Clinical trial NCT03447249
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-03-07; Completion date: 2019-02-05
Enrollment: 385 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy of VX-659 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for F508del and a minimal function mutation (F/MF subjects).

Detailed description:

Arms: arm 1: Participants who received placebo matched to VX-659/TEZ/IVA for 24 weeks in the TC treatment period. arm 2: Participants who received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as fixed-dose combination (FDC) tablets in the morning and IVA 150 mg as mono tablet in the evening for 24 weeks in the TC treatment period.
Interventions: intervention 1: VX-659/TEZ/IVA intervention 2: IVA intervention 3: Placebo
Intervention descriptions: intervention 1: Participants received VX-659/TEZ/IVA orally once daily in the morning. intervention 2: Participants received IVA orally once daily in the evening. intervention 3: Participants received placebo matched VX-659/TEZ/IVA orally once daily in the morning and placebo matched to IVA orally once daily in the evening.

Protocol documents:
Prot_000.pdf: 






Protocol VX17-659-102, Version 3.0 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and 
Safety of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are 
Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF) 
Brief Title 
A Phase 3 Study of VX-659 Combination Therapy in Subjects With Cystic Fibrosis 
Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF) 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3, efficacy and safety 
 
 
Objectives 
Primary Objective 
To evaluate the efficacy of VX-659 in triple combination (TC) with tezacaftor (TEZ) and 
ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for F508del 
and a minimal function mutation (F/MF subjects)  
Secondary Objectives 
 
To evaluate the safety of VX-659 in TC with TEZ and IVA  
 
To evaluate the pharmacodynamics (PD) of VX-659 in TC with TEZ and IVA 
 
To evaluate the pharmacokinetics (PK) of VX-659, TEZ, and IVA when 
administered in TC  
 
 
Endpoints 
Primary Endpoint 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline at Week 4 
Key Secondary Endpoints 
 
Absolute change in ppFEV1 from baseline through Week 24 
 
Number of pulmonary exacerbations (PEx) through Week 24 
 
Absolute change in sweat chloride (SwCl) from baseline through Week 24 
 
Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline through Week 24 
 
Absolute change in body mass index (BMI) from baseline at Week 24 
 
Absolute change in SwCl from baseline at Week 4 
 
Absolute change in CFQ-R respiratory domain score from baseline at Week 4 
Other Secondary Endpoints 
 
Time-to-first PEx through Week 24 
 
Absolute change in BMI z-score from baseline at Week 24 
 
Absolute change in body weight from baseline at Week 24 
 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry 
 
PK parameters of VX-659, TEZ, M1-TEZ, and IVA 


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Number of Subjects 
Approximately 360 subjects will be randomized (1:1) to the TC VX-659/TEZ/IVA arm 
or the triple placebo arm. 
 
 
Study Population 
Male and female subjects with CF who are 12 years of age or older and heterozygous for 
the F508del mutation and an MF mutation (F/MF subjects) 
 
  
Investigational Drug 
Study drug refers to VX-659/TEZ/IVA, IVA, and their matching placebos. 
Active study drugs will be orally administered as 2 fixed-dose combination (FDC) 
film-coated tablets (VX-659/TEZ/IVA) in the morning and as 1 film-coated IVA tablet 
in the evening.  
 
Active substance: VX-659, TEZ (tezacaftor; VX-661), and IVA (ivacaftor; VX-770) 
 
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator (increased Cl− 
secretion) 
 
Strength: 120 mg/50 mg/75 mg 
 
 
 
Active substance: IVA (ivacaftor; VX-770) 
 
Activity: CFTR potentiator (increased Cl− secretion) 
 
Strength: 150 mg 
 
 
Study Duration 
The total study duration is approximately 32 weeks (4 weeks for the Screening Period, 
24 weeks for the Treatment Period, and 4 weeks for the Safety Follow-up Period). 
 
 
Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study.  
 
Approximately 360 subjects will be randomized (1:1) to the TC arm or triple placebo 
arm. The dosages to be evaluated are shown in the table below. Randomization will be 
stratified by ppFEV1 determined during the Screening Period (<70 versus ≥70), age at 
the Screening Visit (<18 versus ≥18 years of age), and sex (male versus female). 
 


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Treatment Arms and Dosages 
Treatment Arm 
VX-659 Dosage 
TEZ Dosage 
IVA Dosage 
TC 
240 mg qd 
100 mg qd 
150 mg q12h 
Triple placebo 
0 mg 
0 mg 
0 mg 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TC: triple combination; TEZ: tezacaftor  
 
 
Assessments 
Efficacy: Spirometry, documentation of events related to health outcomes (e.g., PEx), 
CFQ-R, height (for subjects ≤21 years of age only), and weight  
PD: SwCl 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, physical 
examinations, and ophthalmologic examinations (for subjects <18 years of age) 
PK: VX-659, TEZ, M1-TEZ, and IVA plasma concentrations 
 
 
Statistical Analyses 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline at 
Week 4. The primary null hypothesis to be tested is that the mean absolute change in 
ppFEV1 from baseline is the same for the 2 treatment groups, VX-659/TEZ/IVA and 
placebo. The null hypothesis will be tested at an overall 2-sided significance level of 
0.05. 
An interim analysis (IA) is planned when at least 140 subjects complete the Week 4 Visit 
and at least 100 subjects complete the Week 12 Visit. The IA will be performed by an 
external independent biostatistician who is not involved in and will not influence the 
conduct of the study, and the results will be reviewed by an independent data monitoring 
committee (IDMC). A Lan and DeMets alpha spending function will be applied to 
control the overall type I error rate of 0.05 for the primary endpoints during the IA and 
the final analysis such that an alpha of 0.01 will be preserved for the final analysis. If the 
number of subjects included in the IA is 140, then the primary endpoint of the absolute 
change from baseline in ppFEV1 at Week 4 will be tested at a significance level of 0.044 
during the IA. The actual alpha at the IA (0) will be determined based on the actual 
number of subjects included in the IA. Assuming a within-group SD of 7 percentage 
points and a 5% dropout rate at Week 4, an IA sample size of 70 subjects in each 
treatment group will have approximately 98% power to detect a difference between the 
treatment groups of 5.0 percentage points for the mean absolute change in ppFEV1 from 
baseline at Week 4, based on a 2-sided, 2-sample t-test at a significance level of 0.044.  
If the P value for the primary endpoint at the IA is less than 0, then the efficacy 
boundary has been crossed. If the IDMC declares that the study has crossed the efficacy 
boundary, then the study may be unblinded to a limited Vertex team to prepare 
regulatory submission(s). Members of the limited Vertex unblinded team will not be 
involved in or influence the conduct of the remaining part of the study to protect the 
integrity of the study.  
If the P value fails to cross the efficacy boundary during the IA, then the primary 
endpoint of absolute change in ppFEV1 from baseline at Week 4 will be tested after all 
subjects complete study participation at an alpha of 0.01. Assuming a within-group SD 
of 7 percentage points and a 5% dropout rate at Week 4 and 10% dropout rate at 
Week 24, a final analysis sample size of 180 subjects in each treatment group will have 
approximately 99% power to detect a difference between the treatment groups of 
5.0 percentage points for the mean absolute change in ppFEV1 from baseline at Week 4, 
based on a 2-sided, 2-sample t-test at a significance level of 0.01.  


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The analysis of the primary endpoint during the IA will be based on a mixed-effects 
model for repeated measures (MMRM) with the absolute change from baseline in 
ppFEV1 at Day 15 and Week 4 as the dependent variable. During the final analysis, the 
same model will be implemented, including all available data. The model will include 
treatment group, visit, and treatment-by-visit interaction as fixed effects; with sex (male 
versus female), continuous baseline ppFEV1, and age at screening (<18 versus ≥18 years 
of age) as covariates; and with an unstructured covariance structure for the within-subject 
errors. 
The primary result obtained from the model will be the estimated treatment difference at 
Week 4. The adjusted mean difference at Week 4 with 2-sided 95% confidence intervals 
and 2-sided P values will be provided. Furthermore, the adjusted mean and treatment 
difference at each post-baseline visit, obtained from the model at the final analysis, will 
also be provided. 
The key secondary endpoints will be formally tested only during the final analysis when 
all subjects complete study participation, at the significance level of 0.05, if the primary 
endpoint is statistically significant at either the IA or at the final analysis. 
The safety endpoints include AEs, clinical laboratory values, ECGs, vital signs, and 
pulse oximetry through the Safety Follow-up Visit. The safety analysis will be 
descriptive only. 
 
 
IDMC Reviews 
An IDMC will conduct periodic planned safety review(s) of study data and the planned 
efficacy IA, as outlined in the IDMC charter. 




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Table 3-1 
Study VX17-659-102: Screening 
Event/Assessment 
Screening Period (Day -28 Through Day -1) 
ICF and assent (when applicable) 
X 
Inclusion and exclusion criteria review 
X 
Demographics 
X 
Medical history  
X 
CFQ-Ra  
X 
CFTR genotypeb 
X 
G6PD activity test 
 X 
FSHc 
X 
Serum pregnancy test (all females of childbearing potential)d 
X 
Hematology 
X 
Coagulation 
X 
Serum chemistry 
X 
Urinalysis 
X 
Weight and heighte 
X 
Ophthalmologic examinationf 
X 
Complete physical examination 
X 
Vital signsg 
X 
Pulse oximetryg 
X 
Standard 12-lead ECGh 
X 
Spirometryi 
X 
Medications reviewj 
X 
Sweat chloride 
X 
AEs and SAEs 
Continuous from signing of the ICF through 
completion of study participation 
AE: adverse events; CFQ-R: CF Questionnaire-Revised; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; SAE: serious adverse event 
 a 
The CFQ-R must be completed before the start of any other assessments scheduled for that visit. 
b 
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before 
randomization, a previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who have been 
randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study 
(Section 9.9). 
c 
FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be in the postmenopausal range, as determined by the laboratory performing the test, to 
be considered postmenopausal. 
d 
Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing 
potential and must have a serum pregnancy test. A definition of non-childbearing potential is provided in Section 11.7.7.1. 
e 
Weight and height will be measured with shoes off. 
f 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on the date of informed consent. 
For subjects with documentation of bilateral lens removal, ophthalmologic examinations are not required. The 
ophthalmologic examination does not need to be conducted if there is documentation of an examination meeting the 
protocol requirements that was conducted within 3 months before the date of informed consent (Section 11.7.6). The 
ophthalmologic examination will be conducted by a licensed ophthalmologist or optometrist. 
g 
Vital signs and pulse oximetry will be collected after the subject has been at rest for at least 5 minutes. 
h 
A standard 12-lead ECG will be performed after the subject has been at rest for at least 5 minutes. 
i 
Spirometry may be performed pre- or post-bronchodilator (Section 11.6.1). 
j 
Refer to Section 9.5 for details.  




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Table 3-2 
Study VX17-659-102: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
 
 
 
Day 
1 
Day 15 
(± 3 Days) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days) 
Week 12 
(± 5 Days) 
Week 16 
(± 5 Days) 
Week 20 
(± 5 Days) 
Week 24 
(± 5 Days) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) Days 
After the Last Dose 
of Study Drug (If 
Applicable)c 
Complete physical 
examinationh 
X 
 
X 
 
 
 
 
X 
X 
 
Pregnancy testingi 
urine 
urine 
urine 
urine 
urine 
urine 
urinej  
urine 
serum 
serum 
FSHk 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead ECGl 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital signsm 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Pulse oximetrym 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Spirometryn 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Sweat chlorideo 
X 
 
X 
X 
X 
  
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
X 
X 
Hematology 
Xp 
X 
X 
X 
X 
X 
 
X 
X 
X 
Coagulation 
Xp 
 
 
 
 
 
 
X 
X 
X 
Serum chemistry 
Xp 
X 
X 
X 
X 
X 
 
X 
X 
X 
PK samplingq  
X 
 
X 
X 
X 
X 
 
 
X 
 
 h 
Subjects will have a complete physical examination as defined in Section 11.7.3. Symptom-directed physical examinations will occur at any time during the study if deemed 
necessary by the investigator. 
i  
Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing potential and must have pregnancy tests at the indicated 
 
time points. A definition of non-childbearing potential is provided in Section 11.7.7.1. 
j  
At Week 20, when there is no clinic visit, a urine pregnancy test will be performed with a home kit provided by the study site. Results will be reported to the site by telephone. 
k  
Blood samples for FSH will be measured as needed as outlined in Section 11.7.2. 
l 
All standard 12-lead ECGs will be performed after the subject has been at rest for at least 5 minutes. ECGs will be collected before dosing (as applicable). 
m 
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest for at least 5 minutes (Section 11.7.3 and Section 11.7.4). 
n 
Spirometry assessments must be performed before study drug dosing (Section 9.6.1) and should be performed pre-bronchodilator (Section 11.6.1) at approximately the same 
time at each visit. 
o  
Sweat chloride collection will occur before study drug dosing (Section 11.4). At each time point, 2 samples will be collected, 1 from each arm (left and right). 
p  
Blood samples will be collected before the first dose of study drug. 
q  
PK samples will be collected predose on Day 1, Week 4, Week 8, Week 12, and Week 16. Approximately 40 subjects enrolled in the study will have 4 postdose samples taken 
at 2, 4, 6, and 8 hours after the morning dose at Week 4. All remaining subjects will have 1 postdose sample taken at 1 hour after the morning dose at Week 4. Vertex will 
manage the allocation of the 40 subjects providing more intensive PK sampling across study sites (Section 11.3.1). If study drug is not administered at the Week 4 Visit (i.e., 
due to study drug interruption or permanent discontinuation), a single PK blood sample will be collected at the visit. At the ETT Visit, a single PK blood sample will be 
collected. 


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Table 3-2 
Study VX17-659-102: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
 
 
 
Day 
1 
Day 15 
(± 3 Days) 
Week 4 
(± 5 Days) 
Week 8 
(± 5 Days) 
Week 12 
(± 5 Days) 
Week 16 
(± 5 Days) 
Week 20 
(± 5 Days) 
Week 24 
(± 5 Days) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) Days 
After the Last Dose 
of Study Drug (If 
Applicable)c 
Randomizationt 
X 
 
 
 
 
 
 
 
 
 
Study drug dosingu 
Day 1 through evening before Week 24 
 
 
Study drug count 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Other events related to 
outcomev, w 
Continuous from signing of ICF through completion of study participation 
Medications revieww 
Continuous from signing of ICF through completion of study participation 
Treatments and procedures 
revieww 
Continuous from signing of ICF through completion of study participation 
AEs and SAEsw, x  
Continuous from signing of ICF through completion of study participation 
AE: adverse event; CF: cystic fibrosis; CFQ-R: CF Questionnaire-Revised; ETT: Early Termination of Treatment; FSH: follicle-stimulating hormone; GPS: Global Patient Safety; 
ICF: informed consent form; PD: pharmacodynamic; PEx: pulmonary exacerbation(s); PK: pharmacokinetic; SAE: serious adverse event; 
 
 
 
Randomization may occur on either Day -1 or Day 1, after all eligibility criteria are confirmed. 
u 
The study drug regimen should be administered as outlined in Section 9.6.1. On days of scheduled visits, refer to Section 9.6.1 for the timing of dosing relative to the 
assessment. The final dose of study drug will be administered the evening before the Week 24 Visit. 
v 
Other events related to outcome include assessments relating to PEx, administration of antibiotic therapy for sinopulmonary signs/symptoms, and hospitalizations for CF 
(Section 11.6.4). 
w  
Completion of study participation is defined in Section 9.1.6. 
x  
SAEs that occur after completion of study participation and are considered related to study drug will be reported to Vertex GPS within 24 hours as described in 
Section 13.1.2.2. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 13 
List of Tables............................................................................................................................ 17 
List of Figures .......................................................................................................................... 17 
List of Appendices ................................................................................................................... 17 
List of Abbreviations................................................................................................................ 18 
5 
Introduction.......................................................................................................................... 21 
5.1 
Background ..................................................................................................................... 21 
5.2 
Rationale for the Present Study ...................................................................................... 21 
6 
Study Objectives .................................................................................................................. 22 
6.1 
Primary Objective ........................................................................................................... 22 
6.2 
Secondary Objectives ..................................................................................................... 22 
7 
Study Endpoints ................................................................................................................... 22 
7.1 
Primary Endpoint ............................................................................................................ 22 
7.2 
Secondary Endpoints ...................................................................................................... 22 
7.2.1 
Key Secondary Endpoints ...................................................................................... 22 
7.2.2 
Other Secondary Endpoints .................................................................................... 22 
 
 
8 
Study Population .................................................................................................................. 23 
8.1 
Inclusion Criteria ............................................................................................................ 23 
8.2 
Exclusion Criteria ........................................................................................................... 23 
9 
Study Implementation ......................................................................................................... 25 
9.1 
Study Design .................................................................................................................. 25 
9.1.1 
Screening ................................................................................................................ 26 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 26 
9.1.1.2 
Rescreening ...................................................................................................... 26 
9.1.1.3 
Extension of Screening Period Window .......................................................... 26 
9.1.2 
Treatment Period .................................................................................................... 26 
9.1.3 
Follow-up................................................................................................................ 27 
9.1.4 
Early Termination of Treatment ............................................................................. 27 
9.1.5 
Lost to Follow-up ................................................................................................... 27 
9.1.6 
Completion of Study Participation ......................................................................... 27 
9.1.7 
Independent Data Monitoring Committee .............................................................. 28 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 28 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 28 
9.3.1 
Study Design........................................................................................................... 28 
9.3.2 
Study Drug Dose .................................................................................................... 29 
9.3.3 
Rationale for Study Population............................................................................... 29 
9.3.4 
Rationale for Study Assessments ........................................................................... 29 
9.4 
Study Restrictions ........................................................................................................... 30 
9.4.1 
Prohibited Medications ........................................................................................... 30 




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11.7.1 
Adverse Events ....................................................................................................... 44 
11.7.2 
Clinical Laboratory Assessments ........................................................................... 44 
11.7.3 
Physical Examinations and Vital Signs .................................................................. 46 
11.7.4 
Pulse Oximetry ....................................................................................................... 46 
11.7.5 
Electrocardiograms ................................................................................................. 46 
11.7.6 
Ophthalmologic Examination ................................................................................. 47 
11.7.7 
Contraception and Pregnancy ................................................................................. 47 
11.7.7.1 Contraception ................................................................................................... 47 
11.7.7.2 Pregnancy ......................................................................................................... 49 
12 Statistical and Analytical Plans .......................................................................................... 49 
12.1 Sample Size and Power .................................................................................................. 49 
12.2 Analysis Sets .................................................................................................................. 50 
12.3 Statistical Analysis ......................................................................................................... 51 
12.3.1 
General Considerations ........................................................................................... 51 
12.3.2 
Background Characteristics .................................................................................... 51 
12.3.2.1 Subject Disposition .......................................................................................... 51 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 51 
12.3.2.3 Prior and Concomitant Medications................................................................. 51 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 52 
12.3.2.5 Important Protocol Deviations ......................................................................... 52 
12.3.3 
Efficacy and Pharmacodynamic Analysis .............................................................. 52 
12.3.3.1 Final Analysis .................................................................................................. 52 
12.3.3.1.1 Analysis of Primary Variables .................................................................. 52 
12.3.3.1.2 Analysis of Secondary Variables .............................................................. 53 
 
12.3.3.3 Interim Analysis ............................................................................................... 55 
12.3.3.3.1 Analysis of Primary Variables .................................................................. 55 
12.3.3.3.2 Analysis of Key Secondary Variables ....................................................... 55 
12.3.3.4 Multiplicity Adjustment ................................................................................... 55 
12.3.4 
Safety Analysis ....................................................................................................... 56 
12.3.4.1 Adverse Events................................................................................................. 56 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 57 
12.3.4.3 Electrocardiogram ............................................................................................ 57 
12.3.4.4 Vital Signs ........................................................................................................ 57 
12.3.4.5 Pulse Oximetry ................................................................................................. 58 
12.3.4.6 Physical Examination ....................................................................................... 58 
12.3.4.7 Other Safety Analyses ...................................................................................... 58 
 
 
12.3.6 
Interim and IDMC Analyses ................................................................................... 58 
12.3.6.1 Interim Analyses .............................................................................................. 58 
12.3.6.2 IDMC Analysis ................................................................................................ 59 
12.4 Clinical Pharmacology Analysis .................................................................................... 59 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 59 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 59 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 59 


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13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 59 
13.1.1 
Adverse Events ....................................................................................................... 59 
13.1.1.1 Definition of an Adverse Event........................................................................ 59 
13.1.1.2 Clinically Significant Assessments .................................................................. 60 
13.1.1.3 Documentation of Adverse Events................................................................... 60 
13.1.1.4 Adverse Event Severity .................................................................................... 60 
13.1.1.5 Adverse Event Causality .................................................................................. 61 
13.1.1.6 Study Drug Action Taken ................................................................................ 61 
13.1.1.7 Adverse Event Outcome .................................................................................. 62 
13.1.1.8 Treatment Given............................................................................................... 62 
13.1.2 
Serious Adverse Events .......................................................................................... 62 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 62 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 63 
13.1.2.3 Reporting Serious Adverse Events................................................................... 63 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 64 
13.2 Administrative Requirements ......................................................................................... 64 
13.2.1 
Ethical Considerations ............................................................................................ 64 
13.2.2 
Subject Information and Informed Consent ........................................................... 64 
13.2.3 
Investigator Compliance ......................................................................................... 64 
13.2.4 
Access to Records ................................................................................................... 65 
13.2.5 
Subject Privacy ....................................................................................................... 65 
13.2.6 
Record Retention .................................................................................................... 65 
13.2.7 
Study Termination .................................................................................................. 65 
13.2.8 
End of Study ........................................................................................................... 66 
13.3 Data Quality Assurance .................................................................................................. 66 
13.4 Monitoring ...................................................................................................................... 66 
13.5 Electronic Data Capture ................................................................................................. 66 
13.6 Publications and Clinical Study Report .......................................................................... 67 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 67 
14 References ............................................................................................................................. 68 
APPENDIX A  Eligible MF CFTR Mutations ...................................................................... 70 
15 Protocol Signature Pages .................................................................................................... 73 
15.1 Sponsor Signature Page .................................................................................................. 73 
15.2 Investigator Signature Page ............................................................................................ 74 
 


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List of Tables 
Table 3-1 
Study VX17-659-102: Screening ............................................................................ 9 
Table 3-2 
Study VX17-659-102: Treatment Period and Safety Follow-up Visit ................. 10 
Table 9-1 
Treatment Arms and Dosages ............................................................................... 25 
Table 9-2 
Prohibited Medications ......................................................................................... 31 
Table 10-1 
Study Drug: Strength/Dosing Form/Route ........................................................... 36 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 39 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 45 
Table 11-3 
Acceptable Methods of Contraception.................................................................. 48 
Table 13-1 
Grading of AE Severity ........................................................................................ 61 
Table 13-2 
Classifications for AE Causality ........................................................................... 61 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 61 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 62 
 
List of Figures 
Figure 9-1 
Schematic of the Study Design ............................................................................. 25 
 
List of Appendices 
APPENDIX A 
Eligible MF CFTR Mutations 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
CBC 
complete blood count 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire - Revised 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
Cl− 
chloride ion 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
 
 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ETT 
Early Termination of Treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon corresponding to 
position 508 of the wild-type protein 
F/F 
homozygous for F508del 
F/MF 
heterozygous for F508del and a minimal CFTR function mutation 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
 
 
FEV1 
forced expiratory volume in 1 second 
FRT 
Fischer rat thyroid 
FSH 
follicle-stimulating hormone 
 
 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial (cells) 


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Abbreviation 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act  
HR 
heart rate 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
 
 
 
 
IPD 
important protocol deviation 
IRB 
institutional review board 
IV 
intravenous 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LLN 
lower limit of normal 
LUM 
lumacaftor 
M1-TEZ 
metabolite of TEZ 
MAA 
Marketing Authorization Application 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal CFTR function mutation 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
 
 
N 
number of subjects 
OATP1B1 
organic anion transporting polypeptide 1B1 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PEx 
pulmonary exacerbation 
PI 
pancreatic insufficiency 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 
qd 
once daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing ventricular 
depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
RR 
interval from the onset of 1 QRS complex to the next 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
 
 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
UV 
ultraviolet 
 
  
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious morbidities and 
frequent premature mortality. At present, there is no cure. CF affects approximately 
70,000 individuals worldwide1 (approximately 30,000 in the US1, 2 and 39,000 in the EU3). 
Based on its prevalence, CF qualifies as an orphan disease.4, 5 
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene. The CFTR protein is an epithelial chloride channel that aids in regulating salt and 
water absorption and secretion and pH balance in sweat glands and multiple organs, including 
the lungs, pancreas, and other gastrointestinal organs. Despite progress in the treatment of CF 
with antibiotics and mucolytics, the predicted median age of survival for a person with CF is 
approximately 40 years.2, 6 Progressive loss of lung function is the leading cause of mortality.7 
More effective treatments are needed for CF. 
The most common disease-causing CFTR mutation, F508del, accounts for 70% of the identified 
alleles in people with CF8, and approximately 40% of people with CF are homozygous for 
F508del (F/F).2, 3, 8 
Based on the understanding of the molecular defects caused by CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. Correctors facilitate 
the cellular processing and trafficking to increase the quantity of functional CFTR at the cell 
surface. Potentiators increase the channel open probability of the CFTR protein delivered to the 
cell surface to enhance ion transport. Depending on the amount of residual CFTR channel 
activity in the membrane, and the pathophysiology of that activity (reflecting the CFTR genotype 
of the patient and possibly other factors), both approaches may be required. 
The therapeutic activity of CFTR correctors and potentiators has been established with products 
that were developed by Vertex and approved for the treatment of CF: ivacaftor (IVA) 
monotherapy (Kalydeco®), and lumacaftor (LUM) in combination with IVA (Orkambi®). 
Kalydeco and Orkambi are approved to treat CF in patients with specific CFTR genotypes. A 
second corrector/potentiator combination, tezacaftor (TEZ)/IVA (Symdeko®) is now approved 
in the US. An MAA has been submitted and is under review. 
VX-659 is a next-generation CFTR corrector being developed for administration in triple 
combination (TC) with TEZ/IVA for the treatment of CF.  
5.2 
Rationale for the Present Study 
This study will evaluate the efficacy and safety of VX-659 in TC with TEZ/IVA in subjects with 
CF who are heterozygous for F508del (F) and a second CFTR allele carrying a minimal function 
mutation that is non-responsive to TEZ, IVA, or TEZ/IVA (MF; refer to Appendix A for MF 
mutations). Patients with this genotype (F/MF patients) generally have severe disease and do not 
have approved CFTR modulator therapy available to them; previous studies with TEZ/IVA 
(Study VX14-661-107) and LUM/IVA (Study VX09-809-102) failed to demonstrate efficacy in 
this patient population. Due to this high unmet need, VX-659 is being developed in TC with 
TEZ/IVA for F/MF subjects. The potential for benefit in these patients is supported by in vitro 


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data and clinical data in F/MF subjects; in addition, the TC of VX-659/TEZ/IVA is generally 
safe and well tolerated (refer to VX-659 Investigator’s Brochure). 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of VX-659 in TC with TEZ and IVA in subjects with CF who are 
heterozygous for F508del and a minimal function mutation (F/MF subjects) 
6.2 
Secondary Objectives 
 To evaluate the safety of VX-659 in TC with TEZ and IVA  
 To evaluate the pharmacodynamics (PD) of VX-659 in TC with TEZ and IVA 
 To evaluate the pharmacokinetics (PK) of VX-659, TEZ, and IVA when administered in TC 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change in ppFEV1 from baseline at Week 4 
7.2 
Secondary Endpoints 
7.2.1 
Key Secondary Endpoints 
 Absolute change in ppFEV1 from baseline through Week 24 
 Number of pulmonary exacerbations (PEx) through Week 24 
 Absolute change in SwCl from baseline through Week 24 
 Absolute change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) respiratory domain 
score from baseline through Week 24 
 Absolute change in body mass index (BMI) from baseline at Week 24 
 Absolute change in SwCl from baseline at Week 4 
 Absolute change in CFQ-R respiratory domain score from baseline at Week 4 
7.2.2 
Other Secondary Endpoints 
 Time-to-first PEx through Week 24 
 Absolute change in BMI z-score from baseline at Week 24 
 Absolute change in body weight from baseline at Week 24 
 Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
ECGs, vital signs, and pulse oximetry 
 PK parameters of VX-659, TEZ, M1-TEZ, and IVA 


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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are randomized. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Age 12 years or older, on the date of informed consent. 
4. Confirmed diagnosis of CF as determined by the investigator. 
5. Heterozygous for F508del and an MF mutation (F/MF genotypes, see Appendix A for 
eligible MF mutations). If the screening CFTR genotype result is not received before 
randomization, a previous CFTR genotype laboratory report may be used to establish 
eligibility. Subjects who have been randomized and whose screening genotype does not 
confirm study eligibility must be discontinued from the study (Section 9.9). 
6. Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for 
age, sex, and height (equations of the Global Lung Function Initiative [GLI])9 at the 
Screening Visit. Spirometry measurements must meet American Thoracic Society/European 
Respiratory Society criteria10 for acceptability and repeatability.  
7. Stable CF disease as judged by the investigator. 
8. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
 Clinically significant cirrhosis with or without portal hypertension 
 Solid organ or hematological transplantation. 
 Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, 
and opiates, as deemed by the investigator. 


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 Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (all 3 with no recurrence for the last 5 years) 
2. Any of the following abnormal laboratory values at screening: 
 Hemoglobin <10 g/dL 
 Total bilirubin ≥2 × ULN 
 Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
 Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 
(calculated by the Modification of Diet in Renal Disease Study Equation)11,12 for subjects 
≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation)13 for subjects aged 12 to 17 years (inclusive) 
3. An acute upper or lower respiratory infection, PEx, or changes in therapy (including 
antibiotics) for sinopulmonary disease within 28 days before the first dose of study drug 
(Day 1). 
4. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus). For subjects who have had a history of a positive culture, the 
investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms:  
 The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent. 
 The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent one within the 6 months before the 
date of informed consent. 
5. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug (Day 1).  
6. Ongoing or prior participation in a study of an investigational treatment within 28 days or 
5 terminal half-lives (whichever is longer) before screening. The duration of the elapsed time 
may be longer if required by local regulations.  
7. Use of prohibited medications as defined in Table 9-2, within the specified window before 
the first dose of study drug (Day 1). 
8. Pregnant or nursing females. Females of childbearing potential must have a negative 
pregnancy test at screening (serum test) and Day 1 (urine test). 
9. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be randomized in the study provided that 
 the adult lives independently of and does not reside with the study staff member, and 




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9.1.1 
Screening 
The Screening Period (Day -28 through Day -1) will occur within 28 days before the first dose of 
study drug. 
Screening assessments will be used to confirm that subjects meet the eligibility criteria. The 
investigator (or an appropriate authorized designee) will obtain informed consent and assent, if 
applicable, from each subject before any study procedure takes place. 
9.1.1.1 
Repetition of Screening Assessment(s) 
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may be rescreened once. If a subject is rescreened, all screening assessments will be 
repeated, except for:  
 CFTR genotyping 
 Follicle-stimulating hormone (FSH) level (if serum FSH level was in the postmenopausal 
range as determined by the laboratory performing the test during prior screening) 
 G6PD activity test  
 Ophthalmologic examination (if performed within 3 months of the date of informed consent, 
for subjects <18 years of age ) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
 Repetition of the Screening Period assessments (Section 9.1.1.1) 
 Unexpected operational or logistic delays, or to meet the eligibility criteria 
 Scheduling of ophthalmologic examination (for subjects <18 years of age on the date of 
informed consent, Section 11.7.6) 
 28-day washout period for subjects who have been on an investigational or commercially 
available CFTR modulator (e.g., TEZ/IVA, IVA [Kalydeco], LUM/IVA [Orkambi]; see 
Table 9-2). 
9.1.2 
Treatment Period 
The Treatment Period will be randomized, double-blind, and placebo-controlled. It will last 
approximately 24 weeks (Day 1 through Week 24). Study drug administration details are 
provided in Section 9.6. 


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Randomization will occur before the first dose of study drug during the Treatment Period and 
may occur on either Day 1 or Day -1. Randomization and stratification details are provided in 
Section 9.2. 
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation of study drug treatment through the last scheduled study visit and 
complete the assessments for all study visits, as described in Section 9.1.4. 
9.1.3 
Follow-up 
The Safety Follow-up Visit will occur approximately 28 days after the last dose of study drug for 
subjects who complete study drug dosing and for subjects who prematurely discontinue study 
drug dosing, as described in Section 9.1.4. 
An open-label study will be available for subjects who complete the Week 24 Visit and are 
eligible. The Safety Follow-up Visit is not required for subjects who complete the Week 24 Visit 
and enroll in an open-label study within 28 days after the last dose of study drug. 
9.1.4 
Early Termination of Treatment  
If a subject prematurely discontinues study drug treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the decision to discontinue treatment. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety 
Follow-up Visit, approximately 28 days after their last dose of study drug. The assessments 
performed at the Safety Follow-up Visit are listed in Table 3-2. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
Subjects who prematurely discontinue study drug treatment will continue to complete all 
scheduled study visits for assessments following completion of the ETT Visit, as detailed in 
Table 3-2. Data regarding concomitant antibiotic therapy for sinopulmonary signs/symptoms will 
also continue to be collected for these subjects.  
If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent. 
9.1.5 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
 The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
 The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.6 
Completion of Study Participation 
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 For subjects who complete the Treatment Period and enter an open-label study within 
28 days of the Week 24 Visit: the Week 24 Visit  
 For subjects who complete the Treatment Period and do not enter an open-label study within 
28 days of the Week 24 Visit: the Safety Follow-up Visit 
 For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the Week 24 Visit, ETT Visit, or Safety Follow-up 
Visit (if required) 
 For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9) 
If subjects are lost to follow-up (Section 9.1.5), the date of completion of study participation will 
be defined as the date of the last contact.  
The end of study is defined in Section 13.2.8. 
9.1.7 
Independent Data Monitoring Committee 
This study will be monitored by an independent data monitoring committee (IDMC), which will 
conduct periodic planned safety review(s) of study data and the planned efficacy interim analysis 
(IA) (Section 12.3.6.2). Procedural details of the IDMC structure and function, frequency of 
meetings, and data planned for review will be included in the IDMC charter. The IDMC charter 
will be finalized before the first subject is screened. 
9.2 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized (1:1) to the TC VX-659/TEZ/IVA arm or to the triple placebo arm. 
Randomization will be stratified by ppFEV1 determined during the Screening Period (<70 versus 
≥70), age at the Screening Visit (<18 versus ≥18 years of age), and sex (male versus female).  
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code list will be produced by Vertex Biometrics or a qualified randomization 
vendor. 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
This Phase 3 study will assess the efficacy, safety, PD, and PK of VX-659/TEZ/IVA TC therapy 
in subjects with CF who have F/MF genotypes.  
A randomized, double-blind, controlled study design was selected to ascertain the effects of 
VX-659/TEZ/IVA while avoiding observer bias. Placebo is considered the appropriate 
comparator because efficacy has not been established for a corrector, potentiator, or any 
corrector/potentiator combination in subjects with F/MF genotypes.  
This study will have a 24-week treatment duration to allow for the collection of 
placebo-controlled safety data for this duration and the collection of data for outcomes that 
require longer treatment durations to demonstrate an effect (e.g., PEx and changes in nutritional 
status).  
The primary endpoint is the absolute change in ppFEV1 at Week 4. Previous studies of CFTR 
modulators (IVA, LUM/IVA, and TEZ/IVA) have demonstrated that efficacy related to lung 






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Table 9-2 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
Moderate and strong 
CYP3A or CYP2C9 
inducers 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
VX-659, TEZ, and IVA are metabolized 
extensively via CYP3A4. VX-659 is also 
metabolized by CYP2C9. Therefore, use of 
moderate and strong inducers of CYP3A or 
CYP2C9 and moderate and strong inhibitors of 
CYP3A, which have the potential to alter the 
exposure of VX-659, TEZ, or IVA, will be 
prohibited. 
 
Moderate and strong 
CYP3A inhibitors 
(except 
ciprofloxacin)a 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
Sensitive OATP1B1 
substrates 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
VX-659 is a potential inhibitor of the hepatic 
transporter OATP1B1. Therefore, sensitive 
substrates of OATP1B1, such as HMG-CoA 
reductase inhibitors (“statins”) are prohibited 
during treatment. 
CFTR modulators 
(investigational or 
approved), except for 
study drugs 
None allowed 
within 28 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
until after the last 
dose of study 
drug 
These agents may confound the results of this 
study. 
CYP: cytochrome P450; IVA: ivacaftor; OATP1B1: organic anion transporting polypeptide 1B1; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 
9.4.2 
Exposure to Sunlight 
Subjects will take appropriate measures to minimize exposure to UV radiation (e.g., prolonged 
sunlight, tanning booths) from Day 1 through completion of study participation. 
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected from each subject’s source 
documentation for medications taken within 56 days before the Screening Visit through 
completion of study participation, as defined in Section 9.1.6. 
For subjects who are screened but are not subsequently randomized, details of prior medication 
will be documented only in the subjects’ source documents. 
 Subjects should remain on a stable treatment regimen for their CF from 28 days before the 
Day 1 Visit through completion of study participation. Stable treatment regimen is defined as 
the current treatment regimen for CF that subjects have been following for at least 28 days 
before the Day 1 Visit. Subjects should not initiate long-term treatment with new medication 
from 28 days before the Day 1 Visit through completion of study participation. Guidelines 
for stable treatment regimens for CF are as follows: 
o Subjects who are taking inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 


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o Subjects who cycle onto and off of an inhaled antibiotic should continue on their prior 
schedule. The timing of the first dose of study drug on the Day 1 Visit should be 
synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in 
the cycle onto the inhaled antibiotic. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. The timing of the first dose of study drug on 
the Day 1 Visit should be synchronized as closely as possible (e.g., not more than 
± 3 days) to the first day in the cycle onto 1 of the inhaled antibiotics. 
 Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically, or 
up to 60 mg daily for up to 5 days. 
 Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.6.1. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally. All subjects will receive the same number of tablets each 
day to maintain the blind. Additional information is provided in the Pharmacy Manual. 
Study drug will be administered with a fat-containing meal or snack, such as a standard “CF” 
meal or snack or a standard meal. 
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
2. Study drug will be administered as 2 fixed-dose combination (FDC) TC or placebo tablets in 
the morning and as 1 IVA or placebo tablet in the evening. For each subject, doses of study 
drugs will be taken at approximately the same time (± 2 hours) each day.  
3. The date, amount taken, and time of study drug administration, including whether food was 
taken with each dose, will be recorded for the 2 doses before PK sample collection and the 
dose received on the morning of PK sample collection. 
4. On days of scheduled visits, the morning dose of study drug (TC or placebo) will be 
administered at the site after predose assessments have been completed. A meal or snack will 
be provided by the site for the morning dose of TC or placebo. 
5. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
 If the dose in the clinic will be within 6 hours of the subject’s scheduled morning dose, 
the subject should withhold their morning dose of TC or placebo and the morning dose 
will be administered in the clinic. 
 If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
dose, the subject should take the morning dose of TC or placebo at home.  
 At the Week 4 Visit, the morning dose of TC or placebo must be administered in the 
clinic to enable post-dose PK sampling relative to the morning dose. 


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6. Subjects will be instructed to bring all used and unused materials associated with the study 
drug to the site; study drug will be dispensed at each visit, as appropriate. 
9.6.2 
Missed Doses 
9.6.2.1 
Morning Dose of Study Drug 
If a subject misses the morning dose of study drug (TC or placebo) and recalls within 6 hours, 
the subject should take his/her dose with food. If more than 6 hours but fewer than 12 hours have 
elapsed after his/her usual dosing time, the subject should take the morning dose of TC or 
placebo but skip the evening dose of study drug (IVA or placebo). If more than 12 hours have 
elapsed after his/her usual dosing time, the subject should skip the morning dose of TC or 
placebo and take the evening dose of IVA or placebo.  
9.6.2.2 
Evening Dose of Study Drug 
If a subject misses the evening dose of IVA or placebo and recalls within 6 hours, the subject 
should take his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing 
time, the subject should skip that dose and resume his/her normal schedule for the following 
dose.  
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. Treatment may be interrupted as outlined in 
Section 9.8. If any unacceptable toxicity arises, individual subjects will discontinue dosing 
(Section 9.1.4). 
9.8 
Study Drug Interruption and Stopping Rules 
The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or AST >3 × ULN and total 
bilirubin >2 × ULN that are derived from centrally submitted samples. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 
the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 
 ALT or AST >8 × ULN 
 ALT or AST >5 × ULN for more than 2 weeks 
 ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical jaundice 


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A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Study drug administration must be discontinued if the following criterion is met: 
 Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, study drug administration may be resumed once 
transaminases return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified prior to resumption of study 
drug. Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology. 
9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher, or a rash that is 
considered a serious adverse event. The investigator will notify the medical monitor of any rash 
that results in interruption of study drug, is Grade 3 or higher (Section 13.1.1.4), or is a serious 
adverse event (SAE). Investigators should consider additional evaluation including laboratory 
testing (e.g., complete blood count [CBC] with differential, LFTs), photographs of the rash, and 
dermatology consultation. The investigator may consider resumption of study drug if considered 
clinically appropriate. 
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided that the subject has not withdrawn consent (and assent, as applicable). 
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
 Has a screening CFTR genotype that does not confirm study eligibility if a previous CFTR 
genotype laboratory report was used to establish eligibility. These subjects must be 
discontinued from the study (Section 8.1) 
 Meets any of the stopping (discontinuation) criteria (Section 9.7) 
 Becomes pregnant (Section 11.7.7.2)  


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Subjects who discontinue study drug treatment should return for study assessments, as noted in 
Section 9.1.4. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for an ETT Visit and Safety 
Follow-up Visit, if applicable (see Section 9.1.4), and follow up with the subject regarding any 
unresolved AEs. 
If the subject withdraws consent or assent for the study, no further assessments will be 
performed. Vertex may retain and continue using the study data and samples after the study is 
over, and may use the samples and information in the development of the study compound, and 
for other drugs and diagnostics, in publications and presentations, and for education purposes. If 
the subject withdraws from the study, the study data and samples collected will remain part of 
the study. A subject will not be able to request the withdrawal of his/her information from the 
study data. A subject may request destruction of the samples collected from him/her during the 
study as long as those samples can be identified as his/her samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn before the first dose of study drug on Day 1 may be 
replaced.  
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug Treatment 
Period may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to VX-659/TEZ/IVA, IVA, and their matching placebos. 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
VX-659/TEZ/IVA will be supplied as 2 FDC film-coated tablets (120 mg VX-659/50 mg 
TEZ/75 mg IVA). Matching VX-659/TEZ/IVA placebo tablets will be of similar size and 
appearance and contain 0-mg VX-659, 0-mg TEZ, and 0-mg IVA (Table 10-1). 
IVA (150 mg) will be supplied as tablets containing 150-mg IVA. Matching IVA placebo tablets 
will be of similar size and appearance and contain 0-mg IVA (Table 10-1). 
Blister cards must be stored under conditions noted in the Pharmacy Manual. The investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational product is 
stored in a secured area, under recommended storage conditions, and in accordance with 


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applicable regulatory requirements. To ensure adequate records, all study drugs will be 
accounted for via the drug accountability forms as instructed by Vertex. 
Table 10-1 
Study Drug: Strength/Dosing Form/Route 
Drug Name, Dosing Form, Route 
Strength 
VX-659/TEZ/IVA, FDC tablet, oral 
 
VX-659 
120 mg  
TEZ 
50 mg 
IVA 
75 mg 
VX-659/TEZ/IVA-matching placebo, tablet, oral 
0 mg 
IVA, tablet, oral 
150 mg  
IVA-matching placebo, tablet, oral 
0 mg  
FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site.  
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study.  
10.7 
Blinding and Unblinding 
This will be a double-blind study. 


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10.7.1 
Blinding  
All subjects (and their parents/caregivers/companions), site personnel (including the investigator, 
the site monitor, and the study team), and members of the Vertex study team will be blinded to 
the treatment codes. 
Individuals who may be unblinded include only the following: 
 Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
 Any site personnel for whom this information is important to ensure the safety of the subject 
and her fetus in the event of a pregnancy 
 Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
 Vendor preparing the final (production) randomization list 
 Vertex IWRS Manager 
 Vertex Clinical Supply Chain 
 IDMC 
 External independent biostatistician preparing the unblinded analysis for review by the 
IDMC 
 Bioanalytical contract research organization (CRO) analyzing PK samples and the Vertex 
Bioanalytical personnel who is not a member of the study team but reviews raw data from the 
Bioanalytical CRO. The Vertex Bioanalytical study team member will continue to be 
blinded. 
 Vendor for modeling and simulations performing population PK modeling in preparation for 
regulatory submission(s) 
For the purpose of regulatory submissions, a limited Vertex team may be unblinded to the IA if 
the IDMC declares that the study has crossed the efficacy boundary (Section 12.3.6.1). Members 
of the limited Vertex unblinded team will not be involved in or influence the conduct of the 
remaining part of the study to protect the integrity of the study.  
Access to Spirometry and SwCl Results: 
During the conduct of the study, the Vertex study team will not have access to the spirometry or 
SwCl results after the morning dose on Day 1.  
Shortly before any planned efficacy analysis is conducted, the spirometry and SwCl data will be 
reviewed for data cleaning purposes by a biostatistician who does not have access to the 
treatment codes. 
Individual SwCl test results will not be disclosed to the study sites with the exception of the 
screening values. Subjects and their parents/caregivers/companions should not be informed of 
study-related spirometry results until Vertex has determined that the study has completed 
(i.e., clinical study report [CSR] finalization), regardless of whether the subject has prematurely 
discontinued treatment. 


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10.7.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2. 
Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  
Unblinding: Interim Analysis 
The IA will be performed by an external independent biostatistician who is not involved in and 
will not influence study conduct. The analyses generated by the external independent 
biostatistician will then be reviewed by the IDMC. If the IDMC declares that the study has 
crossed the prespecified efficacy boundary (Section 12.3.6.1), then the study may be unblinded 
by a limited Vertex team to prepare a regulatory submission(s). Members of the limited Vertex 
unblinded team will not be involved in or influence the conduct of the remaining part of the 




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Plasma concentration samples collected from subjects treated with placebo will not be routinely 
analyzed. 
11.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the PK Sample Handling 
Guidelines. 
11.3.3 
Bioanalysis 
Samples will be analyzed using validated analytical methods in compliance with Vertex or 
designee standard operating procedures. A description of the assays and validation data will be 
provided in separate reports. 
11.4 
Pharmacodynamics: Sweat Chloride 
SwCl samples will be collected with an approved collection device. Each collection will occur 
before study drug dosing (Section 9.6.1). At each time point, 2 samples will be collected, 1 from 
each arm (left and right). Sweat samples will be sent to a central laboratory for testing and 
interpretation of results. Specific instructions for the collection, handling, processing, and 
shipping of SwCl samples to the central laboratory will be provided separately. 
See Section 10.7.1 for information about access to SwCl results. 


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11.6 
Efficacy 
11.6.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines10 and according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
 withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
 withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
 withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 


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During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
pre-bronchodilator. During the Treatment Period, spirometry assessments must be performed 
before study drug dosing (Section 9.6.1) at approximately the same time at each visit. In the 
event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
 If a subject’s Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent visit, 
the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
 If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments in Table 3-2) should be performed 
post-bronchodilator. 
 Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. The investigator’s 
assessment of the spirometry results will be used for the screening assessment and determination 
of eligibility. 
See Section 10.7.1 for information about access to spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of GLI.9  
 FEV1 (L) 
11.6.2 
Height and Weight 
Height and weight will be measured with shoes off. Following screening, height will be collected 
only for subjects ≤21 years of age on the date of informed consent. 
11.6.3 
Cystic Fibrosis Questionnaire-Revised 
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF). 
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.15, 16 If there is no validated translation available in the subject’s native language, 
the subject will not complete the questionnaire. Copies of the CFQ-R used will be provided in 
the Study Reference Manual. Validated translations of the CFQ-R, if available, will be provided 
for participating centers in non-English-speaking countries.17, 18 
The CFQ-R will be completed before any other assessments are performed at that visit.  


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Subjects who are 12 and 13 years of age at the date of informed consent will complete the 
CFQ-R Child version themselves, and their parents/caregivers will complete the CFQ-R Parent 
version, at all visits, regardless of whether the subject subsequently turns 14 years of age during 
the study. Subjects 14 years of age and older at the date of informed consent will complete the 
Adolescent/Adult version of the questionnaire themselves at all visits. 
11.6.4 
Other Events Related to Outcome  
11.6.4.1 
Antibiotic Therapy for Sinopulmonary Sign/Symptoms 
New or changed antibiotic therapy (IV, inhaled, or oral) for the following sinopulmonary 
signs/symptoms will be determined and documented at visits as indicated in Table 3-2: 
 Change in sputum 
 New or increased hemoptysis 
 Increased cough 
 Increased dyspnea 
 Malaise, fatigue, or lethargy 
 Temperature above 38°C (equivalent to approximately 100.4°F) 
 Anorexia or weight loss 
 Sinus pain or tenderness 
 Change in sinus discharge 
 Change in physical examination (PE) of the chest 
 Decrease in pulmonary function by 10% 
 Radiographic changes indicative of pulmonary infection 
For this study, PEx is defined as a new or change in antibiotic therapy (IV, inhaled, or oral) 
for any 4 or more of the above signs/symptoms. This definition is based on the definition of a 
PEx used in previous clinical studies, including IVA clinical studies.19, 20  
It is recommended that the study drug not be interrupted during a PEx unless, in the opinion of 
the investigator, it would be in the best interest of the subject. 
11.6.4.2 
Hospitalization for CF 
Subjects will be queried about planned and unplanned hospitalizations lasting ≥24 hours that 
occurred during the study. The dates of hospitalizations and the reasons for hospitalizations will 
be documented. 
For any hospitalization (planned and unplanned), the procedures for safety reporting should also 
be followed. 


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11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, and clinical evaluation of 
vital signs, ECGs, PEs, and pulse oximetry. 
For subjects <18 years of age on the date of informed consent, ophthalmological examinations 
will also be performed at screening (if not done within preceding 3 months) and at Week 24 (or 
ETT Visit or Safety Follow-up Visit). 
11.7.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
11.7.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests. As described below, urine pregnancy tests will either be analyzed by the site or 
at home using a home kit. On Day 1, blood samples will be collected before the first dose of the 
study drug. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs. 
The safety laboratory test panels are shown in Table 11-2. 


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Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total and direct bilirubin 
Alkaline phosphatase 
Aspartate transaminase  
Alanine transaminase 
Amylase 
Lipase 
Gamma-glutamyl transferase 
Protein 
Albumin 
Creatine kinase 
Total cholesterol 
Lactate dehydrogenase  
Hemoglobin 
Erythrocytes 
Mean corpuscular volume 
Platelets 
Reticulocytes  
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation Studies 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
 
Leukocyte esterase 
Nitrite 
Urobilinogen  
Urine protein  
pH 
Urine blood 
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
Note: Haptoglobin may be analyzed if judged to be clinically appropriate by the investigator. 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: Any 
female subject who does not meet the criteria for non-childbearing potential is considered to be 
of childbearing potential and must have a serum pregnancy test at screening. A definition of 
non-childbearing potential is provided in Section 11.7.7.1. Serum pregnancy tests will be 
performed at the study site and analyzed at the central laboratory. Urine pregnancy tests will 
either be performed and analyzed at the site or, when there is no clinic visit scheduled, at home 
by using a home kit provided by the site. Results will be reported to the site by telephone. The 
urine pregnancy test on Day 1 must be negative before the first dose of study drug. Additional 
pregnancy tests may be required according to local regulations and/or requirements. 
FSH: Blood samples for FSH will be measured as needed for any suspected postmenopausal 
female with at least 12 months of continuous spontaneous amenorrhea. Serum FSH levels must 
be in the postmenopausal range as determined by the laboratory performing the test.  
CFTR Genotype (Screening Period Only): CFTR genotyping will be performed for all subjects. 
If the screening CFTR genotype result is not received before randomization, a previous CFTR 
genotype laboratory report may be used to establish eligibility. Subjects who have been 
randomized and whose screening genotype does not confirm study eligibility must be 
discontinued from the study (Section 9.9). 


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


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To ensure the safety of the subjects, a qualified individual at the study site will make 
comparisons to baseline measurements. If the QTcF is increased by >60 msec from the baseline 
or an absolute QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be 
performed approximately 2 to 4 minutes apart to confirm the original measurement. If either of 
the QTcF values from these repeated ECGs remains above the threshold value (>60 msec from 
baseline or ≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement. Further 
details pertaining to ECGs will be provided to sites in the ECG Manual. 
11.7.6 
Ophthalmologic Examination 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on 
the date of informed consent. The examination does not need to be completed if there is 
documentation of bilateral lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
 measurement of best-corrected distance visual acuity of each eye; and 
 pharmacologically dilated examination of the lens with a slit lamp 
The screening examination does not need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of informed consent. 
In addition to the screening ophthalmologic examination, subjects who are <18 years of age on 
the date of informed consent and who have completed at least 12 weeks of study drug treatment 
will have a single ophthalmologic examination at completion of study participation (defined in 
Section 9.1.6), except for those subjects who have withdrawn consent or assent. This 
examination should be completed within 4 weeks before the Week 24 Visit, unless the subject 
prematurely discontinues study drug, in which case this examination should occur by the Safety 
Follow-up Visit (or ETT Visit for subjects who do not complete a Safety Follow-up Visit), as 
described in Table 3-2. 
Any clinically significant abnormal findings will be reported as AEs. 
11.7.7 
Contraception and Pregnancy 
The effects of VX-659 monotherapy or in TC with TEZ and IVA on conception, pregnancy, and 
lactation in humans are not known. VX-659, TEZ, and IVA did not show genotoxic potential in a 
standard battery of in vitro (Ames test, chromosomal aberration, or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies. Reproductive toxicology studies of 
VX-659, TEZ, and IVA have not shown teratogenicity in rats and rabbits. 
11.7.7.1 
Contraception 
Contraception requirement for a couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the Screening Visit through 90 days after the last dose of study drug. 


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 If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 
 If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations) will be considered to be of 
childbearing potential. 
 Same-sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of consent (or 
assent, when applicable), approximately 28 days before the first dose of study drug (unless 
otherwise noted), and until 90 days following the last dose of study drug. Additional 
contraception requirements may need to be followed according to local regulations and/or 
requirements. Acceptable methods of contraception are listed in Table 11-3. 
Table 11-3 
Acceptable Methods of Contraception 
 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
 
 
Hormone-releasing 
Yes 
Nob 
Non-hormone releasing 
Yes 
Yes 
Hormonal contraceptives, if successfully used for at 
least 60 days before the first dose of study drug 
 
Yes 
 
Nob 
 
a 
A female condom cannot be used with a male condom due to risk of tearing.  
b 
Hormone-releasing intrauterine devices and hormonal contraceptives are not considered an acceptable method 
in female study subjects due to potential induction of metabolism by VX-659; however, female subjects are not 
required to discontinue their use of hormone-releasing intrauterine devices or hormonal contraceptives. 


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Additional notes: 
 If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-3.  
 Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
 Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
 For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug, with 
the exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 
11.7.7.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject becomes pregnant during study participation, study drug will be permanently 
discontinued immediately. The investigator will notify the medical monitor and Vertex GPS 
within 24 hours of the site’s knowledge of the subject’s (or partner’s) pregnancy using the 
Pregnancy Information Collection Form. Male subjects with female partners who become 
pregnant during the study must use a male condom to avoid exposure of a potential embryo or 
fetus to study drug via the seminal fluid. 
If confirmed to be on active 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. 
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP), and clinical pharmacologic analysis 
details will be provided in the clinical pharmacology analysis plan (CPAP), both of which will be 
finalized before the clinical data lock for the study and treatment unblinding. 
12.1 
Sample Size and Power 
Approximately 360 subjects will be enrolled and randomized (1:1) to the VX-659/TEZ/IVA arm 
or the triple placebo arm. This sample size was determined to provide adequate power for the 
key secondary endpoint of number of PEx through Week 24. Information regarding the powering 
of primary and key secondary endpoints is provided below. 
Power for Primary Efficacy Endpoint 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline at Week 4. The 
primary null hypothesis to be tested is that the mean absolute change in ppFEV1 from baseline is 
the same for the 2 treatment groups, VX-659/TEZ/IVA and placebo. If the number of subjects 


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included in the IA is 140, the null hypothesis will be tested at a 2-sided significance level of 
0.044 during the IA and at an overall 2-sided significance level of 0.05. 
Assuming a within-group SD of 7 percentage points and a 5% dropout rate at Week 4, an IA 
sample size of 70 subjects in each treatment group will have approximately 98% power to detect 
a difference between the treatment groups of 5.0 percentage points for the mean absolute change 
in ppFEV1 from baseline at Week 4, based on a 2-sided, 2-sample t-test at a significance level of 
0.044. If the P value fails to cross the efficacy boundary during the IA (P value ≥0.044; 
assuming 140 subjects included in the IA), the primary endpoint of absolute change in ppFEV1 
from baseline at Week 4 will be tested after all subjects complete study participation at an alpha 
of 0.01. A final analysis sample size of 180 subjects in each treatment group will have 
approximately 99% power to detect a difference between the treatment groups of 5.0 percentage 
points for the mean absolute change in ppFEV1 from baseline at Week 4, based on a 2-sided, 
2-sample t-test at a significance level of 0.01. All power calculations were based on EAST 
software Version 6.4. 
Power for Selected Key Secondary Endpoints 
A key secondary endpoint is the absolute change in ppFEV1 from baseline through Week 24. 
Assuming a within-group SD of 7 percentage points and a 10% dropout rate at Week 24, a 
sample size of 180 subjects in each treatment group will have approximately 99% power to 
detect a difference between the treatment groups of 5.0 percentage points for the absolute change 
in ppFEV1 from baseline through Week 24, based on a 2-sided, 2-sample t-test at a significance 
level of 0.05. 
Another key secondary endpoint is the number of PEx through Week 24. Assuming a rate of PEx 
for the placebo group of 0.6 over 24 weeks and a 10% dropout rate, with 180 subjects and the 
overdispersion parameter of 0.5 in each treatment group, the power to detect a 40% reduction in 
the PEx rate for TC group compared to placebo group is approximately 80%, based on a 2-sided, 
2-sample negative binomial regression model test for the ratio of rates, at a significance level 
of 0.05.  
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set.  
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified.  
The FAS will include all randomized subjects who carry the intended CFTR allele mutation and 
receive at least 1 dose of study drug. The FAS will be used to summarize subject demographics 
and baseline characteristics, and for all efficacy analyses in which subjects will be analyzed 
according to their randomized treatment group, unless otherwise specified. 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses in which subjects will be analyzed according to the 
treatment they received, unless otherwise specified. 
Additional analysis sets related to the interim analysis will be described in the SAP. 


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12.3 
Statistical Analysis 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). The precision of the measurement for each continuous variable will be specified in the 
SAP. Unless otherwise specified, min and max values will be reported with the same precision as 
the units of the raw data. The mean, median, and SD will be reported to 1 additional decimal 
place. Any values that require a transformation to standard units (metric or SI) will be converted 
with the appropriate precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
The baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For ECG, 
baseline will be defined as the most recent pretreatment measurement (or the average of triplicate 
measurements, if the most recent pretreatment measurement is obtained in triplicate) before the 
first dose of study drug. 
Absolute change from baseline will be calculated as post-baseline value – baseline value. 
The Treatment-emergent (TE) Period will include the time from the first dose of study drug in 
the Treatment Period (TC or Placebo) to 28 days after the last dose of the study drug or to the 
completion of study participation date (as defined in Section 9.1.6), whichever occurs first.  
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in the FAS, included in the Safety Set, completed Treatment Period, completed study, 
prematurely discontinued treatment or study with a breakdown of the reasons for 
discontinuation, and entered an open-label study) will be summarized overall and by treatment 
group.  
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, medical history, and baseline characteristics will be summarized using descriptive 
summary statistics. 
The following demographics and baseline characteristics will be summarized overall and by 
treatment group for the FAS and will include (but are not limited to): sex, race, baseline age, 
baseline weight, baseline height, baseline BMI, baseline ppFEV1, and baseline SwCl. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT) for the FAS. 
No statistical tests will be performed to evaluate baseline imbalance between treatment groups. 
12.3.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug-Dictionary and 
categorized as follows: 


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 Prior medication: any medication that was administered during the 56 days before initial 
dosing of study drug 
 Concomitant medication: medication continued or newly received during the TE Period 
 Post-treatment medication: medication continued or newly received after the TE Period 
A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and if it cannot be determined whether it was taken before the first dose of 
study drug, concomitantly during the TE Period, or after the TE Period, it will be considered in 
all 3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name based on the FAS. Post-treatment medications will be provided separately in an individual 
subject data listing. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure will be summarized overall and by treatment group, based on the Safety Set 
in terms of the duration of treatment a subject received (in days), defined as the last day – the 
first day of study drug plus 1, regardless of study drug interruption.  
Study drug compliance will be summarized overall and by treatment group based on the FAS, 
and will be calculated as: 100 × [1 - (total number of days of study drug interruption) / (duration 
of study drug exposure in days)]. A study drug interruption on a given day is defined as an 
interruption of any study drug on that day. 
In addition, percentage of tablets taken will also be summarized overall and by treatment group 
based on the FAS, and will be calculated as 100  [(total number of tablets dispensed) – (total 
number of tablets returned)] / (total number of tablets planned to be taken per day  duration of 
study drug exposure in days). 
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. The rules for identifying an IPD will be described in the SAP. 
All IPDs will be provided in an individual subject data listing, and summarized, as appropriate. 
12.3.3 
Efficacy and Pharmacodynamic Analysis 
The primary objective of the study is the evaluation of the efficacy of VX-659 in TC with TEZ 
and IVA. The analyses described in this section will be based on the FAS, unless otherwise 
specified. 
12.3.3.1 
Final Analysis 
12.3.3.1.1 
Analysis of Primary Variables 
The primary efficacy variable is the absolute change in ppFEV1 from baseline at Week 4. The 
analysis of this variable will be performed using a mixed-effects model for repeated measures 
(MMRM) with change from baseline at Day 15, Week 4, Week 8, Week 12, Week 16, and 




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from Day 15, Week 4, Week 8, Week 12, Week 16, and Week 24 Visits will be included in 
the model. 
 Absolute change in SwCl from baseline at Week 4: Analysis of this variable will be based 
on an MMRM similar to the analysis of the primary efficacy variable. Data obtained from 
Week 4, Week 8, Week 12, and Week 24 Visits will be included in the model to estimate the 
treatment effect at Week 4. 
 Absolute change in CFQ-R respiratory domain score from baseline at Week 4: Analysis 
of this variable will be based on an MMRM model similar to the analysis of the primary 
efficacy variable. Data obtained from the Week 4, Week 8, Week 12, and Week 24 Visits 
will be included in the model to estimate the treatment effect at Week 4. 
The key secondary endpoints will be formally tested only during the final analysis when all 
subjects have completed study participation and the primary endpoint is statistically significant 
either at the IA or at the final analysis. Additional details will be provided in the SAP. 
Analysis of Other Secondary Variables 
Other secondary efficacy variables include: 
 Time-to-first PEx through Week 24: Time-to-first PEx will be analyzed using the Cox 
regression model. The model will include a fixed effect for treatment, as well as continuous 
baseline ppFEV1, age at screening (<18 versus ≥18 years of age), and sex (male versus 
female) as covariates. A subject who does not experience a PEx during the PEx analysis 
period will be censored at the PEx analysis period end date. If the proportional hazards 
assumption is violated for any of the categorical covariates, a stratified Cox regression will 
be conducted. Additionally, the Kaplan-Meier method will be used to produce a graphical 
presentation of the cumulative exacerbation-free survival rate for each treatment group and to 
estimate the cumulative exacerbation-free survival rate by treatment group. Note: If the 
number of events is <5 in either treatment group, Cox regression will not be performed and 
the analysis of the time-to-first event will be restricted to the Kaplan-Meier method. 
 Absolute change in BMI z-score from baseline at Week 24 (for subjects ≤20 years of age 
at Baseline): Analysis of this variable will be based on an MMRM model similar to the 
analysis of the primary efficacy variable, for subjects ≤20 years of age at Baseline. Data 
obtained from Day 15, Week 4, Week 8, Week 12, Week 16, and Week 24 Visits will be 
included in the model. 
 Absolute change in body weight from baseline at Week 24: Analysis of this variable will 
be based on an MMRM model similar to the analysis of the primary efficacy variable. Data 
obtained from Day 15, Week 4, Week 8, Week 12, Week 16, and Week 24 Visits will be 
included in the model. 
Additional details will be provided in the SAP. 


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12.3.3.3 
Interim Analysis 
12.3.3.3.1 
Analysis of Primary Variables 
During the IA, the analysis of the primary efficacy variable of absolute change in ppFEV1 from 
baseline at Week 4 will be performed using an MMRM with change from baseline at Day 15 and 
Week 4 as the dependent variable. Other details of the model are same as that described for the 
final analysis (Section 12.3.3.1.1).  
 
12.3.3.3.2 
Analysis of Key Secondary Variables 
The following key secondary efficacy and pharmacodynamic variables will be analyzed during 
the IA using an Analysis of Covariance (ANCOVA) model and nominal P value will be 
provided for descriptive purpose: 
1. Absolute change in SwCl from baseline at Week 4 
2. Absolute change in CFQ-R respiratory domain score from baseline at Week 4 
The model will use the change from baseline value at Week 4 as the dependent variable and 
include treatment group as fixed effects with continuous baseline ppFEV1, age at screening (<18 
versus ≥18 years of age), and sex (male versus female) as covariates. 
Additional details will be provided in the SAP. 
12.3.3.4 
Multiplicity Adjustment  
The Lan and DeMets alpha spending function will be applied to the primary endpoint of the 
absolute change in ppFEV1 at Week 4 to control the overall type I error rate of 0.05 such that an 
alpha of 0.01 will be preserved for the final analysis.21 
If the number of subjects included in the IA is 140, the primary endpoint of the absolute change 
from baseline in ppFEV1 at Week 4 will be tested at an alpha of 0.044 during the IA. The actual 
alpha at the IA (0) will be determined based on the actual number of subjects included in the 
IA. If the study does not cross the efficacy boundary during the IA (P value ≥0), then the 
primary endpoint will be tested at an alpha of 0.01 at the final analysis when all subjects 
complete study participation. 
The key secondary endpoints will be formally tested at an alpha of 0.05 at the final analysis 
when all subjects complete study participation only if the primary endpoint is statistically 
significant at the IA or at the final analysis. A hierarchical testing procedure will be used to 
control the type I error rate for the multiple key secondary endpoints tested at an alpha of 0.05. 
For a test at any step to be considered statistically significant within the testing hierarchy, it must 
be statistically significant, and all previous tests (if any) within the hierarchy must be statistically 
significant at the 0.05 level. The testing order of the key secondary endpoints is as follows: 
1. First key secondary endpoint: Absolute change in ppFEV1 from baseline through Week 24  
2. Second key secondary endpoint: Number of PEx through Week 24  


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3. Third key secondary endpoint: Absolute change in SwCl from baseline through Week 24 
4. Fourth key secondary endpoint: Absolute change in CFQ-R respiratory domain from baseline 
through Week 24  
5. Fifth key secondary endpoint: Absolute change in BMI from baseline at Week 24  
6. Sixth key secondary endpoint: Absolute change in SwCl from baseline at Week 4 
7. Seventh key secondary endpoint: Absolute change in CFQ-R respiratory domain score from 
baseline at Week 4 
12.3.4 
Safety Analysis 
All safety analyses will be based on data from the TE Period for all subjects in the Safety Set. 
The overall safety profile of study drug will be assessed based on the following safety and 
tolerability endpoints: 
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
 ECGs 
 Vital signs 
 Pulse oximetry 
All safety data from the TE Period will be summarized by treatment group. 
All safety data will 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 occurred before the first dose date of study drug 
 TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose date of study drug through the end of the TE Period 
 Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after 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 drug treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only, overall and by treatment group, and will 
include the following: 
 All TEAEs 
 TEAEs by strongest relationship  
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 


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 TEAEs leading to treatment interruption 
 Serious TEAEs 
 TEAEs leading to death 
 Grade 3 and Grade 4 TEAEs 
 Frequently reported TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level in the relationship summaries. 
In addition, a listing containing individual subject level AE data for all deaths and other serious 
and significant AEs will be provided separately. All AEs, including pre- and post-treatment AEs, 
will be presented in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, serum chemistry, and coagulation results will be 
summarized in SI units by treatment group at each visit. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criterion 
shift from baseline will also be summarized for select laboratory parameters. The threshold 
analysis criteria and the parameter selection criteria will be provided in the SAP. 
Results of urinalysis and pregnancy tests will be listed in individual subject data listings only. In 
addition, a listing containing individual subject hematology, chemistry, and coagulation values 
outside the reference ranges will be provided. This listing will include data from scheduled and 
unscheduled visits. 
12.3.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided by treatment group at each visit, as applicable, for the following 
ECG interval measurements (in msec): RR, PR, QT, and QT corrected for HR (QTcF), QRS 
duration, and HR (beats per minute). 
The number and percentage of subjects with at least 1 threshold analysis event during the TE 
Period will be summarized overall and by treatment group. The threshold analysis criteria will be 
provided in the SAP. 
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized by treatment group at each visit. The following vital signs 
parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 


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The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criteria 
will be provided in the SAP. 
Additional vital signs analyses may be described in the SAP. 
12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided by treatment group at each visit for the percent of 
oxygen saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
TE Period will be summarized overall and by treatment group. 
12.3.4.6 
Physical Examination 
PE findings will be presented in an individual subject data listing only. 
12.3.4.7 
Other Safety Analyses 
Details of other safety analyses will be included in the SAP. 
12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analyses 
An IA is planned when at least 140 subjects complete the Week 4 Visit and at least 100 subjects 
complete the Week 12 Visit. The IA will be performed by an external independent biostatistician 
who is not involved in and will not influence the conduct of the study, and the results will be 
reviewed by the IDMC. If the P value for the primary endpoint at the IA is less than 0, then the 
efficacy boundary has been crossed. Refer to Section 12.3.3.4 for how 0 is determined. If the 
IDMC declares that the study has crossed the efficacy boundary, then the study may be 
unblinded to a limited Vertex team to prepare a regulatory submission(s). Members of the 
limited Vertex unblinded team will not be involved in or influence the conduct of the remaining 
part of the study to protect the integrity of the study. The study will continue to completion and 
remain double-blinded through Week 24. 
If the study does not cross the efficacy boundary (i.e., the P value for the primary endpoint at the 
IA is ≥ 0), the primary endpoint of the absolute change in ppFEV1 from baseline at Week 4 will 
be tested after all subjects complete study participation at an alpha of 0.01. 


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The key secondary endpoints will be formally tested only during the final analysis when all 
subjects have completed study participation and the primary endpoint is statistically significant 
either at the IA or at the final analysis. The selected key secondary endpoints at Week 4 (Section 
12.3.3.1.2) will be analyzed during the IA and nominal P value will be provided for descriptive 
purposes. 
12.3.6.2 
IDMC Analysis 
The IDMC (Section 9.1.7) will conduct periodic planned safety review(s) of study data and the 
planned efficacy IA. Details of the safety and efficacy review(s) will be described in the IDMC 
charter. 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
The PK analysis of VX-659, TEZ, and IVA may be performed using nonlinear mixed effects 
modeling and/or standard noncompartmental analysis, as data allow. Metabolites, including 
M1-TEZ, may be included in the analyses as supported by data. Descriptive statistics will be 
used to summarize PK parameter values for all analytes. 
A detailed description of the planned PK analysis will be presented in the CPAP. 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
PD assessments to be included in PK/PD analyses may include SwCl, ppFEV1, as well as other 
endpoints such as BMI, BMI z-score, or CFQ-R respiratory domain score. 
A sequential approach will be used to perform the population PK/PD analysis. The Bayesian 
estimates of individual PK parameters from the final population PK model will be used to 
simulate PK profiles for each subject. The simulated VX-659, TEZ, IVA, or metabolite plasma 
concentrations will be used in the potential pharmacological response models to describe 
changes in each endpoint from baseline. Fixed- and random-effect parameter estimates and the 
associated asymptotic SEs will be estimated. Descriptive statistics will be used to summarize 
Bayesian estimates of individual PK/PD parameters obtained from the population PK/PD model. 
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.  


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13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the subject completes study 
participation, as defined in Section 9.1.6. 
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 


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Criteria for Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
28 September 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” 
In considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in the 
CTCAE. The severity of an AE that does not appear in the CTCAE will be determined according 
to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject’s medical record). 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3. 
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 


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
 Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
 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 


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 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through completion of study participation, 
regardless of causality, will be reported by the investigator to Vertex GPS. In addition, all SAEs 
that occur after completion of study participation and are considered related to study drug(s) will 
be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email:
 (preferred choice) 
Fax: 
  
For questions, contact telephone: 
 


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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, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. When determining the age of the subject, other study eligibility criteria, and timing of 
collection applicable assessments, the informed consent will be used as the reference (e.g., age at 
time of informed consent, date of informed consent, timing of AE collection). 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
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/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) and associated regulations, an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 


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 Lack of evaluable and/or complete data 
 Potentially unacceptable risk to study subjects 
 Decision to modify drug development plan 
 Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit or, for subjects who have been lost to 
follow-up, the last contact, whichever occurs later, for the latest completing subject in the study. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
Protocol deviations will be monitored and identified throughout study conduct as outlined in the 
Protocol Deviation Plan. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
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 


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


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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 03 September 2015. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2014 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2015. 
3 
European Cystic Fibrosis Society. 2013 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2016. 
4 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 19 September 2016. 
5 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 19 September 2016. 
6 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: Annual Data Report 2014. Bromley, 
Kent, UK: Cystic Fibrosis Trust; 2015. 
7 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
8 
CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional 
TRanslation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins 
University, the Hospital for Sick Children. Available at: http://www.cftr2.org. Accessed 
09 January 2018. 
9 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
10 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
11 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-
70. 
12 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
13 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78. 
15 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 


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16 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
17 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
18 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
19 
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365(18):1663-72. 
20 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331(10):637-42. 
21 
Lan KK, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-63. 
 
 
 


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APPENDIX A  
Eligible MF CFTR Mutations 
“MF” mutations are a subset of minimal function mutations that are non-responsive to TEZ, 
IVA, or TEZ/IVA. A mutation is considered an MF mutation if it meets at least 1 of the 
following 2 criteria: 
(1) biological plausibility of no translated protein (genetic sequence predicts the complete 
absence of CFTR protein), or 
(2) in vitro testing that supports lack of responsiveness to TEZ, IVA, or TEZ/IVA, and evidence 
of clinical severity on a population basis (as reported in large patient registries). 
Inclusion of MF Mutations Based on In Vitro Testing 
Mutations that were considered to be MF mutations based on in vitro testing met the following 
criteria in in vitro experiments: 
 baseline chloride transport that was <10% of wildtype CFTR 
 an increase in chloride transport of <10% over baseline following the addition of TEZ, 
IVA, or TEZ/IVA in the assay 
These mutations also had evidence of clinical severity on a population basis (per CFTR2 patient 
registry; accessed on 15 February 2016). Patients with these mutations on one allele and F508del 
on the other allele exhibited evidence of clinical severity as defined as: 
 average sweat chloride >86 mmol/L, and 
 prevalence of pancreatic insufficiency (PI) >50% 
These clinical severity criteria do not apply to the individual subjects to be enrolled in the study, 
but were used to categorize each mutation on a population level. 
Eligible MF Mutations 
The list below represents acceptable mutations, which are detectable by an FDA-cleared 
genotyping assay or other method (e.g., sequencing); however, this list may not include every 
eligible mutation, and investigators should contact the medical monitor regarding other 
mutations that may also meet study eligibility criteria. 


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CFTR Mutations Eligible for VX17-659-102 
MF Mutation Category 
Mutation 
 
 
 
 
Nonsense mutations 
Q2X 
L218X 
Q525X 
R792X 
E1104X 
S4X 
Q220X 
G542X 
E822X 
W1145X 
W19X 
Y275X 
G550X 
W882X 
R1158X 
G27X 
C276X 
Q552X 
W846X 
R1162X 
Q39X 
Q290X 
R553X 
Y849X 
S1196X 
W57X 
G330X 
E585X 
R851X 
W1204X 
E60X 
W401X 
G673X 
Q890X 
L1254X 
R75X 
Q414X 
Q685X 
S912X 
S1255X 
L88X 
S434X 
R709X 
Y913X 
W1282X 
E92X 
S466X 
K710X 
Q1042X 
Q1313X 
 
Q98X 
S489X 
Q715X 
W1089X 
Q1330X 
 
Y122X 
Q493X 
L732X 
Y1092X 
E1371X 
 
E193X 
W496X 
R764X 
W1098X 
Q1382X 
 
W216X 
C524X 
R785X 
R1102X 
Q1411X 
Canonical splice mutations  185+1G→T 
711+5G→A 
1717-8G→A 
2622+1G→A 
3121-1G→A 
296+1G→A 
712-1G→T 
1717-1G→A 
2790-1G→C 
3500-2A→G 
296+1G→T 
1248+1G→A 
1811+1G→C 
3040G→C 
 (G970R) 
3600+2insT 
405+1G→A 
1249-1G→A 
1811+1.6kbA→G 
3850-1G→A 
405+3A→C 
1341+1G→A 
1811+1643G→T  3120G→A 
4005+1G→A 
406-1G→A 
1525-2A→G 
1812-1G→A 
3120+1G→A 
4374+1G→T 
621+1G→T 
1525-1G→A 
1898+1G→A 
3121-2A→G 
 
711+1G→T 
1898+1G→C 
 
Small (≤3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
182delT 
1078delT 
1677delTA 
2711delT 
3737delA 
306insA 
1119delA 
1782delA 
2732insA 
3791delC 
306delTAGA 1138insG 
1824delA 
2869insG 
3821delT 
365-366insT 
1154insTC 
1833delT 
2896insAG 
3876delA 
394delTT 
1161delC 
2043delG 
2942insT 
3878delG 
442delA 
1213delT 
2143delT 
2957delT 
3905insT 
444delA 
1259insA 
2183AA→G a 
3007delG 
4016insT 
 
457TAT→G 
1288insTA 
2184delA 
3028delA 
4021dupT 
 
541delC 
1343delG 
2184insA 
3171delC 
4022insT 
 
574delA 
1471delA 
2307insA 
3171insC 
4040delA 
 
663delT 
1497delGG 
2347delG 
3271delGG 
4279insA 
 
849delG  
1548delG 
2585delT 
3349insT 
4326delTC 
 
935delA 
1609del CA 
2594delGT 
3659delC 
Non-small (>3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
CFTRdele1 
CFTRdele16-17b 
1461ins4 
CFTRdele2 
CFTRdele17a,17b 
1924del7 
CFTRdele2,3 
CFTRdele17a-18 
2055del9→A 
CFTRdele2-4 
CFTRdele19 
2105-2117del13insAGAAA 
CFTRdele3-10,14b-16 
CFTRdele19-21 
2372del8 
CFTRdele4-7 
CFTRdele21 
2721del11 
CFTRdele4-11 
CFTRdele22-24 
2991del32 
CFTR50kbdel 
CFTRdele22,23 
3121-977_3499+248del2515 
CFTRdup6b-10 
124del23bp 
3667ins4 
CFTRdele11 
602del14  
4010del4 
 
CFTRdele13,14a 
852del22 
4209TGTT→AA 
 
CFTRdele14b-17b 
991del5 
 


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CFTR Mutations Eligible for VX17-659-102 
MF Mutation Category 
Mutation 
 
 
 
 
Missense mutations that   
 
Are not responsive in 
vitro to TEZ, IVA, or 
TEZ/IVA 
and 
 
%PI>50% and SwCl- 
>86 mmol/L 
A46Db 
V520F 
Y569Db 
N1303K 
 
G85E 
A559Tb 
L1065P 
 
R347P 
R560T 
R1066C 
 
L467Pb 
R560S 
L1077Pb 
 
I507del 
A561E 
M1101K 
 
 
 
 
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; SwCl: sweat chloride; TEZ: tezacaftor 
Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and Functional 
Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital for Sick 
Children. Available at: http://www.cftr2.org/. Accessed 15 February 2016. 
Notes: %PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic 
insufficient; SwCl: mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry. 
a 
Also known as 2183delAA→G.  
b 
Unpublished data. 
 




Protocol VX17-659-102, Version 3.0 
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Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #:  
VX17-659-102 Version #: 
3.0 
Version Date: 
27 April 2018 
Study Title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy 
and Safety of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are 
Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF) 
 
 
I have read Protocol VX17-659-102, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-659, tezacaftor, and ivacaftor and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 47 
Protocol Number: VX17-659-102   
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX17-659-102 Version 3.0 
(Final and Interim Analysis) 
 
 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating 
the Efficacy and Safety of VX-659 Combination Therapy in Subjects 
With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation 
and a Minimal Function Mutation (F/MF) 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 14 MAY 2018 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
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2 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Table of Contents ................................................................................................................... 2 
 
 
 
 
 
 
 
 
4 
Introduction............................................................................................................................ 6 
5 
Study Objectives .................................................................................................................... 6 
5.1 
Primary Objective ............................................................................................................. 6 
5.2 
Secondary Objectives ....................................................................................................... 6 
6 
Study Endpoints ..................................................................................................................... 6 
6.1 
Efficacy and Pharmacodynamic Endpoints ...................................................................... 6 
6.1.1 
Primary Efficacy Endpoint ....................................................................................... 6 
6.1.2 
Secondary Efficacy and Pharmacodynamic Endpoints ............................................ 7 
6.2 
Safety Endpoints ............................................................................................................... 7 
6.3 
Pharmacokinetic Endpoint ................................................................................................ 7 
 
 
7 
Study Design ........................................................................................................................... 8 
7.1 
Overall Design .................................................................................................................. 8 
7.2 
Sample Size and Power .................................................................................................... 8 
7.3 
Randomization .................................................................................................................. 9 
7.4 
Blinding and Unblinding ................................................................................................ 10 
7.5 
Interim Analysis ............................................................................................................. 10 
8 
Analysis Sets ......................................................................................................................... 10 
8.1 
All Subjects Set .............................................................................................................. 10 
8.2 
Full Analysis Set ............................................................................................................. 11 
8.3 
Safety Set ........................................................................................................................ 11 
8.4 
Analysis Sets for IA ........................................................................................................ 11 
8.4.1 
Interim Full Analysis Set ........................................................................................ 11 
8.4.2 
Interim Safety Set ................................................................................................... 11 
9 
Statistical Analysis ............................................................................................................... 11 
9.1 
General Considerations .................................................................................................. 11 
9.2 
Background Characteristics ............................................................................................ 12 
9.2.1 
Subject Disposition ................................................................................................. 12 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 13 
9.2.3 
Medical History ...................................................................................................... 14 
9.2.4 
Prior and Concomitant Medications ....................................................................... 14 
9.2.5 
Study Drug Exposure.............................................................................................. 15 
9.2.6 
Study Drug Compliance ......................................................................................... 15 
9.2.7 
Important Protocol Deviations ................................................................................ 15 
9.3 
Efficacy Analysis ............................................................................................................ 16 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 16 
9.3.1.1 
Definition of Variables ..................................................................................... 16 
9.3.1.2 
Primary Analysis .............................................................................................. 16 


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9.3.2 
Analysis of Key Secondary Variables .................................................................... 18 
9.3.2.1 
Definition of Variables ..................................................................................... 18 
9.3.2.2 
Analysis Method .............................................................................................. 19 
9.3.2.3 
Multiplicity Adjustment ................................................................................... 20 
9.3.3 
Analysis of Other Secondary Variables .................................................................. 20 
9.3.3.1 
Definition of Variables ..................................................................................... 20 
9.3.3.2 
Analysis Method .............................................................................................. 21 
 
 
 
 
 
 
 
 
 
9.4 
Safety Analysis ............................................................................................................... 23 
9.4.1 
Adverse Events ....................................................................................................... 24 
 
 
9.4.2 
Clinical Laboratory ................................................................................................. 25 
9.4.3 
Electrocardiogram .................................................................................................. 26 
9.4.4 
Vital Signs .............................................................................................................. 26 
9.4.5 
Pulse Oximetry ....................................................................................................... 26 
9.4.6 
Physical Examination ............................................................................................. 26 
 
 
 
 
 
 
 
 
 
 
10 SUMMARY OF INTERIM AND DMC ANALYSIS ....................................................... 28 
10.1 Interim Analysis ............................................................................................................. 28 
10.1.1 
General Consideration ............................................................................................ 28 
10.1.2 
Background Characteristics .................................................................................... 28 
10.1.2.1 Subject Disposition .......................................................................................... 28 
10.1.2.2 Demographics and Baseline Characteristics .................................................... 29 
10.1.2.3 Study Drug Exposure ....................................................................................... 29 
10.1.3 
Efficacy Analysis .................................................................................................... 29 
10.1.3.1 Analysis of Primary Efficacy Variable ............................................................ 29 
10.1.3.2 Analysis of Key Secondary Efficacy Variable................................................. 30 
10.1.3.3 Summary of Efficacy Variables ....................................................................... 30 
10.1.4 
Safety Analysis ....................................................................................................... 31 
 
 
10.2 DMC Analysis ................................................................................................................ 31 
10.2.1 
DMC Safety/Efficacy Review ................................................................................ 32 
11 References ............................................................................................................................. 33 
12 List of Appendices................................................................................................................ 34 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ......................... 34 


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Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 37 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ............................................. 38 
 
Appendix E: Imputation Rules for Missing AE dates .............................................................. 41 
Appendix F: Criteria for Threshold Analysis .......................................................................... 42 
 
 


Statistical Analysis Plan (Methods) 
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Statistical Analysis Plan (Methods) 
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4 
INTRODUCTION 
This statistical analysis plan (SAP) for the interim and final analysis is based on the most recent 
approved clinical study protocol (CSP), electronic case report form (eCRF), and eCRF 
completion guidelines. 
This SAP (Methods) documents the planned statistical analyses of efficacy endpoints and safety 
endpoints for the interim analysis (IA) and the final analysis.  
 
 
. 
The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of VX-659 in the 
population heterozygous for the F508del mutation and a minimal function mutation will also be 
evaluated in the study.  Selected analyses related to sweat chloride will be documented in this 
SAP, other PK and PD analyses will be documented separately in the clinical pharmacology 
analysis plan (CPAP) for the study.   
This SAP (Methods) will be finalized and approved prior to IA data lock and treatment 
unblinding for the IA.  Any revisions to the approved SAP will be documented and approved in 
an amendment to the SAP. 
The Vertex Biometrics Department will perform the statistical analysis for the final analysis and 
prepare the analysis package for the IA; SAS (Version 9.4 or higher) will be used to generate all 
statistical outputs (tables, figures, listings, and datasets).  ICON Clinical Research Limited 
(ICON), appointed as the independent biostatistician, will perform the IA according to the DMC 
SAP and present the results to the DMC.  If the DMC declares that the study has crossed the 
efficacy boundary, a limited Vertex unblinded team (independent of the study team) may be 
unblinded to the study and prepare for regulatory submission(s) based on the IA. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the efficacy of VX-659 in triple combination (TC) with tezacaftor (TEZ) and 
ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for F508del and a 
minimal function mutation (F/MF subjects) 
5.2 
Secondary Objectives  
 To evaluate the safety of VX-659 in TC with TEZ and IVA  
 To evaluate the pharmacodynamics (PD) of VX-659 in TC with TEZ and IVA 
 To evaluate the pharmacokinetics (PK) of VX-659, TEZ, and IVA when administered in TC 
6 
STUDY ENDPOINTS 
6.1 
Efficacy and Pharmacodynamic Endpoints 
6.1.1 
Primary Efficacy Endpoint 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline at Week 4 


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6.1.2 
Secondary Efficacy and Pharmacodynamic Endpoints 
The key secondary endpoints are as follows:  
 Absolute change in ppFEV1 from baseline through Week 24 
 Number of pulmonary exacerbations (PEx) through Week 24 
 Absolute change in sweat chloride (SwCl) from baseline through Week 24 
 Absolute change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) respiratory domain 
score from baseline through Week 24 
 Absolute change in body mass index (BMI) from baseline at Week 24 
 Absolute change in SwCl from baseline at Week 4 
 Absolute change in CFQ-R respiratory domain score from baseline at Week 4 
Other secondary endpoints 
 Time-to-first PEx through Week 24 
 Absolute change in BMI z-score from baseline at Week 24 (for subjects ≤20 years of age at 
Baseline) 
 Absolute change in body weight from baseline at Week 24 
6.2 
Safety Endpoints 
Safety and tolerability will be evaluated via the following endpoints: 
 Adverse events (AEs) 
 Clinical laboratory values 
 Standard 12-lead ECGs 
 Vital signs 
 Pulse oximetry 
6.3 
Pharmacokinetic Endpoint 
 PK parameters of VX-659, TEZ, M1-TEZ, and IVA 




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Power for Primary Efficacy Endpoint 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline at Week 4.  The 
primary null hypothesis to be tested is that the mean absolute change in ppFEV1 from baseline is 
the same for the 2 treatment groups, VX-659/TEZ/IVA and placebo.  If the number of subjects 
included in the IA is 140, the null hypothesis will be tested at a 2-sided significance level of 
0.044 during the IA and at an overall 2-sided significance level of 0.05.  See Section 7.5 for 
details on the significance level for hypothesis testing during the IA. 
Assuming a within-group SD of 7 percentage points and a 5% dropout rate at Week 4, an IA 
sample size of 70 subjects in each treatment group will have approximately 98% power to detect 
a difference between the treatment groups of 5.0 percentage points for the mean absolute change 
in ppFEV1 from baseline at Week 4, based on a 2-sided, 2-sample t-test at a significance level of 
0.044.  If the P value fails to cross the efficacy boundary during the IA (P value ≥0.044; 
assuming 140 subjects included in the IA), the primary endpoint of absolute change in ppFEV1 
from baseline at Week 4 will be tested after all subjects complete study participation at an alpha 
of 0.01.  Assuming a 10% dropout rate at Week 24, a final analysis sample size of 180 subjects 
in each treatment group will have approximately 99% power to detect a difference between the 
treatment groups of 5.0 percentage points for the mean absolute change in ppFEV1 from baseline 
at Week 4, based on a 2-sided, 2-sample t-test at a significance level of 0.01.  All power 
calculations were based on EAST software Version 6.4. 
Power for Selected Secondary Endpoints 
A key secondary endpoint is the absolute change in ppFEV1 from baseline through Week 24. 
Assuming a within-group SD of 7 percentage points and a 10% dropout rate at Week 24, a 
sample size of 180 subjects in each treatment group will have approximately 99% power to 
detect a difference between the treatment groups of 5.0 percentage points for the absolute change 
in ppFEV1 from baseline through Week 24, based on a 2-sided, 2-sample t-test at a significance 
level of 0.05. 
A key secondary endpoint is the number of PEx through Week 24.  Assuming a rate of PEx for 
the placebo group of 0.6 over 24 weeks and a 10% dropout rate, with 180 subjects and the 
overdispersion parameter of 0.5 in each treatment group, the power to detect a 40% reduction in 
the PEx rate for VX-659/TEZ/IVA group compared to placebo group is approximately 80%, 
based on a 2-sided, 2-sample negative binomial regression model test for the ratio of rates, at a 
significance level of 0.05.  
7.3 
Randomization 
Subjects will be randomized (1:1) to the VX-659/TEZ/IVA arm or to the triple placebo arm. 
Randomization will be stratified by ppFEV1 determined during the Screening Period (<70 versus 
≥70), age at the Screening Visit (<18 versus ≥18 years of age), and sex (male versus female).  
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code list will be produced by Vertex Biometrics or a qualified randomization 
vendor. 
Randomization will occur before the first dose of study drug during the Treatment Period and 
may occur on either Day 1 or Day -1. 


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7.4 
Blinding and Unblinding 
Refer to Section 10.7 of the CSP for details.  
7.5 
Interim Analysis 
An IA is planned when at least 140 subjects complete the Week 4 Visit and at least 100 subjects 
complete the Week 12 Visit.  The IA will be performed by an external independent 
biostatistician who is not involved in and will not influence the conduct of the study, and the 
results will be reviewed by an independent data monitoring committee (DMC).  A Lan and 
DeMets3 alpha spending function will be applied to control the overall type I error rate of 0.05 
for the primary endpoints during the IA and the final analysis such that an alpha of 0.01 will be 
preserved for the final analysis.  If the number of subjects included in the IA is 140, then the 
primary endpoint of the absolute change from baseline in ppFEV1 at Week 4 will be tested at a 
significance level of 0.044 during the IA.  The actual alpha at the IA (0) will be determined 
based on the actual number of subjects included in the interim Full Analysis Set (see Section 
8.4.1).  
Table 7-2 lists the actual alpha that will be spent at the IA with various numbers of subjects 
included in the interim Full Analysis Set.  The actual number N along with the 0 will be 
communicated to the independent biostatistician and DMC approximately 5 days prior to the IA 
data cutoff date. 
Table 7-2 
The Alpha Spending with Various N at the Interim Analysis  
Sample Size in interim Full Analysis Set (information fraction) 
Alpha at IA (0) 
Alpha at Final (1) 
140 (39%) 
0.0440 
0.01 
180 (50%) 
0.0451 
0.01 
220 (61%) 
0.0465 
0.01 
260 (72%) 
0.0480 
0.01 
300 (83%) 
0.0492 
0.01 
 
If the P value for the primary endpoint at the IA is less than 0, then the efficacy boundary has 
been crossed.  If the DMC declares that the study has crossed the efficacy boundary, then the 
study may be unblinded to a limited Vertex team to prepare regulatory submission(s).  Members 
of the limited Vertex unblinded team will not be involved in or influence the conduct of the 
remaining part of the study to protect the integrity of the study. 
If the P value fails to cross the efficacy boundary during the IA (i.e., P value >= 0), then the 
primary endpoint of absolute change in ppFEV1 from baseline at Week 4 will be tested after all 
subjects complete study participation at an alpha of 0.01. 
Selected key secondary endpoints will be analyzed during the IA with nominal P value provided 
for descriptive purpose (see Section 10.1.3.2). 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set will include all subjects who are randomized or receive at least 1 dose of 
study drug.  This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 


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8.2 
Full Analysis Set  
The Full Analysis Set (FAS) will be defined as all randomized subjects who carry the intended 
CFTR allele mutation and have received at least 1 dose of study drug.  The FAS will be used to 
summarize subject demographics, baseline characteristics, and for all efficacy analyses in which 
subjects will be analyzed according to their randomized treatment group. 
8.3 
Safety Set 
The Safety Set will include all subjects who receive at least 1 dose of study drug.  The Safety Set 
will be used for all safety analyses in which subjects will be analyzed according to the treatment 
they received.  
8.4 
Analysis Sets for IA 
A data cutoff date will be established for the IA as the latter of at least 140 subjects complete 
Week 4 Visit and at least 100 subjects complete Week 12 Visit.  
All subjects randomized or dosed prior to the data cutoff date will be in the scope of the IA.  All 
data reported on or before the data cutoff date will be included in the IA. 
8.4.1 
Interim Full Analysis Set 
The interim Full Analysis Set (iFAS) will include subjects in the FAS whose scheduled Week 4 
Visit is on or before the data cutoff date.  That is, the iFAS will include subjects in the FAS who 
complete the Week 4 Visit or are randomized at least 28 days before the data cutoff date. 
The iFAS will be used during the IA for subject demographics, baseline characteristics, and all 
efficacy analyses in which subjects will be analyzed according to their randomized treatment 
group. 
8.4.2 
Interim Safety Set 
The interim Safety Set (IA Safety Set) will include subjects in the Safety Set who complete the 
Week 4 Visit or receive their first dose of study drug at least 28 days before the data cutoff date. 
The IA Safety Set will be used during the IA for safety analyses in which subjects will be 
analyzed according to the treatment they received. 
9 
STATISTICAL ANALYSIS 
This section discusses the analyses planned for the final analysis.  See Section 10.1 for the 
analyses planned for the IA. 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of CSP.  The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max).  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 


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Baseline value, unless otherwise specified, is defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period. 
Absolute change from baseline will be calculated as post-baseline value - baseline value. 
Relative change from baseline will be calculated as (post-baseline value - baseline 
value)/baseline value. 
Treatment-emergent (TE) period will include the time from the first dose of study drug in the 
Treatment Period until 28 days after the last dose of study drug or to the completion of study 
participation, whichever occurs first. 
Completion of study participation for each individual subject is defined as one of the following:  
 For subjects who complete the Treatment Period and enter an open-label study within 
28 days of the Week 24 Visit: the Week 24 Visit  
 For subjects who complete the Treatment Period and do not enter an open-label study within 
28 days of the Week 24 Visit: the Safety Follow-up Visit 
 For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the Week 24 Visit, Early Termination of Treatment 
Visit, or Safety Follow-up Visit (if required) 
 For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (CSP Section 9.9) 
If subjects are lost to follow-up (CSP Section 9.1.5), the date of completion of study participation 
will be defined as the date of the last contact. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A.  
Incomplete/missing data will not be imputed, unless otherwise specified.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless otherwise specified. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized:  
 All Subjects Set 
 Full Analysis Set 


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 Safety Set 
 Randomized  
 Randomized but not dosed 
The number and percentage (based on the FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
 Completed treatment 
 Prematurely discontinued treatment and the reason for discontinuation  
 Completed study 
 Prematurely discontinued the study and the reason for discontinuation 
 Rollover to open-label study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and overall 
based on the FAS. 
Demographic data will include the following: 
 Age at baseline (in years) 
 Sex (male, female) 
 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, Other, and not collected per local regulations) 
 Geographic region (North America, Europe [including Israel and Australia]) 
Baseline characteristics will include the following: 
 Weight (kg) 
 Height (cm) 
 BMI (kg/m2) 
 BMI z-score (for subjects ≤20 years old at Baseline) 
Stratification categories (in addition to sex) will include the following: 
 Age at the Screening Visit (<18, and ≥18 years) 
 ppFEV1 determined during the Screening Period (<70, and ≥70) 
Disease characteristics will include the following: 
 ppFEV1 at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
 ppFEV1 at baseline (continuous)  


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 Sweat chloride at baseline (continuous) 
 CFQ-R respiratory domain score at baseline (continuous) 
 Prior use of dornase alfa (Yes, No) 
 Prior use of azithromycin (Yes, No) 
 Prior use of inhaled antibiotic (Yes, No) 
 Prior use of any bronchodilator (Yes, No)  
 Prior use of any inhaled bronchodilator (Yes, No)  
 Prior use of any inhaled hypertonic saline (Yes, No) 
 Prior use of any inhaled corticosteroids (Yes, No) 
 Infection with Pseudomonas aeruginosa within 2 years prior to screening (Positive, 
Negative) 
In addition, data listings will also be provided for: 
 Informed consent; 
 Inclusion/Exclusion criteria violation for subjects with any such violations. 
9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA).  For the FAS, medical history will be summarized descriptively by system organ 
class (SOC) and preferred term (PT).  The corresponding data listing will also be provided.  
In addition, the number of subjects reported to have had positive cultures for respiratory 
pathogens within the 2 years prior to screening (i.e., answered yes on the respiratory 
microbiology form) will be summarized for the FAS.  The corresponding data listing will be 
provided.  Hospitalization and clinic visit history in the year prior to the signing of informed 
consent will be listed. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
and categorized as follows: 
Prior medication: any medication that was administered during the 56 days before the first dose 
of study drug, regardless of when it ended. 
Concomitant medication: medication continued or newly received on or after the first dose date 
of study drug through the end of the TE period. 
Post-treatment medication: medication continued or newly received after the TE period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior 
and concomitant, both concomitant and post-treatment, or prior, concomitant, and 
post-treatment.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly during 


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the TE period, or after the TE period, it will be classified as prior, concomitant, and 
post-treatment. 
For the FAS, prior medications and concomitant medications will be summarized descriptively 
by: 1) treatment group and overall, preferred name (PN); and 2) treatment group and overall, 
anatomic class (ATC) level 1, ATC level 2, and PN.  Post-treatment medications will be listed 
for each subject. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix B. 
9.2.5 
Study Drug Exposure  
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug – 
first dose date of study drug + 1, regardless of study drug interruption, and will be summarized 
descriptively. 
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max.  It will also be summarized in categories for Treatment Period: 
≤1 week, >1-≤2 weeks, >2-≤4 weeks, >4-≤8 weeks, >8-≤12 weeks, >12-≤16 weeks, >16-≤20 
weeks, >20-≤24 weeks, and >24 weeks, using counts and percentages.  Additionally, the total 
study drug exposure, defined as the sum total of the study drug exposure across all subjects (in 
patient-weeks and patient-years), will be provided. 
Exposure summaries will be based on the Safety Set, and presented by treatment group and 
overall. 
9.2.6 
Study Drug Compliance 
Study drug compliance will be calculated as: 100  [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)].  A study drug interruption on a given 
day is defined as an interruption of any study drug on that day.  A study drug interruption that 
continues through the end of the study participation (i.e., subject does not resume study drug 
before the end of the study participation) will not be included in the compliance calculation. 
Percentage of study drug compliance will be summarized based on the FAS, and presented by 
treatment group and overall.  Percentage of study drug compliance will be summarized 
descriptively by the number of subjects (n), mean, SD, median, min, and max.  It will also be 
summarized in categories: <80% and ≥80% using frequency tables.  
In addition, percentage of tablets taken will be calculated using the following formula: 
100  [(total number of tablets dispensed) – (total number of tablets returned)] / (total number of 
tablets planned to be taken per day  duration of study drug exposure in days).  Summary similar 
to those for the study drug compliance will be produced based on the FAS. 
9.2.7 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being.  IPD rules will be developed and finalized prior to the IA data lock. 
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to: 


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 Subject was enrolled in the study despite the violation of inclusion/exclusion criteria 
 Subject was less than 80% compliant with study drug for non-safety reason 
 Subject received prohibited concomitant medications 
 Subject received the wrong treatment or incorrect doses  
 Subject remained in the study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. 
IPDs (from the clinical database or from the site deviation log) will be summarized descriptively 
based on the FAS and presented by treatment group and overall.  Additionally, IPDs will be 
provided in an individual subject data listing. 
9.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified. 
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Definition of Variables 
The primary efficacy variable is the absolute change in ppFEV1 from baseline at Week 4.  
Percent predicted FEV1 is the ratio of FEV1 (L) and predicted FEV1 (L), expressed as a 
percentage.  See Appendix C for more details. 
9.3.1.2 
Primary Analysis 
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with change from baseline at Day 15, Week 4, Week 8, Week 12, Week 16, and Week 
24 as the dependent variable. The model will include treatment group, visit, and treatment by 
visit interaction as fixed effects, with continuous baseline ppFEV1, age at screening (<18 versus 
≥18 years of age) and sex (male versus female) as covariates.  The model will be estimated using 
restricted maximum likelihood.  Denominator degrees of freedom for the F-test for fixed effects 
will be estimated using the Kenward-Roger approximation2.  An unstructured covariance 
structure will be used to model the within-subject errors.  If the model estimation does not 
converge, a compound symmetry covariance structure will be used instead.  Conditional on the 
observed data and covariates, missing data will be assumed to be missing at random; 
consequently, no imputation of missing data will be performed. 
The primary result obtained from the model will be the estimated treatment difference at Week 4. 
The adjusted means with 2-sided 95% confidence intervals and 2-sided P values will be 
provided.  Furthermore, the treatment difference at each post-baseline visit obtained from the 
model will also be provided. 




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9.3.2 
Analysis of Key Secondary Variables 
9.3.2.1 
Definition of Variables 
Pulmonary exacerbation (PEx): A PEx is defined as a new event or change in antibiotic therapy 
(IV, inhaled, or oral) for any 4 or more of the following signs/symptoms: 
 Change in sputum 
 New or increased hemoptysis 
 Increased cough 
 Increased dyspnea 
 Malaise, fatigue, or lethargy 
 Temperature above 38°C (equivalent to approximately 100.4°F) 
 Anorexia or weight loss 
 Sinus pain or tenderness 
 Change in sinus discharge 
 Change in physical examination (PE) of the chest 
 Decrease in pulmonary function by 10% 
 Radiographic changes indicative of pulmonary infection 
The PEx analysis period will include the time from the first dose date of study drug until the 
last efficacy assessment, which may be collected up to the Week 24 Visit or the earlier of Day 
169 and the end of study participation if subject does not have the Week 24 Visit. 
The number of PEx through Week 24 is then defined as the total number of PEx for each 
treatment group during the PEx analysis period. 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit.  If one 
of the two arm measurements at a time point is missing, the other will be used as the mean.  A 
volume ≥15 μL is required for an accurate determination of sweat chloride.  Any results reported 
as having volume <15 μL will be considered missing.  Any sweat chloride values reported as 
<10 mmol/L or >160 mmol/L will be considered missing. 
Cystic Fibrosis Questionnaire-Revised (CFQ-R): The CFQ-R1,4,6 is a validated CF-specific 
instrument that measures quality-of-life domains.  This study utilizes three different versions of 
CFQ-R: 
 CFQ-R for Children ages 12 and 13 
 CFQ-R for Adolescents and Adults (subjects 14 years and older) 
 CFQ-R for Parents/Caregivers (subjects 13 years and younger) 
In all three versions, specific question belonging to a domain is scored 1, 2, 3, or 4.  The CFQ-R 
domain score, e.g., physical domain score or respiratory domain score, is defined as a scaled 
score as follows: 


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Scaled score for a domain = 100 × (mean (scores of all questions in the domain) −1)/3, 
where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – 
actual score, so that 1 always represents the worst condition and 4 the best condition.  The 
(scaled) domain score ranges from 0 (worst condition) to 100 (best condition).  The scaled score 
for a specific domain will not be calculated if more than half of the questions in the domain have 
missing scores. 
The (scaled) domain score from the CFQ-R for Children ages 12 and 13 and for Adolescent and 
Adults will be pooled for the analysis purpose. 
Body mass index (BMI): the BMI at each visit is calculated using the weight and height at each 
visit as follows: 
BMI = Weight (kg)
Height (m2) 
 
9.3.2.2 
Analysis Method 
Absolute change in ppFEV1 through Week 24: Analysis of this variable will be based on an 
MMRM that is exactly the same as the primary efficacy variable.  However, the Day 15 Visit 
will not be included in the estimation of the average treatment effect through Week 24 as the 
treatment effect is not expected to reach the steady state at Day 15. 
Number of PEx through Week 24: Analysis of this variable will be performed using a negative 
binomial regression model with a fixed effect for treatment, as well as continuous baseline 
ppFEV1, age at screening (<18 versus ≥18 years of age), and sex (male versus female) as 
covariates.  The logarithm of the subject-specific PEx analysis period duration (in years) will be 
treated as the offset in the model. 
Absolute change in SwCl from baseline through Week 24: Analysis of this PD variable will be 
based on an MMRM similar to the analysis of the primary efficacy variable.  Data obtained from 
Week 4, Week 8, Week 12, and Week 24 Visits will be included in the model and all of these 
visits will be included in the estimation of the average treatment effect through Week 24. 
Absolute change in the CFQ-R respiratory domain score from baseline through Week 24: 
Analysis of this domain will be based on an MMRM similar to the analysis of the primary 
efficacy variable.  Data obtained from Week 4, Week 8, Week 12, Week 16, and Week 24 Visits 
will be included in the model and all of these visits will be included in the estimation of the 
average treatment effect through Week 24. 
Absolute change in BMI from baseline at Week 24: Analysis of this variable will be based on an 
MMRM similar to the analysis of the primary efficacy variable.  Data obtained from Day 15, 
Week 4, Week 8, Week 12, Week 16, and Week 24 Visits will be included in the model. 
Absolute change in SwCl from baseline at Week 4: Analysis of this PD variable will be based on 
an MMRM similar to the analysis of the primary efficacy variable.  Data obtained from Week 4, 
Week 8, Week 12, and Week 24 Visits will be included in the model to estimate the treatment 
effect at Week 4. 
Absolute change in CFQ-R respiratory domain score from baseline at Week 4: Analysis of this 
domain will be based on an MMRM similar to the analysis of the primary efficacy variable.  


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Data obtained from Week 4, Week 8, Week 12, Week 16 and Week 24 Visits will be included in 
the model to estimate the treatment effect at Week 4. 
To assess the longitudinal profile of the efficacy and pharmacodynamic assessments with 
repeated measures up to Week 24, the LS mean (SE) of the within-treatment group change from 
baseline at each post-baseline visit along with the 95% CI will be estimated from the 
corresponding MMRM.  The LS mean (SE) of the treatment difference between VX-
659/TEZ/IVA and triple placebo at each post-baseline visit will be provided along with the 
corresponding 95% CI and P value.  The LS mean (SE) at each visit will also be plotted by 
treatment group.  In addition, the post-baseline raw values and the absolute change from baseline 
at each post-baseline visit will be summarized descriptively (n, mean, SD, median, minimum, 
and maximum). 
9.3.2.3 
Multiplicity Adjustment 
The Lan and DeMets3 alpha spending function will be applied to the primary endpoint of the 
absolute change in ppFEV1 at Week 4 to control the overall type I error rate of 0.05 such that an 
alpha of 0.01 will be preserved for the final analysis.  
If the number of subjects included in the IA is 140, the primary endpoint of the absolute change 
from baseline in ppFEV1 at Week 4 will be tested at an alpha of 0.044 during the IA.  The actual 
alpha at the IA (0) will be determined based on the actual number of subjects included in the 
interim Full Analysis Set.  If the study does not cross the efficacy boundary during the IA (P 
value ≥0), then the primary endpoint will be tested at an alpha of 0.01 at the final analysis 
when all subjects complete the study participation.  See Section 7.5 for more details. 
The key secondary endpoints will be formally tested at an alpha of 0.05 at the final analysis 
when all subjects complete study participation only if the primary endpoint is statistically 
significant at the IA or at the final analysis.  A hierarchical testing procedure will be used to 
control the type I error rate for the multiple key secondary endpoints tested at an alpha of 0.05. 
For a test at any step to be considered statistically significant within the testing hierarchy, it must 
be statistically significant, and all previous tests (if any) within the hierarchy must be statistically 
significant at the 0.05 level.  The testing order of the key secondary endpoints is as follows: 
 Absolute change in ppFEV1 from baseline through Week 24  
 Number of PEx through Week 24  
 Absolute change in SwCl from baseline through Week 24 
 Absolute change in CFQ-R respiratory domain from baseline through Week 24  
 Absolute change in BMI from baseline at Week 24  
 Absolute change in SwCl from baseline at Week 4 
 Absolute change in CFQ-R respiratory domain score from baseline at Week 4 
9.3.3 
Analysis of Other Secondary Variables 
9.3.3.1 
Definition of Variables 
Time-to-first PEx through Week 24: the number of days from the first dose date of study drug to 
the date of the first pulmonary exacerbation during the PEx analysis period.  A subject who does 


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not experience a PEx during the PEx analysis period will be censored at the PEx analysis period 
end date. 
BMI z-score: the BMI score, adjusted for age and sex, will be referred to as BMI-for-age z-score 
(BMI z-score).  The BMI z-score will be calculated by using Centers for Disease Control and 
Prevention (CDC) growth charts8, with the age (in months) used for the calculation defined in 
Appendix A. 
9.3.3.2 
Analysis Method 
Time-to-first PEx through Week 24: Time-to-first PEx will be analyzed using the Cox regression 
model.  The model will include a fixed effect for treatment, as well as continuous baseline 
ppFEV1, age at screening (<18 versus ≥18 years of age), and sex (male versus female) as 
covariates.  Additionally, the Kaplan-Meier method will be used to produce a graphical 
presentation of the cumulative exacerbation-free rate for each treatment group and to estimate 
the cumulative exacerbation-free rate by treatment group. 
Note: If the number of events is <5 in either treatment group, Cox regression will not be 
performed and the analysis of the time-to-first event will be restricted to the Kaplan-Meier 
method. 
Absolute change in BMI z-score from baseline at Week 24 (for subjects ≤20 years of age at 
Baseline): Analysis of this variable will be based on an MMRM similar to the analysis of the 
primary efficacy variable, excluding the covariate of age at screening (<18 versus ≥18 years of 
age), for subjects ≤20 years of age at Baseline.  Data obtained from Day 15, Week 4, Week 8, 
Week 12, Week 16, and Week 24 Visits will be included in the model. 
Absolute change in body weight from baseline at Week 24: Analysis of this variable will be 
based on an MMRM similar to the analysis of the primary efficacy variable.  Data obtained from 
Day 15, Week 4, Week 8, Week 12, Week 16, and Week 24 Visits will be included in the model. 




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9.4 
Safety Analysis 
All safety analyses will be based on data from the TE period for all subjects in the Safety Set.  
Subjects will be analyzed according to the treatment they actually received in the Treatment 
Period.  For subjects receiving study drug from more than one treatment group, the treatment 
group allocation will be the higher treatment group (VX-659/TEZ/IVA > TC Placebo).  
The overall safety profile of the study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values 
 ECGs 


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 Vital signs 
 Pulse oximetry 
Only descriptive analysis of safety will be performed and no statistical testing will be performed. 
9.4.1 
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 occurred before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed on 
or after the first dose date of study drug through the end of the TE period  
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after the TE period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in Appendix E. 
An overview of all TEAEs by treatment group and overall will be summarized in the following 
categories: 
 Number of TEAEs (total number of TEAEs only) 
 Subjects with any TEAEs  
 Subjects with TEAEs by strongest relationship 
 Subjects with TEAEs by maximum severity 
 Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drug) 
 Subjects with TEAEs leading to study drug interruption (interruption of any study drug) 
 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 


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 TEAEs leading to treatment interruption 
 Related TEAEs 
 Serious TEAEs 
 Related serious TEAEs 
 TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event).  When summarizing the number and 
percentages of subjects, subjects with multiple occurrences of the same adverse event or a 
continuing adverse event will be counted once, and only the maximum severity level will be 
presented in the severity summaries, and the strongest relationship level in the relationship 
summaries.  
Additional summary tables will be presented by treatment for TEAEs showing number and 
percentage of subjects 
 All TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set.  In addition, a listing containing 
individual subject adverse event data for TEAEs leading to treatment discontinuation, TEAEs 
leading to treatment interruption, Grade 3/4 TEAEs, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths. 
For all AEs, the eCRF captures the action taken for VX-659/TEZ/IVA pills separately from the 
action taken for IVA monotherapy pills.  As a result, it is possible that, in the final database 
(after database lock), the AE actions taken for the two agents (fixed dose VX-659/TEZ/IVA and 
ivacaftor monotherapy) are different. The summaries and listings of “AE Leading to Treatment 
Dis continuation” and “AE Leading to Treatment Interruption” account for discontinuation and 
interruptions for either agent. 
9.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, coagulation and chemistry results will be 
summarized in SI units at each visit by treatment group. 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the TE period will be summarized by treatment group and overall. The threshold analysis 


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criterion shift from baseline will also be summarized for selected laboratory parameters. The 
threshold analysis criteria are provided in Appendix F.  
For select LFT laboratory tests (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-
emergent value versus the baseline value corresponding to ×ULN (upper limit of normal) will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, 
separately, versus the maximum treatment-emergent value of total bilirubin corresponding to 
×ULN will also be presented by treatment group.  
Results of positive urine/serum pregnancy test will be listed in individual subject data listings 
only. For positive serum pregnancy listing, subjects with serum HCG which are abnormally high 
will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from both scheduled and unscheduled visits.  
9.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit by treatment group for the following ECG 
measurements (in msec): RR interval, PR interval, QT interval, and QTcF interval, QRS 
duration, and Heart Rate (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period will be summarized by treatment group and overall. The threshold analysis criteria are 
provided in Appendix F. 
9.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit by treatment group. The following vital signs 
parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period will be summarized by treatment group and overall.  The threshold analysis criteria 
are provided in Appendix F. 
9.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each visit 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 summarized by treatment group and overall. 
9.4.6 
Physical Examination  
Abnormal PE findings will be presented as an individual subject data listing only. 




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10 
SUMMARY OF INTERIM AND DMC ANALYSIS 
For each DMC meeting and the planned IA, the Vertex Biometrics Department will prepare the 
analysis package using the dummy treatment code and dummy spirometry and SwCl data 
according to the DMC charter and the DMC SAP, respectively; SAS (Version 9.4, or higher) will 
be used to generate all statistical outputs (tables, figures, listings, and datasets). 
ICON Clinical Research Limited (ICON), appointed as the independent biostatistician, will 
perform the IA according to the DMC SAP using the SAS code provided by Vertex Biometrics 
Department, the unblinded treatment code, the real (restricted) spirometry, and the real 
(restricted) sweat chloride data.  Unblinded treatment code, spirometry, and sweat chloride data 
will be transferred directly from relevant vendors to the independent biostatistician.  ICON will 
present the results to the DMC. 
If the study crosses the efficacy boundary according to the pre-specified criterion (Section 7.5), a 
limited Vertex unblinded team may be unblinded to the study.  The limited Vertex unblinded 
team will use the unblinded treatment code and real (restricted) data to generate statistical 
outputs and prepare for submission(s).  Members of the limited Vertex unblinded team will not 
be involved in or influence the conduct of the remaining part of the study to protect the integrity 
of the study.  
10.1 
Interim Analysis 
10.1.1 
General Consideration 
Refer to Section 7.5 for the timing of the IA.  General considerations, reporting conventions, and 
analysis methods specified for the final analysis apply to the IA, unless otherwise specified. 
For the IA purpose, the treatment-emergent (TE) period will include the time from the first 
dose of study drug in the Treatment Period until 28 days after the last dose of study drug, or the 
study participation end date, or the IA data cutoff date, whichever occurs first. 
10.1.2 
Background Characteristics 
10.1.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized:  


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 All Subjects Set 
 Interim Full Analysis Set 
 IA Safety Set 
 Safety Set 
 Randomized  
 Randomized but not dosed 
The number and percentage (based on the iFAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
 Completed Week 4 Visit 
 Prematurely discontinued treatment before Week 4 Visit and the reason for discontinuation 
 Completed Week 12 Visit 
 Prematurely discontinued treatment before Week 12 Visit and the reason for discontinuation 
 Completed treatment 
 Prematurely discontinued treatment and the reason for discontinuation  
 Completed study 
 Prematurely discontinued the study and the reason for discontinuation 
 Rollover to open-label study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation.  
10.1.2.2 
Demographics and Baseline Characteristics 
The same demographics and baseline characteristics specified in Section 9.2.2 will be 
summarized based on the iFAS. 
10.1.2.3 
Study Drug Exposure 
For the purpose of the IA, the study drug exposure will be calculated using the same approach 
specified in Section 9.2.5.  For subjects who are still on study drug at the IA data cutoff date, the 
IA data cutoff date will be used as the last dose date for the exposure calculation. 
Exposure summaries will be provided for subjects in the IA Safety Set as well as for subjects in 
the Safety Set who had been on-study for ≥12 weeks, and will be presented by treatment group 
and overall. 
10.1.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the iFAS, unless otherwise 
specified. 
10.1.3.1 
Analysis of Primary Efficacy Variable 
The analysis of the primary efficacy variable of absolute change in ppFEV1 from baseline at 
Week 4 will be performed using an MMRM with change from baseline at Day 15 and Week 4 as 


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the dependent variable.  The model will include treatment group, visit, and treatment by visit 
interaction as fixed effects, with continuous baseline ppFEV1, age at screening (<18 versus ≥18 
years of age) and sex (male versus female) as covariates.  The model will be estimated using 
restricted maximum likelihood.  Denominator degrees of freedom for the F-test for fixed effects 
will be estimated using the Kenward-Roger approximation2.  An unstructured covariance 
structure will be used to model the within-subject errors.  If the model estimation does not 
converge, a compound symmetry covariance structure will be used instead.  Conditional on the 
observed data and covariates, missing data will be assumed to be missing at random; 
consequently, no imputation of missing data will be performed. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
10.1.3.2 
Analysis of Key Secondary Efficacy Variable 
The following key secondary efficacy variables defined in Section 9.3.2.1 will be analyzed 
during the IA using an ANCOVA model: 
 Absolute change in SwCl from baseline at Week 4 
 Absolute change in CFQ-R respiratory domain score from baseline at Week 4 
The model will use the change from baseline value at Week 4 as the dependent variable and 
include treatment group as fixed effects with continuous baseline ppFEV1, age at screening (<18 
versus ≥18 years of age), and sex (male versus female) as covariates.  The estimated treatment 
difference at Week 4, the adjusted means with 2-sided 95% confidence intervals and nominal 2-
sided P values will be provided. 
Analyses of other efficacy and/or pharmacodynamic variables may be performed if the data are 
deemed sufficient. 
10.1.3.3 
Summary of Efficacy Variables 
The raw and change from baseline in ppFEV1, SwCl and CFQ-R will be summarized 
descriptively (n, mean, SD, median, minimum, and maximum) at baseline and post-baseline 
visits.  For the IA purpose, a visit will be included in the summary if there are ≥20 subjects with 
available data from each treatment group at that visit. 


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10.1.4 
Safety Analysis 
Safety analyses specified in Section 9.4 will be performed during the IA based on the IA Safety 
Set. 
10.2 
DMC Analysis 
The DMC will conduct planned safety/efficacy review(s) of study data as outlined in the DMC 
charter.  For the open session of each DMC meeting, selected tables will be presented for the 
overall treatment group based on the blinded data.  For the closed session, the presentation will 
be by treatment group based on the unblinded data (generated by the independent biostatistician). 


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The timing of DMC meetings is outlined in Table 10-1. 
Table 10-1 DMC Meeting Schedule  
Meeting 
Timing 
Organizational 
Teleconference prior to start of the study 
First Planned Review 
After ≥50 subjects have completed Week 4 
Second Planned 
Review 
Interim analysis of safety and efficacy after ≥140 subjects have 
completed the Week 4 visit and after ≥ 100 subjects have completed the 
Week 12 visit. 
Ad-hoc 
Teleconference on an as-needed basis 
10.2.1 
DMC Safety/Efficacy Review 
To protect the integrity of the treatment assignment and study data, the following steps for the 
flow of data will be executed for the DMC review: 
1. The Vertex Biometrics Department will prepare the SAS codes, SDTM/ADaM data sets,  
and blinded outputs (tables, figures and listings) of safety data using dummy treatment 
codes, dummy (unrestricted) spirometry data, and dummy (unrestricted) sweat chloride 
data; 
2. The IWRS vendor, Bracket, will provide the unblinded treatment codes to the 
independent biostatistician via a secure file transfer protocol, the independent 
biostatistician will verify the treatment assignment against the randomization list 
generated by Cytel; 
3. The spirometry vendor will provide the restricted spirometry data directly to the 
independent biostatistician, via a secure file transfer protocol;  
4. The sweat chloride vendor  will provide the restricted sweat chloride data directly to 
independent biostatistician, via a secure file transfer protocol;  
5. Independent biostatistician will generate the unblinded outputs (tables, figures and 
listings) and provide them directly to the DMC team for their review, via a secure file 
transfer protocol.  
6. The Vertex Biometrics Department will generate any blinded outputs (tables, figures and 
listings), for the open sessions of the DMC meetings, as applicable. 
 


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11 
REFERENCES 
1 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
2 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 Lan KK, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-63. 
4 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life 
for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
5 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
6 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
7 Rubin, DB. and Schenker, N.. Interval estimation from multiply-imputed data: a case study 
using agriculture industry codes. Journal of the American Statistical Association. 1987; 81: 
366–374. 
8 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
 
 


Statistical Analysis Plan (Methods) 
Page 34 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
12 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3 
Safety Assessment  
Serum Chemistry 
Hematology 
Standard 12-lead ECG 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
Use nominal visit 
Vital Signs 
 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 
[1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
Use nominal visit 
Coagulation 
 
Day 1 (Baseline)  
Week 24 
Safety Follow-up 
1 
169 
Not applicable 
1 Pre-dose 
[1, 183] 
Use nominal visit 
Efficacy Assessment and Pharmacodynamic Assessment  
Spirometry  
 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 Pre-dose 
(1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
>183 
Sweat Chloride 
Day 1 (Baseline)  
Week 4 
Week 8 
Week 12 
Week 24 
1 
29 
57 
85 
169 
1 Pre-dose 
(1,  43] 
(43, 71] 
(71,  127] 
(127, 183] 
CFQ-R 
Day 1 (Baseline)  
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
29 
57 
85 
113 
169 
Not applicable 
1 
(1, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
>183 


Statistical Analysis Plan (Methods) 
Page 35 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3 
Weight, Height and BMI (and 
the corresponding z-score) 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 
(1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
>183 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. 
 
3 For lab, ECG and vital sign measurement collected on the date of first dose of study drug, if it cannot be 
determined whether the measurement is before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs 
(VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI and weight z-score): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital Signs 
(VS) page at the Screening Visit. 
Obtain the informed consent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + diff(first 
dose date or post-baseline visit date, informed consent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 


Statistical Analysis Plan (Methods) 
Page 36 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for a 
given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
5. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period.  If multiple ECG measurements are obtained on the same calendar day during the TE period,  
o 
For summary purpose, the calculated average ECG will be used as the ECG value on that day; 
o 
For threshold analysis purpose, all reported ECG values will be used. 
 
 
 




Statistical Analysis Plan (Methods) 
Page 38 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
Appendix C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, 
 
 using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed Mar 26, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed Mar 
26, 2018].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Mar 26, 2018]. 
Data handling rule for spirometry is as follows:  
 Input age and height with at least 2 decimal place 
 Use height at screening regardless if height is collected at other study visits for subjects 
whose age at informed consent is >21 years. For subjects with age <=21 years, height 
collected at the respective visit should be used; if the height at the respective visit is not 
available, the last non-missing record will be used. 
 For race, map the CRF reported Black or African American to Black, all other races in 
CRF (except White) are mapped to 'other'; multiple checks for race in CRF are also 
mapped to 'other'; white is a reference race in the equations and assumes 0 values for all 
race coefficients in the GLI  equations. 
 
 






Statistical Analysis Plan (Methods) 
Page 41 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
Appendix E: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below.  If the imputed AE start 
date is before the study informed consent date, the AE start date will be imputed using the study 
informed consent date. 
 If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site and  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the Treatment Period;  
o else impute the AE start date as the informed consent date. 
 
Imputation rules for partial AE end date are defined below:  
 Impute the AE end date as min (the last day of the month, end of study participation) if day is 
missing, or min (Dec, end of study participation) if month is missing. 
o For the IA purpose, if the end of study date is missing, then the IA data cutoff date 
will be used instead in the imputation 


Statistical Analysis Plan (Methods) 
Page 42 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Appendix F: Criteria for Threshold Analysis 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤ 3xULN) or (AST>ULN - 
≤3xULN) 
(ALT>3x - ≤5xULN) or  (AST>3x - 
≤5xULN) 
(ALT>5x - ≤8xULN) or  (AST>5x - 
≤8xULN) 
(ALT>8x - ≤20xULN) or (AST>8x - 
≤20xULN) 
ALT>20xULN or AST>20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 - ≤5.0xULN 
>5.0 - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


Statistical Analysis Plan (Methods) 
Page 43 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤2.5xULN 
>2.5 - ≤5.0xULN 
>5.0 - ≤20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥30 g/L 
<30 - ≥20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤1.5xULN 
>1.5 - ≤3.0xULN 
>3.0 - ≤6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5 - ≤5xULN 
>5 - ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥75.0 x 10e9 /L 
<75.0 - ≥50.0 x 10e9 /L  
<50.0 - ≥25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)    
<LLN 
>ULN 
No CTCAE 


Statistical Analysis Plan (Methods) 
Page 44 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 x ULN 
CTCAE grade 1-3 
  
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
 
>450 to <500ms (Male) or >470 to <500ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
 
 
 
 


Statistical Analysis Plan (Methods) 
Page 45 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from baseline 
>140 mmHg & >20 mmHg increase from baseline 
>160 mmHg & >10 mmHg increase from baseline 
>160 mmHg & >20 mmHg increase from baseline 
809/770 analyses 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from baseline 
<90 mmHg and >20 mmHg decrease from baseline 
<80 mmHg and >10 mmHg decrease from baseline 
<80 mmHg and >20 mmHg decrease from baseline 
Per HV grade 1, 3, plus shift change 
DBP increased 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from baseline 
>90 mmHg and >10 mmHg increase from baseline 
>100 mmHg and >5 mmHg increase from baseline 
>100 mmHg and >10 mmHg increase from baseline 
 
DBP decreased 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from baseline 
<60 mmHg and >10 mmHg decrease from baseline 
<45 mmHg and >5 mmHg decrease from baseline 
<45 mmHg and >10 mmHg decrease from baseline 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3 
 


Statistical Analysis Plan (Methods) 
Page 46 of 47 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Table 12-6 
Threshold Analysis Criteria for Laboratory Tests (for labeling purpose) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
For labeling purpose 
 
 




Statistical Analysis Plan (Methods) Addendum 
Page 1 of 6 
Protocol Number: VX17-659-102   
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Addendum to Statistical Analysis Plan 
(Methods) 
Protocol Number VX17-659-102 Version 3.0 
(Final and Interim Analysis) 
 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating 
the Efficacy and Safety of VX-659 Combination Therapy in Subjects 
With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation 
and a Minimal Function Mutation (F/MF) 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of Addendum: 9 OCT 2018 
Version Date of SAP: 14 MAY 2018 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 












Statistical Analysis Plan (Methods) Addendum 2 
Page 1 of 4 
Protocol Number: VX17-659-102   
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Addendum 2 to Statistical Analysis Plan 
(Methods) 
Protocol Number VX17-659-102 Version 3.0 
(Final Analysis) 
 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating 
the Efficacy and Safety of VX-659 Combination Therapy in Subjects 
With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation 
and a Minimal Function Mutation (F/MF) 
 
Authors of Addendum 2: 
 
 
Version of Addendum 2: 1.0 
Version Date of Addendum 2: 22 FEB 2019 
 
Original Version Date of SAP: 14 MAY 2018 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) Addendum 2 
Page 2 of 4 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
2 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2 
Efficacy Analysis .............................................................................................................. 4 
5.2.1 
Analysis of Endpoints Based on the Number of Clinical Events ............................. 4 
 




Statistical Analysis Plan (Methods) Addendum 2 
Page 4 of 4 
Protocol Number: VX17-659-102  
 
Vertex Pharmaceuticals Incorporated 
 
 
5.2 
Efficacy Analysis 
5.2.1 
Analysis of Endpoints Based on the Number of Clinical Events 
Number of Pulmonary Exacerbation (PEx) through Week 24: The analysis pre-specified in the 
protocol based on the negative binomial regression model will be performed first. If the negative 
binomial regression does not converge, the analysis will be performed using the Poisson 
regression with the same covariates and offset. 
Note: If the number of events is less than 5 in either treatment group, neither the negative 
binomial regression nor the Poisson regression will be performed and analysis of event counts 
will be based on a Fisher’s Exact test. 
Analysis of the number of PEx requiring hospitalization and/or IV antibiotics therapy, the 
number of planned hospitalizations for CF, and the number of unplanned hospitalizations for 
reasons other than antibiotic therapy for sinopulmonary signs/symptoms will be performed in the 
same manner.