Clinical trial NCT03768089
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-03-20; Completion date: 2019-05-03
Enrollment: 115 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate safety and tolerability of VX-121 in healthy subjects and in subjects with cystic fibrosis (CF).

Detailed description:

Arms: arm 1: Participants received single dose of placebo matched to VX-121. arm 2: Participants received single dose of VX-121 10 milligrams (mg). arm 3: Participants received single dose of VX-121 20 mg. arm 4: Participants received single dose of VX-121 5 mg or matched placebo without milk, followed by open label VX-121 5 mg with milk. arm 5: Participants received single dose of VX-121 40 mg. arm 6: Participants received single dose of VX-121 60 mg. arm 7: Participants received single dose of VX-121 10 mg suspension on Day 1, VX-121 10 mg tablet on Day 9, followed by VX-121 10 mg tablet with milk on Day 17. arm 8: Participants received placebo matched to VX-121 for 10 days. arm 9: Participants received VX-121 10 mg once daily (qd) for 10 days. arm 10: Participants received VX-121 20 mg qd for 10 days. arm 11: Participants received VX-121 40 mg qd for 10 days. arm 12: Participants received VX-121 60 mg qd for 10 days. arm 13: Participants received placebo matched to VX-121/TEZ/IVA for 14 days. arm 14: Participants received VX-121 10 mg qd/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) for 14 days. arm 15: Participants received VX-121 20 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 14 days. arm 16: Participants received VX-121 5 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 14 days. arm 17: Participants received placebo matched to VX-121/TEZ/IVA for 4 weeks. arm 18: Participants received VX-121 5 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks.
Interventions: intervention 1: Placebo (matched to VX-121 suspension) intervention 2: VX-121 (Suspension) intervention 3: TEZ/IVA intervention 4: IVA intervention 5: Placebo (matched to TEZ/IVA) intervention 6: Placebo (matched to IVA) intervention 7: VX-121 (Tablet) intervention 8: Placebo (matched to VX-121 tablet)
Intervention descriptions: intervention 1: Placebo matched to VX-121 suspension for oral administration. intervention 2: Suspension for oral administration. intervention 3: Fixed-dose combination tablet for oral administration. intervention 4: Tablet for oral administration. intervention 5: Placebo matched to TEZ/IVA for oral administration. intervention 6: Placebo matched to IVA for oral administration. intervention 7: Tablet for oral administration. intervention 8: Placebo matched to VX-121 tablet for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 85 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 1/2 Study of VX-121 in Healthy Subjects and 
in Subjects With Cystic Fibrosis  
Vertex Study Number: VX17-121-001 
EudraCT Number: 2018-000126-55 
Date of Protocol: 27 July 2018 (Version 3.0) 
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. 




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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 1/2 Study of VX-121 in Healthy Subjects and in Subjects With Cystic 
Fibrosis 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 1/2 safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and 
efficacy 
 
 
Objectives 
Primary Objectives 
Part A: To evaluate the safety and tolerability of single ascending doses of 
VX-121 in healthy subjects 
Part B: To evaluate the safety and tolerability of multiple ascending doses of 
VX-121 for 10 days in healthy subjects 
Part C: To evaluate the safety and tolerability of multiple ascending doses of 
VX-121 administered in triple combination (TC) with tezacaftor (TEZ)/ivacaftor 
(IVA) for 14 days in healthy subjects  
Part D: To evaluate the safety and tolerability of VX-121 in TC with TEZ/IVA in 
subjects with cystic fibrosis (CF) 
Secondary Objectives 
Part A 
• To evaluate the PK of VX-121 after administration of single ascending doses of 
VX-121 in healthy subjects 
• To evaluate the relative bioavailability (BA) of a tablet formulation of VX-121 
relative to suspension in healthy subjects 
• To evaluate the effect of milk on the PK of VX-121 after administration of 
suspension and tablet formulations 
Part B 
To evaluate the PK of VX-121 after administration of multiple ascending doses of 
VX-121 for 10 days in healthy subjects 
Part C 
• To evaluate the PK of VX-121 after administration of multiple ascending doses 
of VX-121 in TC with TEZ/IVA for 14 days in healthy subjects 
• To evaluate the PK of TEZ, IVA, and their respective metabolites when 
administered in TC with VX-121 for 14 days in healthy subjects 
Part D  
• To evaluate the PK of VX-121 when administered in TC with TEZ/IVA in 
subjects with CF 
• To evaluate the PK of TEZ, IVA, and their respective metabolites when 
administered in TC with VX-121 in subjects with CF 
• To evaluate the PD effect of VX-121 in TC with TEZ/IVA in subjects with CF 
• To evaluate the efficacy of VX-121 in TC with TEZ/IVA in subjects with CF 
 
 
Endpoints 
Primary Endpoint 
Parts A, B, C, and D: Safety and tolerability, based on the assessment of adverse 
events (AEs), laboratory test results, standard 12-lead ECGs, vital signs, and 
spirometry (Part D only) 
 
 


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Secondary Endpoints 
• Parts A, B, C, and D: PK parameter estimates of VX-121 derived from plasma 
concentration-time data 
• Parts C and D: PK parameter estimates for TEZ and metabolites (M1-TEZ and 
M2-TEZ) and IVA and metabolites (M1-IVA and M6-IVA) derived from plasma 
concentration-time data 
• Part D: Sweat chloride levels as a biomarker of PD effects 
• Part D: Spirometry as preliminary evidence of efficacy 
 
 
Number of Subjects 
Approximately 132 subjects: 56 in Part A, 48 in Part B, 16 in Part C, and 12 in 
Part D 
 
 
Study Population 
Parts A, B, and C: Healthy male subjects and female subjects of non-childbearing 
potential between the ages of 18 and 55 years, inclusive 
Part D: Male subjects and female subjects of non-childbearing potential with 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 
 
 
Investigational Drug 
Parts A and B 
 
Active substance: VX-121 
 
Activity: CFTR corrector 
 
Strength and route of administration:  
Suspension: Drug substance will be reconstituted at various concentrations for oral 
administration 
Tablet: 5-mg tablet for oral administration 
 
 
 
Parts C and D 
 
Active substance: VX-121 
 
Activity: CFTR corrector 
 
Strength and route of administration:  
Suspension: Drug substance will be reconstituted at various concentrations for oral 
administration 
Tablet: 5-mg tablet for oral administration 
 
 
 
Active substance: TEZ (VX-661) and IVA (VX-770) 
 
Activity: CFTR corrector and potentiator (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 
 
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 12 days 
for Cohorts A1, A2, A4, A5, and A6, 18 to 20 days for Cohort A3, 26 to 28 days 
for Cohort A9, 18 to 21 days for Part B, 22 to 25 days for Part C, and 


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approximately 7 to 9 weeks for Part D. 
 
 
Study Design 
This is a 4-part, randomized, double-blind, placebo-controlled, single- and 
multiple-dose, first-in-human and first-in-patient dose escalation study of VX-121 
that includes an evaluation of relative BA and the effect of milk on VX-121 
exposure. 
Parts A, B, and C (Healthy Subjects) 
Approximately 7 cohorts are planned for Part A (A1 through A6 and A9), 
approximately 6 cohorts are planned for Part B, and approximately 2 cohorts are 
planned for Part C. Up to 2 additional cohorts each in Parts A, B, and C may be 
enrolled based on data from previous cohorts. 
Approximately 8 subjects in each cohort (except Cohort A9) will be randomized 
3:1 to receive VX-121 (or VX-121 in TC with TEZ/IVA in Part C) or placebo as a 
suspension, under fed conditions. All subjects in Cohort A3 will also receive an 
open-label dose of VX-121 to evaluate the effect of milk on a suspension 
formulation. Cohort A9 will enroll approximately 8 subjects who will receive 
open-label VX-121 to evaluate the BA of a tablet relative to suspension 
formulation and the effect of milk on the tablet formulation. The tablet formulation 
may then be used instead of the suspension in any remaining cohorts of the study if 
supported by preliminary PK data from Cohort A9. The existing restrictions on 
dairy consumption may be removed pending the results from Cohorts A3 and/or 
A9. 
The decision to initiate successive cohorts and dose selection will be based on 
safety and tolerability data from preceding dose group(s) and available PK data 
from a minimum of 6 subjects (to ensure 4 subjects receiving active drug) in the 
preceding cohort.  
Part A includes Cohorts A1 through A6, which are single-dose escalation cohorts. 
Up to 2 additional cohorts (Cohorts A7 and A8) may be enrolled based on data 
from previous cohorts. Cohort A9 is a single-dose cohort evaluating relative BA.  
Cohorts A1 Through A6 (up to A8): VX-121 or placebo will be administered, on 
the morning of Day 1. The starting dose (Cohort A1) will be 10 mg. 
 
 
 
 Dosing will be 
staggered in Cohort A1 so that 2 subjects are dosed (1 with VX-121 and 1 with 
placebo) at least 24 hours before the remaining 6 subjects. Staggering at higher 
doses may be conducted if deemed necessary based on review of emerging safety 
data. The planned doses for Cohorts A1 through A6 are 10 mg, 20 mg, 5 mg, 
40 mg, 60 mg, and up to 90 mg. Doses may be modified based on emerging data. If 
conducted, the dose(s) in Cohorts A7 or A8 may be a replicate of a dose evaluated 
in Cohorts A1 through A6 or may be increased above 90 mg, pending emerging 
safety, tolerability, and PK data from Cohorts A1 through A6.  
Cohort A3: In addition to randomized study drug administration described above, 
after a washout of at least 8 days all subjects will receive an additional 5 mg single 
dose of open-label VX-121 suspension with milk.  
Cohort A9 has an open-label, single sequence design in which subjects will receive 
a single dose of VX-121 on 3 dosing occasions with at least an 8-day washout 
between dosing occasions. VX-121 doses include a single oral dose of suspension, 
a single oral dose of tablet, and a single oral dose of tablet with milk (the planned 
dose is 10 mg for both formulations, but it will not exceed the highest dose that was 
safe and well tolerated in a previous Part A cohort).  
Part B is a 6-cohort, multiple-dose escalation component (Cohorts B1 through B6). 
Up to 2 additional cohorts (Cohorts B7 and B8) may be conducted. Multiple oral 


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doses of VX-121 or placebo will be administered for 10 days once daily (qd). 
The planned doses for Cohorts B1 through B4 are 10 mg qd, 20 mg qd, 40 mg qd, 
and 60 mg qd. Doses may be modified based on emerging data. The doses for 
Cohorts B5 and B6 are to be determined (TBD) based on emerging data. 
Part B may be initiated while Part A is ongoing after review of safety, tolerability, 
and PK data. The total daily dose in the first Part B cohort (Cohort B1) will be at 
least 1 dose level below the highest Part A dose for which safety and tolerability 
results are available and supportive. 
Part C is a 2-cohort, multiple-dose escalation of VX-121 administered in TC with 
TEZ/IVA for 14 days (Cohorts C1 and C2). Up to 2 additional cohorts (Cohorts C3 
and C4) may be conducted.  
The planned doses for Cohorts C1 and C2 are 10 mg qd and 20 mg qd. Doses may 
be modified based on emerging data. 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. 
Part C may be initiated while Parts A and B are ongoing after review of safety, 
tolerability, and PK data.  
The total daily dose in the first Part C cohort (Cohort C1) will be at least 1 dose 
level below the highest total daily Part B dose for which safety and tolerability 
results are available and supportive. Dosing will be staggered in Cohort C1, with 
2 of the 8 subjects receiving study drug (1 subject receiving VX-121 in TC with 
TEZ/IVA and 1 subject receiving triple placebo) at least 24 hours before the 
remaining 6 subjects. Staggering at higher doses may be conducted if deemed 
necessary based on review of emerging safety data. 
Part D (Subjects With CF, F/MF Genotype) 
Part D has a randomized, double-blind, placebo-controlled, parallel-group design. 
After completing the Screening Period, approximately 12 subjects will be 
randomized 3:1 to TC:placebo. Subjects will receive 4 weeks of treatment.  
Screening in Part D will be initiated after the completion of Parts A, B, and C 
(cohorts needed for Part D dose selection only) through the Safety Follow-up Visit. 
The decision to proceed to Part D will be based on an evaluation of safety, 
tolerability, and PK data from completed cohorts in Parts A, B, and C. These data 
will be submitted to the IEC for approval before proceeding to screening for 
Part D. Based on preliminary data from Parts A, B, and C, the planned dose of 
10 mg qd is predicted to provide an approximate AUC0-24h of 10 µg∙h/mL, which is 
within the range of predicted efficacious exposure based on in vitro data. Based on 
emerging safety, tolerability, and PK data from Parts A, B, and C, the planned dose 
for Part D may be lowered to 5 mg qd. The total daily dose of VX-121 in Part D 
will be at least 1 dose level below the highest total daily dose tested in Part C. The 
dosage of TEZ/IVA in the TC 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. 
 
 
Assessments 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical 
evaluation of vital signs, ECGs, physical examinations, and spirometry (Part D). 
Pharmacokinetics 
Blood samples will be collected from all subjects for the evaluation of plasma 
concentrations of VX-121, TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA 
and metabolites (M1-IVA and M6-IVA).  
 


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Pharmacodynamics  
Sweat chloride (Part D) 
Efficacy 
Spirometry (Part D) 
 
 
Statistical Analyses 
Eight subjects per dose cohort randomized 3:1 (active:placebo) is a typical sample 
size for first-in-human studies in healthy subjects and is considered sufficient to 
achieve the objectives of the study. Part D will enroll approximately 12 subjects 
with CF randomized 3:1 (active:placebo) and is considered sufficient to meet the 
objectives of the study. Only descriptive analyses will be provided for the safety 
data comprising AEs, clinical laboratory assessments, ECGs, vital signs, and 
spirometry (Part D only); no statistical hypothesis testing will be performed. The 
PK results for VX-121, TEZ and metabolites, and IVA and metabolites will be 
reported with descriptive statistics. The PD analysis of sweat chloride and efficacy 
analysis of spirometry will be performed using descriptive statistics and a 
mixed-effects model for repeated measures (MMRM). 
 
 
Interim Analyses 
An interim analysis (IA) may be performed for Parts A, B, and C after all subjects 
in Part C have completed the Safety Follow-up Visit.  


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are shown in Table 3-1 through Table 3-7. 
Table 3-1 
Study VX17-121-001: Parts A, B, and C Screening 
Event/Assessment 
Screening Visit 
Day -28 to Day -2 
Informed consent  
X 
Demographics 
X 
Medical history 
X 
Medications reviewa 
X 
Height, weight, BMI, and vital signsb 
X 
Full physical examination 
X 
Standard 12-lead ECGc 
X 
Serum FSH (postmenopausal female subjects only) 
X 
Serum β-hCG (all female subjects) 
X 
Serology (HBsAg, HCV, HIV-1, and HIV-2 Abs) 
X 
Serum chemistry 
X 
Hematology 
X 
Coagulation 
X 
Drug test (urine or blood), including cotinine  
X 
Alcohol test (urine, blood, or breath) 
X 
Urinalysis 
X 
Adverse events 
Continuous from signing of informed consent form (ICF) 
through Safety Follow-up Visit 
 a  
All medications taken from 28 days before the first dose of study drug through the end of the study will be 
recorded. 
b  
Weight and height will be measured with shoes off. Vital signs will be performed after the ECG, after the 
subject has been at rest for at least 5 minutes.  
c  
A standard 12-lead ECG will be performed in the supine position after the subject has been at rest for at least 
5 minutes. The ECG will be done before any other procedures that may affect heart rate, such as blood draws. 


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Table 3-2 
Study VX17-121-001: Part A, Cohorts A1, A2, A4, A5, and A6, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
(7 to 10 Days After Last Dose 
of Study Drug)b 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Inpatient days 
X 
X 
X 
X 
X 
Xc 
 
Outpatient visit 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Weightd 
X 
 
 
 
 
 
 
Standard 12-lead ECGe 
X 
X 
 
 
 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
Full physical examination 
X 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
 
X 
Hematology 
X 
 
X 
 
 
 
X 
Blood for PK analysisg 
 
X 
X 
X 
X 
X 
X 
Drug test (urine or blood), including cotinine 
X 
 
 
 
 
 
 
Alcohol test (urine, blood, or breath) 
X 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
X 
Study drug administrationh 
 
X 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewi 
Continuous from signing of ICF through Safety Follow-up Visit 
Treatment and procedures review 
Continuous from signing of ICF through Safety Follow-up Visit 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. 
b  
Additional PK samples and safety assessments may also be performed at the discretion of the investigator. See Section 9.1.1.4 for details. 
c  
Subjects will be discharged from the CRU on Day 5 after completion of the study visit assessments. 
d  
Weight will be measured with shoes off.  
e  
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes. The ECG will be done before any other procedures 
that may affect heart rate, such as blood draws. On Day 1, ECGs will be collected before dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing.  
f  
Vital signs will be performed after the subject has been at rest for at least 5 minutes. 
g  
Blood samples for PK assessments will be collected on Day 1 before dosing (0 hours), and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), and 96 
(Day 5) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1. At the Safety Follow-up Visit, a single blood sample for PK analysis will be 
collected. 
h  
Study drug will be administered in the fed state (Section 9.6.1). 
i  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 3-3 
Study VX17-121-001: Part A, Cohort A3, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
(7 to 10 Days 
After Last Dose 
of Study Drug)b 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
 
Outpatient visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead ECGe 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Hematology 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Blood for PK analysisg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug test (urine or blood), including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, blood, or breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Study drug administration 
 
Xh 
 
 
 
 
 
 
 
Xi 
 
 
 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewj 
Continuous from signing of ICF through Safety Follow-up Visit 
Treatment and procedures review 
Continuous from signing of ICF through Safety Follow-up Visit 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. 
b  
Additional PK samples and safety assessments may also be performed at the discretion of the investigator. See Section 9.1.1.4 for details.  
c  
Subjects will be discharged from the CRU on Day 16 after completion of the study visit assessments. 
d  
Weight will be measured with shoes off.  
e  
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes. The ECG will be done before any other procedures 
that may affect heart rate, such as blood draws. On Days 1 and 9, ECGs will be collected before dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing.  
f  
Vital signs will be performed after the subject has been at rest for at least 5 minutes. 
g  
Blood samples for PK assessments will be collected on Days 1 and 9 before dosing (0 hours), and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Days 2, 10), 36 (Days 2, 10), 
48 (Days 3, 11), 72 (Days 4, 12), 96 (Days 5, 13), 120 (Days 6, 14), 144 (Days 7, 15), and 168 (Days 8, 16) hours after dosing. Acceptable PK sampling windows are 
provided in Table 11-1. At the Safety Follow-up Visit, a single blood sample for PK analysis will be collected. 
h  
Subjects will be randomized 3:1 to receive VX-121 or placebo. Study drug will be administered in the fed state (Section 9.6.1). 
i  
All subjects will receive open-label VX-121. Study drug will be administered in the fed state and with milk (Section 9.6.1).  
j  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 3-4 
Study VX17-121-001: Part A, Cohort A9, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
(7 to 10 Days After Last 
Dose of Study Drug)b 
-1 
1 
2 
3,4,5, 
6,7,8 
9 
10 
11,12,13, 
14,15,16 
17 
18 
19,20,21, 
22,23,24 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
 
Outpatient visit 
 
 
 
 
 
 
 
 
 
 
X 
Weightd 
X 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
X 
 
 
X 
 
X 
Hematology 
X 
 
X 
 
 
X 
 
 
X 
 
X 
Blood for PK analysisg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug test (urine or 
blood), including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, 
blood, or breath) 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
X 
Study drug 
adminstrationh 
 
X 
 
 
X 
 
 
X 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewi 
Continuous from signing of ICF through Safety Follow-up Visit 
Treatment and procedures 
review 
Continuous from signing of ICF through Safety Follow-up Visit 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. 
b  
Additional PK samples and safety assessments may also be performed at the discretion of the investigator. See Section 9.1.1.4 for details.  
c  
Subjects will be discharged from the CRU on Day 24 after completion of the study visit assessments. 
d  
Weight will be measured with shoes off.  
e  
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes. The ECG will be done before any other procedures 
that may affect heart rate, such as blood draws. On Days 1, 9, and 17, ECGs will be collected before dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
f  
Vital signs will be performed after the subject has been at rest for at least 5 minutes. 
g 
Blood samples for PK assessments will be collected on Days 1, 9, and 17 before dosing (0 hours), and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Days 2, 10, 18), 36 (Days 2, 10, 18), 
48 (Days 3, 11, 19), 72 (Days 4, 12, 20), 96 (Days 5, 13, 21), 120 (Days 6, 14, 22), 144 (Days 7, 15, 23), and 168 (Days 8, 16, 24) hours after dosing. Acceptable PK sampling 
windows are provided in Table 11-1. At the Safety Follow-up Visit, a single blood sample for PK analysis will be collected. 
h  
Study drug will be administered as a suspension in the fed state on the Day 1 Visit, as a tablet in the fed state on the Day 9 Visit, and as a tablet in the fed state and with milk 
on the Day 17 Visit (Section 9.6.1).  
i  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 3-5 
Study VX17-121-001: Part B, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
(7 to 10 Days After 
Last Dose of Study 
Drug)b 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
 
Outpatient visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightd 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Continuous ECGse 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Standard 12-lead ECGf 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Hematology 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
4β-hydroxycholesterol 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Blood for PK analysish 
 
X 
X 
(if qd) 
 
 
X 
X 
(if qd) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug test (urine or blood), 
including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, blood, or 
breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise.  
b  
Additional PK samples and safety assessments may also be performed at the discretion of the investigator. See Section 9.1.1.4 for details. 
c  
Subjects will be discharged from the CRU on Day 14 after completion of the study visit assessments. 
d  
Weight will be measured with shoes off.  
e  
Continuous ECGs will be extracted in up to 10 replicates on Day 1 before dosing at -60, -50, and -40 minutes, and on Day 10 before dosing (at -40 minutes) and at 1, 2, 4, 6, 
8, 10, 12, and 24 hours (Day 11) after dosing. Subjects should be supine or semi-recumbent for at least 15 minutes before these time points.  
f  
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes. The ECG will be done before any other procedures 
that may affect heart rate, such as blood draws. On Days 1 and 5, ECGs will be collected before dosing and at approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
g  
Vital signs will be performed after the subject has been at rest for at least 5 minutes. 
h  
Blood samples for PK assessments will be collected on Days 1 and 5 before dosing (0 hours), 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing (if qd dosing, blood samples will 
also be collected at 24 hours [on Day 2 and Day 6]). The 12- or 24-hour sample will be collected before the next administered dose. On Days 7, 8, and 9, a blood sample will 
be collected before dosing. On Day 10, blood samples for PK assessments will be collected before dosing (0 hours), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24 (Day 11), 36 (Day 11), 
48 (Day 12), 72 (Day 13), and 96 (Day 14) hours after dosing. The acceptable PK sampling windows are provided in Table 11-1. At the Safety Follow-up Visit, a single blood 
sample for PK analysis will be collected. 


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Table 3-5 
Study VX17-121-001: Part B, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
(7 to 10 Days After 
Last Dose of Study 
Drug)b 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study drug administrationi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewj 
Continuous from signing of ICF through Safety Follow-up Visit 
Treatment and procedures 
review 
Continuous from signing of ICF through Safety Follow-up Visit 
 i  
Study drug will be administered in the fed state (Section 9.6.1). The last dose of study drug will be administered on the morning of the Day 10 Visit.  
j  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 3-6 
Study VX17-121-001: Part C, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety 
Follow-up 
(7 to 10 Days 
After Last Dose 
of Study Drug)b 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
 
Outpatient visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Standard 12-lead ECGe 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
 
X 
 
 
 
Xg 
 
 
 
X 
 
 
 
 
X 
Hematology 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Blood for PK analysish 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Drug test (urine or blood), 
including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, blood, or 
breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Study drug administrationi  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise, and will be performed relative to the morning dose only.  
b  
Additional PK samples and safety assessments may also be performed at the discretion of the investigator. See Section 9.1.1.4 for details. 
c 
Subjects will be discharged from the CRU on Day 18 after completion of the study visit assessments. 
d  
Weight will be measured with shoes off.  
e  
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes. The ECG will be done before any other procedures 
that may affect heart rate, such as blood draws. On Days 1 and 7, ECGs will be collected before dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
f 
Vital signs will be performed after the subject has been at rest for at least 5 minutes. 
g  
On Day 10, the following serum chemistry parameters will be measured: lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, aspartate transaminase, 
alanine transaminase, and gamma-glutamyl transferase. 
h  
Blood samples for PK assessments of VX-121, TEZ and metabolites, and IVA and metabolites will be collected on Days 1 and 7 before dosing (0 hours) and at 0.5, 1, 2, 3, 4, 
5, 6, 8, and 12 hours after dosing. The 12-hour sample will be collected before the next administered dose. On Days 2, 3, 4, 5, 8, 10, and 12, blood samples will be collected 
before (morning) dosing. On Day 14, blood samples will be collected before dosing (0 hours), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 (Day 15), 36 (Day 15), 48 (Day 16), 
72 (Day 17), and 96 (Day 18) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1. At the Safety Follow-up Visit, a single blood sample for PK 
analysis will be collected. 
i  
Study drug will be administered in the fed state (Section 9.6.1). The last dose of study drug will be administered on the morning of the Day 14 Visit. 


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Table 3-6 
Study VX17-121-001: Part C, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety 
Follow-up 
(7 to 10 Days 
After Last Dose 
of Study Drug)b 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Medications reviewj 
Continuous from signing of ICF through Safety Follow-up Visit 
Treatment and procedures 
review 
Continuous from signing of ICF through Safety Follow-up Visit 
 j  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 
 


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Table 3-7 
Study VX17-121-001: Part D, Screening, Treatment Period, and Safety Follow-up Visit  
Event/Assessmenta 
Screening 
Visitb 
Treatment Periodc 
ETT 
Visitd 
Safety Follow-up 
28 (± 7) Days 
After Last Dose 
of Study Drug  
Days -28 
to -1 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 1 day) 
Day 29 
(± 1 day) 
Outpatient visits 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Weightf 
X 
X 
X 
X 
X 
X 
X 
Heightf 
X 
 
 
 
 
 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryg 
X 
X 
X 
X 
X 
X 
X 
Physical examinationh 
Complete 
Abbreviated 
Abbreviated 
Abbreviated 
Abbreviated 
Abbreviated 
Complete 
Standard 12-lead ECGi 
X 
X 
X 
X 
X 
X 
X 
Sweat chloridej,k 
X 
X 
X 
X 
X 
X 
X 
Spirometryl 
X 
X 
X 
X 
X 
X 
X 
Urinalysisj 
X 
X 
X 
X 
X 
X 
X 
Serum β-hCG (all female 
subjects) 
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  
To qualify to continue into the Treatment Period, conditions for entry must be satisfied (Section 9.1.2.2).  
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. Additional PK 
samples and safety assessments may also be performed at the discretion of the investigator. See Section 9.1.2.4 for additional details.  
e  
Randomization may occur on the previous day (Day -1) after all conditions for entering the Treatment Period have been confirmed (Section 9.1.2.2). 
f  
Weight and height will be measured with shoes off. 
g  
Vital signs and pulse oximetry will be collected after the subject has been at rest for at least 5 minutes.  
h  
Complete and abbreviated PEs are described in Section 11.7.3.  
i  
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes. The ECG will be done before any other procedures 
that may affect heart rate, such as blood draws. On Days 1 and 15, ECGs will be collected before dosing and 4 hours (± 1 hour) after dosing. ECGs collected on Day 1 before 
dosing will be performed in triplicate.  
j  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred.  
k  
Sweat chloride will be measured in all subjects. See Section 8.2.1 for information about the sweat chloride assessment for study eligibility.  
l  
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. On Days 1 and 15, spirometry will also be performed pre-bronchodilator 5 hours 
(± 1 hour) after study drug administration.  


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Table 3-7 
Study VX17-121-001: Part D, Screening, Treatment Period, and Safety Follow-up Visit  
Event/Assessmenta 
Screening 
Visitb 
Treatment Periodc 
ETT 
Visitd 
Safety Follow-up 
28 (± 7) Days 
After Last Dose 
of Study Drug  
Days -28 
to -1 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 1 day) 
Day 29 
(± 1 day) 
CFTR genotypem 
X 
 
 
 
 
 
 
FSHn 
X 
 
 
 
 
 
 
Serum chemistry and 
hematologyj 
X 
X 
X 
X 
X 
X 
X 
Coagulationj 
X 
X 
X 
X 
X 
 
X 
PK samplingp 
 
X 
X 
X 
X 
X 
  
Randomized study drug 
dosingq 
 
Day 1 through Day 29 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewr 
Continuous from signing of ICF through Safety Follow-up Visit 
Treatment and procedures 
review 
Continuous from signing of ICF through Safety Follow-up Visit 
 m  
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. 
n  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
  
 
p  
Blood samples will be collected for PK analysis of VX-121, TEZ and metabolites, and IVA and metabolites. On Day 1, samples will be collected before dosing (0 hours) and 
at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On Days 8 and 29, a predose sample will be collected before the morning dose of study drug (0 hours). On 
Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours after dosing. Acceptable PK sampling windows are provided in Table 11-1. At the ETT 
Visit, a single blood sample for PK analysis will be collected. 
q  
The last dose of study drug will be the morning dose on the Day 29 Visit. 
r  
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........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 18 
List of Tables............................................................................................................................ 22 
List of Figures .......................................................................................................................... 22 
List of Abbreviations................................................................................................................ 23 
5 
Introduction.......................................................................................................................... 26 
5.1 
Background ..................................................................................................................... 26 
5.2 
Study Rationale .............................................................................................................. 27 
6 
Study Objectives .................................................................................................................. 27 
6.1 
Primary Objectives ......................................................................................................... 27 
6.2 
Secondary Objectives ..................................................................................................... 27 
7 
Study Endpoints ................................................................................................................... 28 
7.1 
Primary Endpoint ............................................................................................................ 28 
7.2 
Secondary Endpoints ...................................................................................................... 28 
8 
Study Population .................................................................................................................. 28 
8.1 
Parts A, B, and C ............................................................................................................ 28 
8.1.1 
Inclusion Criteria .................................................................................................... 28 
8.1.2 
Exclusion Criteria ................................................................................................... 29 
8.2 
Part D .............................................................................................................................. 29 
8.2.1 
Inclusion Criteria .................................................................................................... 29 
8.2.2 
Exclusion Criteria ................................................................................................... 30 
9 
Study Implementation ......................................................................................................... 32 
9.1 
Study Design .................................................................................................................. 32 
9.1.1 
Parts A, B, and C (Healthy Subjects) ..................................................................... 32 
9.1.1.1 
Screening .......................................................................................................... 34 
9.1.1.2 
Treatment Period .............................................................................................. 35 
9.1.1.3 
Follow-up ......................................................................................................... 35 
9.1.1.4 
Early Discontinuation....................................................................................... 35 
9.1.2 
Part D (Subjects With CF) ...................................................................................... 36 
9.1.2.1 
Screening .......................................................................................................... 36 
9.1.2.1.1 Repetition of Screening Assessment(s) ....................................................... 36 
9.1.2.1.2 Rescreening ................................................................................................. 37 
9.1.2.1.3 Extension of Screening Period Window ..................................................... 37 
9.1.2.2 
Treatment Period .............................................................................................. 37 
9.1.2.3 
Follow-up ......................................................................................................... 37 
9.1.2.4 
Early Termination of Treatment....................................................................... 38 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 38 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 38 
9.3.1 
Study Design........................................................................................................... 38 
9.3.2 
Study Drug Dose and Duration .............................................................................. 40 
9.3.3 
Rationale for Study Assessments ........................................................................... 41 


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9.4 
Study Restrictions ........................................................................................................... 42 
9.4.1 
Parts A, B, and C .................................................................................................... 42 
9.4.1.1 
Activity ............................................................................................................. 44 
9.4.2 
Part D ...................................................................................................................... 44 
9.4.2.1 
Prohibited Medications .................................................................................... 44 
9.4.3 
Parts A, B, C, and D ............................................................................................... 45 
9.4.3.1 
Exposure to Sunlight ........................................................................................ 45 
9.5 
Prior and Concomitant Medications ............................................................................... 45 
9.5.1 
Parts A, B, and C .................................................................................................... 45 
9.5.2 
Part D ...................................................................................................................... 45 
9.6 
Administration ................................................................................................................ 46 
9.6.1 
Parts A, B, and C .................................................................................................... 46 
9.6.2 
Part D ...................................................................................................................... 48 
9.7 
Dose Escalation Criteria ................................................................................................. 49 
9.7.1 
Parts A, B, and C .................................................................................................... 49 
9.7.2 
Part D ...................................................................................................................... 50 
9.8 
Stopping Rules ................................................................................................................ 50 
9.8.1 
Parts A, B, and C .................................................................................................... 50 
9.8.2 
Part D ...................................................................................................................... 50 
9.8.3 
Parts A, B, C, and D ............................................................................................... 51 
9.9 
Removal of Subjects ....................................................................................................... 51 
9.10 Replacement of Subjects ................................................................................................ 52 
10 Study Drug Information and Management ....................................................................... 52 
10.1 Preparation and Dispensing ............................................................................................ 53 
10.2 Packaging and Labeling ................................................................................................. 53 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 53 
10.4 Drug Accountability ....................................................................................................... 53 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 54 
10.6 Compliance ..................................................................................................................... 54 
10.6.1 
Parts A, B, and C .................................................................................................... 54 
10.6.2 
Part D ...................................................................................................................... 54 
10.7 Blinding and Unblinding ................................................................................................ 54 
10.7.1 
Blinding .................................................................................................................. 54 
10.7.1.1 Parts A, B, and C .............................................................................................. 54 
10.7.1.2 Part D ............................................................................................................... 55 
10.7.2 
Unblinding .............................................................................................................. 56 
11 Assessments .......................................................................................................................... 57 
11.1 Timing of Assessments ................................................................................................... 57 
11.2 Subject and Disease Characteristics ............................................................................... 57 
11.3 Pharmacokinetics ............................................................................................................ 57 
11.3.1 
Blood Sampling ...................................................................................................... 57 
11.3.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 58 
11.3.3 
Bioanalysis.............................................................................................................. 58 
11.4 Pharmacodynamics ......................................................................................................... 58 
11.4.1 
Sweat Chloride (Part D) ......................................................................................... 58 
 


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11.6 Efficacy ........................................................................................................................... 58 
11.6.1 
Spirometry (Part D) ................................................................................................ 58 
11.7 Safety .............................................................................................................................. 58 
11.7.1 
Adverse Events ....................................................................................................... 59 
11.7.2 
Clinical Laboratory Assessments ........................................................................... 59 
11.7.3 
Physical Examinations and Vital Signs .................................................................. 60 
11.7.4 
Electrocardiograms ................................................................................................. 61 
11.7.4.1 Safety ECGs ..................................................................................................... 61 
11.7.4.2 Continuous ECGs for Cardiodynamic Assessment (Part B) ............................ 61 
11.7.5 
Spirometry (Part D Only) ....................................................................................... 62 
11.7.6 
Contraception and Pregnancy ................................................................................. 62 
11.7.6.1 Contraception ................................................................................................... 62 
11.7.6.2 Pregnancy ......................................................................................................... 64 
12 Statistical and Analytical Plans .......................................................................................... 64 
12.1 Sample Size and Power .................................................................................................. 64 
12.2 Analysis Sets .................................................................................................................. 64 
12.2.1 
All Subjects Set ...................................................................................................... 64 
12.2.2 
Full Analysis Set (Part D Only) .............................................................................. 64 
12.2.3 
Safety Set ................................................................................................................ 64 
12.2.4 
Pharmacokinetic Set ............................................................................................... 65 
12.3 Statistical Analysis ......................................................................................................... 65 
12.3.1 
General Considerations ........................................................................................... 65 
12.3.2 
Background Characteristics .................................................................................... 65 
12.3.2.1 Subject Disposition .......................................................................................... 65 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 65 
12.3.2.3 Prior and Concomitant Medications................................................................. 65 
12.3.2.4 Study Drug Exposure ....................................................................................... 66 
12.3.3 
Efficacy Analysis .................................................................................................... 66 
12.3.3.1 Spirometry (Part D Only) ................................................................................. 66 
12.3.4 
Safety Analysis ....................................................................................................... 66 
12.3.4.1 Adverse Events................................................................................................. 67 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 67 
12.3.4.3 Electrocardiogram ............................................................................................ 67 
12.3.4.3.1 Cardiodynamic ECG Assessment (Part B) ............................................... 68 
12.3.4.4 Vital Signs ........................................................................................................ 68 
12.3.4.5 Physical Examination ....................................................................................... 68 
12.3.5 
Interim and IDMC Analyses ................................................................................... 68 
12.3.5.1 Interim Analysis ............................................................................................... 68 
12.3.5.2 IDMC Analysis ................................................................................................ 68 
12.4 Clinical Pharmacology Analysis .................................................................................... 68 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 68 
12.4.2 
Pharmacodynamic Analysis (Part D Only) ............................................................ 68 
12.4.3 
Pharmacokinetic/Pharmacodynamic Analyses (Part D Only) ................................ 69 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 69 


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13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 69 
13.1.1 
Adverse Events ....................................................................................................... 69 
13.1.1.1 Definition of an Adverse Event........................................................................ 69 
13.1.1.2 Clinically Significant Assessments .................................................................. 69 
13.1.1.3 Documentation of Adverse Events................................................................... 70 
13.1.1.4 Adverse Event Severity .................................................................................... 70 
13.1.1.4.1 Parts A, B, and C ....................................................................................... 70 
13.1.1.4.2 Part D......................................................................................................... 71 
13.1.1.5 Adverse Event Causality .................................................................................. 71 
13.1.1.6 Study Drug Action Taken ................................................................................ 72 
13.1.1.7 Adverse Event Outcome .................................................................................. 72 
13.1.1.8 Treatment Given............................................................................................... 72 
13.1.2 
Serious Adverse Events .......................................................................................... 73 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 73 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 73 
13.1.2.3 Reporting Serious Adverse Events................................................................... 74 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 74 
13.2 Administrative Requirements ......................................................................................... 74 
13.2.1 
Ethical Considerations ............................................................................................ 74 
13.2.2 
Subject Information and Informed Consent ........................................................... 74 
13.2.3 
Investigator Compliance ......................................................................................... 75 
13.2.4 
Access to Records ................................................................................................... 75 
13.2.5 
Subject Privacy ....................................................................................................... 75 
13.2.6 
Record Retention .................................................................................................... 76 
13.2.7 
Study Termination .................................................................................................. 76 
13.2.8 
End of Study ........................................................................................................... 76 
13.3 Data Quality Assurance .................................................................................................. 76 
13.4 Monitoring ...................................................................................................................... 77 
13.5 Electronic Data Capture ................................................................................................. 77 
13.6 Publications and Clinical Study Report .......................................................................... 78 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 79 
14 Reference .............................................................................................................................. 80 
APPENDIX A  Eligible MF CFTR Mutations ...................................................................... 81 
15 Protocol Signature Pages .................................................................................................... 84 
15.1 Sponsor Signature Page .................................................................................................. 84 
15.2 Investigator Signature Page ............................................................................................ 85 
 


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List of Tables 
Table 3-1 
Study VX17-121-001: Parts A, B, and C Screening ............................................... 8 
Table 3-2 
Study VX17-121-001: Part A, Cohorts A1, A2, A4, A5, and A6, Treatment Period 
and Safety Follow-up Visit ..................................................................................... 9 
Table 3-3 
Study VX17-121-001: Part A, Cohort A3, Treatment Period and Safety Follow-up 
Visit ....................................................................................................................... 10 
Table 3-4 
Study VX17-121-001: Part A, Cohort A9, Treatment Period and Safety Follow-up 
Visit ....................................................................................................................... 11 
Table 3-5 
Study VX17-121-001: Part B, Treatment Period and Safety Follow-up Visit ..... 12 
Table 3-6 
Study VX17-121-001: Part C, Treatment Period and Safety Follow-up Visit ..... 14 
Table 3-7 
Study VX17-121-001: Part D, Screening, Treatment Period, and Safety Follow-up 
Visit ....................................................................................................................... 16 
Table 9-1 
Study Design for Parts A, B, and C ...................................................................... 33 
Table 9-2 
Parts A, B, and C: Study Restrictions ................................................................... 42 
Table 9-3 
Part D: Prohibited Medications ............................................................................. 44 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 57 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 59 
Table 11-3 
Contraceptive Requirements ................................................................................. 63 
Table 13-1 
Grading of AE Severity ........................................................................................ 71 
Table 13-2 
Grading of AE Severity ........................................................................................ 71 
Table 13-3 
Classifications for AE Causality ........................................................................... 71 
Table 13-4 
Classifications for Study Drug Action Taken With Regard to an AE .................. 72 
Table 13-5 
Classifications for Outcome of an AE .................................................................. 72 
List of Figures 
Figure 9-1 
Schematic of Study Design for Part D .................................................................. 36 
 


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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-∞ 
AUC from the time of dosing extrapolated to infinity 
AUC0-24h 
AUC from the time of dosing to 24 hours 
β-hCG 
beta-human chorionic gonadotropin 
BA 
bioavailability 
BMI 
body mass index 
CD 
compact disc 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Clˉ 
chloride ion 
Cmax 
maximum observed concentration 
CMC 
chemistry, manufacturing, and controls 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
clinical research organization 
CRU 
clinical research unit 
CSR 
clinical study report 
CYP 
cytochrome P450 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
E-R 
exposure-response 
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 
FEF25%-75% 
forced expiratory flow, midexpiratory phase  
FEV1 
forced expiratory volume in 1 second 
F/MF 
F508del/minimal function 
FPI 
Formulation Preparation Instructions 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity  
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 


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Abbreviation 
Definition 
GI 
gastrointestinal 
GLI 
Global Lung Function Initiative 
GLP 
Good Laboratory Practices 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial (cells) 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LFT 
liver function test 
LLN 
lower limit of normal 
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 
NOAEL 
no-observed-adverse-effect level  
NOEL 
no-observed-effect level 
OATP 
organic anion transporting polypeptide 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval 
PT 
Preferred Term 
q12h 
every 12 hours 
QA 
quality assurance 
QC 
quality control 
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 
QTcB 
QT interval corrected by Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 


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Abbreviation 
Definition 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SET 
study execution team 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
TBD 
to be determined 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor  
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
UV 
ultraviolet 
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 (312 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 
that were developed by Vertex and approved for the treatment of CF: ivacaftor (IVA) 
monotherapy (Kalydeco®), lumacaftor (LUM) in combination with IVA (Orkambi®), and 
tezacaftor (TEZ) in combination with IVA (Symdeko™). Kalydeco, Orkambi, and Symdeko are 
approved to treat CF in patients with specific CFTR genotypes. 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. For the most common CF-causing mutation, F508del, 
the combined effect of either LUM and IVA or TEZ and IVA is increased quantity and function 
of F508del-CFTR at the cell surface. 
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 human bronchial epithelial (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, 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).  


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5.2 
Study Rationale 
This is the first clinical study of VX-121 and it is designed to evaluate the safety, tolerability, 
and pharmacokinetics (PK) of VX-121 as monotherapy and in TC with TEZ/IVA in healthy 
subjects (Parts A, B, and C), as well as the safety, tolerability, PK, pharmacodynamics (PD), and 
efficacy of VX-121 in TC with TEZ/IVA in subjects with CF who are heterozygous for F508del 
and a MF CFTR mutation (F/MF genotype; Part D). Conducting the study in subjects with these 
genotypes investigates the effect of treating 1 responsive allele (F508del). 
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
Part A: To evaluate the safety and tolerability of single ascending doses of VX-121 in healthy 
subjects 
Part B: To evaluate the safety and tolerability of multiple ascending doses of VX-121 for 
10 days in healthy subjects 
Part C: To evaluate the safety and tolerability of multiple ascending doses of VX-121 
administered in TC with TEZ/IVA for 14 days in healthy subjects  
Part D: To evaluate the safety and tolerability of VX-121 in TC with TEZ/IVA in subjects with 
CF 
6.2 
Secondary Objectives 
Part A 
• To evaluate the PK of VX-121 after administration of single ascending doses of VX-121 in 
healthy subjects 
• To evaluate the relative bioavailability (BA) of a tablet formulation of VX-121 relative to 
suspension in healthy subjects 
• To evaluate the effect of milk on the PK of VX-121 after administration of suspension and 
tablet formulations 
Part B 
To evaluate the PK of VX-121 after administration of multiple ascending doses of VX-121 for 
10 days in healthy subjects 
Part C 
• To evaluate the PK of VX-121 after administration of multiple ascending doses of VX-121 in 
TC with TEZ/IVA for 14 days in healthy subjects 
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered in TC 
with VX-121 for 14 days in healthy subjects 


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Part D  
• To evaluate the PK of VX-121 when administered in TC with TEZ/IVA in subjects with CF 
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered in TC 
with VX-121 in subjects with CF 
• To evaluate the PD effect of VX-121 in TC with TEZ/IVA in subjects with CF 
• To evaluate the efficacy of VX-121 in TC with TEZ/IVA in subjects with CF 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Parts A, B, C, and D: Safety and tolerability, based on the assessment of adverse events (AEs), 
laboratory test results, standard 12-lead ECGs, vital signs, and spirometry (Part D only) 
7.2 
Secondary Endpoints 
• Parts A, B, C, and D: PK parameter estimates of VX-121 derived from plasma 
concentration-time data 
• Parts C and D: PK parameter estimates for TEZ and metabolites (M1-TEZ and M2-TEZ) 
and IVA and metabolites (M1-IVA and M6-IVA) derived from plasma concentration-time 
data 
• Part D: Sweat chloride levels as a biomarker of PD effects 
• Part D: Spirometry as preliminary evidence of efficacy 
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 
for the study. 
8.1 
Parts A, B, and C 
8.1.1 
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 subjects and female subjects of non-childbearing potential [as defined in 
Section 11.7.6.1]) will be between the ages of 18 and 55 years, inclusive, and healthy, as 
defined by no clinically relevant abnormalities identified by a detailed medical history, full 
physical examination (PE), including blood pressure and pulse rate measurement, standard 
12-lead ECG, and clinical laboratory tests. 
4. Female subjects must have a negative serum pregnancy test at the Screening Visit. 
5. Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg. 


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8.1.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator or the 
subject’s general practitioner, might confound the results of the study or pose an additional 
risk in administering study drug to the subject. This may include, but is not limited to, history 
of relevant drug or food allergies; history of cardiovascular or central nervous system 
disease; history or presence of clinically significant pathology; history of mental disease; and 
history of cancer. 
2. History of febrile illness or other acute illness within 5 days before the first study drug dose. 
3. Any condition possibly affecting drug absorption (e.g., gastrectomy, cholecystectomy, or 
other GI tract surgery, except appendectomy). 
4. 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. 
5. Blood donation (of approximately 1 pint [500 mL] or more) within 56 days before the first 
study drug dose or have had any significant loss of blood as determined by the investigator 
within 60 days before first study drug dose. 
6. Use of restricted substances, activities, or devices within the specified duration before the 
first study drug dose, as defined in Table 9-2. 
7. A screen positive for alcohol or drug substances listed in Section 11.7.2.  
8. A screen positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, 
or human immunodeficiency virus (HIV) 1 or 2 antibodies. 
9. For Part A (Cohorts A3 and A9): a known or suspected lactose intolerance or milk allergy. 
10. 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. 
8.2 
Part D 
8.2.1 
Inclusion Criteria 
1. Subject will sign and date an 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 subjects and female subjects of non-childbearing potential [as defined in 
Section 11.7.6.1]) 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.  


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Subjects must have a sweat chloride value ≥60 mmol/L at screening or documented in the 
form of a laboratory report in the subject’s medical record. If the sweat chloride value cannot 
be determined from the screening test for a reason other than insufficient sweat volume 
(i.e., because of laboratory error, damaged specimen, or equipment malfunction), it is 
acceptable to use a sweat chloride value that was obtained in a Vertex-sponsored study 
before previous treatment with a CFTR modulator.   
7. Confirmed diagnosis of CF as determined by the investigator. 
8. Subjects must be heterozygous for F508del with a second CFTR allele carrying a mutation 
that is not responsive to TEZ, IVA, or TEZ/IVA therapy (Appendix A). If the screening 
CFTR genotype result is not received before randomization, a previous CFTR genotype 
laboratory report may be used to establish eligibility. Subjects who have been enrolled and 
whose screening genotype does not confirm study eligibility must be discontinued from the 
study (Section 9.9). 
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 9.5.2). 
8.2.2 
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 × 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 


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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 
study drug. 
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 
study drug. 
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, 
including VX-661, VX-440, VX-152, VX-659, and VX-445. 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 9-3, within the specified window before 
the first dose of study drug. 
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 


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• the adult participates in the study at a site other than the site at which the family member 
is employed. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a 4-part, randomized, double-blind, placebo-controlled, single- and multiple-dose, 
first-in-human and first-in-patient dose escalation study of VX-121 that includes an evaluation of 
relative BA and the effect of milk on VX-121 exposure. 
9.1.1 
Parts A, B, and C (Healthy Subjects) 
A schematic of the study design for Parts A, B, and C is shown in Table 9-1. Up to 2 additional 
cohorts each in Parts A (Cohorts A7 and A8), B, and C may be enrolled based on data from 
previous cohorts; these cohorts will follow the corresponding schedule of assessments.  
There is no prespecified ratio of males to females, but reasonable effort will be made to enroll 
females of non-childbearing potential in all dosing cohorts. Subjects will be allowed to 
participate in up to 2 cohorts (subjects may enroll in 2 cohorts in Part A or 1 cohort in Part A and 
1 cohort in either Part B or Part C; see Section 9.1.1.1). 
The decision to initiate successive cohorts and dose selection will be based on safety and 
tolerability data from preceding dose group(s) and available PK data from all subjects in the 
preceding cohort (minimum of 6 subjects to ensure 4 subjects receiving active drug). Refer to 
Section 9.7.1 for dose escalation criteria and Section 9.8.1 for stopping rules. 
Subjects will receive VX-121 as a suspension, under fed conditions. The tablet formulation may 
be used instead of the suspension in any remaining cohorts of the study if supported by 
preliminary PK data from Cohort A9. The existing restrictions on dairy consumption 
(Section 9.4.1) may be removed pending the results from Cohorts A3 and/or A9. 
Staggered Dosing in Cohorts A1 and C1  
Dosing in the first cohort of Parts A and C (Cohorts A1 and C1) will initiate with staggered 
dosing in 2 subjects (1 active, 1 placebo) followed by a minimum 24-hour observation before 
dosing of the remaining subjects in the cohort (Section 9.3.1). Staggering at higher doses may be 
conducted if deemed necessary based on review of emerging safety data. 
Cohort A9 
Cohort A9 will not be initiated until all documentation required to support administration of the 
VX-121 tablet has been submitted to and approved by the competent authority (IRB/IEC, as 
applicable). 


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Table 9-1 
Study Design for Parts A, B, and C 
Part A: Single-dose escalation of VX-121  
Approximately 8 subjects per cohort, randomized 3:1 (VX-121:placebo) except for Cohort A9 
 
Planned Dose 
Cohort A1 
10 mg  
 
 
 
 
 
Cohort A2 
 
20 mg 
 
 
 
 
Cohort A3 
 
 
5 mga 
 
 
 
Cohort A4 
 
 
 
40 mg 
 
 
Cohort A5 
 
 
 
 
60 mg 
 
Cohort A6 
 
 
 
 
 
Up to 90 mg 
 
 
 
 
 
 
 
Cohort A9 (Approximately 8 subjects, open-label VX-121, single sequence)b 
 
 
 
 
Part B: Multiple-dose escalation of VX-121  
Approximately 8 subjects per cohort, randomized 3:1 (VX-121:placebo) 
 
Planned Dosage (qd, 10 days) 
Cohort B1 
10 mg qd 
 
 
 
 
 
Cohort B2 
 
20 mg qd 
 
 
 
 
Cohort B3 
 
 
40 mg qd 
 
 
 
Cohort B4 
 
 
 
60 mg qd 
 
 
Cohort B5 
 
 
 
 
TBD 
 
Cohort B6 
 
 
 
 
 
TBD 
 
Part C: Multiple-dose escalation of VX-121 in TC with TEZ/IVAc 
Approximately 8 subjects per cohort, randomized 3:1 (VX-121/TEZ/IVA:triple placebo) 
 
Planned Dosage (qd, 14 days) 
Cohort C1 
10 mg qd 
 
 
 
 
 
Cohort C2 
 
20 mg qd 
 
 
 
 
 
 
 
 
 
 
 
≥8-day  
Washout 
Day 1: 
Suspension, 
fed (10 mg) 
Day 9: 
Tablet, fed 
(10 mg) 
Dosing Period 1 
Dosing Period 2 
Dosing Period 3 
Day 17: 
Tablet, fed and 
with milk (10 mg) 
≥8-day  
Washout 


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Table 9-1 
Study Design for Parts A, B, and C 
Notes: In Part A, planned doses are shown; any cohort may be initiated at a lower or higher dose level than the 
planned dose based on emerging safety, tolerability, and PK data. No dose increment will be expected to yield greater 
than a 3-fold increase (Cohorts A1 through A3) or a 2-fold increase (all other Part A cohorts and Part B cohorts) in 
exposure from the preceding dose level. Dose escalation criteria and predefined stopping criteria are described in 
Section 9.7.1 and Section 9.8.1. 
a 
In addition to randomized study drug administration depicted above, after a washout of at least 8 days all 
subjects will receive an additional 5 mg single dose of open-label VX-121 suspension with milk to evaluate the 
effect of milk on VX-121 exposure. 
b 
Subjects will receive a single dose of VX-121 on 3 dosing occasions with at least an 8-day washout between 
dosing occasions. VX-121 doses include a single oral dose of suspension, a single oral dose of tablet to evaluate 
the relative BA of the tablet, and a single oral dose of tablet with milk to evaluate the effect of milk on VX-121 
exposure (the planned dose is 10 mg for both formulations, but it will not exceed the highest dose that was safe 
and well tolerated in a previous Part A cohort). 
c 
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. 
 
 
9.1.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1.  
Screening will occur within 28 days before administration of study drug. If the time between 
screening and dosing exceeds 28 days as a result of unexpected operational delays (e.g., delayed 
drug shipment), then subjects do not require rescreening if the Day -1 laboratory results meet the 
eligibility criteria. 
Subjects will be instructed on the study restrictions (Section 9.4). 
A subject who qualified but did not enroll for an earlier cohort may be used in a subsequent 
cohort with no required rescreening if the Day -1 laboratory results meet the eligibility criteria 
and if all other screening data were obtained within 28 days before administration of study drug.  
Individual subjects may enroll in up to 2 cohorts (either 2 cohorts in Part A or 1 cohort in Part A 
and 1 cohort in either Part B or Part C) if at least 21 days has elapsed between the last dose of 
study drug in the first cohort in which they participate and the first dose of study drug in the next 
cohort. All screening assessments must be completed again and eligibility confirmed for 
participation in the next cohort.  
Subjects who do not meet the eligibility criteria may not be rescreened, with the following 
exceptions, all of which require principal investigator approval: 
• Subjects who met all eligibility criteria but had an intercurrent illness (e.g., upper respiratory 
infection with fever) in the 14 days before the first study drug dose that was properly 
evaluated and which resolved fully 
• Subjects who met all eligibility criteria but were not able to obtain required documentation 
within the allotted screening window 
• Subjects who met all eligibility criteria but transiently (for personal reasons) are unable to 
commit to all study procedures 


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• Subjects who met all eligibility criteria but are not randomized for administrative reasons 
(e.g., study drug is not available at the study site) 
• If applicable, subjects who were screened under a prior version of the protocol and did not 
meet any exclusion criterion, with the exception of a criterion that was updated in a 
subsequent version of the protocol 
Repetition of any screening assessment that did not meet eligibility criteria is not permitted, 
unless there is clear evidence of a laboratory error or a damaged specimen (e.g., hemolysis of 
sample).  
The medical monitor should be notified of any decisions made regarding rescreening or retesting. 
9.1.1.2 
Treatment Period 
Subjects will be admitted on Day -1 and will remain in the clinical research unit (CRU) for the 
duration of the Treatment Period. 
Treatment Period assessments are listed in Table 3-2 (Cohorts A1 through A6 [up to A8]), 
Table 3-3 (Cohort A3), Table 3-4 (Cohort A9), Table 3-5 (Part B), and Table 3-6 (Part C). 
The treatment periods for Part A, B, and C will be conducted as described in Section 9.1.1. 
Dosing details are given in Section 9.6.1. 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the medical monitor (or authorized designee) will be 
notified, and the subject will be asked to remain in the CRU until such abnormalities resolve. If 
the subject is unable or unwilling to remain in the CRU, the medical monitor (or authorized 
designee) will be notified, and the investigator will make every effort to arrange follow-up 
evaluations at appropriate intervals to document the course of the abnormalities. 
9.1.1.3 
Follow-up 
Subjects will have a Safety Follow-up Visit 7 to 10 days after the last study drug dose. Safety 
Follow-up Visit assessments are listed in Table 3-2 (Cohorts A1 through A6 [up to A8]), 
Table 3-3 (Cohort A3), Table 3-4 (Cohort A9), Table 3-5 (Part B), and Table 3-6 (Part C).  
9.1.1.4 
Early Discontinuation 
Subjects who prematurely discontinue study drug dosing will be asked to return to the CRU for a 
Safety Follow-up Visit. Safety Follow-up Visit assessments are listed in Table 3-2 (Cohorts A1 
through A6 [up to A8]), Table 3-3 (Cohort A3), Table 3-4 (Cohort A9), Table 3-5 (Part B), and 
Table 3-6 (Part C).  
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. 


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9.1.2 
Part D (Subjects With CF) 
A schematic of the study design for Part D is shown in Figure 9-1, which has a randomized, 
double-blind, placebo-controlled, parallel-group design. After completing the Screening Period, 
approximately 12 subjects will be randomized 3:1 to TC:placebo. 
Screening in Part D will be initiated after the completion of Parts A, B, and C (cohorts needed 
for Part D dose selection only) through the Safety Follow-up Visit. The decision to proceed to 
Part D will be based on an evaluation of safety, tolerability, and PK data from completed cohorts 
in Parts A, B, and C. These data will be submitted to the IEC for approval before proceeding to 
screening for Part D. Refer to Section 9.3.2 for additional details. 
 
Figure 9-1 
Schematic of Study Design for Part D  
 
a 
The planned VX-121 dose for Part D is 10 mg qd. This dose is predicted to provide an approximate AUC0-24h of 
10 µg∙h/mL, which is within the predicted efficacious exposure range based on in vitro data. Based on emerging 
safety, tolerability, and PK data from Parts A, B, and C, the planned dose for Part D may be lowered to 
5 mg qd. The total daily dose of VX-121 in Part D will be at least 1 dose level below the highest total daily dose 
tested in Part C. The dosage of TEZ/IVA in the TC 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. 
 
9.1.2.1 
Screening 
Screening Visit assessments are shown in Table 3-7. 
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. 
9.1.2.1.1 
Repetition of Screening Assessment(s) 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted with the following exceptions:  
• If there is clear evidence of a laboratory error, damaged specimen (e.g., hemolysis of 
sample), or equipment malfunction, collection of a repeat sample for the appropriate 
laboratory test or assessment is permitted.  
• Exclusionary liver function test (LFT) levels may be retested once within 14 days of the 
original screening date. The Vertex medical monitor should be made aware of the repeat 
testing.  
• Assessments required for eligibility may be repeated if permitted, as described in Section 8.2. 
VX-121 + TEZ/IVA 
N = 9 
Placebo 
N = 3 
Treatment Perioda 
4 weeks 
Screening Period 
4 weeks 
Safety Follow-up Period 
4 weeks 


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If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society/European Respiratory Society guidelines,9 repeat 
spirometry evaluation may be performed once. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed 
within the screening window, then the subject is eligible for the study. 
9.1.2.1.2 
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. 
9.1.2.1.3 
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 9.1.2.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Repetition of spirometry assessment if results are of poor quality 
9.1.2.2 
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 3-7. All visits will occur 
within the windows specified. Study drug administration details are provided in Section 9.6.2. 
Subjects 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 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 conditions for entry into the Treatment Period 
have been confirmed. 
9.1.2.3 
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 3-7. 


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9.1.2.4 
Early Termination of Treatment  
If the subject prematurely discontinues study drug, 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 drug 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 3-7. 
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 evaluations 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. 
9.2 
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).  
Parts A, B, and C 
Subjects will be assigned a unique subject number (unique to subject and cohort). Only subjects 
who have completed screening assessments and are eligible for participation in the study will be 
randomized to receive active study drug or placebo during the Treatment Period. A list 
identifying subjects by their subject number will be maintained in the study file at the CRU. 
Part D 
Subjects will be assigned a unique subject number. Only subjects who have completed screening 
assessments and are eligible for participation in the study (and qualify to enter the Treatment 
Period) will be randomized to receive active study drug or placebo during the Treatment Period.  
An interactive web response system (IWRS) will be used to assign subjects to treatment.  
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
Parts A, B, and C 
Parts A (except Cohort A9) and B have a dose-escalation design, with each subject participating 
in only 1 cohort (unless at least 21 days has elapsed before participation in another cohort), to 
avoid PK and/or PD carryover effects.  


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Part C will evaluate the safety, tolerability, and PK of VX-121 administered in TC with 
TEZ/IVA because VX-121 is being developed for use in this TC for the treatment of CF. It will 
also include an evaluation of the PK of TEZ and metabolites, and IVA and metabolites, 
following administration of VX-121 in TC with TEZ/IVA. 
Parts A, B, and C (except Cohort A9) will be randomized, double-blind, and placebo-controlled 
to avoid bias in the collection and evaluation of safety and tolerability data during their conduct. 
Subjects will be randomized 3:1 to receive either active study drugs or placebo. Placebo has been 
chosen as the control treatment to assess whether any observed effects are treatment-related or 
simply related to the study conditions. 
Predictive models suggest that the solubility of VX-121 may decrease in the presence of 
calcium-rich food such as milk and milk products, reducing the absorption and systemic 
exposure of VX-121. Therefore, in addition to randomized study drug administration described 
above, after a washout of at least 8 days all subjects in Cohort A3 will receive a single dose of 
open-label VX-121 suspension with milk to evaluate the effect of milk on VX-121 exposure. 
Staggered Dosing in Cohorts A1 and C1  
Dosing in the first cohort of Parts A and C (Cohorts A1 and C1) will initiate with staggered 
dosing in 2 subjects (1 active, 1 placebo) followed by a minimum 24-hour observation before 
dosing of the remaining subjects in the cohort. Staggering at higher doses may be conducted if 
deemed necessary based on review of emerging safety data. 
Staggered dosing is proposed for Part A because this is the first time VX-121 will be 
administered to humans. In addition, staggered dosing is proposed for Part C because it is the 
first time VX-121 will be administered in TC with TEZ/IVA in humans. Staggered dosing for 
Part B is not considered necessary, because the total daily dose to be evaluated in the first cohort 
(Cohort B1) will be at least 1 dose level below the highest Part A dose for which safety, 
tolerability, and PK results are available and supportive. Therefore, the relative risk to subjects 
dosed in Cohort B1 is less than that of subjects in Cohorts A1 and C1. 
Cohort A9 
Cohort A9 will not be initiated until all documentation required to support administration of the 
VX-121 tablet has been submitted to and approved by the competent authority (IRB/IEC, as 
applicable). 
Subjects in Cohort A9 will receive 3 single doses of VX-121 to evaluate the BA of a tablet (with 
calcium restrictions) relative to the suspension formulation (with calcium restrictions) and the 
effect of milk on the tablet formulation. Each dosing occasion will be separated by at least 
8 days. Based on preliminary clinical data, the interval between dosing occasions is considered 
adequate to minimize any potential for carryover. 
Part D 
Part D will evaluate the safety, tolerability, PK, PD, and efficacy of VX-121 administered in TC 
with TEZ/IVA in subjects with CF who are heterozygous for F508del and a MF CFTR mutation 
(F/MF genotype).  
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 


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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. 
9.3.2 
Study Drug Dose and Duration 
VX-121 Starting Dose 
 
 
 
 
 
Using the lowest of the HED 
values (1.6 mg/kg), assuming a 60-kg human subject, and applying a default safety factor of 10, 
the maximum recommended safe starting dose is estimated to be approximately 10 mg/day. The 
selected starting dose of 10 mg for Cohort A1
 
 
 
Part A VX-121 Dose Escalation 
The planned dose escalation scheme for Part A is shown in Table 9-1. Dose escalation criteria 
for Part A (including the data that will be reviewed before initiating successive cohorts) are 
presented in Section 9.7.1. Stopping rules are presented in Section 9.8.1. Dose escalation may be 
adjusted upward or downward based on emerging safety, tolerability, and PK data.  
For Cohorts A2 and A3 only, PK data will be available from the “lagging” cohort before 
escalation (i.e., Cohort A1 PK results may not be available before escalation to Cohort A2, but 
Cohort A1 PK data will be available before escalation to Cohort A3). Availability of lagging PK 
is appropriate for the lower dose cohorts because the projected exposure at these relatively low 
doses are not expected to approach or exceed the exposure cap based on nonclinical 
NOEL/NOAELs.  
Cohort A9 VX-121 Dose Selection 
The planned oral dose of VX-121 administered in Cohort A9 as suspension and tablet is 10 mg 
for both formulations. The oral dose will not exceed a dose shown to be safe and well tolerated 
in a previous Part A cohort.  
Part B VX-121 Starting Dose and Dose Escalation 
The planned dose escalation scheme for Part B is shown in Table 9-1. The starting dose in Part B 
will be selected based on the safety, tolerability, and PK data in Part A. Cohort B1 will begin 
after evaluation of safety, tolerability, and PK data from at least 1 dose level above the 
corresponding daily dose from Part A to sufficiently establish the safety, tolerability and 
exposure of the study drug after multiple doses.  
Initiation of successive cohorts and dose selection will be based on safety, tolerability, and PK 
data described in Section 9.7.1. PK data through Day 5 is sufficient to predict steady-state 
exposures for the next cohort. 


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Part C VX-121 Starting Dose and Dose Escalation 
The planned dose escalation scheme for Part C is shown in Table 9-1. The starting dose in Part C 
will be selected based on the safety, tolerability, and PK data in Parts A and B. The total daily 
dose in the first Part C cohort (Cohort C1) will be at least 1 dose level below the highest total 
daily Part B dose for which safety and tolerability results are available and supportive. 
Parts B and C Treatment Duration 
The durations of dosing in Part B (10 days) and Part C (14 days) are standard durations for 
multiple-dosing in first-in-human studies and are of sufficient length for an early assessment of 
safety and tolerability and for assessment of steady-state PK. Given that the starting dose in 
Part C will be at least 1 dose level below the highest Part B dose (Section 9.7.1), the cumulative 
exposure in Part C is predicted to be lower than in Part B provided dose-proportional PK and no 
drug-drug interactions that significantly impact VX-121 exposure are observed. 
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 qd; IVA: 150 mg q12h). 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. 
Part D VX-121 Dose Selection 
Screening in Part D will be initiated after the completion of Parts A, B, and C (cohorts needed 
for Part D dose selection only) through the Safety Follow-up Visit. The decision to proceed to 
Part D will be based on an evaluation of safety, tolerability, and PK data from completed cohorts 
in Parts A, B, and C. These data will be submitted to the IEC for approval before proceeding to 
screening for Part D. Based on preliminary data from Parts A, B, and C, the planned dose of 
10 mg qd is predicted to provide an approximate AUC0-24h of 10 µg∙h/mL, which is within the 
range of predicted efficacious exposure based on in vitro data (refer to VX-121 Investigator’s 
Brochure). Based on emerging safety, tolerability, and PK data from Parts A, B, and C, the 
planned dose for Part D may be lowered to 5 mg qd. The total daily dose of VX-121 in Part D 
will be at least 1 dose level below the highest total daily dose tested in Part C; as Part C may not 
include all total daily dose levels tested in Part B, Part D may include a total daily dose that has 
not been tested in Part C but is at least 1 dose level below the highest total daily dose tested in 
Part C. The 4-week treatment duration is considered appropriate for initial evaluation of safety, 
tolerability, and PK of the TC in subjects with CF. 
Administration of VX-121, TEZ, and IVA With Food 
Oral doses of VX-121, TEZ, and IVA will be administered under fed conditions. This is 
consistent with how VX-121, TEZ, and IVA were administered in nonclinical studies, including 
the GLP toxicity studies. In humans, a positive food effect has been established for IVA, and is 
predicted for VX-121. 
9.3.3 
Rationale for Study Assessments 
The majority of safety and PK assessments are standard parameters for Phase 1 clinical studies. 
Rationales for other safety, PK, PD, and efficacy assessments are listed below. 


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4β-hydroxycholesterol 
4β-hydroxycholesterol is an endogenous marker for CYP3A activity.12 Evaluation of 
4β-hydroxycholesterol is being used increasingly to assess potential clinical CYP3A induction. 
In Part B, comparison of 4β-hydroxycholesterol on the Day 10 Visit (predose) relative to 
baseline (Day-1 predose) will be used to evaluate potential induction of CYP3A by VX-121. 
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 declines for VX-121, lung function, as assessed by 
spirometry, will be included in Part D to assess for post-dose declines in spirometric indices. In 
addition, lung function, as assessed by spirometry, will be evaluated for preliminary evidence of 
efficacy. 
Sweat chloride test and CFTR genotyping 
The sweat chloride test is a standard diagnostic tool for CF and is a biomarker of CFTR activity 
in patients with CF. Based on the mechanism of action of VX-121, the sweat chloride test will be 
included as a measure of the PD effect of VX-121 and the TC on CFTR activity. Sweat chloride 
levels will be measured in subjects with CF receiving VX-121 TC or placebo in Part D. Sweat 
chloride levels will be measured at visits before study drug administration, at visits during the 
Treatment Period (when study drug exposures are expected to be at steady-state), and at Safety 
Follow-up Visit (to evaluate off-treatment effects of study drug).  
Continuous ECG monitoring 
Continuous ECG monitoring will be performed in all Part B subjects for later extraction and 
high-precision QTc analysis of 10 ECG replicate measurements. It has been demonstrated that 
evaluation of QTc in early phase clinical studies with a robust dose range can be used to evaluate 
a potential exposure-response (E-R) relationship for QTc, which may be used to replace the 
thorough QTc study for new drugs.14 The ECGs collected by continuous monitoring may or may 
not be analyzed for the purpose of E-R modeling, based on future development decisions for 
VX-121. If analyzed, results of the high-precision QTc analysis and E-R modeling will not be 
included in the clinical study report (CSR), but will be included in a separate report.  
9.4 
Study Restrictions 
9.4.1 
Parts A, B, and C 
Study restrictions are summarized in Table 9-2.  
Table 9-2 
Parts A, B, and C: Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (minimum) 
To 
Depo-Provera®  
6 months before first study drug dose  
Completion of Safety Follow-up Visit 
assessments 
Tobacco- or nicotine-containing 
product 
45 days before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 


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Table 9-2 
Parts A, B, and C: Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (minimum) 
To 
Other investigational drugs or 
devices 
30 days before first study drug dose, 
5 half-lives before first study drug 
dose, or time determined by local 
requirements, whichever is longest 
Completion of Safety Follow-up Visit 
assessments 
VX-121 
21 days before first study drug dose 
First study drug dose 
Hormonal methods of 
contraception (oral, vaginal, or 
patch) or hormonal replacement 
therapies 
28 days before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 
Prescription medications 
14 days or 5 half-lives (whichever is 
longer) before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 
Nonprescription medications 
14 days or 5 half-lives (whichever is 
longer) before first study drug dose. 
Occasional, limited ibuprofen 
(≤800 mg/day) and acetaminophen at 
doses of ≤2 g/day is allowed for pain. 
Completion of Safety Follow-up Visit 
assessments 
Herbal and dietary supplements  
14 days before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 
Grapefruit or grapefruit juice, 
apple or orange juice, vegetables 
from the mustard green family 
(e.g., kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels 
sprouts, mustard), and charbroiled 
meats 
72 hours before first study drug dose  
Until last PK sample is taken 
Milk, milk products (e.g., yogurt, 
cheese, cream), calcium 
supplemented foods (e.g., orange 
juice, juices fortified with added 
calcium), other calcium-rich 
foods (e.g., spinach, kale, bok 
choy, watercress, broccoli, 
sardines, okra, almonds), and 
drugs such as antacidsb 
4 hours before each study drug dose 
4 hours after each study drug dose 
(except when VX-121 will be 
administered in presence of milk) 
Alcohol 
Not more than 28 units per week for 
males and 21 units per week for 
females (where 1 unit is equal to half 
a pint of beer or one 25 ml measure of 
spirits; a small [125 ml] glass of wine 
has 1.4 units) within 6 months before 
the Screening Visit, and none from 
48 hours before admission to the 
CRU. 
Completion of Safety Follow-up Visit 
Assessments 
Caffeine 
24 hours before first study drug dose 
Until last PK sample is taken 


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Table 9-2 
Parts A, B, and C: Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (minimum) 
To 
Strenuous exercise (e.g., heavy 
lifting, weight training, and 
aerobics) 
96 hours before first clinical 
laboratory testing 
Completion of Safety Follow-up 
assessments 
a 
See Section 9.5.1 for guidance on concomitant medications. 
b 
The restrictions on dairy consumption may be removed pending the results from Cohorts A3 and/or A9. 
 
9.4.1.1 
Activity 
In Part B, subjects will be confined for the first 4 hours after dosing on the Day 10 Visit during 
continuous ECG monitoring, except to use the bathroom. After this time, if the equipment setup 
allows, subjects may be ambulatory during the telemetry (Holter monitor) period, but will not 
engage in strenuous activities. If ECG equipment does not allow ambulation, appropriate 
accommodations will be made by the study site to facilitate continuous monitoring (i.e., bedside 
urinals will be provided to accommodate subjects’ excretory needs). 
9.4.2 
Part D 
9.4.2.1 
Prohibited Medications 
Prohibited medications are shown in Table 9-3. VX-121, TEZ, 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, or IVA, will be prohibited. 
VX-121 is a potential inhibitor of the hepatic transporter organic anion transporting polypeptide 
1B1 (OATP1B1). Therefore, sensitive substrates of OATP1B1, such as HMG-Co-A Reductase 
Inhibitors (“statins”) will be prohibited. 
A non-exhaustive list of study prohibitions and cautions for medication will be provided in the 
Study Reference Manual. Food restrictions, including potential dairy restrictions, will also be 
specified in the Study Reference Manual.  
Table 9-3 
Part D: 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)  
None allowed within 28 days before 
the first dose of study drug 
None allowed through the Safety 
Follow-up Visit 
Sensitive OATP1B1 substrates 
None allowed within 14 days before 
the first dose of the study drug  
None allowed through the Safety 
Follow-up Visit 
Note: 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 9.5.2 for guidance on concomitant medications. 


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9.4.3 
Parts A, B, C, and D 
9.4.3.1 
Exposure to Sunlight 
Subjects will take appropriate measures to minimize exposure to UV radiation (e.g., sunlight, 
tanning booths) from the Day 1 Visit through the Safety Follow-up Visit. 
9.5 
Prior and Concomitant Medications 
9.5.1 
Parts A, B, and C 
• Subjects will abstain from medication as described in Table 9-2. 
• All medications taken from 28 days before the first dose of study drug through the end of the 
study will be recorded with indication, route of administration, and start and stop dates of 
administration. All subjects will be questioned about medications at each clinic visit. 
9.5.2 
Part D 
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 
the Day 1 Visit 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 Day 1 Visit. Subjects must not initiate long-term treatment with new 
medication from 28 days before the Day 1 Visit through the Safety Follow-up Visit unless 
discussed and approved by the medical monitor. Guidelines for stable 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. 


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• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.7.5. 
9.6 
Administration 
9.6.1 
Parts A, B, and C 
For all dosing occasions, study drug will be administered under supervision of the investigator or 
authorized designee. VX-121 and matching placebo will be administered as a suspension or 
tablets. TEZ and IVA and their matching placebos will be administered as tablets. 
Study drug will be administered according to the following guidelines: 
• Study drug will be administered after baseline vital signs and ECGs are performed. 
• Study drug should be given to subjects within each Treatment Period, at approximately the 
same time (± 30 minutes) on each dosing occasion. 
• Administration of VX-121 suspension will be followed by 240 mL of water or milk (in 
addition to randomized study drug administration depicted in Table 9-1, subjects in 
Cohort A3 will receive an additional single dose of VX-121 suspension with milk; all other 
suspension administration will be with water). Water will be used and consumed as needed to 
rinse suspension from the dosing vial when administration of VX-121 is followed by milk. A 
taste-masking agent will be given to subjects before and after study drug dosing. Additional 
details will be provided in the Pharmacy Manual, Formulation Preparation Instructions (FPI), 
and the ICF. 
• When multiple study drugs are being administered, study drugs will be administered at the 
same time. 
• When VX-121, TEZ, and IVA are administered as tablets, subjects will swallow the study 
drugs whole, followed by 240 mL of water. Subjects may take additional water, as needed, to 
swallow tablets. 
• To standardize the conditions on PK sampling days, all subjects will be required to refrain 
from lying down (except when required for study procedures), eating, and drinking beverages 
other than water during the first 4 hours after dosing. In Part A and on days of intensive PK 
sampling in Parts B and C, water and clear liquids may be consumed without restriction 
beginning 1 hour after the morning dose. 
Parts A, B, and C 
The meals (described below) given at the time of drug dosing (breakfast in Parts A, B, and C) 
will not contain any milk or milk products (e.g., yogurt, cheese) or other calcium-rich foods. 
These restrictions on dairy consumption (Section 9.4.1) may be removed pending the results 
from Cohorts A3 and/or A9. 
Part A 
Part A, Cohorts A1 Through A6 (up to A8): Single Ascending Dose Escalation 
All cohorts in Part A will be dosed under fed conditions. 


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Subjects must abstain from all food and drink (except water) at least 8 hours before the start of 
the standard breakfast. A standard breakfast, containing approximately 20 g of fat, will be served 
to subjects 30 minutes before dosing. Subjects must complete the entire meal in 30 minutes or 
less; study drug will be administered 30 minutes after the start of the meal. Food will not be 
permitted for at least 4 hours after dosing. Water (including clear liquids) may be consumed 
without restriction beginning 1 hour after dosing. 
Lunch will be provided approximately 4 to 5 hours after dosing. Dinner will be provided 
approximately 9 to 10 hours after dosing.  
An afternoon and/or evening snack will be permitted. 
Part A, Cohort A3: Effect of Milk 
In addition to the above instructions for dosing under fed conditions, on Day 9 (open-label 
VX-121 suspension, fed state and with milk), administration of the VX-121 suspension will be 
followed by a glass of skim milk (240 mL). Water will be consumed with dosing as needed to 
rinse suspension from the dosing vial. Refer to the FPI for additional information. 
Part A, Cohort A9: Relative Bioavailability and Effect of Milk 
On the Day 1, 9, and 17 Visits (fed state), subjects must abstain from all food and drink (except 
water) at least 8 hours before the start of the standard breakfast. A standard breakfast, containing 
approximately 20 g of fat, will be served to subjects 30 minutes before dosing. Subjects must 
complete the entire meal in 30 minutes or less; study drug will be administered 30 minutes after 
the start of the meal. Food will not be permitted for at least 4 hours after dosing. Water 
(including clear liquids) may be consumed without restriction beginning 1 hour after dosing. 
On Day 17 (tablet, fed state and with milk), administration of the VX-121 tablet will occur with 
a glass of skim milk (240 mL) instead of water. 
Lunch will be provided approximately 4 to 5 hours after dosing. Dinner will be provided 
approximately 9 to 10 hours after dosing.  
An evening snack will be permitted. 
Part B 
All cohorts in Part B will be dosed under fed conditions.  
On all days of study drug administration, a standard breakfast (containing approximately 20 g of 
fat) will be served 30 minutes before morning dosing. Subjects must complete the entire meal in 
30 minutes or less; study drug will be administered 30 minutes after the start of the meal. 
On days of intensive PK sampling, subjects must abstain from all food and drink (except water) 
at least 8 hours before the start of the standard breakfast. Food will not be permitted for at least 
4 hours after the morning dose but water and other clear liquids may be consumed without 
restriction beginning 1 hour after the morning dose. 
Part C 
All doses of VX-121, TEZ, and IVA will be administered under fed conditions, consistent with 
the dosing recommendations for TEZ/IVA. 
Subjects will be given a standardized meal (standard breakfast containing approximately 20 g of 
fat; standard dinner containing approximately 30 to 60 g of fat) 30 minutes (for breakfast) or 


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45 minutes (for dinner) before all doses of study drug on the Day 1 to 14 Visits. Subjects must 
complete the meal within 30 minutes (for breakfast) or 45 minutes (for dinner); study drug will 
be administered 30 minutes (for breakfast) or 45 minutes (for dinner) after the start of the meal.  
On days of intensive PK sampling, subjects must abstain from all food and drink (except water) 
at least 8 hours before the start of the standard breakfast. Food will not be permitted for at least 
4 hours after the morning doses but water and clear liquids may be consumed without restriction 
beginning 1 hour after the morning dose.  
9.6.2 
Part D 
Study drug will be administered orally. Subjects will receive the same number of tablets each 
day to maintain the blind. Additional information is provided in the Pharmacy Manual. Food 
restrictions, including potential dairy restrictions, will be specified in the Study Reference 
Manual. 
Study drug will be administered with a fat-containing meal or snack, such as a standard CF 
high-fat, high-calorie meal or snack or a standard meal, according to the following guidelines: 
1. It is recommended that the dose be taken within 30 minutes after the start of the meal or 
snack. 
2. Study drug or placebo will be administered q12h or qd (± 2 hours). VX-121 and TEZ 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. 
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.  
5. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
• If the dose in the clinic will be within 6 hours of the subject’s scheduled morning dose, 
the subject should withhold the morning dose of study drug and the morning dose will be 
administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
dose, the subject should take the morning dose at home. 
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, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 


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subject should skip that dose and resume his/her normal schedule for the following dose. For 
example: 
• If the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
• If the morning dose of study drug should have been taken at approximately 08:00, and more 
than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 14:00), the 
subject would resume dosing with the evening dose at approximately 20:00. 
9.7 
Dose Escalation Criteria 
9.7.1 
Parts A, B, and C 
The decision to initiate successive cohorts and dose selection will be based on safety and 
tolerability data from preceding dose group(s) and available PK data from a minimum of 
6 subjects (to ensure 4 subjects receiving active drug) in the preceding cohort. The investigator, 
Vertex medical monitor, and Vertex Global Patient Safety (GPS) physician will conduct a 
blinded evaluation of all safety data on an ongoing basis, and all Grade 3 or higher laboratory 
abnormalities or AEs (Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) will be evaluated to determine if dosing/dose 
escalation should be continued. A safety report, which includes available PK data and 
justification for selection of the dose, will be prepared by the investigator for the proposed dose 
escalation. 
Part A: The planned dose escalation scheme for Part A is shown in Table 9-1. Doses may be 
adjusted upward or downward based on safety, tolerability, and available PK data from 
preceding dose group(s). No dose increment will be expected to yield greater than a 3-fold 
increase (Cohorts A1 through A3) or a 2-fold increase (all other Part A cohorts) in exposure from 
the preceding dose level. Dose escalation will be stopped when the predefined stopping criteria is 
met (see Section 9.8.1).  
Cohort A2 initiation will be based on safety data (through ≥48 hours postdose) from Cohort A1. 
Cohort A3 initiation and dose selection will be based on safety data (through ≥48 hours 
postdose) from Cohort A2 and PK data (through ≥24 hours postdose) from Cohort A1 
(i.e., lagging PK). For all other Part A cohorts, initiation and dose selection will be based on 
safety data (through ≥48 hours postdose) and PK data (through ≥24 hours postdose) from the 
previous cohort.  
If conducted, the dose(s) in Cohorts A7 or A8 may be a replicate of a dose evaluated in 
Cohorts A1 through A6 or may be increased above 90 mg, pending emerging safety, tolerability, 
and PK data from Cohorts A1 through A6. 
Part B: Part B may be initiated while Part A is ongoing after review of safety, tolerability, and 
PK data. The starting daily dose (Cohort B1) will be at least 1 dose level below the highest 
Part A dose for which safety and tolerability results are supportive. 
The decision to initiate successive cohorts and dose selection will be based on safety data 
through the Day 10 Visit and PK data as available through the Day 5 Visit from the previous 
cohort. Doses may be adjusted upward or downward based on safety, tolerability, and PK data 
from preceding dose group(s). No dose increment will be expected to yield greater than a 2-fold 


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increase in exposure from the preceding dose level. The highest daily dose of VX-121 in Part B 
will not exceed the highest Part A dose for which safety and tolerability results are supportive. 
Stopping rules are presented in Section 9.8.1. 
Part C: Part C may be initiated while Parts A and B are ongoing after review of safety, 
tolerability, and PK data. The starting dose (Cohort C1) will be at least 1 dose level below the 
highest Part B dose for which safety and tolerability results are supportive.  
The decision to initiate successive cohorts and dose selection will be based on safety data 
through the Day 14 Visit and PK data as available through the Day 7 Visit from the previous 
cohort. The highest dose of VX-121 in Part C will not exceed the highest Part B dose for which 
safety and tolerability results are supportive. 
9.7.2 
Part D 
Part D is a single cohort part; dose escalation criteria are not applicable. 
9.8 
Stopping Rules 
9.8.1 
Parts A, B, and C 
Stopping Rules for Cohorts 
In Parts A and B, dose escalation will be stopped if the mean AUC0-∞ (single-dose escalation) or 
AUC0-24h (multiple-dose escalation) of the next dose is predicted to exceed an AUC of 
356 μg⋅h/mL or the Cmax is predicted to exceed 21 μg/mL 
 
Dose escalation will also consider 
individual subject exposure and potential outliers. Exposures in male and female rats were higher 
than the dog at the NOAEL in the rat 28-day GLP toxicity study.  
If a serious adverse event (SAE) occurs that is considered related or possibly related to study 
drug, or if 2 severe (or greater) AEs occur that are considered related or possibly related to study 
drug, then the study will be halted (dosing of study drug in all study subjects will be halted). 
Occurrence of such events will trigger an internal safety review, including discussion between 
the investigator and medical monitor, and notification to regulatory authorities and ethics 
committees, if applicable. If the sponsor decides it is appropriate to restart the study, dosing of 
study drug will be resumed only after approval of a substantial amendment to the Clinical Trial 
Authorization. 
9.8.2 
Part D 
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. 


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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. 
9.8.3 
Parts A, B, C, and D 
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, and subjects may be 
withdrawn at any time at the discretion of the investigator or Vertex for safety, behavior, 
noncompliance (study drug dosing or study procedures), or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided the subject has not withdrawn consent.  


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Subjects will discontinue from study drug dosing and the investigator will notify the medical 
monitor if any of the following occur 
• Pregnancy 
• Unacceptable toxicity 
Subjects who are withdrawn from study drug dosing will complete assessments as described in 
Sections 9.1.1.4 and 9.1.2.4 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 Sections 9.1.1.4 and 
9.1.2.4. 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.  
In Part D, subjects who have been randomized and whose screening CFTR genotype does not 
confirm study eligibility must be discontinued from the study, even if a previous CFTR genotype 
laboratory report was used to establish eligibility. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s) (Part D only), request that the subject return for a Safety 
Follow-up Visit, if applicable (see Sections 9.1.1.3 and 9.1.2.3), and follow up with the subject 
regarding any unresolved AEs. 
If the subject withdraws consent for the study, no further evaluations should be performed, and 
no additional data should be collected. Vertex may retain and continue using the study data and 
samples after the study is over, and may use the samples and information in the development of 
the study compound, and for other drugs and diagnostics, in publications and presentations, and 
for education purposes. If the subject withdraws from the study, the study data and samples 
collected will remain part of the study. A subject will not be able to request the withdrawal of 
his/her information from the study data. A subject may request destruction of the samples 
collected from him/her during the study as long as those samples can be identified as his/her 
samples. 
Stopping rules are presented in Section 9.8. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn before the first dose of study drug on the Day 1 Visit 
may be replaced.  
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to VX-121, TEZ/IVA (VX-661/VX-770), IVA, and their matching placebos.  


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10.1 
Preparation and Dispensing 
Parts A, B, and C 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
When administered as a suspension, drug substance will be reconstituted and then dispensed into 
individual dosing containers, when appropriate, by 2 operators, 1 of whom is a qualified 
pharmacist. Details of dose preparation will be given in the FPI.  
Tablets will be dispensed at the CRU to individual dosing containers by 2 operators, 1 of whom 
is a qualified pharmacist, and following national and local laws and regulations. 
Part D 
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 drug substance and 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 drug substance and matching placebo will be provided to the site and will be 
compounded as a suspension. Refer to the Pharmacy Manual for storage and handling conditions 
for bulk and unit dose suspensions. 
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/IVA (100 mg/150 mg) 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 (150 mg) 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 regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects (Part D only). Subjects will be instructed to return all used and unused 
materials associated with the study drug to the site (Part D only). These materials will be retained 
at the site according to instructions provided by Vertex or its designee until inventoried by the 


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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 
(Part D only) until the study monitor has performed drug accountability. At the end of the study, 
the study monitor will provide instructions as to the disposition of any unused investigational 
product. If the study monitor authorizes destruction at the study site, the investigator will ensure 
that the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Vertex. Destruction will be 
adequately documented. 
10.6 
Compliance  
10.6.1 
Parts A, B, and C 
All doses will be administered under the direct supervision of the investigator or designee. A 
hand-and-mouth check will be done after each dose administration in the CRU to ensure 100% 
study treatment compliance. 
10.6.2 
Part D 
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator will contact the medical monitor to discuss discontinuing the subject 
from the study.  
10.7 
Blinding and Unblinding 
This will be a double-blind study, with the exception of Cohort A9, which will be open-label. 
10.7.1 
Blinding  
10.7.1.1 
Parts A, B, and C 
Blinding of subject treatment assignments will be maintained until database lock. The packaging 
and labeling of study drug will be done to ensure that treatment assignments are blinded within 
each cohort in all parts of the study. 
During the conduct of the study, all study personnel will be blinded to subject treatment 
assignments except for 
• the unblinded site monitor; 
• designated clinical research organization (CRO) performing the PK bioanalysis; 
• Bioanalytical 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;  


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• vendor preparing the unblinded statistical and PK/PD analysis of continuous ECG data 
collected in Part B; 
• the unblinded biostatistician preparing the randomization list as well as an unblinded quality 
control (QC) biostatistician; 
• the dispensing contracted pharmacist;  
• the pharmacy QC/quality assurance (QA) personnel, as applicable; and 
• Vertex GPS and Regulatory Affairs, when required to satisfy regulatory reporting 
requirements. 
The Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. 
A limited Vertex team, which may include members of the Vertex SET, may be unblinded to 
individual subject treatment assignments for the purposes of review of PD, PK/PD, and/or safety 
data. No unblinded data or results of unblinded analyses will be shared with the CRU or with 
blinded Vertex personnel. All instances of unblinding by Vertex personnel will be documented. 
Bioanalytical results (i.e., concentrations of VX-121) will be reported by the Bioanalytical CRO 
using masked IDs for PK analysis. 
10.7.1.2 
Part D 
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 GPS and Regulatory Affairs personnel to satisfy SAE processing and reporting 
regulations 
• Unblinded statistician preparing the final (production) randomization list who is not part of 
the study team 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 
• Vendor preparing the unblinded analysis for the ongoing reviews of data by a limited Vertex 
team (see below) 
• Bioanalytical 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 medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 


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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 
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 will 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.  
Refer to Section 12.3.5.1 for details regarding interim analyses (IAs). 
10.7.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered a 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. 


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Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The schedule of assessments is shown in Table 3-1 through Table 3-7. 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
11.3 
Pharmacokinetics 
11.3.1 
Blood Sampling 
Blood samples will be collected from all subjects for the evaluation of plasma concentrations of 
VX-121, TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and metabolites (M1-IVA and 
M6-IVA).
  
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 
Part 
Sampling Time 
Time From Scheduled Sampling 
Allowed 
Parts A, B, and C 
Predose 
Within 30 minutes before dosing  
 
From 0.25 up to ≤12 hours after study drug dosing 
± 5 minutes 
 
From >12 up to ≤24 hours after study drug dosing 
± 10 minutes 
 
From >24 up to ≤48 hours after study drug dosing 
± 20 minutes 
 
From >48 up to ≤168 hours after study drug 
dosing 
± 30 minutes 
Part D 
Predose 
Within 60 minutes before dosing 
 
From 1 up 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. 


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11.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the PK Sample Handling 
Guidelines.  
11.3.3 
Bioanalysis 
Samples will be analyzed using 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. 
11.4 
Pharmacodynamics 
11.4.1 
Sweat Chloride (Part D) 
Collection of sweat samples will be performed in Part D 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. 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 separately. 
11.6 
Efficacy 
11.6.1 
Spirometry (Part D) 
Refer to Section 11.7.5. 
11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, PEs, and spirometry (Part D). 


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11.7.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.7.2 
Clinical Laboratory Assessments 
In Parts A, B, and C, blood and urine samples will be analyzed at a local laboratory. In Part D, 
blood and urine samples will be analyzed at a central laboratory.  
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. 
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  
Coagulationc 
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: In Part D, glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease Study 
Equation for subjects ≥18 years of age (Section 8.2.2). 
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.  
c 
In Parts A, B, and C, coagulation will only be assessed at screening. 


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Other Clinical Laboratory Assessments as Described in Section 3: 
Serum Pregnancy (β-human chorionic gonadotropin) Tests for All Female Subjects: For Parts A, 
B, and C, serum samples will be analyzed at the local laboratory. For Part D, serum samples will 
be analyzed at the central laboratory for all female subjects.  
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. 
Serology (Parts A, B, and C): HBsAg, HCV antibody, and HIV-1 and HIV-2 antibodies will be 
tested for. 
Drug and Alcohol Screening (Parts A, B, and C): Opiates, methadone, cannabinoids, cocaine, 
amphetamines/methamphetamines, barbiturates, benzodiazepines, cotinine, and alcohol levels 
will be assessed by a blood or urine test; alcohol breath tests are acceptable alternatives for 
alcohol testing. Subjects may undergo random urine drug screen and alcohol testing if deemed 
appropriate by the investigator. Drug screen result must be negative for all subjects to receive 
study drug. 
CFTR Genotype (Part D): CFTR genotyping will be performed for all subjects (Section 8.2.1). 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
In Part D, 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. 
11.7.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital sign assessments 
can be performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes, ears, nose, 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, respiration 
rate, and pulse oximetry (Part D only). The subject will be instructed to rest for at least 5 minutes 
before vital signs are assessed.  


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11.7.4 
Electrocardiograms 
11.7.4.1 
Safety ECGs 
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.  
Study sites should use QTcF unless they receive approval in advance from the medical monitor 
to use QTcB. 
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. 
11.7.4.2 
Continuous ECGs for Cardiodynamic Assessment (Part B) 
In Part B, continuous ECGs will be obtained as noted in Table 3-5 using a Global 
Instrumentation (Manlius, NY, USA) M12R ECG continuous 12-lead digital recorder, supplied 
by iCardiac Technologies. The continuous 12-lead digital ECG data will be stored onto Secure 
Digital memory cards. ECGs to be used in the analyses will be selected by predetermined time 
points as defined in Table 3-5, and will be read centrally by ERT. At each protocol-specified 
time point, 10 ECG replicates will be extracted from a 5-minute “ECG window” (typically, the 
last 5 minutes of the 15-minute period when the subject is maintained in a supine or 
semi-recumbent quiet position).  
The following principles will be followed in ERT’s core laboratory: 
• ECG analysts are blinded to the subject, visit, and treatment allocation 
• Baseline and on-treatment ECGs for a particular subject will be over-read on the same lead 
and will be analyzed by the same reader. 
• The primary analysis lead is lead II. If lead II is not analyzable, then the primary lead of 
analysis will be changed to another lead for the entire subject data set. 
The ECG data collected by continuous monitoring may or may not be analyzed, or the analysis 
may be restricted initially to 1 or more cohorts. The decision to analyze the ECG data will be 
based on future development decisions for VX-121. 


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11.7.5 
Spirometry (Part D Only) 
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) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-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. Postdose 
spirometry assessments will be performed as noted in Table 3-7. 
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 3-7) 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. 
11.7.6 
Contraception and Pregnancy 
The effects of VX-121 monotherapy or in TC with TEZ and IVA on conception, pregnancy, and 
lactation in humans are not known. VX-121, TEZ, and IVA did not show genotoxic potential in a 
standard battery of in vitro (Ames test, chromosomal aberration, or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies.  
11.7.6.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below: 


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• There are no contraceptive requirements for female subjects. Only females of 
non-childbearing potential will be enrolled (Section 8). 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 
Notes: All other females (including females with tubal ligations) are considered to be of 
childbearing potential and are not eligible for the study. Female subjects must have a 
negative serum pregnancy test at the Screening Visit in order to be eligible for the study. 
• There are no contraceptive requirements for males subjects with female partners of 
non-childbearing potential (as defined above).  
• For male subjects with female partners of childbearing potential, study participation requires 
the male subject to use a condom to avoid exposure of a potential embryo or fetus to study 
drug via the seminal fluid. In addition, study participation requires a commitment from the 
subject that at least 1 acceptable method of contraception will be used as a couple. Refer to 
Table 11-3 for more details. 
Table 11-3 
Contraceptive Requirements  
Male subjects and their female 
(non-study) partners of 
childbearing potentiala 
Male subjects must use a condom with or without spermicide.a In addition, at 
least 1 of the following acceptable methods must be used as a couple:  
• 
Vasectomy performed at least 6 months previously, with a documented 
negative postvasectomy semen analysis for sperm. 
• 
Bilateral tubal occlusion (e.g., ligation) performed at least 6 months 
previously. 
• 
Continuous use of an intrauterine device for at least 90 days before the 
first dose of study drug, throughout study drug treatment, and until 7 days 
after the last dose of study drug. 
• 
Hormonal contraceptives, if successfully used for at least 60 days before 
the first dose of study drug, throughout study drug treatment, and until 
7 days after the last dose of study drug. 
Note: There are no contraception requirements for female subjects (who will be of non-childbearing potential) and 
male subjects with female partners of non-childbearing potential. 
a 
Male subjects must use a condom to avoid exposure of the female partner (and a potential embryo or fetus) to 
study drug via the seminal fluid. Condom must be used during the period starting from the first dose of study 
drug until 7 days after the last dose of study drug. 
 
Additional notes: 
• Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
• 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. 


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11.7.6.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a 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 safety analyses and clinical pharmacology for 
this study. Safety statistical analysis details will be provided in the statistical analysis plan (SAP) 
for this study, and clinical pharmacologic analysis details will be provided in the clinical 
pharmacology analysis plan (CPAP), both of which will be finalized before clinical database 
lock. 
Final analyses will take place after all subjects have completed the study, all data have been 
entered in the clinical study database, and the database has been locked. 
12.1 
Sample Size and Power 
No formal sample size calculations have been performed. The number of subjects participating in 
each cohort of Parts A, B, and C is typical for first-in-human studies in healthy subjects and is 
considered sufficient to achieve the objectives of the study. Approximately 12 subjects in Part D 
is considered sufficient to meet the objectives of the study for this early assessment in subjects 
with CF. 
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 (Part D Only) 
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 for the Safety Set.  


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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, 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 
Only descriptive analyses will be performed; no statistical hypothesis testing will be done. 
Continuous variables will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, SD, SE, median, minimum value, and maximum value. 
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. 
For Parts A, B, and C, the Treatment-emergent (TE) Period will be from the first dose date of 
study drug to (1) the Safety Follow-up Visit for subjects who have a Safety Follow-up Visit, or 
(2) 7 days after the last dose of study drug for subjects who do not have a Safety Follow-up Visit. 
For Part D, the TE Period will be from first dose date of study drug to 28 days after the last dose 
date of study drug.  
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 Safety Set, included in the FAS, completing Treatment Period, completing the Safety 
Follow-up Visit, and discontinuing study with a breakdown of the reasons for discontinuation) 
will be summarized for the All Subjects Set. 
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, BMI, medical history, baseline safety parameters, and baseline sweat chloride. 
These characteristics will be summarized for the Safety Set. No statistical tests will be done to 
evaluate baseline imbalances between groups. 
12.3.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
and presented in 2 parts: 
1. Prior medication: Medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended 
2. Concomitant medication: Medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of study 
drug, or medication with missing stop date 


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If a medication start date is on or after the date of initial dosing of the study drug, then the 
medication will be summarized as concomitant medication regardless of whether the medication 
end date is missing or not. If a medication end date is before the date of initial dosing of the 
study drug, then the medication will be summarized as prior medication regardless of whether 
the medication start date is missing or not. Note that medication that started before initial dosing 
of the study drug and continued after initial dosing will be summarized as prior medication and 
separately as concomitant medication. 
Prior medications will be listed only. Concomitant medications will be summarized using 
preferred name. 
12.3.2.4 
Study Drug Exposure 
Exposure to study drug in Parts C and D (i.e., duration of treatment) 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. 
Duration of treatment will be summarized by means of descriptive summary statistics for Parts C 
and D only. 
Dosing administration will be presented in an individual subject data listing for all parts. 
12.3.3 
Efficacy Analysis 
12.3.3.1 
Spirometry (Part D Only) 
The following parameters of FEV1 (L), forced vital capacity (FVC) (L), FEV1/FVC (ratio), and 
forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) will be summarized using 
descriptive statistics for the FAS. 
In addition, a mixed-effects model for repeated measures (MMRM) with change from baseline 
for percent predicted forced expiratory volume in 1 second (ppFEV1) as the dependent variable 
will be performed for the FAS. The model will include treatment group, visit, and 
treatment-by-visit interaction as fixed effects. 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.  
Descriptive analyses of the change from baseline will be performed for VX-121 TC and placebo. 
Adjusted means and 2-sided 95% CIs of the treatment effect through Day 29 (averaged over 
Day 15 and 29), with P values for all within-group comparisons, will be estimated within 
MMRM. 
12.3.4 
Safety Analysis 
Safety is the 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 


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• Vital signs 
• Spirometry (Part D only) 
Safety analyses will be based on the Safety Set. No statistical hypothesis testing will be 
conducted. 
For safety variables, the baseline value will be defined as the most recent non-missing 
measurement collected before the initial administration of study drug. 
All safety data will be presented in individual subject data listings. 
12.3.4.1 
Adverse Events 
AEs will be coded according to MedDRA. The number and percentage of subjects experiencing 
an AE will be summarized by the MedDRA System Organ Class (SOC) and Preferred Term 
(PT). AEs will be classified as pretreatment or treatment-emergent. 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF up 
to the start of study drug dosing. 
TEAEs during the Treatment Period are defined as any AE that worsened (either in severity 
or seriousness) or that was newly developed at or after the first dose date of study drug through 
the end of the TE Period for the Treatment Period. 
Only TEAEs will be summarized in tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study drug. Some rules that will apply to the 
summarization of AEs are (1) a subject with multiple occurrences of the same AE or a 
continuing AE will be counted only once; (2) only the maximum severity level will be presented 
in the severity summary; and (3) only the worst relationship level will be presented in the 
relationship summary. 
AEs leading to death, other SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the Safety Follow-up Visit will be listed in an individual subject data 
listing, including pretreatment AEs. 
12.3.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using SI units. Observed and 
change from baseline values for hematology and clinical chemistry results will be summarized at 
each scheduled time point. Urinalysis results will be listed only in individual subject data 
listings. These results will not be summarized. Clinically significant abnormal laboratory 
findings will be reported as AEs. 
12.3.4.3 
Electrocardiogram 
A summary of raw values and change from baseline values will be provided at each scheduled 
visit for the following ECG measurements: PR, QT, QRS, and QTc intervals and heart rate. In 
addition, the number and percentage of subjects by maximum on-treatment value of QT/QTc 
intervals, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and ≤500 msec, and 
>500 msec, as well as maximum on-treatment change from baseline value of QT/QTc intervals, 
categorized as ≤0 msec, >0 and ≤30 msec, >30 and ≤60 msec, and >60 msec, will be provided. 
Clinically significant abnormal findings will be reported as AEs. 


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12.3.4.3.1 
Cardiodynamic ECG Assessment (Part B) 
If it is determined that the continuous ECG data will be analyzed, a separate analysis plan will be 
created for the evaluation of the continuous ECG data, including the Cardiodynamic ECG 
Assessment and Concentration-QTc Analysis. 
12.3.4.4 
Vital Signs 
The following vital signs will be summarized at each scheduled time point: systolic and diastolic 
blood pressure (mm Hg), body temperature (°C), pulse rate (beats per minute), and respiratory 
rate (breaths per minute). Clinically significant abnormal findings in vital signs will be reported 
as AEs. 
12.3.4.5 
Physical Examination 
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
An IA of the continuous ECG data may be performed after all subjects in Part B have completed 
the Safety Follow-up Visit (see Section 12.3.4.3.1). These results will be reviewed by a small 
unblinded Vertex team. 
An IA may be performed for Parts A, B, and C after all subjects in Part C have completed the 
Safety Follow-up Visit.  
12.3.5.2 
IDMC Analysis 
Not applicable 
12.4 
Clinical Pharmacology Analysis 
A detailed analysis plan that addresses the PK objectives of the study will be presented in the 
CPAP. 
12.4.1 
Pharmacokinetic Analysis 
The PK parameters of VX-121, TEZ and metabolites, and IVA and metabolites will be estimated 
using standard noncompartmental analysis methods. The analysis of PK results for all analytes 
will be based on the PK Set and will be described using descriptive statistics. Further details of 
the PK analyses will be provided in the CPAP. 
12.4.2 
Pharmacodynamic Analysis (Part D Only) 
The sweat chloride assessment will be performed in Part D to evaluate the effect of VX-121 on 
sweat chloride levels. The analysis of sweat chloride data will be based on the FAS and will be 
summarized using descriptive statistics. 


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In addition, the same MMRM model as for ppFEV1 will be used to analyze the change from 
baseline for sweat chloride. Adjusted means and 2-sided 95% CIs of the treatment effect through 
Day 29 (averaged over Day 15 and 29), with P values for all within-group comparisons, will be 
estimated within MMRM. 
12.4.3 
Pharmacokinetic/Pharmacodynamic Analyses (Part D Only) 
Correlations between sweat chloride results and PK parameters may be analyzed. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 


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13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects in Parts A, B, and C who do not have a Safety Follow-up Visit, 10 days 
after the last dose of study drug 
• For enrolled subjects in Part D who do not have a Safety Follow-up Visit, the earliest of 
o 28 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 9.1.2.4) 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject’s source documents. The following data will be documented 
for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
13.1.1.4.1 
Parts A, B, and C 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007, Center for Biologics Evaluation and Research, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/Vaccines/ucm074775.htm (Accessed November 2017). The severity of an AE that does not 
appear in this scale 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  
 
13.1.1.4.2 
Part D 
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 13-2. 
Table 13-2 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-3. 
Table 13-3 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject’s medical record). 


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Table 13-3 
Classifications for AE Causality 
Classification 
Definition 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-4.  
Table 13-4 
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. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-5. 
Table 13-5 
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. 


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13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are considered related 
to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 


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severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email:
 (preferred choice) 
Fax: 
  
For questions, contact telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject 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. 


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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 
Parts A, B, and C 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data provided to Vertex, study reports, and communications relating to 
the study will identify subjects by assigned subject numbers and access to subject names linked 
to such numbers shall be limited to the site and the study physician and shall not be disclosed to 
Vertex. As required by applicable laws and regulations in the countries in which the study is 
being conducted, the investigator will allow Vertex and/or its representatives access to all 
pertinent medical records to allow for the verification of data gathered 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. 
Part D 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 


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Parts A, B, C, and D 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) and associated regulations an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• 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 in the study. 
13.3 
Data Quality Assurance 
Parts A, B, and C 
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. Vertex 
will provide, or assess and approve, any electronic data capture (EDC) tools. 


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The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Data collected during the study, including results from screening, will be recorded in 
a data capture system for each enrolled subject. Each subject’s set of captured data records, once 
complete, will be signed and dated by the investigator. 
Part D 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based 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 
Parts A, B, and C 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the data captured for the study/SAE Forms for 
completeness and clarity, 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 data 
captured for the study/SAE Forms and source documents. The study site monitor will ensure that 
the investigation is conducted according to the protocol design and regulatory requirements. 
Part D 
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  
Parts A, B, and C 
Sites will use an EDC tool to record data for each enrolled subject.  
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness 
of the data reported. The investigator is required to prepare and maintain adequate and accurate 


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case histories designed to record all observations and other data pertinent to the study for each 
study participant, including the dates and details of study procedures, AEs, other observations, 
and subject status.  
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 data reported to Vertex, including 
any changes made, to endorse the final submitted data for the subjects for whom the investigator 
is responsible.  
Part D 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator's 
study file. 
13.6 
Publications and Clinical Study Report 


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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 11 July 2018. 
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 11 July 2018. 
3 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 11 July 2018. 
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 
15 May 2018. 
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 
Kasichayanula S, Boulton DW, Luo W-L, Rodrigues AD, Yang Z, Goodenough A, et al. 
Validation of 4Β-hydroxycholesterol and evaluation of other endogenous biomarkers for 
the assessment of CYP3A activity in healthy subjects. Br J Pharmacol. 2014;78(5):1122-
34. 
13 
Vertex Pharmaceuticals Incorporated. Lumacaftor (VX-809) Investigator's Brochure, 
Version 7.0. Report date: 27 March 2014. 
14 
Darpo B, Benson C, Dota C, Ferber G, Garnett C, Green CL, et al. Results from the IQ-
CSRC prospective study support replacement of the thorough QT study by QT 
assessment in the early clinical phase. Clin Pharmacol Ther. 2015;97(4):326-35. 
 


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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 VX17-121-001 (Part D) 
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 
 


Protocol VX17-121-001, Version 3.0 
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Vertex Pharmaceuticals Incorporated 
 
CFTR Mutations Eligible for VX17-121-001 (Part D) 
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. 
 




Protocol VX17-121-001, Version 3.0 
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15.2 
Investigator Signature Page 
Protocol #:  
VX17-121-001 Version #: 
3.0 
Version Date: 
27 JUL 2018 
Study Title: A Phase 1/2 Study of VX-121 in Healthy Subjects and in Subjects With Cystic 
Fibrosis 
 
 
I have read Protocol VX17-121-001, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-121, tezacaftor, and ivacaftor and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan Methods, Version 2.0                                                                                            Page 1 of 34                              
Protocol Number: VX17-121-001 (Version 3.0 dated 27Jul2018) 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods) 
Protocol Number: VX17-121-001 Version 3.0 
(Final Analysis) 
 
A Phase 1/2 Study of VX-121 in Healthy Subjects and  
in Subjects With Cystic Fibrosis 
 
Author of SAP: 
 
Version: 2.0 
Version Date of SAP: 28 August 2018 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210, 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. 


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2 
TABLE OF CONTENTS 
1 
Title Page .............................................................................................................................. 1 
2 
Table of contents ................................................................................................................ 2 
4 
Introduction .......................................................................................................................... 5 
5 
Study Objectives ................................................................................................................. 5 
5.1 
Primary Objectives ........................................................................................................... 5 
5.2 
Secondary Objectives ....................................................................................................... 6 
6 
Study Endpoints.................................................................................................................. 6 
6.1 
Primary Endpoints ............................................................................................................ 6 
6.2 
Secondary Endpoints ........................................................................................................ 7 
7 
Study Design ........................................................................................................................ 7 
7.1 
Parts A, B, and C (Healthy Subjects) ............................................................................... 7 
7.2 
Part D (Subjects With CF) ................................................................................................ 9 
7.3 
Sample Size and Power .................................................................................................. 10 
7.4 
Randomization ................................................................................................................ 10 
7.5 
Replacement ................................................................................................................... 11 
7.6 
Blinding and Unblinding ................................................................................................ 11 
8 
Analysis Sets ..................................................................................................................... 11 
8.1 
All Subjects Set .............................................................................................................. 11 
8.2 
Full Analysis Set (Part D Only) ...................................................................................... 11 
8.3 
Safety Set ........................................................................................................................ 11 
9 
Statistical Analysis ........................................................................................................... 12 
9.1 
General Considerations .................................................................................................. 12 
9.2 
Background Characteristics ............................................................................................ 15 
9.2.1 
Subject Disposition ................................................................................................. 15 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 15 
9.2.3 
Medical History ...................................................................................................... 15 
9.2.4 
Prior and Concomitant Medications ....................................................................... 16 
9.2.5 
Study Drug Exposure and Compliance .................................................................. 17 
9.2.6 
Important Protocol Deviations ................................................................................ 17 
9.3 
Efficacy Analysis ............................................................................................................ 18 


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9.3.1 
Spirometry (Part D Only) ....................................................................................... 18 
9.4 
Safety Analysis ............................................................................................................... 18 
9.4.1 
Adverse Events ....................................................................................................... 19 
9.4.2 
Clinical Laboratory Assessments ........................................................................... 20 
9.4.3 
Electrocardiogram .................................................................................................. 21 
9.4.4 
Vital Signs .............................................................................................................. 21 
9.4.5 
Pulse Oximetry (Part D) ......................................................................................... 22 
9.4.6 
Physical Examination ............................................................................................. 22 
 
 
9.6 
Pharmacodynamic Analysis (Part D Only) .................................................................... 22 
10 Interim and IDMC Analyses ............................................................................................ 23 
10.1 Interim Analysis ............................................................................................................. 23 
10.2 IDMC Analysis ............................................................................................................... 23 
11 References .......................................................................................................................... 23 
12 Appendices ......................................................................................................................... 23 
Appendix A: Analysis Visit Windows (Part D Only) .............................................................. 23 
Appendix B: Details of GLI Equations for Calculating ppFEV1 ............................................. 26 
Appendix C: Imputation Rules for Missing AE dates ............................................................. 27 
Appendix D: Criteria for Threshold Analysis .......................................................................... 29 
 
 




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4 
INTRODUCTION 
The statistical analysis plan (SAP) describes the statistical methods to be used for the analyses of 
safety and efficacy data to support the preparation of regulatory submissions and the final 
analysis based on the most recent approved clinical study protocol (CSP), the most recent 
approved electronic case report form (eCRF), and the most recent approved eCRF completion 
guidelines. 
This SAP addresses the objectives of the study and describes the planned safety and efficacy 
analyses and data presentations.
 
. Analyses 
and data presentations for Parts A, B and C will be generated by 
 
 using SAS® Version 9.4 or higher (SAS Institute, Cary, North 
Carolina, USA). Analyses and data presentations for Part D will be performed by Vertex 
Pharmaceuticals Incorporated (Vertex) Biometrics Department using SAS® Version 9.4 or 
higher. 
This SAP will be finalized and approved prior to the database lock. Any revisions to the 
approved SAP will be documented and approved in an amendment to the SAP prior to the 
clinical database lock for the final analysis, and any changes made to the SAP after the clinical 
database lock will be documented and discussed in the clinical study report for this study. 
The analysis and reporting of the pharmacokinetic (PK) objective of the study will be described 
in the Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the 
Clinical Pharmacology Department at Vertex. 
5 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
Part A: To evaluate the safety and tolerability of single ascending doses of VX-121 in healthy 
subjects 
Part B: To evaluate the safety and tolerability of multiple ascending doses of VX-121 for 10 
days in healthy subjects 
Part C: To evaluate the safety and tolerability of multiple ascending doses of VX-121 
administered in triple combination (TC) with tezacaftor (TEZ)/ ivacaftor (IVA) for 14 days in 
healthy subjects 


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Part D: To evaluate the safety and tolerability of VX-121 in TC with TEZ/IVA in subjects with 
cystic fibrosis (CF) 
5.2 
Secondary Objectives 
Part A 
 To evaluate the PK of VX-121 after administration of single ascending doses of VX-121 in 
healthy subjects 
 To evaluate the relative bioavailability (BA) of a tablet formulation of VX-121 relative to 
suspension in healthy subjects 
 To evaluate the effect of milk on the PK of VX-121 after administration of suspension and 
tablet formulations 
Part B 
 To evaluate the PK of VX-121 after administration of multiple ascending doses of VX-121 
for 10 days in healthy subjects 
Part C 
 To evaluate the PK of VX-121 after administration of multiple ascending doses of VX-121 in 
TC with TEZ/IVA for 14 days in healthy subjects 
 To evaluate the PK of TEZ, IVA, and their respective metabolites when administered in TC 
with VX-121 for 14 days in healthy subjects 
Part D 
 To evaluate the PK of VX-121 when administered in TC with TEZ/IVA in subjects with CF 
 To evaluate the PK of TEZ, IVA, and their respective metabolites when administered in TC 
with VX-121 in subjects with CF 
 To evaluate the PD effect of VX-121 in TC with TEZ/IVA in subjects with CF 
 To evaluate the efficacy of VX-121 in TC with TEZ/IVA in subjects with CF 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoints 
Parts A, B, C, and D: Safety and tolerability will be based on the assessment of adverse events 
(AEs), laboratory test results, standard 12-lead electrocardiograms (ECGs), vital signs, and 
spirometry (Part D only) 


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6.2 
Secondary Endpoints 
 Parts A, B, C, and D: PK parameter estimates of VX-121 derived from plasma 
concentration-time data 
 Parts C and D: PK parameter estimates for TEZ and metabolites (M1-TEZ and M2-TEZ) 
and IVA and metabolites (M1-IVA and M6-IVA) derived from plasma concentration-time 
data 
 Part D: Sweat chloride levels as a biomarker of PD effects 
 Part D: Spirometry as preliminary evidence of efficacy 
7 
STUDY DESIGN 
7.1 
Parts A, B, and C (Healthy Subjects) 
This is a 4-part, randomized, double-blind, placebo-controlled, single- and multiple-dose, 
first-in-human and first-in-patient dose escalation study of VX-121 that includes an evaluation of 
relative BA and the effect of milk on VX-121 exposure. 
A schematic of the study design for Parts A, B, and C is shown in Table 7-1. Up to 2 additional 
cohorts each in Parts A (Cohorts A7 and A8), B, and C may be enrolled based on data from 
previous cohorts; these cohorts will follow the corresponding schedule of assessments.  
There is no prespecified ratio of males to females, but reasonable effort will be made to enroll 
females of non-childbearing potential in all dosing cohorts. Subjects will be allowed to 
participate in up to 2 cohorts (subjects may enroll in 2 cohorts in Part A or 1 cohort in Part A and 
1 cohort in either Part B or Part C; see Section 9.1.1.1 of the protocol ). 
The decision to initiate successive cohorts and dose selection will be based on safety and 
tolerability data from preceding dose group(s) and available PK data from all subjects in the 
preceding cohort (minimum of 6 subjects to ensure 4 subjects receiving active drug). Refer to 
Section 9.7.1 of the protocol for dose escalation criteria and Section 9.8.1 of the protocol for 
stopping rules. 
Subjects will receive VX-121 as a suspension, under fed conditions. The tablet formulation may 
be used instead of the suspension in any remaining cohorts of the study if supported by 
preliminary PK data from Cohort A9. The existing restrictions on dairy consumption (Section 
9.4.1 of the protocol) may be removed pending the results from Cohorts A3 and/or A9. 


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Staggered Dosing in Cohorts A1 and C1  
Dosing in the first cohort of Parts A and C (Cohorts A1 and C1) will initiate with staggered 
dosing in 2 subjects (1 active, 1 placebo) followed by a minimum 24-hour observation before 
dosing of the remaining subjects in the cohort (Section 9.1.1 of the protocol). Staggering at 
higher doses may be conducted if deemed necessary based on review of emerging safety data. 
Cohort A9 
Cohort A9 will not be initiated until all documentation required to support administration of the 
VX-121 tablet has been submitted to and approved by the competent authority (IRB/IEC, as 
applicable). 
Table 7-1 
Study Design for Parts A, B, and C 
Part A: Single-dose escalation of VX-121  
Approximately 8 subjects per cohort, randomized 3:1 (VX-121:placebo) except for Cohort A9 
 
Planned Dose 
Cohort A1 
10 mg  
 
 
 
 
 
Cohort A2 
 
20 mg 
 
 
 
 
Cohort A3 
 
 
5 mga 
 
 
 
Cohort A4 
 
 
 
40 mg 
 
 
Cohort A5 
 
 
 
 
60 mg 
 
Cohort A6 
 
 
 
 
 
Up to 90 mg 
 
 
 
 
 
 
 
Cohort A9 (Approximately 8 subjects, open-label VX-121, single sequence)b 
 
 
 
 
Part B: Multiple-dose escalation of VX-121  
Approximately 8 subjects per cohort, randomized 3:1 (VX-121:placebo) 
 
Planned Dosage (qd, 10 days) 
Cohort B1 
10 mg qd 
 
 
 
 
 
Cohort B2 
 
20 mg qd 
 
 
 
 
Cohort B3 
 
 
40 mg qd 
 
 
 
Cohort B4 
 
 
 
60 mg qd 
 
 
Cohort B5 
 
 
 
 
TBD 
 
Cohort B6 
 
 
 
 
 
TBD 
≥8-day  
Day 1: 
Suspension, 
fed (10 mg) 
Day 9: 
Tablet, fed 
(10 mg) 
Dosing Period 1 
Dosing Period 2 
Dosing Period 3 
Day 17: 
Tablet, fed and 
with milk (10 mg) 
≥8-day  


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Table 7-1 
Study Design for Parts A, B, and C 
 
Part C: Multiple-dose escalation of VX-121 in TC with TEZ/IVAc 
Approximately 8 subjects per cohort, randomized 3:1 (VX-121/TEZ/IVA:triple placebo) 
 
Planned Dosage (qd, 14 days) 
Cohort C1 
10 mg qd 
 
 
 
 
 
Cohort C2 
 
20 mg qd 
 
 
 
 
 
 
 
 
 
 
 
Notes: In Part A, planned doses are shown; any cohort may be initiated at a lower or higher dose level than the 
planned dose based on emerging safety, tolerability, and PK data. No dose increment will be expected to yield greater 
than a 3-fold increase (Cohorts A1 through A3) or a 2-fold increase (all other Part A cohorts and Part B cohorts) in 
exposure from the preceding dose level. Dose escalation criteria and predefined stopping criteria are described in 
Section 9.7.1 and Section 9.8.1 of the protocol. 
a 
In addition to randomized study drug administration depicted above, after a washout of at least 8 days all 
subjects will receive an additional 5 mg single dose of open-label VX-121 suspension with milk to evaluate the 
effect of milk on VX-121 exposure. 
b 
Subjects will receive a single dose of VX-121 on 3 dosing occasions with at least an 8-day washout between 
dosing occasions. VX-121 doses include a single oral dose of suspension, a single oral dose of tablet to evaluate 
the relative BA of the tablet, and a single oral dose of tablet with milk to evaluate the effect of milk on VX-121 
exposure (the planned dose is 10 mg for both formulations, but it will not exceed the highest dose that was safe 
and well tolerated in a previous Part A cohort). 
c 
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. 
 
7.2 
Part D (Subjects With CF) 
A schematic of the study design for Part D is shown in Figure 7-1, which has a randomized, 
double-blind, placebo-controlled, parallel-group design. After completing the Screening Period, 
approximately 12 subjects will be randomized 3:1 to TC:placebo. 
Screening in Part D will be initiated after the completion of Parts A, B, and C (cohorts needed 
for Part D dose selection only) through the Safety Follow-up Visit. The decision to proceed to 
Part D will be based on an evaluation of safety, tolerability, and PK data from completed cohorts 
in Parts A, B, and C. These data will be submitted to the IEC for approval before proceeding to 
screening for Part D. Refer to Section 9.3.2 of the protocol for additional details. 


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Figure 7-1 
Schematic of Study Design for Part D  
 
a 
The planned VX-121 dose for Part D is 10 mg qd. This dose is predicted to provide an approximate AUC0-24h of 
10 µg∙h/mL, which is within the predicted efficacious exposure range based on in vitro data. Based on emerging 
safety, tolerability, and PK data from Parts A, B, and C, the planned dose for Part D may be lowered to 
5 mg qd. The total daily dose of VX-121 in Part D will be at least 1 dose level below the highest total daily dose 
tested in Part C. The dosage of TEZ/IVA in the TC 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. 
7.3 
Sample Size and Power 
No formal sample size calculations have been performed. The number of subjects participating in 
each cohort of Parts A, B, and C is typical for first in human studies in healthy subjects and is 
considered sufficient to achieve the objectives of the study. Approximately 12 subjects in Part D 
is considered sufficient to meet the objectives of the study for this early assessment in subjects 
with CF. 
7.4 
Randomization 
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).  
Parts A, B, and C 
Subjects will be assigned a unique subject number (unique to subject and cohort). Only subjects 
who have completed screening assessments and are eligible for participation in the study will be 
randomized to receive active study drug or placebo during the Treatment Period. A list 
identifying subjects by their subject number will be maintained in the study file at the CRU. 
Part D 
Subjects will be assigned a unique subject number. Only subjects who have completed screening 
assessments and are eligible for participation in the study (and qualify to enter the Treatment 
Period) will be randomized to receive active study drug or placebo during the Treatment Period.  
VX-121 + TEZ/IVA 
N = 9 
Placebo 
N = 3 
Treatment Perioda 
4 weeks 
Screening Period 
4 weeks 
Safety Follow-up Period 
4 weeks 


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An interactive web response system (IWRS) will be used to assign subjects to treatment.  
7.5 
Replacement 
Subjects who withdraw or are withdrawn before the first dose of study drug on the Day 1 Visit 
may be replaced.  
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex's discretion. 
7.6 
Blinding and Unblinding 
Refer to the Section 10.7 of the protocol for details. 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
For subjects other than those from Cohort A9, the All Subjects Set will include all subjects who 
were randomized or received at least 1 dose of study drug.  
For subjects from Cohort A9, the All Subjects Set will include all subjects who were assigned a 
subject identification number or received at least 1 dose of study drug. 
The All Subjects Set will be used for individual subject data listings, and the disposition 
summary table, unless specified otherwise. 
 
8.2 
Full Analysis Set (Part D Only) 
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. 
8.3 
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 for the Safety Set.  


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9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of CSP. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables.  
Continuous data will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, standard deviation (SD), median, minimum value (min), and 
maximum value (max). 
Categorical data will be summarized using frequency counts and percentages. Percentages will 
be presented to 1 decimal place, unless otherwise specified. 
Treatment-emergent (TE) Period 
For subjects participating in Part A (excluding Cohorts A3 and A9), Parts B and C, the TE 
Period will be from the first dose date of study drug to (1) the Safety Follow-up Visit for 
subjects who have a Safety Follow-up Visit, or (2) 7 days after the last dose of study drug for 
subjects who do not have a Safety Follow-up Visit. 
For subjects participating in Cohort A3 in Part A, 2 TE periods will be analyzed: 
 TE Period 1 (suspension [fed]) will begin from the administration of study drug on Day 1 
(1) until the administration of  VX-121 in fed state and with milk, or (2) the Safety Follow-up 
Visit for subjects who do not have the dose of VX-121 in fed state and with milk, and have a 
Safety Follow-up Visit, or (3) 7 days after the last dose of study drug for subjects who do not 
have the dose of VX-121 in fed state and with milk, and do not have a Safety Follow-up 
Visit. 
 TE Period 2 (suspension [fed and with milk]) will begin from the administration of 
study drug on Day 9 through the Safety Follow-up Visit or 7 days after the last dose of 
study drug, whichever comes first.  
For subjects participating in Cohort A9 in Part A, 3 TE periods will be analyzed: 
 TE Period 1 (suspension [fed]) will begin from the administration of study drug on Day 
1 (1) until the administration of of VX-121 tablet in the fed state, or (2) the Safety 
Follow-up Visit for subjects who do not have  the dose of VX-121 tablet in the fed state 
and have a Safety Follow-up Visit, or (3) 7 days after the last dose of study drug for 
subjects who do not have the dose of VX-121 tablet in the fed state and do not have a 
Safety Follow-up Visit. 


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 TE Period 2 (tablet [fed]) will begin from administration of VX-121 tablet in the fed 
state (1) until the administration of  VX-121 tablet in the fed state and with milk, or (2) 
the Safety Follow-up Visit for subjects who do not have the dose of VX-121 tablet in the 
fed state and with milk and have a Safety Follow-up Visit, or (3) 7 days after the last dose 
of study drug for subjects who do not have the dose of VX-121 tablet in the fed state and 
with milk, and do not have a Safety Follow-up Visit. 
 TE Period 3 (tablet [fed and with milk]) will begin from the administration of VX-121 
tablet in fed state and with milk through the Safety Follow-up Visit or 7 days after the 
last dose of study drug for subjects who do not have a Safety Follow-up Visit..  
For subjects participating in Part D, the TE Period will be from first dose date of study drug to 
Safety Follow-up Visit for subjects who have a safety follow-up visit; or 28 days after the last 
dose date of study drug for subjects who do not have a safety follow-up visit. 
Treatment Groups 
The Treatment Groups in Part A (excluding Cohorts A3 and A9), B, C and D will be defined as 
the corresponding VX-121 dose groups. 
The 2 Treatment Groups in Cohort A3 will correspond to suspension [fed] and suspension [fed 
and with milk] respectively. 
The 3 Treatment Groups in Cohort A9 will correspond to suspension [fed], tablet [fed] and tablet 
[fed and with milk] respectively. 
Baseline value 
The baseline value will be defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected before the first dose of study drug. If a pre-dose measurement is missing 
and no drug-free unscheduled assessments are performed before the first dose of the study, the 
baseline will be missing. For ECG, the baseline value will be defined as the most recent non-
missing measurement (or the average of triplicate measurements, if the most recent non-missing 
measurements are obtained in triplicate), before the first dose of study drug of the Treatment 
Period. 
Absolute change from baseline will be calculated as post-baseline value – baseline value. 
Relative change from baseline will be calculated as (post-baseline value – baseline 
value)/baseline value. 


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Visit Window: For Parts A, B and C, the majority of assessments are predicted to be on 
schedule. Visit windows will not add significant value to the analysis and will not be applied. For 
Part D, the analysis visit windows for protocol-defined visits are provided in Appendix A. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate. 
Incomplete/missing data (e.g., dates, post-baseline values) will not be imputed, unless 
otherwise specified; i.e., all missing values and missing post-baseline values will remain as 
missing in all statistical analyses and listings, unless otherwise specified. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers. 
All subject level data, including those derived, will be presented in the individual subject data 
listings; listings will be based on the All Subjects Set. 
Unless otherwise specified, the analyses will be presented by treatment group/treatment 
sequence. Separate summary tables will be produced for each part. The number of cohorts and 
the dose levels of each cohort are subject to change to reflect the actual cohorts enrolled and dose 
levels.   
The treatment group and treatment sequence for all cohorts in each part will be labeled as 
follows. 
- Part A (Cohorts A1, A2 and A4 through A6, or A7, A8 when applicable): Placebo, VX-121 10 
mg, VX-121 20 mg,  VX-121 40 mg, VX-121 60 mg, VX-121 90 mg and VX-121 Total.  
- Part A (Cohort A3): Placebo and VX-121 5 mg within the sequence of Placebo -> VX-121 (fed 
with milk) ; VX-121 5 mg  and VX-121 5 mg [fed with milk] within the sequence of VX-121 5 
mg  -> VX-121 5 mg (fed with milk) , and VX-121 Total. 
- Part A (Cohort A9): VX-121 10 mg suspension [fed], VX-121 10 mg tablet [fed], and VX-121 
10 mg tablet [fed with milk] 
- Part B: Placebo, VX-121 10 mg qd,  VX-121 20 mg qd, VX-121 40 mg qd, VX-121 60 mg qd, 
and VX-121 Total 


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- Part C: Triple Placebo, VX-121 10 mg qd + TEZ 100 mg qd/IVA 150 mg q12h, and VX-121 
20 mg qd+ TEZ 100 mg qd/IVA 150 mg q12h, and VX-121 Total when there are more than one 
TC doses. 
- Part D: Triple Placebo, and VX-121 TBD mg + TEZ 100 mg qd/IVA 150 mg q12h. 
9.2 
Background Characteristics 
9.2.1 
Subject Disposition 
Disposition summary will be based on the All Subjects Set. 
The number and percentage of subjects in the following disposition categories will be 
summarized by treatment group/treatment sequence and overall for each part: 
 Randomized 
 Safety Set 
 Full Analysis Set 
The number and percentage (based on Safety Set) of subjects in each of the following disposition 
categories will be summarized by treatment group/treatment sequence and overall, when 
applicable: 
 Completed study drug treatment 
 Prematurely discontinued treatment and the reason for discontinuation  
 Completed study 
 Prematurely discontinued the study and the reason for discontinuation  
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics summary will be based on the Safety Set. 
Demographics and baseline characteristics (age, sex, race, ethnicity, weight, height, body mass 
index (BMI) and etc.) will be summarized overall and by treatment group for Parts A 
(Cohorts A1, A2 and A4 through A6, or A7, A8 when applicable), B, C, and D and by treatment 
sequence for Cohorts A3 and A9. 
No statistical tests will be done to evaluate baseline imbalances between groups. 
9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). For the Safety Set, medical history will be summarized descriptively by system 


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organ class and preferred term and by treatment group/treatment sequence and overall for each 
part. The corresponding data listing will also be provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
September 2017, Format B2 or higher. Medications used in the study will be categorized as prior 
and/or concomitant medications as follows: 
1. Prior medication: Medication that started before the first dose of study drug, regardless 
of when dosing of the medication ended 
2. Concomitant medication: Medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date 
If a medication start date is on or after the date of initial dosing of the study drug, then the 
medication will be summarized as concomitant medication regardless of whether the medication 
end date is missing or not. If a medication end date is before the date of initial dosing of the 
study drug, then the medication will be summarized as prior medication regardless of whether 
the medication start date is missing or not. Note that medication that started before initial dosing 
of the study drug and continued after initial dosing will be summarized as prior medication and 
separately as concomitant medication. 
Missing or partial dates will be imputed for medication. Algorithm for missing or partial start 
date is: 
Missing day: first day of the month is imputed; 
Missing month: January is imputed; 
Missing year: not imputed. 
Algorithm for missing or partial end date is: 
Missing day: last day of the month is imputed; 
Missing month: December is imputed (31 December if day is also missing); 
Missing year: not imputed. 
Missing data algorithms will be reviewed to ensure the algorithms work. For example, end date 
will not be before the start date after the imputation.  
For Cohorts A3 and A9, concomitant medications will be assigned to each TE period based on 
the start date of the medication and the study drug administration dates (concomitant medications 
taken during the TE period will be assigned to the TE period, and so forth). 


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Note that a concomitant medication may be assigned to multiple TE periods. 
Prior medications will not be summarized, but will only be listed based on All Subjects Set. 
Concomitant medications will be summarized using preferred name by treatment 
group/treatment sequence and overall for each part. Concomitant Medications summary will be 
based on the Safety Set. 
Prior and concomitant non-drug therapy will also be listed based on All Subjects Set. 
9.2.5 
Study Drug Exposure and Compliance 
Study drug exposure in Parts B, C and D (i.e., duration of treatment) will be summarized by 
treatment group and overall for the Safety Set.  
Study drug exposure (in days) will be defined as (last date of dosing – first date of dosing) + 1. 
The study drug administration will be presented in an individual subject listing. 
Compliance analysis will be provided for Part D only based on the FAS, and will be presented by 
treatment group and overall. Study drug compliance will be calculated as: 100 × [1 - (total 
number of days of study drug interruption) / (duration of study drug exposure in days)]. A study 
drug interruption on a given day is defined as an interruption of any study drugs on that day. 
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max.  It will also be summarized in categories: <80% and ≥80% using 
frequency tables. 
In addition, percentage of tablets taken will be calculated using the following formula: 100 x 
[(total number of tablets dispensed for the Treatment Period) – (total number of tablets returned] 
/ (total number of tablets planned to be taken per day x duration of study drug exposure in days).  
Summary similar to the study drug compliance will be produced based on the FAS for Part D 
only. 
9.2.6 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. IPD rules will be developed and finalized before database lock. 
IPDs will be identified by the PD review team according to PD plan.  
IPDs will be provided in an individual subject data listing.  


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9.3 
Efficacy Analysis  
9.3.1 
Spirometry (Part D Only) 
The spirometry parameters:  FEV1 (L), forced vital capacity (FVC) (L), FEV1/FVC (ratio), and 
forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) and their corresponding percent 
predicted values (percentage point) and change from baseline will be summarized by treatment 
group using descriptive statistics for the FAS. Percent predicted FEV1 is the ratio of FEV1 (L) 
and predicted FEV1 (L), expressed as a percentage.  See Appendix B for more details.  
In addition, a mixed-effects model for repeated measures (MMRM) with change from baseline at 
Day 15 and Week 4 predose for percent predicted forced expiratory volume in 1 second 
(ppFEV1) as the dependent variable will be performed for the FAS. The model will include 
treatment group, visit, and treatment-by-visit interaction as fixed effects. 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.  
 The adjusted means and 2-sided 95% CIs of the treatment effect through Day 29 (averaged over 
Day 15 and 29), with corresponding P values for all within-group comparisons, will be estimated 
using MMRM.  
In addition, the adjusted mean and 95% CI of the within-treatment difference at each post-
baseline visit through Day 29 for each treatment group will be provided along with the p-value.   
9.4 
Safety Analysis 
Safety is the 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 as specified in the CSP. 
 ECG outcomes 
 Vital signs (including pulse oximetry [Part D only]) 
 Spirometry (Part D only) 
All safety analyses will be performed by treatment group/treatment sequence for each part as 
applicable based on the Safety Set. All safety data will be presented in the individual subject data 


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listings based on the All Subjects Set. No statistical hypothesis testing will be performed for 
safety analysis. 
Table 9-1 shows the safety summaries (e.g., raw value, change from baseline, incidence, and 
clinical abnormalities and etc) that will be summarized for TEAEs, clinical lab values, 12-lead 
ECGs, vital signs, spirometry and physical examination. Details are provided in the 
corresponding subsections.  
The incidence of TEAEs will be summarized. TEAE summaries will include the following: all 
TEAEs (regardless of severity or relationship to study drug), serious adverse events (SAEs), 
TEAE severity, TEAE relationship, and discontinuations of study drug treatment due to TEAEs. 
For the non-AE safety evaluations (clinical laboratory, ECGs and vital signs), raw values, and 
changes from baseline will be summarized as indicated in Table 9-1. For example, an “X” under 
the raw value column (third column) means that the “Raw value” for the safety evaluation will 
be summarized in tables; an “X” under the “Change from Baseline” column (fourth column) 
means that change will be summarized in tables.  
Throughout this section, “change” refers to absolute change from baseline. 
Table 9-1   Summaries Planned for Safety Data 
Safety Assessment 
Incidence 
Raw Value 
Change from 
Baseline 
Clinical 
Abnormalities 
Threshold 
Analysis  
TEAEs 
X 
 
 
NA 
 
Hematology/and 
chemistry  
 
X 
X 
Listing only 
X (Part D only) 
Coagulation 
 
X (Part D 
only) 
X (Part D only) 
 
 
Urinalysis 
 
Listing only 
 
 
 
12-lead ECG 
 
X 
X 
 
X (Part D only) 
Vital signs 
 
X 
X 
 
X (Part D only) 
Spirometry (Part D) 
 
X 
X 
NA 
 
Physical Examination 
 
Listing only 
 
NA  
 
ECG: electrocardiogram; TEAEs: treatment-emergent adverse events; NA: Not applicable; X: safety assessment will 
be summarized in tables  
9.4.1 
Adverse Events 
AEs will be coded according to MedDRA (Version 20.1 or above). The number and percentage 
of subjects experiencing an AE will be summarized by the MedDRA System Organ Class (SOC) 
and Preferred Term (PT). AEs will be classified as pretreatment or treatment-emergent. 
Pretreatment AEs are defined as AEs that were reported or worsened (either in severity or 
seriousness) after signing the ICF up to the start of study drug dosing. 


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Treatment-emergent adverse events (TEAEs) for all cohorts except Cohorts A3 and A9 are 
defined as any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose date of study drug during the Treatment Period through the end of the TE 
Period for the Treatment Period. 
For Cohort A3 and A9, TEAEs will be assigned to each treatment group based on the start date 
of the AE and the start of study drug administration dates within the corresponding TE Period.  
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs 
corresponding to the Treatment Period. Unless otherwise specified, TEAE refers to TEAE during 
the Treatment Period. 
Details for imputing missing or partial start dates of adverse events are described in Appendix C, 
which is applicable to Part D only. 
AE summary tables will be presented for TEAEs only and will include the following: (1) 
Overview of TEAEs (2) all TEAE; (3) related (defined as possibly related, related, or missing) 
TEAEs; (4) serious TEAEs; (5) TEAEs by severity; (6) TEAEs by relationship; and (7) TEAEs 
leading to treatment discontinuation.  
Summaries will be presented using frequency counts and percentages by treatment 
group/treatment sequence for each part (i.e., number and percentage of subjects with an event); 
for the summary table of TEAE Overview, an additional column of overall will be provided. 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event will be counted once, and only the maximum severity level will be 
presented in the severity summaries, and the strongest relationship level in the relationship 
summaries.  
In addition, a listing containing individual subject AEs leading to death, SAEs, dose interruption, 
and discontinuation will be listed separately. All AEs through the Safety Follow-up Visit will be 
listed in an individual subject data listing, including pretreatment AEs. 
9.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using SI units. Continuous 
hematology, clinical chemistry and coagulation (Part D only) results including baseline and 
change from baseline values will be summarized at each scheduled time point by treatment 
group/treatment sequence for each part using descriptive statistics. 


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For Part D, the number and percentage of subjects meeting at least 1 threshold analysis criterion 
event, during the TE period for Treatment Period, will be summarized by treatment group. The 
threshold analysis criteria are provided in Appendix D.  
Clinically significant abnormal laboratory findings will be reported as AEs.  
9.4.3 
Electrocardiogram 
A summary of raw values and change from baseline values will be provided for each scheduled 
time point by treatment group/treatment sequence for each part during the TE Period for the 
following 12-lead ECG measurements using descriptive statistics: RR interval, PR interval, QT 
interval, QTcF interval, QRS duration, and Heart Rate (beats per minute). 
For Part D, the number and percentage of subjects meeting at least 1 threshold analysis criterion 
during the TE period for the Treatment Period will be summarized by treatment group. The 
threshold analysis criteria are provided in Appendix D. 
In addition, the number and percentage of subjects by maximum value of QT/QTc intervals 
during the TE period, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and 
≤500 msec, and >500 msec, as well as maximum change from baseline value of QT/QTc 
intervals during the TE period, categorized as ≤0 msec, >0 msec and ≤30 msec, >30 msec and 
≤60 msec, and >60 msec will be tabulated based on scheduled and unscheduled 12-lead ECG 
measurements by treatment group/treatment sequence for each part. 
Clinically significant abnormal findings will be reported as AEs. 
9.4.4 
Vital Signs 
A summary of raw values and change from baseline values will be provided for each scheduled 
time point by treatment group/treatment sequence for each part using descriptive statistics for the 
following vital signs measurements: BMI (kg/m2), weight (kg), height (cm), systolic and 
diastolic blood pressure (mm Hg), body temperature (°C), pulse rate (beats per minute), and 
respiratory rate (breaths per minute). 
For Part D, the number and percentage of subjects meeting at least 1 threshold analysis criterion 
during the TE period for the Treatment Period will be summarized by treatment group. The 
threshold analysis criteria are provided in Appendix D. 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits.  
Clinically significant abnormal findings in vital signs will be reported as AEs. 


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9.4.5 
Pulse Oximetry (Part D) 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each visit by treatment group, for the percent of 
oxygen saturation. 
9.4.6 
Physical Examination 
Physical examination (PE) results will be presented in individual subject data listings only. 
Clinically relevant changes identified after screening will be reported as AEs. 
 
9.6 
Pharmacodynamic Analysis (Part D Only)  
The sweat chloride value for a given visit will be calculated as the mean of the non-missing 
sweat chloride measurements obtained on the left and right arms at that visit.  If one of the two 
arm measurements at a time point is missing, the other will be used as the mean.  A volume ≥15 
μL is required for an accurate determination of sweat chloride.  Any results reported as having 
volume <15 μL will be considered missing. Any sweat chloride values reported as <10 mmol/L 
or >160 mmol/L will be considered missing.  
The analysis of sweat chloride data will be based on the FAS. A summary of raw values and 
change from baseline values will be provided at each scheduled visit by treatment group and 
overall using descriptive statistics. 
The same MMRM model as for ppFEV1 will be used to analyze the change from baseline for 
sweat chloride. Adjusted means and 2-sided 95% CIs of the treatment effect through Day 29 
(averaged over Day 15 and 29), with 2-sided P values for all within-group comparisons, will be 
estimated using MMRM. 


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In addition, a listing containing individual subject data at scheduled and unscheduled visits will 
be provided. 
10 
INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis 
An IA of the continuous ECG data may be performed after all subjects in Part B have completed 
the Safety Follow-up Visit. These results will be reviewed by a small unblinded Vertex team. 
 
10.2 
IDMC Analysis 
Not applicable 
11 
REFERENCES 
Not applicable. 
12 
APPENDICES 
Appendix A: Analysis Visit Windows (Part D Only) 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4 
(in study days) 
Safety Assessment 
Serum Chemistry 
Hematology 
Coagulation 
Vital Signs (including Weight and 
BMI) 
Baseline  
Day 8 
Day 15 
Day 29 
Safety Follow-up 
1 
8 
15 
29 
Not applicable 
1 Pre-dose 
(15, 12] 
(12, 22] 
(22, 43] 
Use nominal visit 
Standard 12-lead ECG 
Baseline 
Day 1 Postdose  
 
Day 8 
Day 15 Predose 
and Postdose 
Day 29 
Safety Follow-up 
1 
Not applicable 
 
8 
Not applicable 
 
 
29 
Not applicable 
1 Pre-dose 
Use nominal visit 
(1, 12] 
Use nominal visit 
 
(22, 43] 
Use nominal visit 
Efficacy Assessment and Pharmacodynamic Assessment  
Spirometry 
Sweat Chloride  
 
Baseline  
Day 8 
Day 15 
Day 29 
Safety Follow-up 
1 
8 
15 
29 
Not applicable 
1 Pre-dose 
(1, 12] 
(12, 22] 
(22, 43] 
>43 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4 
(in study days) 
Notes: 
 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. 
 
3 For lab, ECG and vital sign measurement collected on the date of first dose of study drug in Treatment Period, if it 
cannot be determined whether the measurement is before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >43, then the ETT visit 
will be mapped into Safety Follow-up analysis visit.  
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs 
(VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
 
2. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up or the last study drug administration date from EX SDTM domain, as appropriate.   
3. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for a 
given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
4. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period (or the average of triplicate measurements, if the most recent non-missing measurement is 
obtained in triplicate). If multiple ECG measurements are obtained on the same calendar day during the TE 
period,  
o 
For summary purpose, the calculated average ECG will be used as the ECG value on that day (except 
for Day 1 and Day 15 for ECG in Part D); 
o 
For threshold analysis purpose, all reported ECG values will be used. 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4 
(in study days) 
5. Day 1 post dose could be included in the Analysis Visit Window. 
 
 


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Appendix B: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed Mar 26, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed Mar 
26, 2018].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Mar 26, 2018]. 
 Data handling rule for spirometry is as follows:  
 Input age with at least 2 decimal place 
 Use age at each corresponding visit and height at screening.  
 For race, map CRF black or AA to black, all other races in CRF (except white) are 
mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; white is a 
reference race in the equations and assumes 0 values for all race coefficients in the GLI 
equations. 
 
 


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Appendix C: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the study informed consent date, the AE start date will be imputed using the study 
informed consent date. 
 If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site and  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the Treatment Period;  
o else impute the AE start date as the informed consent date. 


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Imputation rules for partial AE end date are defined below:  
 
Impute the AE end date as min (the last day of the month, end of study participation) if day is 
missing, or min (Dec, end of study participation) if month is missing. 
 
 


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Appendix D: Criteria for Threshold Analysis 
Table 12-2 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or 
(AST>ULN - ≤  3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x 
- ≤  5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - 
≤    8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x 
- ≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


Statistical Analysis Plan Methods, Version 2.0                                                            Page 30 of 34                                                            
Protocol Number: VX17-121-001 (Version 3.0 dated 27Jul2018) 
Vertex Pharmaceuticals Incorporated 
 
Table 12-2 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine Kinase 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L 
above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 


Statistical Analysis Plan Methods, Version 2.0                                                            Page 31 of 34                                                            
Protocol Number: VX17-121-001 (Version 3.0 dated 27Jul2018) 
Vertex Pharmaceuticals Incorporated 
 
Table 12-2 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
  
Table 12-3 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 


Statistical Analysis Plan Methods, Version 2.0                                                            Page 32 of 34                                                            
Protocol Number: VX17-121-001 (Version 3.0 dated 27Jul2018) 
Vertex Pharmaceuticals Incorporated 
 
Table 12-3 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
QTc 
Borderline 
Prolonged* 
Additional 
 
 
>450 ms (Male) and <500ms; >470 ms and 
<500ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 
Table 12-4 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
 
809/770 analyses 


Statistical Analysis Plan Methods, Version 2.0                                                            Page 33 of 34                                                            
Protocol Number: VX17-121-001 (Version 3.0 dated 27Jul2018) 
Vertex Pharmaceuticals Incorporated 
 
Table 12-4 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
 
 
 


Statistical Analysis Plan Methods, Version 2.0                                                            Page 34 of 34                                                            
Protocol Number: VX17-121-001 (Version 3.0 dated 27Jul2018) 
Vertex Pharmaceuticals Incorporated 
 
Table 12-4 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3