176 
2.166 
-0.138 
2.453 
0.256 
1.438 
-0.048 
-0.263 
12 
-0.307 
2.548 
-0.224 
2.710 
0.085 
1.936 
-0.084 
-0.162 
13 
-0.486 
2.962 
-0.342 
2.975 
-0.121 
2.476 
-0.141 
-0.018 
14 
-0.472 
3.010 
-0.337 
3.035 
-0.115 
2.536 
-0.123 
-0.050 
15 
-0.318 
2.789 
-0.226 
2.889 
0.170 
2.120 
-0.070 
-0.140 
16 
0.074 
2.140 
0.058 
2.425 
0.663 
1.299 
0.018 
-0.289 
17 
0.053 
2.223 
0.148 
2.310 
0.505 
1.618 
-0.095 
-0.087 
Female 
6 
-0.288 
2.182 
-0.172 
2.117 
 
 
-0.109 
0.059 
7 
-0.250 
2.158 
-0.135 
2.132 
 
 
-0.104 
-0.030 
8 
-0.276 
2.295 
-0.176 
2.362 
-0.283 
2.990 
-0.103 
-0.066 
9 
-0.294 
2.330 
-0.200 
2.452 
0.025 
2.062 
-0.097 
-0.104 
10 
-0.344 
2.507 
-0.230 
2.571 
0.051 
2.028 
-0.120 
-0.043 
11 
-0.308 
2.460 
-0.204 
2.526 
0.078 
2.006 
-0.089 
-0.105 
12 
-0.219 
2.312 
-0.107 
2.342 
0.225 
1.804 
-0.115 
-0.021 
13 
-0.117 
2.196 
-0.042 
2.294 
0.418 
1.504 
-0.051 
-0.148 
14 
0.041 
1.920 
0.105 
2.021 
0.574 
1.257 
-0.063 
-0.103 
15 
0.203 
1.662 
0.253 
1.787 
0.599 
1.281 
-0.043 
-0.139 
Source: Reference (Wang X, 1993) (Tables 4 and 5) 
 
 
 
 
 
 
 
 
 
 
 
 
 






Statistical Analysis Plan Module 1: Methods 
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10.7 Appendix G: Imputation Rules for Missing AE Start Dates 
 
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. 
 
 


Statistical Analysis Plan Module 1: Methods 
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10.8 Appendix H: Threshold Analysis Criteria 
Table  10-8 
Threshold Criteria for Laboratory Tests 
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 
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 
<LLN – ≥ 3.0 mmol/L 
<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 


Statistical Analysis Plan Module 1: Methods 
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Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L  
CTCAE grade 1-3 
 
Amylase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Lipase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Direct bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
Same 
Criteria 
as 
Total 
Bilirubin 
 
No CTCAE  
Not in DILI Guidance 
 
GGT  
>ULN - ≤ 2.5 x ULN 
>2.5 –  ≤ 5.0 x ULN 
>5.0 –  ≤ 20.0 x ULN  
>20.0 x ULN 
CTCAE grade 1-4 
Calcium 
Hypercalcemia 
>ULN - ≤ 2.9 mmol/L  
>2.9 – ≤ 3.1 mmol/L  
>3.1 – ≤ 3.4 mmol/L  
>3.4 mmol/L 
CTCAE grade 1-4 
Hypocalcemia 
<LLN - ≥ 2.0 mmol/L 
<2.0 – ≥1.75 mmol/L  
<1.75 – ≥ 1.5 mmol/L  
<1.5 mmol/L  
CTCAE grade 1-4 
Magnesium 
 
Hypermagnesemia 
>ULN - ≤ 1.23 mmol/L 
>1.23 – ≤ 3.30 mmol/L 
>3.30 mmol/L 
CTCAE grade 1, 3, 4 
 
No CTCAE grade 2 
Hypomagnesemia 
<LLN - ≥ 0.5 mmol/L 
<0.5 – ≥ 0.4 mmol/L 
<0.4 – ≥ 0.3 mmol/L  
<0.3 mmol/L  
CTCAE grade 1-4 
Bicarbonate 
 
<LLN 
>ULN 
No CTCAE 
Inorganic 
phosphate 
Hypophosphatemia 
<LLN - ≥ 0.8 mmol/L 
<0.8 – ≥ 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 
FDA DILI Guidance and CTCAE 
 


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Vertex Pharmaceuticals Incorporated 
 
 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
ALT or AST 
ALT>3xULN or AST>3xULN 
FDA DILI Guidance  
Alkaline 
Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN  
>20.0 x ULN  
FDA DILI Guidance and CTCAE 
 
Total Bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
FDA DILI Guidance and CTCAE 
 
 
ALT 
and 
Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance 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) 
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 Module 1: Methods 
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Protocol Number: VX15-661-112, Version 1.0, 07 May 2018 
 
Vertex Pharmaceuticals Incorporated 
 
 
Table  10-9 
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 Module 1: Methods 
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Protocol Number: VX15-661-112, Version 1.0, 07 May 2018 
 
Vertex Pharmaceuticals Incorporated 
 
 
Table  10-10 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 
 
 
 


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Vertex Pharmaceuticals Incorporated 
 
 
Table  10-11 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 
 
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 
 


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Vertex Pharmaceuticals Incorporated 
 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3 
 
 


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Vertex Pharmaceuticals Incorporated 
 
 
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2. Sheik J, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes D Jr. Computed 
tomography correlates with improvement with ivacaftor in cystic fibrosis patients with 
G551D mutation. J Cyst Fibros. 2015;14(1):84-9. 
3. 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. 
4. 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. 
8. Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm.