Clinical trial NCT03224351
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2017-08-08; Completion date: 2018-02-28
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double-blind, placebo- and tezacaftor/ivacaftor (TEZ/IVA)-controlled, parallel-group, 3-part, multicenter study designed to evaluate the safety and efficacy of VX-659 in triple combination (TC) with TEZ and IVA in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).

Detailed description:

Arms: arm 1: Participants received placebo matched to VX-659/TEZ/IVA in TC treatment period for 4 weeks and placebo matched TEZ/IVA in washout period for 4 days. arm 2: Participants received VX-659 80 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days. arm 3: Participants received VX-659 240 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days. arm 4: Participants received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days. arm 5: Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks. arm 6: Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks. arm 7: Participants received placebo matched to VX-659/TEZ/VX-561 in TC treatment period for 4 weeks. arm 8: Participants received VX-659 400 mg qd/TEZ 100 mg qd/VX-561 200 mg qd in TC treatment period for 4 weeks.
Interventions: intervention 1: VX-659 intervention 2: TEZ/IVA intervention 3: IVA intervention 4: Placebo (matched to VX-659/TEZ/IVA) intervention 5: TEZ intervention 6: VX-561 intervention 7: Placebo (matched to VX-659/TEZ/VX-561)
Intervention descriptions: intervention 1: Tablet for oral administration. intervention 2: TEZ/IVA fixed-dose combination tablet for oral administration. intervention 3: Tablet for oral administration. intervention 4: Placebo matched to VX-659 and TEZ/IVA. intervention 5: Tablet for oral administration. intervention 6: Tablet for oral administration. intervention 7: Placebo matched to VX-659, TEZ and VX-561.

Protocol documents:
Prot_000.pdf: 


Protocol VX16-659-101, Version 3.0
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Summary of Changes to the Protocol 
The previous version of this protocol (Version 2.0, 30 June 2017) was amended to create the 
current version (Version 3.0, 01September 2017). The protocol history is provided below.
Protocol History
Version and Date of Protocol
Comments
Version 1.0, 03 March 2017
Original version
Version 2.0, 30 June 2017
Added study drug doses, revised elements of the study design including 
treatment arms, sample size, and study duration, and revised 
inclusion/exclusion criteria. 
Version 3.0, 01 September 2017
Current version
Key changes in the current version of the protocol are summarized below.
Change and Rationale
Affected Sections
Added Part 3 to evaluate VX-659 in triple combination with TEZ/VX-561
(deuterated IVA)
Global
Incorporated Administrative Letter #1 which clarified that the pretreatment 
(screening) ppFEV1 value used for stratification refers to the last ppFEV1
measurement before treatment with VX-659 
Sections 9.1.3, 9.3.1, and 
Table 3-2
For Part 2, extended the window for the Day -14 Visit from Day -15 to Day -3 to 
allow scheduling flexibility
Table 3-2
Specified required pregnancy tests and clarified that additional testing may be 
needed per country-specific regulations, 
 
.
Section 11.7.2
Typographical and administrative changes were also made to improve the clarity of the 
document.


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2
PROTOCOL SYNOPSIS
Title
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy 
of VX-659 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis
Brief Title
A Study Evaluating the Safety and Efficacy of VX-659 Combination Therapy in Subjects With 
Cystic Fibrosis
Clinical Phase 
and Study Type 
Phase 2 safety and efficacy
Objectives
Primary Objectives
Parts 1 and 2: To evaluate the safety and tolerability of VX-659 in triple combination (TC) 
with tezacaftor (TEZ) and ivacaftor (IVA)
Part 3 (optional): To evaluate the safety and tolerability of VX-659 in TC with TEZ and 
VX-561 (also known as CTP-656, deuterated IVA)
All parts: To evaluate the efficacy of VX-659 in TC with TEZ and either IVA or VX-561
Secondary Objectives
Parts 1 and 2: To evaluate the pharmacodynamic (PD) effects of VX-659 in TC with TEZ and 
IVA on CFTR function
Part 3 (optional): To evaluate the PD effects of VX-659 in TC with TEZ and VX-561 on 
CFTR function
All parts: 
•
To evaluate the pharmacokinetics (PK) of VX-659 when administered in TC with TEZ and 
either IVA or VX-561
•
To evaluate the PK of TEZ, IVA, VX-561 and their respective metabolites when 
administered with VX-659 (as applicable)
Endpoints
Primary Endpoints
•
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values, standard 12-lead ECGs, vital signs, and pulse oximetry
•
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through the Day 29 Visit
Secondary Endpoints
•
Absolute change in sweat chloride concentrations from baseline through the Day 29 Visit 
•
Relative change in ppFEV1 from baseline through the Day 29 Visit 
•
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline at the Day 29 Visit 
•
PK parameters of VX-659, TEZ, M1-TEZ, IVA, M1-IVA, and VX-561
Number of 
Subjects
Up to approximately 105 subjects will be randomized: approximately 54 subjects in Part 1, 
approximately 27 subjects in Part 2, and approximately 24 subjects in Part 3.
Study 
Population
Male and female subjects 18 years of age or older with CF
Part 1 and Part 3: heterozygous for F508del and a minimal CFTR function mutation that is 
not expected to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes) 
Part 2: homozygous for F508del (F/F genotype)


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Investigational 
Drug
Active substance: VX-659
Activity: CFTR corrector (increased Cl−secretion)
Strength and route of administration: 80-mg VX-659 tablet for oral administration
Active substance: IVA (ivacaftor; VX-770)
Activity: CFTR potentiator (increased Cl−secretion)
Strength and route of administration: 150-mg IVA film-coated tablet for oral administration
Active substance: TEZ (tezacaftor; VX-661) and IVA 
Activity: CFTR corrector and potentiator (increased Cl−secretion)
Strength and route of administration: 100-mg TEZ/150-mg IVA fixed-dose combination 
film-coated tablet for oral administration 
Active substance: TEZ 
Activity: CFTR corrector (increased Cl−secretion)
Strength and route of administration: 50-mg TEZ tablet for oral administration 
Active substance: VX-561 (deuterated ivacaftor)
Activity: CFTR potentiator (increased Cl−secretion)
Strength and route of administration: 50-mg VX-561 tablet for oral administration
Study Duration
Part 1: Total duration is approximately 13 weeks. Subjects will receive study drug for 
approximately 5 weeks: 4 weeks in Period 1 followed by 4 days in Period 2.
Part 2: Total duration is approximately 20 weeks. Subjects will receive study drug for 
12 weeks: 4 weeks during the Run-in Period, 4 weeks in Period 1, and 4 weeks in Period 2.
Part 3: Total duration is approximately 12 weeks. Subjects will receive study drug for 4 weeks 
in Period 1
Study Design
This is a Phase 2, randomized, double-blind, placebo- and TEZ/IVA-controlled, 3-part, 
multicenter study. All parts will be conducted concurrently. Part 1 and Part 2 include a 4-week 
screening period, 2 dosing periods (a TC dosing period, Period 1, and a VX-659 washout 
period, Period 2), and a 4-week safety follow-up period. Part 2 also includes a 4-week Run-in 
Period prior to Period 1. Part 3 is optional and includes a 4-week screening period, a TC 
dosing period (Period 1), and a 4-week safety follow-up period. The treatment arms and doses 
of VX-659, TEZ, and IVA or VX-561 to be evaluated are shown below. Subjects may not 
participate in more than 1 part.
To maintain the blind, matching placebo tablets will be administered, as applicable, so that all 
subjects receive the same number of tablets within a given dosing period.
Randomization will be stratified by ppFEV1. Schematics of the study design are shown below. 
Part 1: Subjects With F/MF Genotypes




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Assessments
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, physical 
examinations (PEs)
Efficacy: spirometry, CFQ-R
PD: sweat chloride
PK: VX-659, TEZ, M1-TEZ, IVA, M1-IVA, VX-561
Statistical 
Analyses
Primary Objectives
The safety analysis will be descriptive only.
The primary efficacy endpoint is the absolute change from baseline through the Day 29 Visit 
for ppFEV1
All ppFEV1 hypothesis tests will be performed within the mixed-effects model for repeated 
measures (MMRM) framework at a 5% alpha level, with appropriate adjustment for baseline 
covariates. The null within-group hypothesis of no difference in the mean absolute change 
from baseline through the Day 29 Visit for ppFEV1 in all treatment groups, by part, will be 
tested using MMRM. The adjusted means and 2-sided 95% confidence intervals of the average 
treatment effects through the Day 29 Visit for all within-group and between-group 
comparisons will be estimated within MMRM.
Secondary Objectives
The PD endpoint is the absolute change in sweat chloride from baseline through the 
Day 29 Visit. In Part 1, the null hypothesis of the lack of a decreasing dose-response trend in 
the mean absolute change from baseline through the Day 29 Visit for sweat chloride between 
the TC dose groups and placebo will be tested using a multiple comparisons procedure based 
on the 1-sided maximum t-statistic. The adjusted means and 2-sided 95% confidence intervals 
of the average treatment effects through the Day 29 Visit, for all within-group and 
between-group comparisons, will be estimated within MMRM.
Interim 
Analyses
Interim analyses (IAs) may be conducted for any part of the study after at least 50% of subjects 
in the part have completed the Day 15 Visit. Each IA will only include data for a single part of 
the study.
IDMC Reviews
An independent monitoring committee (IDMC) will conduct safety reviews of study data as 
outlined in the IDMC charter. 


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3
SCHEDULE OF ASSESSMENTS
Schedules of Assessments are provided in Table 3-1 for Part 1, Table 3-2 for Part 2, and Table 
3-3 for Part 3. All visits will be scheduled relative to the Day 1 Visit (first dose of VX-659 or 
VX-659 matched placebo). 
Informed consent must be completed before any assessments are done at the Screening Visit. 
The Cystic Fibrosis Questionnaire-Revised (CFQ-R) assessment must be completed before any 
other assessment at the clinic visits when it is required. Other assessments may be performed in 
any order when more than 1 assessment is required at a particular time point. All assessments 
will be performed before dosing, unless noted otherwise.


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Table 3-1
Study VX16-659-101 Part 1 (Subjects with F/MF genotypes): Schedule of Assessments
Event/Assessmenta
Screening Period
Treatment Period (5 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dose
Period 1c (4 weeks)
Period 2
Screening Visit 
Days -28 to -1
Stratification 
Visitd
Day -27 to -1
Day 1 
Day 15
(2 days)
Day 29
(2 days)
Day 33 Visite
Informed consent
X
Randomizationf
X
Study drug dosingg
Day 1 through Day 33 Visit
Demographics 
X
Medical history
X
CFTR genotypeh
X
Heighti
X
Weighti
X
X
X
X
X
X
a
All assessments will be performed predose, unless noted otherwise. Assessments that are collected predose and postdose will only be collected once if study 
drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment).
b
If the 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 study drug treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If 
the ETT Visit occurs 3 or more weeks after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit (a separate Safety Follow-up 
Visit is not required).
c
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 9.1.4.
d
The spirometry assessment used for stratification must be performed at least 14 days after the last dose of any previous CFTR modulator treatment. 
Therefore, subjects being treated with 1 or more CFTR modulators (investigational or approved) within 14 days of the Screening Visit must have a separate 
Stratification Visit at least 14 days after the subject’s last CFTR modulator dose. For subjects not being treated with any CFTR modulators within 14 days of 
the Screening Visit, the Screening Visit spirometry assessment can be used for stratification.
e
The Day 33 Visit may occur 3 to 6 days after the actual date of the Day 29 Visit.
f
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period (see 
footnote c) have been confirmed.
g
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-659 in Part 1 Period 1 will be the morning dose on the Day 29 Visit. The last dose of TEZ/IVA in 
Part 1 Period 2 will be the morning dose on the Day 33 Visit. Refer to Section 9.7 for details.
h
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 (see inclusion criterion 6). 
i
Weight and height will be measured with shoes off. 


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Table 3-1
Study VX16-659-101 Part 1 (Subjects with F/MF genotypes): Schedule of Assessments
Event/Assessmenta
Screening Period
Treatment Period (5 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dose
Period 1c (4 weeks)
Period 2
Screening Visit 
Days -28 to -1
Stratification 
Visitd
Day -27 to -1
Day 1 
Day 15
(2 days)
Day 29
(2 days)
Day 33 Visite
Physical examinationj
Complete
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Complete
Vital signsk
X
X
X
X
X
X
X
Pulse oximetryk
X
X
X
X
X
X
X
Standard 12-lead 
ECGl
X
X
X
X
X
X
Sweat chloridem,p
X
X
X
X
X
X
X
Spirometryn
X
X
X
X
X
X
X
X
CFQ-Ro,p
X
X
X
Urinalysisp
X
X
X
X
X
X
Pregnancy test 
(females of 
childbearing 
potential)
Serum
Urine
Urine
Serum
Serum
FSHq
X
j
Complete and abbreviated physical examinations (PEs) are described in Section 11.7.3. Symptom-directed PEs can be done at any time at the discretion of 
the investigator or healthcare provider.
k
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes.
l
Standard 12-lead ECGs will be performed after the subject has been rested for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be collected before 
dosing and 5 hours (± 1 hour) after dosing. At other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the Day 1 Visit before 
dosing will be performed in triplicate. 
m
See inclusion criterion 5 for information about the sweat chloride assessment for study eligibility. Sweat chloride assessments should be done at 
approximately the same time at every study visit during the Treatment Period and follow-up.
n
At the Screening Visit, spirometry may be done pre- or post-bronchodilator. At other study visits, spirometry will be done pre-bronchodilator, before the 
in-clinic dose of study drugs, and should be performed at approximately the same time at every visit. On the Day 1 and 15 Visits, spirometry will also be 
performed 5 hours (± 1 hour) after the in-clinic dose of study drugs.
o
CFQ-R must be completed before the start of any other assessments scheduled at that visit.
p
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1) if randomization has occurred.
q
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea.


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Table 3-1
Study VX16-659-101 Part 1 (Subjects with F/MF genotypes): Schedule of Assessments
Event/Assessmenta
Screening Period
Treatment Period (5 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dose
Period 1c (4 weeks)
Period 2
Screening Visit 
Days -28 to -1
Stratification 
Visitd
Day -27 to -1
Day 1 
Day 15
(2 days)
Day 29
(2 days)
Day 33 Visite
G6PD activity testr
X
Serum chemistry and 
hematologyp
X
X
X
X
X
X
X
Coagulationp
X
X
X
X
X
X
PK samplings
X
X
X
X
X
AEs, medicationsu, 
treatments, and 
procedures
Continuous from signing of the ICF through the Safety Follow-up Visit
r
Blood samples will be collected for the G6PD activity test.
s
Blood samples will be collected for PK analysis of study drugs and metabolites. On the Day 1 Visit, samples will be collected before (0 hours) and 1, 2, 4, 
and 6 hours after the in-clinic dose. On the Day 15 Visit, samples will be collected before (0 hours) and 1, 2, 4, 6, and 8 hours after the in-clinic dose. On the 
Day 29 and Day 33 Visits, a single sample will be collected before the in-clinic dose. At the ETT Visit, a single sample will be collected.
Refer to Section 9.5 for details.


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Table 3-2
Study VX16-659-101 Part 2 (Subjects with F/F genotype): Schedule of Assessments
Event/Assessmenta
Screening Period
Run-in (4 weeks)
Treatment Period (8 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dosec
Period 1 (4 weeks)d
Period 2 (4 weeks)
Screening Visit 
Days -56 to -29
Day -28 
(1 day)
Day -14
(Days -15 to -3)
Day 1
Day 15
(2 days)
Day 29
(2 days)
Day 43
(3 days)
Day 57
(3 days)
Informed consent
X
Randomizatione
X
Study drug dosingf
Day -28 to Day -1 
Day 1 to 29
Day 29 to 57
Demographics 
X
Medical history
X
CFTR genotypeg
X
Heighth
X
Weighth
X
X
X
X
X
X
X
X
X
Physical 
examinationi
Complete
Complete
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Complete
Vital signsj
X
X
X
X
X
X
X
X
X
a
All assessments will be performed predose, unless noted otherwise. Assessments that are collected predose and postdose will only be collected once if study 
drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment).
b
If the 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 study drug treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If 
the ETT Visit occurs 3 or more weeks after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit (a separate Safety Follow-up 
Visit is not required).
c
Part 2 subjects who meet criteria specified in Section 9.1.5 will not have a Safety Follow-up Visit.
d
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 9.1.4.
e
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period (see 
footnote d) have been confirmed.
f
On days of scheduled visits, the in-clinic dose of study drug will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-659 in Part 2 Period 1 will be the morning dose on the Day 29 Visit. The last dose of TEZ/IVA in 
Part 2 Period 2 will be the morning dose on the Day 57 Visit. Refer to Section 9.7 for details.
g
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 (see inclusion criterion 6).
h
Weight and height will be measured with shoes off.
i
Complete and abbreviated PEs are described in Section 11.7.3. Symptom-directed PEs can be done at any time at the discretion of the investigator or 
healthcare provider.
j
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes.


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Table 3-2
Study VX16-659-101 Part 2 (Subjects with F/F genotype): Schedule of Assessments
Event/Assessmenta
Screening Period
Run-in (4 weeks)
Treatment Period (8 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dosec
Period 1 (4 weeks)d
Period 2 (4 weeks)
Screening Visit 
Days -56 to -29
Day -28 
(1 day)
Day -14
(Days -15 to -3)
Day 1
Day 15
(2 days)
Day 29
(2 days)
Day 43
(3 days)
Day 57
(3 days)
Pulse oximetryj
X
X
X
X
X
X
X
X
X
Standard 12-lead 
ECGk
X
X
X
X
X
X
X
X
X
Sweat chloridel,o
X
X
X
X
X
X
X
X
Spirometrym
X
X
X
X
X
X
X
X
X
CFQ-Rn,o
X
X
X
X
X
Urinalysiso
X
X
X
X
X
X
X
X
X
Pregnancy test (all 
females of 
childbearing 
potential)
Serum
Urine
Urine
Urine
Urine
Serum
Serum
FSHp
X
G6PD activity testq
X
Serum chemistry 
and hematologyo
X
X
X
X
X
X
X
X
X
Coagulationo
X
X
X
X
X
X
X
k
Standard 12-lead ECGs will be performed after the subject has been rested for at least 5 minutes. On Day 1 and 15 Visits, ECGs will be collected before 
dosing and 5 hours (± 1 hour) after dosing. At other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the Day 1 Visit before 
dosing will be performed in triplicate.
l
See inclusion criterion 5 for information about the sweat chloride assessment for study eligibility. Sweat chloride assessments should be done at 
approximately the same time at every study visit during the Treatment Period and follow-up.
m
The ppFEV1 assessment for stratification of randomization will be done at the Day -14 Visit. See Section 9.3.1. At the Screening Visit, spirometry may be 
done pre- or post-bronchodilator. At other study visits, spirometry will be done pre-bronchodilator, before the in-clinic dose of study drugs, and should be 
performed at approximately the same time at every visit. On the Day 1 and 15 Visits, spirometry will also be performed 5 hours (± 1 hour) after the in-clinic 
dose of study drugs. 
n
CFQ-R must be completed before the start of any other assessments scheduled at that visit.
o
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1) if randomization has occurred.
p
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea.
q
Blood samples will be collected for the G6PD activity test.


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Table 3-2
Study VX16-659-101 Part 2 (Subjects with F/F genotype): Schedule of Assessments
Event/Assessmenta
Screening Period
Run-in (4 weeks)
Treatment Period (8 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dosec
Period 1 (4 weeks)d
Period 2 (4 weeks)
Screening Visit 
Days -56 to -29
Day -28 
(1 day)
Day -14
(Days -15 to -3)
Day 1
Day 15
(2 days)
Day 29
(2 days)
Day 43
(3 days)
Day 57
(3 days)
PK samplingr
X
X
X
X
X
AEs, medicationst, 
treatments, and 
procedures
Continuous from signing of the ICF through the Safety Follow-up Visit
r
Blood samples will be collected for PK analysis of study drugs and metabolites. On the Day 1 Visit, samples will be collected before (0 hours) and 1, 2, 4, 
and 6 hours after the in-clinic dose. On the Day 15 Visit, samples will be collected before (0 hours) and 1, 2, 4, 6, and 8 hours after the in-clinic dose. On the 
Day 29 and 43 Visits, a single sample will be collected before the in-clinic dose. At the ETT Visit, a single sample will be collected.
Refer to Section 9.5 for details.


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Table 3-3
Study VX16-659-101 Part 3 (Subjects with F/MF genotypes): Schedule of Assessments
Event/Assessmenta
Screening Period
Treatment Period (4 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dose
Period 1c (4 weeks)
Screening Visit 
Days -28 to -1
Stratification 
Visitd
Days -27 to-3
Day 1 
Day 15
(2 days)
Day 29
(2 days)
Informed consent
X
Randomizatione
X
Study drug dosingf
Day 1 through Day 29 Visit
Demographics 
X
Medical history
X
CFTR genotypeg
X
Heighth
X
Weighth
X
X
X
X
X
X
a
All assessments will be performed predose, unless noted otherwise. Assessments that are collected predose and postdose will only be collected once if study 
drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment).
b
If the 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 study drug treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If 
the ETT Visit occurs 3 or more weeks after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit (a separate Safety Follow-up 
Visit is not required).
c
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 9.1.4.
d
The spirometry assessment used for stratification must be performed at least 14 days after the last dose of any previous CFTR modulator treatment. 
Therefore, subjects being treated with 1 or more CFTR modulators (investigational or approved) within 14 days of the Screening Visit must have a separate 
Stratification Visit at least 14 days after the subject’s last CFTR modulator dose. For subjects not being treated with any CFTR modulators within 14 days of 
the Screening Visit, the Screening Visit spirometry assessment can be used for stratification.
e
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period (see 
footnote c) have been confirmed.
f
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-659 and TEZ/VX-561 in Part 3 Period 1 will be the morning dose on the Day 29 Visit. Refer to 
Section 9.7 for details.
g
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 (see inclusion criterion 6). 
h
Weight and height will be measured with shoes off. 


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Table 3-3
Study VX16-659-101 Part 3 (Subjects with F/MF genotypes): Schedule of Assessments
Event/Assessmenta
Screening Period
Treatment Period (4 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dose
Period 1c (4 weeks)
Screening Visit 
Days -28 to -1
Stratification 
Visitd
Days -27 to-3
Day 1 
Day 15
(2 days)
Day 29
(2 days)
Physical examinationi
Complete
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Complete
Vital signsj
X
X
X
X
X
X
Pulse oximetryj
X
X
X
X
X
X
Standard 12-lead 
ECGk
X
X
X
X
X
X
Sweat chloridel,o
X
X
X
X
X
X
Spirometrym
X
X
X
X
X
X
X
CFQ-Rn,o
X
X
X
Urinalysiso
X
X
X
X
X
X
Pregnancy test 
(females of 
childbearing 
potential)
Serum
Urine
Urine
Serum
Serum
FSHp
X
i
Complete and abbreviated physical examinations (PEs) are described in Section 11.7.3. Symptom-directed PEs can be done at any time at the discretion of 
the investigator or healthcare provider.
j
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes.
k
Standard 12-lead ECGs will be performed after the subject has been rested for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be collected before 
dosing and 5 hours (± 1 hour) after dosing. At other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the Day 1 Visit before 
dosing will be performed in triplicate. 
l
See inclusion criterion 5 for information about the sweat chloride assessment for study eligibility. Sweat chloride assessments should be done at 
approximately the same time at every study visit during the Treatment Period and follow-up.
m
At the Screening Visit, spirometry may be done pre- or post-bronchodilator. At other study visits, spirometry will be done pre-bronchodilator, before the 
in-clinic dose of study drugs, and should be performed at approximately the same time at every visit. On the Day 1 and 15 Visits, spirometry will also be 
performed 5 hours (± 1 hour) after the in-clinic dose of study drugs.
n
CFQ-R must be completed before the start of any other assessments scheduled at that visit.
o
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1) if randomization has occurred.
p
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea.


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Table 3-3
Study VX16-659-101 Part 3 (Subjects with F/MF genotypes): Schedule of Assessments
Event/Assessmenta
Screening Period
Treatment Period (4 weeks)
ETT
Visitb
Safety 
Follow-up
28 (7) Days 
After Last Dose
Period 1c (4 weeks)
Screening Visit 
Days -28 to -1
Stratification 
Visitd
Days -27 to-3
Day 1 
Day 15
(2 days)
Day 29
(2 days)
G6PD activity testq
X
Serum chemistry and 
hematologyo
X
X
X
X
X
X
Coagulationo
X
X
X
X
X
X
PK samplingr
X
X
X
X
AEs, medicationst, 
treatments, and 
procedures
Continuous from signing of the ICF through the Safety Follow-up Visit
q
Blood samples will be collected for the G6PD activity test.
r
Blood samples will be collected for PK analysis of study drugs and metabolites. On the Day 1 Visit, samples will be collected before (0 hours) and 1, 2, 4, 
and 6 hours after the in-clinic dose. On the Day 15 Visit, samples will be collected before (0 hours) and 1, 2, 4, 6, and 8 hours after the in-clinic dose. On the 
Day 29 Visit  a single sample will be collected before the in-clinic dose  At the ETT Visit, a single sample will be collected.
t
Refer to Section 9.5 for details.


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4
TABLE OF CONTENTS
1
Title Page............................................................................................................................1
Summary of Changes to the Protocol......................................................................................2
2
Protocol Synopsis ...............................................................................................................3
3
Schedule of Assessments ....................................................................................................7
4
Table of Contents .............................................................................................................17
List of Tables .......................................................................................................................21
List of Figures ......................................................................................................................21
Glossary of Terms ................................................................................................................22
5
Introduction......................................................................................................................24
5.1
Background.................................................................................................................24
5.2
Rationale for This Study..............................................................................................25
6
Study Objectives...............................................................................................................25
6.1
Primary Objectives......................................................................................................25
6.2
Secondary Objectives..................................................................................................25
7
Study Endpoints...............................................................................................................26
7.1
Primary Endpoints.......................................................................................................26
7.2
Secondary Endpoints...................................................................................................26
8
Study Population..............................................................................................................26
8.1
Inclusion Criteria.........................................................................................................26
8.2
Exclusion Criteria........................................................................................................27
9
Study Implementation......................................................................................................29
9.1
Study Design...............................................................................................................29
9.1.1
Screening.............................................................................................................30
9.1.1.1
Repetition of Screening Assessment(s)..........................................................31
9.1.1.2
Rescreening...................................................................................................31
9.1.1.3
Extension of Screening Period Window.........................................................31
9.1.2
Run-in Period (Part 2)..........................................................................................31
9.1.3
Randomization.....................................................................................................32
9.1.4
Treatment Period .................................................................................................32
9.1.5
Follow-up............................................................................................................32
9.1.6
Early Termination of Treatment...........................................................................33
9.1.7
Independent Data Monitoring Committee ............................................................33
9.2
Method of Assigning Subjects to Treatment Groups....................................................33
9.3
Rationale for Study Design and Study Drug Regimens................................................33
9.3.1
Study Design .......................................................................................................33
9.3.2
Study Drug Dose and Duration ............................................................................34
9.3.3
Rationale for Study Population ............................................................................35
9.3.4
Rationale for Study Assessments .........................................................................35
9.4
Prohibited Medications................................................................................................35
9.5
Prior and Concomitant Medications.............................................................................36
9.6
Study Restrictions .......................................................................................................37
9.6.1
Exposure to Sunlight............................................................................................37
9.7
Study Drug Administration..........................................................................................37
9.8
Dose Modification for Toxicity ...................................................................................38
9.9
Stopping Rules............................................................................................................38


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9.10 Removal of Subjects....................................................................................................39
9.11 Replacement of Subjects .............................................................................................40
10 Study Drug Administration and Management................................................................40
10.1 Preparation and Dispensing .........................................................................................40
10.2 Packaging and Labeling ..............................................................................................40
10.3 Study Drug Supply, Storage, and Handling .................................................................40
10.4 Drug Accountability....................................................................................................41
10.5 Disposal, Return, or Retention of Unused Drug...........................................................41
10.6 Compliance.................................................................................................................41
10.7 Blinding and Unblinding .............................................................................................41
10.7.1
Blinding...............................................................................................................41
10.7.2
Unblinding ..........................................................................................................42
11 Assessments ......................................................................................................................44
11.1 Timing of Assessments................................................................................................44
11.2 Subject and Disease Characteristics.............................................................................44
11.3 Pharmacokinetics ........................................................................................................44
11.3.1
Blood Sampling...................................................................................................44
11.3.2
Processing and Handling of Pharmacokinetic Samples.........................................45
11.3.3
Bioanalysis ..........................................................................................................45
11.4 Pharmacodynamics......................................................................................................45
11.6 Efficacy.......................................................................................................................45
11.6.1
Spirometry...........................................................................................................45
11.6.2
Cystic Fibrosis Questionnaire-Revised.................................................................46
11.7 Safety..........................................................................................................................46
11.7.1
Adverse Events....................................................................................................46
11.7.2
Clinical Laboratory Assessments .........................................................................47
11.7.3
Physical Examinations and Vital Signs ................................................................48
11.7.4
Pulse Oximetry....................................................................................................49
11.7.5
Electrocardiograms..............................................................................................49
11.7.6
Pregnancy and Contraception...............................................................................49
11.7.6.1
Contraception................................................................................................49
11.7.6.2
Pregnancy......................................................................................................51
12 Statistical and Analytical Plans .......................................................................................51
12.1 Sample Size and Power ...............................................................................................51
12.1.1
Primary Objectives ..............................................................................................51
12.1.1.1
Safety and Tolerability ..................................................................................51
12.1.1.2
Efficacy.........................................................................................................51
12.1.2
Secondary Objectives ..........................................................................................52
12.2 Analysis Sets...............................................................................................................52
12.3 Statistical Analysis ......................................................................................................53
12.3.1
General Considerations........................................................................................53
12.3.2
Background Characteristics .................................................................................53
12.3.2.1
Subject Disposition........................................................................................53
12.3.2.2
Demographics and Baseline Characteristics...................................................53
12.3.2.3
Prior and Concomitant Medications...............................................................54


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12.3.2.4
Study Drug Exposure and Compliance ..........................................................54
12.3.2.5
Important Protocol Deviations.......................................................................54
12.3.3
Efficacy Analysis.................................................................................................55
12.3.3.1
Analysis of Primary Efficacy Variables .........................................................55
12.3.3.2
Analysis of Secondary Efficacy Variables .....................................................55
12.3.4
Pharmacodynamic Analysis.................................................................................55
12.3.5
Safety Analysis....................................................................................................56
12.3.5.1
Adverse Events..............................................................................................56
12.3.5.2
Clinical Laboratory Assessments...................................................................57
12.3.5.3
Electrocardiogram.........................................................................................57
12.3.5.4
Vital Signs.....................................................................................................57
12.3.5.5
Pulse Oximetry..............................................................................................58
12.3.5.6
Physical Examination ....................................................................................58
12.3.5.7
Other Safety Analysis....................................................................................58
12.3.6
Interim and IDMC Analyses................................................................................58
12.3.6.1
Interim Analysis............................................................................................58
12.3.6.2
IDMC Analyses.............................................................................................58
12.4 Clinical Pharmacology Analyses .................................................................................58
12.4.1
Pharmacokinetic Analysis....................................................................................58
13 Procedural, Ethical, Regulatory, and Administrative Considerations...........................59
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................................................................59
13.1.1.3
Documentation of Adverse Events.................................................................59
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................................................................................61
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......................................63
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................................................................................................64
13.2.5
Subject Privacy....................................................................................................64
13.2.6
Record Retention.................................................................................................65
13.2.7
Study Termination...............................................................................................65
13.3 Data Quality Assurance...............................................................................................65


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13.4 Monitoring ..................................................................................................................66
13.5 Electronic Data Capture ..............................................................................................66
13.6 Publications and Clinical Study Report........................................................................66
13.6.1
Publication of Study Results ................................................................................66
13.6.2
Clinical Study Report ..........................................................................................67
14 References.........................................................................................................................68
Appendix A
CFTR Mutations That Are Predicted to Result in a CFTR Protein With 
Minimal Function (Part 1 and Part 3)...........................................................................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 VX16-659-101 Part 1 (Subjects with F/MF genotypes): Schedule of 
Assessments.........................................................................................................8
Table 3-2
Study VX16-659-101 Part 2 (Subjects with F/F genotype): Schedule of 
Assessments.......................................................................................................11
Table 3-3
Study VX16-659-101 Part 3 (Subjects with F/MF genotypes): Schedule of 
Assessments.......................................................................................................14
Table 9-1
Key Study Elements by Part...............................................................................29
Table 9-2
Treatment Arms and Planned Doses by Part.......................................................29
Table 9-3
Prohibited Medications ......................................................................................36
Table 10-1
Study Drug: Strength/Formulation/Route...........................................................40
Table 11-1
Acceptable Pharmacokinetic Sampling Windows...............................................44
Table 11-2
Safety Laboratory Test Panels............................................................................47
Table 11-3
Acceptable Methods of Contraception................................................................50
Table 12-1
Contrast Coefficients for the Multiple Comparisons Procedure in Part 1 ............52
Table 13-1
Grading of AE Severity......................................................................................60
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 ................................................................61
List of Figures
Figure 9-1
Schematic of Study Design ................................................................................30


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Glossary of Terms
Abbreviation
Term
AE
adverse event
ALT
alanine transaminase
AST
aspartate transaminase
BMI
body mass index
CF
cystic fibrosis
CFQ-R
Cystic Fibrosis Questionnaire-Revised
CFTR
cystic fibrosis transmembrane conductance regulator protein
CFTR
cystic fibrosis transmembrane conductance regulator gene
Cl-
chloride ion
CPAP
clinical pharmacology analysis plan
CRF
case report form
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DNA
deoxyribonucleic acid
EC90
concentration at which effect is at 90% of the maximum
ECG
electrocardiogram
EDC
electronic data capture
EENT
eyes, ears, nose, and throat
Emax
maximum effect
ETT
early termination of treatment
F/F
homozygous for F508del
F/MF
heterozygous for F508del and a minimal CFTR function mutation that is not expected to respond to 
TEZ, IVA, or TEZ/IVA
F508del
CFTR gene mutation with an in-frame deletion of a phenylalanine codon corresponding to position 
508 of the wild-type protein
F508del
CFTR protein lacking the phenylalanine normally found at position 508 of the wild-type protein
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEF25%-75%
forced expiratory flow at 25%-75% of forced vital capacity
FEV1
forced expiratory volume in 1 second
FSH
follicle-stimulating hormone
FVC
forced vital capacity
G6PD
glucose-6-phosphate dehydrogenase
GCP
Good Clinical Practice
GLI
Global Lung Function Initiative
GPS
Global Patient Safety (Vertex)
HBE
human bronchial epithelial (cells)
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
IA
interim analysis
ICF
informed consent form


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Abbreviation
Term
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IPD
important protocol deviation
IRB
institutional review board
IVA
ivacaftor (VX-770)
IWRS
interactive web response system
LLN
lower limit of normal
LUM
lumacaftor (VX-809)
MCP
multiple comparisons procedure
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effects model for repeated measures
OATP1B1
organic anion transporting polypeptide 1B1
PD
pharmacodynamic, pharmacodynamics
PE
physical examination
PI
pancreatic insufficiency
PK
pharmacokinetics
ppFEV1
percent predicted forced expiratory volume in 1 second
PR
PR interval
q12h
every 12 hours
qd
daily
QRS
portion of an ECG comprising the Q, R, and S waves, together representing ventricular 
depolarization
QTc
QT interval corrected
QTcB
QT interval corrected by Bazett’s formula
QTcF
QT interval corrected by Fridericia’s formula
RR
interval from the onset of 1 QRS complex to the next
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SI
International System
SUSAR
suspected, unexpected, serious adverse reaction
SwCl
sweat chloride
TBD
to be determined
TC
triple combination
TE
treatment emergent
TEAE
treatment-emergent adverse event
TEZ
tezacaftor (VX-661)
ULN
upper limit of normal
US
United States
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 32,000 in the European 
Union3). Based on its prevalence, CF qualifies as an orphan disease.4, 5
CF is caused by reduced 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.
More than 2000 mutations of the CFTR gene have been identified.8 Most of these mutations are 
not associated with CF disease or are very rare. Currently, the CFTR2 database contains 
information on only 322 of these identified mutations, with sufficient evidence to define 
281 mutations as disease-causing.9 The most common disease-causing CFTR mutation, F508del, 
accounts for 70% of the identified alleles in people with CF, with nearly half of all people with 
CF are homozygous for F508del.
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. 
Tezacaftor (TEZ; VX-661) is a first-generation CFTR corrector that improves the processing and 
trafficking of the F508del-CFTR protein, resulting in an increase in the quantity of 
F508del-CFTR protein at the cell surface. IVA increases the open-channel probability of the 
F508del-CFTR protein that has been delivered to the cell surface by TEZ, thereby enhancing 
total chloride transport. The combined effect of TEZ and IVA is increased quantity and function 
of F508del-CFTR at the cell surface.


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VX-659 is a next-generation CFTR corrector. In vitro, VX-659 improves the processing and 
trafficking of F508del-CFTR, thereby increasing the quantity of functional F508del-CFTR 
protein at the cell surface.10 The effect of VX-659 was additive to the effect of TEZ. The CFTR 
protein delivered to the cell surface by VX-659 alone or in combination with TEZ
(VX-659/TEZ) was potentiated by IVA.10 In human bronchial epithelial (HBE) cells studied in 
vitro, the triple combination (TC) of VX-659, TEZ, and IVA (VX-659/TEZ/IVA) increased 
CFTR chloride transport more than any of the dual combinations (VX-659/TEZ, VX-659/IVA, 
and TEZ/IVA) or individual components (VX-659, TEZ, and IVA) under most conditions 
studied.10
VX-561 (also known as CTP-656 and C-10355) is a deuterated isotope of IVA with a specific 
pattern of 9 substituted deuteriums. In vitro data indicate similar potency of VX-561 in HBE 
cells relative to IVA.11 Safety pharmacology and nonclinical toxicology studies of VX-561 
demonstrate a similar safety profile relative to IVA. Phase 1 clinical studies in healthy subjects 
have shown that VX-561 had a reduced rate of clearance, increased exposure, greater plasma 
levels at 24 hours, and a longer half-life compared to IVA, thereby supporting once daily dosing.
5.2
Rationale for This Study
This is the second clinical study of VX-659 and is designed to evaluate the safety and efficacy of 
VX-659 in TC with TEZ and either IVA or VX-561 in subjects with CF who are heterozygous 
for F508del with a second CFTR allele carrying a minimal function (MF) mutation that is not 
expected to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes) and homozygous for F508del
(F/F genotype).
Data from nonclinical studies of VX-659, TEZ, IVA, and VX-561 and the current unmet medical 
need for new treatments for CF support clinical development of VX-659 in combination with 
other CFTR modulators for the treatment of CF.
6
STUDY OBJECTIVES
6.1
Primary Objectives
Parts 1 and 2: To evaluate the safety and tolerability of VX-659 in TC with TEZ and IVA
Part 3 (optional): To evaluate the safety and tolerability of VX-659 in TC with TEZ and VX-561 
All parts: To evaluate the efficacy of VX-659 in TC with TEZ and either IVA or VX-561
6.2
Secondary Objectives
Parts 1 and 2: To evaluate the pharmacodynamic (PD) effects of VX-659 in TC with TEZ and 
IVA on CFTR function
Part 3 (optional): To evaluate the PD effects of VX-659 in TC with TEZ and VX-561 on CFTR 
function
All parts: 

To evaluate the pharmacokinetics (PK) of VX-659 when administered in TC with TEZ and 
either IVA or VX-561

To evaluate the PK of TEZ, IVA, VX-561 and their respective metabolites when 
administered with VX-659 (as applicable)


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7
STUDY ENDPOINTS
7.1
Primary Endpoints

Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, vital signs, and pulse oximetry

Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through the Day 29 Visit
7.2
Secondary Endpoints

Absolute change in sweat chloride concentrations from baseline through the Day 29 Visit 

Relative change in ppFEV1 from baseline through the Day 29 Visit 

Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline at the Day 29 Visit 

PK parameters of VX-659, TEZ, M1-TEZ, IVA, M1-IVA, and VX-561
8
STUDY POPULATION
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are randomized (Part 1 and Part 3) or receive TEZ/IVA in the 
Run-in Period (Part 2).
8.1
Inclusion Criteria
1. Subject will sign and date an informed consent form (ICF).
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures.
3. Subjects will be aged 18 years or older on the date of informed consent.
4. Body weight ≥35 kg.
5. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening. If 
the initial screening collection results in insufficient sweat volume, then the sweat chloride 
collection may be repeated once, after approval by the medical monitor. 

Parts 1 and 3: Subjects must have a sweat chloride value ≥60 mmol/L at screening or 
documented in the form of a laboratory report in the subject’s medical record. If the 
sweat chloride value cannot be determined from the screening test for a reason other than 
insufficient sweat volume (i.e., because of laboratory error, damaged specimen, or 
equipment malfunction), it is acceptable to use a sweat chloride value that was obtained 
before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator.

Part 2: For subjects with a sweat chloride value ≥60 mmol/L at screening or documented 
in the form of a laboratory report in the subject’s medical record, medical monitor 
approval is not required. For subjects with a sweat chloride value <60 mmol/L at 
screening and no documented historical value ≥60 mmol/L, medical monitor approval is 
required based on documented evidence of chronic sinopulmonary disease manifested by 
at least 1 of the following:


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o
Persistent colonization/infection with typical CF pathogens, including but not limited 
to, Staphylococcus aureus, Haemophilus influenzae, and/or Pseudomonas aeruginosa
o
Chronic cough and sputum production
o
Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, 
hyperinflation)
o
Nasal polyps, chronic sinusitis, or radiographic or computed tomographic 
abnormalities of the paranasal sinuses
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR
genotype result is not received before randomization, a previous CFTR genotype laboratory 
report may be used as a source document to establish eligibility and avert the risk of 
screening period expiration. Note: Subjects who have been randomized and whose screening 
genotype does not confirm study eligibility must be discontinued from the study 
(Section 9.10).

Part 1 and Part 3: Heterozygous for F508del with a second CFTR allele carrying an MF 
mutation that is not expected to respond to TEZ, IVA, or TEZ/IVA (Appendix A)

Part 2: Homozygous for F508del
7. FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height (equations of the 
Global Lung Function Initiative [GLI])12 at the Screening Visit. Spirometry measurements 
must meet American Thoracic Society/European Respiratory Society criteria13 for 
acceptability and repeatability.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF treatment regimen through the planned end of treatment or, 
if applicable, the Safety Follow-up Visit.
8.2
Exclusion Criteria
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject. 
2. History of clinically significant cirrhosis with or without portal hypertension.
3. Risk factors for Torsade de Pointes, including but not limited to, history of any of the 
following: familial long QT syndrome, chronic hypokalemia, heart failure, left ventricular 
hypertrophy, chronic bradycardia, myocardial infarction, cardiomyopathy, history of 
arrhythmia (ventricular or atrial fibrillation), obesity, acute neurologic events (subarachnoid 
hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or 
autonomic neuropathy.
4. Current or past history of peptic ulcer disease.
5. History of hemolysis.
6. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, defined as G6PD activity less than 
the lower limit of normal (LLN) or 70% of the mean of the LLN and the upper limit of 
normal (ULN), whichever is greater.


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7. 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 
transpeptidase, or alkaline phosphatase ≥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)14, 15
8. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for sinopulmonary disease within 28 days before the first dose of 
study drug.
9. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For 
subjects who have had a history of a positive culture in the past, the investigator will apply 
the following criteria to establish whether the subject is free of infection with such 
organisms: 

The subject has had 2 respiratory tract cultures negative for these organisms within the 
12 months before the screening visit, with no subsequent positive cultures.

These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was 
obtained within 6 months before the screening visit.
10. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug.
11. A standard digital ECG demonstrating QTc >450 msec at screening. If QTc exceeds 
450 msec for the screening ECG, the ECG should be repeated 2 more times during the 
Screening Period, and the subject will be excluded if the average of the 3 QTc values is 
>450 msec. Study sites should use QTcF unless they receive approval in advance from the 
medical monitor to use QTcB (Section 11.7.5).
12. History of solid organ or hematological transplantation.
13. History of alcohol or drug of abuse in the past year, including but not limited to, cannabis, 
cocaine, and opiates, as deemed by the investigator.
14. Ongoing or prior participation in a study of an investigational treatment other than a CFTR 
modulator within 28 days or 5 terminal half-lives (whichever is longer) before screening. The 
duration of the elapsed time may be longer if required by local regulations. 
15. Use of prohibited medications as defined in Table 9-3, within the specified window before 
the first dose of study drug.
16. Pregnant or nursing females. Females of childbearing potential must have a negative 
pregnancy test at screening and the Day 1 Visit (Part 1 and Part 3) or Day -28 Visit (Part 2).
17. 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 






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9.1.1.1
Repetition of Screening Assessment(s)
If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society/European Respiratory Society guidelines13, repeat 
spirometry may be performed.
Repeating individual screening assessment(s) that did not meet eligibility criteria is not 
permitted, with the following exceptions that require the approval of the medical monitor:

If there is clear evidence of a damaged sample, laboratory error, or equipment malfunction, 
collection of a repeat sample for the appropriate laboratory test or assessment may be 
permitted.

Exclusionary liver function tests results, which may be retested once within 14 days of the 
original screening date.

Assessments required for eligibility that may be repeated as described in Sections 8.1
and 8.2.
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 only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated except for CFTR genotyping, FSH level 
(if serum FSH level was ≥40 mIU/mL during prior screening), G6PD activity test, and sweat 
chloride level. If a subject is rescreened, the new screening window will begin once 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, without medical monitor 
approval, for the following reasons:

Repetition of Screening Period assessments (Section 9.1.1.1)

Unexpected operational or logistic delays, or to meet the eligibility criteria

To enable a subject’s eligibility for this study to be determined before the subject 
discontinues previous CFTR modulator treatment (e.g., so that subjects can have screening 
assessments done while they are continuing to receive CFTR modulator treatment but have a 
washout period of at least 2 weeks before performing spirometry for stratification of 
randomization in this study and a washout period of at least 4 weeks before the Day 1 Visit in 
Part 1 and Part 3) (see Section 9.1.3 and Section 9.1.4).
A subject may have the Screening Period window extended for an additional 2 weeks (total of 
4 weeks) with medical monitor approval.
9.1.2
Run-in Period (Part 2)
The Run-in Period will have a total duration of 4 weeks and is designed to establish a reliable 
on-treatment (TEZ/IVA) baseline for the Treatment Period. The first dose of TEZ/IVA will be 
administered in the morning at the Day -28 Visit. The last dose of IVA within the Run-in Period 
will be administered in the evening of Day -1 (1 day before the Day 1 Visit). 


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Study eligibility for Part 2 subjects will be confirmed before the first dose of TEZ/IVA in the 
Run-in Period (on the Day -28 Visit).
Study visits during the Run-in Period will occur as shown in Table 3-2. All visits will occur 
within the windows specified.
9.1.3
Randomization
For all parts, randomization will be stratified by ppFEV1 values (<70 vs ≥70).
For subjects in Part 1 and Part 3, the spirometry assessment used for stratification must be 
performed at least 14 days after the last dose of any previous CFTR modulator treatment. 
Therefore, subjects being treated with 1 or more CFTR modulators (investigational or approved) 
within 14 days of the Screening Visit must have a separate Stratification Visit at least 14 days 
after the subject’s last CFTR modulator dose. For subjects not being treated with any CFTR 
modulators within 14 days of the Screening Visit, the Screening Visit spirometry assessment can 
be used for stratification. 
For subjects in Part 2, the ppFEV1 assessment for stratification of randomization will be done at 
the Day -14 Visit. See Section 9.3.1.
Randomization will occur before the first dose of VX-659/control and may be done on either 
Day -1 or the Day 1 Visit, after all inclusion and exclusion criteria have been satisfied and the 
criteria for entry into the Treatment Period have been confirmed (see Section 9.1.4).
For Part 2, subjects who prematurely discontinue TEZ/IVA during the Run-in Period will not be 
randomized or participate in the Treatment Period, unless they rescreen and complete a 4-week 
Run-in Period (Section 9.1.2).
9.1.4
Treatment Period
To be eligible to continue into the Treatment Period, subjects must have stable CF disease 
(consistent with the inclusion and exclusion criteria) and have remained on stable CF medication 
regimen during the 28 days before the Day 1 Visit AND must not have had an acute non-CF 
illness within 14 days before the Day 1 Visit.
The total duration of treatment with study drug is approximately 5 weeks for Part 1 (Period 1 + 
Period 2), 12 weeks for Part 2 (Run-in + Period 1 + Period 2), and 4 weeks for Part 3 (Period 1 
only). The duration of treatment with TC or placebo (Parts 1 and 3, Period 1) or TC or TEZ/IVA 
(Part 2, Period 1) is approximately 4 weeks. Study drug administration details are provided in 
Section 9.7.
9.1.5
Follow-up
There will be an outpatient Safety Follow-up Visit occurring 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.
A subject who was enrolled in Study VX14-661-110 and then enrolled in Part 2 of this study can 
re-enroll in Study 661-110 after completing this study. If the subject completes the Day 57 Visit 
of this study and then re-enters Study 661-110, the subject will not have a Safety Follow-up Visit 
in this study.


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9.1.6
Early Termination of Treatment 
If a subject prematurely discontinues treatment at any time after enrollment, an Early 
Termination of Treatment (ETT) Visit should be scheduled as soon as possible after the decision 
to terminate study drug 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. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
If a subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. Vertex may retain and continue to use any data collected before such withdrawal of 
consent.
9.1.7
Independent Data Monitoring Committee
This study will be monitored by an independent data monitoring committee (IDMC), which will 
conduct reviews of safety data from all parts of the study as outlined in the IDMC charter. The 
IDMC charter, which will be finalized before the first subject is screened, will include procedural 
details of the IDMC structure and function, triggers for meetings, and plans for data to be 
reviewed.
9.2
Method of Assigning Subjects to Treatment Groups
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
Stratification of Randomization
The extent of response to CFTR modulator treatment may depend on the subject’s ppFEV1 value 
(an index of disease severity) before the start of study drug dosing. Therefore, randomization in 
all parts will be stratified by pretreatment ppFEV1 values, defined as the last ppFEV1
measurement before treatment with VX-659. For Parts 1 and 3, this value is determined at 
screening, except for those subjects who require a Stratification Visit, in which case the value is 
determined at that visit. For Part 2, the pretreatment ppFEV1 value is determined at the Day -14 
Visit during the Run-In Period.  
Control Treatments
Part 1 and Part 3: Efficacy has not been demonstrated for a corrector, potentiator, or any 
corrector/potentiator combination in subjects with F/MF genotypes. A Phase 3 study of 
TEZ/IVA in subjects with F/MF genotypes (Study VX14-661-107) was terminated following a 
planned interim futility analysis, which showed that the combination of TEZ/IVA did not result 
in a prespecified improvement in ppFEV1. Because there is no effective treatment for this 
population, a placebo arm will be included as the control in Part 1 and Part 3. 


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Part 2: A Phase 3 study of TEZ/IVA (Study VX14-661-106) demonstrated a clinically 
meaningful benefit in subjects with the F/F genotype16; therefore, TEZ/IVA is the active control.
Run-in Period
Part 2 will have a 4-week run-in period to establish a reliable on-treatment (TEZ/IVA) baseline 
for comparison to Period 1, when subjects will additionally receive VX-659 or placebo.
Period 2
Part 1 and Part 2 include a second dosing period (Period 2), during which subjects will be 
administered TEZ/IVA. In Part 1, Period 2 is 4 days and is included to enable a more thorough 
evaluation of VX-659 exposure-response relationships by conducting PK and PD assessments 
during the VX-659 washout. In Part 2, Period 2 is 4 weeks to enable an assessment of PD and 
efficacy endpoints after VX-659 is washed out.
9.3.2
Study Drug Dose and Duration
VX-659 Dosage 
Part 1 will evaluate 3 dose levels of VX-659 in TC with TEZ/IVA in subjects with F/MF 
genotypes. The high dose of VX-659 to be evaluated as part of the TC is 400 mg qd. In healthy 
subjects in Study VX16-659-001, VX-659 monotherapy was shown to be safe and well tolerated 
at multiple doses up to 400 mg qd for 10 days, and VX-659 was safe and well tolerated at 
multiple doses up to 200 mg q12h in TC with TEZ 100 mg qd/IVA 150 mg q12h for 14 days.
The dose levels evaluated in Part 1 are expected to provide clinical benefit (based on in vitro 
data) and will provide a range of exposure for exposure-response analyses of efficacy and safety. 
The TC-high dose will also be used in Part 2 and Part 3. Dose- and exposure-response 
information obtained for the TC in Part 1 (subjects with F/MF genotypes) is expected to be 
applicable to other populations with F508del, including F/F, based on the similar potency of the 
TC in HBE cells that have 1 copy or 2 copies of F508del.10
TEZ Dosage
In all study parts, the TEZ dosage will be 100 mg qd, which is the same total dosage evaluated in 
Phase 3 studies of TEZ/IVA.
IVA Dosage
When administered in combination with VX-659, the IVA dosage will be 150 mg q12h. A 
dosage of 150 mg q12h is being used in Phase 3 studies of TEZ/IVA and is also the approved 
IVA monotherapy dosage for patients aged 12 years and older (150 mg q12h). 
VX-561 Dosage
The VX-561 dosage will be 200 mg qd, based on preliminary PK and safety results for VX-561 
from Study VX16-770-018, which evaluated the relative bioavailabity of the 50-mg tablet of 
VX-561 being used in the current study, and Study VX16-659-001, which is evaluating VX-561 
200 mg qd in combination with VX-659 (400 mg qd) and TEZ (100 mg qd). A VX-561 dose of 
200 mg qd in TC with VX-659 and TEZ is predicted to provide similar exposure of deuterated 
IVA relative to that of IVA following a dose of 150 mg q12h.




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9.5
Prior and Concomitant Medications
Information about all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the Screening Visit through the Safety Follow-up Visit, if applicable, will be recorded in 
each subject’s source documents. For subjects who are screened but not subsequently 
randomized, details of prior medication will only be documented in the subjects’ source 
documents.

Subjects must remain on a stable medication (and supplement) regimen for their CF from 
28 days before the Day 1 Visit through the Safety Follow-up Visit. Stable medication 
regimen is defined as the current medication regimen for CF that subjects have been 
following for at least 28 days before the Day 1 Visit. Subjects must not initiate long-term 
treatment with new medication from 28 days before the Day 1 Visit through the 
Safety Follow-up Visit unless discussed and approved by the medical monitor. Guidelines for 
stable medication regimens for CF are as follows:


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o
Subjects who are taking daily inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study.
o
Subjects who 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 (and 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 (and 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 prednisone or prednisolone 60 mg qd for up to 5 days without prior approval of the 
medical monitor.

Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.6.1.
9.6
Study Restrictions
9.6.1
Exposure to Sunlight
Subjects will take appropriate measures to minimize exposure to ultraviolet (UV) radiation 
(e.g., sunlight, tanning booths) from Day 1 through the Safety Follow-up Visit.
9.7
Study Drug Administration
Study drug will be administered orally. In each part, subjects in all groups will receive the same 
number of tablets at each dosing occasion 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, according to the following guidelines:
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 qd (± 2 hours) or q12h (± 2 hours). For each subject, doses 
of study drugs will be taken at approximately the same time each day. For example, if dosing 
is q12h, the morning dose could be taken at 08:00 every morning and the evening dose could 
be taken at 20:00 every evening throughout the study.
3. 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 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 study drug.
5. Subjects will be instructed to bring all used and unused study drug to the site; study drug will 
be dispensed at each visit, as appropriate.


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Missed Doses
If a subject misses a dose and recalls the missed dose within 6 hours (q12h dosing) or within 
12 hours (qd dosing), the subject should take his/her dose with food. If more than 6 hours (q12h 
dosing) or 12 hours (qd dosing) have elapsed after his/her usual dosing time, the subject should 
skip that dose and resume his/her normal schedule for the following dose. Examples are provided 
below:
If study drug is administered q12h:

if the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible.

if the morning dose of study drug should have been taken at approximately 08:00, and more 
than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 14:00), the 
subject would resume dosing with the evening dose at approximately 20:00.
If study drug is administered qd:

if the dose of study drug should have been taken at approximately 08:00, and the subject 
remembers before 20:00 that he/she forgot to take his/her dose, he/she should take the dose 
with food as soon as possible.

if the dose of study drug should have been taken at approximately 08:00, and more than 
12 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 20:00), the 
subject would resume dosing the following day at approximately 08:00. 
9.8
Dose Modification for Toxicity 
If any unacceptable toxicity arises, individual subjects will discontinue dosing (Section 9.1.6). 
No dose modifications for toxicity are allowed.
9.9
Stopping Rules
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, or 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), and 
the medical monitor must be notified, 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

Indirect bilirubin >2 × ULN (defined as ULN for total bilirubin minus ULN for direct 
bilirubin)


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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 either of the following criteria 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, 
or alcohol ingestion) is identified, regardless of whether transaminase levels have improved

Subsequent indirect bilirubin values confirm the initial value as >2 × ULN (defined as ULN 
for total bilirubin minus ULN for direct bilirubin), in association with decreased haptoglobin
If an alternative, reversible cause of transaminase elevation and/or increased bilirubin or clinical 
jaundice has been identified, study drug administration may be resumed once transaminases or 
bilirubin return to baseline or are ≤2 × ULN, whichever is higher. Approval of the medical 
monitor is required before resumption of study drug. Upon resumption of study drug, 
transaminases and bilirubin should be assessed weekly for 4 weeks. If a protocol-defined 
transaminase or bilirubin elevation interruption threshold recurs during Period 1 or Period 2 
(with confirmation of the initial elevation by repeat testing within 48 to 72 hours), then study 
drugs must be permanently discontinued, regardless of the presumed etiology.
All subjects in whom treatment is discontinued for elevated transaminases and/or bilirubin 
should have these levels monitored closely until levels normalize or return to baseline.
9.10
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 reasons, behavior, noncompliance with study drug dosing or study procedures, 
ineligibility, or administrative reasons. 
Whenever possible, subjects who have been withdrawn from study drug treatment will continue 
on study, however, Vertex retains the right to remove a subject from the study.
Subjects who have been randomized and whose screening CFTR genotype does not confirm 
study eligibility must be discontinued from the study, even if a previous CFTR genotype 
laboratory report was used to establish eligibility.
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 a Safety Follow-up Visit, if 
applicable (see Section 9.1.6), and follow up with the subject regarding any unresolved AEs.
If the subject withdraws consent for the study, no further evaluations will be performed and no 
additional data will be collected. Vertex may retain and continue to use the study data and 
samples collected. The study data and the samples may be used for the development of the study 
compound, other drugs, or diagnostics, in publications and presentations, or 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. Any 
information that already has been obtained from the samples will continue to be used.


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9.11
Replacement of Subjects
Subjects who withdraw or are withdrawn before the first dose of study drug may be replaced. 
Subjects who withdraw or are withdrawn for non-safety reasons during the study drug treatment 
period may be replaced at Vertex’s discretion.
10
STUDY DRUG ADMINISTRATION AND MANAGEMENT
Study drug refers to VX-659, TEZ, TEZ/IVA, IVA, VX-561, 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 included in the Pharmacy Manual.
10.3
Study Drug Supply, Storage, and Handling
VX-659 and matching placebo will be supplied as tablets of similar size and appearance 
containing 80 mg VX-659 and 0 mg VX-659, respectively (Table 10-1).
TEZ/IVA (100 mg/150 mg) and matching placebo will be supplied as film-coated tablets of 
similar size and appearance containing 100 mg TEZ/150 mg IVA and 0 mg TEZ/0 mg IVA, 
respectively (Table 10-1). 
IVA (150 mg) and matching placebo will be supplied as film-coated tablets of similar size and 
appearance containing 150 mg IVA and 0 mg IVA, respectively (Table 10-1).
TEZ and matching placebo will be supplied as tablets of similar size and appearance containing 
50 mg TEZ and 0 mg TEZ, respectively (Table 10-1). 
VX-561 and matching placebo will be supplied as tablets of similar size and appearance 
containing 50 mg VX-561 and 0 mg VX-561, respectively (Table 10-1).
Blister cards must be stored under conditions noted in the Pharmacy Manual. The investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational product is 
stored in a secured area, under recommended storage conditions, and in accordance with 
applicable regulatory requirements. To ensure adequate records, all study drugs will be 
accounted for via the drug accountability forms as instructed by Vertex.
Table 10-1
Study Drug: Strength/Formulation/Route
Drug Name
Strength/Formulation/ Route
VX-659
80-mg tablet, oral
VX-659-matching placebo
0-mg tablet, oral
TEZ/IVA fixed-dose
100-mg/150-mg tablet; oral
TEZ/IVA-matching placebo
0-mg/0-mg tablet; oral
IVA
150-mg tablet, oral
IVA-matching placebo
0-mg tablet, oral


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Table 10-1
Study Drug: Strength/Formulation/Route
Drug Name
Strength/Formulation/ Route
TEZ
50-mg tablet, oral
TEZ-matching placebo
0-mg tablet, oral
VX-561
50-mg tablet, oral
VX-561-matching placebo
0-mg tablet, oral
IVA: ivacaftor; TEZ: tezacaftor
10.4
Drug Accountability
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of study drug received; study drug dispensed to the subjects; and study drug returned by 
the subjects. Subjects will be instructed to return all used 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 until inventoried by the study monitor. The study monitor will 
review study drug records and inventory throughout the study.
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. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented.
10.6
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 will contact the medical monitor to discuss discontinuing the subject 
from the study. 
10.7
Blinding and Unblinding
This will be a double-blind study.
10.7.1
Blinding
All subjects, site personnel (including the investigator, the site monitor, and the study team), and 
the Vertex study team will be blinded to the treatment codes with the exception of the following: 


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
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

Unblinded statistician preparing the final (production) randomization list who is not part of 
the study team

Vertex IWRS Manager

Vertex Clinical Supply Chain

IDMC

Vendor performing the interim analyses (IAs) and preparing the unblinded analysis for the 
ongoing reviews of efficacy and safety data, and the IDMC 

Bioanalytical contract research organization (CRO) analyzing PK samples and Vertex 
Bioanalytical personnel who are not members of the study team may review raw data from 
Bioanalytical CRO. 

Vertex Modeling and Simulation personnel or vendor conducting the population PK and 
PK/PD analyses

Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time
Blinding of Sweat Chloride and Spirometry Results: 

The Vertex study team will not have access to sweat chloride or spirometry results after a 
subject receives the first dose of study drug on the Day 1 Visit until after the data are 
unblinded for full review per Section 12.3.6.1. 

Sites, subjects, and their parents/caregivers/companions should not be informed of a subject’s 
study-related sweat chloride results until after the subject’s last study visit, even if the subject 
prematurely discontinues treatment. 

Subjects and their parents/caregivers/companions should not be informed of the subject’s 
study-related spirometry results until after the subject’s last study visit, even if the subject 
prematurely discontinues treatment.
10.7.2
Unblinding
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 


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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.
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 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.
Unblinded Reviews of Data by Vertex for Administrative Purposes (Planning, 
Decision-making, and Regulatory Submission)
A limited Vertex team will be unblinded and have access to safety, efficacy, and PD data for the 
purpose of conducting ongoing reviews of safety and efficacy data for planning and enabling 
clinical development. Members of the limited unblinded Vertex team will not be part of the 
Vertex study team and will not be involved in or influence the conduct of the study.
Unblinding: Interim Analysis Results
Interim analyses may be conducted for any part of the study after at least 50% of subjects in the 
part have completed the Day 15 Visit (see Section 12.3.6.1). Each IA will only include data for a 
single part of the study. The results of these analyses will be reviewed by a limited Vertex team. 
When an IA is performed after all subjects in a part have completed the Safety Follow-up Visit, 
results from that part will be unblinded for full review by the Vertex study team. 


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11
ASSESSMENTS
The Schedules of Assessments are shown in Table 3-1 (Part 1), Table 3-2 (Part 2), and Table 3-3
(Part 3).
11.1
Timing of Assessments
The CFQ-R assessment must be completed before any other assessment at the clinic visits when 
it is required. Other assessments may be performed in any order when more than 1 assessment is 
required at a particular time point.
11.2
Subject and Disease Characteristics
Subject and disease characteristics include demographics, medical history, height, and weight.
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, past medical and surgical histories, and any allergies.
Height and weight will be measured with shoes off.
11.3
Pharmacokinetics
11.3.1
Blood Sampling
Blood samples will be collected to determine plasma concentrations of VX-659, TEZ, M1-TEZ, 
IVA, M1-IVA, and VX-561. These samples may also be used for evaluation of VX-659 or 
VX-561 metabolites, for evaluation of additional TEZ or IVA metabolites, for further evaluation 
of the bioanalytical method, and for exploratory analyses that provide information on the 
metabolic pathways used by or affected by VX-659; these results may not be included in the 
clinical study report.
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations.  
Table 11-1
Acceptable Pharmacokinetic Sampling Windows
Sampling Time
Time From Scheduled Sampling Allowed
Predose
- 60 minutes
From 0.25 up to ≤8 hours after study drug dosing
± 15 minutes
For each visit with a PK blood draw, a record of study drug administration will be collected as 
described in Section 9.7. The collection date and exact time that each PK blood sample is drawn 
will also be recorded.
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard operating 
procedures.
Plasma concentration samples collected from subjects treated with placebo will not be routinely 
analyzed.


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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 1 or more validated analytical methods in compliance with 
Vertex or designee standard operating procedures. A description of the assay and validation data 
will be provided in separate reports.
11.4
Pharmacodynamics
Collection of sweat samples will be done with an approved collection device. 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. Individual sweat chloride test results 
will not be disclosed to the study sites after those from pre-dose on the Day 1 Visit. Specific 
instructions for collection, handling, processing, and shipping of sweat chloride samples to the 
central laboratory will be provided separately. See Section 10.7.1 for information about blinding 
of sweat chloride results.
11.6
Efficacy
11.6.1
Spirometry
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines13 and the following additional guidelines:
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have

withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment;

withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and

withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment.
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilators. At all other visits, all spirometry assessments should be performed 


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“pre-bronchodilator.” During the Treatment Period, spirometry assessments must be performed 
before the in-clinic dose of study drug, at approximately the same time at each visit.
If a subject forgets to withhold bronchodilator(s), spirometry should be performed according to 
the following:

If a subject’s Day 1 Visit 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 the Day 1 Visit, the subject forgets to withhold his/her dose of bronchodilator, 
spirometry should be performed post-bronchodilator, and all subsequent spirometric 
measurements should be performed post-bronchodilator.

Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator.
If more than 1 spirometry assessment is required at a visit, bronchodilators will be withheld until 
completion of the last scheduled spirometry assessment.
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.
See Section 10.7.1 for information about blinding of spirometry results.
The measured spirometric values listed below will be converted to percent predicted values using 
the GLI standards.12

FEV1 (L)

Forced vital capacity (FVC) (L)

FEV1/FVC (ratio)

Forced expiratory flow (FEF25%-75%) (L/s)
11.6.2
Cystic Fibrosis Questionnaire-Revised
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.18, 19 The CFQ-R will be completed before any other study assessments are 
performed at the study visit. The questionnaires provide information about demographics; 
general quality of life, school, work, or daily activities; and symptom difficulties (pertaining to 
CF). Copies of the CFQ-R 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.20, 21
11.7
Safety
Safety evaluations will include AEs, clinical laboratory assessments, ECGs, clinical evaluation 
of vital signs, pulse oximetry, and physical examinations (PEs).
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 


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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 which will be performed and analyzed at the site. Fasting is not required. The 
safety laboratory test panels are shown in Table 11-2. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs.
Table 11-2
Safety Laboratory Test Panels
Serum Chemistry
Hematologya
Urinalysisb
Glucose
Blood urea nitrogenc
Creatinine
Sodium
Potassium
Calcium
Chloride
Magnesium
Bicarbonate
Phosphate 
Total bilirubin, direct bilirubin
Alkaline phosphatase
Aspartate transaminase
Alanine transaminase
Lactate dehydrogenase
Gamma-glutamyl transpeptidase
Protein
Albumin
Lipase
Haptoglobind
Creatine kinase
Cholesterol
Triglycerides
Hemoglobin
Erythrocytes
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume
Reticulocytes
Platelets
Leukocytes
Differential (absolute and percent):
Eosinophils
Basophils
Neutrophils
Lymphocytes 
Monocytes
Coagulation Studies
Activated partial thromboplastin time 
Prothrombin time
Prothrombin time International
Normalized Ratio
Leukocyte esterase
Nitrite
Urobilinogen 
Urine protein 
pH
Urine blood
Specific gravity 
Urine ketones 
Urine bilirubin 
Urine glucose 
a
Blood smears will be saved for future evaluation, if needed.
b
If urine is positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of urine will be 
performed for leukocytes, erythrocytes, crystals, bacteria, and casts.
c
If blood urea nitrogen cannot be collected, urea may be substituted.
d
Haptoglobin will be analyzed only if there is evidence of possible hemolysis as determined by the site.


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Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential:
Serum samples will be analyzed for β-human chorionic gonadotropin at the central laboratory. 
Urine pregnancy tests will be performed at the site. The urine pregnancy test must be negative 
before the first dose of study drug (Day 1 Visit for Part 1 and Part 3; Day -28 Visit for Part 2). 
Pregnancy tests shown in Table 3-1, Table 3-2, and Table 3-3 are required in all countries. 
s. Additional urine pregnancy tests may be required according to country-specific regulations 
and/or requirements.
Follicle-stimulating Hormone (Screening Period only): Blood sample for FSH will be measured 
for any suspected postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be within the postmenopausal reference range of the 
performing laboratory to be considered postmenopausal.
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 9.10).
G6PD Activity Test (Screening Period only): Blood samples will be collected for the G6PD 
activity test, which will be performed in an established laboratory that runs the assay routinely.
The use of a local laboratory that routinely runs quantitative G6PD activity assays is acceptable 
as an alternative to the central laboratory.
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate. 
For purposes of study conduct, the central laboratory must be used for all laboratory tests with 
the exception of the G6PD activity test. 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 will be done at screening and select study visits. At other visits, 
symptom-directed PEs can be done at the discretion of the investigator or healthcare provider. 
A complete PE includes a review of the following systems: head/neck/thyroid; 
eyes/ears/nose/throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After screening, any clinically significant abnormal findings in PEs
will be reported as AEs. 
The abbreviated PE will include an assessment of the following body systems: EENT, 
cardiovascular system, respiratory system, abdomen, and skin.
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the seated position. 
Vital signs will be assessed according to Table 3-1, Table 3-2, and Table 3-3.


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11.7.4
Pulse Oximetry
Arterial oxygen saturation by pulse oximetry will be measured after at least a 5-minute rest 
(seated) and before study drug dosing. At visits when study drug is taken at the site, pulse 
oximetry will be collected before the morning dose. This is a noninvasive measure of oxygen 
delivery to the tissues and has been correlated with clinical status and lung function.
11.7.5
Electrocardiograms
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Table 3-1, Table 3-2, and Table 3-3. Additional standard 12-lead ECGs will be performed at any 
other time if clinically indicated. 
A subject should be rested for at least 5 minutes before an ECG is performed.
The ECG traces will be manually read at the study site at the Screening Visit and Safety 
Follow-up Visit. A printout of the ECG traces will be made for safety review by the investigator 
and maintained with source documentation. Clinically significant ECG abnormalities occurring 
during the study through the Safety Follow-up Visit will be recorded as AEs.
Study sites should use QTcF unless they receive approval from the medical monitor to use 
QTcB.
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >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. A subject with a 
QTcF value above the threshold will discontinue dosing. Further details pertaining to ECGs will 
be provided to sites in a separate document (ECG Manual).
11.7.6
Pregnancy and Contraception
The effects of VX-659 monotherapy or in TC with TEZ and IVA or VX-561 on conception, 
pregnancy, and lactation in humans are not known. VX-659, TEZ, IVA, and VX-561 did not 
show genotoxic potential in a standard battery of in vitro (Ames test or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies. VX-659, TEZ, and IVA also did 
not show genotoxic potential in chromosomal aberration studies. Reproductive toxicology 
studies of VX-659, TEZ, and IVA have not shown teratogenicity in rats and rabbits.
11.7.6.1
Contraception
Contraception requirement for the couple is waived for the following:

True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the Screening Visit through 90 days after the last dose of study drug.

If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 


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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 and females who do not have 
a documented bilateral oophorectomy) 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, 
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 6 months or more 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; however, female subjects are not required to discontinue their use of hormone-
releasing intrauterine devices or hormonal contraceptives.
Additional notes:

Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug.


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
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 must not plan to 
become pregnant during the study or within 90 days after the last study drug dose.
11.7.6.2
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 or the female partner of a male subject becomes pregnant while participating 
in the study, other than a female partner as the result of artificial insemination using sperm 
banked by the male subject before the first dose of study drug, 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.
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 safety analyses and clinical pharmacology 
analyses for this study. Safety statistical analysis details will be provided in the statistical 
analysis plan (SAP) for this study, and clinical pharmacologic analysis details will be provided in 
the clinical pharmacology analysis plan (CPAP), both of which will be finalized before clinical 
database lock.
Final analyses will take place after all subjects have completed the study, all data have been 
entered in the clinical study database, and the database has been locked.
12.1
Sample Size and Power
12.1.1
Primary Objectives 
The primary objectives of the study are the evaluation of safety and tolerability, and efficacy of 
VX-659 in TC with TEZ and either IVA or VX-561. The sample size calculations described 
below are deemed adequate to evaluate the objectives of the study, based on clinical and 
statistical considerations.
12.1.1.1
Safety and Tolerability
The primary safety endpoint is the incidence of AEs. Approximately 105 subjects will be 
randomized in the study with approximately 81 subjects receiving VX-659 in TC. The sample 
size for each treatment group will provide sufficient data for a descriptive analysis of AEs. 
12.1.1.2
Efficacy
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through the 
Day 29 Visit in all parts. A sample size of 18 subjects per treatment group provides at least 90% 
power to detect a mean within-group change of 7 percentage points.


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12.1.2
Secondary Objectives 
A secondary objective of the study is the evaluation of the PD effect of VX-659 in TC with TEZ 
and either IVA or VX-561. 
The absolute change from baseline through the Day 29 Visit in sweat chloride concentrations is a 
secondary endpoint used to evaluate the PD objective of the study. In Part 1, a test for a 
decreasing dose-response trend between placebo and the TC dose groups will be performed 
using a multiple comparisons procedure (MCP). The procedure consists of testing the null 
hypothesis of the lack of a decreasing dose-response trend versus a decreasing trend using the 
1-sided maximum t-statistic that controls the type I error at alpha = 5%. The procedure requires a 
family of candidate dose-response models to be prespecified, that covers the range of plausible 
and diverse dose-response profiles. 
The candidate models that best describe the expected decreasing dose-response profile of the TC 
groups compared to placebo include a linear model, a maximum effect (Emax) model, and a 
sigmoid Emax model. The contrasts (i.e., linear combinations of the treatment group means 
through the Day 29 Visit) selected to perform the MCP and that capture the shape of these 
candidate models are described in Table 12-1. 
Table 12-1
Contrast Coefficients for the Multiple Comparisons Procedure in Part 1
Candidate Model
Placebo
TC-low
TC-mid
TC-high
Linear
3.0
1.0
-1.0
-3.0
Emax
3.0
-1.0
-1.0
-1.0
Sigmoid Emax
1.0
1.0
-1.0
-1.0
Emax: maximum effect; TC: triple combination
A total sample size of 54 subjects in Part 1 will provide at least 90% power to detect a 
dose-response trend with MCP. 
12.2
Analysis Sets
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. An additional analysis set related to the Run-in Period in Part 2 will be defined in the 
statistical analysis plan (SAP), as appropriate.
The All Subjects Set will include all subjects who were randomized or received at least 1 dose
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 
The FAS will include all randomized subjects who carry the intended CFTR allele mutation and
received at least 1 dose of study drug in Period 1. The FAS will be used to summarize subject 
demographics and baseline characteristics, and for all PD and efficacy analyses, unless otherwise 
specified. Subjects will be analyzed according to the treatment to which they were randomized.
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, unless otherwise specified. Subjects will be analyzed 
according to the treatment they received. If a subject received at least 1 dose of a higher dose TC 
treatment, the subject will be analyzed in the higher dose TC treatment group. For the purpose of 
analysis, the priority order of increasing study drug treatment will be defined as placebo, 
TC-low, TC-mid, and TC-high. 


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12.3
Statistical Analysis
This section presents a summary of the planned statistical analyses of the PD, efficacy, and 
safety endpoints of the study. Statistical analysis details will be provided in the SAP. 
12.3.1
General Considerations
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, SE, median, minimum value, and maximum value. The 
precision of the measurement for each continuous variable will be specified in the SAP. Unless 
otherwise specified, minimum and maximum values will be reported with the same precision as 
the units of the raw data. The mean, median, SD, and SE will be reported to 1 additional decimal 
place. Any values that require a transformation to standard units (metric or International System 
[SI]) will be converted with the appropriate precision.
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place.
The baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period (i.e., the Day 1 Visit). For ECG, baseline will be defined as the most recent 
pretreatment measurement (or the average of triplicate measurements, if the most recent 
pretreatment measurement is obtained in triplicate) before the first dose of study drug in Period 1 
(i.e., the Day 1 visit).
Absolute change from baseline will be calculated as postbaseline value – baseline value.
Relative change from baseline will be calculated as (postbaseline value – baseline 
value)/baseline value.
The Treatment-emergent (TE) Period will include the time from the first dose in Period 1 to the 
Safety Follow-up Visit or 28 days after the last dose of the study drug for subjects who do not 
complete the Safety Follow-up Visit. Only data collected up to the end of study for a subject will 
be included in the analysis. An additional TE period related to the Run-in Period for Part 2 will 
be defined in the SAP, as appropriate.
There will be no multiplicity adjustment for performing multiple hypothesis tests.
The rules for handling missing data due to treatment or study discontinuation will be described in 
the SAP.
All data will be summarized for each part, separately, unless specified otherwise.
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/Safety 
Follow-up Visit, and discontinued treatment or study with a breakdown of the reasons for 
discontinuation) will be summarized overall and by treatment group.
12.3.2.2
Demographics and Baseline Characteristics
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized using descriptive summary statistics.


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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, age, weight, 
height, body mass index, ppFEV1, and sweat chloride. 
No statistical tests will be performed to evaluate baseline imbalance between treatment groups.
12.3.2.3
Prior and Concomitant Medications
Medications used in this study will be coded using the World Health Organization-Drug 
Dictionary Enhanced and categorized for analysis as the following:

Prior medication: any medication that started before initial dosing of study drug, regardless 
of when it ended

Concomitant medication: medication continued or newly received 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.
An additional classification of concomitant medications related to the Run-in Period for Part 2 
will be defined in the SAP, as appropriate.
12.3.2.4
Study Drug Exposure and Compliance
Exposure to study drug will be summarized for the Safety Set in terms of duration of treatment a 
subject received (in days), defined as the last day minus the first day of study drug plus 1.
Dosing compliance based on number of tablets taken, will be summarized for the FAS, and will 
be derived 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).
Dosing compliance based on study drug exposure, will be derived as 100 × [1 - (total number of 
days of study drug interruption) / (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.
IPDs will be provided in an individual subject data listing.


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12.3.3
Efficacy Analysis
12.3.3.1
Analysis of Primary Efficacy Variables
The primary efficacy variable is the absolute change from baseline for ppFEV1 through the 
Day 29 Visit in all parts. The analysis will be performed using a mixed-effects model for 
repeated measures (MMRM) with change from baseline as the dependent variable. The model 
will include treatment group, visit, and treatment-by-visit interaction as fixed effects, subject as 
random effect, and the continuous baseline ppFEV1 as a covariate. The model will be estimated 
using restricted maximum likelihood. Denominator degrees of freedom for the F test for fixed 
effects will be estimated using the Kenward-Roger approximation. An unstructured covariance 
structure will be used to model the within-subject errors to account for repeated measures within 
a subject. If the model estimation does not converge, a compound symmetry covariance structure 
will be used. Conditional on observed data and covariates, missing data due to treatment or study 
discontinuation will be assumed to be missing at random.
Adjusted means and 95% confidence intervals of the average treatment effects through the 
Day 29 Visit, as applicable, with 2-sided P values, will be estimated within MMRM using Least 
Squares Means via PROC MIXED in SAS, for all within-group and between-group comparisons.
Sensitivity analyses for handling missing data due to treatment or study discontinuation will be 
described in the SAP. 
Additional supportive analyses using Period 2 in Parts 1 and 2 will be described in the SAP. 
Subgroup analyses will also be described in the SAP.
There will be no multiplicity adjustment for performing multiple hypothesis tests.
12.3.3.2
Analysis of Secondary Efficacy Variables
The secondary efficacy variables are relative change in ppFEV1 from baseline through the 
Day 29 Visit and absolute change in the CFQ-R respiratory domain score from baseline at the 
Day 29 Visit. Analysis of secondary efficacy variables will be similar to that performed for the 
primary efficacy variable. Additional details of these analyses will be provided in the SAP.
12.3.4
Pharmacodynamic Analysis
Estimation of Treatment Effects
In a separate MMRM model, adjusted means and 95% confidence intervals of the average 
treatment effects through the Day 29 Visit, with 2-sided P values, for all within-group and 


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between-group comparisons will be estimated within MMRM, with appropriate adjustment for 
covariates.
Additional details of the analysis will be provided in the SAP.
12.3.5
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 will be summarized by treatment group and overall, for each part.
All safety data will be presented in individual subject data listings.
12.3.5.1
Adverse Events
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows: 

Pretreatment AE: any AE that started before the first dose of study drug

TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of study drug through the end of the TE Period

Post-treatment AE: any AE that increased in severity or that was newly developed beyond 
the TE Period
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs.
AE summary tables will be presented for TEAEs only, overall and by treatment group for each 
part, and will include the following:

All TEAEs

TEAEs by strongest relationship 

TEAEs by maximum severity

TEAEs leading to treatment discontinuation

Serious TEAEs

TEAEs leading to death

Frequently reported TEAEs


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Summaries will be presented by MedDRA System Organ Class and Preferred Term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event). When 
summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once, only the maximum 
severity level will be presented in the severity summaries, and the 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.
12.3.5.2
Clinical Laboratory Assessments
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, chemistry, and coagulation results will be 
summarized in SI units overall and by treatment group at each scheduled visit.
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group for each part. The threshold analysis 
criterion shift from baseline will also be summarized for selected laboratory parameters. The 
threshold analysis criteria and the parameter selection criteria will be provided in the SAP.
Results of urinalysis and the serum pregnancy test will be listed in individual subject data listings 
only. In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from 
scheduled and unscheduled visits.
12.3.5.3
Electrocardiogram
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided overall and by treatment group for each part, at each scheduled 
visit and time point, as applicable, for the following ECG interval measurements (in msec): RR, 
PR, QT, and QT corrected for heart rate (QTcF), QRS duration, and heart rate (beats per minute).
The number and percentage of subjects meeting a threshold analysis criterion 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 will be described in the SAP.
12.3.5.4
Vital Signs
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized overall and by treatment group at each scheduled visit. The 
following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), body temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per 
minute).
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group for each part. The threshold analysis 
criteria will be provided in the SAP.
Additional vital signs analyses will be described in the SAP.




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13
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
13.1
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting
13.1.1
Adverse Events
13.1.1.1
Definition of an Adverse Event
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed. 
An AE is considered serious if it meets the definition in Section 13.1.2.1. 
13.1.1.2
Clinically Significant Assessments
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed 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 ICF is signed until the following time points:

For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent)

For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit


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
For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of
o
28 days after the last dose of study drug, or
o
the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug (see 
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 Criteria for 
Adverse Events (CTCAE), Version 4.03, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
August 2015). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In 
considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in the 
CTCAE. The severity of an AE that does not appear in the CTCAE will be determined according 
to the definitions in Table 13-1.  
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 


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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
Not applicable
Action taken regarding study drug administration does not apply. 
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible.
AE: adverse event
13.1.1.7
Adverse Event Outcome
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4.
Table 13-4
Classifications for Outcome of an AE
Classification
Definition
Recovered/Resolved
Resolution of an AE with no residual signs or symptoms
Recovered/Resolved With 
Sequelae
Resolution of an AE with residual signs or symptoms
Not Recovered/Not 
Resolved (Continuing)
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing


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


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“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 the Safety Follow-up Visit, 
regardless of causality, will be reported by the investigator to Vertex GPS. In addition, all SAEs 
that occur after the Safety Follow-up Visit and are considered related to study drug(s) will be 
reported to Vertex GPS within 24 hours.
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the 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: 
 
Contact Telephone: 
13.1.2.4
Expedited Reporting and Investigator Safety Letters
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities 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 independent ethics committees (IECs). 
It is the responsibility of the investigator or designee to promptly notify the local institutional 
review board (IRB)/local IEC of all unexpected serious adverse drug reactions involving risk to 
human subjects.


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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
The investigator (or an appropriate authorized designee) will obtain informed consent from each 
subject before any study procedure takes place. The method of obtaining and documenting the 
informed consent and the contents of the consent will comply with ICH GCP and all applicable 
laws and regulations and will be subject to approval by Vertex or its designee.
13.2.3
Investigator Compliance
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities.
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log. 
13.2.4
Access to Records
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use
and disclosure of information related to the research set forth in this protocol. 
13.2.5
Subject Privacy
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 


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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 and associated regulations (“HIPAA”) 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

Lack of evaluable and/or complete data

Potentially unacceptable risk to study subjects

Decision to modify drug development plan

Decision by the FDA or other regulatory authority
Written notification that includes the reason for the clinical study termination is required.
13.3
Data Quality Assurance
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of
responsibilities and procedures for ensuring adequate and correct study documentation.
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 


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personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application. 
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database.
13.4
Monitoring
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed.
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements.
13.5
Electronic Data Capture
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible. 
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status.
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected. 
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible. 
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a CD or other electronic media will be placed in the investigator’s study file.
13.6
Publications and Clinical Study Report
13.6.1
Publication of Study Results
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study.


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The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study.
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between Vertex and the investigator and/or the 
investigator’s institution.
13.6.2
Clinical Study Report 
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 






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Appendix A CFTR Mutations That Are Predicted to Result in a CFTR Protein With 
Minimal Function (Part 1 and Part 3)
Per the study eligibility criteria, heterozygous F508del-CFTR subjects in Part 1 and Part 3 must 
have a second CFTR allele containing a mutation that is predicted to result in a CFTR protein 
with minimal function and not expected to respond to TEZ, IVA, or TEZ/IVA. These CFTR
mutations were defined using 3 major sources: 

biological plausibility for the mutation to respond (i.e., mutation class)

evidence of clinical severity on a population basis (per CFTR2 patient registry; accessed on 
15 February 2016)
o
average sweat chloride >86 mmol/L, and
o
prevalence of pancreatic insufficiency (PI) >50%

in vitro testing
o
mutations resulting in baseline chloride transport <10% of wild-type CFTR were 
considered minimal function
o
mutations resulting in chloride transport <10% of wild-type CFTR following the addition 
of TEZ and/or IVA were considered nonresponsive 
The clinical severity criteria (average sweat chloride >86 mmol/L and %PI >50%) do not apply 
to the individual subjects to be enrolled in this study, but were used to classify the mutation 
status on a population level.
The list below represents acceptable mutations, which are detectable by an FDA-cleared 
genotyping assay; 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 VX16-659-101, Part 1 and Part 3
Criteria
Mutation
Truncation mutations 
%PI >50% and/or 
SwCl- >86 mmol/L
no full-length protein 
S4X
C276X
G542X
R792X
E1104X
G27X
Q290X
G550X
E822X
R1158X
Q39X
G330X
Q552X
W846X
R1162X
W57X
W401X
R553X
Y849X
S1196X
E60X
Q414X
E585X
R851X
W1204X
R75X
S434X
G673X
Q890X
L1254X
E92X
S466X
Q685X
S912X
S1255X
Q98X
S489X
R709X
Y913X
W1282X
Y122X
Q493X
K710X
W1089X
Q1313X
E193X
W496X
L732X
Y1092X
E1371X
L218X
C524X
R764X
W1098X
Q1382X
Q220X
Q525X
R785X
R1102X
Q1411X
Splice mutations 
%PI >50% and/or 
SwCl- >86 mmol/L
no or little mature 
mRNA  
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
405+1G→A
1248+1G→A
1811+1G→C
3040G→C 
(G970R)
3600+2insT
405+3A→C
1249-1G→A
1811+1.6kbA→G
3850-1G→A
406-1G→A
1341+1G→A
1812-1G→A
3120G→A
4005+1G→A
621+1G→T
1525-2A→G
1898+1G→A
3120+1G→A
4374+1G→T
711+1G→T
1525-1G→A
1898+1G→C
3121-2A→G
Small (≤3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations
%PI >50% and/or 
SwCl- >86 mmol/L
garbled and/or 
truncated protein
182delT
1119delA
1782delA
2732insA
3876delA
306insA
1138insG
1824delA
2869insG
3878delG
365-366insT
1154insTC
2043delG
2896insAG
3905insT
394delTT
1161delC
2143delT
2942insT
4016insT
442delA
1213delT
2183AA→G a
2957delT
4021dupT
444delA
1259insA
2184delA
3007delG
4040delA
457TAT→G
1288insTA
2184insA
3028delA
4279insA
541delC
1471delA
2307insA
3171delC
4326delTC
574delA
1497delGG
2347delG
3659delC
663delT
1548delG
2585delT
3737delA
935delA
1609del CA
2594delGT
3791delC
1078delT
1677delTA
2711delT
3821delT
Non-small (>3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations
%PI >50% and/or 
SwCl- >86 mmol/L
garbled and/or 
truncated protein
CFTRdele2,3
1461ins4
2991del32
CFTRdele22,23
1924del7
3667ins4
124del23bp
2055del9→A
4010del4
852del22
2105-
2117del13insAGAAA
4209TGTT→AA
991del5
2721del11


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CFTR Mutations Eligible for VX16-659-101, Part 1 and Part 3
Criteria
Mutation
Class II, III, IV mutations 
not responsive to IVA 
alone or in combination 
with TEZ or LUM 

%PI>50% and/or 
SwCl >86 mmol/L
AND

Not responsive in vitro 
to IVA alone or in 
combination with TEZ 
or LUM
A46Db
V520F
Y569Db
N1303K
G85E
A559Tb
L1065P
R347P
R560T
R1066C
L467Pb
R560S
L1077Pb
I507del
A561E
M1101K
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.
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; LUM: lumacaftor; PI: pancreatic 
insufficiency; SwCl: sweat chloride; TEZ: tezacaftor 
Note: %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.




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15.2
Investigator Signature Page
Protocol #:
VX16-659-101
Version #:
3.0
Version Date:
01 September 2017
Study Title: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and 
Efficacy of VX-659 Combination Therapy in Subjects Aged 18 Years and Older With Cystic 
Fibrosis
I have read Protocol VX16-659-101, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-659, tezacaftor, ivacaftor, and VX-561
(CTP-656) 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 57 
Protocol Number: VX16-659-101 Version 3.0 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX16-659-101 Version 3.0 
 
 
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate 
the Safety and Efficacy of VX-659 Combination Therapy in Subjects 
Aged 18 Years and Older With Cystic Fibrosis 
 
Authors of SAP: 
 
 
Version: Version 1.0 
Version Date of SAP: 19 Sep 2017 
 
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) 
Protocol VX16-659-101, Version 3.0 
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1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................................. 2 
2 
Modifications .................................................................................................................................... 4 
2.1 
Modifications to the Approved Clinical Study Protocol ............................................................ 4 
2.2 
Modifications to the Approved Statistical Analysis Plan ........................................................... 4 
2.3 
Modifications to the Approved DMC Charter ........................................................................... 4 
3 
Introduction ..................................................................................................................................... 5 
4 
Study Objectives .............................................................................................................................. 5 
4.1 
Primary Objective ...................................................................................................................... 5 
4.2 
Secondary Objectives ................................................................................................................. 5 
5 
Study Endpoints ............................................................................................................................... 6 
5.1 
Efficacy Endpoint ....................................................................................................................... 6 
5.1.1 
Primary Efficacy Endpoint ................................................................................................. 6 
5.1.2 
Secondary Efficacy Endpoints ........................................................................................... 6 
5.2 
Safety Endpoints ........................................................................................................................ 6 
6 
Study Design ..................................................................................................................................... 6 
6.1 
Overall Design ............................................................................................................................ 6 
6.2 
Sample Size and Power .............................................................................................................. 9 
6.2.1 
Primary Objectives ............................................................................................................. 9 
6.2.1.1 
Safety and Tolerability ................................................................................................. 9 
6.2.1.2 
Efficacy ........................................................................................................................ 9 
6.2.2 
Secondary Objectives ......................................................................................................... 9 
6.3 
Randomization ......................................................................................................................... 10 
6.4 
Blinding and Unblinding .......................................................................................................... 10 
6.4.1 
Blinding ............................................................................................................................ 10 
6.4.2 
Blinding ............................................................................................................................ 10 
6.4.3 
Unblinding ........................................................................................................................ 11 
7 
Analysis Sets ................................................................................................................................... 12 
7.1 
All Subjects Set ........................................................................................................................ 12 
7.2 
Full Analysis Set ...................................................................................................................... 12 
7.3 
Safety Set .................................................................................................................................. 13 
7.3.1 
Parts 1 and 3 ..................................................................................................................... 13 
7.3.2 
Part 2 ................................................................................................................................. 13 
8 
Statistical Analysis ......................................................................................................................... 13 
8.1 
General Considerations ............................................................................................................ 13 
8.2 
Background Characteristics ...................................................................................................... 15 
8.2.1 
Subject Disposition ........................................................................................................... 15 
8.2.2 
Demographics and Baseline Characteristics .................................................................... 16 
8.2.3 
Prior and Concomitant Medications ................................................................................. 17 
8.2.4 
Study Drug Exposure ....................................................................................................... 18 
8.2.5 
Study Drug Compliance ................................................................................................... 18 
8.2.6 
Important Protocol Deviations ......................................................................................... 19 
8.3 
Efficacy Analysis ..................................................................................................................... 19 
8.3.1 
Primary Efficacy Variable ................................................................................................ 19 
8.3.1.1 
Primary Analysis of the Primary Efficacy Variable .................................................. 20 


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8.3.2 
Analysis of Secondary Efficacy Variables ....................................................................... 21 
8.3.2.1 
Relative change in ppFEV1 from baseline through Day 29 (All Parts) ..................... 22 
8.3.2.2 
Absolute change in the CFQ-R respiratory domain score from baseline at Day 29 
(All Parts) ................................................................................................................... 22 
8.3.2.3 
Multiplicity adjustment .............................................................................................. 22 
8.3.3 
Analysis of Other Efficacy Variables (All Parts) ............................................................. 22 
8.3.3.1 
Absolute change in CFQ-R non-respiratory domain scores from baseline at Day 29 
(All Parts) ................................................................................................................... 22 
8.3.5 
Pharmacodynamic Analysis ............................................................................................. 23 
8.3.5.1 
Primary Analysis of the Dose Response trend of absolute change in sweat chloride 
from baseline through the Day 29 Visit (Part 1) ........................................................ 24 
8.3.5.2 
Absolute Change in Sweat Chloride from Baseline through the Day 29 Visit (All 
Parts) .......................................................................................................................... 24 
 
 
8.4 
Safety Analysis ......................................................................................................................... 25 
8.4.1 
Adverse Events ................................................................................................................. 26 
8.4.2 
Clinical Laboratory ........................................................................................................... 27 
8.4.3 
Electrocardiogram ............................................................................................................ 27 
8.4.4 
Vital Signs ........................................................................................................................ 27 
8.4.5 
Pulse Oximetry ................................................................................................................. 28 
8.4.6 
Physical Examination ....................................................................................................... 28 
8.4.7 
Other Safety Analysis ....................................................................................................... 28 
8.4.7.1 
Post-dose Spirometry ................................................................................................. 28 
9 
Interim and IDMC Analyses ........................................................................................................ 28 
9.1 
Interim Analysis ....................................................................................................................... 28 
9.1.1 
Summary of the Flow of Data for Interim Analyses ........................................................ 28 
9.2 
IDMC Analysis ........................................................................................................................ 29 
10 References ...................................................................................................................................... 30 
11 List of Appendices ......................................................................................................................... 31 
Appendix A: Schedule of Assessments ............................................................................................. 31 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................................... 41 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ........................... 44 
Appendix D: Important Protocol Deviation Rules ............................................................................. 45 
Appendix E: Details of GLI Equations for Calculating ppFEV1 ....................................................... 46 
Appendix F: Details of CFQ-R Analysis and Scoring Manual.......................................................... 47 
Appendix G: Imputation Rules for Missing AE dates ....................................................................... 48 
Appendix H: Criteria for Threshold Analysis .................................................................................... 51 
 


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2 
MODIFICATIONS  
2.1 
Modifications to the Approved Clinical Study Protocol 
Key changes in the current version of the SAP are summarized below. 
Change and Rationale 
Affected Sections 
Treatment-emergent (TE) period has been revised to be from first dose date 
of study drug in the Treatment Period until 28 days after the last dose date of 
study drug or end of study date (based on end of study visit in CRFs), 
whichever occurs first. 
Section 8.1 
2.2 
Modifications to the Approved Statistical Analysis Plan 
This is the 1st version of Statistical Analysis Plan for the final analysis.   
2.3 
Modifications to the Approved DMC Charter 
Not Applicable. 
 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical study 
protocol (CSP), Version 3.0, dated 01 Sep 2017, approved electronic case report form (eCRF), Version 
1.4, dated 10 Aug 2017, and approved eCRF completion guidelines, Version 1.0, dated 14 Jul 2017. 
This SAP will be used to perform interim analyses (IAs) for each part after 50% of subjects in the part 
have completed the Day 15 Visit. In addition, this SAP will be used to perform final analysis that will 
occur after all subjects in each part have completed the Safety Follow-Up Visit.  
This is a Phase 2, randomized, double-blind, placebo- and TEZ/IVA-controlled, parallel-group, 
multicenter study to evaluate the safety and efficacy of VX-659 combination therapy in subjects aged 
18 years and older with cystic fibrosis. 
This SAP (Methods) documents the planned statistical analyses of efficacy endpoints and safety 
endpoints. 
Vertex Biometrics will perform the statistical analysis for each IA, and the final analysis. SAS® 
Version 9.4 or higher software 
 will be used to generate all 
statistical outputs (tables, figures, listings, and datasets).  
The SAP (Methods) will be finalized and approved prior to the data cut for the first IA. Any revisions 
to the approved SAP will be documented and approved in an amendment to the SAP prior to the 
clinical database lock for the final analysis. Any changes made to the SAP Methods after the clinical 
database lock has occurred will be documented in the clinical study report for this study.  
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
Parts 1 and 2: To evaluate the safety and tolerability of VX-659 in triple combination (TC) with 
tezacaftor (TEZ) and ivacaftor (IVA) 
Part 3 (optional): To evaluate the safety and tolerability of VX-659 in TC with TEZ and VX-561 (also 
known as CTP-656, deuterated IVA) 
All parts: To evaluate the efficacy of VX-659 in TC with TEZ and either IVA or VX-561 
4.2 
Secondary Objectives  
Parts 1 and 2: To evaluate the pharmacodynamic (PD) effects of VX-659 in TC with TEZ and IVA on 
CFTR function 
Part 3 (optional): To evaluate the PD effects of VX-659 in TC with TEZ and VX-561 on CFTR 
function 
All parts:  
• To evaluate the pharmacokinetics (PK) of VX-659 when administered in TC with TEZ and either 
IVA or VX-561 
• To evaluate the PK of TEZ, IVA, VX-561 and their respective metabolites when administered with 
VX-659 (as applicable)  


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5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoint 
5.1.1 
Primary Efficacy Endpoint 
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through the Day 29 Visit 
5.1.2 
Secondary Efficacy Endpoints 
• Absolute change in sweat chloride concentrations from baseline through the Day 29 Visit  
• Relative change in ppFEV1 from baseline through the Day 29 Visit  
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from 
baseline at the Day 29 Visit  
5.2 
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 
• Spirometry 
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 2, randomized, double-blind, placebo- and TEZ/IVA-controlled, parallel-group, 3-part, 
multicenter study. All parts will be conducted concurrently. Subjects may not participate in more than 
1 part. 
Key study elements of each part are summarized in Table 6-1, treatment arms and planned doses are 
shown in Table 6-2, and a schematic of the study design is shown in Figure 6-1. Study visits and 
assessments are shown in Table 11-1 (Part 1), Table 11-2 (Part 2), and Table 11-3 (Part 3). 
Table 6-1 
Key Study Elements by Part 
Element 
Part 1 
Part 2 
Part 3 (optional) 
Study population 
 
 
 
Genotype(s) 
F/MF 
F/F 
F/MF 
Age 
≥18 years 
≥18 years 
≥18 years 
ppFEV1 criteria 
≥40 to ≤90  
≥40 to ≤90 
≥40 to ≤90  
Number of subjects 
Approximately 54 
Approximately 27 
Approximately 24 
Randomization 
 
 
 
Ratio 
1:1:2:2 (placebo:TC-low: 
TC-mid:TC-high) 
1:2 (TEZ/IVA:TC-high) 
1:3 (placebo:TC2-high) 
Stratification 
ppFEV1
 (<70, ≥70) 
ppFEV1
 (<70, ≥70) 
ppFEV1
 (<70, ≥70) 




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Part 3: Subjects with F/MF Genotypes (optional) 
 
F/F: homozygous for F508del; F/MF: heterozygous for F508del and a minimal CFTR function mutation that is not expected to respond 
to TEZ, IVA, or TEZ/IVA; IVA: ivacaftor; N: number of subjects; TEZ: tezacaftor; TC: triple combination  
Note: To maintain the blind, matching placebo tablets will be administered, as applicable, so that all subjects receive the same number of 
tablets within a given dosing period. 


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6.2 
Sample Size and Power 
6.2.1 
Primary Objectives  
The primary objectives of the study are the evaluation of safety and tolerability, and efficacy of 
VX-659 in TC with TEZ and either IVA or VX-561. The sample size calculations described 
below are deemed adequate to evaluate the objectives of the study, based on clinical and 
statistical considerations. 
6.2.1.1 
Safety and Tolerability 
The primary safety endpoint is the incidence of AEs. Approximately 105 subjects will be 
randomized in the study with approximately 81 subjects receiving VX-659 in TC. The sample 
size for each treatment group will provide sufficient data for a descriptive analysis of AEs.  
6.2.1.2 
Efficacy 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through the 
Day 29 Visit in all parts. A sample size of 18 subjects per treatment group provides at least 90% 
power to detect a mean within-group change of 7 percentage points. 
6.2.2 
Secondary Objectives  
A secondary objective of the study is the evaluation of the PD effect of VX-659 in TC with TEZ 
and either IVA or VX-561.  
The absolute change from baseline through the Day 29 Visit in sweat chloride concentrations is a 
secondary endpoint used to evaluate the PD objective of the study. In Part 1, a test for a 
decreasing dose-response trend between placebo and the TC dose groups will be performed 
using a multiple comparisons procedure (MCP). The procedure consists of testing the null 
hypothesis of the lack of a decreasing dose-response trend versus a decreasing trend using the 
1-sided maximum t-statistic that controls the type I error at alpha = 5%. The procedure requires a 
family of candidate dose-response models to be prespecified, that covers the range of plausible 
and diverse dose-response profiles.  


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6.3 
Randomization 
For all parts, randomization will be stratified by ppFEV1 values (<70 vs ≥70). 
For subjects in Part 1 and Part 3, the spirometry assessment used for stratification must be 
performed at least 14 days after the last dose of any previous CFTR modulator treatment. 
Therefore, subjects being treated with 1 or more CFTR modulators (investigational or approved) 
within 14 days of the Screening Visit must have a separate Stratification Visit at least 14 days 
after the subject’s last CFTR modulator dose. For subjects not being treated with any CFTR 
modulators within 14 days of the Screening Visit, the Screening Visit spirometry assessment can 
be used for stratification.  
For subjects in Part 2, the ppFEV1 assessment for stratification of randomization will be done at 
the Day -14 Visit. See Section 9.3.1 of the protocol. 
Randomization will occur before the first dose of VX-659/control and may be done on either 
Day -1 or the Day 1 Visit, after all inclusion and exclusion criteria have been satisfied and the 
criteria for entry into the Treatment Period have been confirmed (see Section 9.1.4 of the 
protocol). 
For Part 2, subjects who prematurely discontinue TEZ/IVA during the Run-in Period will not be 
randomized or participate in the Treatment Period, unless they rescreen and complete a 4-week 
Run-in Period (Section 9.1.2 of the protocol). 
6.4 
Blinding and Unblinding 
6.4.1 
Blinding  
This will be a double-blind study. 
6.4.2 
Blinding 
All subjects, site personnel (including the investigator, the site monitor, and the study team), and 
the Vertex study team will be blinded to the treatment codes with the exception of the following:  
• Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the subject 
and her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
• Unblinded statistician preparing the final (production) randomization list who is not part of 
the study team 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 
• Independent Data Monitoring Committee (IDMC) 
• Vendor performing the interim analyses (IAs) and preparing the unblinded analysis for the 
ongoing reviews of efficacy and safety data, and the IDMC 


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• Bioanalytical contract research organization (CRO) analyzing PK samples and Vertex 
Bioanalytical personnel who are not members of the study team may review raw data from 
Bioanalytical CRO.  
• Vertex Modeling and Simulation personnel or vendor conducting the population PK and 
PK/PD analyses 
• Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
Blinding of Sweat Chloride and Spirometry Results:  
• The Vertex study team will not have access to sweat chloride or spirometry results after a 
subject receives the first dose of study drug on the Day 1 Visit until after the data are 
unblinded for full review per Section 12.3.6.1 of the protocol.  
• Sites, subjects, and their parents/caregivers/companions should not be informed of a subject’s 
study-related sweat chloride results until after the subject’s last study visit, even if the subject 
prematurely discontinues treatment.  
• Subjects and their parents/caregivers/companions should not be informed of the subject’s 
study-related spirometry results until after the subject’s last study visit, even if the subject 
prematurely discontinues treatment. 
6.4.3 
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. 
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. 


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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 of the protocol. 
Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 
Vertex GPS or designee will 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. 
Unblinded Reviews of Data by Vertex for Administrative Purposes (Planning, 
Decision-making, and Regulatory Submission) 
A limited Vertex team will be unblinded and have access to safety, efficacy, and PD data for the 
purpose of conducting ongoing reviews of safety and efficacy data for planning and enabling 
clinical development. Members of the limited unblinded Vertex team will not be part of the 
Vertex study team and will not be involved in or influence the conduct of the study. 
Unblinding: Interim Analysis Results 
Interim analyses (IAs) may be conducted for any part of the study after at least 50% of subjects 
in the part have completed the Day 15 Visit (see Section 12.3.6.1 of the protocol). Each IA will 
only include data for a single part of the study. The results of these analyses will be reviewed by 
a limited Vertex team. When an IA is performed after all subjects in a part have completed the 
Safety Follow-up Visit, results from that part will be unblinded for full review by the Vertex 
study team.  
7 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set and Safety Set.  
7.1 
All Subjects 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.  
7.2 
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 in Period 1. The FAS will 
be used to summarize subject demographics and baseline characteristics, and for all PD and 
efficacy analyses, unless specified otherwise. Subjects will be analyzed according to the 
treatment they were randomized to. 


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7.3 
Safety Set 
7.3.1 
Parts 1 and 3 
The Safety Set will include all subjects who received at least 1 dose of study drug in the 
Treatment Period. The Safety Set will be used for all safety analyses, unless otherwise specified. 
Subjects will be analyzed according to the treatment they received.  
If a subject received at least 1 dose of a higher TC treatment group, the subject will be analyzed 
in the higher dose TC treatment group (in increasing priority order of triple placebo, TC-low, 
TC-mid, and TC-high or TC2-high).  
7.3.2 
Part 2  
The Safety Set for the Run-in Period will include all subjects who received at least 1 dose of 
TEZ/IVA in the Run-in Period. This Safety Set will be used for individual subject data listings 
for the Run-in Period, unless specified otherwise.  
The Safety Set for the Treatment Period will include all subjects who received at least 1 dose 
of study drug in Period 1 of the Treatment Period. This Safety Set will be used for all safety 
analyses for the Treatment Period, unless specified otherwise. 
If a subject received at least 1 dose of a higher TC treatment group, the subject will be analyzed 
in the higher dose TC treatment group (in increasing priority order of TEZ/IVA and TC-high).  
Note: The safety analysis will focus on the Safety Set for the Treatment Period only, unless 
otherwise specified.  
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The analysis will be performed for each part, and presented by treatment group and overall, for 
the Treatment Period, unless specified otherwise. The treatment groups are defined as follows:  
• Part 1: F508del/MF genotype group 
o Placebo, TC-low, TC-mid, and TC-high.  
• Part 2: F508del/F508del genotype group 
o TEZ/IVA and TC-high.  
• Part 3: F508del/MF genotype group 
o Placebo and TC2-high.  
The Schedule of Assessments is provided in Appendix A. 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.  
All individual subject data for those randomized or dosed with any amount of study drug will be 
presented in data listings. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, standard error (SE), median, minimum value (min), and 
maximum value (max). SE may not be reported for safety summary tables.  


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Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug on Day 1 
of the Treatment Period. For ECG, baseline will be defined as the most recent non-missing 
measurement (or the average of triplicate measurements, if the most recent non-missing 
measurement is obtained in triplicate), before the first dose of study drug on Day 1 of the 
Treatment Period. 
Absolute change from baseline will be calculated as postbaseline value – baseline value. 
Relative change from baseline will be calculated as (postbaseline value – baseline 
value)/baseline value. 
Treatment-emergent (TE) period for Parts 1 and 3 will be  from the first dose date of study 
drug in the Treatment Period until 28 days after the last dose date of study drug or end of study 
date (based on end of study visit in CRFs), whichever occurs first. 
For Part 2, the TE period will be defined separately for the Run-In Period, and the Treatment 
Period: 
The TE period for the Run-in Period will be from the first dose date of study drug in the Run-in 
Period to: (1) the first dose date of study drug in the Treatment Period for subjects who complete 
the Run-in Period and continue to the Treatment Period, or (2) 28 days after the last dose date of 
study drug in the Run-in Period or end of study date (based on end of study visit in CRFs), 
whichever occurs first, for subjects who do not continue to the Treatment Period (e.g., subjects 
who do not meet the criteria to enter the Treatment Period and re-enter Study 661-110). The TE 
period for the Treatment Period will be from first dose date of study drug in the Treatment 
Period to 28 days after the last dose date of study drug or end of study date (based on end of 
study visit in CRFs), whichever occurs first.  
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline and last on-treatment measurements 
• In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
• In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix B.  
Spirometry (ppFEV1) will be used for both efficacy and safety purposes. For efficacy analysis, the 
assessments will follow the visit windowing rules for efficacy. For safety analysis, the assessments at 
pre-dose and 5 hours postdose on nominal days 1 and 15 will be used.   
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 


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Multiplicity: There will be no multiplicity adjustment for performing multiple hypothesis tests, 
unless specified otherwise. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
For the Treatment Period in all Parts, subject disposition will be summarized as described below. 
The number of subjects in the following categories will be summarized by treatment group and 
overall, for Parts 1 and 3:  
• All Subjects Set (randomized or dosed ) 
• Randomized  
• Safety Set 
• Randomized but not dosed in Period 1 of the Treatment Period 
• Full Analysis Set (FAS) 
The number of subjects in the following categories will be summarized by treatment group and 
overall for Part 2:  
• Randomized or dosed in the Period 1 of the Treatment Period 
• Randomized 
• Safety Set for the Treatment Period 
• Randomized but not dosed in Period 1 of the Treatment Period 
• Full Analysis Set (FAS) 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
• Completed study drug treatment (separately by Periods 1 and 2 for both Part 1 and Part 2) 
• Prematurely discontinued treatment and the reason for discontinuation (i.e., discontinued 
all study drugs) (separately by Periods 1 and 2 for both Part 1 and Part 2) 
• Completed study (i.e., completed Safety Follow-up Visit or completed all study drugs 
and re-entered Study 661-110 without Safety Follow-up per protocol) 
• Prematurely discontinued the study and the reason for discontinuation  
For the Run-in Period in Part 2, a separate disposition table will be provided with the following 
categories:  
• Safety Set for the Run-in Period 
• Enrolled but not dosed in the Run-in Period  
• Completed treatment in the Run-in Period (i.e., completed randomization) 
• Prematurely discontinued  treatment during the Run-in Period and the reason for treatment 
discontinuation (i.e., discontinued all study drugs in the Run-in Period) 


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• Prematurely discontinued the study during the Run-in Period and the reason for study 
discontinuation 
A listing will be provided by part, for subjects who discontinued treatment (including the Run-in 
Period in Part 2) or who discontinued study with reasons for discontinuation. A randomization 
listing of subjects will also be provided, by part. 
8.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized based on the 
FAS, and presented by treatment group and overall, for each part, as applicable. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
Stratification categories will include the following: 
• ppFEV1 at stratification (< 70 and ≥ 70) 
For Parts 1 and 3, ppFEV1 stratification (<70 versus ≥70) will be performed at 
Stratification Visit for subjects being treated with 1 or more CFTR modulators 
(investigational or approved) within 14 days of the Screening Visit. For subjects not 
being treated with any CFTR modulators within 14 days of the Screening Visit, the 
Screening Visit spirometry assessment can be used for stratification.  
For subjects in Part 2, the ppFEV1 assessment for stratification of randomization will be 
done at the Day -14 Visit. 
Disease characteristics will include the following: 
• ppFEV1 at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, >90) 
• ppFEV1 at baseline (continuous)  
• Sweat Chloride at baseline (continuous) 
• FEV1 (L) at baseline (continuous) 
• CFQ-R Respiratory Symptoms domain at baseline (continuous) 
• Prior use of dornase alfa before first dose of study drug  in the Treatment Period (Yes, 
No) 


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• Prior use of inhaled antibiotic before first dose of study drug in the Treatment 
Period(Yes, No) 
• Prior use of any bronchodilator before first dose of study drug in the Treatment Period 
(Yes, No)  
• Prior use of any inhaled bronchodilator before first dose of study drug in the Treatment 
Period (Yes, No)  
• Prior use of any inhaled hypertonic saline before first dose of study drug in the Treatment 
Period (Yes, No) 
• Prior use of any inhaled corticosteroids before first dose of study drug in the Treatment 
Period (Yes, No) 
• Infection with Pseudomonas aeruginosa at baseline (Positive, Negative) 
A summary of medical history will be provided by MedDRA System Organ Class (SOC) and 
Preferred Term (PT) for the FAS. In addition, the number of subjects reported to have had 
positive cultures for respiratory pathogens in 2 years prior to screening will be summarized for 
the FAS. Further, the CFTR genotype for each subject will be provided in an individual subject 
data listing.  
8.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHODDE) and categorized as follows: 
For Parts 1 and 3:  
Prior medication: any medication that started before the first dose date of study drug, regardless 
of when the medication 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. 
For Part 2:  
Prior medication: any medication that started before the first dose date of study drug in the 
Run-in Period, regardless of when the medication ended. 
Concomitant medication during the Run-in Period: medication continued or newly received 
on or after the first dose date of study drug during the Run-in Period through the end of the TE 
period for the Run-in Period. 
Concomitant medication during the Treatment Period: medication continued or newly 
received on or after the first dose date of study drug during the Treatment Period through the end 
of the TE period for the Treatment 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 


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post-treatment. In Part 2, concomitant may be concomitant during the Run-in Period, or 
concomitant during the Treatment Period, or both.  
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, or after 
the TE period, it will be classified as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by preferred name.  
Summaries of medications will be based on the FAS, and presented by treatment group and 
overall for each part.  
Post-treatment medications will be listed by subject.  
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 
8.2.4 
Study Drug Exposure  
Study drug exposure (in days) will be calculated as: last dose date of study drug – first dose 
date of study drug + 1 day, regardless of study drug interruption, and will be summarized 
descriptively. Study drug exposure will be summarized for the overall study drug period, which 
includes the Treatment Period for Parts 1 and 3, and the Run-in Period and the Treatment Period 
for Part 2. Further, study drug exposure for the Treatment Period in Part 2 will also be 
summarized descriptively.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, SE, median, min, and max. It will also be summarized in categories for Treatment 
Period: ≤2 weeks, >2- ≤4 weeks, and > 4 weeks (for Parts 1 and 3); and ≤2 weeks, >2- ≤4 weeks, 
>4 - ≤8 weeks, >8 weeks (for Part 2), using counts and percentages. Additionally, the total study 
drug exposure, defined as the sum total of the study drug exposure across all subjects (in patient-
weeks), will be provided. 
Exposure summaries will be based on the Safety Set, and presented by treatment group and 
overall, for each part. For Part 2, exposure summaries will be based on the Safety Set for the 
Treatment Period.  
8.2.5 
Study Drug Compliance 
Percentage of tablets taken 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). The maximum percentage of tablets taken will 
be 100%.  
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 will be determined by an interruption of all drugs on that day. 
Percentage of tablets taken and study drug compliance will be summarized descriptively by the 
number of subjects (n), mean, SD, SE, median, min, and max. It will also be summarized in 
categories: <80% and ≥80% using frequency tables.  


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For all parts, study drug compliance and percentage of tablets taken will be summarized for 
Period 1 in the Treatment Period only.  
Percentage of tablets taken and study drug compliance summaries will be based on the FAS, and 
presented by treatment group and overall, for each part. 
8.2.6 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. IPD rules will be developed and finalized before database lock. 
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to: 
• Subject was enrolled in the study despite the violation of inclusion/exclusion criteria 
• Subject was less than 80% compliant with study drug  
• 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 will be provided in an individual subject data listing for each part. Details of the IPD rules 
are provided in Appendix D. 
8.3 
Efficacy Analysis  
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified.  
The analysis will include all available measurements through the last scheduled Treatment 
Period visit including measurements after treatment discontinuation, per the visit windowing 
rules described in Appendix B.  
Except the sensitivity analyses, the post-dose measurements on the same day (e.g. days when 
spirometry is repeated pre- and post-dose) will not be used for any model-based analyses, but 
only reported in descriptive safety analyses. 
8.3.1 
Primary Efficacy Variable 
The primary efficacy variable is the absolute change from baseline in ppFEV1 (in percentage 
units) through Day 29 in each part.  
ppFEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage. The 
predicted FEV1 will be calculated using the Quanjer GLI-2012 Regression Equations and 
Lookup Tables1, adjusting for age, height, sex and ethnicity. Details are provided in Appendix E. 


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8.3.1.1 
Primary Analysis of the Primary Efficacy Variable 
8.3.1.1.1 
All Parts: Period 1 in the Treatment Period 
The null hypothesis to be tested is that the mean absolute within-group change from baseline in 
ppFEV1 through Day 29 is zero for VX-659 in TC with TEZ and either IVA or VX-561, for each 
part, separately. A 2-sided p-value of 0.05 or less will be interpreted as sufficient evidence to 
reject the null hypothesis.  
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with change from baseline in ppFEV1 as the dependent variable for each part, 
separately. For Part 1, the analysis will include 4 treatment groups: placebo, TC-low, TC-mid, 
and TC-high. For Part 2, the analysis will include 2 treatment groups: placebo + TEZ/IVA, and 
TC-high (VX-659 + TEZ/IVA). For Part 3, the analysis will include 2 treatment groups: placebo 
and TC2-high (VX-659+TEZ+VX-561). The model will include treatment group, visit, and 
treatment-by-visit interaction as fixed effects and subject as a random effect, with the continuous 
baseline ppFEV1 as a covariate, and will include all data from each treatment group and visit 
during Period 1 in the analysis. The model will be estimated using restricted maximum 
likelihood. Denominator degrees of freedom for the F test for fixed effects will be estimated 
using the Kenward-Roger approximation. An unstructured covariance structure will be used to 
model the within-subject errors. If the model estimation does not converge, a reduced compound 
symmetry covariance structure will be used instead. Conditional on the observed data and 
covariates, missing ppFEV1 data due to treatment or study discontinuation will be assumed to be 
missing at random; consequently, no imputation of missing data will be performed.  
The adjusted means and 95% confidence intervals (CI) of the average treatment effect through 
Day 29 for each TC, with a 2-sided p-value will be estimated within MMRM using PROC 
MIXED in SAS, for all within-treatment and between-treatment comparisons, for each part, 
separately. Contrasts based on the fixed effects in the model, defined at the baseline covariate 
mean for the combined treatment groups using unique subjects in the FAS who have at least one 
post-baseline measurement through Day 29, will be used to estimate the average treatment effect 
across post-baseline visits through Day 29.  
Further, the adjusted mean and 95% CI of the treatment difference between each TC group and 
placebo or TEZ/IVA at each post-baseline visit through Day 29 will be provided along with the 
corresponding p-value, for each part. In addition, the adjusted mean and 95% CI of the within-
treatment difference at each post-baseline visit through Day 29 for each treatment group will be 
provided along with the p-value, for each part.  
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline visit 
through Day 29 will be plotted by treatment group, for each part. In addition, a waterfall plot 
showing the subject-level absolute change in ppFEV1 at Day 29 will be presented, by treatment 
group.  
The primary analysis will use pre-dose measurements only. The post-dose measurements on the 
same day will be used for sensitivity analysis as described in the next section. 
In addition, for each part, descriptive analyses of the change from baseline will be performed for 
all treatment groups by post-baseline visit through the safety follow-up visit. 


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8.3.2 
Analysis of Secondary Efficacy Variables 
The secondary efficacy variables include: 
• Relative change in ppFEV1 from baseline through the Day 29 Visit 


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• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline at the Day 29 Visit 
8.3.2.1 
Relative change in ppFEV1 from baseline through Day 29 (All Parts)  
The relative change in ppFEV1 from baseline through the Day 29 Visit is defined in Section 8.1. 
Analysis of this variable will be based on an MMRM model, similar to the primary analysis of 
the primary efficacy variable in each part. The tabular presentation of results will also be similar. 
8.3.2.2 
Absolute change in the CFQ-R respiratory domain score from 
baseline at Day 29 (All Parts)  
The absolute change in the CFQ-R respiratory domain score from baseline at the Day 29 Visit 
will use the 'Adolescents and Adults' Version for ages 14 and above at baseline, and will be 
based on the CFQ-R scaled scores, as described in Appendix F. Analysis of this variable will be 
based on an MMRM model, similar to the analysis of the primary efficacy variable in Parts 1, 2 
and 3. Sex, the continuous baseline ppFEV1, and the continuous baseline CFQ-R respiratory 
domain score will be used as covariates in each part.  
In Part 2, a supportive analysis will be based on fitting a fully saturated model to the CFQ-R 
respiratory domain score in the Day 43 and Day 57 Visits during Period 2, using randomized 
group, visit, and the group-by-visit interaction effect as a fixed effect, and sex, continuous 
baseline ppFEV1 and continuous baseline CFQ-R respiratory domain score as covariates in the 
MMRM model. The other aspects of the MMRM model will be similar to that of the primary 
analysis. 
The tabular presentation of results for the average treatment effect across visits will be similar to 
the primary analysis of the primary efficacy variable. The adjusted mean (with 95% CI) obtained 
from the model-based analysis at each post-baseline visit in Period 2 will be plotted by group, 
and combined with the corresponding plot for Period 1.  
In addition, for all parts a waterfall plot showing the subject-level absolute change in CFQ-R at 
Day 29 will be presented, by treatment group. 
8.3.2.3 
Multiplicity adjustment 
There will be no multiplicity adjustment to control the overall type 1 error rate for secondary 
efficacy variables. 
8.3.3 
Analysis of Other Efficacy Variables (All Parts) 
Other efficacy variables include: 
• Absolute change in CFQ-R non-respiratory domain scores from baseline at the Day 29 
Visit 
Only descriptive analyses will be performed.  
8.3.3.1 
Absolute change in CFQ-R non-respiratory domain scores from 
baseline at Day 29 (All Parts)  
The Adolescent/Adult version includes the following non-respiratory domains: Body Image, 
Digestive Symptoms, Eating Problems, Emotional Functioning, Health Perceptions, Physical 
Functioning, Role Functioning, Social Functioning, Treatment Burden, Vitality, and Weight.  


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The absolute change in CFQ-R non-respiratory domain scores from baseline at Day 29 will use 
the 'Adolescents and Adults' Version for ages 14 and above at baseline, and will be based on the 
CFQ-R scaled scores, as described in Appendix F. Descriptive analyses will be performed for all 
treatment groups by post-baseline visit.  
8.3.5 
Pharmacodynamic Analysis 
The sweat chloride measurement 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. 
The analysis of the PD effect of VX-659 in combination with TEZ and either IVA or VX-561 in 
Parts 1, 2, and 3 on sweat chloride concentrations will be described in this section.  


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Descriptive analyses of the change from baseline will also be performed for all treatment groups 
by post-baseline visit. 
8.3.5.1 
Primary Analysis of the Dose Response trend of absolute change in 
sweat chloride from baseline through the Day 29 Visit (Part 1) 
The null hypothesis to be tested is that the dose response of the mean absolute change from 
baseline through the Day 29 Visit for sweat chloride is not decreasing between placebo and the 3 
dose levels of VX-659 with TEZ/IVA in Part 1. The test will be performed using the MCP 
procedure with the pre-specified contrasts provided in Section 6.2.2, within a linear MMRM 
framework using PROC GLIMMIX in SAS. The model will include treatment group, visit, and 
treatment-by-visit interaction as fixed effects and subject as a random effect, with continuous 
baseline ppFEV1 and continuous baseline sweat chloride as covariates, and will include all data 
from all treatment groups and visits through the Day 29 Visit for analysis. The dose response test 
will be based on the 1-sided maximum t-statistic of the individual t-statistics for the multiple pre-
specified contrasts at alpha = 5%, based on the treatment group means through the Day 29 Visit, 
using an unstructured covariance structure for the within-subject errors. If the model estimation 
does not converge, a reduced compound symmetry covariance structure will be used instead. 
The tabular presentation of results for the average treatment effect across visits will be similar to 
the primary analysis of the primary efficacy variable for all parts. The corresponding p-value for 
the decreasing dose response trend will be provided. 
In addition, descriptive analyses of the change from baseline will be performed for all treatment 
groups by post-baseline visit.  
8.3.5.2 
Absolute Change in Sweat Chloride from Baseline through the Day 
29 Visit (All Parts) 
The analysis of the absolute change in sweat chloride from baseline through the Day 29 Visit 
will be based on an MMRM model similar to the analysis of the primary efficacy variable, with 
the continuous baseline ppFEV1 and continuous baseline sweat chloride as covariates. The 
presentation of results will also be similar. 
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline visit 
through the Day 29 Visit in the Period 1 will be plotted by treatment group, for each part.  
A waterfall plot showing the subject-level absolute change in sweat chloride at Day 29 will be 
presented, by treatment group for each part.  
In addition, for each part, descriptive analyses of the change from baseline will be performed for 
all treatment groups by post-baseline visit.  


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8.4 
Safety Analysis 
For Parts 1 and 3, all safety analyses will be based on data from the TE Period for all subjects in 
the Safety Set. For Part 2, all safety analyses will be based on the TE Period for the Treatment 
Period for all subjects in the corresponding Safety Set for the Treatment Period. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
• ECGs 
• Vital signs 
• Pulse oximetry 
• Spirometry 
All safety data will be summarized by treatment group and overall, for each part. 
 


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8.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
For Parts 1 and 3:  
Pretreatment AE: any AE that started 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 beyond the TE period 
For Part 2:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE during the Run-in Period: any AE that worsened (either in severity or seriousness) or 
that was newly developed at or after the first dose date of study drug through the end of the TE 
period for the Run-in Period 
TEAE during the Treatment Period: any AE that worsened (either in severity or seriousness) 
or that was newly developed at or after the first dose date of study drug through the end of the 
TE period for the Treatment Period  
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed beyond 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 G. 
AE summary tables will be presented for TEAEs only, for the TE period for Parts 1 and 3, or the 
TE period for the Treatment Period in Part 2, by treatment group and overall, for each part 
respectively, as applicable, for the following:  
• 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 all study 
drug) 
• Subjects with TEAEs Leading to Study Drug Interruption (Interruption of all study drug) 
• Subjects with Serious TEAEs 
• Subjects with TEAE 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 


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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.  
All AEs, including pre-treatment AEs, TEAEs for all applicable periods, and post-treatment AEs, 
will be presented in an individual subject data listing based on the All Subjects Set. Further, 
subjects who enrolled from Study 661-110 will be identified from the subject ID in the listing. 
8.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, chemistry, and coagulation results will be 
summarized in SI units at each scheduled visit, by treatment group and part.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event, 
during the TE period for Parts 1 and 3, or the TE period for Treatment Period for Part 2, will be 
summarized by treatment group and overall for each part. The threshold analysis criterion shift 
from baseline will also be summarized for selected laboratory parameters.  The threshold 
analysis criteria are provided in Appendix H.  
For select LFT laboratory test (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-
emergent value versus the baseline value corresponding to ×ULN (upper limit of normal) will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, 
separately, versus the maximum treatment-emergent value of total bilirubin corresponding to 
×ULN will also be presented by treatment group, for each part.  
Results of abnormal urinalysis and positive urine/serum pregnancy test will be listed in 
individual subject data listings only.  
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
outside the normal reference ranges will be provided. This listing will include data from both 
scheduled and unscheduled visits.  
8.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each scheduled visit and time point, by treatment group, for 
each part, for the following ECG interval measurements (in ms): RR, PR, QT, and QT corrected 
for HR (QTcF), QRS duration, and HR (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period for Parts 1 and 3, or the TE period for the Treatment Period in Part 2, will be 
summarized by treatment group and overall, for each part. The threshold analysis criteria are 
provided in Appendix H. 
8.4.4 
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 scheduled visit, for each part, as 
applicable. The following vital signs parameters will be summarized: systolic and diastolic blood 


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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 for Parts 1 and 3, or the TE period for the Treatment Period in Part 2, will be 
summarized by treatment group and overall, for each part. The threshold analysis criteria are 
provided in Appendix H. 
8.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each scheduled visit, for the percent of oxygen 
saturation, by treatment group, for each part. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period for Parts 1 and 3, or the TE period for the Treatment Period in Part 2, will be summarized 
by treatment group and overall, for each part. 
8.4.6 
Physical Examination  
PE findings will be presented as an individual subject data listing only. 
8.4.7 
Other Safety Analysis 
8.4.7.1 
Post-dose Spirometry 
A summary of the pre-dose values for ppFEV1 and change from pre-dose value for the post-dose 
ppFEV1 value at 5 hours post-dose will be presented on nominal visits Day 1 and Day 15, by 
treatment group, for each part. Further, a box plot of differences (post-dose - pre-dose) will be 
presented by visit and treatment group, for each part.  
9 
INTERIM AND IDMC ANALYSES 
9.1 
Interim Analysis 
A separate IA may be performed after all subjects in Part 1, Part 2, and Part 3 have completed 
the Safety Follow-up Visit. All data from the part will be unblinded after the data from that part 
are cleaned for analysis and a data cut is performed. The Vertex Study Team will be unblinded to 
the interim analysis results. 
In addition, IAs may be performed for each part after 50% of subjects in the part have completed 
the Day 15 Visit. These results will be reviewed by a limited Vertex team. 
9.1.1 Summary of the Flow of Data for Interim Analyses 
To protect the integrity of the treatment assignment and study data, the following steps for the 
flow of data will be executed for each interim analysis performed after at least 50% of the 
subjects have completed the Day 15 visit in each part: 
1. The blinded Vertex Biometrics group will prepare the SAS codes, SDTM/ADaM data 
sets, and blinded outputs (tables, figures and listings) of safety, efficacy and PD data 
using dummy treatment codes, dummy spirometry data, and dummy sweat chloride data; 


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2. The IWRS vendor, Bracket, will provide the unblinded treatment codes to the unblinded 
Vertex Biometrics team, via Kiteworks; 
3. Biomedical Systems (BMS) will provide the unblinded spirometry data to unblinded 
Vertex Biometrics team, via Kiteworks; ICON Central Labs will provide the unblinded 
sweat chloride data to  unblinded Vertex Biometrics team, via Kiteworks;  
4. An unblinded Vertex Biometrics group will generate the unblinded outputs and provide 
them directly to the limited Vertex team for their review. 
 
9.2 
IDMC Analysis  
The IDMC’s objectives and operational details were defined in a separate document (IDMC 
Charter) which was finalized before the first subject was screened in the study. The IDMC’s 
planned safety reviews of study data are outlined in the IDMC Charter and IDMC Statistical 
Analysis Plan. Further, planned ongoing reviews of key study data by the limited Vertex team 
are also described in the IDMC Statistical Analysis Plan. 
 


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10 
REFERENCES 
1Quanjer 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. 
 
 


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11 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 


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Table 11-1 
Study VX16-659-101 Part 1 (Subjects with F/MF genotypes): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
Treatment Period (5 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Period 1c (4 weeks) 
Period 2 
Screening Visit 
Days -28 to -1 
Stratification 
Visitd 
Day -27 to -1 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 33 Visite  
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationf 
 
 
X 
 
 
 
 
 
Study drug dosingg 
 
 
Day 1 through Day 33 Visit 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
CFTR genotypeh 
X 
 
 
 
 
 
 
 
Heighti 
X 
 
 
 
 
 
 
 
Weighti 
X 
 
X 
X 
X 
 
X 
X 
                                                 
a 
All assessments will be performed predose, unless noted otherwise. Assessments that are collected predose and postdose will only be collected once if study 
drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b 
If the 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 study drug treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If 
the ETT Visit occurs 3 or more weeks after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit (a separate Safety Follow-up 
Visit is not required). 
c 
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 9.1.4. 
d 
The spirometry assessment used for stratification must be performed at least 14 days after the last dose of any previous CFTR modulator treatment. 
Therefore, subjects being treated with 1 or more CFTR modulators (investigational or approved) within 14 days of the Screening Visit must have a separate 
Stratification Visit at least 14 days after the subject’s last CFTR modulator dose. For subjects not being treated with any CFTR modulators within 14 days of 
the Screening Visit, the Screening Visit spirometry assessment can be used for stratification. 
e 
The Day 33 Visit may occur 3 to 6 days after the actual date of the Day 29 Visit. 
f 
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period (see 
footnote c) have been confirmed. 
g 
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-659 in Part 1 Period 1 will be the morning dose on the Day 29 Visit. The last dose of TEZ/IVA in 
Part 1 Period 2 will be the morning dose on the Day 33 Visit. Refer to Section 9.7 for details. 
h 
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 (see inclusion criterion 6).  


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Table 11-1 
Study VX16-659-101 Part 1 (Subjects with F/MF genotypes): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
Treatment Period (5 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Period 1c (4 weeks) 
Period 2 
Screening Visit 
Days -28 to -1 
Stratification 
Visitd 
Day -27 to -1 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 33 Visite  
Physical examinationj 
Complete 
 
Abbrev. 
Abbrev. 
Abbrev. 
 
Abbrev. 
Complete 
Vital signsk 
X 
 
X 
X 
X 
X 
X 
X 
Pulse oximetryk 
X 
 
X 
X 
X 
X 
X 
X 
Standard 12-lead 
ECGl 
X 
 
X 
X 
X 
 
X 
X 
Sweat chloridem,p  
X 
 
X 
X 
X 
X 
X 
X 
Spirometryn 
X 
X 
X 
X 
X 
X 
X 
X 
CFQ-Ro,p 
 
 
X 
X 
X 
 
 
 
Urinalysisp 
X 
 
X 
X 
X 
 
X 
X 
Pregnancy test 
(females of 
childbearing 
potential) 
Serum 
 
Urine 
 
Urine 
 
Serum 
Serum 
FSHq 
X 
 
 
 
 
 
 
 
                                                                                                                                                                                                                         
i 
Weight and height will be measured with shoes off.  
j 
Complete and abbreviated physical examinations (PEs) are described in Section 11.7.3. Symptom-directed PEs can be done at any time at the discretion of 
the investigator or healthcare provider. 
k 
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
l 
Standard 12-lead ECGs will be performed after the subject has been rested for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be collected before 
dosing and 5 hours (± 1 hour) after dosing. At other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the Day 1 Visit before 
dosing will be performed in triplicate.  
m 
See inclusion criterion 5 for information about the sweat chloride assessment for study eligibility. Sweat chloride assessments should be done at 
approximately the same time at every study visit during the Treatment Period and follow-up. 
n 
At the Screening Visit, spirometry may be done pre- or post-bronchodilator. At other study visits, spirometry will be done pre-bronchodilator, before the 
in-clinic dose of study drugs, and should be performed at approximately the same time at every visit. On the Day 1 and 15 Visits, spirometry will also be 
performed 5 hours (± 1 hour) after the in-clinic dose of study drugs. 
o 
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
p 
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1) if randomization has occurred. 


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Table 11-1 
Study VX16-659-101 Part 1 (Subjects with F/MF genotypes): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
Treatment Period (5 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Period 1c (4 weeks) 
Period 2 
Screening Visit 
Days -28 to -1 
Stratification 
Visitd 
Day -27 to -1 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 33 Visite  
G6PD activity testr 
X 
 
 
 
 
 
 
 
Serum chemistry and 
hematologyp 
X 
 
X 
X 
X 
X 
X 
X 
Coagulationp 
X 
 
X 
X 
X 
 
X 
X 
PK samplings 
 
 
X 
X 
X 
X 
X 
 
AEs, medicationsu, 
treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                                                                                                                                                                                         
q  
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
r  
Blood samples will be collected for the G6PD activity test. 
s  
Blood samples will be collected for PK analysis of study drugs and metabolites. On the Day 1 Visit, samples will be collected before (0 hours) and 1, 2, 4, 
and 6 hours after the in-clinic dose. On the Day 15 Visit, samples will be collected before (0 hours) and 1, 2, 4, 6, and 8 hours after the in-clinic dose. On the 
Day 29 and Day 33 Visits, a single sample will be collected before the in-clinic dose. At the ETT Visit, a single sample will be collected. 
u  
Refer to Section 9.5 for details. 


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Table 11-2 
Study VX16-659-101 Part 2 (Subjects with F/F genotype): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
 
Run-in (4 weeks) 
Treatment Period (8 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dosec 
Period 1 (4 weeks)d 
Period 2 (4 weeks) 
Screening Visit 
Days -56 to -29 
Day -28 
(± 1 day) 
Day -14 
(Days -15 to -3) 
Day 1 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomizatione 
 
 
 
X 
 
 
 
 
 
 
Study drug dosingf 
 
Day -28 to Day -1  
Day 1 to 29 
Day 29 to 57 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
CFTR genotypeg 
X 
 
 
 
 
 
 
 
 
 
Heighth 
X 
 
 
 
 
 
 
 
 
 
Weighth 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationi 
Complete 
Complete 
Abbrev. 
Abbrev. 
Abbrev. 
Abbrev. 
 
Abbrev. 
Abbrev. 
Complete 
Vital signsj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
                                                 
a 
All assessments will be performed predose, unless noted otherwise. Assessments that are collected predose and postdose will only be collected once if study 
drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b 
If the 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 study drug treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If 
the ETT Visit occurs 3 or more weeks after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit (a separate Safety Follow-up 
Visit is not required). 
c  
Part 2 subjects who meet criteria specified in Section 9.1.5 will not have a Safety Follow-up Visit. 
d 
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 9.1.4. 
e 
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period (see 
footnote d) have been confirmed. 
f 
On days of scheduled visits, the in-clinic dose of study drug will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-659 in Part 2 Period 1 will be the morning dose on the Day 29 Visit. The last dose of TEZ/IVA in 
Part 2 Period 2 will be the morning dose on the Day 57 Visit. Refer to Section 9.7 for details. 
g 
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 (see inclusion criterion 6). 
h 
Weight and height will be measured with shoes off. 
i 
Complete and abbreviated PEs are described in Section 11.7.3. Symptom-directed PEs can be done at any time at the discretion of the investigator or 
healthcare provider. 


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Table 11-2 
Study VX16-659-101 Part 2 (Subjects with F/F genotype): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
 
Run-in (4 weeks) 
Treatment Period (8 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dosec 
Period 1 (4 weeks)d 
Period 2 (4 weeks) 
Screening Visit 
Days -56 to -29 
Day -28 
(± 1 day) 
Day -14 
(Days -15 to -3) 
Day 1 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Pulse oximetryj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Standard 12-lead 
ECGk 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Sweat chloridel,o 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Spirometrym 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
CFQ-Rn,o 
 
 
 
X 
X 
X 
X 
X 
 
 
Urinalysiso 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
  
Urine 
 
Urine 
 
Urine 
Serum 
Serum 
FSHp 
X 
 
 
 
 
 
 
 
 
 
G6PD activity testq 
X 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematologyo 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
Coagulationo 
X 
X 
 
X 
X 
X 
 
 
X 
X 
                                                                                                                                                                                                                         
j 
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
k 
Standard 12-lead ECGs will be performed after the subject has been rested for at least 5 minutes. On Day 1 and 15 Visits, ECGs will be collected before 
dosing and 5 hours (± 1 hour) after dosing. At other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the Day 1 Visit before 
dosing will be performed in triplicate. 
l 
See inclusion criterion 5 for information about the sweat chloride assessment for study eligibility. Sweat chloride assessments should be done at 
approximately the same time at every study visit during the Treatment Period and follow-up. 
m 
The ppFEV1 assessment for stratification of randomization will be done at the Day -14 Visit. See Section 9.3.1. At the Screening Visit, spirometry may be 
done pre- or post-bronchodilator. At other study visits, spirometry will be done pre-bronchodilator, before the in-clinic dose of study drugs, and should be 
performed at approximately the same time at every visit. On the Day 1 and 15 Visits, spirometry will also be performed 5 hours (± 1 hour) after the in-clinic 
dose of study drugs.  
n 
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
o 
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1) if randomization has occurred. 
p 
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
q 
Blood samples will be collected for the G6PD activity test. 


Statistical Analysis Plan (Methods) 
Protocol VX16-659-101, Version 3.0 
Page 37 of 57 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 11-2 
Study VX16-659-101 Part 2 (Subjects with F/F genotype): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
 
Run-in (4 weeks) 
Treatment Period (8 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dosec 
Period 1 (4 weeks)d 
Period 2 (4 weeks) 
Screening Visit 
Days -56 to -29 
Day -28 
(± 1 day) 
Day -14 
(Days -15 to -3) 
Day 1 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
PK samplingr 
 
 
 
X 
X 
X 
X 
 
X 
 
AEs, medications , 
treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                 
r 
Blood samples will be collected for PK analysis of study drugs and metabolites. On the Day 1 Visit, samples will be collected before (0 hours) and 1, 2, 4, 
and 6 hours after the in-clinic dose. On the Day 15 Visit, samples will be collected before (0 hours) and 1, 2, 4, 6, and 8 hours after the in-clinic dose. On the 
Day 29 and 43 Visits, a single sample will be collected before the in-clinic dose. At the ETT Visit, a single sample will be collected. 
Refer to Section 9.5 for details. 
 


 
 
Table 11-3 
Study VX16-659-101 Part 3 (Subjects with F/MF genotypes): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
Treatment Period (4 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Period 1c (4 weeks) 
Screening Visit 
Days -28 to -1 
Stratification 
Visitd 
Days -27 to-3 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Informed consent 
X 
 
 
 
 
 
 
Randomizatione 
 
 
X 
 
 
 
 
Study drug dosingf 
 
 
Day 1 through Day 29 Visit 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
CFTR genotypeg 
X 
 
 
 
 
 
 
Heighth 
X 
 
 
 
 
 
 
Weighth 
X 
 
X 
X 
X 
X 
X 
                                                 
a 
All assessments will be performed predose, unless noted otherwise. Assessments that are collected predose and postdose will only be collected once if study 
drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b 
If the 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 study drug treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If 
the ETT Visit occurs 3 or more weeks after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit (a separate Safety Follow-up 
Visit is not required). 
c 
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 9.1.4. 
d 
The spirometry assessment used for stratification must be performed at least 14 days after the last dose of any previous CFTR modulator treatment. 
Therefore, subjects being treated with 1 or more CFTR modulators (investigational or approved) within 14 days of the Screening Visit must have a separate 
Stratification Visit at least 14 days after the subject’s last CFTR modulator dose. For subjects not being treated with any CFTR modulators within 14 days of 
the Screening Visit, the Screening Visit spirometry assessment can be used for stratification. 
e 
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period (see 
footnote c) have been confirmed. 
f 
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-659 and TEZ/VX-561 in Part 3 Period 1 will be the morning dose on the Day 29 Visit. Refer to 
Section 9.7 for details. 
g 
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 (see inclusion criterion 6).  
h 
Weight and height will be measured with shoes off.  


 
 
Table 11-3 
Study VX16-659-101 Part 3 (Subjects with F/MF genotypes): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
Treatment Period (4 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Period 1c (4 weeks) 
Screening Visit 
Days -28 to -1 
Stratification 
Visitd 
Days -27 to-3 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Physical examinationi 
Complete 
 
Abbrev. 
Abbrev. 
Abbrev. 
Abbrev. 
Complete 
Vital signsj 
X 
 
X 
X 
X 
X 
X 
Pulse oximetryj 
X 
 
X 
X 
X 
X 
X 
Standard 12-lead 
ECGk 
X 
 
X 
X 
X 
X 
X 
Sweat chloridel,o 
X 
 
X 
X 
X 
X 
X 
Spirometrym 
X 
X 
X 
X 
X 
X 
X 
CFQ-Rn,o 
 
 
X 
X 
X 
 
 
Urinalysiso 
X 
 
X 
X 
X 
X 
X 
Pregnancy test 
(females of 
childbearing 
potential) 
Serum 
 
Urine 
 
Urine 
Serum 
Serum 
FSHp 
X 
 
 
 
 
 
 
                                                 
i 
Complete and abbreviated physical examinations (PEs) are described in Section 11.7.3. Symptom-directed PEs can be done at any time at the discretion of 
the investigator or healthcare provider. 
j 
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
k 
Standard 12-lead ECGs will be performed after the subject has been rested for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be collected before 
dosing and 5 hours (± 1 hour) after dosing. At other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the Day 1 Visit before 
dosing will be performed in triplicate.  
l 
See inclusion criterion 5 for information about the sweat chloride assessment for study eligibility. Sweat chloride assessments should be done at 
approximately the same time at every study visit during the Treatment Period and follow-up. 
m 
At the Screening Visit, spirometry may be done pre- or post-bronchodilator. At other study visits, spirometry will be done pre-bronchodilator, before the 
in-clinic dose of study drugs, and should be performed at approximately the same time at every visit. On the Day 1 and 15 Visits, spirometry will also be 
performed 5 hours (± 1 hour) after the in-clinic dose of study drugs. 
n 
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
o 
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1) if randomization has occurred. 
p  
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 


 
 
Table 11-3 
Study VX16-659-101 Part 3 (Subjects with F/MF genotypes): Schedule of Assessments 
Event/Assessmenta 
Screening Period 
Treatment Period (4 weeks) 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Period 1c (4 weeks) 
Screening Visit 
Days -28 to -1 
Stratification 
Visitd 
Days -27 to-3 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
G6PD activity testq 
X 
 
 
 
 
 
 
Serum chemistry and 
hematologyo 
X 
 
X 
X 
X 
X 
X 
Coagulationo 
X 
 
X 
X 
X 
X 
X 
PK samplingr 
 
 
X 
X 
X 
X 
 
AEs, medicationst, 
treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                 
q  
Blood samples will be collected for the G6PD activity test. 
r  
Blood samples will be collected for PK analysis of study drugs and metabolites. On the Day 1 Visit, samples will be collected before (0 hours) and 1, 2, 4, 
and 6 hours after the in-clinic dose. On the Day 15 Visit, samples will be collected before (0 hours) and 1, 2, 4, 6, and 8 hours after the in-clinic dose. On the 
Day 29 Visit, a single sample will be collected before the in-clinic dose. At the ETT Visit, a single sample will be collected. 
  
Refer to Section 9.5 for details. 


Statistical Analysis Plan (Methods) 
Page 41 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Safety Assessment (Part 1) 
Serum Chemistry 
Hematology 
Vital Signs (excluding 
Weight) 
 
Day 1 (Baseline)  
Day 15 
Day 29 
 
Day 33 
 
Safety Follow-up 
1 
15 
29 
 
33 
 
61 
≤1 Pre-dose 
[1, 22] 
Use nominal visit, otherwise 
use (22, 31] 
Use nominal visit, otherwise 
use (31, 47] 
Use nominal visit 
Coagulation 
Vital Signs (Weight only) 
 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
61 
≤1 Pre-dose 
[1, 22] 
(22,45] 
Use nominal visit 
Standard 12-lead ECG 
Day 1 (Baseline; before dosing) 
Day 1 (5 hours after dosing)  
Day 15 (before dosing and 5 hours 
after dosing) 
Day 29 
Safety Follow-up 
1 
1 
15 
 
29 
61 
Use nominal visit for all 
visits 
Spirometry 
Day 1  (5 hours post dose) 
Day 15 (5 hours post dose) 
1 
15 
Use nominal visit 
Use nominal visit 
Safety Assessment (Part 2) 
Serum Chemistry 
Hematology 
Vital Signs (including 
Weight) 
 
Day 1 (Baseline)  
Day 15 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
15 
29 
43 
57 
85 
≤1 Pre-dose 
[1,22] 
(22, 36] 
(36, 50] 
(50, 71] 
Use nominal visit 
Coagulation 
 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
85 
≤1 Pre-dose 
[1,22] 
(22, 57] 
Use nominal visit 
Standard 12-lead ECG  
Day 1 (Baseline; before dosing) 
Day 1 (5 hours after dosing)  
Day 15 (before dosing and 5 hours 
after dosing) 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
1 
15 
 
29 
43 
57 
85 
Use nominal visit for all 
visits 
                                                 
 
 
 


Statistical Analysis Plan (Methods) 
Page 42 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Spirometry 
Day 1  (5 hours post dose) 
Day 15 ( 5 hours post dose) 
1 
15 
Use nominal visit 
Use nominal visit 
Safety Assessment (Part 3) 
Serum Chemistry 
Hematology 
Coagulation 
Vital Signs (including 
Weight)  
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
57 
≤1 Pre-dose 
[1,22] 
(22, 43] 
Use nominal visit 
Standard 12-lead ECG  
Day 1 (Baseline; before dosing) 
Day 1 (5 hours after dosing)  
Day 15 (before dosing and 5 hours 
after dosing) 
Day 29 
Safety Follow-up 
1 
1 
15 
 
29 
57 
Use nominal visit for all 
visits 
Spirometry 
Day 1  (5 hours post dose) 
Day 15 ( 5 hours post dose) 
1 
15 
Use nominal visit 
Use nominal visit 
Efficacy Assessment (Part 1) 
Spirometry  
Sweat Chloride 
 
Day 1 (Baseline; before dosing)  
Day 15 (predose)# 
Day 29 
 
Day 33 
 
Safety Follow-up 
1 
15 
29 
 
33 
 
61 
≤1 Pre-dose 
[1, 22] 
Use nominal visit, otherwise 
use (22, 31] 
Use nominal visit, otherwise 
use (31, 47] 
Use nominal visit 
CFQ-R 
Day 1  
Day 15  
Day 29 
1 
15 
29 
≤1 
[1, 22] 
(22, 45] 
Efficacy Assessment (Part 2) 
Spirometry  
Sweat Chloride 
CFQ-R 
Day 1 (Baseline; before dosing)  
Day 15 (predose)# 
Day 29 
Day 43 
Day 57 
Safety Follow-up (Spirometry 
only) 
1 
15 
29 
43 
57 
85 
≤1 Pre-dose 
[1,22] 
(22, 36] 
(36, 50] 
(50, 71] 
Use nominal visit 
Efficacy Assessment (Part 3) 
Spirometry  
Sweat Chloride 
CFQ-R 
Day 1 (Baseline; before dosing)  
Day 15 (predose)# 
Day 29 
Safety Follow-up (no CFQ-R) 
1 
15 
29 
57 
≤1 Pre-dose 
[1,22] 
(22, 43] 
Use nominal visit 
Notes: 
a   Visit name is used to report data in tables, listings and figures. 
 
b   Target day time point per protocol is predose, except for ECG and SP measurements. 
#  Postdose of spirometry may be used for imputation 
 
The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered 


Statistical Analysis Plan (Methods) 
Page 43 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
missing for the visit. 
2. If there is more than 1 numerical measurement available within the same visit window, use the following 
rules:  
a. 
For efficacy parameters: if there are multiple measurements within a visit window, the measurement at 
the scheduled visit will be used. Otherwise, 
i. If there are no measurements at the scheduled visit, then the measurement closest to the target day 
will be used; or 
ii. If there are multiple measurements with the same distance to the target day, the latest 
measurement will be used.   
b. For safety parameters: if there are multiple measurements within a visit window,   
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements within the same distance from the target day, the latest 
measurement will be used. 
iii. For tables of extreme lab measurements based on ULN or LLN, convert the lab measurements into 
×ULN or ×LLN first, and then select the extreme measurement. 
 
Derived Variables: 
1. Age (in years) at first dose date  
Obtain age at screening (in days) in yy mm format (e.g., 24 years, 6 months) from screening vital signs page, and 
add 0.5 month to convert to days. 
Obtain screening date from Date of Visit (DOV) page. 
Then age (in years) at first dose date = integer part of {[(first dose date-screening date) in days + age at screening (in 
days)]/365.25}. 
Correspondingly, age (in months) at first dose date = integer part of 12*{[(first dose date-screening date) in days + 
age at screening (in days)]/365.25}. 
2. Age (in years) at post-baseline visit (for use in calculation of percent predicted spirometry variables) 
Age (in years) at post-baseline visit = [(post-baseline visit date – screening date) in days + age at screening (in 
days)]/365.25 
3. Missing First Dose Date or Last Dose Date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date is missing at final analysis, use maximum of Early Treatment Termination (ETT) visit date and 
last study drug administration date from EX SDTM domain (excluding PK dosing dates). When a subject is lost to 
follow up without ETT, impute the last dose date as the last treatment period visit date. 
4. Missing Date for Drug Interruption 
If the dates for drug interruption are completely missing or partially missing and it cannot be determined in which 
period the interruption occurred, then assume the interruption occurred during the Treatment Period (Period 1) for 1 
day. 
5. Sweat Chloride: 
The qualified left arm and right arm SWCL assessments on Day 1 with end date/time for a given arm up to 30 
minutes after first dose time will be considered for baseline. If Day 1 value is unavailable or invalid, screening value 
will qualify as baseline. 


Statistical Analysis Plan (Methods) 
Page 44 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date (in 
practical, use Jan. 01, 2000 to impute). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (in 
practical, use Dec. 31, 2050 to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Table 11-5 
Prior, Concomitant, and Post Categorization of a Medication in Parts 1 and 3 
Medication Start Date 
Medication Stop Date 
< First Dose Date of Study 
Drug 
≥ First Dose Date and ≤ 
End Date of TE Period 
> End Date of TE Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post 
Table 11-6 
Prior, Concomitant, and Post Categorization of a Medication in Part 2 
Medication Start Date 
 
Medication Stop Date 
< First Dose 
Date of Run-in 
TE Period 
≥ First Dose Date and ≤ 
End Date of Run-in TE 
Period  
≥ First Dose Date and ≤ End 
Date of Treatment TE Period  
> End Date of 
Treatment TE 
Period  
< First dose date of Run-in 
TE period  
P 
PC1 
PC1C2 
PC1C2A 
≥ First dose date and  
≤ End date of Run-in  TE 
Period 
- 
C1 
C1C2 
C1C2A 
≥ First dose date and  
≤ End date of Treatment TE 
Period 
- 
- 
C2 
C2A 
> End date of Treatment TE 
Period 
- 
- 
- 
A 
P: Prior; C1: Concomitant during the Run-in Period; C2: Concomitant during the Treatment Period; A: Post 
 
 


Statistical Analysis Plan (Methods) 
Page 45 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix D: Important Protocol Deviation Rules  
An important protocol deviation (IPD) is any protocol deviation that has the potential to 
significantly impact the completeness, accuracy and/or reliability of the study data or that may 
significantly affect a subject’s rights, safety, or well-being.    
The rules for identifying important protocol deviations (IPDs) will be finalized prior the database 
lock. The rules will be developed by the Protocol Deviation Review Team (PDRT) consisting of 
Clinical Operations Study Lead (COSL), the Medical Monitor (MM), the Primary Clinical Data 
Manager (PCDM), Clinical Pharmacology lead (CPL), and the Study Biostatistician (SB). This 
team will review protocol deviations from screening throughout study conduct to develop rules 
for identifying IPDs.   
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to: 
• Subject entered the study despite violation of an inclusion or exclusion criteria 
• Subject received the wrong treatment or incorrect doses  
• Subject received excluded concomitant medications 
• Subject remained in study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but the PDRT should 
categorize them as IPDs only if they have the potential to significantly impact the completeness, 
accuracy and/or reliability of the study data or that may significantly affect a subject’s rights, 
safety, or well-being.  
The following potential protocol deviations will be identified from the clinical database in 
addition to those identified through the site deviation log. The team then will review the 
identified list following the above procedure to categorize if a particular occurrence as below is 
an important deviation. 
 
Important programmable protocol deviations before the first dose 
Stratification error will be detected based on comparing the IWRS stratification with the clinical 
database.  
For Parts 1 and 3, ppFEV1 stratification (<70 versus ≥70) will be performed at Stratification Visit 
for subjects being treated with 1 or more CFTR modulators (investigational or approved) within 
14 days of the Screening Visit. For subjects not being treated with any CFTR modulators within 
14 days of the Screening Visit, the Screening Visit spirometry assessment can be used for 
stratification.  
For subjects in Part 2, the ppFEV1 assessment for stratification of randomization will be done at 
the Day -14 Visit. 
Important programmable protocol deviations during the Treatment Period 
1. Compliance < 80%  
2. Use of prohibited medications 
3. Actual treatment received is different from the randomized treatment  
 


Statistical Analysis Plan (Methods) 
Page 46 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix E: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% 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: 
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja 
Stanojevic, Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-2012-
regression-equations-and-lookup-tables.aspx 
Accessed Sep 11, 2017.  
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, 
Janet Stocks. Version 19 July 2015. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/it-
engineers-and-manufacturers.aspx 
Accessed Sep 11, 2017.   
GLI-2012 - SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx 
Accessed  Sep 11, 2017. 
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 study visit 
• For race, map CRF black or AA 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 coeffiecients in the       
GLI  equations. 
 
 


Statistical Analysis Plan (Methods) 
Page 47 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix F: Details of CFQ-R Analysis and Scoring Manual 
The CFQ-R is a valid CF-specific instrument that measures quality-of-life domains. This study 
uses CFQ-R for Adolescents and Adult (subjects 14 years and older) in this study. CFQ-R for 
Adolescents and Adult (subjects 14 years and older) has a total of 50 questions to form 12 
domains. Question 43, which is scored 1, 2, 3, 4, or 5, is not used in calculating any domains; all 
the other 49 questions are scored 1, 2, 3, or 4. 
To calculate the score for each domain, the response scores on the negatively phrased questions 
are reversed (reversed scores = 5 – response scores) so that 1 always represents the worst 
condition and 4 always represents the best condition. In each domain, in cases where individual 
questions were skipped, the missing scores are imputed with the mean score of the non-missing 
questions for that domain.  
The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition). It is 
calculated as follows: 
Scaled score for a domain = 100 × (mean(scores of all questions in that domain) - 1)/3 
The scaled score for a specific domain will not be calculated if more than half of the questions in 
the domain have missing scores. 
Table 11-7 provides the questions included in each domain, the questions with the reversed 
scores, as well as the CFQ-R for Adolescents and Adults. The CFQ-R scoring manual is also 
attached. 
Table 11-7 
CFQ-R for Adolescents and Adults (subjects 14 years and older)  
 
Domain 
Questions 
 
Reversed questions 
Maximum number of 
missing questions 
Total 
Individual 
Physical 
8 
1, 2, 3, 4, 5, 13, 19, 20 
13 
4 
Role 
4 
35, 36, 37, 38 
35 
2 
Vitality 
4 
6, 9, 10, 11 
6, 10 
2 
Emotion 
5 
7, 8, 12, 31, 33 
- 
2 
Social 
6 
22, 23, 27, 28, 29, 30 
23, 28, 30 
3 
Body 
3 
24, 25, 26 
- 
1 
Eat 
3 
14, 21, 50 
- 
1 
Treatment burden 
3 
15, 16, 17 
15, 17 
1 
Health perceptions 
3 
18, 32, 34 
18, 32, 34 
1 
Weight 
1 
39 
- 
0 
Respiration* 
6 
40, 41, 42, 44, 45, 46 
43 
3 
Digestion 
3 
47, 48, 49 
- 
1 
*: Question 43 not used to calculate a domain.  
 
The CFQ-R scoring manual is attached.  
CFQR scoring 
manual.pdf
 


Statistical Analysis Plan (Methods) 
Page 48 of 57 
Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix G: Imputation Rules for Missing AE dates  
H.1 Parts 1 and 3 
Imputation rules for missing or partial AE start date for Parts 1 and 3 are defined below. 
• 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 with 
no imputation.  
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 the AE will be considered as TEAE for the 
Treatment Period.  
o else the AE will be considered as a pretreatment AE. 
 
H.2 Part 2 
Imputation rules for missing or partial AE start date for Part 2 are defined below. 
• 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  


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Vertex Pharmaceuticals Incorporated 
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else if AE start year and month are equal to the month and year of first dose 
date of the Run-in Period, then impute the AE start day as the day of first dose 
date of the Run-in Period;  
 else impute the AE start day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then impute the AE start day as the day of first dose date of the Run-in Period;  
 if AE start year and month are equal to the month and year of first dose date 
of the Run-in Period, then impute the AE start day as the day of first dose date 
of the Run-in Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else if AE start year is equal to the year of first dose date of the Run-in Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Run-in Period;  
 else impute the AE start month as January and day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then impute the AE start day as the day of first dose date of the Run-in Period;  
 if AE start year is equal to the year of first dose date of the Run-in Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Run-in Period;  
 else impute the AE start month as January and day as 1. 
o else 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 with 
no imputation.  


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Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
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 the AE will be considered as TEAE for the 
Treatment Period.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then the AE will be considered as TEAE for the Run-in Period. 
o else the AE will be considered as a pretreatment AE. 
 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, end of study) if day is missing, 
or min (Dec, end of study) if month is missing. 
 
 


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Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix H: Criteria for Threshold Analysis 
Table 11-8 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or 
(AST>ULN - ≤  3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x 
- ≤  5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - 
≤    8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x 
- ≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-8 
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 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L 
above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-8 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
  
Table 11-9 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-9 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
QTc 
Borderline 
Prolonged* 
Additional 
 
 
>450 ms (Male) and <500ms; >470 ms and 
<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.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 
Table 11-10 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 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-10 Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
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 
 
 
 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX16-659-101 Version 3.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-10 Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
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) 
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Protocol Number: VX16-659-101 Version 3.0 
 
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