Conditions: Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 597
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of VX-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA) in CF participants who are homozygous for F508del, heterozygous for F508del and a gating (F/G) or residual function (F/RF) mutation, or have at least 1 other TCR CF transmembrane conductance regulator (CFTR) gene mutation and no F508del mutation.

Detailed description:

Arms:
arm 1: Following elexacftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) run-in period of 4 weeks, participants received ELX 200 milligram (mg) once daily (qd) /TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for 52 weeks. arm 2: Following ELX/TEZ/IVA run-in period of 4 weeks, participants received VX-121 20 mg qd/TEZ 100 mg qd/D-IVA 250 mg qd in the treatment period for 52 weeks.

Interventions: intervention 1: VX-121/TEZ/D-IVA intervention 2: ELX/TEZ/IVA intervention 3: IVA intervention 4: Placebo (matched to VX-121/TEZ/D-IVA) intervention 5: Placebo (matched to ELX/TEZ/IVA) intervention 6: Placebo (matched to IVA)
Intervention descriptions: intervention 1: Fixed-dose combination tablets for oral administration. intervention 2: Fixed-dose combination tablets for oral administration. intervention 3: Tablet for oral administration. intervention 4: Placebo matched to VX-121/TEZ/D-IVA for oral administration. intervention 5: Placebo matched to ELX/TEZ/IVA for oral administration. intervention 6: Placebo matched to IVA for oral administration.

Protocol document:
Prot_000.pdf: 
Page 1 of 72 
 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, Randomized, Double-blind, Controlled 
Study Evaluating the Efficacy and Safety of VX-121 
Combination Therapy in Subjects With Cystic 
Fibrosis Who Are Homozygous for F508del, 
Heterozygous for F508del and a Gating (F/G) or 
Residual Function (F/RF) Mutation, or Have At Least 
1 Other Triple Combination Responsive CFTR 
Mutation and No F508del Mutation 
Vertex Study Number: VX20-121-103 
IND Number: 142001 
EudraCT Number: 2021-000694-85  
Date of Protocol: 19 August 2021 (Version 3.0) 
Replaces Version 2.0, dated 12 July 2021  
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


Protocol VX20-121-103, Version 3.0 
Page 2 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Summary of Changes to the Protocol 
The previous version of this protocol (Version 2.0, 12 July 2021) was amended to create the 
current version (Version 3.0, 19 August 2021). The protocol history is provided below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 27 April 2021 
Original version 
Version 2.0, 12 July 2021 
Added exclusion criteria that subjects cannot participate in an interventional 
study of a non-investigational treatment from screening through end of study 
participation; 
Updated acceptable methods of contraception based on supporting nonclinical 
data 
Version 3.0, 19 August 2021 
Current version 
 
 
Key changes in the current version of the protocol are summarized below. 
Change and Rationale 
Affected Sections  
Expanded study population to include subjects who have at least 1 CFTR 
mutation identified as responsive to ELX/TEZ/IVA based on in vitro 
data and no F508del mutation (TCR/non-F) (in addition to subjects 
homozygous for F508del or heterozygous for F508del and either a gating 
or residual function mutation).  
Global 
Increased planned sample size and Treatment Period duration  
Global 
Study endpoints were updated to reflect the change in Treatment Period 
duration 
Sections 2, 7, and 12.3.3 
Liver function test elevations, creatine kinase elevations, rash, cataracts, 
hypoglycemia, and neuropsychiatric events were designated as adverse 
events of special interest 
Section 12.3.4 
Hemoglobin A1c was added to the hematology panel to assess pancreatic 
endocrine function 
Section 9.3.4, Table 3-1, Table 3-2, 
and Table 11-2 
Analysis of primary and key secondary endpoints through Week 24 will 
be estimated by averaging Weeks 16 and 24 
Sections 2 and 12.3.3.1 
Stratification by genotype group was updated to be based on F/F, F/G, 
F/RF, and TCR/non-F genotypes 
Sections 2, 9.2, and 12.3.3 
Rationale for the non-inferiority margin for primary analysis of the 
primary endpoint was provided 
Section 12.1 
Clarified that it is the responsibility of the investigator to report 
unexpected serious adverse drug reactions to the local IRB/IEC if 
allowed by local regulations  
Section 13.1.2.3 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 


Protocol VX20-121-103, Version 3.0 
Page 3 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety 
of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous 
for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) 
Mutation, or Have At Least 1 Other Triple Combination Responsive CFTR Mutation and No 
F508del Mutation 
  
Brief Title 
A Phase 3 Study of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Who 
Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual 
Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive CFTR 
Mutation and No F508del Mutation 
 
 
Clinical Phase 
and Clinical 
Study Type  
Phase 3, efficacy and safety  
 
 
Objectives 
Primary Objective 
To evaluate the efficacy of VX-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA) in cystic 
fibrosis (CF) subjects who are homozygous for F508del, heterozygous for F508del and a 
gating (F/G) or residual function (F/RF) mutation, or have at least 1 other triple combination 
responsive (TCR) CFTR mutation and no F508del mutation 
Secondary Objectives 
• 
To evaluate the safety of VX-121/TEZ/D-IVA 
• 
To evaluate the pharmacokinetics (PK) of VX-121/TEZ/D-IVA 
 
 
Endpoints 
Primary Endpoint  
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) through Week 24 
Key Secondary Endpoints 
• 
Absolute change from baseline in sweat chloride (SwCl) through Week 24 
• 
Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data 
from Study VX20-121-102) 
• 
Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data 
from Study VX20-121-102) 
Other Secondary Endpoints 
• 
Number of pulmonary exacerbations (PEx) through Week 52 
• 
Absolute change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) 
Respiratory Domain (RD) score through Week 24 
• 
Absolute change from baseline in ppFEV1 through Week 52 
• 
Absolute change from baseline in SwCl through Week 52 
• 
Proportion of subjects with SwCl <60 mmol/L through Week 24 
• 
Proportion of subjects with SwCl <30 mmol/L through Week 24 
• 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry 


Protocol VX20-121-103, Version 3.0 
Page 4 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Other Endpoints 
• 
Proportion of subjects with SwCl <60 mmol/L through Week 52 
• 
Proportion of subjects with SwCl <30 mmol/L through Week 52 
• 
Absolute change from baseline in body mass index (BMI) at Week 52 
• 
Absolute change from baseline in BMI z-score at Week 52 
• 
Absolute change from baseline in weight at Week 52 
• 
Absolute change from baseline in CFQ-R RD score through Week 52 
• 
PK parameters of VX-121, TEZ, and D-IVA  
 
 
Number of 
Subjects 
Approximately 550 subjects will be randomized (1:1) to the VX-121/TEZ/D-IVA group or 
the elexacaftor (ELX)/TEZ/ivacaftor (IVA) group. 
 
 
Study 
Population 
Male and female subjects with CF who are 12 years of age or older with the following 
genotypes: homozygous for F508del; heterozygous for F508del and either a gating (F/G) or 
residual function (F/RF) mutation; or at least 1 TCR mutation identified as responsive to 
ELX/TEZ/IVA and no F508del mutation (TCR/non-F).   
 
 
Investigational 
Drug 
Study drug refers to VX-121/TEZ/D-IVA, ELX/TEZ/IVA, IVA, and their matching 
placebos. 
Active study drugs will be orally administered as either 2 fixed-dose combination (FDC) 
film-coated VX-121/TEZ/D-IVA tablets in the morning, or as 2 FDC film-coated 
ELX/TEZ/IVA tablets in the morning and as 1 film-coated IVA tablet in the evening. 
 
Active substance: VX-121, TEZ (VX-661), and D-IVA (VX-561) 
 
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator (increased Cl− secretion) 
 
Strength and route of administration: 10 mg VX-121/50 mg TEZ/125 mg D-IVA; oral 
administration 
 
 
 
Active substance: ELX (VX-445), TEZ (VX-661), and IVA (VX-770) 
 
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator (increased Cl− secretion) 
 
Strength and route of administration: 100 mg ELX/50 mg TEZ/75 mg IVA; oral 
administration 
 
 
 
Active substance: IVA (ivacaftor; VX-770) 
 
Activity: CFTR potentiator (increased Cl− secretion) 
 
Strength and route of administration: 150 mg; oral administration 
 
 
Study Duration 
The total study duration is approximately 64 weeks (4 weeks for the Screening Period, 
4 weeks for the Run-in Period, 52 weeks for the Treatment Period, and 4 weeks for the 
Safety Follow-up Period). 
 
 
Study Design 
This is a Phase 3, randomized, double-blind, ELX/TEZ/IVA-controlled, parallel-group, 
multicenter study.  
All subjects entering the Run-in Period will receive ELX 200 mg qd/TEZ 100 mg qd/IVA 
150 mg every 12 hours (q12h). Following completion of the Run-in Period, approximately 
550 subjects will be randomized (1:1) to the VX-121/TEZ/D-IVA group or ELX/TEZ/IVA 


Protocol VX20-121-103, Version 3.0 
Page 5 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
group. The dosages to be evaluated are shown in the table below. Randomization will be 
stratified by age at the Screening Visit (<18 versus ≥18 years of age), ppFEV1 determined 
during the Run-in Period (Day -14 clinic assessment; <70 versus ≥70), SwCl determined 
during the Run-in Period (Day -14 assessment; <30 versus ≥30 mmol/L), prior CFTR 
modulator use (yes versus no), and genotype group (F/F, F/G, F/RF, and TCR/non-F).  
Figure 2-1 
VX20-121-103 Study Design 
 
D-IVA: deutivacaftor; ELX: elexacaftor; IVA: ivacaftor; N: number of subjects; TEZ: 
tezacaftor 
Note: The figure is not drawn to scale. 
Treatment Groups and Dosages 
Treatment Group 
VX-121 
ELX 
TEZ 
D-IVA 
IVA 
VX-121/TEZ/D-IVA 
20 mg qd 
0 mg 
100 mg qd 
250 mg qd 
0 mg 
ELX/TEZ/IVA 
0 mg 
200 mg qd 
100 mg qd 
0 mg 
150 mg q12h 
D-IVA: deutivacaftor; ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once 
daily; TEZ: tezacaftor 
 
 
Assessments 
Efficacy: Spirometry, SwCl, CFQ-R, documentation of events related to health outcomes 
(e.g., PEx), height, and weight 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, physical 
examinations, and ophthalmologic examinations (for subjects <18 years of age on the date of 
informed consent) 
PK: VX-121, TEZ, D-IVA, ELX, IVA, and relevant metabolite plasma concentrations 
Exploratory: Treatment Satisfaction Questionnaire for Medication (TSQM), Cystic Fibrosis 
Impact Questionnaire (CF-IQ), DNA sample (optional), inflammatory mediators, blood 
biomarker sample, RNA sample (optional), and sputum samples 
 
 
Statistical 
Analyses 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through 
Week 24 (estimated by averaging Weeks 16 and 24). The primary null hypothesis to be 
tested is that the mean absolute change from baseline in ppFEV1 through Week 24 for 
VX-121/TEZ/D-IVA is inferior by >3 percentage points compared to ELX/TEZ/IVA. The 
null hypothesis will be tested at a 1-sided significance level of 0.025. 
Assuming a within-group SD of 8 and 10% drop-out rate at Week 24 and a treatment 
difference of 0 between VX-121/TEZ/D-IVA and ELX/TEZ/IVA, a sample size of 
275 subjects in each group for a total of 550 subjects will have more than 95% power to test 
the primary hypothesis for the primary endpoint, based on a 1-sided, 2-sample t-test at a 
significance level of 0.025. 


Protocol VX20-121-103, Version 3.0 
Page 6 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
The primary analysis of the primary endpoint will be conducted with clinic spirometry data 
only and will be performed using a mixed-effects model for repeated measures (MMRM) 
with absolute change from baseline in ppFEV1 at Day 15, Week 4, Week 8, Week 16, and 
Week 24 as the dependent variable. The model will include treatment group, visit, and 
treatment-by-visit interaction as fixed effects, with continuous baseline ppFEV1, continuous 
baseline SwCl, age at screening (<18 versus ≥18 years of age), and genotype group (F/F, 
F/G, F/RF, and TCR/non-F) as covariates. An unstructured covariance structure will be used 
to model the within-subject errors. 
The primary result obtained from the model will be the estimated treatment difference 
through Week 24. The primary null hypothesis will be rejected and non-inferiority 
demonstrated if the lower bound of the 95% CI is ≥-3.0. 
 
 
DMC Reviews 
A data monitoring committee (DMC) will conduct safety reviews of study data as outlined in 
the DMC Charter. 


Protocol VX20-121-103, Version 3.0 
Page 7 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are shown in Table 3-1 and Table 3-2. 
All visits will be scheduled relative to the Day 1 Visit (first dose of randomized study drug in the 
Treatment Period). 
Study visits should be performed in the clinic as specified in Table 3-1 and Table 3-2, if at all 
possible. The Screening Visit, Day -28 Visit, Day -14 Visit, Day 1 Visit, Week 24 Visit, and 
Week 52 Visit must be performed in clinic (Section 9.1.8). 
All questionnaires completed on the day of the study visit must be completed prior to any other 
assessments, with Cystic Fibrosis Questionnaire–Revised (CFQ-R) completed first. CF-IQ, 
PGIS, and PGIC must be completed on the same day, and CF-IQ must be performed before PGIS 
or PGIC (as applicable). Remaining assessments may be performed in any order when more than 
1 assessment is required at a particular time point. All assessments will be performed before 
study drug dosing (Section 9.6.1), unless noted otherwise.  
Table 3-1 
Study VX20-121-103: Screening 
Event/Assessment 
Screening Visit 
Day -56 
Through 
Day -29 
 
Comments 
ICF and assent (when applicable)  
X 
 
Demographics 
X 
 
Medical history 
X 
 
CFQ-R 
X 
Section 11.5.3 
CF-IQ 
X 
Section 11.4.6 
CFTR genotype 
X 
If the CFTR genotype result is not received before the 
first dose of ELX/TEZ/IVA in the Run-in Period, a 
previous CFTR genotype laboratory report may be used 
to establish eligibility (Section 8.1). Subjects who have 
been enrolled and whose screening genotype does not 
confirm study eligibility must be discontinued from the 
study (Section 9.9). 
FSH 
X 
Postmenopausal female subjects only; Section 11.6.2 
Serum pregnancy test (all female 
subjects) 
X 
Section 11.6.2 
Serum chemistry 
X 
Section 11.6.2 
Hematology 
X 
Section 11.6.2 
HbA1c 
X 
HbA1c will be collected as part of the hematology blood draw  
(Section 11.6.2) 
Coagulation 
X 
Section 11.6.2 
Urinalysis 
X 
Section 11.6.2 
Height and weight 
X 
Measured with shoes off 


Protocol VX20-121-103, Version 3.0 
Page 8 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 3-1 
Study VX20-121-103: Screening 
Event/Assessment 
Screening Visit 
Day -56 
Through 
Day -29 
 
Comments 
Ophthalmologic examination 
X 
Conducted by an ophthalmologist or optometrist, only for 
subjects <18 years of age on the date of informed consent 
(Section 11.6.6). The screening examination does not 
need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was 
conducted within 3 months before the date of informed 
consent. 
Complete physical examination 
X 
Section 11.6.3 
Vital signs 
X 
Collected after the subject has been at rest for at least 
5 minutes (Section 11.6.3) 
Pulse oximetry 
X 
Collected after the subject has been at rest for at least 
5 minutes (Section 11.6.4) 
Standard 12-lead ECG 
X 
Collected after the subject has been at rest for at least 
5 minutes (Section 11.6.5) 
Spirometry 
X 
Performed pre- or post-bronchodilator (Section 11.5.1).  
Sweat chloride 
X 
Section 11.5.2 
Medications review 
X 
Section 9.5 
AEs and SAEs 
Continuous 
from signing of 
ICF (and assent 
form) through 
completion of 
study 
participation 
Section 13.1; completion of study participation is defined 
in Section 9.1.7 
AE: adverse event; CF-IQ: Cystic Fibrosis Impact Questionnaire; CFQ-R: Cystic Fibrosis Questionnaire – 
Revised; FSH: follicle-stimulating hormone; HbA1c: hemoglobin A1c; ICF: informed consent form; SAE: 
serious adverse event 


Protocol VX20-121-103, Version 3.0 
Page 9 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 3-2 
Study VX20-121-103: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
Treatment Periodb 
ETT 
Visitc 
Safety 
Follow-up Visit 
28 (± 7) Days 
After the Last 
Dose of Study 
Drug (If 
Applicable)d 
Comments 
Day -28 
(± 1 Day) 
Day -14  
(Day -15 
to Day -3) 
 
 
 
Day 1 
Day 15 
(± 3 Days) 
Weeks 4, 
8, 12, 16 
(± 5 Days) 
Weeks 
20, 28, 32, 
40, 44, 48 
(± 5 Days) 
Weeks 24 
and 36 
(± 5 Days) 
Week 52 
(± 5 Days) 
Clinic visit 
X 
X 
X 
X 
Xe 
 
X 
X 
X 
X 
See Section 9.1.8 for use of remote 
measures in extenuating 
circumstances.  
Telephone contact 
 
 
 
 
 
X 
 
 
 
 
Assess the subject’s status, any 
AEs, concomitant medications, 
treatments, and procedures. 
Inclusion and 
exclusion criteria 
review 
X 
 
 
 
 
 
 
 
 
 
Section 8 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Randomization may occur on either 
Day -1 or Day 1, after all eligibility 
criteria are confirmed (Section 
9.1.3). 
CFQ-R 
 
 
X 
 
Weeks 8 
and 16 
 
Week 24  
X 
X 
 
Completed before the start of any 
other assessments on the day of the 
study visit (Section 11.5.3). 
 
a 
All assessments will be performed before dosing unless noted otherwise.  
b  
To enter the Treatment Period, conditions for entry must be satisfied (Section 9.1.3). 
c  
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to discontinue treatment (Section 9.1.5). Subjects who 
prematurely discontinue treatment during the Run-in Period will complete an ETT Visit and Safety Follow-up Visit, as applicable. Subjects who prematurely discontinue study drug treatment during 
the Treatment Period should continue to complete all scheduled study visits for assessments following completion of the ETT Visit (and Safety Follow-up Visit, if applicable). 
d  
The Safety Follow-up Visit is required for all subjects, unless otherwise specified (Section 9.1.4). For subjects who complete an ETT Visit 3 weeks or later following the last dose of study drug, the 
ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required (Section 9.1.5).  
e 
The Week 12 Visit may be performed either in the clinic or as a home health visit, if permitted by local regulations. See Section 9.1.8 for use of remote measures in extenuating circumstances. All 
home health visits must have a consultation between the subject and investigator (i.e., in person, phone, or telemedicine video conference). This consultation should occur within 2 business days 
before or after the home health visit and can be outside the visit window. 
 
 


Protocol VX20-121-103, Version 3.0 
Page 10 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 3-2 
Study VX20-121-103: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
Treatment Periodb 
ETT 
Visitc 
Safety 
Follow-up Visit 
28 (± 7) Days 
After the Last 
Dose of Study 
Drug (If 
Applicable)d 
Comments 
Day -28 
(± 1 Day) 
Day -14  
(Day -15 
to Day -3) 
 
 
 
Day 1 
Day 15 
(± 3 Days) 
Weeks 4, 
8, 12, 16 
(± 5 Days) 
Weeks 
20, 28, 32, 
40, 44, 48 
(± 5 Days) 
Weeks 24 
and 36 
(± 5 Days) 
Week 52 
(± 5 Days) 
TSQM 
X 
 
X 
 
 
 
 
X 
X 
 
May be completed within 5 days 
prior to the study visit. All 
questionnaires completed on the 
day of the study visit must be 
completed prior to any other 
assessments, with CFQ-R 
completed first. All subjects will 
complete the TSQM at the 
Day -28 Visit; only subjects 
<18 years of age on the date of 
informed consent will complete the 
TSQM at subsequent visits 
(Section 11.4.5).  
CF-IQ 
X 
 
X 
 
Week 4 
 
Week 24 
X 
 
 
May be completed within 5 days 
prior to the study visit. CF-IQ, 
PGIS, and PGIC must be 
completed on the same day, and 
CF-IQ must be performed before 
PGIS and PGIC (as applicable). All 
questionnaires completed on the 
day of the study visit must be 
completed prior to any other 
assessments, with CFQ-R 
completed first (Section 11.4.6). 
PGIS 
X 
 
X 
 
Week 4 
 
 
 
 
 
PGIC 
 
 
X 
 
Week 4 
 
 
 
 
 
Height and weight 
X 
 
X 
X 
Weeks 4, 
8, 16 
 
X 
X 
X 
X 
Measured with shoes off. 
Following screening, height will be 
collected only for subjects 
≤21 years of age on the date of 
informed consent 


Protocol VX20-121-103, Version 3.0 
Page 11 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 3-2 
Study VX20-121-103: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
Treatment Periodb 
ETT 
Visitc 
Safety 
Follow-up Visit 
28 (± 7) Days 
After the Last 
Dose of Study 
Drug (If 
Applicable)d 
Comments 
Day -28 
(± 1 Day) 
Day -14  
(Day -15 
to Day -3) 
 
 
 
Day 1 
Day 15 
(± 3 Days) 
Weeks 4, 
8, 12, 16 
(± 5 Days) 
Weeks 
20, 28, 32, 
40, 44, 48 
(± 5 Days) 
Weeks 24 
and 36 
(± 5 Days) 
Week 52 
(± 5 Days) 
Ophthalmologic 
examination 
 
 
 
 
 
 
 
X 
X 
 
Subjects <18 years of age on the 
date of informed consent and have 
completed at least 12 weeks of 
study drug treatment will have a 
single ophthalmologic examination 
conducted by a licensed 
ophthalmologist or optometrist 
within 4 weeks prior to completion 
of study participation 
(Section 11.6.6). This examination 
should be completed within 
4 weeks before the Week 52 Visit, 
unless the subject prematurely 
discontinues study drug, in which 
case this examination should occur 
by the Safety Follow-up Visit (or 
ETT Visit for subjects who do not 
complete a Safety Follow-up Visit) 
(Section 9.1.5). 
Physical 
examination 
Abbrev 
 
Complete 
 
 
 
 
Complete 
Complete 
 
Symptom-directed PEs may be 
performed at any time if deemed 
necessary by the investigator 
(Section 11.6.3). 
Pregnancy testing 
Urine 
 
Urine 
 
Urinef 
Urinef 
Urine 
Urine 
Serum 
Serum 
All female subjects (Section 11.6.2) 
FSH 
 
 
 
 
 
 
 
 
 
 
Blood samples for FSH will be 
measured as needed as outlined in 
Section 11.6.2. 
Standard 12-lead 
ECG 
X 
 
X 
X 
Weeks 4, 
8, 16 
 
X 
X 
X 
X 
After the subject has been at rest 
for at least 5 minutes, and before 
dosing (as applicable) 
(Section 11.6.5)  
Vital signs 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
After the subject has been at rest 
for at least 5 minutes, and before 
dosing (as applicable) 
(Section 11.6.3) 
 
f  
When there is no clinic visit (e.g., Week 12, Week 20), a urine pregnancy test will be performed with a home kit provided by the study site. Results will be reported to the site by telephone. 


Protocol VX20-121-103, Version 3.0 
Page 12 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 3-2 
Study VX20-121-103: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
Treatment Periodb 
ETT 
Visitc 
Safety 
Follow-up Visit 
28 (± 7) Days 
After the Last 
Dose of Study 
Drug (If 
Applicable)d 
Comments 
Day -28 
(± 1 Day) 
Day -14  
(Day -15 
to Day -3) 
 
 
 
Day 1 
Day 15 
(± 3 Days) 
Weeks 4, 
8, 12, 16 
(± 5 Days) 
Weeks 
20, 28, 32, 
40, 44, 48 
(± 5 Days) 
Weeks 24 
and 36 
(± 5 Days) 
Week 52 
(± 5 Days) 
Pulse oximetry 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
After the subject has been at rest 
for at least 5 minutes, and before 
dosing (as applicable) 
(Section 11.6.4) 
Spirometry 
(in-clinic) 
 
X 
X 
X 
Weeks 4, 
8, 16 
 
X 
X 
X 
X 
Should be performed 
pre-bronchodilator, before dosing, 
and at approximately the same time 
at each visit. If the visit is 
performed as a home health visit, 
spirometry may be performed using 
a mobile device (Section 9.1.8). 
Spirometry (mobile 
device) 
 
X 
X 
 
 
 
 
 
 
 
Spirometry with a mobile device 
should be performed at home and 
as applicable (Section 9.1.8) 
Sweat chloride 
 
X 
X 
X 
Weeks 4 
and 16 
 
X 
X 
X 
 
Will be performed before dosing 
(Section 11.5.2) 
Serum chemistry 
X 
 
Xg  
X 
X 
 
X 
X 
X 
X 
Section 11.6.2 
Hematology 
X 
 
Xg 
X 
X 
 
X 
X 
X 
X 
Section 11.6.2 
HbA1c 
 
 
Xg 
 
Week 12 
 
Week 24 
X 
 
 
HbA1c will be collected as part of 
the hematology blood draw 
(Section 11.6.2) 
Coagulation 
X 
 
Xg 
 
Week 12 
 
X 
X 
X 
X 
Section 11.6.2 
Urinalysis 
X 
 
X 
 
Week 12 
 
X 
X 
X 
X 
Section 11.6.2 
PK sampling  
 
 
Predose 
and 2 
hours 
postdose 
Predose 
Weeks 4, 
8, 16: 
predose 
 
Week 24: 
predose 
 
X 
 
Refer to Table 11-1 for acceptable 
PK sampling windows.  
At the ETT Visit, a single PK blood 
sample will be collected. 
DNA sample 
(optional) 
 
 
X 
 
 
 
 
 
 
 
If permitted by local regulations 
(Section 11.4.1) 
Inflammatory 
mediator samples 
X 
 
X 
 
Week 4 
 
Week 24 
X 
 
 
Section 11.4.2 
Blood sample for 
RNA (optional) 
X 
 
X 
 
Week 4 
 
Week 24  
X 
 
 
If permitted by local regulations 
(Section 11.4.3) 
Blood biomarker 
samples 
X 
 
X 
 
Week 4 
 
Week 24 
X 
 
 
Section 11.4.3 
 
g  
Blood samples will be collected before the first dose of study drug in the Treatment Period. 


Protocol VX20-121-103, Version 3.0 
Page 13 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 3-2 
Study VX20-121-103: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
Treatment Periodb 
ETT 
Visitc 
Safety 
Follow-up Visit 
28 (± 7) Days 
After the Last 
Dose of Study 
Drug (If 
Applicable)d 
Comments 
Day -28 
(± 1 Day) 
Day -14  
(Day -15 
to Day -3) 
 
 
 
Day 1 
Day 15 
(± 3 Days) 
Weeks 4, 
8, 12, 16 
(± 5 Days) 
Weeks 
20, 28, 32, 
40, 44, 48 
(± 5 Days) 
Weeks 24 
and 36 
(± 5 Days) 
Week 52 
(± 5 Days) 
Sputum samples  
X 
 
X 
 
 
 
Week 24 
X 
 
 
Sputum samples will be collected 
from subjects who can produce a 
sample spontaneously (Section 
11.4.4). 
Run-in 
ELX/TEZ/IVA 
dosing 
Day -28 through Day -1 
 
 
 
Section 9.1.2 
Run-in 
ELX/TEZ/IVA 
drug count 
X 
X 
X 
 
 
 
 
 
 
 
 
Randomized study 
drug dosing 
 
 
Day 1 through evening before Week 52 Visit 
 
 
Section 9.6 
Randomized study 
drug counth 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
Other events related 
to outcome 
Continuous from signing of ICF through completion of study participation 
Section 11.5.4; completion of study 
participation is defined in 
Section 9.1.7 
Medications review 
Continuous from signing of ICF through completion of study participation 
Section 9.5; completion of study 
participation is defined in 
Section 9.1.7 
Treatments and 
procedures review 
Continuous from signing of ICF through completion of study participation 
Completion of study participation is 
defined in Section 9.1.7 
AEs and SAEs  
Continuous from signing of ICF through completion of study participation 
Section 13.1; completion of study 
participation is defined in 
Section 9.1.7 
AE: adverse event; CF: cystic fibrosis; CF-IQ: Cystic Fibrosis Impact Questionnaire; CFQ-R: CF Questionnaire-Revised; ELX: elexacaftor; ETT: Early Termination of Treatment; FSH: follicle-
stimulating hormone; HbA1c: hemoglobin A1c; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; PGIC: Patient Global Impression of Change; PGIS: Patient Global 
Impression of Severity; PK: pharmacokinetic; SAE: serious adverse event; TEZ: tezacaftor; TSQM: Treatment Satisfaction Questionnaire for Medication 
  
h  
Study drug count will be assessed at in-clinic visits. 


Protocol VX20-121-103, Version 3.0 
Page 14 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 14 
List of Tables............................................................................................................................ 18 
List of Figures .......................................................................................................................... 18 
List of Appendices ................................................................................................................... 18 
List of Abbreviations................................................................................................................ 19 
5 
Introduction.......................................................................................................................... 22 
5.1 
Background ..................................................................................................................... 22 
5.2 
Study Rationale .............................................................................................................. 22 
6 
Study Objectives .................................................................................................................. 23 
6.1 
Primary Objective ........................................................................................................... 23 
6.2 
Secondary Objectives ..................................................................................................... 23 
7 
Study Endpoints ................................................................................................................... 23 
7.1 
Primary Endpoint ............................................................................................................ 23 
7.2 
Secondary Endpoints ...................................................................................................... 23 
7.2.1 
Key Secondary Endpoints ...................................................................................... 23 
7.2.2 
Other Secondary Endpoints .................................................................................... 23 
7.3 
Other Endpoints .............................................................................................................. 24 
8 
Study Population .................................................................................................................. 24 
8.1 
Inclusion Criteria ............................................................................................................ 24 
8.2 
Exclusion Criteria ........................................................................................................... 25 
9 
Study Implementation ......................................................................................................... 26 
9.1 
Study Design .................................................................................................................. 26 
9.1.1 
Screening ................................................................................................................ 27 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 27 
9.1.1.2 
Rescreening ...................................................................................................... 27 
9.1.1.3 
Extension of Screening Period Window .......................................................... 28 
9.1.2 
ELX/TEZ/IVA Run-in Period ................................................................................ 28 
9.1.3 
Treatment Period .................................................................................................... 28 
9.1.4 
Follow-up................................................................................................................ 29 
9.1.5 
Early Termination of Treatment ............................................................................. 29 
9.1.5.1 
Discontinuation During the Run-in Period ...................................................... 29 
9.1.5.2 
Discontinuation During the Treatment Period ................................................. 29 
9.1.6 
Lost to Follow-up ................................................................................................... 30 
9.1.7 
Completion of Study Participation ......................................................................... 30 
9.1.8 
Use of Remote Measures in Extenuating Circumstances ....................................... 30 
9.1.9 
Data Monitoring Committee ................................................................................... 31 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 31 
9.3 
Rationale for Study Elements ......................................................................................... 31 
9.3.1 
Study Design........................................................................................................... 31 
9.3.2 
Study Population..................................................................................................... 32 


Protocol VX20-121-103, Version 3.0 
Page 15 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
9.3.3 
Study Drug Dose .................................................................................................... 32 
9.3.4 
Rationale for Study Assessments ........................................................................... 33 
9.4 
Study Restrictions ........................................................................................................... 33 
9.4.1 
Prohibited Medications ........................................................................................... 33 
9.5 
Prior and Concomitant Medications ............................................................................... 34 
9.6 
Administration ................................................................................................................ 35 
9.6.1 
Dosing ..................................................................................................................... 35 
9.6.2 
Missed Doses .......................................................................................................... 36 
9.7 
Dose Modification for Toxicity ...................................................................................... 36 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 36 
9.8.1 
Liver Function Tests ............................................................................................... 36 
9.8.2 
Rash ........................................................................................................................ 37 
9.9 
Removal of Subjects ....................................................................................................... 37 
9.10 Replacement of Subjects ................................................................................................ 38 
10 Study Drug Information and Management ....................................................................... 38 
10.1 Preparation and Dispensing ............................................................................................ 38 
10.2 Packaging and Labeling ................................................................................................. 39 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 39 
10.4 Drug Accountability ....................................................................................................... 39 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 40 
10.6 Compliance ..................................................................................................................... 40 
10.7 Blinding and Unblinding ................................................................................................ 40 
10.7.1 
Blinding .................................................................................................................. 40 
10.7.2 
Unblinding .............................................................................................................. 41 
11 Assessments .......................................................................................................................... 42 
11.1 Subject and Disease Characteristics ............................................................................... 42 
11.2 Pharmacokinetics ............................................................................................................ 42 
11.2.1 
Blood Sampling ...................................................................................................... 42 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 43 
11.2.3 
Bioanalysis.............................................................................................................. 43 
11.3 Pharmacodynamics ......................................................................................................... 43 
11.4 Exploratory Assessments ................................................................................................ 43 
11.4.1 
Pharmacogenomics ................................................................................................. 43 
11.4.2 
Inflammatory Mediators ......................................................................................... 43 
11.4.3 
Other Blood Biomarkers ......................................................................................... 43 
11.4.4 
Microbiology and Other Sputum Biomarkers ........................................................ 43 
11.4.5 
Treatment Satisfaction Questionnaire for Medication ............................................ 44 
11.4.6 
Other Questionnaires .............................................................................................. 44 
11.5 Efficacy ........................................................................................................................... 45 
11.5.1 
Spirometry .............................................................................................................. 45 
11.5.2 
Sweat Chloride ....................................................................................................... 46 
11.5.3 
Cystic Fibrosis Questionnaire-Revised .................................................................. 46 
11.5.4 
Other Events Related to Outcome .......................................................................... 46 
11.5.4.1 Antibiotic Therapy for Sinopulmonary Sign/Symptoms ................................. 46 
11.5.4.2 Hospitalization for CF ...................................................................................... 47 
11.5.5 
Height and Weight .................................................................................................. 47 


Protocol VX20-121-103, Version 3.0 
Page 16 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
11.6 Safety .............................................................................................................................. 47 
11.6.1 
Adverse Events ....................................................................................................... 47 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 47 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 49 
11.6.4 
Pulse Oximetry ....................................................................................................... 49 
11.6.5 
Electrocardiograms ................................................................................................. 49 
11.6.6 
Ophthalmologic Examination ................................................................................. 50 
11.6.7 
Contraception and Pregnancy ................................................................................. 50 
11.6.7.1 Contraception ................................................................................................... 50 
11.6.7.2 Pregnancy ......................................................................................................... 52 
12 Statistical Analysis ............................................................................................................... 52 
12.1 Sample Size and Power .................................................................................................. 52 
12.2 Analysis Sets .................................................................................................................. 53 
12.3 Statistical Analysis ......................................................................................................... 54 
12.3.1 
General Considerations ........................................................................................... 54 
12.3.2 
Background Characteristics .................................................................................... 54 
12.3.3 
Efficacy Analysis .................................................................................................... 54 
12.3.3.1 Analysis of Primary Endpoint .......................................................................... 54 
12.3.3.2 Analysis of Secondary Endpoints .................................................................... 55 
12.3.3.3 Multiplicity Adjustment ................................................................................... 56 
12.3.3.4 Analysis of Other Endpoints ............................................................................ 56 
12.3.4 
Safety Analysis ....................................................................................................... 56 
12.4 Interim Analysis ............................................................................................................. 56 
12.5 Data Monitoring Committee Analysis ............................................................................ 57 
12.6 Clinical Pharmacology Analysis .................................................................................... 57 
12.6.1 
Pharmacokinetic Analysis ...................................................................................... 57 
12.6.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 57 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 57 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 57 
13.1.1 
Adverse Events ....................................................................................................... 57 
13.1.1.1 Definition of an Adverse Event........................................................................ 57 
13.1.1.2 Clinically Significant Assessments .................................................................. 57 
13.1.1.3 Documentation of Adverse Events................................................................... 58 
13.1.1.4 Adverse Event Severity .................................................................................... 58 
13.1.1.5 Adverse Event Causality .................................................................................. 59 
13.1.1.6 Study Drug Action Taken ................................................................................ 59 
13.1.1.7 Adverse Event Outcome .................................................................................. 60 
13.1.1.8 Treatment Given............................................................................................... 60 
13.1.2 
Serious Adverse Events .......................................................................................... 60 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 60 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 61 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 62 
13.2 Administrative Requirements ......................................................................................... 62 
13.2.1 
Product Complaints ................................................................................................ 62 
13.2.2 
Ethical Considerations ............................................................................................ 62 


Protocol VX20-121-103, Version 3.0 
Page 17 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
13.2.3 
Subject Information and Informed Consent ........................................................... 62 
13.2.4 
Investigator Compliance ......................................................................................... 62 
13.2.5 
Access to Records ................................................................................................... 63 
13.2.6 
Subject Privacy ....................................................................................................... 63 
13.2.7 
Record Retention .................................................................................................... 63 
13.2.8 
Study Termination .................................................................................................. 64 
13.2.9 
End of Study ........................................................................................................... 64 
13.3 Data Quality Assurance .................................................................................................. 64 
13.4 Monitoring ...................................................................................................................... 64 
13.5 Electronic Data Capture ................................................................................................. 64 
13.6 Confidentiality and Disclosure ....................................................................................... 65 
13.7 Publications and Clinical Study Report .......................................................................... 65 
13.7.1 
Publication of Study Results ................................................................................... 65 
13.7.2 
Clinical Study Report ............................................................................................. 66 
14 References ............................................................................................................................. 67 
APPENDIX A: Examples of Eligible Mutations ...................................................................... 69 
15 Protocol Signature Pages .................................................................................................... 71 
15.1 Sponsor Signature Page .................................................................................................. 71 
15.2 Investigator Signature Page ............................................................................................ 72 
 


Protocol VX20-121-103, Version 3.0 
Page 18 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
List of Tables 
Table 3-1 
Study VX20-121-103: Screening ............................................................................ 7 
Table 3-2 
Study VX20-121-103: Run-in Period, Treatment Period, and Safety Follow-up 
Visit ......................................................................................................................... 9 
Table 9-1 
Treatment Period Groups and Dosages ................................................................. 27 
Table 9-2 
Prohibited Medications ......................................................................................... 34 
Table 10-1 
Study Drug; Strength/Dosage Form/Route ........................................................... 39 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 42 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 48 
Table 11-3 
Acceptable Methods of Contraception.................................................................. 51 
Table 13-1 
Grading of AE Severity ........................................................................................ 59 
Table 13-2 
Classifications for AE Causality ........................................................................... 59 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 59 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 60 
List of Figures 
Figure 2-1 
VX20-121-103 Study Design ................................................................................. 5 
Figure 9-1 
VX20-121-103 Study Design ............................................................................... 26 
 
List of Appendices 
APPENDIX A 
Examples of Eligible Gating and Residual Function Mutations 


Protocol VX20-121-103, Version 3.0 
Page 19 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
AUC 
area under the concentration versus time curve 
BA 
bioavailability 
BMI 
body mass index 
CBC 
complete blood count 
CD 
compact disc 
CF 
cystic fibrosis 
CF-IQ 
Cystic Fibrosis Impact Questionnaire 
CFQ-R 
Cystic Fibrosis Questionnaire - Revised 
CFTR 
CF transmembrane conductance regulator protein 
CFTR 
CF transmembrane conductance regulator gene 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
D-IVA 
deutivacaftor 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ELX 
elexacaftor 
ETT 
Early Termination of Treatment 
EU 
European Union 
F 
F508del CFTR mutation 
F/F 
homozygous for F508del 
F/G 
heterozygous for F508del and a gating mutation 
F/RF 
heterozygous for F508del and a residual function mutation 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon corresponding to 
position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 


Protocol VX20-121-103, Version 3.0 
Page 20 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Abbreviation 
Definition 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HbA1c 
hemoglobin A1c 
HBE 
human bronchial epithelial 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IL-8 
interleukin-8 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
institutional review board 
IV 
intravenous 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LFT 
liver function test 
LUM 
lumacaftor 
max 
maximum  
MF 
minimal function 
min 
minimum  
MMRM 
mixed-effects model for repeated measures 
OATP1B1 
organic anion transporting polypeptide 1B1 
P 
probability 
PD 
pharmacodynamic 
PE 
physical examination 
PEx 
pulmonary exacerbations 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
P-gp 
P-glycoprotein 
PIs 
principal investigators 
PK 
pharmacokinetic(s) 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PPS 
Per-protocol Set 
PRO 
patient-reported outcome 
q12h 
every 12 hours 


Protocol VX20-121-103, Version 3.0 
Page 21 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Abbreviation 
Definition 
qd 
once daily 
QTcF 
QT interval corrected by Fridericia’s formula 
RD 
Respiratory Domain 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SUSAR 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TCR 
triple combination responsive 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
t-test 
statistical test used when the independent variable is binary and the dependent variable is 
continuous 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
WBC 
white blood cell 
 
 


Protocol VX20-121-103, Version 3.0 
Page 22 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive genetic disease with serious morbidities and 
frequent premature mortality. CF affects more than 80,000 individuals worldwide 
(approximately 31,000 in the US and 49,000 in the EU).1-4  
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.5 CFTR is a channel that regulates the flow of chloride and other anions across 
epithelia in multiple organs and tissues, including the lungs, pancreas and other gastrointestinal 
organs, and sweat glands.6 Despite progress in the treatment of CF with antibiotics and 
mucolytics, the current median age at death among people with CF is approximately 30 years, 
and the predicted median age of survival is approximately 47 years.1, 2 More effective treatments 
are needed for CF. 
The most common disease-causing mutation is F508del: approximately 85.3% of people with CF 
in the US and 80.6% in Europe have at least one F508del allele.1, 2 
At present CF does not have a cure. CFTR modulators (i.e., correctors and potentiators) represent 
a major advancement in the treatment of CF because they are systemic therapies that target the 
underlying cause of the disease and have been shown to improve CF survival by modifying the 
course of disease.7, 8 The clinical testing and regulatory approval of CFTR modulators in certain 
countries for the treatment of people with CF caused by specific CFTR genotypes have 
established the therapeutic value of specific regimens developed by Vertex. These treatment 
regimens include ivacaftor (IVA) monotherapy (Kalydeco™), lumacaftor (LUM)/IVA dual 
combination therapy (Orkambi™), tezacaftor (TEZ)/IVA dual combination therapy 
(Symdeko™, Symkevi™), and elexacaftor (ELX)/TEZ/IVA triple combination (TC) therapy 
(Trikafta™, Kaftrio™).  
Deutivacaftor (D-IVA, VX-561) is a CFTR potentiator and is a deuterated isotope of IVA with a 
specific pattern of 9 substituted deuteriums. In vitro data indicate similar potency of D-IVA in 
human bronchial epithelial (HBE) cells relative to IVA. Nonclinical and clinical data 
demonstrate a similar safety profile relative to IVA, and pharmacokinetic (PK) data support once 
daily (qd) dosing (refer to VX-121/TEZ/D-IVA Investigator’s Brochure). 
VX-121 is a CFTR corrector that improves the processing and trafficking of mutated CFTR in 
vitro, 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 either IVA or 
D-IVA. In HBE cells derived from people homozygous for F508del (F/F-HBE) and people 
heterozygous for F508del and a minimal function (MF) CFTR mutation (F/MF-HBE cells) and 
studied in vitro, the TC of VX-121, TEZ, and IVA (VX-121/TEZ/IVA) increased CFTR chloride 
transport more than the dual combinations of VX-121/TEZ or VX-121/IVA under most 
conditions (refer to VX-121/TEZ/D-IVA Investigator’s Brochure).  
5.2 
Study Rationale 
This study will evaluate the efficacy and safety of VX-121/TEZ/D-IVA in CF subjects who are 
homozygous for F508del (F/F), heterozygous for F508del and a gating (F/G) or residual function 
(F/RF) mutation, or have at least 1 triple combination responsive (TCR) CFTR mutation 


Protocol VX20-121-103, Version 3.0 
Page 23 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
identified as responsive to ELX/TEZ/IVA and do not have an F508del mutation (TCR/non-F). 
While ELX/TEZ/IVA is approved in certain regions for subjects with these genotypes, there 
remains a need for more highly effective CFTR modulators that can restore CFTR function 
(e.g., CFTR-mediated chloride transport) toward levels seen in carriers (who do not develop CF) 
in as many patients with CF as possible. The potential for benefit in these patients is supported 
by in vitro data and clinical data in F/MF subjects and F/F subjects; in addition, 
VX-121/TEZ/D-IVA is generally safe and well tolerated (refer to VX-121/TEZ/D-IVA 
Investigator’s Brochure).  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of VX-121/TEZ/D-IVA in CF subjects who are homozygous for 
F508del, heterozygous for F508del and a gating (F/G) or residual function (F/RF) mutation, or 
have at least 1 other TCR CFTR mutation and no F508del mutation 
6.2 
Secondary Objectives 
• To evaluate the safety of VX-121/TEZ/D-IVA 
• To evaluate the PK of VX-121/TEZ/D-IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) through Week 24 
7.2 
Secondary Endpoints 
7.2.1 
Key Secondary Endpoints 
• Absolute change from baseline in sweat chloride (SwCl) through Week 24 
• Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data from 
Study VX20-121-102) 
• Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data from 
Study VX20-121-102)  
7.2.2 
Other Secondary Endpoints 
• Number of pulmonary exacerbations (PEx) through Week 52 
• Absolute change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) 
Respiratory Domain (RD) score through Week 24 
• Absolute change from baseline in ppFEV1 through Week 52 
• Absolute change from baseline in SwCl through Week 52 
• Proportion of subjects with SwCl <60 mmol/L through Week 24 
• Proportion of subjects with SwCl <30 mmol/L through Week 24 


Protocol VX20-121-103, Version 3.0 
Page 24 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
ECGs, vital signs, and pulse oximetry 
7.3 
Other Endpoints 
• Proportion of subjects with SwCl <60 mmol/L through Week 52 
• Proportion of subjects with SwCl <30 mmol/L through Week 52 
• Absolute change from baseline in body mass index (BMI) at Week 52 
• Absolute change from baseline in BMI z-score at Week 52 
• Absolute change from baseline in weight at Week 52 
• Absolute change from baseline in CFQ-R RD score through Week 52 
• PK parameters of VX-121, TEZ, and D-IVA 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Subjects aged 12 years or older, on the date of informed consent 
4. Confirmed diagnosis of CF as determined by the investigator 
5. Subject has one of the following genotypes: 1) homozygous for F508del; 2) heterozygous for 
F508del and a gating (F/G) mutation; 3) heterozygous for F508del and a residual function 
(F/RF) mutation; 4) at least 1 other TCR CFTR mutation identified as responsive to 
ELX/TEZ/IVA and no F508del mutation. See Appendix A for examples of qualifying 
mutations. If the screening CFTR genotype result is not received before randomization, a 
previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who 
have been enrolled and whose screening genotype does not confirm study eligibility must be 
discontinued from the study (Section 9.9).  
6. For subjects currently receiving Vertex CFTR modulator therapy, FEV1 value ≥40% and 
≤90% of predicted mean for age, sex, and height (equations of the Global Lung Function 
Initiative [GLI])9 at the Screening Visit. All subjects not currently receiving Vertex CFTR 
modulator therapy must have an FEV1 value ≥40% and ≤80% of predicted mean. Spirometry 
measurements must meet American Thoracic Society/European Respiratory Society criteria10 
for acceptability and repeatability.  
7. Stable CF disease as judged by the investigator. 


Protocol VX20-121-103, Version 3.0 
Page 25 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
8. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2 
Exclusion Criteria 
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug(s) to the subject. This 
includes, but is not limited to, the following: 
• Hepatic cirrhosis with portal hypertension, moderate hepatic impairment (Child Pugh 
Score 7 to 9), or severe hepatic impairment (Child Pugh Score 10 to 15). 
• Solid organ or hematological transplantation. 
• Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, 
and opiates, as deemed by the investigator. 
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (all 3 with no recurrence for the last 5 years). 
2. History of intolerance to study drug that would pose an additional risk to the subject in the 
opinion of the investigator. (e.g., subjects with a history of liver function test [LFT] 
elevations requiring treatment interruption or discontinuation, allergy or hypersensitivity to 
the study drug). 
3. Any of the following abnormal laboratory values at screening: 
• Hemoglobin <10 g/dL 
• Total bilirubin ≥2 × upper limit of normal (ULN) 
• Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 
(calculated by the Modification of Diet in Renal Disease Study Equation)11,12 for subjects 
≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation)13 for subjects aged 12 to 17 years (inclusive). 
4. An acute upper or lower respiratory infection, PEx, or changes in therapy (including 
antibiotics) for sinopulmonary disease within 28 days before the first dose of ELX/TEZ/IVA 
in the Run-in Period (Day -28). 
5. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus). For subjects who have had a history of a positive culture, the 
investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms:  
• The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent. 
• The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 


Protocol VX20-121-103, Version 3.0 
Page 26 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
separated by at least 3 months, and the most recent one within the 6 months before the 
date of informed consent. 
6. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
ELX/TEZ/IVA in the Run-in Period (Day -28).  
7. Ongoing or prior participation in a study of an investigational treatment other than a Vertex 
CFTR modulator within 28 days or 5 terminal half-lives (whichever is longer) before 
screening, or participation in an interventional study of a non-investigational treatment from 
screening through end of study participation. The duration of the elapsed time may be longer 
if required by local regulations. 
8. Use of prohibited medications as defined in Table 9-2, within the specified window before 
the first dose of ELX/TEZ/IVA in the Run-in Period (Day -28). 
9. Pregnant or breast-feeding females. Female subjects must have a negative pregnancy test at 
screening (serum test) and Run-in Period/Day -28 (urine test). 
10. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be enrolled in the study provided that 
• the adult lives independently of and does not reside with the study staff member, and 
• the adult participates in the study at a site other than the site at which the family member 
is employed. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, randomized, double-blind, ELX/TEZ/IVA-controlled, parallel-group, 
multicenter study. A schematic of the study design is shown in Figure 9-1.   
Figure 9-1 
VX20-121-103 Study Design 
 
 
 
 
 
 
 
 
 
D-IVA: deutivacaftor; ELX: elexacaftor; IVA: ivacaftor; N: number of subjects; TEZ: tezacaftor 
Note: The figure is not drawn to scale.  
VX-121/TEZ/D-IVA 
N = 275 
ELX/TEZ/IVA 
N = 275 
Treatment Period 
ELX/TEZ/IVA Run-in  
Period 
Screening 
Period 
Safety Follow-up 
Day -56 through 
Day -29 
Day -28 through 
Day -1 
Day -1 or Day 1  
Randomization
52 Weeks  
Open-label Study 
28 days 


Protocol VX20-121-103, Version 3.0 
Page 27 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 Approximately 550 subjects will be enrolled in the study.  
• Approximately 80% of total subjects will have the F/F genotype, remaining subjects will 
have F/G, F/RF, or TCR/non-F genotypes 
• Up to approximately 15% of total subjects may be enrolled with SwCl values <30 mmol/L at 
screening  
Study drug is defined in Section 10. 
All subjects entering the Run-in Period will receive ELX 200 mg qd/TEZ 100 mg qd/IVA 
150 mg every 12 hours (q12h). Following completion of the Run-in Period, approximately 
550 subjects will be randomized 1:1 to the VX-121/TEZ/D-IVA group or the ELX/TEZ/IVA 
group for the Treatment Period. The dosages to be evaluated are shown in Table 9-1. 
Randomization will be stratified; details are provided in Section 9.2.  
Table 9-1 
Treatment Period Groups and Dosages 
Treatment Group 
VX-121 
ELX 
TEZ 
D-IVA 
IVA 
VX-121/TEZ/D-IVA 
20 mg qd 
0 mg 
100 mg qd 
250 mg qd 
0 mg 
ELX/TEZ/IVA 
0 mg 
200 mg qd 
100 mg qd 
0 mg 
150 mg q12h 
D-IVA: deutivacaftor; ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
Note: Study drug administration is described in Section 9.6. 
Study visits and assessments to be conducted are shown in Table 3-1 and Table 3-2. All visits 
will occur within the windows specified. 
9.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1. 
The Screening Period (Day -56 through Day -29) will occur within 28 days before the first dose 
of ELX/TEZ/IVA in the Run-in Period. 
Screening assessments will be used to confirm that subjects meet the eligibility criteria. The 
investigator (or an appropriate authorized designee) will obtain informed consent and assent, if 
applicable, from each subject before any study procedure takes place. 
9.1.1.1 
Repetition of Screening Assessment(s) 
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may be rescreened once. If a subject is rescreened, all screening assessments will be 
repeated, except for:  
• CFTR genotyping 
• Follicle-stimulating hormone (FSH) level (if serum FSH level was in the postmenopausal 
range as determined by the laboratory performing the test during prior screening) 
• Ophthalmologic examination (if performed within 3 months of the date of informed consent, 
for subjects <18 years of age on the date of informed consent) 


Protocol VX20-121-103, Version 3.0 
Page 28 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Scheduling of ophthalmologic examination (for subjects <18 years of age on the date of 
informed consent, Section 11.6.6) 
9.1.2 
ELX/TEZ/IVA Run-in Period 
The Run-in Period has a 4-week duration and is designed to establish a reliable on-treatment 
(ELX/TEZ/IVA) baseline for the Treatment Period. The first dose of open-label ELX/TEZ/IVA 
will be administered at the Day -28 Visit. Female subjects must have a negative pregnancy test at 
Day -28 before receiving study drug. The last dose of open-label ELX/TEZ/IVA will be 
administered on Day -1 (1 day before the Day 1 Visit). 
On Day -14, spirometry (clinic and mobile) and SwCl will be assessed. The Day -14 clinic 
spirometry and SwCl assessments will be used for stratification of randomization (Section 9.2).  
Subjects who prematurely discontinue study drug treatment during the Run-in Period will not be 
randomized or participate in the Treatment Period (Section 9.1.5.1). 
9.1.3 
Treatment Period 
Treatment Period assessments are listed in Table 3-2.  
The Treatment Period will be randomized, double-blind, and ELX/TEZ/IVA-controlled. It will 
last approximately 52 weeks (Day 1 through Week 52). Study drug administration details are 
provided in Section 9.6. 
Randomization will occur before the first dose of study drug during the Treatment Period and 
may occur on either Day 1 or Day -1. Randomization and stratification details are provided in 
Section 9.2. 
To enter the Treatment Period, subjects must have stable CF disease (as judged by the 
investigator) and have remained on a stable CF treatment regimen during the Run-in Period. 
Female subjects also must have a negative pregnancy test at Day 1 before receiving randomized 
study drug. If these conditions are not met (for example, if the subject has an acute upper or 
lower respiratory infection, PEx, or changes in therapy [including antibiotics] for sinopulmonary 
disease within 28 days before the Day 1 Visit [first dose of study drug in the Treatment Period]), 
the subject is considered a run-in failure and cannot enter the Treatment Period or rescreen.  
The Week 12 Visit may be performed either in the clinic or as a home health visit, if permitted 
by local regulations. All home health visits must have a consultation between the subject and 
investigator (i.e., in person, phone, or telemedicine video conference). This consultation should 
occur within 2 business days before or after the home health visit and can be outside the visit 
window. Additional details regarding home health visits will be provided in the Study Reference 
Manual.  


Protocol VX20-121-103, Version 3.0 
Page 29 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation of study drug treatment through the last scheduled study visit 
(Section 9.1.5). 
9.1.4 
Follow-up 
The Safety Follow-up Visit will occur approximately 28 (± 7) days after the last dose of study 
drug for subjects who complete study drug dosing and for subjects who prematurely discontinue 
study drug dosing, as described in Section 9.1.5. The assessments performed at the Safety 
Follow-up Visit are listed in Table 3-2. 
An open-label study will be available for subjects who complete the Week 52 Visit and are 
eligible. The Safety Follow-up Visit is not required for subjects who complete the Treatment 
Period and transition within 28 days of the last dose of study drug to either:  
• a commercially available Vertex CFTR modulator regimen, 
• a managed access program-supplied Vertex CFTR modulator regimen, 
• or, an open-label study or other qualified Vertex study. 
9.1.5 
Early Termination of Treatment  
If a subject prematurely discontinues study drug treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the decision to discontinue treatment. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety 
Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug.  
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required.  
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study (Section 9.9). 
9.1.5.1 
Discontinuation During the Run-in Period 
Subjects who prematurely discontinue study drug treatment during the Run-in Period will not be 
randomized or participate in the Treatment Period. These subjects will complete an ETT Visit 
and Safety Follow-up Visit (as applicable).  
9.1.5.2 
Discontinuation During the Treatment Period 
Subjects who prematurely discontinue study drug treatment during the Treatment Period should 
continue to complete all scheduled study visits for assessments following completion of the ETT 
Visit (and Safety Follow-up Visit, if applicable), as detailed in Table 3-2.  


Protocol VX20-121-103, Version 3.0 
Page 30 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
9.1.6 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.7 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as one of the following: 
• For subjects who complete the Treatment Period and transition to either an open-label study 
or other qualified Vertex study, a commercially available Vertex CFTR modulator regimen, 
or a managed access program-supplied Vertex CFTR modulator regimen within 28 days of 
the Week 52 Visit: the Week 52 Visit  
• For subjects who complete the Treatment Period and do not transition to either an open-label 
study or other qualified Vertex study, a commercially available Vertex CFTR modulator 
regimen, or a managed access program-supplied Vertex CFTR modulator regimen within 
28 days of the Week 52 Visit: the Safety Follow-up Visit 
• For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest completed study visit up to and including the 
Week 52 Visit, ETT Visit, or Safety Follow-up Visit (if required) 
• For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9) 
If subjects are lost to follow-up (Section 9.1.6), the date of completion of study participation will 
be defined as the date of the last contact.  
The end of study is defined in Section 13.2.9. 
9.1.8 
Use of Remote Measures in Extenuating Circumstances 
Study visits should be performed in the clinic as specified in Section 3, Table 3-1, and Table 3-2, 
if at all possible. However, under extenuating circumstances, specific alternative measures may 
be implemented (e.g., if a subject is unable to travel to the study site due to safety concerns 
and/or local restrictions related to COVID-19 or other emerging events) in order to ensure the 
safety of subjects, site investigators, and site personnel while maintaining compliance with GCP 
and minimizing impact to the integrity of the study. The decision whether to conduct study visits 
remotely or in clinic will be at the discretion of the investigator; if the investigator determines 
that study visits will be conducted remotely, the medical monitor should be notified. The 
Screening Visit, Day -28 Visit, Day -14 Visit, Day 1 Visit, Week 24 Visit, and Week 52 Visit 
must be performed in clinic. 
The following remote measures may be implemented. Additional details can be found in the 
Study Reference Manual. 
• 
Consent or reconsent may be obtained remotely in writing (or verbally, with follow-up 
written confirmation), as allowed by local regulations.  


Protocol VX20-121-103, Version 3.0 
Page 31 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
• Study drug may be shipped directly from the site to the subject, as applicable and as allowed 
by local regulations. 
• Study visits (except for those noted above) may be conducted as in-home visits by qualified 
personnel. 
• Study assessments to evaluate safety and efficacy may be performed or overseen by qualified 
personnel conducting the in-home visits.  
9.1.9 
Data Monitoring Committee 
Safety and tolerability data will be reviewed by a data monitoring committee (DMC) to ensure 
the safety of the subjects. Procedural details of the DMC’s structure and function, frequency of 
meetings, and data planned for review will be in the DMC charter. The DMC charter will be 
finalized before the first subject is screened.  
9.2 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized (1:1) to the VX-121/TEZ/D-IVA group or the ELX/TEZ/IVA 
group. Randomization will be stratified by age at the Screening Visit (<18 versus ≥18 years of 
age), ppFEV1 determined during the Run-in Period (Day -14 clinic assessment; <70 versus ≥70), 
SwCl determined during the Run-in Period (Day -14 assessment; <30 versus ≥30 mmol/L), prior 
CFTR modulator use (yes versus no), and genotype group (F/F, F/G, F/RF, and TCR/non-F). If 
the Day -14 ppFEV1 and/or SwCl values are not valid or not available, the most recent available 
clinic-assessed ppFEV1 and/or SwCl value will be used for stratification. 
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code list will be produced by Vertex Biometrics or a qualified randomization 
vendor. 
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
This Phase 3 study will assess the efficacy and safety of VX-121/TEZ/D-IVA therapy in CF 
subjects who have at least 1 responsive CFTR mutation (e.g., subjects with F/F, F/G, F/RF, or 
TCR/non-F genotypes). 
A randomized, double-blind, ELX/TEZ/IVA-controlled study design was selected to ascertain 
the effects of VX-121/TEZ/D-IVA while avoiding observer bias. ELX/TEZ/IVA is considered 
an appropriate active control since it is an approved standard of care for treatment of patients 
who have at least 1 responsive CFTR mutation in certain regions.  
A 4-week Run-in Period was incorporated into this study to establish a reliable on-treatment 
(ELX/TEZ/IVA) baseline for comparison during the Treatment Period. 
A 52-week treatment duration was selected to characterize the safety and efficacy of 
VX-121/TEZ/D-IVA compared to ELX/TEZ/IVA. The primary endpoint is absolute change 
from baseline in ppFEV1 through Week 24. Based on prior experience with CFTR modulators, 
24 weeks is adequate to compare the efficacy of VX-121/TEZ/D-IVA versus ELX/TEZ/IVA on 
the endpoints being evaluated. 


Protocol VX20-121-103, Version 3.0 
Page 32 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
9.3.2 
Study Population 
This study will evaluate the treatment effect of VX-121/TEZ/D-IVA in subjects who have at 
least 1 responsive CFTR mutation. As described in Section 9.3.3, subjects who have at least 
1 F508del allele (e.g., F/F, F/G, and F/RF genotypes) are expected to respond to 
VX-121/TEZ/D-IVA based on results from a Phase 2 study conducted in F/MF and F/F subjects. 
This study will also enroll subjects who have at least 1 TCR CFTR mutation that is responsive to 
ELX/TEZ/IVA treatment based on in vitro data and do not have an F508del mutation. These 
TCR mutations were identified to be responsive to ELX/TEZ/IVA using a robust in vitro assay 
that has demonstrated a strong relationship between in vitro responsiveness and clinical 
response.  
Given the progressive nature of CF, there is a strong rationale for treating patients earlier in life. 
Experience with CFTR modulators in adolescent subjects ≥12 to <18 years of age, including 
with ELX/TEZ/IVA, suggests that the exposures and safety profile of VX-121/TEZ/D-IVA will 
be similar in adolescents and adults, which supports evaluation of VX-121/TEZ/D-IVA in 
adolescents in the present study.  
9.3.3 
Study Drug Dose 
ELX/TEZ/IVA 
ELX/TEZ/IVA will be administered as ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h, 
which is the approved dosing regimen for Trikafta (Kaftrio) in subjects 12 years of age and 
older. 
VX-121 
The VX-121 dose of 20 mg qd was selected for Phase 3 based on an assessment of the benefit-
risk profile from the Phase 2 Study VX18-121-101 (Study 121-101) Part 1 and the relative 
bioavailability (BA) of VX-121 Form A compared to Form D in Study VX19-121-003 (Study 
121-003). 
Study 121-101 evaluated a range of VX-121 (Form A) doses (5 mg qd, 10 mg qd, and 20 mg qd) 
in TC with TEZ 100 mg qd/D-IVA 150 mg qd for 4 weeks in F/MF subjects. Treatment with 
VX-121 10 mg qd in TC with TEZ/D-IVA resulted in clinically meaningful improvements in 
ppFEV1 and SwCl compared to the placebo group, with minimal additional improvement at a 
higher dose of VX-121 20 mg in TC with TEZ/D-IVA. VX-121/TEZ/D-IVA was generally safe 
and well tolerated in all dose groups, and no differences in the safety profile of 
VX-121/TEZ/D-IVA were observed across the dose groups.  
In addition to the Phase 2 efficacy study, Study 121-003 evaluated the relative BA of a fixed-
dose combination (FDC) of VX-121 (Form D) 20 mg/TEZ 100 mg/D-IVA 150 mg compared to 
separate tablets of VX-121 (Form A), TEZ, and D-IVA at the same dose. Results showed that 
VX-121 Form D had ~55% lower Cmax and ~50% lower AUC compared to VX-121 Form 
A. Therefore, a dose of VX-121 20 mg qd Form D was selected for Phase 3 to achieve similar 
exposures as the VX-121 10 mg (Form A) dose.  
TEZ  
Based on results from Studies VX17-121-001 and 121-101, exposures of TEZ and its metabolites 
at the approved dose of TEZ 100 mg qd in combination with VX-121/IVA or VX-121/D-IVA 
were similar to historical exposures. The dose of TEZ to be evaluated in Phase 3 will be 100 mg 


Protocol VX20-121-103, Version 3.0 
Page 33 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
qd, which is part of the approved dosing regimens for Symdeko (Symkevi) and Trikafta 
(Kaftrio). 
D-IVA 
The D-IVA dose of 250 mg qd was selected for Phase 3 based on assessment of the benefit-risk 
profile from the Phase 2 Study VX18-561-101 (Study 561-101) as well as PK data and exposure-
response modeling. 
A Phase 2 monotherapy dose-ranging study (Study 561-101) was conducted that evaluated 
D-IVA at 25 mg qd, 50 mg qd, 150 mg qd, and 250 mg qd for 12 weeks in subjects with a gating 
mutation who were receiving stable IVA treatment. Treatment with D-IVA 250 mg qd resulted 
in similar ppFEV1 and SwCl values as the IVA 150 mg q12h group, with greater improvements 
in SwCl compared to the D-IVA 150 mg qd group. Treatment with D-IVA 150 mg qd and 
250 mg qd was safe and well tolerated, and D-IVA exposures seen at 250 mg qd are consistent 
with prior IVA clinical experience. 
9.3.4 
Rationale for Study Assessments 
The efficacy endpoints being evaluated (spirometry, SwCl, CFQ-R, PEx, and anthropometric 
measurements) are widely accepted and generally recognized as reliable, accurate, and relevant 
to the study of individuals with CF. On the Day -14 and Day 1 Visits, spirometry will be 
collected using a mobile device to establish baseline values on the mobile device. SwCl was 
evaluated in the registration study of IVA (Kalydeco), TEZ/IVA combination therapy (Symdeko, 
Symkevi), and ELX/TEZ/IVA (Trikafta, Kaftrio). Spirometry and CFQ-R assessments were 
evaluated in the registration studies of IVA (Kalydeco), LUM/IVA combination therapy 
(Orkambi), TEZ/IVA combination therapy (Symdeko, Symkevi), and ELX/TEZ/IVA (Trikafta, 
Kaftrio). 
All safety and PK assessments are standard measurements for clinical studies in drug 
development. Hemoglobin A1c (HbA1c) is included to assess pancreatic endocrine function. 
Obstruction of airways with thick mucus, chronic bacterial infection of the airways, and the 
inflammatory response all play a role in causing lung damage in CF. Therefore, assessment of 
inflammatory mediators and other biomarkers is included. 
The Treatment Satisfaction Questionnaire for Medication (TSQM) is included as an additional 
endpoint, and is a widely used generic measure of satisfaction with medication and has been 
demonstrated to be a valid and reliable measure of satisfaction in patients with CF.14 The 
domains of the TSQM measure effectiveness, side effects, convenience, and global satisfaction. 
Because treatment satisfaction is not measured with the other health-related quality-of-life 
measures in this study, the TSQM is included as a study assessment. CF-IQ is also included as an 
additional endpoint to assess life impacts of CF and complement the CFQ-R and TSQM. Patient 
Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) are 
included to assess a subject’s perceived severity/change of disease. 
9.4 
Study Restrictions 
9.4.1 
Prohibited Medications 
Table 9-2 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medication will be provided in the Study Reference Manual. 


Protocol VX20-121-103, Version 3.0 
Page 34 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 9-2 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
Moderate and 
strong CYP3A 
inducers 
None allowed 
within 14 days 
before the first dose 
of ELX/TEZ/IVA 
on Day -28 
None allowed 
through 
completion of 
study 
participation 
VX-121, ELX, TEZ, IVA, and D-IVA are 
metabolized extensively via CYP3A4. 
Therefore, use of moderate and strong inducers 
and inhibitors of CYP3A, which have the 
potential to alter the exposure of VX-121, ELX, 
TEZ, IVA, and D-IVA, will be prohibited. 
Moderate and 
strong CYP3A 
inhibitors (except 
ciprofloxacin) 
Non-Vertex CFTR 
modulators 
(investigational or 
approved) 
None allowed 
within 28 days or 
5 terminal half-lives 
(whichever is 
longer) before 
screening  
None allowed 
through 
completion of 
study 
participation  
These agents may confound the results of this 
study. 
Vertex CFTR 
modulators 
(investigational or 
approved), except 
for study drugs 
None allowed from 
the first dose of 
ELX/TEZ/IVA on 
Day -28 
None allowed 
until after the 
last dose of 
study drug 
 
These agents may confound the results of this 
study. 
D-IVA: deutivacaftor; ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected from each subject’s source 
documentation for medications taken within 56 days before the Screening Visit through 
completion of study participation, as defined in Section 9.1.7. 
• Subjects should remain on a stable treatment regimen for their CF from 28 days before the 
Run-in/Day -28 through completion of study participation. Stable treatment regimen is 
defined as the current treatment regimen for CF that subjects have been following for at least 
28 days before the Run-in/Day -28. Subjects may remain on Vertex CFTR modulators 
(investigational or approved) during the Screening Period and may transition directly to the 
Run-in/Day -28 without a washout (Table 9-2). Subjects should not initiate long-term 
treatment with new medication from 28 days before the Run-in/Day -28 through completion 
of study participation. Guidelines for stable treatment regimens for CF are as follows:  
o Subjects who are taking inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who cycle onto and off of an inhaled antibiotic should continue on their prior 
schedule. The timing of the first dose of ELX/TEZ/IVA in the Run-in Period should 
be synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in 
the cycle onto the inhaled antibiotic. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. The timing of the first dose of 
ELX/TEZ/IVA in the Run-in Period should be synchronized as closely as possible 


Protocol VX20-121-103, Version 3.0 
Page 35 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
(e.g., not more than ± 3 days) to the first day in the cycle onto 1 of the inhaled 
antibiotics. 
• Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically. 
Subjects cannot receive prednisone or prednisolone at doses >60 mg qd for longer than a 
5-day period. 
• TEZ/IVA is a weak inhibitor of OATP1B1, and ELX and M23-ELX are potential inhibitors 
of OATP1B1 and OATP1B3. Administration of VX-121/TEZ/D-IVA or ELX/TEZ/IVA may 
increase systemic exposure of substrates of OATP1B1/1B3, which may increase or prolong 
their therapeutic effect and adverse reactions; therefore, caution and appropriate monitoring 
should be used when coadministration of study drugs with medicinal products that are 
substrates of OATP1B1/1B3, such as statins, glyburide, nateglinide, and repaglinide, is 
required.  
• IVA and D-IVA are weak inhibitors of P-glycoprotein (P-gp). Administration of IVA or 
D-IVA may increase systemic exposure of medicinal products that are sensitive substrates of 
P-gp, which may increase or prolong their therapeutic effect and adverse reactions. Digoxin 
or other substrates of P-gp with a narrow therapeutic index, such as cyclosporine, everolimus, 
sirolimus, and tacrolimus, should be used with caution and appropriate monitoring.  
• IVA and D-IVA may inhibit CYP2C9; therefore, during coadministration with warfarin, 
additional monitoring of the international normalized ratio is recommended. Other medicinal 
products that are CYP2C9 substrates for which exposure may be increased include 
glimepiride and glipizide; these should be used with caution. 
• Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.5.1. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally. All subjects will receive the same number of tablets each 
day to maintain the blind. Additional information is provided in the Pharmacy Manual. 
Study drug will be administered with a fat-containing meal or snack, such as a standard “CF” 
meal or snack or a standard meal.  
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
2. Study drug will be administered as FDC tablets (e.g., 2 VX-121/TEZ/D-IVA or matching 
placebo tablets; 2 ELX/TEZ/IVA or matching placebo tablets) in the morning and as 1 IVA 
or matching placebo tablet in the evening. For each subject, doses of study drugs will be 
taken at approximately the same time (± 2 hours) each day.  
3. The date, amount taken, and time of study drug administration, including whether food was 
taken with each dose, will be recorded for the 2 doses before PK sample collection and the 
dose received on the morning of PK sample collection. 
4. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. A meal or snack will be provided by the site 
for the morning dose of study drug. 


Protocol VX20-121-103, Version 3.0 
Page 36 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
5. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
• If the dose in the clinic will be within 6 hours of the subject’s scheduled morning dose, 
the subject should withhold their morning dose of 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 of study drug at home.  
• At the Day 1 Visit, the morning dose of study drug must be administered in the clinic to 
enable predose and/or postdose PK sampling relative to the morning dose.  
6. Subjects will be instructed to bring all used and unused materials associated with the study 
drug to the site; study drug will be dispensed at each visit, as appropriate. 
9.6.2 
Missed Doses 
If 6 hours or less have passed since the missed morning or evening dose, the subject should take 
the missed dose as soon as possible and continue on the original schedule. 
Morning dose: If more than 6 hours have passed since the missed morning dose, the subject 
should take the missed dose as soon as possible and should not take the evening dose. 
Evening dose: If more than 6 hours have passed since the missed evening dose, the subject 
should not take the missed dose. The next scheduled morning dose should be taken at the usual 
time. 
Morning and evening doses should not be taken at the same time. 
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. Treatment may be interrupted as outlined in 
Section 9.8. If any unacceptable toxicity arises, individual subjects will discontinue dosing 
(Section 9.9). 
9.8 
Study Drug Interruption and Stopping Rules 
The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or AST >3 × ULN and total 
bilirubin >2 × ULN that are derived from centrally submitted samples. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 
the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 


Protocol VX20-121-103, Version 3.0 
Page 37 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
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 the following criterion is met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, study drug administration may be resumed once 
transaminases return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified prior to resumption of study 
drug. Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology.  
9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher, or a rash that is 
considered a serious adverse event (SAE). The investigator will notify the medical monitor of 
any rash that results in interruption of study drug, is Grade 3 or higher (Section 13.1.1.4), or is an 
SAE. Investigators should consider additional evaluation including laboratory testing 
(e.g., complete blood count [CBC] with differential, LFTs), photographs of the rash, and 
dermatology consultation. The investigator may consider resumption of study drug if considered 
clinically appropriate.  
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. A subject 
who withdraws from study drug treatment will continue to be followed unless the subject 
withdraws consent (and assent, as applicable).  


Protocol VX20-121-103, Version 3.0 
Page 38 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Has a screening CFTR genotype that does not confirm study eligibility if a previous CFTR 
genotype laboratory report was used to establish eligibility. These subjects must be 
discontinued from the study (Section 8.1) 
• Meets any of the stopping (discontinuation) criteria (Section 9.8) 
• Becomes pregnant (Section 11.6.7.2) 
Subjects who discontinue study treatment early should continue to return for study assessments, 
as noted in Section 9.1.5.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for an ETT Visit and Safety 
Follow-up Visit, if applicable (see Section 9.1.4), and follow up with the subject regarding any 
unresolved AEs. 
If a subject withdraws consent or assent for the study, no further assessments will be performed. 
Vertex may retain and continue using the study data and samples after the study ends, and may 
use the samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn before the first dose of study drug on Day 1 of the 
Treatment Period may be replaced. 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
During the Run-in Period, study drug refers to ELX/TEZ/IVA and IVA.  
During the Treatment Period, study drug refers to VX-121/TEZ/D-IVA and matching placebo, 
ELX/TEZ/IVA and matching placebo, and IVA and matching placebo.  
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 


Protocol VX20-121-103, Version 3.0 
Page 39 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details about packaging, 
labeling, and dispensing for study drug will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
VX-121/TEZ/D-IVA will be supplied as FDC film-coated tablets containing 10 mg 
VX-121/50 mg TEZ/125 mg D-IVA. Matching VX-121/TEZ/D-IVA placebo tablets will be of 
similar size and appearance and contain 0 mg VX-121/0 mg TEZ/0 mg D-IVA (Table 10-1). 
ELX/TEZ/IVA will be supplied as FDC film-coated tablets containing 100 mg ELX/50 mg 
TEZ/75 mg IVA. Matching ELX/TEZ/IVA placebo tablets will be of similar size and appearance 
and contain 0 mg ELX/0 mg TEZ/0 mg IVA (Table 10-1). 
IVA will be supplied as a tablet containing 150 mg IVA. Matching IVA placebo tablets will be 
of similar size and appearance and contain 0 mg IVA (Table 10-1). 
Blister cards must be stored under conditions noted in the Pharmacy Manual. The investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational product is 
stored in a secured area, under recommended storage conditions, and in accordance with 
applicable regulatory requirements. To ensure adequate records, all study drugs will be 
accounted for via the drug accountability forms as instructed by Vertex. 
Table 10-1 
Study Drug; Strength/Dosage Form/Route 
Drug Name, Dosage Form, Route 
Strength 
VX-121/TEZ/D-IVA, FDC tablet, oral 
 
VX-121 
10 mg 
TEZ 
50 mg 
D-IVA 
125 mg 
VX-121/TEZ/D-IVA-matching placebo, tablet, oral 
0 mg 
ELX/TEZ/IVA, FDC tablet, oral 
 
ELX 
100 mg 
TEZ 
50 mg 
IVA 
75 mg 
ELX/TEZ/IVA-matching placebo, tablet, oral 
0 mg 
IVA, tablet, oral 
150 mg 
IVA-matching placebo, tablet, oral 
0 mg 
D-IVA: deutivacaftor; ELX: elexacaftor; FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study.  


Protocol VX20-121-103, Version 3.0 
Page 40 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. Additional details will be provided in the Pharmacy Manual. The study 
monitor must review the drug accountability documentation on a regular basis. The study 
monitor will promptly communicate to Vertex any discrepancies he/she is unable to resolve with 
the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
The principal investigator (PI), study site staff, including pharmacy personnel will assist Vertex 
with any recall activities (as applicable) and place impacted investigational medicinal product 
(IMP) in quarantine when requested. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study.   
10.7 
Blinding and Unblinding 
This is a double-blind study.  
10.7.1 
Blinding  
All subjects (and their parents/caregivers/companions), site personnel (including the investigator, 
the site monitor, and the study team), and members of the Vertex study team will be blinded to 
the treatment codes. 
Individuals who may be unblinded include only the following: 
• Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the subject 
and her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
• Vendor preparing the final (production) randomization list 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 


Protocol VX20-121-103, Version 3.0 
Page 41 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
• DMC 
• Vendor preparing the unblinded analysis of safety data for review by the DMC  
• Analysts or vendor for modeling and simulations performing population PK modeling in 
preparation for regulatory submission(s) 
• Bioanalytical contract research organization (CRO) analyzing PK samples and the Vertex 
Bioanalytical personnel who is not a member of the study team but reviews raw data from the 
Bioanalytical CRO. The Vertex Bioanalytical study team member will continue to be 
blinded. 
Access to Spirometry and SwCl Results: 
During the conduct of the study, the Vertex study team will not have access to the spirometry or 
SwCl results after the first dose of study drug on Day 1 of the Treatment Period, with the 
exception of spirometry related to adverse event reporting. 
Shortly before any planned efficacy analysis is conducted, the spirometry and SwCl data will be 
reviewed for data cleaning purposes by a limited Vertex team that does not have access to the 
treatment codes. 
Individual SwCl test results will not be disclosed to the study sites with the exception of the 
Screening Visit and Day -14 values. Subjects and their parents/caregivers/companions should not 
be informed of study-related spirometry results until Vertex has determined that the study has 
completed (i.e., clinical study report [CSR] finalization), regardless of whether the subject has 
prematurely discontinued treatment.  
10.7.2 
Unblinding 
At the initiation of the study, study site personnel will be instructed on the method for breaking 
the blind. The unblinding method will be either manual or electronic. 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss unblinding. 
If investigators deem it unnecessary to unblind immediately, they will first attempt to contact the 
medical monitor to discuss unblinding. If investigators have tried but are unable to reach the 
medical monitor, they will use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding. 
Contact information for the medical monitor (or appropriate backup) will be in a separate 
document. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with Vertex, the CRO, or any site 
personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 


Protocol VX20-121-103, Version 3.0 
Page 42 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety, unblind individual 
subjects at any time.  
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 and Table 3-2.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, medical and surgical histories, and any allergies. 
Height and weight will be measured with shoes off. Height will be collected at screening for all 
subjects. Following screening, height will be collected only for subjects ≤21 years of age on the 
date of informed consent. 
11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling 
Blood samples will be collected to determine plasma concentrations of VX-121, TEZ, D-IVA, 
ELX, IVA, and relevant metabolites. These samples may also be used for further evaluation of 
the bioanalytical method, or for exploratory analyses that provide information on the metabolic 
pathways used by or affected by any study drugs. 
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations. The exact time of the sample 
collection will be noted. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose 
-60 minutes 
2 hours after study drug dosing 
± 15 minutes 
 
Blood samples will be collected as shown in Table 3-2. 
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. 


Protocol VX20-121-103, Version 3.0 
Page 43 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard operating 
procedures. 
11.2.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be in the PK Sample Handling Guidelines.  
11.2.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
11.3 
Pharmacodynamics 
While SwCl is a pharmacodynamic measure of CFTR function, it is also a measure of efficacy 
and is discussed in Section 11.5.2. 
11.4 
Exploratory Assessments 
These data will be used for internal exploratory purposes. Detailed procedures for the collection 
of blood samples and additional procedures for processing and handling samples for 
pharmacogenomics analysis will be provided in a separate document.  
11.4.1 
Pharmacogenomics 
An optional single blood sample (DNA Sample) will be collected for potential exploratory 
evaluation of associations between DNA markers with PK, pharmacodynamics (PD), treatment 
response, AEs, and health and disease, especially CF, for subjects who choose to participate in 
this assessment (if permitted by local regulations). 
11.4.2 
Inflammatory Mediators 
Blood samples (inflammatory mediator samples) will be collected at the time points noted in 
Table 3-2 and tested to assess markers related to inflammation. These may include, but are not 
limited to, C-reactive protein (CRP), immunoglobulin G (IgG), white blood cell (WBC, 
leukocyte) count, and interleukin-8 (IL-8). Specific instructions for the collection, processing, 
storage, and shipment of inflammatory mediator samples will be provided in the Laboratory 
Manual. 
11.4.3 
Other Blood Biomarkers 
Additional blood samples for plasma and serum will be collected and banked for potential future 
exploratory evaluation of other blood biomarkers (e.g., proteins, peptides, lipids, metabolites, 
etc.) in relation to PK, PD, treatment response, AEs, and various disease manifestations of CF.  
Optional blood samples (RNA Sample) may be collected (if permitted by local regulations) for 
potential exploratory evaluation of associations between RNA markers with PK, PD, treatment 
response, and AEs.  
11.4.4 
Microbiology and Other Sputum Biomarkers 
Sputum samples will be collected at the time points noted in Table 3-2 from subjects who can 
produce a sample spontaneously. Each sample will be processed and frozen for potential 


Protocol VX20-121-103, Version 3.0 
Page 44 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
exploratory evaluation of microbiology analysis and sputum biomarkers (which may include, but 
are not limited to, qualitative and quantitative bacterial and viral assessments including genomic 
analyses, analysis of immune cells, inflammatory markers, proteins, peptides, lipids, and 
endogenous metabolites) in relation to PK, PD, treatment response, AEs, and various disease 
manifestations of CF. 
Specific instructions for the collection, processing, aliquoting, storage, and shipment of sputum 
samples will be provided in the Laboratory Manual.  
11.4.5 
Treatment Satisfaction Questionnaire for Medication 
The TSQM is a widely used generic measure of satisfaction with medication. The domains of the 
TSQM measure effectiveness, side effects, convenience, and global satisfaction. Because 
treatment satisfaction is not measured with the other health-related quality-of-life measures in 
this study, the TSQM will be included as an assessment for this purpose. Translations of the 
TSQM will be provided for participating centers with non-English-speaking populations.  
All subjects should be instructed to complete the TSQM questionnaire on the Day -28 Visit 
based on their experience of their current medication regimen over the prior 2 to 3 weeks. Only 
subjects <18 years of age on the date of informed consent will complete the TSQM at subsequent 
visits; these subjects should be instructed to complete the TSQM based on their experience of the 
study drug over the prior 2 to 3 weeks. Subjects who discontinue study drug prematurely or who 
have interrupted study drug will still complete the TSQM basing their experience of the study 
drug if taken during the prior 2 to 3 weeks. If study drug was not taken during this period, the 
responses should be based on their experience of their current medication regimen. 
TSQM may be completed within 5 days prior to the study visit. All questionnaires completed on 
the day of the study visit must be completed prior to any other assessments, with CFQ-R 
completed first. 
11.4.6 
Other Questionnaires 
The CF-IQ is a 23-item measure of patient-reported life impacts of CF across 5 domains: control 
and burden of CF treatment, physical activity, social activity, emotional, and work/school 
limitations. The CF-IQ measures each concept using a 5- or 7-point verbal rating scale and 
specifies a 7-day recall period for retrospective questions. The CF-IQ was developed to 
characterize the patients’ experience of living with CF and to measure the impact of CF and CF 
treatment on patients’ lives. The CF-IQ is designed to complement existing, more symptom-
focused, CF-specific patient-reported outcome (PRO) measures like the CFQ-R. Translations of 
the CF-IQ will be provided for participating centers with non-English-speaking populations.  
For purposes of validating CF-IQ, PGIS and PGIC will be performed per Table 3-2 in order to 
assess a subject’s perceived severity/change of disease. Details regarding CF-IQ validation will 
be provided in a separate document. 
CF-IQ, PGIS, and PGIC may be completed within 5 days prior to the study visit. CF-IQ, PGIS, 
and PGIC must be completed on the same day, and CF-IQ must be performed before PGIS or 
PGIC (as applicable). All questionnaires completed on the day of the study visit must be 
completed prior to any other assessments, with CFQ-R completed first.  


Protocol VX20-121-103, Version 3.0 
Page 45 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
11.5 
Efficacy 
11.5.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines10 and according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
pre-bronchodilator. During the Treatment Period, spirometry assessments must be performed 
before study drug dosing (Section 9.6.1) at approximately the same time at each visit. In the 
event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
• If a subject’s Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent visit, 
the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
• If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments in Table 3-2) should be performed 
post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
Spirometers will be provided to be used for all study assessments. During study visits, 
spirometry assessments will be conducted per Table 3-1 and Table 3-2 and will be performed on 
more than one spirometer as applicable. All spirometry data will be transmitted to a centralized 
spirometry service for quality review. The investigator’s assessment of the spirometry results 
will be used for the screening assessment and determination of eligibility. 
See Section 10.7.1 for information about access to spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of GLI.9 
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 


Protocol VX20-121-103, Version 3.0 
Page 46 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
• Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.5.2 
Sweat Chloride 
SwCl samples will be collected with an approved collection device. Each collection will occur 
before study drug dosing (Section 9.6.1). At each time point, 2 samples will be collected, 1 from 
each arm (left and right). Sweat samples will be sent to a central laboratory for testing and 
interpretation of results. Specific instructions for the collection, handling, processing, and 
shipping of SwCl samples to the central laboratory will be provided separately. 
See Section 10.7.1 for information about access to SwCl results. 
11.5.3 
Cystic Fibrosis Questionnaire-Revised 
The CFQ-R provides information about demographics; general quality of life, school, work, or 
daily activities; and symptom difficulties (pertaining to CF).  
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.15, 16 If there is no validated translation available in the subject’s native language, 
the subject will not complete the questionnaire. Copies of the CFQ-R used will be provided in 
the Study Reference Manual. Validated translations of the CFQ-R, if available, will be provided 
for participating centers with non-English-speaking populations.17, 18  
The CFQ-R will be completed before any other assessments are performed on the day of the 
study visit.  
Subjects who are either 12 or 13 years of age on the date of informed consent will complete the 
CFQ-R Child version themselves, and their parents/caregivers will complete the CFQ-R Parent 
version, at all visits, regardless of whether the subject subsequently turns 14 years of age during 
the study. Subjects 14 years of age and older on the date of informed consent will complete the 
Adolescent/Adult version of the questionnaire themselves at all visits. 
11.5.4 
Other Events Related to Outcome 
11.5.4.1 
Antibiotic Therapy for Sinopulmonary Sign/Symptoms 
New or changed antibiotic therapy (intravenous [IV], inhaled, or oral) for the following 
sinopulmonary signs/symptoms will be determined and documented at visits as indicated in 
Table 3-2: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 


Protocol VX20-121-103, Version 3.0 
Page 47 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
For this study, PEx is defined as a new or change in antibiotic therapy (IV, inhaled, or oral) 
for any 4 or more of the above signs/symptoms. This definition is based on the definition of a 
PEx used in previous clinical studies, including IVA clinical studies.19, 20  
It is recommended that the study drug not be interrupted during a PEx unless, in the opinion of 
the investigator, it would be in the best interest of the subject. 
11.5.4.2 
Hospitalization for CF 
Subjects will be queried about planned and unplanned hospitalizations lasting ≥24 hours that 
occurred during the study. The dates of hospitalizations and the reasons for hospitalizations will 
be documented. 
For any hospitalization (planned and unplanned), the procedures for safety reporting should also 
be followed. 
11.5.5 
Height and Weight 
Height and weight will be measured with shoes off. Height will be collected at screening for all 
subjects. Following screening, height will be collected only for subjects ≤21 years of age on the 
date of informed consent. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, PEs, and pulse oximetry. 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with current ICH E6 GCP 
Guidelines. Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs.  
11.6.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests. As described below, urine pregnancy tests will either be analyzed by the site or 
at home using a home kit. On Day 1, blood samples will be collected before the first dose of 
study drug in the Treatment Period. Specific instructions for the collection, processing, and 
shipment of samples will be provided in a separate Laboratory Manual. 
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. 


Protocol VX20-121-103, Version 3.0 
Page 48 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin, 
indirect bilirubin 
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Cholesterol  
Lactate dehydrogenase 
Hemoglobin  
Hemoglobin A1cc 
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be done, 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 
Hemoglobin A1c will be assessed per Table 3-1 and Table 3-2. 
Pregnancy (β-human chorionic gonadotropin) Tests: All female subjects, regardless of 
childbearing potential, will complete the pregnancy tests outlined in Table 3-1 and Table 3-2. 
Serum pregnancy tests will be performed at the study site and analyzed at the central laboratory. 
Urine pregnancy tests will either be performed and analyzed at the site or, when there is no clinic 
visit scheduled, at home by using a home kit provided by the site. Results will be reported to the 
site by telephone. The urine pregnancy test on Day -28 must be negative before the first dose of 
study drug in the Run-in Period. The urine pregnancy test on Day 1 must be negative before the 
first dose of study drug in the Treatment Period. Additional pregnancy tests may be required 
according to local regulations and/or requirements. 
FSH: Blood samples for FSH will be measured as needed for any postmenopausal female with at 
least 12 months of continuous spontaneous amenorrhea. Serum FSH levels must be in the 
postmenopausal range as determined by the laboratory performing the test. Refer to Section 
11.6.7.1 for details regarding contraception guidelines. 
CFTR Genotype (Screening Period Only): CFTR genotyping will be performed for all subjects. 
If the screening CFTR genotype result is not received before randomization, a previous CFTR 
genotype laboratory report may be used to establish eligibility (Section 8.1). Subjects who have 
been enrolled and whose screening genotype does not confirm study eligibility must be 
discontinued from the study (Section 9.9). 


Protocol VX20-121-103, Version 3.0 
Page 49 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
11.6.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider. 
A complete PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, 
nose, and throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After screening, any clinically significant abnormal findings in PEs 
will be reported as AEs.  
The abbreviated PE will include an assessment of the following body systems: head, neck, and 
thyroid; EENT; cardiovascular system; respiratory system; skin; and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate and will be assessed before dosing (as applicable). The subject will be instructed 
to rest for at least 5 minutes before vital signs are assessed.  
11.6.4 
Pulse Oximetry 
Pulse oximetry is a noninvasive measure of oxygen delivery to the tissues and has been 
correlated with clinical status and lung function. Arterial oxygen saturation by pulse oximetry 
will be assessed following at least a 5-minute rest. At visits when study drug is taken at the site, 
pulse oximetry will be collected before study drug dosing (Section 9.6.1). 
11.6.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position and before dosing (as applicable). 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through completion of study participation will be recorded as AEs.  
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 


Protocol VX20-121-103, Version 3.0 
Page 50 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
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. If study sites cannot 
evaluate QTcF they should discuss alternatives with the medical monitor. 
11.6.6 
Ophthalmologic Examination 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on 
the date of informed consent. The examination does not need to be completed if there is 
documentation of bilateral lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically-dilated examination of the lens with a slit lamp. 
The screening examination does not need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of informed consent. 
In addition to the screening ophthalmologic examination, subjects who are <18 years of age on 
the date of informed consent and who have completed at least 12 weeks of study drug treatment 
will have a single ophthalmologic examination within 4 weeks prior to completion of study 
participation (Section 9.1.7), except for those subjects who have withdrawn consent or assent 
(Table 3-2). This examination should be completed within 4 weeks before the Week 52 Visit, 
unless the subject prematurely discontinues study drug, in which case this examination should 
occur by the Safety Follow-up Visit (or ETT Visit for subjects who do not complete a Safety 
Follow-up Visit), as described in Section 9.1.5. 
Any clinically significant abnormal findings will be reported as AEs. 
11.6.7 
Contraception and Pregnancy 
The effects of VX-121, ELX, TEZ, IVA, and D-IVA on conception, pregnancy, and lactation in 
humans are not known. VX-121, ELX, TEZ, IVA, and D-IVA did not show genotoxic potential 
in a standard battery of in vitro (Ames test, chromosomal aberration, or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies. Reproductive toxicology studies of 
VX-121, ELX, TEZ, and IVA have not shown teratogenicity in rats and rabbits. 
11.6.7.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below: 
Contraception for the couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the Screening Visit through 90 days after the last dose of study drug. 
• If the male is infertile (e.g., bilateral orchiectomy). For cases of presumed complete bilateral 
absence of the vas deferens of a male subject, infertility must be documented by the 


Protocol VX20-121-103, Version 3.0 
Page 51 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
investigator before the first dose of ELX/TEZ/IVA in the Run-in Period (e.g., examination of 
a semen specimen or by demonstration of the absence of the vas deferens by ultrasound). 
• If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH level 
within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations and females who do not have 
a documented bilateral oophorectomy/salpingo-oophorectomy) will be considered to be of 
childbearing potential. 
• Exclusive same sex relationships. 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of effective 
contraception will be used as a couple. Acceptable methods of contraception must be in 
successful use from signing of consent, approximately 28 days before the first dose of 
ELX/TEZ/IVA in the Run-in Period (unless otherwise noted), and until 90 days following the 
last dose of study drug. Additional contraception requirements may need to be followed 
according to local regulations and/or requirements. Acceptable methods of contraception are 
listed in Table 11-3. 
Table 11-3 
Acceptable Methods of Contraception 
Method 
Male Subjects and Their 
Female (Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy 6 months or more previously, with a 
documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Documented bilateral tubal ligation performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without 
spermicidea 
Yes 
Yes 
Female barrier contraception (such as 
diaphragm, cervical cap, or sponge) with 
spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at 
least 90 days before the first dose of study drug. 
Yes 
Yes 
Oral, patch, implanted, or injected hormonal 
contraceptives, if used consistently and correctly 
for at least 60 days before the first dose of study 
drug 
Yes 
Yes 
Notes: At least 1 acceptable method of contraception must be used by couples not exempt from the contraception 
requirement. The first dose of study drug refers to the first dose of ELX/TEZ/IVA in the Run-in Period.  
a 
A female condom cannot be used with a male condom due to risk of tearing. 


Protocol VX20-121-103, Version 3.0 
Page 52 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Additional notes: 
• Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active with a 
partner of the opposite sex. 
• Male subjects must not donate sperm during the period starting from the first dose of 
ELX/TEZ/IVA in the Run-in Period until 90 days after the last dose of study drug. 
• Female subjects of childbearing potential should not plan to become pregnant during the 
study or within 90 days after the last dose of study drug. For male subjects with a female 
partner of childbearing potential, the couple should not plan to become pregnant during the 
study or within 90 days after the last dose of study drug, with the exception of couples who 
plan to become pregnant by artificial insemination using sperm banked by the male subject 
before the first dose of ELX/TEZ/IVA in the Run-in Period or sperm from another source. 
• Male subjects whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the subject received study 
drug), or is otherwise already pregnant before the male subject’s first dose of ELX/TEZ/IVA 
in the Run-in Period, must be compliant with the contraception requirements. In this 
scenario, the male subject and his female partner must commit to using a male condom (to 
ensure there is no exposure of the fetus to study drug) from signing consent through 90 days 
after the last dose of study drug. 
• Female subjects should not breast-feed a child from signing consent through 90 days 
following the last dose of study drug. 
• Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or authorized designee on an individual basis. 
11.6.7.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a subject, or the female partner of a male subject, becomes pregnant while participating in the 
study, the study drug will be permanently discontinued immediately. The investigator will 
1) notify the medical monitor and Vertex GPS within 24 hours of the site’s knowledge of the 
subject’s (or partner’s) pregnancy, and 2) send the Pregnancy Information Collection Form to 
Vertex GPS. 
A subject (or their partner, if relevant) who becomes pregnant while on study will be followed 
until the end of the pregnancy, and the infant will be followed for 1 year after birth, provided 
informed consent is obtained. A separate ICF will be provided to explain these follow-up 
activities. Pregnancy itself is not an AE.  
12 
STATISTICAL ANALYSIS 
12.1 
Sample Size and Power 
Approximately 550 subjects will be enrolled and randomized (1:1) to the VX-121/TEZ/D-IVA 
group or the ELX/TEZ/IVA group. Information regarding the powering of the primary and 
selected key secondary efficacy endpoint is presented below. 


Protocol VX20-121-103, Version 3.0 
Page 53 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Power for Primary Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through Week 24. 
The primary null hypothesis to be tested is that the mean absolute change in ppFEV1 from 
baseline through Week 24 for VX-121/TEZ/D-IVA is inferior by >3 percentage points compared 
to ELX/TEZ/IVA.  
The non-inferiority margin represents a clinically acceptable loss of effectiveness as outlined in 
regulatory guidances. Furthermore, a statistical approach using the Rothmann method 
recommends that the non-inferiority margin preserve at least 50% of the treatment effect of the 
active control (ELX/TEZ/IVA) compared to placebo, where the treatment effect is estimated by 
the lower bound of the 95% CI.21, 22 In the overall population eligible for this study, the lower 
bound of the 95% CI of the treatment effect is approximately 12 percentage points for ppFEV1. 
The selected non-inferiority margin of 3 percentage points is consistent with this statistical 
method and the non-inferiority margin for ppFEV1 used in clinical studies evaluating 
symptomatic CF treatments.23, 24 
The null hypothesis will be tested at a 1-sided significance level of 0.025. 
Assuming a within-group SD of 8 and 10% drop-out rate at Week 24 and a treatment difference 
of 0 between VX-121/TEZ/D-IVA and ELX/TEZ/IVA, a sample size of 275 subjects in each 
group for a total of 550 subjects will have more than 95% power to test the primary hypothesis 
for the primary endpoint, based on a 1-sided, 2-sample t-test at a significance level of 0.025.  
Power for Analysis of Selected Key Secondary Efficacy Endpoint 
A key secondary efficacy endpoint is the absolute change in SwCl from baseline through 
Week 24. Assuming a within-group SD of 14 mmol/L and a 10% dropout rate at Week 24, a 
sample size of 275 subjects in each treatment group will have more than 95% power to detect a 
difference between the treatment groups of -5 mmol/L for the absolute change in SwCl from 
baseline through Week 24, based on a 2-sided, 2-sample t-test at a significance level of 0.05. 
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), Safety Set, 
and Per-protocol Set (PPS). 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 
The FAS will include all randomized subjects who carry the intended CFTR allele mutation(s) 
and received at least 1 dose of study drug during the Treatment Period. The FAS will be used to 
summarize subject demographics and baseline characteristics, and for analyses of all efficacy 
endpoints in which subjects will be analyzed according to their randomized treatment group, 
unless otherwise specified. 
The Safety Set for the Run-in Period will include all subjects who received at least 1 dose of 
study drug in the Run-in Period. This safety set will be used only for individual subject data 
listings, unless otherwise specified. 
The Safety Set for the Treatment Period will include all subjects who received at least 1 dose 
of study drug during the Treatment Period. The Safety Set will be used for all safety analyses in 


Protocol VX20-121-103, Version 3.0 
Page 54 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
which subjects will be analyzed according to the treatment they actually received, unless 
otherwise specified.   
The PPS will be a subset of FAS after excluding subjects with certain important protocol 
deviations and other situations; details will be provided in the statistical analysis plan (SAP).  
12.3 
Statistical Analysis 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the SAP, which will be finalized before the clinical data lock for the 
study. 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
number of subjects (n), mean, SD, median, minimum value (min), and maximum value (max).  
Categorical variables will be summarized using counts and percentages.  
Baseline unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period (i.e., the Day 1 Visit). For SwCl, baseline will be defined as the average of the 
Day -14 and Day 1 values. If either the Day -14 or the Day 1 value are missing, the other will be 
used as the average. 
Absolute change from baseline will be calculated as post-baseline value – baseline value.  
The Treatment-emergent (TE) Period for the Run-in Period will be from the first dose date 
of study drug in the Run-in Period to (1) the first dose date of study drug in the Treatment Period 
for subjects who complete the Run-in Period and continue to the Treatment Period, or 
(2) 28 days after the last dose date of study drug in the Run-in Period or to the completion of 
study participation date (as defined in Section 9.1.7), whichever occurs first, for subjects who do 
not continue to the Treatment Period (e.g., subjects who do not meet the conditions to enter the 
Treatment Period).  
The TE Period for the Treatment Period will include the time from the first dose date of study 
drug in the Treatment Period to 28 days after the last dose of the study drug or to the completion 
of study participation date, whichever occurs first. 
12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, exposure, compliance, and important protocol deviations will be summarized. 
Details of the analysis will be provided in the SAP. 
12.3.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified. Only the principal features of the efficacy analysis will be presented in this section. 
Additional details will be included in the SAP. 
12.3.3.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through Week 24 
(estimated by averaging Weeks 16 and 24). The primary analysis will be conducted with clinic 
spirometry data only and will be performed using a mixed-effects model for repeated measures 


Protocol VX20-121-103, Version 3.0 
Page 55 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
(MMRM) with absolute change from baseline in ppFEV1 at Day 15, Week 4, Week 8, Week 16, 
and Week 24 as the dependent variable. The model will include treatment group, visit, and 
treatment-by-visit interaction as fixed effects, with continuous baseline ppFEV1, continuous 
baseline SwCl, age at screening (<18 versus ≥18 years of age), and genotype group (F/F, F/G, 
F/RF, TCR/non-F) as covariates; if there is non-convergence due to small number of subjects in 
either F/G, F/RF, or TCR/non-F, the genotype group will be considered with two levels: F/F and 
non-F/F. The model will be estimated using restricted maximum likelihood. Denominator 
degrees of freedom for the F test for fixed effects will be estimated using the Kenward-Roger 
approximation. An unstructured covariance structure will be used to model the within-subject 
errors. If the model estimation does not converge, a compound symmetry covariance structure 
will be used instead. Conditional on the observed data and covariates, missing data will be 
assumed to be missing at random; therefore, no imputation of missing data will be performed.  
The primary result obtained from the model will be the estimated treatment difference through 
Week 24. The adjusted mean with a 2-sided 95% CI will be provided. The primary null 
hypothesis will be rejected and non-inferiority demonstrated if the lower bound of the 95% CI is 
≥-3.0. The estimated within group change from baseline and the treatment difference at each 
post-baseline visit will also be provided, obtained from the model.  
The primary null hypothesis of non-inferiority described above will be tested based on the FAS.  
If the lower bound of the 95% CI is greater than 0, then superiority for the primary endpoint is 
demonstrated and the 2-sided P value for superiority will be calculated. 
Sensitivity analyses for handling missing data will be described in the SAP.  
Supportive analyses and subgroup analyses (as appropriate) will also be described in the SAP. 
12.3.3.2 
Analysis of Secondary Endpoints 
Analysis of Key Secondary Variables 
• Absolute change from baseline in SwCl through Week 24: The analysis of this variable will 
be based on an MMRM similar to the analysis of the primary endpoint above, with absolute 
change from baseline in SwCl at Day 15, Week 4, Week 16, and Week 24 as the dependent 
variable. The primary result obtained from the model will be the estimated treatment 
difference through Week 24. The LS mean estimate with a 2-sided 95% CI and a 2-sided 
P value will be provided. The estimated within group change from baseline and the treatment 
difference at each post-baseline visit, obtained from the model, will also be provided. 
• Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data from 
Study VX20-121-102): The response corresponding to SwCl <60 mmol/L through Week 24 
based on pooling data from FAS of this study and from Study VX20-121-102 (which has a 
similar study design and will evaluate CF subjects with other genotypes) will be analyzed. 
Details of this analysis will be described in the SAP. 
• Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data from 
Study VX20-121-102): The response corresponding to SwCl <30 mmol/L through Week 24 
based on data pooled from the FAS of this study and from Study VX20-121-102 will be 
analyzed. Details of this analysis will be specified in the SAP. 


Protocol VX20-121-103, Version 3.0 
Page 56 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Analysis of Other Secondary Variables 
The other secondary variables include: number of PEx through Week 52, absolute change from 
baseline in CFQ-R RD score through Week 24, absolute change from baseline in ppFEV1 
through Week 52, absolute change from baseline in SwCl through Week 52, proportion of 
subjects with SwCl <60 mmol/L through Week 24, and proportion of subjects with SwCl 
<30 mmol/L through Week 24. The analysis details for these variables will be described in the 
SAP. 
12.3.3.3 
Multiplicity Adjustment 
A hierarchical testing procedure will be used to control the overall type I error at an alpha of 
0.05. The key secondary endpoints will be formally tested at an alpha of 0.05 only if the primary 
analysis of absolute change from baseline in ppFEV1 through Week 24 is statistically significant, 
i.e., null hypothesis of inferiority has been rejected. For a test at any step to be considered 
statistically significant within the testing hierarchy, it must be statistically significant, and all 
previous tests (if any) within the hierarchy must be statistically significant at the 0.05 level 
2-sided (1-sided 0.025 level for the primary endpoint). Additional details will be provided in the 
SAP. 
12.3.3.4 
Analysis of Other Endpoints 
The analysis details of other endpoints will be described in the SAP. 
12.3.4 
Safety Analysis 
All safety analyses will be based on the data from the TE period for the Treatment Period for all 
subjects in the corresponding Safety Set for the Treatment Period, unless otherwise specified. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability assessments:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis as 
applicable) 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
• Ophthalmological examinations 
Only descriptive analysis of safety will be performed and no statistical testing will be performed. 
The safety data during the Run-in Period will only be presented in listings, unless otherwise 
specified. Additional details will be provided in the SAP. 
LFT elevations, creatine kinase elevations, rash, cataracts, hypoglycemia, and neuropsychiatric 
events will be designated as AEs of special interest. 
12.4 
Interim Analysis 
No interim analysis will be performed. 


Protocol VX20-121-103, Version 3.0 
Page 57 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
12.5 
Data Monitoring Committee Analysis 
The DMC (Section 9.1.9) will conduct safety reviews of study data as outlined in the DMC 
Charter. 
12.6 
Clinical Pharmacology Analysis 
12.6.1 
Pharmacokinetic Analysis 
The PK analysis of VX-121, TEZ, and D-IVA may be performed using nonlinear mixed-effects 
modeling and/or standard noncompartmental analysis, as data allow. Metabolites, including 
M1-TEZ, may be included in the analyses as supported by data. Descriptive statistics will be 
used to summarize PK parameter values for all analytes. 
A detailed description of the planned PK analysis will be presented in the clinical pharmacology 
analysis plan (CPAP). 
12.6.2 
Pharmacokinetic/Pharmacodynamic Analyses 
PD assessments to be included in PK/PD analyses may include SwCl, ppFEV1, as well as other 
endpoints such as CFQ-R RD score. 
A sequential approach will be used to perform the population PK/PD analysis. The Bayesian 
estimates of individual PK parameters from the final population PK model will be used to 
simulate PK profiles for each subject. The simulated VX-121, TEZ, D-IVA, or metabolite 
plasma concentrations will be used in the potential pharmacological response models to describe 
changes in each endpoint from baseline. Fixed- and random-effect parameter estimates and the 
associated asymptotic SEs will be estimated. 
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). 


Protocol VX20-121-103, Version 3.0 
Page 58 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the subject completes study 
participation, as defined in Section 9.1.7. 
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 case report 
form (CRF) and source document. AEs for subjects who are screened but not subsequently 
enrolled will be recorded only in the subject’s source documents. The following data will be 
documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed July 
2021). When considering the severity of an AE in a pediatric subject, the investigator will 
consider that reference ranges for pediatric clinical laboratory parameters may differ from those 
in the CTCAE. The severity of an AE described by a term that does not appear in the CTCAE 
will be determined according to the definitions in Table 13-1.  


Protocol VX20-121-103, Version 3.0 
Page 59 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 13-1 
Grading of AE Severity  
Classification 
Description 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Grade 4 (Life-
threatening) 
Life-threatening consequences; urgent intervention indicated  
Grade 5 (Death) 
Death related to adverse event 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed July 2021) 
ADL: activities of daily living; AE: adverse event 
Note: A semi-colon indicates ‘or’ within the description of the grade. 
a 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
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 


Protocol VX20-121-103, Version 3.0 
Page 60 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event 
a 
Refer to Sections 9.7 and 9.8 for directions regarding what drug actions are permitted per protocol.  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to followup) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 


Protocol VX20-121-103, Version 3.0 
Page 61 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
• 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 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
completion of study participation, regardless of causality, will be reported by the investigator to 
Vertex GPS within 24 hours of identification. In addition, all SAEs that occur after the 
completion of study participation and are considered related to study drug(s) will be reported to 
Vertex GPS within 24 hours of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
completion of study participation, 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: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159  
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after the completion of study participation and are considered related to study 
drug(s) will be recorded on the Vertex Clinical Trial 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 


Protocol VX20-121-103, Version 3.0 
Page 62 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
drug(s) will be assessed only as related (includes possibly related) or not related (includes 
unlikely related), and severity assessment will not be required. For the purposes of study 
analysis, if the event has not resolved at the end of the study reporting period, it will be 
documented as ongoing. For purposes of regulatory safety monitoring, the investigator is 
required to follow the event to resolution and report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IEC, and 
participating investigators in accordance with current ICH E2A 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/IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects, if allowed by local 
regulations. 
13.2 
Administrative Requirements 
13.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint.   
Product complaints are to be reported to Vertex. 
13.2.2 
Ethical Considerations 
The study will be conducted in accordance with the current ICH E6 GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable) before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
current ICH E6 GCP Guidelines and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
13.2.4 
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, 


Protocol VX20-121-103, Version 3.0 
Page 63 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
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.  
13.2.5 
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.  
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 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. 


Protocol VX20-121-103, Version 3.0 
Page 64 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
13.2.8 
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. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation per 
current ICH E6 GCP Guidelines. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. 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. 
13.4 
Monitoring 
The study will be monitored by Vertex or its designee in accordance with written 
procedures. Monitoring and auditing procedures developed or approved by Vertex for these 
activities comply with GCP regulatory requirements and guidelines. 
The monitoring strategy may include onsite, remote, and central monitoring activities, in 
accordance with local regulations. The study site monitor will ensure that the study is conducted 
according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the electronic data 
capture (EDC) application sufficient to permit study site personnel to enter or correct 
information in the CRFs on the subjects for which they are responsible.  


Protocol VX20-121-103, Version 3.0 
Page 65 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
will be placed in the investigator’s study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).25  
Publication Planning: Vertex staff along with the lead PIs, the steering committee, and/or the 
publication committee will work together to develop a publication plan.  
Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria26: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  


Protocol VX20-121-103, Version 3.0 
Page 66 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  
Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors (ICMJE) criteria for authorship will not be listed as authors, but their 
contribution will be acknowledged and specified either as a group (e.g., “study investigators”) or 
individually (e.g., “served as scientific advisor”).  
Publication Review: As required by a separate clinical study agreement, Vertex must have the 
opportunity to review all publications, including any manuscripts, abstracts, oral/slide 
presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration.  
13.7.2 
Clinical Study Report  
A CSR, written in accordance with the current ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


Protocol VX20-121-103, Version 3.0 
Page 67 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
14 
REFERENCES 
1 
Cystic Fibrosis Foundation. 2019 Patient Registry Annual Data Report. Bethesda, MD: 
2020. 
2 
European Cystic Fibrosis Society. 2018 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: 2020. 
3 
Ruseckaite R, Ahern S, Ranger T, Dean J, Gardam M, Bell S, et al. The Australian Cystic 
Fibrosis Data Registry Annual Report, 2017. Monash University: Department of 
Epidemiology and Preventative Medicine; March 2019, Report #20. 
4 
Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry 2019 Annual Data 
Report. Toronto, Ontario: Cystic Fibrosis Canada; 2020. 
5 
Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. 
Identification of the cystic fibrosis gene: Chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
6 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
7 
Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. Assessment 
of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor 
therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation 
(PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107-18. 
8 
Sawicki GS, McKone E, Pasta DJ, Wagener J, Johnson C, Konstan MW. The effect of 
ivacaftor on the rate of lung function decline in CF patients with a G551D-CFTR 
mutation. J Cyst Fibros. 2014;13:S6. 
9 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
10 
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. 
Standardization of spirometry 2019 update. An official American Thoracic Society and 
European Respiratory Society technical statement. Am J Respir Crit Care Med. 
2019;200(8):e70-e88. 
11 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-
70. 
12 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
13 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78. 
14 
Regnault A, Balp M-M, Kulich K, Viala-Danten M. Validation of the Treatment 
Satisfaction Questionnaire for Medication in patients with cystic fibrosis. J Cyst Fibros. 
2012;11(6):494-501. 
15 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 


Protocol VX20-121-103, Version 3.0 
Page 68 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
16 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
17 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
18 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
19 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331(10):637-42. 
20 
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365(18):1663-72. 
21 
VanDevanter DR, Heltshe, S.L., Spahr, J., Beckett, V.V., Daines, C.L., Dasenbrook, 
E.C., Gibson, R.L., Jain, R., Sanders, D.B., Goss, C.H., Flume, P.A.,. Rationalizing 
endpoints for prospective studies of pulmonary exacerbation treatment response in cystic 
fibrosis. J Cyst Fibros. 2017;16(5):607-15. 
22 
Schumi J, Wittes, J.T. Through the looking glas: understanding non-inferiority. Trials. 
2011;12(106):1-12. 
23 
Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, et al. Safety, 
efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The 
EAGER trial. J Cyst Fibros. 2011;10(1):54-61. 
24 
Mayer-Hamblett N, Nichols, D.P., Odem-Davis, K., Riekert, K.A., Sawicki, G.S., et al. 
Evaluating the impact of stopping chronic therapies after modulator drug therapy in 
cystic fibrosis: the SIMPLIFY clinical trial study design. Ann Am Thorac Soc. 
2021;18(8):1397-405. 
25 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
26 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 18 
August 2021. 
 


Protocol VX20-121-103, Version 3.0 
Page 69 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
APPENDIX A: EXAMPLES OF ELIGIBLE MUTATIONS 
As described in Section 8.1, subjects with one of the following genotypes qualify to be screened 
for the study: 1) homozygous for F508del; 2) heterozygous for F508del and a gating (F/G) 
mutation; 3) heterozygous for F508del and a residual function (F/RF) mutation; 4) at least 
1 other TCR CFTR mutation identified as responsive to ELX/TEZ/IVA and no F508del 
mutation.  
Examples of qualifying gating and residual function mutations are presented below. Additional 
mutations may subsequently qualify under these conditions; investigators should contact the 
medical monitor with questions about such mutations. Qualifying TCR CFTR mutations are also 
presented below. 
Examples of Eligible Gating and Residual Function Mutations 
711+3A>G 
L206W 
K1060T 
2789+5G>A 
R347H 
A1067T 
3272-26A>G 
R352Q 
G1069R 
3849+10kbC>T 
A455E 
R1070Q 
E56K 
S549N  
R1070W 
P67L 
S549R  
F1074L 
R74W 
G551D 
D1152H 
D110E 
G551S 
G1244E 
D110H 
D579G 
S1251N 
R117C 
E831X 
S1255P 
R117H 
S945L 
D1270N 
G178R  
S977F 
G1349D 
E193K 
F1052V 
 
 
 
CFTR Mutations Responsive to ELX/TEZ/IVA Based on In Vitro Data 
3141del9 
E822K 
G1244E 
L997F 
R117P 
S945L 
546insCTA 
F191V 
G1249R 
L1077P 
R170H 
S977F 
A46D 
F311del 
G1349D 
L1324P 
R258G 
S1159F 
A120T 
F311L 
H139R 
L1335P 
R334L 
S1159P 
A234D 
F508C 
H199Y 
L1480P 
R334Q 
S1251N 
A349V 
F508C;S1251N † 
H939R 
M152V 
R347H 
S1255P 
A455E 
F575Y 
H1054D 
M265R 
R347L 
T338I 
A554E 
F1016S 
H1085P 
M952I 
R347P 
T1036N 
A1006E 
F1052V 
H1085R 
M952T 
R352Q 
T1053I 
A1067T 
F1074L 
H1375P 
M1101K 
R352W 
V201M 
D110E 
F1099L 
I148T 
P5L 
R553Q 
V232D 
D110H 
G27R 
I175V 
P67L 
R668C 
V456A 
D192G 
G85E 
I336K 
P205S 
R751L 
V456F 
D443Y 
G126D 
I502T 
P574H 
R792G 
V562I 
D443Y;G576A;R668C † 
G178E 
I601F 
Q98R 
R933G 
V754M 
D579G 
G178R 
I618T 
Q237E 
R1066H 
V1153E 
D614G 
G194R 
I807M 
Q237H 
R1070Q 
V1240G 
D836Y 
G194V 
I980K 
Q359R 
R1070W 
V1293G 
D924N 
G314E 
I1027T 
Q1291R 
R1162L 
W361R 


Protocol VX20-121-103, Version 3.0 
Page 70 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
CFTR Mutations Responsive to ELX/TEZ/IVA Based on In Vitro Data 
D979V 
G463V 
I1139V 
R31L 
R1283M 
W1098C 
D1152H 
G480C 
I1269N 
R74Q 
R1283S 
W1282R 
D1270N 
G551D 
I1366N 
R74W 
S13F 
Y109N 
E56K 
G551S 
K1060T 
R74W;D1270N † 
S341P 
Y161D 
E60K 
G576A 
L15P 
R74W;V201M † 
S364P 
Y161S 
E92K 
G576A;R668C † 
L165S 
R74W;V201M;D1270N † 
S492F 
Y563N 
E116K 
G622D 
L206W 
R75Q 
S549N 
Y1014C 
E193K 
G628R 
L320V 
R117C 
S549R 
Y1032C 
E403D 
G970D 
L346P 
R117G 
S589N 
 
E474K 
G1061R 
L453S 
R117H 
S737F 
 
E588V 
G1069R 
L967S 
R117L 
S912L 
 
† 
Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist 
independent of the presence of mutations on the other allele. 
 
 


Protocol VX20-121-103, Version 3.0 
Page 71 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX20-121-103 
Version #: 
3.0 
Version Date: 
19 August 2021 
Study Title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy 
and Safety of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Who Are 
Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function 
(F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive CFTR Mutation 
and No F508del Mutation 
This clinical study protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


Protocol VX20-121-103, Version 3.0 
Page 72 of 72 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
15.2 
Investigator Signature Page 
Protocol #:  VX20-121-103 
Version #: 
3.0 
Version Date: 
19 August 2021 
Study Title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy 
and Safety of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Who Are 
Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function 
(F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive CFTR Mutation 
and No F508del Mutation 
 
 
I have read Protocol VX20-121-103, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-121, ELX, TEZ, D-IVA, IVA, and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods) 
Protocol Number VX20-121-103 Version 3.0 
(Final Analysis) 
 
Author of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 19 September 2023 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating 
the Efficacy and Safety of VX-121 Combination Therapy in Subjects 
With Cystic Fibrosis Who Are Homozygous for F508del, 
Heterozygous for F508del and a Gating (F/G) or Residual Function 
Mutation (F/RF), or Have At Least 1 Other Triple Combination 
Responsive CFTR Mutation and No F508del Mutation 


Statistical Analysis Plan (Methods) 
Page 2 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
1 
TABLE OF CONTENTS 
1 
Table of Contents ................................................................................................................... 2 
2 
Modifications .......................................................................................................................... 4 
2.1 
Modifications to the Approved Clinical Study Protocol .................................................. 4 
2.2 
Modifications to the Approved Statistical Analysis Plan ................................................. 4 
2.3 
Modifications to the Approved DMC Charter .................................................................. 4 
3 
Introduction............................................................................................................................ 5 
4 
Study Objectives .................................................................................................................... 5 
4.1 
Primary Objective ............................................................................................................. 5 
4.2 
Secondary Objectives ....................................................................................................... 5 
5 
Study Endpoints ..................................................................................................................... 5 
5.1 
Primary Endpoint .............................................................................................................. 5 
5.2 
Key Secondary Endpoints ................................................................................................ 6 
5.3 
Other Secondary Endpoints .............................................................................................. 6 
5.4 
Other Endpoints ................................................................................................................ 6 
6 
Study Design ........................................................................................................................... 6 
6.1 
Overall Design .................................................................................................................. 6 
6.2 
Sample Size and Power .................................................................................................... 7 
6.2.1 
Power for Primary Analysis of Primary Efficacy Endpoint ..................................... 7 
6.2.2 
Power for Analysis of Selected Key Secondary Efficacy Endpoint ......................... 8 
6.3 
Randomization .................................................................................................................. 8 
6.4 
Blinding and Unblinding .................................................................................................. 8 
7 
Analysis Sets ........................................................................................................................... 8 
7.1 
All Subjects Set ................................................................................................................ 8 
7.2 
Full Analysis Set ............................................................................................................... 8 
7.3 
Pooled Full Analysis Set .................................................................................................. 8 
7.4 
Safety Set .......................................................................................................................... 9 
8 
Statistical Analysis ................................................................................................................. 9 
8.1 
General Considerations .................................................................................................... 9 
8.2 
Background Characteristics ............................................................................................ 10 
8.2.1 
Subject Disposition ................................................................................................. 10 
8.2.2 
Demographics and Baseline Characteristics ........................................................... 11 
8.2.3 
Medical History ...................................................................................................... 12 
8.2.4 
Prior and Concomitant Medications ....................................................................... 12 
8.2.5 
Study Drug Exposure.............................................................................................. 13 
8.2.6 
Study Drug Compliance ......................................................................................... 14 
8.2.7 
Important Protocol Deviations ................................................................................ 14 
8.3 
Efficacy Analysis ............................................................................................................ 14 
8.3.1 
Analysis of Primary Efficacy Variable ................................................................... 14 
8.3.1.1 
Definition of Primary Efficacy Variable .......................................................... 14 
8.3.1.2 
Definition of Primary Estimand ....................................................................... 14 
8.3.1.3 
Primary Analysis .............................................................................................. 15 
8.3.1.4 
Supplementary Analysis................................................................................... 16 
8.3.1.5 
Subgroup Analysis ........................................................................................... 16 
8.3.2 
Analysis of Key Secondary Efficacy Variables ..................................................... 16 


Statistical Analysis Plan (Methods) 
Page 3 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
8.3.2.1 
Definition of Variables ..................................................................................... 16 
8.3.2.2 
Analysis Method .............................................................................................. 17 
8.3.2.3 
Multiplicity Adjustment ................................................................................... 18 
8.3.3 
Analysis of Other Secondary Variables .................................................................. 18 
8.3.3.1 
Definition of Variables ..................................................................................... 18 
8.3.3.2 
Analysis Method .............................................................................................. 19 
8.3.4 
Analysis of Other Endpoints ................................................................................... 20 
8.3.4.1 
Definition of Variables ..................................................................................... 20 
8.3.4.2 
Analysis Method .............................................................................................. 20 
8.3.5 
Analysis of Additional Efficacy Variables ............................................................. 21 
8.3.5.1 
Analysis of Additional Spirometry Variables .................................................. 21 
8.3.5.2 
Analysis of Other CFQ-R Variables ................................................................ 22 
8.3.5.3 
Analysis of Additional Variables for Pulmonary Exacerbations and 
Hospitalization ................................................................................................. 22 
8.4 
Safety Analysis ............................................................................................................... 23 
8.4.1 
Adverse Events ....................................................................................................... 24 
8.4.2 
Clinical Laboratory ................................................................................................. 25 
8.4.3 
Electrocardiogram .................................................................................................. 26 
8.4.4 
Vital Signs .............................................................................................................. 26 
8.4.5 
Pulse Oximetry ....................................................................................................... 26 
8.4.6 
Ophthalmologic Examinations ............................................................................... 27 
8.4.7 
Physical Examination ............................................................................................. 27 
8.4.8 
Supportive Safety Analysis .................................................................................... 27 
8.4.8.1 
Adverse Events of Special Interest .................................................................. 27 
8.5 
Additional Analysis ........................................................................................................ 27 
8.5.1 
Analysis of TSQM Domains .................................................................................. 27 
8.5.2 
Analysis of Additional Variables for SwCl ............................................................ 28 
9 
Summary of Interim and DMC Analysis........................................................................... 28 
9.1 
Interim Analysis ............................................................................................................. 28 
9.2 
DMC Analysis ................................................................................................................ 28 
10 References ............................................................................................................................. 29 
11 List of Appendices................................................................................................................ 30 
 


Statistical Analysis Plan (Methods) 
Page 4 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
2 
MODIFICATIONS 
2.1 
Modifications to the Approved Clinical Study Protocol 
Not Applicable. 
2.2 
Modifications to the Approved Statistical Analysis Plan 
This is the first version of the Statistical Analysis Plan. 
2.3 
Modifications to the Approved DMC Charter 
Not Applicable. 


Statistical Analysis Plan (Methods) 
Page 5 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
3 
INTRODUCTION 
This statistical analysis plan (SAP) is the planned statistical analysis for Study VX20-121-103 
(Study 103) and is based on the most recent approved clinical study protocol (CSP), the most 
recent approved electronic case report form (eCRF), and the most recent eCRF completion 
guidelines. 
Study 103 is a Phase 3, randomized, double-blind, elexacaftor/tezacaftor/ivacaftor 
(ELX/TEZ/IVA)-controlled, parallel group, multicenter study evaluating the efficacy and safety 
of vanzacaftor (VX-121)/tezacaftor/deutivacaftor (VNZ/TEZ/D-IVA) in cystic fibrosis (CF) 
subjects who are homozygous for F508del (F/F), heterozygous for F508del and a gating (F/G) or 
residual function (F/RF) mutation, or have at least 1 triple combination responsive (TCR) CFTR 
mutation identified as responsive to ELX/TEZ/IVA and do not have an F508del mutation 
(TCR/non-F). This SAP (Methods) documents the planned final analyses and data presentation 
for Study 103. For some of these analyses, the Study 103 data are pooled with data from Study 
VX20-121-102 (Study 102) which is running in parallel with a similar study design and aims to 
evaluate similar outcomes using a different patient population. 
The Vertex Pharmaceuticals Incorporated (Vertex) Biometrics Department will perform the 
statistical analysis of the efficacy and safety data. SAS® Version 9.4 Software (SAS Institute, 
Cary, North Carolina, USA) or higher will be used to generate all statistical outputs (tables, 
figures, listings, and datasets). 
The SAP (Methods) will be finalized and approved prior to clinical database lock and treatment 
unblinding. Any revisions to the approved SAP will be documented and approved in an 
amendment to the SAP prior to the clinical database lock. 
The analysis addressing the pharmacokinetic (PK) objective of the study will be described in the 
Clinical Pharmacology Analysis Plan which will be developed separately by the Clinical 
Pharmacology department at Vertex. 
4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
To evaluate the efficacy of VNZ/TEZ/D-IVA in CF subjects who are homozygous for F508del, 
heterozygous for F508del and a gating (F/G) or residual function (F/RF) mutation, or have at 
least 1 other TCR CFTR mutation and no F508del mutation 
4.2 
Secondary Objectives 
• To evaluate the safety of VNZ/TEZ/D-IVA 
• To evaluate the PK of VNZ/TEZ/D-IVA 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) through Week 24 


Statistical Analysis Plan (Methods) 
Page 6 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
5.2 
Key Secondary Endpoints 
• Absolute change from baseline in sweat chloride (SwCl) through Week 24 
• Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data from 
Study 102) 
• Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data from 
Study 102) 
5.3 
Other Secondary Endpoints 
• Number of pulmonary exacerbations (PEx) through Week 52 
• Absolute change from baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) 
Respiratory Domain (RD) score through Week 24 
• Absolute change from baseline in ppFEV1 through Week 52 
• Absolute change from baseline in SwCl through Week 52 
• Proportion of subjects with SwCl <60 mmol/L through Week 24 
• Proportion of subjects with SwCl <30 mmol/L through Week 24 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values, electrocardiograms (ECGs), vital signs, and pulse oximetry 
5.4 
Other Endpoints 
• Proportion of subjects with SwCl <60 mmol/L through Week 52 
• Proportion of subjects with SwCl <30 mmol/L through Week 52 
• Absolute change from baseline in body mass index (BMI) at Week 52 
• Absolute change from baseline in BMI z-score at Week 52 
• Absolute change from baseline in weight at Week 52 
• Absolute change from baseline in CFQ-R RD score through Week 52 
• PK parameters of VNZ, TEZ, and D-IVA 
6 
STUDY DESIGN 
6.1 
Overall Design 
Study 103 is a Phase 3, randomized, double-blind, ELX/TEZ/IVA-controlled, parallel-group, 
multicenter study. A schematic of the study design is provided in Figure 6-1. 




Statistical Analysis Plan (Methods) 
Page 8 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
study, the lower bound of the 95% CI of the treatment effect for ELX/TEZ/IVA is approximately 
12 percentage points for ppFEV1. The selected non-inferiority margin of 3 percentage points is 
consistent with this statistical method and the non-inferiority margin for ppFEV1 used in clinical 
studies evaluating symptomatic CF treatments3,4. 
The null hypothesis will be tested at a 1-sided significance level of 0.025. 
Assuming a within-group standard deviation (SD) of 8 and a 10% drop-out rate at Week 24 and a 
treatment difference of 0 between VNZ/TEZ/D-IVA and ELX/TEZ/IVA, a sample size of 275 
subjects in each group for a total of 550 subjects will have more than 95% power to test the 
primary hypothesis for the primary endpoint, based on a 1-sided, 2-sample t-test at a significance 
level of 0.025. 
6.2.2 
Power for Analysis of Selected Key Secondary Efficacy Endpoint 
A key secondary efficacy endpoint is the absolute change from baseline in SwCl through Week 
24. Assuming a within-group SD of 14 mmol/L and a 10% drop-out rate at Week 24, a sample 
size of 275 subjects in each treatment group will have more than 95% power to detect a 
difference between the treatment groups of -5 mmol/L for the absolute change from baseline in 
SwCl through Week 24, based on a 2-sided, 2-sample t-test at a significance level of 0.05. 
6.3 
Randomization 
Approximately 550 subjects will be randomized (1:1) to the VNZ/TEZ/D-IVA group or the 
ELX/TEZ/IVA group. Randomization will be stratified by age at the Screening Visit (<18 versus 
≥18 years of age), ppFEV1 determined during the Run-in Period (Day -14 clinic assessment; <70 
versus ≥70 percentage points), SwCl determined during the Run-in Period (Day -14 assessment; 
<30 versus ≥30 mmol/L), prior CFTR modulator use (yes versus no), and genotype group (F/F, 
F/G, F/RF, and TCR/non-F). 
6.4 
Blinding and Unblinding 
This is a double-blind study. Please refer to Section 10.7 of the Study 103 CSP for details. 
7 
ANALYSIS SETS 
7.1 
All Subjects Set 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 
7.2 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended CFTR 
genotype and received at least 1 dose of study drug during the Treatment Period. The FAS will 
be used to summarize subject demographics and baseline characteristics and for analyses of all 
efficacy endpoints in which subjects will be analyzed according to their randomized treatment 
group, unless otherwise specified. 
7.3 
Pooled Full Analysis Set 
The Pooled Full Analysis Set (PFAS) will include all randomized subjects from this study 
(Study 103) and from Study 102 who carry the intended CFTR genotype and received at least 1 


Statistical Analysis Plan (Methods) 
Page 9 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
dose of study drug during the Treatment Period. The PFAS will be used only for pooled analysis 
of selected endpoints. 
7.4 
Safety Set 
The Safety Set for the Run-in Period will include all subjects who received at least 1 dose of 
ELX/TEZ/IVA during the Run-in Period. This safety set will be used for safety-related outputs 
during the Run-in Period, unless otherwise specified. 
 
The Safety Set for the Treatment Period will include all subjects who received at least 1 dose 
of study drug during the Treatment Period. This safety set will be used for all safety analyses 
during the Treatment Period in which subjects will be analyzed according to the treatment they 
actually received, unless otherwise specified. 
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The Schedule of Assessments is provided in the CSP for Study 103. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value: 
For all safety endpoints: 
• Unless otherwise specified, baseline will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in 
the Treatment Period (i.e., the Day 1 Visit). 
For all efficacy endpoints: 
• Except for SwCl, baseline will be defined as the pre-dose Day 1 value. If the pre-dose 
Day 1 value is missing, the most recent pre-dose, non-missing value on or after the Day -
14 visit, including unscheduled visits, will be used as baseline. 
• For SwCl, baseline will be defined as the average of the two most recent pre-dose, non-
missing values on or after the Day -14 visit, including unscheduled visits. If only 1 non-
missing value is available during this interval, the available value will be considered as 
baseline. 
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. 


Statistical Analysis Plan (Methods) 
Page 10 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
The Treatment-emergent (TE) Period for the Run-in Period will be from the first dose date 
of study drug in the Run-in Period to (1) the first dose date of study drug in the Treatment Period 
for subjects who complete the Run-in Period and continue to the Treatment Period, or (2) 28 
days after the last dose date of study drug in the Run-in Period or to the completion of study 
participation date, whichever occurs first, for subjects who do not continue to the Treatment 
Period (e.g., subjects who do not meet the conditions to enter the Treatment Period). 
The TE Period for the Treatment Period will be from the first dose date of study drug in the 
Treatment Period (VNZ/TEZ/D-IVA or ELX/TEZ/IVA) to 28 days after the last dose date of 
study drug in the Treatment Period or to the completion of study participation date, whichever 
occurs first. 
The PEx analysis period through Week 52 will be from the first dose date of study drug in the 
Treatment Period to the last efficacy assessment, which may be collected up to the Week 52 
Visit or the earlier of Day 365 and the completion of study participation date if a subject does not 
have the Week 52 Visit. 
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 and maximum and minimum change 
from baseline values during the TE Period for the Treatment Period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix . 
Incomplete/missing data: Details on how to handle missing data are described in subsequent 
sections when applicable. 
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless otherwise specified. 
Multiplicity: The multiplicity adjustment procedure for the primary and key secondary 
endpoints is described in 8.3.2.3. All other P values are nominal. 
8.2 
Background Characteristics 
8.2.1 
Subject Disposition 
A disposition table will be provided for the Run-in Period with the following categories: 
• All Subjects Set 
• Safety Set for the Run-in Period 
The number and percentage (based on the Safety Set for the Run-in Period) of subjects in each of 
the following disposition categories will be summarized: 
• Completed Run-in Period treatment 
• Prematurely discontinued Run-in Period treatment and the reason for treatment 
discontinuation 
• Prematurely discontinued study in the Run-in Period and the reason for study discontinuation 


Statistical Analysis Plan (Methods) 
Page 11 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
A separate disposition table will be provided for the Treatment Period with the following 
categories: 
• Randomized 
• Safety Set for the Treatment Period 
• Full Analysis Set (FAS) 
• Randomized but not dosed 
The number and percentage (based on the FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation 
• Completed study 
• Prematurely discontinued study and the reason for discontinuation 
• Rollover to open-label extension study 
A listing will be provided for subjects who discontinued treatment (including both the Run-in 
Period and the Treatment Period) or who discontinued study with reasons for discontinuation. 
8.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and overall 
based on the FAS. 
Demographic data will include the following: 
• Age at Day 1 (in years) 
• Sex (male; female) 
• Ethnicity (Hispanic or Latino; Not Hispanic or Latino; Not Collected per Local Regulations) 
• Race (White; Black or African American; Northeast Asian; Southeast Asian; Other Asian; 
Asian (Region Not Reported); American Indian or Alaska Native; Native Hawaiian or Other 
Pacific Islander; Other; Multiracial; Not Collected per Local Regulations) 
• Geographic region (North America [including United States and Canada]; Rest of the World 
[including Europe, Israel, Australia, and New Zealand]) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• BMI z-score (for subjects ≤20 years old at Baseline) 
Stratification categories will include the following: 
• Age at the Screening Visit (<18; ≥18 years) 


Statistical Analysis Plan (Methods) 
Page 12 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
• ppFEV1 at Day -14 (<70; ≥70 percentage points) 
• SwCl at Day -14 (<30; ≥30 mmol/L) 
• Prior CFTR modulator Use (Yes; No) 
• Genotype group (F/F, F/G, F/RF, TCR/non-F) 
Disease characteristics will include the following: 
• ppFEV1 at baseline (<40; ≥ 40 to <70; ≥70 to ≤90; >90 percentage points) 
• ppFEV1 at baseline (continuous) 
• Sweat chloride at baseline (<30; ≥30 to <60; ≥60 mmol/L) 
• Sweat chloride at baseline (continuous) 
• CFQ-R respiratory domain score at baseline (adult and child version only) (continuous) 
• Prior use of dornase alfa before first dose of study drug in the Treatment Period (Yes; No) 
• Prior use of azithromycin before first dose of study drug in the Treatment Period (Yes; No) 
• Prior use of inhaled antibiotic before first dose of study drug in the Treatment Period (Yes; 
No) 
• Prior use of any bronchodilator before first dose of study drug in the Treatment Period (Yes; 
No) 
• Prior use of inhaled hypertonic saline before first dose of study drug in the Treatment Period 
(Yes; No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening (Positive; 
Negative) 
In addition, data listings will also be provided for: 
• Informed consent 
• Inclusion/exclusion criteria violation for subjects with any such violations 
8.2.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). For the FAS, medical history will be summarized descriptively by System Organ 
Class (SOC) and Preferred Term (PT). This summary will be provided by treatment group and 
overall. The corresponding data listing will also be provided. 
In addition, the number of subjects reported to have had positive cultures for respiratory 
pathogens within the 2 years prior to screening (i.e., answered yes on the respiratory 
microbiology form) will be summarized by treatment group and overall for the FAS. The 
corresponding data listing will be provided. 
8.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug) 
and categorized as follows: 


Statistical Analysis Plan (Methods) 
Page 13 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Prior medication: any medication that was administered during the 56 days before the first dose 
of study drug in the Treatment Period excluding the ones that started in the Run-in Period. For 
subjects who discontinue during the Run-in Period and whose first dose of study drug in the 
Treatment Period is not available, prior medication will be any medication that was administered 
during the 56 days before the last dose of study drug in the Run-in Period excluding the ones that 
started after the first dose in the Run-in Period. 
Concomitant medication during the Run-in Period: medication continued or newly received 
during the TE Period for the Run-in Period 
Concomitant medication during the Treatment Period: medication continued or newly 
received during the TE Period for the Treatment Period 
Post-treatment medication: medication continued or newly received after: 
• the TE Period for the Run-in Period if the subject did not receive study drug in the Treatment 
Period 
• the TE Period for the Treatment Period for subjects who received study drug in the 
Treatment Period 
A given medication may be classified as any combination of the above categories: for example, 
prior and concomitant during the Run-in Period, concomitant during the Treatment Period and 
post-treatment, or concomitant for both periods and post-treatment. 
If a medication has a completely missing or partially missing start/stop date and if it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly, or after 
the TE Period, it will be classified as prior, concomitant for both periods, and post-treatment. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix . 
Prior medications and concomitant medications will be summarized descriptively for the FAS 
using frequency tables by: 1) treatment group and overall, Preferred Name (PN); and 2) 
treatment group and overall, Anatomical Therapeutic Chemical class (ATC) level 1, ATC level 
2, and PN. 
Prior medications and concomitant medications during the Run-in Period will be summarized 
together in one summary table. Post-treatment medications will be listed in the all medications 
listing. 
8.2.5 
Study Drug Exposure 
Study drug exposure will be summarized by treatment group and overall for the Treatment 
Period only based on the Safety Set for the Treatment Period. 
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug 
during the Treatment Period – first dose date of study drug during the Treatment Period + 1, 
regardless of study drug interruption. 
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by interval (≤1 week; >1 to ≤2 
weeks; >2 to ≤4 weeks; >4 to ≤12 weeks; >12 to ≤24 weeks; >24 to ≤36 weeks; >36 to ≤52 
weeks; >52 weeks) using counts and percentages. Additionally, the total study drug exposure, 


Statistical Analysis Plan (Methods) 
Page 14 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
defined as the sum total of the study drug exposure across all subjects (in patient-weeks and 
patient-years), will be provided. 
8.2.6 
Study Drug Compliance 
Study drug compliance will be summarized by treatment group and overall for the Treatment 
Period only based on the FAS. 
Study drug compliance will be calculated as: 100  [1 - (total number of days of study drug 
interruption during the Treatment Period) / (duration of study drug exposure in days during the 
Treatment Period)]. A study drug interruption on a given day is defined as an interruption of any 
study drug on that day. 
Percentage of study drug compliance will be summarized descriptively by the number of subjects 
(n), mean, SD, median, min, and max. It will also be summarized in categories (<80%; ≥80%) 
using frequency tables. 
8.2.7 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly impact the 
completeness, accuracy, or reliability of key study data or that may significantly affect a 
subject’s rights, safety or well-being. IPDs will be identified by the PD review team according to 
the protocol deviation plan which will be finalized before the database lock. 
IPDs will be summarized descriptively based on the FAS and presented by treatment group and 
overall. Additionally, IPDs will be provided in an individual subject data listing. 
8.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified. The analysis of the below secondary endpoints will be performed based on the PFAS 
in order to increase the power for the analyses: 
• Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data from 
Study 102) 
• Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data from 
Study 102) 
The primary and key secondary endpoints will be formally tested for statistical significance, and 
the tests will be subject to multiplicity control (see 8.3.2.3 for details). The endpoints involving 
ppFEV1 and SwCl which are not primary or key secondary will be supportive and analyzed 
similarly to the corresponding primary and key secondary endpoints; the P value presented will 
be nominal. 
8.3.1 
Analysis of Primary Efficacy Variable 
8.3.1.1 
Definition of Primary Efficacy Variable 
The primary efficacy variable is the absolute change from baseline in ppFEV1 through Week 24 
(estimated by averaging Weeks 16 and 24). Percent predicted FEV1 is the ratio of observed FEV1 
(L) and predicted FEV1 (L), expressed as a percentage. See Appendix  for more details. 
8.3.1.2 
Definition of Primary Estimand 
The primary estimand is defined as the following and is presented in Appendix : 


Statistical Analysis Plan (Methods) 
Page 15 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
• Treatment: VNZ/TEZ/D-IVA versus ELX/TEZ/IVA 
• Population: Study population represented by inclusion and exclusion criteria 
• Variable: Absolute change from baseline (after ELX/TEZ/IVA run-in) in ppFEV1 through 
Week 24 (estimated by averaging Weeks 16 and 24) 
• Handling of intercurrent events (ICE): 
o The treatment policy strategy will be used to handle the use of non-study drug CFTR 
modulators for >3 days in either the Run-in Period or the Treatment Period prior to 
Week 24, which means that observed ppFEV1 values will be used, if available, after 
this prohibited medication use. 
o The treatment policy strategy will be used to handle treatment discontinuation prior to 
Week 24, which means that observed ppFEV1 values will be used, if available, after 
treatment discontinuation. 
• Population level summary: Difference in variable means between VNZ/TEZ/D-IVA and 
ELX/TEZ/IVA groups 
8.3.1.3 
Primary Analysis 
The primary null hypothesis to be tested is that the mean for the primary efficacy variable for 
VNZ/TEZ/D-IVA is inferior by >3 percentage points compared to ELX/TEZ/IVA. The primary 
analysis of the primary estimand will be performed using a mixed-effects model for repeated 
measures (MMRM) with change from baseline at Day 15, Week 4, Week 8, Week 16, and Week 
24 as the dependent variable. The model will include fixed categorical effects for treatment, visit, 
age at screening (<18 versus ≥18 years of age), genotype group (F/F, F/G, F/RF, TCR/non-F), 
and treatment-by-visit interaction, with baseline ppFEV1 and baseline SwCl as continuous 
covariates. The model will be estimated using restricted maximum likelihood. Denominator 
degrees of freedom for the F-test for fixed effects will be estimated using the Kenward-Roger 
approximation5. An unstructured covariance structure will be used to model the within-subject 
errors. If the model estimation does not converge, genotype group will be considered with two 
levels (F/F and non-F/F) or removed from the model, and if non-convergence persists, an 
alternative covariance structure like compound symmetry will be used. Conditional on the 
observed data and covariates, missing data will be assumed to be missing at random (MAR). 
The primary result obtained from the model will be the estimated treatment difference through 
Week 24 (estimated by averaging Weeks 16 and 24). The adjusted mean with a 2-sided 95% CI 
and the 1-sided P value for non-inferiority will be provided. The primary null hypothesis will be 
rejected, and non-inferiority demonstrated, if the lower bound of the CI is ≥-3.0. 
The primary null hypothesis of non-inferiority described above will be tested based on the FAS. 
If non-inferiority for the primary endpoint is demonstrated, and if the lower bound of the same 
95% CI is greater than 0, then superiority for the primary endpoint is also demonstrated, and the 
2-sided P value for superiority will be presented. 
The estimated within-group change from baseline and treatment difference at each post-baseline 
visit, obtained from the model, will be provided. The estimated within-group change and its 
standard error (SE) at each post-baseline visit will also be plotted by treatment group. 


Statistical Analysis Plan (Methods) 
Page 16 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
8.3.1.4 
Supplementary Analysis 
8.3.1.4.1 
Alternative Estimand using Hypothetical Strategy 
An alternative estimand will be defined similarly to the primary estimand with the exception that 
ICE will be addressed using the hypothetical strategy. In the hypothetical strategy, observed 
values after ICE will be set to missing to provide a conservative and robust test of non-inferiority 
for the primary endpoint. Supplementary analysis of this alternative estimand will be performed 
similarly to the primary analysis as specified in 8.3.1.3. Additional details are presented in 
Appendix . 
8.3.1.5 
Subgroup Analysis 
Subgroup analyses of the primary efficacy endpoint will be performed for each of the following 
subgroups: 
• Age at screening (<18; ≥18 years) 
• ppFEV1 at baseline (<70; ≥70 percentage points) 
• SwCl at baseline (<30; ≥30 mmol/L) 
• Sex (male; female) 
• Geographic region (North America [including United States and Canada]; Rest of the World 
[including Europe, Israel, Australia, and New Zealand]) 
The MMRM used for the primary analysis of the primary estimand (8.3.1.3) will be used for the 
subgroup analyses, where the same model will be applied to each category of the subgroup. Note 
that for the subgroup analysis based on age, the term age at screening (<18 versus ≥18 years of 
age) will be removed from the MMRM. The adjusted means with 2-sided 95% CIs will be 
provided. Furthermore, the estimated treatment difference through Week 24 (estimated by 
averaging Weeks 16 and 24) in different categories within a subgroup will also be presented in a 
forest plot. Note: The results from the subgroup analyses should be interpreted with caution in 
the cases where sample sizes are small. 
8.3.2 
Analysis of Key Secondary Efficacy Variables 
The tests for absolute change from baseline in SwCl through Week 24 (continuous variable) 
based on the FAS and the proportion of subjects with SwCl <60 mmol/L and SwCl <30 mmol/L 
through Week 24 based on the PFAS will be subject to multiplicity control. Note that the within-
study analyses of the proportion of subjects with SwCl <60 mmol/L through Week 24 and the 
proportion of subjects with SwCl <30 mmol/L through Week 24 based on the FAS are Other 
Secondary Endpoints and are not subject to multiplicity control; analyses of these endpoints are 
described in 8.3.3. 
8.3.2.1 
Definition of Variables 
Sweat chloride (SwCl): The SwCl value at 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 


Statistical Analysis Plan (Methods) 
Page 17 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
>160 mmol/L will be considered missing. Any sweat chloride values reported as <10 mmol/L 
will be imputed as 10 mmol/L. 
8.3.2.2 
Analysis Method 
Absolute change from baseline in SwCl through Week 24: 
The estimand for the absolute change from baseline in SwCl through Week 24 is defined as the 
following: 
• Treatment: VNZ/TEZ/D-IVA versus ELX/TEZ/IVA 
• Population: Study population represented by inclusion and exclusion criteria 
• Variable: Absolute change from baseline (after ELX/TEZ/IVA run-in) in SwCl through 
Week 24 (estimated by averaging Weeks 16 and 24) 
• Handling of ICE: Same as the primary estimand (8.3.1.2) 
• Population level summary: Difference in variable means between VNZ/TEZ/D-IVA and 
ELX/TEZ/IVA groups 
The analysis of absolute change from baseline in SwCl through Week 24 will be based on an 
MMRM similar to the primary analysis of the primary estimand (8.3.1.3), with absolute change 
from baseline in SwCl at Day 15, Week 4, Week 16, and Week 24 as the dependent variable. The 
estimated treatment difference through Week 24 (estimated by averaging Weeks 16 and 24) will 
be presented along with the 2-sided 95% CI and P value. The estimated within-group change 
from baseline and treatment difference at each post-baseline visit, obtained from the model, will 
be provided. The estimated within-group change and its SE at each post-baseline visit will also 
be plotted by treatment group. 
Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data from 
Study 102): 
The estimand for the proportion of subjects with SwCl <60 mmol/L through Week 24 is defined 
as the following: 
• Treatment: VNZ/TEZ/D-IVA versus ELX/TEZ/IVA 
• Population: Pooled study population represented by inclusion and exclusion criteria 
• Variable: Response defined as SwCl <60 mmol/L through Week 24 (estimated by 
averaging Weeks 16 and 24) 
• Handling of ICE: Same as the primary estimand (8.3.1.2) 
• Population level summary: Odds ratio comparing the response rates in VNZ/TEZ/D-IVA 
and ELX/TEZ/IVA groups 
The response corresponding to SwCl <60 mmol/L at each visit through Week 24 in the PFAS 
will be analyzed using a generalized estimating equations (GEE) model. The model will include 
fixed categorical effects for treatment, age at screening (<18 versus ≥18 years of age), genotype 
group (F/MF, F/F, F/G, F/RF, TCR/non-F), visit, and treatment-by-visit interaction, with 
baseline ppFEV1 and baseline SwCl as continuous covariates. A logit link function and an 
unstructured working correlation matrix will be used in the GEE model. If the model estimation 


Statistical Analysis Plan (Methods) 
Page 18 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
does not converge, genotype group will be considered with three levels (F/MF, F/F, and Other) 
or removed from the model, and if non-convergence persists, an alternative covariance structure 
like compound symmetry will be used. The estimated odds ratio through Week 24 (estimated by 
averaging Weeks 16 and 24) along with the 2-sided 95% CI and P value will be presented. The 
estimates for each visit through Week 24 will also be presented. The number and proportion of 
subjects with SwCl <60 mmol/L at each post-baseline visit through Week 24 will be 
descriptively summarized by treatment group. 
Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data from 
Study 102): 
The estimand and analysis will be similar to that for the pooled analysis of proportion of subjects 
with SwCl <60 mmol/L through Week 24. 
8.3.2.3 
Multiplicity Adjustment 
A hierarchical testing procedure will be used to control the overall type I error at an alpha of 
0.05. The key secondary endpoints will be formally tested at an alpha level of 0.05 only if the 
primary analysis of absolute change from baseline in ppFEV1 through Week 24 is statistically 
significant, i.e., if the null hypothesis of inferiority has been rejected. For a test at any step to be 
considered statistically significant within the testing hierarchy, it must be statistically significant, 
and all previous tests (if any) within the hierarchy must be statistically significant at the 0.05 
level (one-sided 0.025 level for the primary endpoint). The testing order of the key secondary 
endpoints is as follows: 
• Absolute change from baseline in SwCl through Week 24 
• Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data from 
Study 102) 
• Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data from 
Study 102) 
8.3.3 
Analysis of Other Secondary Variables 
8.3.3.1 
Definition of Variables 
Pulmonary exacerbation (PEx): A PEx is defined as a new or change in antibiotic therapy (IV, 
inhaled, or oral) for any 4 or more of the following signs/symptoms: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 


Statistical Analysis Plan (Methods) 
Page 19 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
• Change in sinus discharge 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
The number of PEx through Week 52 is defined as the total number of PEx during the PEx 
analysis period (defined in 8.1). 
Cystic Fibrosis Questionnaire – Revised (CFQ-R): The CFQ-R6, 7, 8 is a validated CF-specific 
instrument that measures quality-of-life domains. This study utilizes three different versions of 
CFQ-R: 
• CFQ-R for Children Ages 12 and 13 (subjects 13 years and younger on the date of 
informed consent) 
• CFQ-R for Adolescents and Adults (subjects 14 years and older on the date of informed 
consent) 
• CFQ-R for Parents/Caregivers (subjects 13 years and younger on the date of informed 
consent) 
In all three versions, specific questions belonging to a domain are scored 1, 2, 3, or 4. The CFQ-
R domain score, e.g., physical domain score or respiratory domain score, is defined as a scaled 
score as follows: 
Scaled score for a domain = 100  × (mean (scores of all questions in the domain) −1)/3, 
where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – 
actual score, so that 1 always represents the worst condition and 4 the best condition. The 
(scaled) domain score ranges from 0 (worst condition) to 100 (best condition). The scaled score 
for a specific domain will not be calculated if more than half of the questions in the domain have 
missing scores. 
The (scaled) domain score from the CFQ-R for Children Ages 12 and 13 and for Adolescents 
and Adults will be pooled for analysis purposes. 
8.3.3.2 
Analysis Method 
Number of PEx through Week 52: The number of PEx through Week 52 will be analyzed, and 
the estimated PEx rate (per year, with 48 weeks as 1 year) will be presented. The difference in 
PEx rate and the associated 95% CI will also be provided. 
Absolute change from baseline in CFQ-R Respiratory Domain (RD) score through Week 
24: The analysis of absolute change from baseline in CFQ-R RD score through Week 24 will be 
based on an MMRM similar to the primary analysis of the primary estimand (8.3.1.3), with 
absolute change from baseline in CFQ-R RD score at Week 8, Week 16, and Week 24 as the 
dependent variable. The estimated treatment difference through Week 24 (estimated by 
averaging Weeks 16 and 24) will be presented along with the 2-sided 95% CI. The estimated 
within group change from baseline and treatment difference at each post-baseline visit, obtained 
from the model, will be provided. 


Statistical Analysis Plan (Methods) 
Page 20 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Absolute change from baseline in ppFEV1 through Week 52: Analysis of this endpoint will 
be based on an MMRM similar to the primary analysis of the primary estimand (8.3.1.3), with 
the addition of data from Week 36 and Week 52. The estimated change through Week 52 will be 
based on averaging estimates from Weeks 16, 24, 36 and 52. The post-baseline raw values and 
the absolute change from baseline at each post-baseline visit through Week 52 will be 
summarized descriptively (n, mean, SD, median, min, max). 
Absolute change from baseline in SwCl through Week 52: Analysis of this endpoint will be 
based on an MMRM similar to that for absolute change from baseline in SwCl through Week 24 
(8.3.2.2), with the addition of data from Week 36 and Week 52. The estimated change through 
Week 52 will be based on averaging estimates from Weeks 16, 24, 36 and 52. The post-baseline 
raw values and the absolute change from baseline at each post-baseline visit through Week 52 
will be summarized descriptively (n, mean, SD, median, min, max). 
Proportion of subjects with SwCl <60 mmol/L through Week 24 (within-study): Analysis of 
this endpoint will be based on a GEE model similar to that for the proportion of subjects with 
SwCl <60 through Week 24 using the PFAS (8.3.2.2), but instead will be based on the FAS. 
Proportion of subjects with SwCl <30 mmol/L through Week 24 (within-study): Analysis of 
this endpoint will be based on a GEE model similar to that for the proportion of subjects with 
SwCl <30 through Week 24 using the PFAS (8.3.2.2), but instead will be based on the FAS. 
8.3.4 
Analysis of Other Endpoints 
8.3.4.1 
Definition of Variables 
Body Mass Index (BMI): The BMI at each visit is calculated using the weight and height at 
each visit as follows: 
BMI = Weight (kg)
Heightଶ (mଶ) 
BMI z-score: The BMI-for-age z-score, adjusted for age and sex, will be referred to as BMI z-
score. The BMI z-score will be calculated using the Centers for Disease Control and Prevention 
(CDC) growth charts9, with age (in months) used for the calculation defined in Appendix . 
8.3.4.2 
Analysis Method 
Proportion of subjects with SwCl <60 mmol/L through Week 52 (within-study): Analysis of 
this endpoint will be based on a GEE model similar to that for the proportion of subjects with 
SwCl <60 through Week 24 using the FAS (8.3.3.2), with the addition of data from Week 36 and 
Week 52. 
Proportion of subjects with SwCl <30 mmol/L through Week 52 (within-study): Analysis of 
this endpoint will be based on a GEE model similar to that for the proportion of subjects with 
SwCl <30 through Week 24 using the FAS (8.3.3.2), with the addition of data from Week 36 and 
Week 52. 
Absolute change from baseline in BMI at Week 52: Analysis of this variable will be based on 
an MMRM similar to the primary analysis of the primary estimand (8.3.1.3). Data obtained from 
Day 15, Week 4, Week 8, Week 16, Week 24, Week 36, and Week 52 will be included in the 
model. The estimated treatment difference at Week 52 will be presented along with the 2-sided 
95% CI. The post-baseline raw values and the absolute change from baseline at each post-


Statistical Analysis Plan (Methods) 
Page 21 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
baseline visit through Week 52 will be summarized descriptively (n, mean, SD, median, min, 
max), in addition. 
Absolute change from baseline in BMI z-score at Week 52 (for subjects ≤20 years of age at 
Baseline): Analysis of this variable will be based on an MMRM similar to the primary analysis 
of the primary estimand (8.3.1.3), excluding the term age at screening (<18 versus ≥18 years of 
age), for subjects ≤20 years of age at Baseline. Data obtained from Day 15, Week 4, Week 8, 
Week 16, Week 24, Week 36, and Week 52 will be included in the model. In case of 
convergence issues, genotype group may be removed or may be considered with two levels F/F 
and non-F/F. The estimated treatment difference at Week 52 will be presented along with the 2-
sided 95% CI. The post-baseline raw values and the absolute change from baseline at each post-
baseline visit through Week 52 will be summarized descriptively (n, mean, SD, median, min, 
max), in addition. 
Absolute change from baseline in weight at Week 52: Analysis of this variable will be based 
on an MMRM similar to the primary analysis of the primary estimand (8.3.1.3). Data obtained 
from Day 15, Week 4, Week 8, Week 16, Week 24, Week 36, and Week 52 will be included in 
the model. The estimated treatment difference at Week 52 will be presented along with the 2-
sided 95% CI. The post-baseline raw values and the absolute change from baseline at each post-
baseline visit through Week 52 will be summarized descriptively (n, mean, SD, median, min, 
max), in addition. 
Absolute change from baseline in CFQ-R RD score through Week 52: Analysis of this 
domain will be based on an MMRM similar to that for absolute change from baseline in CFQ-R 
RD score through Week 24 (8.3.3.2), with the addition of data from Week 52. The estimated 
change through Week 52 will be based on averaging estimates from Weeks 16, 24, and 52. The 
estimated treatment difference through Week 52 will be presented along with the 2-sided 95% 
CI. The post-baseline raw values and the absolute change from baseline at each post-baseline 
visit through Week 52 will be summarized descriptively (n, mean, SD, median, min, max), in 
addition. 
8.3.5 
Analysis of Additional Efficacy Variables 
8.3.5.1 
Analysis of Additional Spirometry Variables 
Summary statistics for raw values and for change from baseline of the following spirometry 
measurements will be presented by treatment group at each visit: 
• FEV1: 
o Absolute change from baseline in FEV1 (L) 
o Relative change from baseline in FEV1 (%) 
o Absolute change from baseline in percent predicted FEV1 (percentage points) 
o Relative change from baseline in percent predicted FEV1 (%) 
• FVC: 
o Absolute change from baseline in FVC (L) 
o Relative change from baseline in FVC (%) 
o Absolute change from baseline in percent predicted FVC (percentage points) 


Statistical Analysis Plan (Methods) 
Page 22 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
o Relative change from baseline in percent predicted FVC (%) 
• FEV1/FVC: 
o Absolute change from baseline in FEV1/FVC 
o Relative change from baseline in FEV1/FVC (%) 
o Absolute change from baseline in percent predicted FEV1/FVC 
o Relative change from baseline in percent predicted FEV1/FVC (%) 
8.3.5.2 
Analysis of Other CFQ-R Variables 
Descriptive summary statistics for raw values and for change from baseline of the CFQ-R non-
respiratory domain scores will be presented by treatment group at each visit. 
8.3.5.3 
Analysis of Additional Variables for Pulmonary Exacerbations 
and Hospitalization 
The analysis period for all variables in this section will be the PEx analysis period. 
 
Pulmonary Exacerbations: 
In addition to the other secondary endpoint described in 8.3.3.2, PEx will be further analyzed as 
described below: 
• Time-to-first event (in days): 
o Time-to-first PEx 
o Time-to-first PEx requiring hospitalization 
o Time-to-first PEx requiring intravenous (IV) antibiotic therapy 
o Time-to-first PEx requiring hospitalization or IV antibiotic therapy 
• Number of events: 
o Number of PEx requiring hospitalizations through Week 52 
o Number of PEx requiring IV antibiotic therapy through Week 52 
o Number of PEx requiring hospitalization or IV antibiotic therapy through Week 52 
• Duration of events: 
o Number of days with PEx through Week 52 
o Number of days with PEx requiring hospitalization through Week 52 
o Number of days with PEx requiring IV antibiotic therapy through Week 52 
o Number of days with PEx requiring hospitalization or IV antibiotic therapy through 
Week 52 
Hospitalization: 
• Number of events: 
o Number of planned hospitalizations for CF (i.e., antibiotic therapy) through Week 52 


Statistical Analysis Plan (Methods) 
Page 23 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
o Number of all unplanned hospitalizations for reasons other than antibiotic therapy for 
sinopulmonary signs/symptoms through Week 52 
• Duration of events: 
o Number of days of planned hospitalizations for CF (i.e., antibiotic therapy) through Week 
52 
o Number of days of all unplanned hospitalizations for reasons other than antibiotic therapy 
for sinopulmonary signs/symptoms through Week 52 
Analysis of PEx/Hospitalization Variables: 
For the time-to-event variables, the analysis time will be the number of days from the first dose 
date of study drug in the Treatment Period to the date of the first defined event during the PEx 
analysis period. A subject who does not experience the event during the PEx analysis period will 
be censored at the PEx analysis period end date for that event. The analysis of time-to-event will 
be based on the Kaplan Meier method; the corresponding plot will be presented. 
For the number of events variables, subjects with multiple defined events during the PEx 
analysis period will be counted multiple times. A descriptive summary of the number of events 
along with the observed event rate will be provided. 
The annualized duration of events for each subject will be the total number of days with the 
defined event times 48 weeks, divided by the total number of weeks in the study up to the end of 
the PEx analysis period. The annualized duration will be descriptively summarized. 
8.4 
Safety Analysis 
All safety analyses will be based on data from the TE Period for the Treatment Period for all 
subjects in the Safety Set for the Treatment Period, unless otherwise specified. Subjects will be 
analyzed according to the treatment they actually received in the Treatment Period, as applicable. 
Subjects receiving study drug from more than one treatment group will be allocated to the 
VNZ/TEZ/D-IVA group. 
The overall safety profile of the study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• ECGs 
• Vital signs 
• Pulse oximetry 
• Ophthalmological examinations (for subjects <18 years of age on the date of informed 
consent) 
Only descriptive analysis of safety will be performed, and no statistical testing will be 
performed. 


Statistical Analysis Plan (Methods) 
Page 24 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
8.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs during the Run-in 
Period, TEAEs during the Treatment Period, or post-treatment AEs, defined as follows: 
Pretreatment AE: any AE that occurred before the first dose date of study drug in the Run-in 
Period 
TEAE during the Run-in Period: any AE that worsened (either in severity or seriousness) or 
that was newly developed on or after the first dose date of study drug in the Run-in Period 
through the end of the TE Period for the Run-in Period 
TEAE during the Treatment Period: any AE that worsened (either in severity or seriousness) 
or that was newly developed on or after the first dose date of study drug in the Treatment Period 
through the end of the TE Period for the Treatment Period 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after: 
• the TE Period for the Run-in Period if the subject did not receive treatment in the 
Treatment Period 
• the TE Period for the Treatment Period if the subject received treatment in the Treatment 
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 . 
An overview of all TEAEs by treatment group and overall will be summarized in the following 
categories: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs 
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drugs) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drugs) 
• Subjects with Grade 3+ TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAE leading to death 


Statistical Analysis Plan (Methods) 
Page 25 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
The following summary tables of TEAEs will be presented by treatment group: 
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Grade 3+ TEAEs 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, and only the maximum severity level will be presented in 
the severity summaries and the strongest relationship level in the relationship summaries. 
Additional summary tables will be presented by treatment for TEAEs showing number and 
percentage of subjects: 
• All TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs for all applicable periods, and post-treatment AEs, 
will be presented in an individual subject data listing based on the All Subjects Set. In addition, 
separate listings containing individual subject AE data for TEAEs leading to study drug 
discontinuation, TEAEs leading to study drug interruption, Grade 3+ TEAEs, all SAEs, and 
deaths will be provided, with a flag indicating the TEAE status for SAEs and deaths. 
The following tables for the Run-in Period will be presented overall based on the Safety Set for 
the Run-in Period: 
• An overview of TEAEs during the Run-in Period 
• All TEAEs during the Run-in Period by SOC and PT 
8.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, coagulation, and chemistry results will be 
summarized in SI units at each visit by treatment group. 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the TE Period for the Treatment Period will be summarized by treatment group. The 
threshold analysis criterion shift from baseline will also be summarized for select laboratory 
parameters. The threshold analysis criteria are provided in Appendix . 


Statistical Analysis Plan (Methods) 
Page 26 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
For select liver function laboratory tests (alanine transaminase [ALT], aspartate transaminase 
[AST], alkaline phosphatase [ALP], and total bilirubin), a scatterplot of the maximum TE value 
versus the baseline value corresponding to xULN (upper limit of normal) will be presented. 
Further, a scatterplot of the maximum TE value of ALT and AST, separately, versus the 
maximum TE value of total bilirubin corresponding to xULN will also be presented by treatment 
group. For ALT, AST, and total bilirubin, box-and-whisker plots will be used to display raw 
values at each visit by treatment group. 
Results of positive serum/urine pregnancy tests will be listed in individual subject data listings 
only. For the positive serum pregnancy listing, subjects with serum HCG which are abnormally 
high will be selected. 
In addition, listings containing individual subject hematology, chemistry, coagulation, and 
urinalysis values will be provided. The listings will include data from both scheduled and 
unscheduled visits. A listing of subjects who meet the criteria of [(ALT>3xULN or 
AST>3xULN) and TBILI>2xULN] at any visit will be provided. This listing will include data 
from all visits (including unscheduled visits) and present values for ALT, AST, ALP, and total 
bilirubin. 
8.4.3 
Electrocardiogram 
A summary of observed values and change from baseline values will be provided at each visit by 
treatment group for the following treatment-emergent ECG measurements (in msec): RR 
interval, PR interval, QT interval, QTcF interval, QRS duration, and heart rate (beats/minute). 
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 . 
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
8.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit by treatment group. The following vital signs 
parameters will be summarized: systolic and diastolic blood pressure (mmHg), body temperature 
(ºC), pulse rate (beats/minute), and respiratory rate (breaths/minute). 
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 . 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits. 
8.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each visit by treatment group for the percent of 
oxygen saturation. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 


Statistical Analysis Plan (Methods) 
Page 27 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Period for the Treatment Period will be summarized by treatment group. The reference range for 
normal oxygen saturation is specified as >95%, and <=95% for low oxygen saturation. 
8.4.6 
Ophthalmologic Examinations 
Ophthalmologic examination results will be presented in individual subject data listings only. 
8.4.7 
Physical Examination 
Abnormal PE findings will be presented in individual subject data listings only. 
8.4.8 
Supportive Safety Analysis 
8.4.8.1 
Adverse Events of Special Interest 
For this study, elevated transaminases, creatine kinase elevations, rash, cataracts, hypoglycemia, 
and neuropsychiatric events as determined by MedDRA PTs in Appendix  are considered 
adverse events of special interest (AESI). 
For AESI during the TE Period for the Treatment Period, the following categories will be 
summarized by treatment group: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with related events 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
8.5 
Additional Analysis 
This section describes analysis of TSQM domains. Analyses of other exploratory assessments 
mentioned in the protocol may be described in a separate document. The description of analyses 
of additional variables of SwCl is also included. 
8.5.1 
Analysis of TSQM Domains 
TSQM is a widely used generic measure of satisfaction with medication and has been 
demonstrated to be a valid and reliable measure of satisfaction in patients with CF10. It consists 
of 14 items to form 4 domains: effectiveness (items 1, 2, 3), side effects (items 4, 5, 6, 7, 8), 
convenience (items 9, 10, 11), and global satisfaction (items 12, 13, 14). The score of each 
domain is a scaled score that ranges from 0 (least satisfied) to 100 (most satisfied). Scaled score 
for each domain can be calculated using the scale scoring algorithm11. 
Absolute change from baseline in TSQM domains at Week 52 (only for subjects aged ≥12 
years to <18 years at the date of informed consent) will be analyzed descriptively. 


Statistical Analysis Plan (Methods) 
Page 28 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
8.5.2 
Analysis of Additional Variables for SwCl 
Proportion of subjects with SwCl <60 mmol/L through Week 52 (pooled with data from 
Study 102): Analysis of this endpoint will be based on a GEE model similar to that for the 
proportion of subjects with SwCl <60 through Week 24 using the PFAS (8.3.2.2), with the 
addition of data from Week 36 and Week 52. 
Proportion of subjects with SwCl <30 mmol/L through Week 52 (pooled with data from 
Study 102): Analysis of this endpoint will be based on a GEE model similar to that for the 
proportion of subjects with SwCl <30 through Week 24 using the PFAS (8.3.2.2), with the 
addition of data from Week 36 and Week 52. 
9 
SUMMARY OF INTERIM AND DMC ANALYSIS 
9.1 
Interim Analysis 
No interim analysis is planned for this study. 
9.2 
DMC Analysis 
The DMC will conduct planned safety reviews of study data as outlined in the DMC Charter. For 
the open session of each DMC meeting, selected tables will be presented for the overall 
treatment group based on blinded data. For the closed session, the analysis presentation will be 
by treatment group based on unblinded data (generated by the independent biostatistician). 


Statistical Analysis Plan (Methods) 
Page 29 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
10 
REFERENCES 
1 VanDevanter D.R., Heltshe, S.L., Spahr, J., et.al. Rationalizing endpoints for prospective 
studies of pulmonary exacerbation treatment response in cystic fibrosis. J Cyst Fibros. 
2017;16(5):607-15. 
2 Schumi J., Wittes, J.T., Through the looking glass: understanding non-inferiority. Trials. 
2011;12(106):1-12. 
3 Konstan M.W., Flume P.A., Kappler M., et.al. Safety, efficacy and convenience of tobramycin 
inhalation powder in cystic fibrosis patients: the EAGER trial. J Cyst Fibros. 2011;10(1):54-
61. 
4 Mayer-Hamblett N., Nichols, D.P., Odem-Davis, K., et.al., Evaluating the impact of stopping 
chronic therapies after modulator drug therapy in cystic fibrosis: the SIMPLIFY clinical trial 
study design. Ann Am Thorac Soc. 2021;18(8):1397-405. 
5 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
6 Goss C.H., Quittner A.L., Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
7 Modi A.C., Quittner A.L., Validation of a disease-specific measure of health-related quality of 
life for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
8 Quittner A.L., Modi A., Cruz I. Systematic review of health-related quality of life measures for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
9 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
10 Regnault A., Balp M.M., Kulich K., et.al. Validation of the Treatment Satisfaction 
Questionnaire for Medication in patients with cystic fibrosis. J Cyst Fibros. 2012;11(6):494-
501. 
11 Atkinson M.J., Kumar R., Cappelleri J.C., et.al. Hierarchical Construct Validity of the 
Treatment Satisfaction Questionnaire for Medication (TSQM Version II) among Outpatient 
Pharmacy Customers. Value in Health. (2005);8:S9-S24. 
 
 


Statistical Analysis Plan (Methods) 
Page 30 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
11 
LIST OF APPENDICES 
 
 


Statistical Analysis Plan (Methods) 
Page 31 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3,4 
(in study days) 
Safety Assessments 
• Pulse oximetry 
• Serum chemistry 
• Hematology (except HbA1c) 
• Vital signs (excluding BMI, 
height, weight) 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Week 36 
Week 52 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
253 
365 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 211] 
(211, 309] 
(309, 379] 
Use nominal visit 
HbA1c (%) 
Day 1 (Baseline) 
Week 12 
Week 24 
Week 52 
1 
85 
169 
365 
1 Pre-dose 
[1, 127] 
(127, 267] 
(267, 379] 
Standard 12-lead ECG 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 8 
Week 16 
Week 24 
Week 36 
Week 52 
Safety Follow-up 
1 
15 
29 
57 
113 
169 
253 
365 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 309] 
(309, 379] 
Use nominal visit 
Coagulation 
Day 1 (Baseline) 
Week 12 
Week 24 
Week 36 
Week 52 
Safety Follow-up 
1 
85 
169 
253 
365 
Not applicable 
1 Pre-dose 
[1, 127] 
(127, 211] 
(211, 309] 
(309, 379] 
Use nominal visit 
Efficacy Assessments5 
• Spirometry (in-clinic) 
• Height, weight, BMI, and z-
scores 
Baseline 
Day 15 
Week 4 
Week 8 
Week 16 
Week 24 
Week 36 
Week 52 
Safety Follow-up 
- 
15 
29 
57 
113 
169 
253 
365 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 309] 
(309, 379] 
>379 


Statistical Analysis Plan (Methods) 
Page 32 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3,4 
(in study days) 
Sweat Chloride 
Baseline 
Day 15 
Week 4 
Week 16 
Week 24 
Week 36 
Week 52 
- 
15 
29 
113 
169 
253 
365 
1 Pre-dose 
[1, 22] 
(22, 71] 
(71, 141] 
(141, 211] 
(211, 309] 
(309, 379] 
CFQ-R 
Baseline 
Week 8 
Week 16 
Week 24 
Week 52 
- 
57 
113 
169 
365 
1 Pre-dose 
[1, 85] 
(85, 141] 
(141, 267] 
(267, 379] 
TSQM 
Baseline 
Week 52 
- 
365 
1 Pre-dose 
[1, 379] 
Notes: 
1 Visit name for analysis purposes 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. If the latest measurement cannot be determined, and there are both scheduled and 
unscheduled visits, then the unscheduled visit will be selected. 
 
3 For measurements collected on the date of first dose of study drug in the Treatment Period, if it cannot be 
determined whether a measurement is before or after the first dose: 
a. 
Scheduled measurements will be treated as pre-dose observations. 
b. Unscheduled measurements will be treated as post-dose observations. 
 
4 For safety assessments, the Safety Follow-up analysis visit will be based on the nominal Safety Follow-up visit. 
If a subject does not have a nominal Safety Follow-up visit but has an early termination of treatment (ETT) visit 
with study day >379, then the ETT visit will be mapped to the Safety Follow-up analysis visit. 
 
5 For efficacy assessments, if a subject has a nominal Safety Follow-up visit with study day >379, then the nominal 
Safety Follow-up visit will be mapped to the Safety Follow-up analysis visit; else if a subject does not have a 
nominal Safety Follow-up visit with study day >379 but has an ETT visit with study day >379, then the ETT visit 
will be mapped to the Safety Follow-up analysis visit; else if there are multiple assessments with study day >379, 
then the earliest record will be selected as the Safety Follow-up analysis visit. 
 
Derived Variables: 
1. Age (in years) at first dose date and at nominal visits (for demographics, listings, 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 15.22 days to convert to days. 
Obtain the informed consent date. 


Statistical Analysis Plan (Methods) 
Page 33 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3,4 
(in study days) 
Then, age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for calculation of BMI and z-scores, as applicable): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from the VS 
page at the Screening Visit. 
Obtain the informed consent date. 
Then, age (in months) at nominal visit = integer part of {[age at informed consent (in months) + 0.5 + diff 
(nominal, informed consent date) in months]} + 0.5. 
3. Missing first dose date or last dose date: 
If the first dose date is missing, use the Day 1 visit date to impute. 
If the last dose date is missing or a partial date is reported, the last dose date will be imputed based on, in 
descending order of priority, the ETT visit date, the last visit date before the Safety Follow-up visit, or the last 
study drug administration date from the EC SDTM domain, as appropriate. The imputation algorithm will 
ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for 
a given arm up to 30 minutes after the first dose time in the Treatment Period will be considered for baseline. 
5. Electrocardiogram: 
Baseline is defined as the most recent pre-treatment measurement before the first dose of study drug in the 
Treatment Period. If multiple ECG measurements are obtained on the same calendar day during the TE Period 
for the Treatment Period, 
o 
For summary purposes, the calculated average ECG will be used as the ECG value on that day; 
o 
For threshold analysis purposes, all reported ECG values will be used. 
 
 


Statistical Analysis Plan (Methods) 
Page 34 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month. 
b. If DAY and Month are both missing, use the first day of the year. 
c. If DAY, Month, and Year are all missing, use a date before the first dose date (in 
practice, use the informed consent date to impute). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month, and Year are all missing, assign ‘continuing’ status to stop date 
(in practice, use the End of Study Date to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Table 11-2 
Prior, Concomitant, and Post Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Run-in TE Period 
≥ First Dose Date of 
Run-in TE Period and 
< End Date of Run-in 
TE Period 
≥ First Dose Date of 
Treatment TE Period 
and ≤ End Date of 
Treatment TE Period 
> End Date of 
Treatment TE Period 
< First Dose Date of Run-in 
TE Period 
P 
PC1 
PC1C2 
PC1C2A 
≥ First Dose Date of Run-in 
TE Period and < End Date of 
Run-in TE Period 
- 
C1 
C1C2 
C1C2A 
≥ First Dose Date of 
Treatment TE Period and ≤ 
End Date of Treatment TE 
Period 
- 
- 
C2 
C2A 
> End Date of Treatment TE 
Period 
- 
- 
- 
A 
P: Prior; C1: Concomitant during the Run-in Period; C2: Concomitant during the Treatment Period; A: Post 
 
The same imputation rules will be followed to address missing and/or partial dates for non-
pharmacological treatments/procedures. 
 
 


Statistical Analysis Plan (Methods) 
Page 35 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Appendix C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for the 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. Global Lung Function Initiative. [online] Available at: 
https://www.ers-education.org/lr/show-details/?idP=138978 [Accessed Sep 2023]. 
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. Global Lung Function Initiative. [online] Available at: https://www.ers-
education.org/lr/show-details/?idP=138979 [Accessed Sep 2023]. 
Sanja Stanojevic. GLI-2012 - SAS Macro. Global Lung Function Initiative. [online] Available 
at: https://www.ers-education.org/lr/show-details/?idP=138988 [Accessed Sep 2023]. 
The data handling rule for spirometry is as follows: 
• Input age with at least 2 decimal places 
• Use height at screening, regardless of if height is collected at other study visits, for 
subjects whose age at informed consent is >21 years. For subjects with age ≤21 years, 
height collected at the respective visit should be used. 
• For race, race is Black if, on the CRF, Black or African American is the only race 
selected. Race is Northeast Asian if Northeast Asian is the only race selected. Race is 
Southeast Asian if Southeast Asian is the only race selected. Race is White if White is the 
only race selected. Race is Other for all other races, including multiple selections. 




Statistical Analysis Plan (Methods) 
 
Page 37 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Appendix E: Imputation Rules for Missing AE Dates 
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the 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 in 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 in 
the Treatment Period, then impute the AE start day as the day of first dose 
date in the Treatment Period; 
 else, if AE start year and month are equal to the month and year of first dose 
date in the Run-in Period, then impute the AE start day as the day of first dose 
date in the Run-in Period; 
 else, impute the AE start day as 1. 
o Else, if the full (or partial) AE end date is NOT before the first dose date in the Run-
in Period, then 
 if AE start year and month are equal to the month and year of first dose date in 
the Run-in Period, then impute the AE start day as the day of first dose date in 
the Run-in Period; 
 else, impute the AE start day as 1. 
o Else, impute the AE start day as 1. 
Compare the imputed AE start date with the TE Period to determine whether the AE is 
pretreatment AE, TEAE during the Run-in Period, TEAE during the Treatment Period, 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 in the Treatment 
Period or AE end date is missing, then 
 if AE start year is equal to the year of first dose date in the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date in the Treatment Period; 
 else, if AE start year is equal to the year of first dose date in the Run-in 
Period, then impute the AE start month and day as the month and day of first 
dose date in the Run-in Period; 
 else, impute the AE start month as January and day as 1. 
o Else, if the full (or partial) AE end date is NOT before the first dose date in the Run-
in Period, then 


Statistical Analysis Plan (Methods) 
 
Page 38 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
 if AE start year is equal to the year of first dose date in the Run-in Period, then 
impute the AE start month and day as the month and day of the first dose date 
in the Run-in Period; 
 else, impute the AE start month as January and day as 1. 
o Else, impute the AE start month as January and day as 1. 
Compare the imputed AE start date with the TE Period to determine whether the AE is 
pretreatment AE, TEAE during the Run-in Period, TEAE during the Treatment Period, or 
post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start date is missing or AE start date is completely missing: 
o If the full (or partial) AE end date is NOT before the first dose date in the Treatment 
Period or AE end date is missing, then impute the AE start date as the date of first 
dose date in the Treatment Period. 
o Else, if the full (or partial) AE end date is NOT before the first dose date in the Run-
in Period, then impute the AE start date as first dose date in the Run-in Period. 
o Else, impute AE start date as the informed consent date. 
 
All imputation should ensure that the imputed AE start date is not before the informed consent 
date. 
 
Imputation rules for partial AE end dates are defined below: 
For a partial AE end date, impute 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. 
 
 


Statistical Analysis Plan (Methods) 
 
Page 39 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Appendix F: Criteria for Threshold Analysis 
Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20xULN 
>20xULN 
FDA DILI Guidance Jul 
2009. 
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20xULN 
>20xULN 
FDA DILI Guidance Jul 
2009. 
ALT or AST 
(ALT>ULN - ≤ 3xULN) or (AST>ULN - ≤ 3xULN) 
(ALT>3x - ≤ 5xULN) or (AST>3x - ≤ 5xULN) 
(ALT>5x- ≤ 8xULN) or (AST>5x - ≤ 8xULN) 
(ALT>8x - ≤ 20xULN) or (AST>8x - ≤ 20xULN) 
ALT>20xULN or AST> 20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2.5xULN 
>2.5x – ≤ 5x ULN 
>5x – ≤ 20x ULN 
>20x ULN 
FDA DILI Guidance Jul 
2009. 
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2xULN 
>2x – ≤ 3xULN  
>3x – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 
2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2xULN 
>2x – ≤ 3xULN  
>3x – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 
2009. 
Indirect Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2xULN 
>2x – ≤ 3xULN 
>3x – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 
2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 
2009. 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 
2009. 
(ALT or AST) and Total Bilirubin 
(ALT>3xULN or AST>3xULN) and TBILI>2×ULN FDA DILI Guidance Jul 
2009. 


Statistical Analysis Plan (Methods) 
 
Page 40 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤ 2.5xULN 
>2.5x –  ≤ 5xULN 
>5x –  ≤ 20xULN 
>20xULN 
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 
>ULN -  ≤ 1.5xULN 
>1.5x - ≤ 2xULN 
>2x - ≤ 5xULN 
>5xULN 
Criteria based upon 
CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5x - ≤ 3xULN 
>3x - ≤ 6xULN 
>6xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤ 1.5xULN 
>1.5x - ≤ 2xULN 
>2x - ≤ 5xULN 
>5xULN 
Criteria based upon 
CTCAE 
Total protein 
<LLN 
>ULN 
No CTCAE 
Creatine Kinase 
>ULN - ≤ 2.5xULN 
>2.5x - ≤ 5xULN 
>5x - ≤ 10xULN 
>10xULN 
CTCAE grades 1-4 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L 
< 80 g/L 
CTCAE grade 1-3 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L 
<50.0 – ≥ 25.0 x 10e9 /L 
<25.0 x 10e9 /L 
CTCAE grade 1-4 
Platelet increased 
>ULN 
No CTCAE available 
Reticulocytes/Erythrocytes (%) 
<LLN 
>ULN 
No CTCAE 


Statistical Analysis Plan (Methods) 
 
Page 41 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Coagulation 
Activated partial thromboplastin time 
(PTT) 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
 
Table 11-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 beats per minute (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 msec 
≥300 msec 
≥200 msec and increase from baseline ≥40 msec 
≥200 msec and increase from baseline ≥100 msec 
 
QRS 
>110 msec 
>160 msec 
Increase from baseline ≥20 msec 
Increase from baseline ≥40 msec 
 
QTc 
>450 msec and <500 msec (Male); 
>470 msec and <500 msec (Female) 
≥500 msec 
 
Increase from baseline >10 msec 
Increase from baseline >20 msec 
Increase from baseline >40 msec 
Increase from baseline >60 msec 
To be applied to any kind of QT 
correction formula. 


Statistical Analysis Plan (Methods) 
 
Page 42 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Table 11-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
Note: Based on CPMP 1997 guideline. 
 
Table 11-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis 
Comments 
Pulse Rate 
Same as above in ECG category 
 
SBP increased 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from baseline 
>140 mmHg & >20 mmHg increase from baseline 
>160 mmHg & >10 mmHg increase from baseline 
>160 mmHg & >20 mmHg increase from baseline 
809/770 analyses 
SBP decreased 
<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) 
 
Page 43 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Table 11-5 
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 
 
Table 11-6 
Threshold Analysis Criteria for Laboratory Tests 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
For labeling purpose 
 
 


Statistical Analysis Plan (Methods) 
 
Page 44 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
Appendix G: Adverse Events of Special Interest 
Table 11-7 MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms [1] 
Transaminase Elevations 
Alanine aminotransferase abnormal, Alanine aminotransferase 
increased, Aspartate aminotransferase abnormal, Aspartate 
aminotransferase increased, Transaminases abnormal, Transaminases 
increased, Liver function test abnormal, Liver function test increased, 
Hypertransaminasaemia, Hepatic enzyme abnormal, Hepatic enzyme 
increased 
Rash 
AGEP-DRESS overlap, Acute generalised exanthematous pustulosis, 
Anal rash, Cutaneous vasculitis, Dermatitis, Dermatitis allergic, 
Dermatitis atopic, Dermatitis bullous, Dermatitis exfoliative, Dermatitis 
exfoliative generalised, Drug eruption, Drug hypersensitivity, Drug 
reaction with eosinophilia and systemic symptoms, Epidermal necrosis, 
Epidermolysis, Erythema multiforme, Erythrodermic atopic dermatitis, 
Exfoliative rash, Fixed eruption, Generalised bullous fixed drug 
eruption, Immune-mediated dermatitis, Lichen planus pemphigoides, 
Mucocutaneous rash, Mucocutaneous toxicity, Nodular rash, 
Oculomucocutaneous syndrome, Penile dermatitis, Perioral dermatitis, 
Periorbital dermatitis, Rash, Rash erythematous, Rash follicular, Rash 
macular, Rash maculo-papular, Rash maculovesicular, Rash 
morbilliform, Rash papular, Rash papulosquamous, Rash pruritic, Rash 
pustular, Rash rubelliform, Rash scarlatiniform, Rash vesicular, SJS-
TEN overlap, Scrotal dermatitis, Severe cutaneous adverse reaction, 
Skin exfoliation, Skin necrosis, Skin toxicity, Stevens-Johnson 
syndrome, Systemic contact dermatitis, Toxic epidermal necrolysis, 
Toxic skin eruption, Type IV hypersensitivity reaction, Urticaria, 
Urticaria papular, Urticaria vesiculosa, Urticarial dermatitis, Urticarial 
vasculitis, Vasculitic rash 
Cataracts 
Atopic cataract, Cataract, Cataract congenital, Cataract cortical, 
Cataract diabetic, Cataract nuclear, Cataract subcapsular, Lens 
discolouration, Lenticular opacities, MYH9-related disease, Radiation 
cataract, Toxic cataract 
Hypoglycemia 
Blood glucose decreased, Hypoglycaemia, Glycopenia, 
Hyperinsulinaemic hypoglycaemia, Hypoglycaemia unawareness, 
Hypoglycaemic coma, Hypoglycaemic encephalopathy, Hypoglycaemic 
seizure, Hypoglycaemic unconsciousness, Shock hypoglycaemic 
Creatine Kinase Elevations 
Blood creatine phosphokinase increased, Blood creatine phosphokinase 
MM increased, Blood creatine phosphokinase MB increased, Blood 
creatine phosphokinase BB increased, Muscle enzyme increased, 
Rhabdomyolysis, Myoglobinuria, Myoglobin urine present 
Neuropsychiatric Events 
Abnormal behaviour, Adjustment disorder with anxiety, Adjustment 
disorder with depressed mood, Adjustment disorder with mixed anxiety 
and depressed mood, Aggression, Agitated depression, Anger, 
Anhedonia, Anticipatory anxiety, Antisocial behaviour, Anxiety, 
Anxiety disorder, Assisted suicide, Attention deficit hyperactivity 


Statistical Analysis Plan (Methods) 
 
Page 45 of 45 
Protocol Number: VX20-121-103 
Vertex Pharmaceuticals Incorporated 
 Confidential Information 
disorder, Behaviour disorder, Behavioural insomnia of childhood, 
Belligerence, Brain fog, Childhood depression, Completed suicide, 
Decreased interest, Depressed mood, Depression, Depression suicidal, 
Depressive symptom, Discouragement, Disturbance in attention, 
Dysania, Dysphoria, Feeling abnormal, Feeling guilty, Feeling of 
despair, Feelings of worthlessness, Generalised anxiety disorder, 
Helplessness, Hostility, Illness anxiety disorder, Initial insomnia, 
Insomnia, Intentional overdose, Intentional self-injury, Irritability, 
Major depression, Memory impairment, Mental disorder, Mental 
fatigue, Middle insomnia, Mixed anxiety and depressive disorder, 
Paradoxical insomnia, Persistent depressive disorder, Physical abuse, 
Physical assault, Poisoning deliberate, Psychophysiologic insomnia, 
Self-injurious ideation, Suicidal behaviour, Suicidal ideation, Suicide 
attempt, Suicide threat, Suspected suicide, Suspected suicide attempt, 
Terminal insomnia 
[1] The preferred terms (PTs) listed in the table are based on the MedDRA version applicable at the time of 
finalization of the SAP. If the MedDRA version is upgraded at the time of the analysis, the corresponding PTs 
based on the upgraded version will be used in the analysis of adverse events of special interest.