A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis
Phase: PHASE2
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated

Page 1 of 74
1
TITLE PAGE
VERTEX PHARMACEUTICALS INCORPORATED
Clinical Study Protocol
A Phase 2, Randomized, Double-blind, Controlled 
Study to Evaluate the Safety and Efficacy of VX-121 
Combination Therapy in Subjects Aged 18 Years and 
Older With Cystic Fibrosis
Vertex Study Number: VX18-121-101
EudraCT Number: 2018-002496-18
Date of Protocol: 09 May 2019 (Version 4.0)
Replaces Version 3.0, dated 04 March 2019
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue
Boston, MA 02210-1862, USA
CONFIDENTIAL
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them.

Protocol VX18-121-101, Version 4.0
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Vertex Pharmaceuticals Incorporated
2
PROTOCOL SYNOPSIS
Title
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and 
Efficacy of VX-121 Combination Therapy in Subjects Aged 18 Years and Older With 
Cystic Fibrosis
Brief Title
A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in 
Subjects With Cystic Fibrosis
Clinical Phase and 
Clinical Study Type 
Phase 2, safety and efficacy 
Objectives
Primary Objectives
Parts 1 (Subjects with F/MF genotypes) and 2 (Optional; Subjects with the F/F 
genotype) 
• To evaluate the safety and tolerability of VX-121 in triple combination (TC) with 
tezacaftor (TEZ)/VX-561 (deuterated ivacaftor [IVA])
• To evaluate the efficacy of VX-121 in TC with TEZ/VX-561
Secondary Objectives
Parts 1 and 2
• To evaluate the pharmacodynamic (PD) effect of VX-121 in TC with TEZ/VX-561
• To evaluate the pharmacokinetics (PK) of VX-121 when administered in TC with 
TEZ/VX-561
• To evaluate the PK of TEZ, VX-561, and their respective metabolites when 
administered in TC with VX-121
Endpoints
Primary Endpoints
• Safety and tolerability, based on the assessment of adverse events (AEs), laboratory 
test results, standard 12-lead ECGs, vital signs, and spirometry 
• Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) from baseline through Day 29
Secondary Endpoints
• Absolute change in sweat chloride concentrations from baseline through Day 29
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory 
domain score from baseline at Day 29
• PK parameters of VX-121, TEZ, VX-561, 
 and relevant metabolites 

Protocol VX18-121-101, Version 4.0
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Number of Subjects
Approximately 108 subjects (including optional parts): 54 in Part 1, 27 in Part 2, 
 
Study Population
Parts 1 
Male subjects and female subjects with cystic fibrosis (CF), 
heterozygous for F508del and a minimal CFTR function mutation that is not 
responsive to TEZ, IVA, or TEZ/IVA (F/MF genotypes), ages 18 and older
Part 2: Male subjects and female subjects with CF, homozygous for F508del
(F/F genotype), ages 18 and older
Investigational Drug
Active substance: VX-121
Activity: CFTR corrector (increased Cl−secretion)
Strength and route of administration: 5-mg tablet for oral administration
Active substance: TEZ (VX-661) 
Activity: CFTR corrector (increased Cl−secretion)
Strength and route of administration: 50-mg TEZ tablet for oral administration
Active substance: VX-561
Activity: CFTR potentiator (increased Cl−secretion)
Strength and route of administration: 50-mg VX-561 tablet for oral administration
Active substance: TEZ (VX-661) and IVA (VX-770)
Activity: CFTR corrector and potentiator (increased Cl−secretion)
Strength and route of administration: 100-mg TEZ/150-mg IVA, film-coated 
fixed-dose combination (FDC) tablet for oral administration
Active substance: IVA (VX-770)
Activity: CFTR potentiator (increased Cl−secretion)
Strength and route of administration: 150-mg film-coated tablet for oral 
administration
Study Duration
Excluding the Screening Period, the study duration for each subject is 9 to 11 weeks 
for Parts 1 
 and 15 to 17 weeks for Part 2.
Study Design
This is a Phase 2,
randomized, double-blind, placebo- and TEZ/IVA-controlled, 
proof-of-concept study of VX-121. Study parts may be conducted in parallel or 
sequentially.
Randomization will be stratified by ppFEV1. Schematics of the study design are shown 
in Figure 2-1, Figure 2-2, 
 
Part 1: Subjects with F/MF genotypes 
Part 1 evaluates VX-121 in TC with TEZ/VX-561 as shown in Figure 2-1. 
The Washout Period (18 ± 3 days) is included to enable a more thorough evaluation of 
VX-121 exposure-response relationships by conducting PK and PD assessments 
during the VX-121 washout. 

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Planned Doses
• TC-5 mg is optional. The planned VX-121 doses of 5 mg, 10 mg, and 20 mg qd may 
be adjusted based on emerging data from subjects with CF in Part D of 
Study VX17-121-001 (Study 001). However, no more than 3 dose levels of VX-121 
will be evaluated, and the highest dose will not exceed 20 mg qd.
• The dosage of TEZ and VX-561 will be TEZ 100 mg daily (qd) and VX-561 150 mg 
qd.
Figure 2-1
VX18-121-101 Study Design for Part 1 (F/MF Genotypes)
Part 2 (Optional): Subjects with F/F genotype
Part 2, an optional part of the study, which will be conducted at the sponsor’s 
discretion, evaluates VX-121 in TC with TEZ/VX-561 as shown in Figure 2-2.
All subjects are required to complete the TEZ/IVA Run-in Period to establish a 
reliable on-treatment (TEZ/IVA) baseline. The 4-week Washout Period is included to 
evaluate the effect on PD and efficacy endpoints as subjects step down from TC to 
TEZ/IVA, after the VX-121 washout.
Planned Doses
• Part 2 will evaluate the same VX-121 dose (20 mg qd) used in Part 1. This dose may 
be adjusted downward based on emerging data from Part D of Study 001.
• The dosage of TEZ and VX-561 will be TEZ 100 mg qd and VX-561 150 mg qd.
• The dosage of TEZ/IVA will be TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h). 
Figure 2-2
VX18-121-101 Study Design for Part 2 (F/F Genotype)
TEZ/IVA
TC-20 mg
(VX-121/TEZ/VX-561)
Placebo + TEZ/IVA
TEZ/IVA
Run-in 
Period
(4 weeks)
Washout 
Period
(4 weeks)
Treatment Period
(4 weeks)
N = 9
N = 18
Safety 
Follow-up 
Period
(4 weeks)
Screening 
Period
(4 weeks)
TC-20 mg (VX-121/TEZ/VX-561)
TC-10 mg (VX-121/TEZ/VX-561)
TC-5 mg (VX-121/TEZ/VX-561)
Triple Placebo
N = 18
N = 18
N = 9
N = 9
TEZ/
VX-561
Washout Period
(18 ± 3 days) 
Treatment Period
(4 weeks)
Safety 
Follow-up 
Period
(4 weeks)
Screening 
Period
(4 weeks)
Dual Pbo

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Assessments
Safety: AEs, clinical laboratory assessments, clinical evaluation of vital signs, ECGs, 
physical examinations, spirometry
Efficacy: Spirometry, CFQ-R respiratory domain 
PD: Sweat chloride 
PK: VX-121, TEZ, VX-561, 
, and relevant metabolites
Statistical Analyses
A sample size of 18 subjects per treatment group provides at least 90% power to detect 
a mean within-treatment change of 7 percentage points. These calculations assumed a 
standard deviation of 8 percentage points for the absolute change from baseline in 
ppFEV1.
To analyze the absolute change from baseline in ppFEV1 through Day 29, a primary 
endpoint in Parts 1, 2, 
 a mixed-effects model for repeated measures (MMRM) 
with change from baseline for ppFEV1 at Days 15 and 29 as the dependent variable 
will be performed for each part. The null within-group hypothesis of no difference in 
the mean absolute change from baseline through Day 29 for ppFEV1, in all treatment 
groups, by part, will be tested using MMRM. The adjusted means and 2-sided 95% CIs 
of the average treatment effects through Day 29 for all within-group comparisons will 
be estimated within MMRM. P values will also be provided for these comparisons. All 
ppFEV1 hypothesis tests will be performed within the MMRM framework at a 5% 
alpha level, with appropriate adjustment for baseline covariates.
P values reported for all endpoints other than the primary endpoint should be 
considered nominal as no adjustment for multiplicity will be performed.
Descriptive analyses will be provided for the safety data comprising AEs, clinical 
laboratory assessments, ECGs, vital signs, and spirometry; no statistical hypothesis 
testing will be performed. The PK results for VX-121, TEZ, VX-561, 
 and 
relevant metabolites will be reported with descriptive statistics.
IDMC Reviews
An independent data 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 in Table 3-1, Table 3-2,
Table 3-1
Study VX18-121-101: Part 1, Screening, Treatment Period, Washout Period, and Safety Follow-up Visit 
Event/Assessmenta
Screening Visitb
Treatment Period
Washout Visit
ETT
Visitc
Safety 
Follow-up 
28 (7) Days 
After Last Dose 
of Study Drugd
Day -28
to Day -1
Day 1 
Day 2e
Day 8
(1 day)
Day 15
(2 days)
Day 29
(2 days)
Day 47
(3 days)
Outpatient visits
X
X
X
X
X
X
X
X
X
Informed consent
X
Randomizationf
X
Demographics 
X
Medical history
X
CFQ-Rg,h
X
X
X
Weighti
X
X
X
X
X
X
X
Heighti
X
Vital signsj
X
X
X
X
X
X
X
X
X
Pulse oximetryj
X
X
X
X
X
X
X
X
X
Physical examinationk
Complete
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Complete
Complete
Standard 12-lead 
ECGl
X
X
X
X
X
X
X
Sweat chlorideh,m
X
X
X
X
Xn
X
X
a
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once if study drug is not administered on the 
day of the visit (i.e., premature discontinuation of study drug treatment).
b
All screening results must be reviewed before randomization, unless noted otherwise.
c
If the subject prematurely discontinues study drug, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug treatment (Section 9.1.6). A final PK sample will be 
drawn from subjects who discontinue study drug for any reason (except withdrawal of consent). Safety assessments may also be performed at the discretion of the investigator..
d
Study drug refers to VX-121, TEZ, VX-561, and matching placebos.
e
Approximately 20 subjects enrolled in the study will have spirometry performed at 24 hours (± 2 hours) after the first dose. Only subjects participating in this spirometry assessment are required to 
complete the Day 2 Visit; this assessment should be performed predose on Day 2. Vertex will work with study sites to manage the allocation of subjects participating in the 24-hour postdose 
spirometry assessment. See Section 11.5.1 for more details.
f
Randomization may occur on the previous day (Day -1) after eligibility has been confirmed.
g
The CFQ-R must be completed before any other assessments scheduled at relevant visits. 
h
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred.
i
Weight and height will be measured with shoes off.
j
Vital signs and pulse oximetry will be collected after the subject has been at rest for at least 5 minutes (Sections 11.6.3 and 11.6.4).
k
Complete and abbreviated PEs are described in Section 11.6.3. 
l
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes (Section 11.6.5). The ECG will be done before any other procedures that may 
affect heart rate, such as blood draws. ECGs collected on Day 1 before dosing will be performed in triplicate. 
m
See Section 8.1 for information about the sweat chloride assessment for study eligibility. 
n
Sweat chloride and ppFEV1 assessments should be done within 2 hours before study drug dosing in the morning (Sections 11.3 and 11.5.1). 

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Table 3-1
Study VX18-121-101: Part 1, Screening, Treatment Period, Washout Period, and Safety Follow-up Visit 
Event/Assessmenta
Screening Visitb
Treatment Period
Washout Visit
ETT
Visitc
Safety 
Follow-up 
28 (7) Days 
After Last Dose 
of Study Drugd
Day -28
to Day -1
Day 1 
Day 2e
Day 8
(1 day)
Day 15
(2 days)
Day 29
(2 days)
Day 47
(3 days)
Spirometryo
X
X
X
X
X
X
Xn
X
X
Urinalysish
X
X
X
X
X
X
X
β-hCGq
serum
urine
urine
serum
serum
CFTR genotyper
X
FSHs
X
Serum chemistry and 
hematologyh
X
X
X
X
X
X
X
Coagulationh
X
X
X
X
X
X
X
PK samplingu
X
X
X
X
X
X
X
o
Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose of study drugs, and should be performed at 
approximately the same time at every other study visit. 
q
The serum β-hCG test is to be performed for all female subjects at screening. Subsequent urine or serum β-hCG tests are to be performed as indicated for women of childbearing potential. A 
definition of non-childbearing potential is provided in Section 11.6.7.1.
r
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 (Section 8.1). 
s
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea.
u
Blood samples will be collected for PK analysis of VX-121, TEZ and metabolites, and VX-561 and metabolites. On Day 1, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 
hours after dosing (relative to the morning dose). Samples will also be collected at 24 hours after dosing on Day 1 (i.e., predose on Day 2) for subjects participating in the Day 2 Visit (see Footnote e). 
On Days 8, 15, and 29, a predose sample will be collected before the morning dose of study drug (0 hours). On Day 47, a single predose sample will be collected before study drug dosing in the 
morning. Acceptable PK sampling windows are provided in Table 11-1. At the ETT Visit, a single blood sample for PK analysis will be collected. 

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Table 3-1
Study VX18-121-101: Part 1, Screening, Treatment Period, Washout Period, and Safety Follow-up Visit 
Event/Assessmenta
Screening Visitb
Treatment Period
Washout Visit
ETT
Visitc
Safety 
Follow-up 
28 (7) Days 
After Last Dose 
of Study Drugd
Day -28
to Day -1
Day 1 
Day 2e
Day 8
(1 day)
Day 15
(2 days)
Day 29
(2 days)
Day 47
(3 days)
TEZ/VX-561 or 
placebo dosingv
Day 1 through Washout Visit
VX-121 or placebo 
dosingw
Day 1 through Day 29
Adverse events
Continuous from signing of ICF through Safety Follow-up Visit
Medications reviewx
Continuous from signing of ICF through Safety Follow-up Visit
Treatment and 
procedures review
Continuous from signing of ICF through Safety Follow-up Visit
v
The last dose of study drug will be the morning dose at the Washout Visit.
w
The last dose of study drug will be the morning dose on the Day 29 Visit.
x
All medications taken from 28 days before the Screening Period through the end of the study will be recorded.

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Table 3-2
Study VX18-121-101: Part 2 (Optional), Screening, Run-in Period, Treatment Period, Washout Period, and Safety Follow-up 
Visit
Event/Assessmenta
Screening 
Visitb
Run-in Period
Treatment Periodc
Washout Period
ETT
Visitd
Safety 
Follow-up 
28 (7) Days 
After Last 
Dose of Study 
Druge,f
Day -56
to Day -29
Day -28 
(1 day)
Day -14g
(+ 13 days)
Day 1 
Day 8
(1 day)
Day 15
(2 days)
Day 29
(2 days)
Day 43
(3 days)
Day 57
(3 days)
Outpatient visits
X
X
X
X
X
X
X
X
X
X
X
Informed consent
X
Randomizationh
X
Demographics 
X
Medical history
X
CFQ-Ri,j
X
X
X
X
Weightk
X
X
X
X
X
X
X
X
X
X
Heightk
X
Vital signsl
X
X
X
X
X
X
X
X
X
X
Pulse oximetryl
X
X
X
X
X
X
X
X
X
X
Physical examinationm
Complete
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Abbrev.
Complete
Complete
Standard 12-lead ECGn
X
X
X
X
X
X
X
X
X
X
Sweat chloridej,o
X
X
X
X
X
Xp
Xp
X
Spirometryq
X
Xr
X
X
X
X
Xp
Xp
X
X
a
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once if study drug is not administered on the 
day of the visit (i.e., premature discontinuation of study drug treatment).
b
All screening results must be reviewed before the Run-in Period.
c
To qualify to continue into the Treatment Period, conditions for entry must be satisfied (Section 9.1.3). 
d
If the subject prematurely discontinues study drug, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug treatment (Section 9.1.6). A final PK sample will be 
drawn from subjects who discontinue study drug for any reason (except withdrawal of consent). Safety assessments may also be performed at the discretion of the investigator. 
e
Part 2 subjects who meet criteria specified in Section 9.1.5 will not have a Safety Follow-up Visit. 
f
Study drug refers to VX-121, TEZ, VX-561, TEZ/IVA, IVA, and matching placebos.
g
Assessments at this visit may be performed postdose.
h
Randomization may occur on the previous day (Day -1) after all conditions for entering the Treatment Period have been confirmed (Section 9.1.3).
i
The CFQ-R must be completed before any other assessments scheduled at relevant visits. 
j
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
k
Weight and height will be measured with shoes off.
l
Vital signs and pulse oximetry will be collected after the subject has been at rest for at least 5 minutes (Sections 11.6.3 and 11.6.4).
m
Complete and abbreviated PEs are described in Section 11.6.3. 
n
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes (Section 11.6.5). The ECG will be done before any other procedures that may 
affect heart rate, such as blood draws. ECGs collected on Day 1 before dosing will be performed in triplicate. 
o
See Section 8.1 for information about the sweat chloride assessment for study eligibility. 
p
Sweat chloride and ppFEV1 assessments should be done within 2 hours before study drug dosing in the morning (Sections 11.3 and 11.5.1).
q
Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose of study drugs (except at the Day -14 Visit 
when spirometry may be performed postdose), and should be performed at approximately the same time at every other study visit. See Section 11.5.1 for more details.

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Table 3-2
Study VX18-121-101: Part 2 (Optional), Screening, Run-in Period, Treatment Period, Washout Period, and Safety Follow-up 
Visit
Event/Assessmenta
Screening 
Visitb
Run-in Period
Treatment Periodc
Washout Period
ETT
Visitd
Safety 
Follow-up 
28 (7) Days 
After Last 
Dose of Study 
Druge,f
Day -56
to Day -29
Day -28 
(1 day)
Day -14g
(+ 13 days)
Day 1 
Day 8
(1 day)
Day 15
(2 days)
Day 29
(2 days)
Day 43
(3 days)
Day 57
(3 days)
Urinalysisj
X
X
X
X
X
X
X
X
X
X
β-hCGt
serum
urine
urine
urine
urine
serum
serum
CFTR genotypeu
X
FSHv
X
Serum chemistry and 
hematologyj
X
X
X
X
X
X
X
X
X
X
Coagulationj
X
X
X
X
X
X
X
X
r
The ppFEV1 assessment for stratification of randomization will be done at the Day -14 Visit. See Section 9.1.2 and Section 9.2.
t
The serum β-hCG test is to be performed for all female subjects at Screening. Subsequent urine or serum β-hCG tests are to be performed as indicated for women of childbearing potential. A 
definition of non-childbearing potential is provided in Section 11.6.7.1.
u
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before the Run-in Period, a previous CFTR genotype laboratory report may be used to 
establish eligibility (Section 8.1).
v
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea.

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Table 3-2
Study VX18-121-101: Part 2 (Optional), Screening, Run-in Period, Treatment Period, Washout Period, and Safety Follow-up 
Visit
Event/Assessmenta
Screening 
Visitb
Run-in Period
Treatment Periodc
Washout Period
ETT
Visitd
Safety 
Follow-up 
28 (7) Days 
After Last 
Dose of Study 
Druge,f
Day -56
to Day -29
Day -28 
(1 day)
Day -14g
(+ 13 days)
Day 1 
Day 8
(1 day)
Day 15
(2 days)
Day 29
(2 days)
Day 43
(3 days)
Day 57
(3 days)
PK samplingx
X
X
X
X
X
X
X
TEZ/IVA dosingy
Day -28 to evening on Day -1
Evening of Day 29 through 
Day 57
VX-121/TEZ/VX-561 or 
TEZ/IVA dosingz
Day 1 through Day 29
Adverse events
Continuous from signing of ICF through Safety Follow-up Visit
Medications reviewaa
Continuous from signing of ICF through Safety Follow-up Visit
Treatment and procedures 
review
Continuous from signing of ICF through Safety Follow-up Visit
x
Blood samples will be collected for PK analysis of VX-121, TEZ and metabolites, and VX-561 and metabolites. On Day 1, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 
8 hours after dosing (relative to the morning dose). On Days 8, 15, and 29, a predose sample will be collected before the morning dose of study drug (0 hours). On Days 43 and 57, a single blood 
sample for PK analysis will be collected before the morning dose of TEZ/IVA. Acceptable PK sampling windows are provided in Table 11-1. At the ETT Visit, a single blood sample for PK analysis 
will be collected.
y
The final dose during the Run-in Period will be administered on Day -1, the evening before the Day 1 Visit. The final dose during the Washout Period will be the morning dose on the Day 57 Visit.
z
The last dose of VX-121/TEZ/VX-561 or TEZ/IVA will be the morning dose on the Day 29 Visit.
aa
All medications taken from 28 days before the Screening Period through the end of the study will be recorded.

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4
TABLE OF CONTENTS
1
Title Page............................................................................................................................1
2
Protocol Synopsis ...............................................................................................................3
3
Schedule of Assessments ....................................................................................................7
4
Table of Contents .............................................................................................................15
List of Tables .......................................................................................................................19
List of Figures ......................................................................................................................19
List of Abbreviations............................................................................................................20
5
Introduction......................................................................................................................23
5.1
Background.................................................................................................................23
5.2
Study Rationale...........................................................................................................24
6
Study Objectives...............................................................................................................24
6.1
Primary Objectives......................................................................................................24
6.2
Secondary Objectives..................................................................................................24
7
Study Endpoints...............................................................................................................25
7.1
Primary Endpoints.......................................................................................................25
7.2
Secondary Endpoints...................................................................................................25
8
Study Population..............................................................................................................25
8.1
Inclusion Criteria.........................................................................................................25
8.2
Exclusion Criteria........................................................................................................26
9
Study Implementation......................................................................................................28
9.1
Study Design...............................................................................................................28
9.1.1
Screening.............................................................................................................30
9.1.1.1
Repetition of Screening Assessment(s)..........................................................30
9.1.1.2
Rescreening...................................................................................................30
9.1.1.3
Extension of Screening Period Window.........................................................30
9.1.2
TEZ/IVA Run-in Period (Part 2)..........................................................................31
9.1.3
Treatment Period .................................................................................................31
9.1.4
Washout Period ...................................................................................................31
9.1.5
Follow-up............................................................................................................32
9.1.6
Early Termination of Treatment...........................................................................32
9.1.7
Lost to Follow-up ................................................................................................32
9.1.8
Independent Data Monitoring Committee ............................................................32
9.2
Method of Assigning Subjects to Treatment Groups....................................................33
9.3
Rationale for Study Elements ......................................................................................33
9.3.1
Study Design .......................................................................................................33
9.3.2
Study Drug Dose and Duration ............................................................................34
9.3.3
Rationale for Study Assessments .........................................................................35
9.4
Study Restrictions .......................................................................................................36
9.4.1
Prohibited Medications........................................................................................36
9.5
Prior and Concomitant Medications.............................................................................36
9.6
Administration ............................................................................................................37
9.7
Dose Modification for Toxicity ...................................................................................38

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9.8
Study Drug Interruption and Stopping Rules ...............................................................38
9.9
Removal of Subjects....................................................................................................39
9.10 Replacement of Subjects .............................................................................................40
10 Study Drug Information and Management.....................................................................40
10.1 Preparation and Dispensing .........................................................................................41
10.2 Packaging and Labeling ..............................................................................................41
10.3 Study Drug Supply, Storage, and Handling .................................................................41
10.4 Drug Accountability....................................................................................................41
10.5 Disposal, Return, or Retention of Unused Drug...........................................................41
10.6 Compliance.................................................................................................................42
10.7 Blinding and Unblinding .............................................................................................42
10.7.1
Blinding...............................................................................................................42
10.7.2
Unblinding ..........................................................................................................43
11 Assessments ......................................................................................................................44
11.1 Subject and Disease Characteristics.............................................................................44
11.2 Pharmacokinetics ........................................................................................................44
11.2.1
Blood Sampling...................................................................................................44
11.2.2
Processing and Handling of Pharmacokinetic Samples.........................................44
11.2.3
Bioanalysis ..........................................................................................................44
11.3 Pharmacodynamics: Sweat Chloride............................................................................45
11.5 Efficacy.......................................................................................................................46
11.5.1
Spirometry...........................................................................................................46
11.5.2
Cystic Fibrosis Questionnaire-Revised.................................................................47
11.6 Safety..........................................................................................................................47
11.6.1
Adverse Events....................................................................................................47
11.6.2
Clinical Laboratory Assessments .........................................................................47
11.6.3
Physical Examinations and Vital Signs ................................................................49
11.6.4
Pulse Oximetry....................................................................................................49
11.6.5
Electrocardiograms..............................................................................................49
11.6.6
Spirometry...........................................................................................................50
11.6.7
Contraception and Pregnancy...............................................................................50
11.6.7.1
Contraception................................................................................................50
11.6.7.2
Pregnancy......................................................................................................52
12 Statistical and Analytical Plans .......................................................................................52
12.1 Sample Size and Power ...............................................................................................52
12.2 Analysis Sets...............................................................................................................53
12.2.1
All Subjects Set ...................................................................................................53
12.2.2
Full Analysis Set..................................................................................................53
12.2.3
Safety Set ............................................................................................................53
12.2.4
Pharmacokinetic Set ............................................................................................53

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12.3 Statistical Analysis ......................................................................................................53
12.3.1
General Considerations........................................................................................53
12.3.2
Background Characteristics .................................................................................54
12.3.2.1
Subject Disposition........................................................................................54
12.3.2.2
Demographics and Baseline Characteristics...................................................54
12.3.2.3
Prior and Concomitant Medications...............................................................54
12.3.2.4
Study Drug Exposure ....................................................................................54
12.3.2.5
Important Protocol Deviations.......................................................................55
12.3.3
Safety Analysis....................................................................................................55
12.3.3.1
Adverse Events..............................................................................................55
12.3.3.2
Clinical Laboratory Assessments...................................................................56
12.3.3.3
Electrocardiogram.........................................................................................56
12.3.3.4
Vital Signs.....................................................................................................57
12.3.3.5
Pulse Oximetry..............................................................................................57
12.3.3.6
Physical Examination ....................................................................................57
12.3.4
Efficacy Analysis.................................................................................................57
12.3.4.1
Spirometry ....................................................................................................57
12.3.4.2
Analysis of CFQ-R........................................................................................58
12.3.5
Pharmacodynamic Analysis.................................................................................58
12.3.7
Interim and Independent Data Monitoring Committee Analyses ..........................58
12.3.7.1
Interim Analysis............................................................................................58
12.3.7.2
Independent Data Monitoring Committee Analysis........................................58
12.4 Clinical Pharmacology Analysis..................................................................................58
12.4.1
Pharmacokinetic Analysis....................................................................................58
12.4.2
Pharmacokinetic/Pharmacodynamic Analyses .....................................................59
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.................................................................60
13.1.1.4
Adverse Event Severity .................................................................................60
13.1.1.5
Adverse Event Causality................................................................................61
13.1.1.6
Study Drug Action Taken..............................................................................61
13.1.1.7
Adverse Event Outcome................................................................................62
13.1.1.8
Treatment Given............................................................................................62
13.1.2
Serious Adverse Events .......................................................................................62
13.1.2.1
Definition of a Serious Adverse Event...........................................................62
13.1.2.2
Reporting and Documentation of Serious Adverse Events .............................63
13.1.2.3
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

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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
13.2.8
End of Study........................................................................................................65
13.3 Data Quality Assurance...............................................................................................66
13.4 Monitoring ..................................................................................................................66
13.5 Electronic Data Capture ..............................................................................................66
13.6 Publications and Clinical Study Report........................................................................67
13.6.2
Clinical Study Report ..........................................................................................67
14 Reference ..........................................................................................................................68
APPENDIX A 
Eligible MF CFTR Mutations....................................................................70
15 Protocol Signature Pages .................................................................................................73
15.1 Sponsor Signature Page...............................................................................................73
15.2 Investigator Signature Page.........................................................................................74

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List of Tables
Table 3-1
Study VX18-121-101: Part 1, Screening, Treatment Period, Washout Period, and 
Safety Follow-up Visit .........................................................................................7
Table 3-2
Study VX18-121-101: Part 2 (Optional), Screening, Run-in Period, Treatment 
Period, Washout Period, and Safety Follow-up Visit ..........................................10
Table 9-1
Prohibited Medications ......................................................................................36
Table 11-1
Acceptable Pharmacokinetic Sampling Windows...............................................44
Table 11-2
Safety Laboratory Test Panels............................................................................48
Table 11-3
Acceptable Methods of Contraception................................................................51
Table 13-1
Grading of AE Severity......................................................................................61
Table 13-2
Classifications for AE Causality.........................................................................61
Table 13-3
Classifications for Study Drug Action Taken With Regard to an AE ..................61
Table 13-4
Classifications for Outcome of an AE ................................................................62
List of Figures
Figure 2-1
VX18-121-101 Study Design for Part 1 (F/MF Genotypes)..................................5
Figure 2-2
VX18-121-101 Study Design for Part 2 (F/F Genotype).......................................5
Figure 9-1
VX18-121-101 Study Design for Part 1 (F/MF Genotypes)................................28
Figure 9-2
VX18-121-101 Study Design for Part 2 (F/F Genotype).....................................29

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List of Abbreviations
Abbreviation
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase
AST
aspartate transaminase
AUC
area under the concentration versus time curve
AUC0-24h
AUC from the time of dosing to 24 hours
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
CD
compact disc
CF
cystic fibrosis
CFQ-R
CF Questionnaire-Revised
CFTR
CF transmembrane conductance regulator gene
CFTR
CF transmembrane conductance regulator protein
CI
confidence interval
CMC
chemistry, manufacturing, and controls
CPAP
clinical pharmacology analysis plan
CRF
case report form
CRO
clinical research organization
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
predose concentration
CYP
cytochrome P450
ECG
electrocardiogram
EDC
electronic data capture
EENT
eyes, ears, nose, and throat
ETT
Early Termination of Treatment
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
FDC
fixed-dose combination
 
FEV1
forced expiratory volume in 1 second
F/F
F508del/F508del
F/MF
F508del/minimal function
FSH
follicle-stimulating hormone
 
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLI
Global Lung Function Initiative

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Abbreviation
Definition
GPP
Good Publication Practices
GPS
Global Patient Safety
HBE
human bronchial epithelial (cells)
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
ICF
informed consent form
ICH
International Council for Harmonization
ICMJE
International Committee of Medical Journal Editors
IDMC
independent data monitoring committee
IEC
independent ethics committee
IPD
important protocol deviation
IRB
institutional review board
IVA
ivacaftor
IWRS
interactive web response system
LS
least squares
LUM
lumacaftor
MedDRA
Medical Dictionary for Regulatory Activities
MF
minimal function
min
minimum value
MMRM
mixed-effects model for repeated measures
N
number of subjects
OATP
organic anion transporting polypeptide
P
probability
pbo
placebo
PD
pharmacodynamic, pharmacodynamics
PE
physical examination
PI
pancreatic insufficient
PK
pharmacokinetic, pharmacokinetics
ppFEV1
percent predicted forced expiratory volume in 1 second
PR
PR interval
PT
Preferred Term
q12h
every 12 hours
qd
daily
QRS
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization
QT
QT interval
QTc
QT interval corrected
QTcF
QT interval corrected by Fridericia’s formula
RR
interval from the onset of 1 QRS complex to the next
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SET
study execution team
SI
SI units (International System of Units)
SOC
System Organ Class

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Abbreviation
Definition
SUSAR
suspected, unexpected, serious adverse reaction
SwCl
sweat chloride
TC
triple combination
TE
treatment-emergent
TEAE
treatment-emergent adverse event
TEZ
tezacaftor 
ULN
upper limit of normal
UV
ultraviolet
WHO-DD
World Health Organization-Drug Dictionary 

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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 more than 
70,000 individuals worldwide.1 Based on its prevalence, CF qualifies as an orphan disease.2, 3
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 (GI) 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.4, 5 Progressive loss of lung function is the leading cause of mortality.6
There are more than 2000 variants described in the CFTR gene. The most commonly seen 
variants that are clearly associated with CF have been identified (336 to date), but many rare 
cases remain uncharacterized.7
Based on the understanding of the molecular defects caused by these 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 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 CFTR genotype of the patient, both 
approaches may be required to ameliorate lung disease in patients with CF. 
The therapeutic activity of CFTR correctors and potentiators has been established with products 
developed by Vertex Pharmaceuticals Incorporated and approved for the treatment of CF in 
patients with specific CFTR genotypes: ivacaftor (IVA) monotherapy (Kalydeco®), lumacaftor 
(LUM) in combination with IVA (Orkambi®), and tezacaftor (TEZ) in combination with IVA 
(Symdeko™/ Symkevi®). TEZ and LUM are first-generation CFTR correctors that improve the 
processing and trafficking of mutated CFTR protein, resulting in an increase in the quantity of 
protein at the cell surface. IVA increases the open-channel probability of the mutated CFTR 
protein that has been delivered to the cell surface, thereby enhancing total chloride transport. 
VX-561 (formerly known as CTP-656) is a deuterated isotope of IVA with a specific pattern of 
9 substituted deuteriums. In vitro data indicate similar potency of VX-561 in human bronchial 
epithelial (HBE) cells relative to IVA. 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 (refer to VX-561 Investigator’s Brochure).
VX-121 is a next-generation CFTR corrector. In vitro, VX-121 also improves the processing and 
trafficking of mutated CFTR, thereby increasing the quantity of functional protein at the cell 
surface. The effect of VX-121 was additive to the effect of TEZ. The CFTR protein delivered to 
the cell surface by VX-121 alone or in combination with TEZ (VX-121/TEZ) was potentiated by 
IVA. In HBE cells derived from people homozygous for F508del and people heterozygous for 
F508del and a minimal function (MF) CFTR mutation (F/MF-HBE cells) and studied in vitro, 

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the triple combination (TC) of VX-121, TEZ, and IVA (VX-121/TEZ/IVA) increased CFTR 
chloride transport more than the dual combination of VX-121 and either TEZ or IVA under most 
conditions studied (refer to VX-121 Investigator’s Brochure). 
5.2
Study Rationale
This is the second clinical study of VX-121 and Part 1 is designed to evaluate the safety and 
efficacy of VX-121 in TC with TEZ/VX-561 in subjects with CF who are heterozygous for 
F508del and a MF CFTR mutation (F/MF genotypes). Conducting the study in subjects with 
these genotypes investigates the effect of treating 1 responsive allele (F508del). Additionally, the 
safety and efficacy of VX-121 in TC with TEZ/VX-561 will be evaluated in subjects with CF 
who are homozygous for F508del (F/F genotype) in Part 2, 
 
 if the sponsor chooses to conduct these optional parts of 
the study based on overall development goals for the program and results from other studies. 
6
STUDY OBJECTIVES
6.1
Primary Objectives
Parts 1 (Subjects with F/MF genotypes) and 2 (Optional; Subjects with the F/F genotype)

To evaluate the safety and tolerability of VX-121 in TC with TEZ/VX-561 (deuterated IVA) 

To evaluate the efficacy of VX-121 in TC with TEZ/VX-561
6.2
Secondary Objectives
Parts 1 and 2

To evaluate the pharmacodynamic (PD) effect of VX-121 in TC with TEZ/VX-561 

To evaluate the pharmacokinetics (PK) of VX-121 when administered in TC with 
TEZ/VX-561 

To evaluate the PK of TEZ, VX-561, and their respective metabolites when administered in 
TC with VX-121 

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7
STUDY ENDPOINTS
7.1
Primary Endpoints

Safety and tolerability, based on the assessment of adverse events (AEs), laboratory test 
results, standard 12-lead ECGs, vital signs, and spirometry

Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through Day 29
7.2
Secondary Endpoints

Absolute change in sweat chloride concentrations from baseline through Day 29

Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline at Day 29

PK parameters of VX-121, TEZ, VX-561,
 and relevant metabolites
8
STUDY POPULATION
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible.
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 (male and female) aged 18 years or older on the date of informed consent.
4. Female subjects must have a negative serum pregnancy test at the Screening Visit.
5. Body weight ≥35 kg.
6. 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. 
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. 
7. Confirmed diagnosis of CF as determined by the investigator.
8. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR
genotype result is not received before the Run-in Period (Part 2) or randomization 
(Parts 1
 a previous CFTR genotype laboratory report may be used to establish 

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eligibility. Subjects who have been enrolled and whose screening genotype does not confirm 
study eligibility must be discontinued from the study (Section 9.9).

Parts 1 
 Heterozygous for F508del with a second CFTR allele carrying a mutation 
that does not produce a protein, or produces a protein that is not responsive to TEZ, IVA, 
or TEZ/IVA therapy (Appendix A)

Part 2: Homozygous for F508del
9. Subjects must have a forced expiratory volume in 1 second (FEV1) ≥40% and ≤90% of 
predicted normal for age, sex, and height (equations of the Global Lung Function Initiative 
[GLI])8 at the Screening Visit. Spirometry measurements must meet American Thoracic 
Society/European Respiratory Society criteria9 for acceptability and repeatability.
10. Stable CF disease as judged by the investigator. 
11. Willing to remain on a stable CF treatment regimen (other than protocol-specified changes in 
CFTR modulator regimen) through the Safety Follow-up Visit (Section 9.5).
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 and other ventricular arrhythmias, 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. Any of the following abnormal laboratory values at screening:

Hemoglobin <10 g/dL

Total bilirubin ≥2 × upper limit of normal (ULN)

Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN

Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2
(calculated by the Modification of Diet in Renal Disease Study Equation)10,11 for subjects 
≥18 years of age
5. 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 
TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period 
(Parts 1
).

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6. 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, the investigator will apply the 
following criteria to establish whether the subject is free of infection with such organisms: 

The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent.

The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent 1 within the 6 months before the date 
of informed consent.
7. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period 
(Parts 1 
).
8. Standard 12-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 
450 msec, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will 
be used to determine the subject’s eligibility.
9. History of solid organ or hematological transplantation.
10. History of alcohol or drug abuse in the past year, including, but not limited to, cannabis, 
cocaine, and opiates, as deemed by the investigator.
11. Ongoing or prior participation in a study of an investigational treatment with the exception of 
the following:

Ongoing or prior participation in an investigational study of a Vertex CFTR modulator. A 
washout period of 28 days must elapse before Day 1.

For prospective subjects with ongoing or prior participation in all other interventional 
studies, a washout period of 28 days or 5 terminal half-lives (whichever is longer) must 
elapse before screening. The duration of the elapsed time may be longer if required by 
local regulations.

Ongoing participation in a noninterventional study (including observational studies and 
studies requiring assessments without administration of study drug or assignment to other 
interventions) is permitted.
12. Use of prohibited medications as defined in Table 9-1, within the specified window before 
the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the 
Treatment Period (Parts 1 
).

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13. Subject, or close relative of the subject, is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be enrolled in the study provided that 

the adult lives independently of and does not reside with the study staff member, and

the adult participates in the study at a site other than the site at which the family member 
is employed.
14. Pregnant or nursing female subjects.
9
STUDY IMPLEMENTATION
9.1
Study Design
This is a Phase 2, 
 proof-of-concept study of VX-121. Study parts may be conducted in 
parallel or sequentially.
A schematic of the study design for Part 1 is shown in Figure 9-1, which has a randomized, 
double-blind, placebo-controlled, parallel-group design and evaluates VX-121 in TC with 
TEZ/VX-561.
Figure 9-1
VX18-121-101 Study Design for Part 1 (F/MF Genotypes)
FDC: fixed-dose combination; F/MF: F508del/minimal function; N: number of subjects; pbo: placebo; 
PD: pharmacodynamic; PK: pharmacokinetic; ppFEV1: percent predicted forced expiratory volume in 1 second; qd: 
daily; TC: triple combination; TEZ: tezacaftor
Note: Randomization will be stratified by ppFEV1.
a
The planned VX-121 doses of 5 mg, 10 mg, and 20 mg qd may be adjusted based on emerging data from 
subjects with CF in Part D of Study VX17-121-001 (Study 001). However, no more than 3 dose levels of 
VX-121 will be evaluated, and the highest dose will not exceed 20 mg qd.
b
The dosage of TEZ and VX-561 will be TEZ 100 mg qd and VX-561 150 mg qd. 
c
The Washout Period (18 ± 3 days) is included to enable a more thorough evaluation of VX-121 
exposure-response relationships by conducting PK and PD assessments during the VX-121 washout.
d
TC-5 mg is optional.
TC-20 mg (VX-121/TEZ/VX-561)
TC-10 mg (VX-121/TEZ/VX-561)
TC-5 mgd (VX-121/TEZ/VX-561)
Triple Pbo
N = 18
N = 18
N = 9
N = 9
TEZ/
VX-561
Washout Periodb,c
(18 ± 3 days) 
Treatment Perioda,b
(4 weeks)
Safety 
Follow-up 
Period
(4 weeks)
Screening 
Period
(4 weeks)
Dual Pbo

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A schematic of the study design for Part 2 is shown in Figure 9-2, which has a randomized, 
double-blind, TEZ/IVA-controlled, parallel-group design and evaluates VX-121 in TC with 
TEZ/VX-561. Part 2 is an optional part of the study, which will be conducted at the sponsor’s 
discretion.
Figure 9-2
VX18-121-101 Study Design for Part 2 (F/F Genotype)
FDC: fixed-dose combination; F/F: F508del/F508del; IVA: ivacaftor; N: number of subjects; pbo: placebo; 
PD: pharmacodynamic; ppFEV1: percent predicted forced expiratory volume in 1 second; q12h: every 12 hours; 
qd: daily; TC: triple combination; TEZ: tezacaftor
Note: Randomization will be stratified by ppFEV1.
a
All subjects are required to complete the TEZ/IVA Run-in Period to establish a reliable on-treatment 
(TEZ/IVA) baseline.
b
The dosage of TEZ/IVA will be TEZ 100 mg qd/IVA 150 mg q12h, which will be administered as 
TEZ 100 mg/IVA 150 mg FDC in the morning and IVA 150 mg in the evening.
c
Part 2 will evaluate the same VX-121 dose (20 mg qd) used in Part 1. This dose may be adjusted downward 
based on emerging data from Part D of Study 001. The dosage of TEZ and VX-561 will be TEZ 100 mg qd and 
VX-561 150 mg qd.
d
The 4-week Washout Period is included to evaluate the effect on PD and efficacy endpoints as subjects step 
down from TC to TEZ/IVA, after the VX-121 washout.
TEZ/IVA
TC-20 mg
(VX-121/TEZ/VX-561)
Pbo + TEZ/IVA
TEZ/IVA
Run-in 
Perioda,b
(4 weeks)
Washout 
Periodb,d
(4 weeks)
Treatment Periodb,c
(4 weeks)
N = 9
N = 18
Safety 
Follow-up 
Period
(4 weeks)
Screening 
Period
(4 weeks)

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9.1.1
Screening
Screening Visit assessments are shown in Table 3-1, Table 3-2, 
The Screening Period will occur within 28 days before the first dose of study drug. The site 
investigator (or designee) will confirm and document study eligibility before randomization.
9.1.1.1
Repetition of Screening Assessment(s)
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject is eligible for the study.
9.1.1.2
Rescreening
Subjects may be rescreened only once. If a subject is rescreened, all screening assessments will 
be repeated except for CFTR genotyping, follicle-stimulating hormone (FSH) level (if serum 
FSH level was ≥40 mIU/mL during prior screening), 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
The Screening Period window may be extended by 2 weeks for the following reasons:

Repetition of the Screening Period assessments (Section 9.1.1.1)

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
Unexpected operational or logistic delays, or to meet the eligibility criteria

Repetition of spirometry assessment if results are of poor quality
9.1.2
TEZ/IVA Run-in Period (Part 2)
The TEZ/IVA Run-in Period of Part 2 is 4 weeks. Subjects will be evaluated as outpatients.
Study visits during the Run-in Period will occur as shown in Table 3-2. Study drug 
administration details are provided in Section 9.6.
On the Day -14 Visit, spirometry and sweat chloride will be assessed. The Day -14 Visit 
spirometry assessment will be used for stratification of randomization (Section 9.2).
Study eligibility will be confirmed before the first dose of TEZ/IVA in the Run-in Period (on the 
Day -28 Visit). 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 
another 4-week Run-in Period (Section 9.1.1.2).
9.1.3
Treatment Period
The Treatment Period will last approximately 4 weeks. Subjects will be evaluated as outpatients.
Study visits during the Treatment Period will occur as shown in Table 3-1, Table 3-2, 
 
 All visits will occur within the windows specified. Study drug administration details 
are provided in Section 9.6.  
Subjects in Part 2 must meet both of the following conditions to qualify to continue into the 
Treatment Period:

Must have stable CF disease (as judged by the investigator) and have remained on a stable 
CF medication regimen during the 28 days before the Day 1 Visit. (For example, subjects 
cannot have an acute upper or lower respiratory infection, pulmonary exacerbation, or 
changes in therapy [including antibiotics] for pulmonary disease within 28 days before the 
first dose of study drug in the Treatment Period.) 

Must not have had an acute non-CF illness (e.g., gastroenteritis) within the 14 days before the 
first dose of study drug in the Treatment Period.
If these conditions are not met, subjects in Part 2 may not be randomized and enter into the 
Treatment Period.
Randomization will occur before the first dose of study drug during the Treatment Period and 
will occur on the Day 1 Visit (or Day -1) after eligibility has been confirmed (Parts 1 
) or 
conditions for entry into the Treatment Period have been confirmed (Part 2). Randomization and 
stratification details are provided in Section 9.2.
9.1.4
Washout Period
The Washout Periods will last approximately 18 days (Parts 1 
) and 4 weeks (Part 2).
Study visits during the Washout Period will occur as shown in Table 3-1, Table 3-2, 
 
 Study drug administration details are provided in Section 9.6.

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9.1.5
Follow-up
Subjects will have a Safety Follow-up Visit approximately 28 days after the last study drug dose. 
Safety Follow-up Visit assessments are listed in Table 3-1, Table 3-2, 
The Safety Follow-up is not required for subjects in Part 2 who continue onto a 
commercially-available, physician-prescribed CFTR modulator within 28 days of completing the 
Day 57 Visit.
9.1.6
Early Termination of Treatment
If the subject prematurely discontinues study treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the subject decides to terminate study 
drug. Subjects who prematurely discontinue study treatment will also be required to complete the 
Safety Follow-up Visit, approximately 28 days after their last dose of study drug. The 
assessments performed at the Safety Follow-up Visit are listed in Table 3-1, Table 3-2,
 
Subjects who discontinue from study drug dosing for any reason (except withdrawal of consent) 
will have a final PK blood sample drawn as soon as possible after the decision to discontinue 
study drug is made. Additional safety assessments may also be performed at the discretion of the 
investigator, including possible consultation with a specialist consultant. The Vertex medical 
monitor will be informed about these additional assessments, and any additional data collected 
(e.g., as the result of an outside consultation) will be considered part of the study record to 
provide the most complete safety profile of the 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 the subject withdraws consent for the study, no further assessments should be performed, and 
no additional data should be collected. Vertex may retain and continue to use any data and 
samples collected before such withdrawal of consent.
9.1.7
Lost to Follow-up
A subject will be considered lost to follow-up if both of the following occur:

The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit).

The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts.
9.1.8
Independent Data Monitoring Committee
This study will be monitored by an independent data monitoring committee (IDMC) to ensure 
the safety of the subjects. 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.

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9.2
Method of Assigning Subjects to Treatment Groups
A randomization list for each part will be produced by Vertex Biostatistics or a qualified 
randomization vendor. The Vertex study biostatistician will review and approve the dummy 
randomization list. The final randomization list will be reviewed and approved by a designated 
unblinded biostatistician who is not a member of the study execution team (SET). 
Subjects will be assigned a unique subject number. Only subjects who have completed screening 
assessments and are eligible for participation in the study (and completed the Run-in Period and 
qualify to enter the Treatment Period [Part 2]) will be randomized to receive active study drug or 
placebo or active control during the Treatment Period. 
Randomization will be stratified by ppFEV1 determined during screening (Day -28 to Day -1 
assessment; <70 versus ≥70) in Parts 1 
and the TEZ/IVA Run-in Period (Day -14 
assessment; <70 versus ≥70) in Part 2. If the Day -14 ppFEV1 value is not valid or not available, 
the most recent available ppFEV1 value before the date of randomization will be used for 
stratification.
An interactive web response system (IWRS) will be used to assign subjects to treatment. 
9.3
Rationale for Study Elements
9.3.1
Study Design
Parts 1 
Parts 1 
 will evaluate the safety, tolerability, PK, PD, and efficacy of VX-121 administered 
in TC with TEZ/VX-561 (Part 1) 
 in subjects with CF with F/MF genotypes. 
Efficacy has not been established for a corrector, potentiator, or any corrector/potentiator 
combination in subjects with F/MF genotypes. Because there is no effective treatment for this 
population, a placebo arm will be included as the control treatment to assess whether any 
observed effects are treatment-related or simply related to the study conditions.
The Washout Period (18 ± 3 days; Section 9.1.4) is included to enable a more thorough 
evaluation of VX-121 exposure-response relationships by conducting PK and PD assessments 
during the VX-121 washout.
Part 2
Part 2 will evaluate the safety, tolerability, PK, PD, and efficacy of VX-121 in TC with 
TEZ/VX-561 in subjects with CF with the F/F genotype, if the sponsor chooses to conduct this 
optional part of the study.
The efficacy and safety of TEZ/IVA in F/F subjects have been demonstrated in 
Study VX14-661-106 (Study 661-106).12 Therefore, placebo/TEZ/IVA has been chosen as the 
control treatment to assess whether any observed effects are treatment-related or simply related 
to the study conditions. 
A 4-week TEZ/IVA Run-in Period (Section 9.1.2) is included to establish a reliable on-treatment 
(TEZ/IVA) baseline for the Treatment Period.
The 4-week Washout Period (Section 9.1.4) is included to evaluate the effect on PD and efficacy 
endpoints as subjects step down from TC to TEZ/IVA, after the VX-121 washout.

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Parts 1, 2, 
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 TC study drug dosing. Some subjects in Part 2 
(subjects with the F/F genotype) may be receiving treatment with LUM/IVA or TEZ/IVA at 
screening, while some subjects may not be receiving treatment with CFTR modulators. It is 
unlikely that subjects enrolling in Parts 1
 (subjects with F/MF genotypes) are receiving 
LUM/IVA or TEZ/IVA at screening, as the benefit of these drugs has not been established in 
patients with F/MF genotypes. Therefore, randomization will be stratified by the ppFEV1 value 
determined during screening for Parts 1 
 and during the TEZ/IVA Run-in Period, after at 
least 13 days of TEZ/IVA (Day -14 assessment), in Part 2. 
9.3.2
Study Drug Dose and Duration
VX-121 Dose Selection
Part 1 will evaluate up to 3 dose levels of VX-121 (5 mg, 10 mg, and 20 mg qd) in TC with 
TEZ/VX-561. TC-5 mg is optional. The planned doses of 5 mg, 10 mg, and 20 mg in Part 1 may 
be adjusted based on emerging data from subjects with CF in Part D of Study 001. However, no 
more than 3 dose levels of VX-121 will be assessed, and the highest dose will not exceed 
20 mg qd. In healthy subjects in Study 001, VX-121 was shown to be safe and well tolerated at 
multiple doses up to 60 mg qd when administered as monotherapy for 10 days and up to 
20 mg qd in TC for 14 days. In Part D of Study 001, a dose of 5 mg qd in TC for 28 days is 
under evaluation in subjects with CF (F/MF genotypes).
The dose levels in Part 1 are expected to provide clinical benefit (based on in vitro data) and will 
provide a wide range of VX-121 exposure for exposure-response analyses of safety and efficacy. 
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 an F508del mutation, 
including F/F, based on similar potency of the TC in HBE cells that have 1 copy or 2 copies of 
F508del.
Parts 2 
 will evaluate VX-121 at a dose of 20 mg qd. This dose may be adjusted downward 
based on emerging data from subjects with CF in Part D of Study 001.
TEZ and IVA Doses
The doses of TEZ and IVA are the same as those evaluated in Phase 3 studies of TEZ/IVA 
combination therapy (TEZ: 100 mg daily [qd]; IVA: 150 mg every 12 hours [q12h]), as well 
those evaluated in TC with VX-121 in healthy subjects in Part C of Study 001. These doses of 
TEZ and IVA are appropriate for evaluation in the TC based on in vitro experiments with 
VX-121 that evaluated similar levels of TEZ and IVA exposure after correction for 
protein-binding.
VX-561 Dosage
A VX-561 dose of 150 mg qd was selected for evaluation based on PK, safety, and efficacy 
results from prior studies of VX-561 administered as monotherapy or in TC with other 
next-generation correctors. A 150-mg qd dose of VX-561 results in similar PK parameters as 
IVA when administered alone at a dose of 150 mg q12h, including AUC0-24h and Ctrough. The 
VX-561 dose selection accounts for differences in the PK profile relative to IVA dosed q12h. 

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VX-561 has been dosed up to 225 mg qd for 7 days in a Phase 1 study and up to 200 mg qd for 
4 weeks in a Phase 2 study of subjects with CF. 
Treatment Duration
Parts 1, 2 
 will have a 4-week treatment duration because previous studies of CFTR 
modulators (IVA, LUM/IVA, and TEZ/IVA) have demonstrated that efficacy related to lung 
function (ppFEV1) can be reliably established using an endpoint at Week 4. In these studies, 
rapid improvements in ppFEV1 are observed by Day 15, with a separation between the active 
treatment and placebo groups that is sustained through 24 weeks of treatment. These studies 
were conducted in patients with different genotypes, baseline ppFEV1, and age groups, using 
CFTR modulators that had different magnitudes of response.
Administration of VX-121, TEZ, and VX-561 or IVA With Food
Oral doses of VX-121, TEZ, and VX-561 or IVA will be administered under fed conditions. This 
is consistent with how VX-121, TEZ, and IVA were administered in healthy subjects in 
Study 001. A positive food effect has been established for IVA and VX-561, and is predicted for 
VX-121.
9.3.3
Rationale for Study Assessments
The PK assessments and the majority of safety assessments are standard measurements for 
clinical studies in drug development. 
The PD and efficacy endpoints being evaluated (sweat chloride, spirometry, and patient-reported 
outcomes) are widely accepted and generally recognized as reliable, accurate, and relevant to the 
study of individuals with CF. Sweat chloride was evaluated in the registration study of IVA 
(Kalydeco), and spirometry and CFQ-R assessments were evaluated in the registration studies of 
IVA (Kalydeco) and LUM/IVA combination therapy (Orkambi). 
Rationales for other safety and PD assessments are listed below.
Spirometry
Mild post-dose declines in lung function have been observed after the initial dose with another 
CFTR corrector not included in the current study (LUM).13 Although nonclinical toxicity results 
do not indicate a risk of lung function decline for VX-121, lung function, as assessed by 
spirometry, will be included to assess for post-dose declines in spirometric indices. 

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9.4
Study Restrictions
9.4.1
Prohibited Medications
Prohibited medications are shown in Table 9-1. VX-121, TEZ, VX-561, and IVA are 
metabolized extensively via CYP3A. Therefore, use of moderate and strong inducers or 
inhibitors of CYP3A, which have the potential to alter the exposure of VX-121, TEZ, VX-561, 
or IVA will be prohibited. VX-121 is a potential inhibitor of the hepatic transporter organic 
anion transporting polypeptide 1B1 (OATP1B1). Therefore, substrates of OATP1B1, such as 
HMG-Co-A Reductase Inhibitors (“statins”) are prohibited during treatment.
A non-exhaustive list of study prohibitions and cautions for medication will be provided in the 
Study Reference Manual. 
Table 9-1
Prohibited Medications
Medicationa
Timing of Restriction
Start of Restriction
End of Restriction
Moderate and strong CYP3A 
inducers
None allowed within 14 days before 
the first dose of study drug 
None allowed through the Safety 
Follow-up Visit
Moderate and strong CYP3A 
inhibitors (except ciprofloxacin)
None allowed within 14 days before 
the first dose of study drug 
None allowed through the Safety 
Follow-up Visit
CFTR modulators other than study 
drug (e.g., Kalydeco, Orkambi, 
TEZ/IVA) 
Parts 1
None allowed within 
28 days before the first dose of study 
drug
Part 2: None allowed after the first 
dose of study drug
Parts 1 
None allowed through 
the Safety Follow-up Visit
Part 2: None allowed through 
Day 57.
OATP1B1 substrates
None allowed within 14 days before 
the first dose of the study drug 
None allowed through the Safety 
Follow-up Visit
IVA: ivacaftor; OATP1B1: organic anion transporting polypeptide 1B1; TEZ: tezacaftor
Notes: The first dose of study drug refers to the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose 
of study drug in the Treatment Period (Parts 1 
). The use of prohibited medication by subjects with medical 
needs will be addressed on a case-by-case basis with the medical monitor.
a
See Section 9.5 for guidance on concomitant medications.
9.5
Prior and Concomitant Medications
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the Screening Period through the Safety Follow-up Visit, if applicable, will be recorded in 
each subject’s source documents. For subjects who are screened but are not subsequently 
randomized in the study, details of prior medication will be documented only in the subjects’ 
source documents.

Subjects must remain on a stable CF medication (and supplement) regimen (other than 
protocol-specified changes in CFTR modulator regimen) for their CF from 28 days before 

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the start of the TEZ/IVA Run-in Period (Part 2) or 28 days before the Day 1 Visit 
(Parts 1
) through the Safety Follow-up Visit. Stable CF medication regimen is defined 
as the current medication regimen for CF that subjects have been following for at least 
28 days before the start of the TEZ/IVA Run-in Period (Part 2) or 28 days before the Day 1 
Visit (Parts 1 
). Subjects must not initiate long-term treatment with new medication 
from 28 days before the start of the TEZ/IVA Run-in Period (Part 2) or 28 days before the 
Day 1 Visit (Parts 1 
) through the Safety Follow-up Visit unless discussed and approved 
by the medical monitor. Guidelines for stable CF medication regimens for CF are as follows: 
o
Subjects who are taking daily inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study.
o
Subjects who cycle onto and off 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 or equivalent 
(chronically), or prednisone or prednisolone 60 mg/day 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 11.5.1.
9.6
Administration
Study drug will be administered orally, and subjects will swallow study drug whole, followed by 
240 mL of water. Subjects may take additional water, as needed, to swallow tablets. Subjects 
will receive the same number of tablets each day to maintain the blind. Additional information is 
provided in the Pharmacy Manual.
Study drug will be administered with a fat-containing meal or snack, such as a standard CF meal 
or snack or a standard meal, 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 q12h or qd (± 2 hours). VX-121, TEZ, and VX-561 will be 
administered qd and IVA will be administered q12h. For each subject, all doses of study 
drugs will be taken at approximately the same time each day. For example, the morning dose 
could be taken at 08:00 every morning and the evening dose could be taken at 20:00 every 
evening throughout the study.
3. 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.

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4. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. The meal or snack will be provided by the 
site for the morning dose of study drug. For the Day -14 Visit in Part 2, study drug does not 
need to be administered at the site for that visit.
5. A subject’s morning dose can be delayed by up to 6 hours to accommodate predose 
assessments on clinic visit days.
6. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused study 
drug to the site; study drug will be dispensed at each visit, as appropriate.
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 the dose with food. If more than 6 hours 
(q12h dosing) or 12 hours (qd dosing) have elapsed after the usual dosing time, the subject 
should skip that dose and resume the 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 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 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.
9.7
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.
9.8
Study Drug Interruption and Stopping Rules
In subjects who have interrupted study drug for >72 hours for any reason, the investigator should 
resume study drug only after a thorough investigation of the cause for interruption. The 
investigator should evaluate the subject’s clinical stability and only resume study drug after the 
subject is clinically stable and there is no comorbidity or condition 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.

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The medical monitor should be notified of a discontinuation of study drug or an interruption of 
study drug that lasts >72 hours for any reason and of the resumption of study drug after such 
interruption.
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) 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
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 subsequent ALT or AST values confirm the 
initial elevation that satisfied the interruption rule (above), and no convincing alternative 
etiology (e.g., acetaminophen use, viral hepatitis, alcohol ingestion) is identified, regardless of 
whether transaminase levels have improved.
All subjects in whom treatment is discontinued for elevated transaminases and/or bilirubin 
should have these levels monitored closely until levels normalize or return to baseline.
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. Regardless of the duration of 
interruption, the medical monitor should be notified prior to resumption of study drug. Upon 
resumption of study drug, transaminases and bilirubin should be assessed weekly until the Safety 
Follow-up Visit. If a protocol-defined transaminase or bilirubin elevation interruption threshold 
recurs with rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology.
Individuals who develop AEs will be monitored closely; consideration should be given to the 
need for additional safety assessments and possible consultation (e.g., with a dermatologist, GI 
specialist, or other specialist consultant). Any additional data collected (e.g. as a result of an 
outside consultation) will be considered part of the study record to provide the most complete 
safety profile of the study drug.
9.9
Removal of Subjects 
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 

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for safety, behavior, noncompliance with study procedures, or administrative reasons. A subject 
who withdraws from study drug treatment will continue to be followed unless the subject 
withdraws consent. 
Subjects will discontinue from study drug dosing and the investigator will notify the medical 
monitor if any of the following occur

Pregnancy

Meets any of the stopping (discontinuation) criteria (Section 9.8) or has other unacceptable 
toxicity as determined by the investigator
Subjects who are withdrawn from study drug dosing will complete assessments as described in 
Section 9.1.6 and may have additional PK samples collected as deemed appropriate by the 
investigator in consultation with the Vertex medical monitor. Consideration should be given to 
the need for additional safety assessments as described in Section 9.1.6. The investigator will use 
clinical judgment to determine whether assessments after study drug discontinuation should 
occur while the subject remains confined in the clinical unit or can be completed as outpatient 
visits. 
Subjects who have been enrolled 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 9.1.5), and follow up with the subject regarding any unresolved AEs.
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a 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.
Stopping rules are presented in Section 9.8.
9.10
Replacement of Subjects
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
periods may be replaced at Vertex’s discretion.
10
STUDY DRUG INFORMATION AND MANAGEMENT
Study drug refers to VX-121, TEZ, VX-561, TEZ/IVA, IVA, and their matching placebos. 

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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
Vertex will supply the VX-121 tablets, TEZ tablets, VX-561 tablets, TEZ/IVA fixed-dose 
combination (FDC) tablets, IVA tablets, and all matching placebos. Study drug labeling will be 
in compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing will be included in the Pharmacy Manual. 
10.3
Study Drug Supply, Storage, and Handling
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.
VX-121 and matching placebo will be supplied as tablets of similar size and appearance 
containing 5 mg VX-121 and 0 mg VX-121, respectively.
TEZ and matching placebo will be supplied as white tablets of similar size and appearance 
containing 50 mg TEZ and 0 mg TEZ, respectively.
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.
TEZ/IVA and matching placebo will be supplied as light yellow film-coated tablets of similar 
size and appearance containing 100 mg TEZ/150 mg IVA and 0 mg TEZ/0 mg IVA, 
respectively. 
IVA and matching placebo will be supplied as light blue film-coated tablets of similar size and 
appearance containing 150 mg IVA and 0 mg IVA, respectively.
All study drugs will be stored in accordance with the drug label or the Pharmacy Manual.
10.4
Drug Accountability
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee 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.

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10.6
Compliance 
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count.
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject. 
10.7
Blinding and Unblinding
This will be a double-blind study, with the exception of the Run-in and Washout Periods of 
Part 2, which will be open-label.
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: 

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 
or the male subject’s partner 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 unblinded analysis for any needed reviews of safety, PD, and efficacy 
data

Bioanalytical contract research organization (CRO) analyzing PK samples and Vertex 
Bioanalytical personnel who are not members of the SET but review raw data from the 
Bioanalytical CRO. The Vertex Bioanalytical SET member will continue to be blinded.

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
The Vertex study team and lead investigator(s) will also conduct blinded reviews of all available 
safety and PK data after all subjects within a cohort complete the Day 29 Visit.

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Sweat Chloride and Spirometry Blinding: 

During the conduct of the study, the Vertex study team will not have access to the spirometry 
or sweat chloride results after the morning dose on the Day 1 Visit. 

Sites, subjects, and their parents/caregivers/companions should not be informed of their 
study-related sweat chloride results during the Treatment Period regardless of whether the 
subject has prematurely discontinued treatment.

Subjects and their parents/caregivers/companions should not be informed of their 
study-related spirometry results during the Treatment Period regardless of whether the 
subject has prematurely discontinued treatment.
A limited Vertex team independent of the study team may be unblinded and have access to 
safety, PD, and efficacy data for the purpose of conducting ongoing data reviews for planning 
and enabling clinical development, regulatory, and chemistry, manufacturing, and controls 
(CMC) decisions. 
10.7.2
Unblinding
At the initiation of the study, study site personnel will be instructed on the method for breaking 
the blind. The unblinding method will be either manual or electronic.
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 unblinding. 
If investigators deem it unnecessary to unblind immediately, they will first attempt to contact the 
medical monitor to discuss 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.
Contact information for the medical monitor (and an appropriate backup) is included in the 
medical monitoring plan.
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 Vertex, the 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.
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety, unblind individual 
subjects at any time. 

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11
ASSESSMENTS
The schedule of assessments is shown in Table 3-1, Table 3-2,
11.1
Subject and Disease Characteristics
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight.
11.2
Pharmacokinetics
11.2.1
Blood Sampling
Blood samples will be collected from subjects for the evaluation of plasma concentrations of 
VX-121, TEZ, VX-561, 
. These samples may also be used for evaluation of metabolites 
of TEZ,
 and VX-561
 
 
Plasma concentration samples collected from subjects treated with placebo will not be routinely 
analyzed.
Based on emergent data, the number of sampling points for VX-121 plasma may be reduced 
and/or time points may be modified. Actual sampling times may change upon agreement of the 
clinical pharmacologist and investigator. 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. 
Table 11-1
Acceptable Pharmacokinetic Sampling Windows
Sampling Time
Time From Scheduled Sampling Allowed
Predose
Within 60 minutes before dosing
Predose on Day 2 (Part 1)
24 hours (± 2 hours) after the first dose for subjects who 
participate in the Day 2 Visit
From 1 to ≤8 hours after study drug dosing
± 15 minutes
Samples collected outside of these acceptable windows will be considered protocol deviations. 
For each visit with a PK blood draw, a record of study drug administration will be collected as 
described in Section 9.6. The collection date and exact time that each PK blood sample is drawn 
will also be recorded.
11.2.2
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 in the Laboratory Manual. 
11.2.3
Bioanalysis
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports.

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11.3
Pharmacodynamics: Sweat Chloride
Collection of sweat samples will be performed using the Macroduct® (Wescor, Logan, UT) 
collection device.
At each time point, 2 samples will be collected, 1 from each arm (left and right). Additionally, 
sweat collections will be performed on any single day during screening. At the Washout Visit(s) 
for all Parts, sweat chloride assessments should be done within 2 hours before study drug dosing 
in the morning. Collection of sweat chloride will not overlap with any other study assessments.
Sweat samples will be sent to a central laboratory for analysis of sweat chloride concentrations. 
Sweat chloride results for individual subjects will not be disclosed to the study sites.
Specific instructions for collection, handling, processing, and shipping of sweat chloride samples 
to the central laboratory will be provided in a separate Laboratory Manual.
See Section 10.7.1 for information about blinding of sweat chloride results.

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11.5
Efficacy
11.5.1
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines.9
Spirometry will be performed as outlined below:
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have

withheld their short-acting bronchodilators (e.g., albuterol and ipratropium bromide 
[Atrovent®]) for more than 4 hours before the spirometry assessment;

withheld their twice daily, 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-bronchodilator. At all other visits, all spirometry assessments should be performed 
“pre-bronchodilator”. During the Treatment Period, spirometry assessments must be performed 
before the morning dose of study drugs at approximately the same time at each visit. For the 
Day -14 Visit in Part 2, spirometry may be performed postdose. 
As noted in Table 3-1, an optional cohort in Part 1 may have spirometry performed at 24 hours 
(± 2 hours) after the first dose (subjects will return to the site to complete the 24-hour postdose 
assessment; this assessment should be performed predose on Day 2). Vertex will work with 
study sites to manage the allocation of subjects participating in the 24-hour postdose spirometry 
assessment. 
At the Washout Visit(s) for all Parts, spirometry assessments should be done within 2 hours 
before study drug dosing in the morning.
In the event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following:

If a subject’s Day 1 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 (according to the schedule of assessments detailed in Table 3-1, Table 3-2, 
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.

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See Section 10.7.1 for information about blinding of spirometry results.
11.5.2
Cystic Fibrosis Questionnaire-Revised 
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.16, 17 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.18, 19
11.6
Safety
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, PEs, spirometry, and pulse oximetry.
11.6.1
Adverse Events
All AEs will be assessed, documented, and reported in accordance with ICH GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided.
11.6.2
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 at the site. 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Section 3. Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs (see Section 13.1).
The safety laboratory test panels are shown in Table 11-2.

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Table 11-2
Safety Laboratory Test Panels
Serum Chemistry
Hematology
Urinalysisa
Glucose 
Blood urea nitrogenb
Creatinine
Sodium
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate 
Total bilirubin
Direct bilirubin
Alkaline phosphatase 
Aspartate transaminase 
Alanine transaminase 
Amylase 
Lipase 
Gamma-glutamyl transferase
Protein 
Albumin 
Creatine kinase
Total cholesterol 
Lactate dehydrogenase
Hemoglobin 
Erythrocytes
Mean corpuscular volume
Platelets 
Reticulocytes (absolute)
Leukocytes 
Differential (absolute and percent):
Eosinophils
Basophils 
Neutrophils
Lymphocytes
Monocytes 
Coagulation
Activated partial thromboplastin time 
Prothrombin time
Prothrombin time International 
Normalized Ratio 
Leukocyte esterase 
Nitrite 
Urobilinogen 
Urine protein 
pH
Urine blood 
Specific gravity 
Urine ketones 
Urine bilirubin 
Urine glucose 
Note: Glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease Study Equation for 
subjects ≥18 years of age (Section 8.2).
a
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts.
b
If blood urea nitrogen cannot be collected, urea may be substituted. 
Other Clinical Laboratory Assessments as Described in Section 3:
Pregnancy Testing:

Serum β-hCG tests will be done at screening for all female subjects (Table 3-1, Table 3-2, 

Serum and urine β-hCG tests will be done at the noted visits subsequent to screening for 
women of childbearing potential only (Table 3-1, Table 3-2, 
The pregnancy tests at screening and Day 1 (Parts 1 
 or screening and Day -28 (Part 2) 
must be negative before receiving the first dose of study drug for all women of childbearing 
potential.
If a urine pregnancy test is positive, the pregnancy will be confirmed with a serum β-hCG test. If 
pregnancy is confirmed, the procedures outlined in Section 11.6.7.2 will be followed.
FSH: Blood samples 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: CFTR genotyping will be performed for all subjects (Section 8.1).

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Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate. 
For purposes of study conduct, the central laboratory must be used for all laboratory tests. 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.
11.6.3
Physical Examinations and Vital Signs
A physical examination (PE) of all body systems and vital signs assessment will be performed at 
screening and select study visits. At other visits, symptom-directed PEs and symptom-directed 
vital signs assessments can be performed at the discretion of the investigator or designated 
healthcare provider.
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs.
The abbreviated PE will include an assessment of the following body systems: EENT, 
cardiovascular system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed. 
11.6.4
Pulse Oximetry 
Pulse oximetry is a noninvasive measure of oxygen delivery to the tissues and has been 
correlated with clinical status and lung function. Arterial oxygen saturation by pulse oximetry 
will be measured after at least a 5-minute rest and before study drug dosing. 
11.6.5
Electrocardiograms
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines:

The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws.

The subject will be instructed to rest for at least 5 minutes before having an ECG.

The test should be performed in the supine position
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.
If study sites cannot use QTcF they should discuss alternatives with the Medical Monitor.

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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.
11.6.6
Spirometry 
Refer to Section 11.5.1.
11.6.7
Contraception and Pregnancy
The effects of VX-121 monotherapy or in TC with TEZ and IVA or VX-561 on conception, 
pregnancy, and lactation in humans are not known. VX-121, TEZ, IVA, and VX-561 did not 
show genotoxic potential in a standard battery of in vitro (Ames test, chromosomal aberration, or 
micronucleus in cultured mammalian cells) and in vivo (rodent micronucleus) studies. In 
preliminary embryo-fetal developmental toxicity studies in rats and rabbits, VX-121 was 
determined to be non-teratogenic, and there were no adverse maternal and embryo/fetal 
developmental effects up to the highest dose evaluated.
11.6.7.1
Contraception
Study participation requires compliance with the contraception guidelines outlined below:
Contraception for the couple is waived for the following:

True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation 
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 
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/salpingo-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 will 
be used as a couple. Acceptable methods of contraception are listed in Table 11-3.

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Table 11-3
Acceptable Methods of Contraception
Method
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
Documented tubal ligation 4 weeks or more 
previously
Yes
Yes
Male or female condom with or without 
spermicidea
Yes
No
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide
Yes
No
Continuous use of an intrauterine device for at 
least 90 days before the first dose of study drug.
Yes
Yes
Oral, patch, implanted, or injected hormonal 
contraceptives, if used consistently and correctly
for at least 60 days before the first dose of study 
drug
Yes
See footnote b
Notes: At least 1 acceptable method of contraception must be used by couples not exempt from the contraception 
requirement. 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. 
The first dose of study drug refers to the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose of 
study drug in the Treatment Period (Parts 1 
 
a
A female condom cannot be used with a male condom due to risk of tearing.
b
Combination (estrogen and progestogen containing) and implantable or injectable progestogen-only hormonal 
contraception are considered acceptable methods of contraception. Progestogen-only oral hormonal 
contraception is NOT considered an acceptable method of contraception.
Additional notes:

Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active with a 
partner of the opposite sex.

Male subjects must not donate sperm during the period starting from the first dose of 
TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period 
(Parts 1 
 until 90 days after the last dose of study drug.

Female subjects of childbearing potential should not plan to become pregnant during the 
study or within 90 days after the last dose of study drug. For male subjects with a female 
partner of childbearing potential, the couple should not plan to become pregnant during the 
study or within 90 days after the last dose of study drug, with the exception of couples who 
plan to become pregnant by artificial insemination using sperm banked by the male subject 
before the first dose of study drug or sperm from another source.

Male subjects whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the subject received study 
drug), or is otherwise already pregnant before the male subject’s first dose of study drug, 
must be compliant with the contraception requirements. In this scenario, the male subject and 

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his female partner must commit to using a male condom (to ensure there is no exposure of 
the fetus to study drug) from signing consent through 90 days after the last dose of study 
drug.

Female subjects should not nurse a child from signing consent through 90 days following the 
last dose of study drug.

Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or authorized designee on an individual basis.
11.6.7.2
Pregnancy
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug.
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, 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 analyses on safety, efficacy, and clinical 
pharmacology for this study. Statistical analysis details on safety and efficacy 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
The primary objectives of Parts 1, 2, 
 are the evaluation of safety, tolerability, and efficacy 
of VX-121 in TC with TEZ/VX-561 
 in subjects with CF. The sample size 
calculations described below are deemed adequate to evaluate the primary objectives, based on 
clinical and statistical considerations.
Safety and Tolerability
The primary safety endpoints are safety and tolerability. Approximately 108 subjects with CF 
will be enrolled in the study with approximately 81 subjects receiving VX-121 in TC with either 
TEZ/VX-561 
. The sample size for each treatment group will provide sufficient data 
for a descriptive analysis of AEs. 
Efficacy
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through Day 29. 
A sample size of 18 subjects per treatment group provides at least 90% power to detect a mean 

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within-treatment change of 7 percentage points. These calculations assumed a standard deviation 
of 8 percentage points for the absolute change from baseline in ppFEV1 and were based on 
EAST, Version 6.4.1.
12.2
Analysis Sets
12.2.1
All Subjects Set 
The All Subjects Set is defined as all subjects who were randomized or received at least 1 dose 
of study drug. The All Subjects Set will be used for individual subject data listings and 
disposition summary tables, unless otherwise specified. 
12.2.2
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended CFTR
allele mutation and have received at least 1 dose of study drug in the Treatment Period. The FAS 
will be used for all PD and efficacy analyses in which subjects will be analyzed according to 
their randomized treatment group, unless otherwise specified.
12.2.3
Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. All safety, 
demographics, baseline characteristics, study drug exposure, and concomitant medications will 
be summarized using the Safety Set. 
12.2.4
Pharmacokinetic Set 
The PK Set will include all subjects who received at least 1 dose of study drug and for whom the 
primary PK data are considered sufficient and interpretable. The PK Set will be used to 
summarize PK plasma data. 
12.3
Statistical Analysis
This section presents a summary of the planned statistical analyses of safety, efficacy, PK, and 
PD for this study. Statistical analysis details will be provided in the SAP for this study, which 
will be finalized before clinical database lock.
12.3.1
General Considerations
Continuous variables will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, SD, median, minimum value, and maximum value. Categorical 
variables will be summarized using counts and percentages.
All individual subject data for subjects who were randomized or received at least 1 dose of study 
drug will be presented in individual subject data listings.
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. 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. Further details on 
baseline definition will be provided in SAP.
Absolute change from baseline will be calculated as post-baseline value – baseline value.

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The Treatment-Emergent (TE) Period will be from first dose date of TC to 28 days after the 
last dose date of study drug, or the completion date of study participation, whichever comes 
earlier. An additional TE Period related to the Run-in Period for Part 2 will be defined in the 
SAP, as appropriate.
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, All Subjects Set; completed Treatment Period, completed 
study/Safety Follow-up Visit, and discontinued treatment or study with a breakdown of the 
reasons for discontinuation for the FAS) will be summarized overall and by treatment group.
12.3.2.2
Demographics and Baseline Characteristics
Demographic and other baseline characteristics will include, but are not limited to age, sex, race, 
weight, height, body mass index (BMI), medical history, baseline spirometry parameters, and 
baseline sweat chloride. These characteristics will be summarized for the FAS. No statistical 
tests will be done to evaluate baseline imbalances between groups.
12.3.2.3
Prior and Concomitant Medications
Medications used in this study will be coded using the WHO-DD and categorized as the 
following for the purpose of analysis:

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 in Part 2 
will be defined in the SAP, as appropriate.
12.3.2.4
Study Drug Exposure
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.

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Dosing compliance based on study drug exposure, as primary, will be summarized for the FAS, 
and will be derived as 100 × [1 - (total number of days of study drug interruption) / (duration of 
study drug exposure in days)].
Dosing compliance based on number of tablets taken, as secondary, 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).
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.
12.3.3
Safety Analysis
Safety is a primary objective of this study. The overall safety profile of VX-121 will be assessed 
in terms of the following primary (safety) endpoints:

Incidence of treatment-emergent adverse events (TEAEs)

Clinical laboratory values (including coagulation studies)

ECG outcomes

Vital signs

Spirometry 
Safety analyses will be based on the Safety Set. No statistical hypothesis testing will be 
conducted.
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.
12.3.3.1
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.

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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
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT)
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once, only the maximum 
severity level will be presented in the severity summaries, and the strongest relationship level in 
the relationship summaries. In addition, a listing containing individual subject level AE data for 
all deaths and other serious and significant AEs will be provided separately. All AEs, including 
pre- and post-treatment AEs, will be presented in individual subject data listings.
12.3.3.2
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. This listing will include data from scheduled and unscheduled visits.
12.3.3.3
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 (HR) (QTcF), QRS duration, and HR (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 may be described in the SAP.

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12.3.3.4
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 may be described in the SAP.
12.3.3.5
Pulse Oximetry 
For the treatment-emergent pulse oximetry 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 for the percent of oxygen saturation by pulse oximetry.
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
TE Period will be summarized overall and by treatment group.
12.3.3.6
Physical Examination
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs.
12.3.4
Efficacy Analysis 
12.3.4.1
Spirometry 
The absolute change from baseline for ppFEV1 through Day 29 is a primary endpoint in Parts 1, 
2, 
. The within-group comparisons in the absolute change from baseline for ppFEV1
through Day 29 will be the primary analysis. A mixed-effects model for repeated measures 
(MMRM) with change from baseline for ppFEV1 at Days 15 and 29 as the dependent variable 
will be performed for the FAS for each part. The null within-group hypothesis of no difference in 
the mean absolute change from baseline through Day 29 for ppFEV1, in all treatment groups, by 
part, will be tested. 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. A compound symmetry covariance structure will be used to model the within-
subject errors. Conditional on the fixed effects, missing data due to treatment or study 
discontinuation will be assumed to be missing at random. 

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Adjusted means and 95% CIs of the average treatment effects through Day 29 (averaged over 
Days 15 and 29), as applicable, will be estimated within MMRM using least squares (LS) means 
via PROC MIXED in SAS, for all within-group comparisons in all parts. P values will also be 
provided for these comparisons. In addition, adjusted means and 95% CIs for the absolute 
change from baseline for ppFEV1 through Day 29 will be estimated for between-group 
comparisons.
For endpoints other than primary, no multiplicity adjustments will be made and the 
corresponding P values for these endpoints will be considered as nominal.
12.3.4.2
Analysis of CFQ-R
One of the secondary efficacy variables is absolute change in the CFQ-R respiratory domain 
score from baseline at Day 29. Analysis of this secondary efficacy variable will be similar to that 
for the absolute change from baseline in ppFEV1. Additional details of these analyses will be 
provided in the SAP.
12.3.5
Pharmacodynamic Analysis 
The absolute change in sweat chloride from baseline through Day 29 is a secondary endpoint 
used to evaluate the PD objective of the study. Analysis of sweat chloride will be similar to that 
for the absolute change from baseline in ppFEV1. Adjusted means and 95% CIs of the average 
treatment effects through Day 29, for all within-group and between-group comparisons for each 
part, separately, will be estimated within MMRM, with appropriate adjustment for covariates. 
P values will also be provided for all within-group comparisons. 
Additional details of the analysis will be provided in the SAP.
12.3.7
Interim and Independent Data Monitoring Committee Analyses
12.3.7.1
Interim Analysis
Not applicable
12.3.7.2
Independent Data Monitoring Committee Analysis
The IDMC (Section 9.1.7) will conduct safety review of study data. IDMC analyses will be 
conducted as outlined in the IDMC Charter.
12.4
Clinical Pharmacology Analysis
12.4.1
Pharmacokinetic Analysis
Individual concentration values of VX-121, TEZ, 
, VX-561, and respective metabolites will 
be listed, and summary statistics for concentrations of VX-121, TEZ,
 and VX-561 by 
treatment will be provided. Population PK analyses will be presented in a separate report.

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12.4.2
Pharmacokinetic/Pharmacodynamic Analyses
PD assessments to be included in PK/PD analyses may include sweat chloride, ppFEV1, as well 
as CFQ-R. Comparison between postdose and predose values will be performed and expressed as 
a change from baseline. 
A sequential approach will be used to perform the population PK/PD analysis. The Bayesian 
estimates of individual PK parameters from the final population PK model will be used to 
simulate PK profiles for each subject. The simulated VX-121, TEZ, VX-561, 
, or metabolite 
plasma concentrations will be used in the potential pharmacological response models to describe 
changes in each endpoint from baseline. Fixed- and random-effect parameter estimates and the 
associated asymptotic SEs will be estimated. Descriptive statistics will be used to summarize 
Bayesian estimates of individual PK/PD parameters obtained from the population PK/PD model.
A detailed description of the planned population PK/PD analysis will be presented in the 
Modeling and Simulation Plan.
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

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Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator.
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE.
13.1.1.3
Documentation of Adverse Events
All AEs will be collected from the time the ICF is signed until the following times:

For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent)

For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit

For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of
o
35 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 will be 
recorded only in the subject’s source documents. The following data will be documented for 
each AE:

Description of the event

Classification of “serious” or “nonserious”

Date of first occurrence and date of resolution (if applicable)

Severity 

Causal relationship to study drug(s) 

Action taken 

Outcome 

Concomitant medication or other treatment given
13.1.1.4
Adverse Event Severity
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
November 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” The 
severity of an AE that does not appear in the CTCAE will be determined according to the 
definitions in Table 13-1. 

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Table 13-1
Grading of AE Severity 
Classification
Definition
Mild (Grade 1)
Mild level of discomfort and does not interfere with regular activities
Moderate (Grade 2)
Moderate level of discomfort and significantly interferes with regular activities
Severe (Grade 3)
Significant level of discomfort and prevents regular activities
Life-threatening (Grade 4)
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death 
13.1.1.5
Adverse Event Causality
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories 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 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 in Table 13-3.
Table 13-3
Classifications for Study Drug Action Taken With Regard to an AE
Classification
Definition
Dose not changed
Study drug dose not changed in response to an AE
Dose reduced
Study drug dose reduced in response to an AE
Drug interrupted
Study drug administration interrupted in response to an AE 
Drug withdrawn
Study drug administration permanently discontinued in response to an AE
Not applicable
Action taken regarding study drug administration does not apply. 
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible.

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13.1.1.7
Adverse Event Outcome
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4.
Table 13-4
Classifications for Outcome of an AE
Classification
Definition
Recovered/resolved
Resolution of an AE with no residual signs or symptoms
Recovered/resolved with 
sequelae
Resolution of an AE with residual signs or symptoms
Not recovered/not 
resolved (continuing)
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing
Fatal
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE.
Unknown
Outcome of an AE is not known (e.g., a subject lost to follow up)
13.1.1.8
Treatment Given
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE.
13.1.2
Serious Adverse Events
13.1.2.1
Definition of a Serious Adverse Event
An SAE is any AE that meets any of the following outcomes:

Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation 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 

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associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE.
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.
13.1.2.2
Reporting and Documentation of Serious Adverse Events
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS within 24 hours of identification. 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 of identification. 
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, the SAE Form will be completed for new/initial events as well as to 
report follow-up information on previously reported events. Investigators are asked to report 
follow-up information as soon as it becomes available to ensure timely reporting to health 
authorities. 
Please send completed SAE Forms to Vertex GPS via:
Email: 
(preferred choice)
Fax:
 
For questions, contact telephone: 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) 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 the outcome to Vertex using the SAE Form.
13.1.2.3
Expedited Reporting and Investigator Safety Letters
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs. 

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It is the responsibility of the investigator or designee to promptly notify the local IRB/IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects.
13.2
Administrative Requirements
13.2.1
Ethical Considerations
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations.
13.2.2
Subject Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from the 
subject before study participation. The method of obtaining and documenting the informed 
consent and assent (if applicable) and the contents of the consent will comply with ICH GCP and 
all applicable laws and regulations and will be subject to approval by Vertex or its designee.
13.2.3
Investigator Compliance
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities.
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from 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 will be limited to the site and the study physician and will not be disclosed to Vertex. 

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As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection.
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will 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.
13.2.8
End of Study
The end of study is defined as the last scheduled visit (or contact) of the last subject.

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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 subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application. 
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database.
13.4
Monitoring
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed.
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements.
13.5
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible. 
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status.
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 them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible. 
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator’s 
study file.

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13.6
Publications and Clinical Study Report
13.6.2
Clinical Study Report 
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations. 

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14
REFERENCE
1
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 24 March 2019.
2
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 24 March 2019.
3
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: https://www.ema.europa.eu/en/committees/committee-orphan-
medicinal-products-comp. Accessed 24 March 2019.
4
Cystic Fibrosis Foundation. Patient Registry: 2016 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2017.
5
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: 2015 Annual Data Report. London, 
UK: Cystic Fibrosis Trust; 2016.
6
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88.
7
CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional 
TRanslation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins 
University, the Hospital for Sick Children. Available at: http://www.cftr2.org. Accessed 
24 March 2019.
8
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43.
9
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38.
10
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-
70.
11
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54.
12
Vertex Pharmaceuticals Incorporated. Tezacaftor/Ivacaftor (VX-661)/VX-770) 
Investigator's Brochure, Version 1.0. Report date: 06 October 2017.
13
Vertex Pharmaceuticals Incorporated. Lumacaftor (VX-809) Investigator's Brochure, 
Version 7.0. Report date: 27 March 2014.

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16
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86.
17
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54.
18
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76.
19
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85.
20
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4.
21
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018.

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APPENDIX A 
Eligible MF CFTR Mutations
“MF” mutations are a subset of minimal function mutations that are non-responsive to TEZ, 
IVA, or TEZ/IVA. A mutation is considered an MF mutation if it meets at least 1 of the 
following 2 criteria:
(1) biological plausibility of no translated protein (genetic sequence predicts the complete 
absence of CFTR protein), or
(2) in vitro testing that supports lack of responsiveness to TEZ, IVA, or TEZ/IVA, and evidence 
of clinical severity on a population basis (as reported in large patient registries).
Inclusion of MF Mutations Based on In Vitro Testing
Mutations that were considered to be MF mutations based on in vitro testing met the following 
criteria in in vitro experiments:

baseline chloride transport that was <10% of wild-type CFTR

an increase in chloride transport of <10% over baseline following the addition of TEZ, 
IVA, or TEZ/IVA in the assay
These mutations also had evidence of clinical severity on a population basis (per CFTR2 patient 
registry; accessed on 15 May 2018). Patients with these mutations on one allele and F508del on 
the other allele exhibited evidence of clinical severity as defined as:

average sweat chloride >86 mmol/L, and

prevalence of pancreatic insufficiency (PI) >50%
These clinical severity criteria do not apply to the individual subjects to be enrolled in the study, 
but were used to categorize each mutation on a population level.
Eligible MF Mutations
The list below represents acceptable mutations, which are detectable by an FDA-cleared 
genotyping assay or other method (e.g., sequencing); however, this list may not include every 
eligible mutation, and investigators should contact the medical monitor regarding other 
mutations that may also meet study eligibility criteria.

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CFTR Mutations Eligible for VX18-121-101 (Parts 1 
MF Mutation Category
Mutation
Nonsense mutations
Q2X
L218X
Q525X
R792X
E1104X
S4X
Q220X
G542X
E822X
W1145X
W19X
Y275X
G550X
W882X
R1158X
G27X
C276X
Q552X
W846X
R1162X
Q39X
Q290X
R553X
Y849X
S1196X
W57X
G330X
E585X
R851X
W1204X
E60X
W401X
G673X
Q890X
L1254X
R75X
Q414X
Q685X
S912X
S1255X
L88X
S434X
R709X
Y913X
W1282X
E92X
S466X
K710X
Q1042X
Q1313X
Q98X
S489X
Q715X
W1089X
Q1330X
Y122X
Q493X
L732X
Y1092X
E1371X
E193X
W496X
R764X
W1098X
Q1382X
W216X
C524X
R785X
R1102X
Q1411X
Canonical splice mutations 
185+1G→T
711+5G→A
1717-8G→A
2622+1G→A
3121-1G→A
296+1G→A
712-1G→T
1717-1G→A
2790-1G→C
3500-2A→G
296+1G→T
1248+1G→A
1811+1G→C
3040G→C 
(G970R)
3600+2insT
405+1G→A
1249-1G→A
1811+1.6kbA→G
3850-1G→A
405+3A→C
1341+1G→A
1811+1643G→T
3120G→A
4005+1G→A
406-1G→A
1525-2A→G
1812-1G→A
3120+1G→A
4374+1G→T
621+1G→T
1525-1G→A
1898+1G→A
3121-2A→G
711+1G→T
1898+1G→C
Small (≤3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations
182delT
1078delT
1677delTA
2711delT
3737delA
306insA
1119delA
1782delA
2732insA
3791delC
306delTAGA
1138insG
1824delA
2869insG
3821delT
365-366insT
1154insTC
1833delT
2896insAG
3876delA
394delTT
1161delC
2043delG
2942insT
3878delG
442delA
1213delT
2143delT
2957delT
3905insT
444delA
1259insA
2183AA→G a
3007delG
4016insT
457TAT→G
1288insTA
2184delA
3028delA
4021dupT
541delC
1343delG
2184insA
3171delC
4022insT
574delA
1471delA
2307insA
3171insC
4040delA
663delT
1497delGG
2347delG
3271delGG
4279insA
849delG
1548delG
2585delT
3349insT
4326delTC
935delA
1609del CA
2594delGT
3659delC
Non-small (>3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations
CFTRdele1
CFTRdele16-17b
1461ins4
CFTRdele2
CFTRdele17a,17b
1924del7
CFTRdele2,3
CFTRdele17a-18
2055del9→A
CFTRdele2-4
CFTRdele19
2105-2117del13insAGAAA
CFTRdele3-10,14b-16
CFTRdele19-21
2372del8
CFTRdele4-7
CFTRdele21
2721del11
CFTRdele4-11
CFTRdele22-24
2991del32
CFTR50kbdel
CFTRdele22,23
3667ins4
CFTRdup6b-10
124del23bp
4010del4
CFTRdele11
602del14
4209TGTT→AA
CFTRdele13,14a
852del22
CFTRdele14b-17b
991del5

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CFTR Mutations Eligible for VX18-121-101 (Parts 1 
MF Mutation Category
Mutation
Missense mutations that  

Are not responsive in 
vitro to TEZ, IVA, or 
TEZ/IVA
and

%PI >50% and SwCl-
>86 mmol/L
A46Db
V520F
Y569Db
N1303K
G85E
A559Tb
L1065P
R347P
R560T
R1066C
L467Pb
R560S
L1077Pb
I507del
A561E
M1101K
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; SwCl: sweat chloride; TEZ: tezacaftor
Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and Functional 
Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital for Sick 
Children. Available at: http://www.cftr2.org/. Accessed 15 May 2018.
Notes: %PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic 
insufficient; SwCl: mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry.
a
Also known as 2183delAA→G. 
b
Unpublished data.

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' 
15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol#: 
VX18-121-101 j Version#: 
4.0 
1 Version Date: 
09 May 2019 
Study Title: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and 
Efficacy ofVX-121 Combination Therapy in Subjects Aged 18 Years and Older With Cystic 
Fibrosis 
This clinical study protocol has been reviewed and approved by the sponsor. 
Vertex Pharmaceuticals Incorporated 
 

Protocol VX18-121-101, Version 4.0
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Vertex Pharmaceuticals Incorporated
15.2
Investigator Signature Page
Protocol #: 
VX18-121-101
Version #:
4.0
Version Date:
09 May 2019
Study Title: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and 
Efficacy of VX-121 Combination Therapy in Subjects Aged 18 Years and Older With Cystic 
Fibrosis
I have read Protocol VX18-121-101, Version 4.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-121, tezacaftor, VX-561, and ivacaftor 
and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential.
Printed Name
Signature
Date